WELCOME BACK TO DAY TWO OF THE
PRACTICUM.
WE HAVE A VERY FULL SCHEDULE
TODAY AND GREAT SESSIONS ON
RIGOR AND REPRODUCIBILITY FIRST
THEN EFFICACY AND SAFETY AND
THEN A FEW SPECIAL PRESENTATIONS
AT THE END OF THE DAY.
THANK YOU SO MUCH, YESTERDAY,
FOR ALL YOUR GREAT QUESTIONS.
PLEASE KEEP SUBMITTING THEM.
THAT REALLY ADDS TO THE SUCCESS
OF THIS PRACTICUM.
JUST A REMINDER, PLEASE SUBMIT
ALL TECHNICAL ISSUES, PROBLEMS
YOU'RE HAVING IN WEBEX INTO THE
CHAT BOX, AND PLEASE SUBMIT
QUESTIONS FOR THE PRESENTER IN
THE Q & A PANEL, AND DIRECT
THOSE TO ALL PANELISTS.
OUR FIRST SESSION TODAY IS RIGOR
AND REPRODUCIBILITY IN DIETARY
SUPPLEMENTS RESEARCH.
IT IS MODERATED BY DR. SANEM
HOSBAS COSKUN.
SHE JOINED THE OFFICE OF DIETARY
SUPPLEMENTS IN 2020 AS
SCIENTIFIC CONSULTANT TO THE
BIOCHEMIST WHO SUPPORTS THE
ANALYTICAL METHODS AND REFERENCE
MATERIALS PROGRAM.
THANK YOU, SANEM.
>> THANK YOU.
WELCOME, EVERYONE, TO SESSION
4 OF THE PRACTICUM, RIGOR AND
REPRODUCIBILITY IN DIETARY
SUPPLEMENTS RESEARCH.
WE HAVE TWO SPEAKERS IN THIS
SESSION AND THERE WILL BE TIME
TO ANSWER YOUR QUESTIONS AFTER
EACH PRESENTATION.
OUR FIRST SPEAKER TODAY IS
DR. ADAM KUSZAK.
DR. KUSZAK JOINED THE ODS,
OFFICE OF DIETARY SUPPLEMENTS,
IN TWEB 14.
2014.
HE I WOULD LIKE TO WELCOME
DR. KUSZAK WITH HIS TALK ON
ANALYTICAL CHARACTERIZATION OF
DIETARY SUPPLEMENTS: METHODS,
STANDARDS AND QUALITY ASSURANCE.
DR. KUSZAK?
I'M ADAM KUSZAK AND IT IS MY
PLEASURE TO PRESENT AT THIS ODS
RESEARCH PRACTICUM.
I'LL BE GOING OVER THE
ANALYTICAL CHARACTERIZATION OF
DIETARY SUPPLEMENTS, DESCRIBING
ITS IMPORTANCE AND COVERING
ASPECTS OF METHODS, STANDARDS
AND QUALITY ASSURANCE.
THE FUNDAMENTAL QUESTION FOR US
TODAY ON QUALITY AND METHODS IS,
HOW DO YOU KNOW EXACTLY WHAT YOU
ARE MANUFACTURING, SELLING,
CONSUMING, OR STUDYING?
OUR OBJECTIVES FOR UNDERSTANDING
DIETARY SUPPLEMENT
CHARACTERIZATION ARE TO GO OVER
THE CONCEPTS OF IDENTITY,
PURITY, QUALITY, AND
COMPOSITION.
WE'LL DISCUSS AN OVERVIEW OF THE
ANALYTICAL CHALLENGES AND NEEDS
IN RESEARCH, AND WE'LL ALSO TALK
ABOUT THE USE OF REFERENCE
MATERIALS AND RELIABLE
ANALYTICAL METHODS TO SUPPORT
RIGOROUS RESEARCH AND TO SUPPORT
ITS TRANSLATION TO IMPROVE
PUBLIC HEALTH.
NOW THE CORE ISSUE AND CHALLENGE
IS THE FACT THAT BY DEFINITION,
DIETARY SUPPLEMENTS CAN BE
COMPLEX.
WE'VE HEARD THE LEGISLATIVE
DEFINITION OF DIETARY
SUPPLEMENTS IN THE U.S., WHICH
COVERS A LOT OF GROUND.
VITAMIN, MINERALS, METABOLITES,
PLANT MATERIAL, FUNGI, ET
CETERA.
AND OF COURSE SUPPLEMENTS CAN
CONTAIN INGREDIENTS FROM EACH OF
THESE CHEMICAL CATEGORIES, WHICH
COMPLICATES ATTEMPTS TO
ANALYTICALLY CHARACTERIZE THEIR
COMPOSITION.
AS DESCRIBED IN EARLIER TALKS IN
OUR PROGRAM, THE INCLUSION OF
BOTANICALS AS DIETARY
SUPPLEMENTS CAN BRING ADDITIONAL
LAYERS OF COMPLEXITY TO
STANDARDIZATION AND QUALITY
ASSURANCE.
IN DEALING WITH A VARIETY OF
FORMULATION MATRIX TYPES,
TABLETS, LIQUIDS, GUMMIES, ET
CETERA, THESE ALL CAN CREATE
SIGNIFICANT ANALYTICAL
CHALLENGES.
FROM A COMMERCIAL POINT OF VIEW,
AS WE'VE HEARD, IT IS THE
DIETARY SUPPLEMENT HEALTH AND
EDUCATION ACT OF 1994 WHICH
ESTABLISHES HOW SUPPLEMENTS ARE
REGULATED IN THE U.S.
THE CODE OF FEDERAL REGULATIONS
DESCRIBES THE DETAILS OF HOW FDA
REGULATES SUPPLEMENT
MANUFACTURERS, AND IT OUTLINES
CURRENT GOOD MANUFACTURING
PRACTICES THAT THEY MUST FOLLOW.
IT IS THE MANUFACTURERS'
RESPONSIBILITY TO ESTABLISH
SPECIFICATIONS FOR THE IDENTITY,
PURITY, COMPOSITION, AND
STRENGTH OF THEIR PRODUCTS.
AND BOTH INCOMING INGREDIENTS
AND OUTGOING PRODUCTS ARE TO BE
TESTED AGAINST THOSE
SPECIFICATIONS.
NOW IMPORTANTLY, REGULATORS AND
REGULATIONS THAT DON'T MANDATE
THAT A PARTICULAR METHOD OR
TECHNOLOGY BE USED, BUT INSTEAD
THEY STIPULATE THAT METHODS MUST
BE FIT-FOR-PURPOSE AND
SCIENTIFICALLY VALID.
NOW ON THE SIDE OF BIOMEDICAL
RESEARCH ON THE HEALTH EFFECTS
OF DIETARY SUPPLEMENTS,
ANALYTICAL CHARACTERIZATION OF
EXPERIMENTAL MATERIALS IS
ESSENTIAL FOR SUPPORTING
RIGOROUS BASIC AND CLINICAL
RESEARCH ON THE MECHANISMS OF
ACTION, METABOLISM, SAFETY, AND
HEALTH OUTCOMES OF DIETARY
SUPPLEMENTS.
AND OVERALL, A THOROUGH
CHARACTERIZATION OF THE REAGENTS
USED IN RESEARCH IS A CRITICAL
COMPONENT OF BUILDING
REPRODUCIBILITY, SUPPORTING
COMPARABILITY, AND ULTIMATELY
LENDING CREDIBILITY TO THE
RESEARCH.
THERE ARE MULTIPLE GUIDELINES
FOR ACADEMIC LABS AND FUNDING
CRITERIA THAT OUTLINE THE
IMPORTANCE OF AUTHENTICATING AND
THOROUGHLY CHARACTERIZING
NATURAL PRODUCT REAGENTS.
INCLUDING BOTANICAL-DERIVED
REAGENTS THAT YOU OFTEN FIND IN
DIETARY SUPPLEMENTS.
SO HERE ARE SOME EXAMPLES FROM
THE LITERATURE EMPHASIZING THE
NEED FOR CLINICAL TRIALS TO
SUFFICIENTLY DESCRIBE BOTANICAL
AND DIETARY SUPPLEMENT RESEARCH
REAGENTS.
AS IT IS QUITE DIFFICULT, YOU
CAN IMAGINE, IF NOT IMPOSSIBLE
TO INTERPRET AND REPRODUCE A
CLINICAL STUDY THAT DESCRIBES
EXPERIMENTAL INTERVENTION AS
SIMPLY ECHINACEA.
WHAT IS NEEDED INSTEAD IS A
CAREFUL ASSESSMENT OF THE
REAGENT OR INTERVENTION'S
AUTHENTICITY, ITS BIOACTIVE AND
MARKER COMPOUNDS, AND A CHECK
FOR POSSIBLE CONTAMINANTS.
NIH ALSO HAS GUIDANCE STRESSING
THE IMPORTANCE OF AUTHENTICATION
AND BATCH TO BATCH
REPRODUCIBILITY FOR RESEARCH
MATERIALS, AS WELL AS
QUANTIFICATION AND
STANDARDIZATION OF BIOACTIVE
COMPOUNDS USED IN RESEARCH.
SO WHAT DO WE MEAN WHEN WE'RE
TALKING ABOUT CHARACTERIZATION
OF SUPPLEMENTS AND PRODUCT
INTEGRITY?
GENERALLY SPEAKING, A QUALITY
PRODUCT HAS THE DESIRED
INGREDIENTS, IT MEETS LABEL
CLAIMS FOR THE AMOUNT PRESENT,
AND IT IS FREE OF CONTAMINANTS.
TO BE MORE TECHNICAL, PRODUCT
INTEGRITY ENTAILS FOUR
FUNDAMENTAL PARAMETERS:
IDENTITY, PURITY, COMPOSITION,
AND QUALITY.
EACH OF THESE PARAMETERS BRINGS
ITS OWN SET OF CHALLENGES, WHICH
MANUFACTURERS AND RESEARCHERS
NEED TO CONSIDER.
AGAIN, THE QUESTION COMES DOWN
TO, HOW DO YOU KNOW EXACTLY WHAT
YOU ARE MAKING, SELLING,
CONSUMING, OR STUDYING?
SO LET'S START WITH ISSUES OF
IDENTIFYING DIETARY INGREDIENTS
AND SUPPLEMENT PRODUCTS.
AND THE FIRST STEP IS NAMING.
SO LET'S IMAGINE A SCENARIO
WHERE YOU'RE LOOKING TO RESEARCH
MECHANISMS OR CLINICAL EFFECTS
OF COENZYME Q10.
YOU GO TO A COMPANY'S CATALOG
LOOKING TO PURCHASE REAGENTS,
AND IT MAY BE OF NO SURPRISE
THAT THERE CAN BE MANY DIFFERENT
ACCEPTED NAMES FOR THE SAME
CHEMICAL ENTITY.
COQ10, EU UBIQUINONE, HOWEVERU
NEED TO BE CAREFUL.
YOU MIGHT CONSIDER USING
ODIBINONE BUT THAT IS A
SYNTHETICALLY DERIVED DRUG
VERSION APPROVED AS A DRUG IN
SOME REGULATORY ENTITIES.
AND THAT DIFFERENCE IN CHEMICAL
COMPOSITION MIGHT INFLUENCE THE
RESULTS OF YOUR RESEARCH.
BOTANICAL INGREDIENTS BRING
THEIR OWN COMPLEXITIES IN NAMING
WHICH MIGHT CREATE CONFUSION.
THERE ARE UPWARDS OF 3,000 PLANT
SPECIES SOLD IN COMMERCE AND
NAMING DOES NOT ALWAYS EQUAL
IDENTIFYING.
LET'S TAKE A LOOK AT CURCUMIN
INGREDIENTS.
ACCEPTED COMMON NAMES MIGHT
EQUATE ONE SPECIES TO A WHOLELY
DIFFERENT SPECIES, SEEN HERE
WITH DESCRIBING TURMERIC SIMILAR
TO SAFFRON OR GINGER.
IN THE CONTEXT OF HERBAL
MEDICINES, THE USE OF
TRADITIONAL AND REGIONAL NAMES
IS ALSO AN IMPORTANT
CONSIDERATION WHEN SOURCING
INGREDIENTS.
FURTHERMORE, IN TODAY'S GLOBAL
SYSTEM OF SOURCING BOTANICAL
INGREDIENTS WHERE MANUFACTURERS
DO NOT NECESSARILY HAVE CONTROL
OVER THEIR SUPPLY CHAIN, THERE
ARE INSTANCES WHERE REGIONAL
NAMES MAY CONFUSE
IDENTIFICATION.
HERE'S A TABLE OF SEVERAL
UNRELATED PLANT SPECIES.
THEY ARE ALL CLOAK ALL REFE
TYPE OF GINSENG, BUT IMPORTANTLY
THESE HAVE ALL BEEN FOUND TO BE
IMPROPERLY SOLD AS JUST SIMPLY
GINSENG, JUST CONFUSING THE
INGREDIENT WITH PANEX GINSENG.
MANY OF THESE NAMING ISSUES
ARISE BECAUSE PLANT NAMES ARE
OFTEN BASED ON MORPHOLOGICAL
FEATURES, NOT THE CHEMICAL
COMPOSITION OR GENETICS OF THE
PLANT.
ON THE ONE HAND, DISTINCT
SPECIES HAVING SIMILAR NAMES CAN
BE RATHER BENIGN.
FOR EXAMPLE, GERMAN AND ROMAN
CAM
CHAMOMILE HAVE SIGNIFICANTLY
DIFFERENT PHYTOCHEMICAL
PROFILES.
YOU MAY ALREADY BE FAMILIAR WITH
THE CASE OF CHINESE STAR ANISE
WHERE THE FRUIT OF THE CHINESE
FORM HAS MEDICINAL USES BUT
FRUIT FROM JAPANESE STAR ANISE
AND THE FRUIT CONTAIN TOXIC
CONSTITUENTS AND OBVIOUSLY WOULD
NOT BE THE ONES TO USE FOR YOUR
RESEARCH OR YOUR PRODUCT.
AND OF COURSE IDENTIFICATION
CHALLENGES INCREASE AS
INGREDIENTS ARE INCREASINGLY
PROCESSED.
MANUFACTURERS AND RESEARCHERS
ARE ROUTINELY FACED WITH THE
QUESTION OF WHETHER A FINALLY
GROUND POWDER OR A LIQUID
EXTRACT IS THE DESIRED BOTANICAL
INGREDIENT.
FOR EXAMPLE, ARE ANY ONE OR ALL
OF THESE PREPARATIONS ACTUALLY
GOLDENSEAL?
IN THESE SITUATION,
CHARACTERIZATION EFFORTS MUST
OFTEN TURN TO ANALYTICAL
CHEMISTRY APPROACHES.
NOW IN TERMS OF PURITY, FOR VICE
MINES AND
VITAMINS AND MINERALS, WHETHER
THE INGREDIENTS ARE BIOACTIVE
AND BIOAVAILABLE IN CERTAIN
FORMS, OR BOTANICAL
PREPARATIONS, PURITY ISSUES ALSO
INCLUDE THE USE OF PROPER PLANT
PARTS, THE ABSENCE OF
POTENTIALLY HARMFUL MICROBES,
PESTICIDES, TOXINS, AND
UNDECLARED SYNTHETIC SUBSTANCES
LIKE STIMULANTS HAVE BEEN FOUND
TO BE A CONCERN IN CERTAIN TYPES
OF PRODUCTS MARKETED AS SUCH.
NOW A VERY IMPORTANT
CONSIDERATION IS THAT BOTANICAL
COMPOSITION IS INHERENTLY
VARIABLE AND CHARACTERIZATION
NEEDS TO TAKE THIS INTO ACCOUNT.
THE PLANT PART, THE CLIMATE AND
HARVESTING CONDITIONS AND
GENETIC HYBRIDIZATION, THESE ALL
CAN DRAMATICALLY ALTER A PLANT'S
PHYTOCHEMICAL PROFILE.
SIMILARLY, PROCESSING CONDITIONS
CAN SIGNIFICANTLY AFFECT THE
FINAL COMPOSITION OF
PHYTOCHEMICALS IN A SUPPLEMENT
PRODUCT OR RESEARCH REAGENT.
AQUEOUS OR ALCOHOL EXTRACTION
CAN YIELD VERY DIFFERENT
MIXTURES OF BIOACTIVE COMPOUNDS.
IN THE FORMULATION MATRIX CAN
INFLUENCE THINGS LIKE
DISINTEGRATION AND DISSOLUTION
OF THE FORMULATION.
AND, THEREFORE, ALTER ITS
BIOAVAILABILITY.
AS A CONSEQUENCE OF THESE
FACTORS, MYRIAD CHEMICAL
DIVERSITY AND VARIABILITY, IT
CAN BE QUITE CHALLENGING TO
MEASURE AND MAINTAIN CONSISTENCY
IN FINISHED PRODUCTS.
AGAIN, IT IS THE RESPONSIBILITY
OF MANUFACTURERS TO SET
SPECIFICATIONS FOR WHAT
DETERMINES QUALITY.
FOR EXAMPLE, SETTING MINIMUM AND
MAXIMUM CONCENTRATIONS FOR
ACTIVE OR MARKER COMPOUNDS,
SETTING LIMITS ON UNDESIRABLE
CONSTITUENTS.
MANUFACTURERS MUST DEMONSTRATE
THOSE QUALITY SPECIFICATIONS ARE
BEING MET.
WHEN IT COMES TO TESTING AGAINST
THOSE SPECIFICATIONS, REMEMBER
THAT REGULATIONS DO NOT MANDATE
THE PARTICULAR METHOD OR
TECHNOLOGY BE USED.
RATHER, THEY STIPULATE THAT
METHODS MUST BE FIT-FOR-PURPOSE
AND SCIENTIFICALLY VALID.
SO WHAT DOES FIT-FOR-PURPOSE
MEAN?
A FIT-FOR-PURPOSE METHOD IS ONE
DEMONSTRATED TO BE SENSITIVE,
ACCURATE, PRECISE, AND SPECIFIC
FOR THE ANALYTE OF INTEREST.
AND IT ALSO IS A METHOD THAT IS
DEMONSTRATED TO BE RELIABLE AND
REPRODUCIBLE.
SO A NONSPECIFIC METHOD CAN HAVE
ITS PLACE IN A LAB, BUT IT
SHOULD NOT STABBED ALONE.
IMAGINE THE ISSUE THAT CAN ARISE
WHEN, FOR EXAMPLE, A COUNT ALL
METHOD THAT MEASURES NITROGEN
CONTENT AS A PROXY FOR PROTEIN
IS USED AS A SOLE MEASUREMENT.
IF THERE IS AN ADULT RANGE OF
MOTION WITH NITROGEN HAD BEEN
RICH MELAMINE OR UREA, THAT
METHOD IS NOT GOING TO
DISTINGUISH BETWEEN THE
CONTAMINANT AND REAL PROTEIN.
SO WHAT KINDS OF METHODS ARE
NEEDED AND USED?
HOW ARE REAGENTS, PRODUCTS, AND
INGREDIENTS CHARACTERIZED?
A WIDE ARRAY OF ANALYTICAL
METHODS ARE EMPLOYED TO IDENTIFY
AND QUANTIFY CHEMICAL
CONSTITUENTS OF INTEREST.
CHROMATOGRAPHY METHODS OR
CHEMICAL SEPARATION,
SPECTROSCOPY AND MASS SPEC
APPROACHES TO MEASURE ANALYTES,
HYBRID COMBINATIONS OF THESE AS
WELL AS GENOMIC ANALYSES TO
IDENTIFY NATURAL PRODUCT SOURCE
MATERIALS.
AND MULTIPLE TECHNIQUES ARE
OFTEN COUPLED FOR MORE POWERFUL
ANALYSES.
FOR EXAMPLE, A CHROMATOGRAPHIC
SEPARATION OF PHYTOCHEMICALS
FOLLOWED BY A MASS SPEC ANALYSIS
TO QUANTIFY INDIVIDUAL PEAKS.
IN NEWER ANALYTICAL PARADIGMS,
NON-TARGETED ANALYTICAL METHODS
ARE BEING DEVELOPED WHICH CAN
STATISTICALLY CLASSIFY SAMPLES
BASED ON THEIR CHEMICAL OR
METABALOME FIPGER PRINT.
FINGERPRINT.
A NEAR INFRARED SPECTROSCOPY
DATA USED TO THEN MODEL WHETHER
THOSE POWDERS WE SAW EARLIER ARE
INDEED GOLDEN SEAL ROOT OR ONE
OF THE COMMON ADULTERANTS.
NOW YOU MAY BE AWARE FROM
RESEARCH ARTICLES OR NEWS
REPORTS ABOUT DNA-BASED
ANALYTICAL METHODS BEING APPLIED
TO DIETARY SUPPLEMENTS.
WHILE GENETIC TECHNIQUES CAN BE
A POWERFUL APPROACH, ONE MUST
CAREFULLY CONSIDER WHEN IT IS
FIT-FOR-PURPOSE.
IMPORTANTLY, A DNA ANALYSIS,
IT'S NOT GOING TO DIFFERENTIATE
BETWEEN PLANT PARTS, IT'S NOT
GOING TO TELL BUT ABOUT CHEMIL
COMPOSITION.
DATA ANALYSES CAN BE CONFOUNDED
BY EXTENSIVE GENETIC
HYBRIDIZATION THAT IS OBSERVED
IN PLANTS, AND THE DNA
AMPLIFICATION PRIMERS THAT ARE
USED, THEY MAY HAVE POOR
SELECTIVITY FOR DIFFERENTIATING
BETWEEN DIFFERENT BUT CLOSELY
RELATED SPECIES.
NOW THAT ALL BEING SAID,
INNOVATIVE NEXT GENERATION
SEQUENCING APPROACHES ARE
PROVING USEFUL AS COMPLEMENTARY
APPROACH ALONG WITH CHEMICAL
ANALYSES.
AND SEQUENCE REFERENCE LIBRARIES
LIKE THOSE AT THE FDA ARE
BECOMING MORE AND MORE ROBUST IN
THEIR CONTENT AND THEIR ABILITY
TO DIFFERENTIATE PLANT SPECIES.
SO NOW THAT WE HAVE SOME
IMPORTANT CONCEPTS UNDER OUR
BELTS, LET'S TAKE A LOOK AT A
BRIEF EXAMPLE OF SUPPLEMENT
CHARACTERIZATION.
THE UNITED STATES PHARMACOMONO
GRAPH IS ONE STANDARD RESOURCE
THAT ESTABLISHES A DEFINITION OF
WHAT CONSTITUTES QUALITY FOR
GINKGO BILOBA LEAF INGREDIENTS.
IT ESTABLISHES KEY CHEMICAL
ANALYTES AND CONCENTRATION
RANGES FOR BOTH DESIRABLE AND
POTENTIALLY HARMFUL
CONSTITUENTS.
SUCH AS FLAVONOL GLYCOSIDES, AND
GINKGOLIC ACIDS.
A VARIETY OF ANALYTICAL METHODS
CAN BE APPLIED TO A POWDERED
LEAF SAMPLE TO ASCERTAIN WHETHER
A MANUFACTURER'S SPECIFICATIONS
FOR INGREDIENTS HAVE BEEN MET.
YOU CAN SEE LIQUID
CHROMATOGRAPHY SEPARATION AND
MASS SPEC QUANTIFICATION OF
FLAVONOIDS AND TERPENE LACK ,
THEY CAN ALSO BE DETECTED BY
THIN LAYER CHROMATOGRAPHY AS
WELL.
IMPORTANT TO NOTE HERE, NO
SINGLE ANALYSIS IS QUANTIFYING
ALL OF THE IMPORTANT ANALYTES.
YOU OFTEN NEED A NUMBER OF
COMPLEMENTARY METHODS TO
SUFFICIENTLY CHARACTERIZE
DIETARY SUPPLEMENT INGREDIENTS
AND PRODUCTS.
NOW WHILE MANUFACTURERS ARE
RESPONSIBLE FOR TESTING, THERE
ARE MANY THIRD PARTY
LABORATORIES AND CONTRACT
RESEARCH ORGANIZATIONS WHO OFFER
STANDARDIZATION AND ANALYTICAL
SERVICES TO HELP COMPLY WITH
REGULATIONS AND ENSURE PRODUCT
QUALITY.
THERE ARE ALSO VOLUNTARY
INDEPENDENT CERTIFICATION
PROGRAMS AVAILABLE TO
MANUFACTURERS.
FOR EXAMPLE, NSF INTERNATIONAL
WILL TEST PRODUCTS TO VERIFY
INGREDIENT CLAIMS AND ALSO
ASSURE CONSUMERS THAT CERTAIN
CONTAMINANTS ARE NOT PRESENT.
THE USP CERTIFICATION PROGRAM
PERFORMS SIMILAR TESTING AND IT
ALSO AUDITS MANUFACTURERS FOR
COMPLIANCE TO GOOD MANUFACTURING
PRACTICES.
SO THESE ARE LABELS,
CERTIFICATION LABELS THAT YOU
CAN FIND ON THE PRODUCTS'
LABELING.
THERE ARE ALSO EFFORTS AT
CERTAIN FEDERAL AGENCIES TO
SUPPORT AND ADVANCE SUPPLEMENT
CHARACTERIZATION.
NOVEL ANALYTICAL METHODS ARE
BEING DEVELOPED BY SCIENTISTS AT
USDA, SOME OF WHICH IS FUNDED BY
THE NIH OFFICE OF DIETARY
SUPPLEMENTS.
FDA SCIENTISTS ARE ROUTINELY
DEVELOPING NEW ANALYTICAL
METHODOLOGY, OFTEN WITH A LEG
REGULATORY FOCUS ON IDENTIFYING
CONTAMINANTS AND ADULTERANTS.
HERE AT NIH, THE PRODUCT
INTEGRITY POLICY IS AN EFFORT TO
ENSURE THAT FUNDED RESEARCH
APPROPRIATELY CHARACTERIZES
NATURAL PRODUCTS USED AS
EXPERIMENTAL REAGENTS.
AND THE NATIONAL TOXICOLOGY
PROGRAM AT THE NATIONAL
INSTITUTE OF ENVIRONMENTAL
HEALTH SCIENCES, THEY HAVE A
PROGRAM DEDICATED TO EVALUATING
THE CHEMICAL COMPOSITION AND
POSSIBLE TOXICITIES OF BOTANICAL
DIETARY SUPPLEMENTS.
AT THE OFFICE OF DIETARY
SUPPLEMENTS, THE AN ANALYTICAL
METHODS PROGRAM IS DISTINCTLY
FOCUSED ON THE ISSUES OF
RELIABLE CHARACTERIZATION.
THEY SUPPORT EFFORTS IN METHOD
DEVELOPMENT AND VALIDATION,
REFERENCE MATERIAL PRODUCTION,
AND LABORATORY QUALITY ASSURANCE
EXERCISES.
THESE ARE ALL DESIGNED TO WORK
TOGETHER TO HELP SCIENTISTS
BETTER ANSWER QUESTIONS THAT
THEY HAVE ABOUT THEIR BOTANICAL
PRODUCT OR RESEARCH SAMPLE, AND
ULTIMATELY DRIVE TO ENHANCED
FOUNDATION FOR RIGOROUS RESEARCH
AND INDUSTRY ANALYSES.
OVERALL, AMRM'S ROLE IS TO
PROVIDE THE RESOURCES NECESSARY
TO ADDRESS THE ANALYTICAL
CHALLENGES WE'VE OUTLINED.
THESE RESOURCES ARE INTENDED TO
MEET THE NEEDS OF ALL
STAKEHOLDER, HELPING THEM TO
ASSESS QUALITY CONTROL TO ENSURE
LABEL CLAIMS ARE BEING MET, TO
DEVELOP STANDARDS AND TO COMPLY
WITH AND ENFORCE REGULATIONS.
SO NOW TO BRIEFLY DISCUSS THE
DIFFERENT AMRM PROGRAM AREAS, O
DS AMRM FUNDED DEVELOPMENT
ACTIVITIES ARE PERFORMED BY
FEDERAL PARTNERS.
FOR EXAMPLE, THEY'VE DEVELOPED
TARGETED AND NON-TARGETED
APPROACHES, QUANTIFYING
PHYTOSTEROLS IN SUPPLEMENTAL
EXTRACT OR DIFFERENTIATING AN
AUTHENTICATED BLACK KOHOSH ON
RELATED SPECIES BASED ON
PHYTOCHEMICAL PRO TILE FILES.
IN ADDITION TO PROMOTING METHOD
DEVELOPMENT, THEY ALSO SUPPORT
STUDIES OF QUANTITATIVE CHEMICAL
METHODS, WHERE A METHODS
RELIABILITY AND ITS FITNESS FOR
PURPOSE IS DEMONSTRATED THROUGH
THE MEASUREMENT OF KEY
PERFORMANCE PARAMETERS SUCH AS
ITS PRECISION, LIMIT OF
DETECTION, SPECIFICITY,
REPRODUCIBILITY, ET CETERA.
AMRM'S SUPPORT OF METHOD
VALIDATION HAS BEEN ACCOMPLISHED
THROUGH TWO MAIN APPROACHES.
CURRENTLY ODS UTILIZES NIH GRANT
FUNDING OPPORTUNITY
ANNOUNCEMENTS TO SUPPORT
RESEARCHERS IN THE PERFORMANCE
OF VALIDATION STUDIES FOR THE
ANALYTICAL METHODS THEY'VE
DEVELOPED.
SO THESE GRANT FUNDING
OPPORTUNITIES ARE FOCUSED ON
METHODS THAT QUANTIFY CHEMICAL
CONSTITUENTS, THEIR METABOLITES,
OR ADULTERANTS IN EITHER
EXPERIMENTAL REAGENTS LIKE THE
EXTRACTS, THE TABLETS, THE
GUMMIES USED IN RESEARCH, OR
CLINICAL SPECIMENS.
PLASMA OR TISSUE SAMPLES
COLLECTED AS PART OF RESEARCH TO
DETERMINE MECHANISMS OF ACTION
OR PHARMACOKINETIC STUDIES.
SHOWN HERE ARE JUST A FEW OF THE
PUBLICATIONS THAT HIGHLIGHT HOW
THIS GRANT FUNDING ASPECT OF THE
AMRM PROGRAM HELPS INVESTIGATORS
DEMONSTRATE THE PERFORMANCE OF
THEIR STATE OF THE ART METHODS,
LOOKING AT NEW METHODS TO
UNDERSTAND THE FLAVONOL LIPIDS
FOUND IN EXTRACTS, COMPARING THE
AVAILABILITY, THE INTAKE AND THE
OUTPUT OF RED CLOVER ISOFLAVONES
LOOKING AT THE AMOUNT IN THE
SUPPLEMENT AND ALSO IN HUMAN
SERUM.
SO THIS TYPE OF METHOD
VALIDATION ADDS CONFIDENCE TO
BIOMEDICAL RESEARCH ON THE LINKS
BETWEEN DIETARY INGREDIENTS,
THEIR METABOLITES, MECHANISMS OF
ACTION AND ULTIMATE HEALTH
OUTCOME.
HISTORICALLY, THE AMRM PROGRAM
HAS ALSO SUPPORTED METHOD
STANDARDIZATION EFFORTS THAT PRO
PLOAT THE
PROMOTE THE OFFICIAL ANALYSIS
FOR DIETARY SUPPLEMENTS AND
BOTANICALS.
THESE OFFICIAL METHODS, FOR
EXAMPLE, CHROMATOGRAPHIC
SEPARATION OF NON-VOLATILE
GINGER CONSTITUENTS IN PLANT
PARTS, EXTRACTS AND SUPPLEMENT
PRODUCTS THEE ARE ESTABLISHED BY
THE STANDARD SETTING
ORGANIZATION AOAC INTERNATIONAL.
AND THE RESULTING OFFICIAL
METHODS OF ANALYSIS AS WELL AS
GUIDELINES FOR METHOD VALIDATION
STUDIES, THESE ARE AVAILABLE TO
MANUFACTURERS AND RESEARCHERS
ALIKE.
NOW WITH ALL THIS TALK OF METHOD
DEVELOPMENT AND VALIDATION, HOW
CAN RESEARCHERS KNOW THAT THEIR
METHODS ARE GENERATING THE RIGHT
ANSWERS FOR QUANTIFICATION OR
IDENTIFICATION?
THIS IS WHERE REFERENCE
MATERIALS ARE VITAL FOR RESEARCH
AND PRODUCT TESTING.
REFERENCE MATERIALS ARE
AUTHENTICATED HOMO GENIUS
PREPARATIONS WITH WELL
CHARACTERIZED COMPOSITION AND/OR
PROPERTIES.
FOR EXAMPLE, THESE REFERENCE
MATERIALS FOR GINKGO BILOBA
LEAVES HAVE CERTIFIED MEASURED
VALUES FOR FLAVONOIDS AND TRACE
HEAVY METALS.
REFERENCE MATERIALS ARE USED TO
VERIFY THE ACCURACY OF SPECIFIC
MEASUREMENTS, AND TO SUPPORT THE
DEVELOPMENT OF NEW MEASUREMENT
METHODS.
HERE'S AN EXAMPLE OF REFERENCE
MATERIAL IN ACTION.
AMRM CONTRACTED WITH A COMPANY
TO PRODUCE A MIXTURE SOLUTION OF
NINE KEY CONSTITUENTS OF KAVA
KAVA.
THIS MIXTURE WAS DEVELOPED TO
HAVE KNOWN AMOUNTS OF SPECIFIC
KAVALECTONES AND FLAHAVEKAVAINS.
SO WE SEE HERE IN THESE
CHROMATOGRAMS CONFIRMATION THAT
A METHOD CAN SEPARATE FROM
EXTRACT AND CAPSULE PREPARATION
IN THE BLUE TRACES AND THAT
THOSE SEPARATED AND IDENTIFIED
PEAKS, THEY DO ALIGN WITH THE
REFERENCE MATERIALS' CHEMICAL
CONSTITUENTS IN THE RED TRACE.
BECAUSE THE REFERENCE MATERIAL
HAS A KNOWN COMPOSITION BY MASS,
THE AMOUNT OF EACH CONSTITUENT
IN THE KAVA INGREDIENT HERE AND
ALSO IN THE CAPSULE PRODUCT CAN
BE DETERMINED.
IN THIS WAY, REFERENCE MATERIALS
PROVIDE RESEARCHERS THE MEANS TO
TEST, IMPROVE AND VALIDATE THEIR
METHOD PERFORMANCE.
THROUGH THE COLLABORATIVE WORK
AT THE NATIONAL STANDARDS
TECHNOLOGY, AMRM HAS ALSO MADE
AVAILABLE OVER 30 METRICS-BASED
REFERENCE MATERIALS FOR SOME OF
THE MOST POPULAR BOTANICALS AND
TIE TRI
DIETARY SUPPLEMENTS.
THE MATERIAL IS IN A FORM
RELEVANT TO THE DIETARY
SUPPLEMENT ANALYST.
SUCH AS A GROUND ROOT, A
MULTIVITAMIN AND MULTI-MINERAL
TABLET, OR A FISH OIL EXTRACT.
AS SHOWN HERE IS A SELECTION OF
THE AVAILABLE MATERIALS WITH THE
MEASURED ANALYTES INDICATED.
AND MANY OF THESE SUCH AS GINKGO
BILOBA, ST. JOHN'S WORT, GREEN
TEA AND SOME OTHERS ARE
AVAILABLE AS A SUITE OF
MATERIALS COVERING POWDERS,
EXTRACTS AND TABLET
FORMULATIONS.
FINALLY, AMRM ALSO FUNDS THE
ADMINISTRATION OF LABORATORY
QUALITY ASSURANCE PROGRAMS.
THESE ARE VOLUNTARY PROGRAMS
WHERE PARTICIPATING LABS MEASURE
NUTRITION NAND AND COX CLOJ
ELEMENTS, VITAMINS, FATTY ACIDS,
CONTAMINANTS AND BOTANICAL
MARKERS IN SAMPLES DISTRIBUTED
BY NIST.
PARTICIPATING LABS THEN REPORT
BACK THE RESULTS, AND THESE
EXERCISES ARE A MEANS FOR THE
COMMUNITY OF LABS TO IDENTIFY
ANALYTICAL PROBLEM AREAS,
COMPARE THEIR METHODS, AND
REDUCE ANY BIASES THAT THEY FIND
IN THEIR MEASUREMENTS.
SO AN EXAMPLE OF THAT HERE IS A
QUALITY ASSURANCE PROGRAM
EXERCISE WHERE PARTICIPANT LABS
MEASURE FOR CUMINOIDS IN
EXTRACTS AND WITH A CERTIFIED
TRUE VALUE FOR ONE OF THE
CURCUMINOIDS AND ALSO A TARGET
ANALYTICAL RANGE IN BETWEEN THE
ORANGE LINES.
THE PARTICIPATING LABS WERE ABLE
TO SEE IF THEIR RESULTS FELL IN
THAT ACCEPTABLE RANGE OR NOT.
THEY'RE THEREFORE ABLE TO
DETERMINE IS THEIR PERFORMANCE
WITH THEIR ANALYTICAL
METHODOLOGY ACCEPTABLE.
ALL RIGHT.
WELL, WE'VE COVERED A LOT OF
GROUND TODAY.
THE MAIN TAKEAWAYS ARE THAT THE
CHEMICAL COMPOSITION OF DIETARY
SUPPLEMENTS CAN BE VERY COMPLEX.
COMBINATIONS OF MULTIPLE VIED
MINES, MINERALS, PROTEIN AND
BOTANICAL INGREDIENTS MAKE
CHEMICAL ANALYSIS QUITE
CHALLENGING.
FURTHER, THE FORMULATION CAN
VARY FROM BATCH TO BATCH.
HOWEVER, DESPITE THESE
CHALLENGES, RELIABLE RESEARCH
AND CONSISTENT PRODUCT QUALITY
DEPENDS UPON THOROUGH
CHARACTERIZATION OF THE
SUPPLEMENTS USED IN CLINICAL
INVESTIGATIONS OR SOLD ON THE
MARKET.
AND THERE ARE MULTIPLE FEDERAL
AND INDUSTRY PROGRAMS THAT WORK
TO SUPPORT THIS LEVEL OF
CHARACTERIZATION AND PROMOTE
RIGOROUS RESEARCH.
THE PROGRAMS I DISCUSSED TODAY,
THEY WOULDN'T BE POSSIBLE
WITHOUT THE WORK OF MANY PEOPLE.
MY COLLEAGUES AT ODS, AND THE
TEAMS AT USDA, NIST, AND I ALSO
MENTIONED SOME OF THE WORK AT
SIRILIANT.
SO THANK YOU VERY MUCH FOR YOUR
ATTENTION.
IT'S BEEN MY PLEASURE TO SPEAK
WITH YOU TODAY.
AND I WILL TRANSITION TO A Q & A
SESSION.
>>THANK YOU, DR. KUSZAK, FOR
THIS VERY INFORMATIVE
PRESENTATION.
NOW WE HAVE LIKE 10 MINUTES FOR
THE QUESTIONS AND YOU CAN SUBMIT
THEM IN THE Q & A BOX.
FOR THE Q & A SESSION, DR. JOE
BEST IS WITH US WITH HIS
EXTENSIVE KNOWLEDGE.
HE IS THE ACTING DIRECTOR OF THE
ODS AND THE FORMER DIRECTOR OF
THE ANALYTICAL METHODS AND
REFERENCE MATERIALS PROGRAM.
SO WELCOME, JOE.
>> THANK YOU.
>> I WOULD LIKE TO START WITH A
QUESTION.
IF A LABORATORY WOULD LIKE TO
USE A REFERENCE MATERIAL BUT
DON'T HAVE THE SAME
ANALYTICAL -- THAT HAS BEEN USED
FOR THE DEVELOPMENT OF THE SRM,
CAN THIS LAB HELP OUTCOMES BY
USING THE REFERENCE MATERIAL
WITHOUT ADAPTING THE SAME
ANALYTICAL METHOD?
>> ACTUALLY THE WHOLE POINT OF
THESE REFERENCE MATERIALS IS
THAT THEY ARE METHOD-AGNOSTIC.
THE REASON THAT THEY'RE ANALYZED
BY NIST WHEN THE REFERENCE
MATERIALS ARE BEING DEVELOPED IS
TO CHARACTERIZE A MATERIAL.
THERE'S NOTHING THAT SAYS THAT
YOU HAVE TO USE THE EXACT SAME
TECHNOLOGY.
THE GOAL IS TO GET THE SAME
ANSWERS AS WERE PROVIDED IN THE
CERTIFICATE OF ANALYSIS, AND YOU
CAN USE WHATEVER METHOD YOU NEED
TO DO THAT.
SANEM, YOU'RE A PERSON WHO WORKS
AT NIST, SO YOU CAN CHIME IN ON
THIS AS WELL IF YOU WISH.
IT'S JUST NOT ME.
THERE'S TWO EXPERTS IN THIS
SESSION.
>> OKAY, THANK YOU.
SO YEAH, I'M WORKING ON THIS,
THIS IS EXACTLY HOW -- WHY WE
ARE DOING THIS.
ANY LABORATORY WANTS TO USE
REFERENCE MATERIALS DOESN'T HAVE
TO USE THE SAME EXACT METHOD.
WHAT WE ARE DOING IS, WE ARE
DEVELOPING ANALYTICAL METHODS,
WE ARE TRYING TO WORK WITH THE
BEST METHOD TO IDENTIFY THE
COMPOUNDS, ACCURATE AMOUNTS, AND
YOU CAN JUST USE YOUR OWN METHOD
AND COMPARE THE REFERENCE
MATERIALS WITH THE METHODS THAT
YOU DEVELOPED YOURSELF.
SO THANK YOU.
I'M GOING TO FOLLOW WITH THE
SECOND QUESTION.
WHO SHOULD BE CONTACTED IF YOU
WANT TO BE PART OF THE
PARTICIPATION LABS IN ANALYZING
STANDARD SAMPLES?
>> WE WILL ADD THAT TO THE CHAT.
WE'LL HAVE THE URL AND THE EMAIL
CONTACT INFORMATION FOR THAT
PROGRAM.
SO IT'S NIST.
THEY HAVE A FORMAL PROGRAM
DIRECTOR THERE, I'M TRYING TO
THINK OF THE CONTACT EMAIL.
SANEM, YOU MAY KNOW THAT.
>> CAROL LYNN IS COORDINATING SO
WE CAN INCLUDE HER EMAIL LINK IN
THE CHAT BOX SO YOU CAN FIND
THOSE INFORMATION THERE.
IS THERE A DATABASE FOR
ANALYTICAL MATERIALS?
>> THERE IS ONE.
THERE IS ONE IN DEVELOPMENT, ODS
IS PUTTING ONE TOGETHER IN
CONJUNCTION WITH NIST, AND THE
AOAC INTERNATIONAL, ADAM
MENTIONED THAT EARLIER, HAS A
TECHNICAL DIVISION ON REFERENCE
MATERIALS.
AND THEY ARE ALSO IN THE PROCESS
OF DEVELOPING A REFERENCE
MATERIAL LIST.
I CAN'T GIVE YOU A TIMELINE WHEN
THAT WILL BE AVAILABLE, BUT YOU
CAN CONTACT EITHER ADAM OR
MYSELF AND I WILL PROVIDE YOU
THE INFORMATION TO KEEP TRACK.
THERE'S ALSO A LIST OF MATERIALS
ON THE ODS AMRM WEBSITE, I
BELIEVE, BUT IT'S NOT A FULLY
FUNCTIONAL SEARCHABLE DATABASE
JUST YET.
>> OKAY, NEXT QUESTION.
CAN YOU DISCUSS WHAT
CONSTITUTES -- CLINICAL
FORMULATION THAT IS THE PLANT
MATERIALS GOING TO -- GOING INTO
MANUFACTURED PRODUCT IS LIKELY
TO BE A COMPOSITION OF PLANTS OR
PLANT PARTS, SO HOW DOES ONE
KNOW WHEN SUFFICIENT SAMPLING
HAS BEEN ACCOMPLISHED?
>> THERE ARE ACTUALLY STANDARD
PARADIGMS FOR SAMPLING PLANS FOR
THIS SORT OF THING.
FDA PROVIDES GUIDANCE BY
ANALYTICAL METHOD VALIDATION.
AND AOAC ALSO PROVIDES GUIDANCE.
SO THERE'S THE AOAC VALIDATION
PROTOCOLS THAT ARE IN APPENDIX K
OF THE OFFICIAL METHODS OF
ANALYSIS THAT PROVIDES THE
TECHNIQUES FOR VALIDATING
METHODS OR GENERAL APPROACHES TO
VALIDATING METHODS.
AND THE SAMPLING PLANS ARE ALL
PART OF THAT METHODS
DEVELOPMENT.
AGAIN, IF YOU WRITE TO ADAM OR
MYSELF, WE'D BE HAPPY TO SEND
YOU THOSE RESOURCES.
THE
>> OKAY.
THANK YOU, JOE.
THERE ARE NO MORE QUESTIONS
COMING UP.
I THINK THE PRESENTATION WAS
VERY INFORMATIVE AND YOUR
QUESTIONS WERE VERY DETAILED, SO
THANK YOU ALL.
SO I'M GOING TO CONTINUE WITH
OUR NEXT SPEAKER.
THANK YOU.
OUR NEXT SPEAKER IN THIS SESSION
IS DR. BARBARA SORKIN.
DR. BARBARA SORKIN JOINED ODS AS
DIRECTOR OF THE BOTANICAL
RESEARCH CENTERS PROGRAM IN
2011.
BEFORE MOVING TO ODS, DR. SORKIN
WAS RESPONSIBLE FOR
ADMINISTRATING EXTRAMURAL
RESEARCH IN THE AREAS OF
ANTIOXIDANTS, HEALTH AGING
CANCER AND SLEEP AT NIH NATIONAL
CENTER FOR COMPLEMENTARY AND
INTEGRATIVE HEALTH.
TODAY, DR. SORKIN WILL TALK
ABOUT HOW CONCEPTS OF EFFICACY,
SAFETY AND IDENTITY ARE
ADDRESSED IN STUDYING BOTANICALS
AND PLANT-DERIVED INGREED YEBTS.
AND INGREDIENTS
AND SHE WILL PROVIDE AN OVERVIEW
OF THE NIH CENTERS FOR ADVANCING
RESEARCH ON BOTANICALS AND OTHER
NATURAL PRODUCTS, CARBON
PROGRAM.
I'D LIKE TO WELCOME DR. SORKIN
TO DISCUSS THE CHALLENGES IN
RESEARCH ON BOTANICAL DIETARY
SUPPLEMENTS.
WELCOME, DR. SORKIN.
THANK YOU ALL FOR YOUR INTEREST,
THANK YOU, SANEM, FOR YOUR HELP
AND FOR THE INTRODUCTION.
DR. KUSZAK [INAUDIBLE] I WANT TO
TELL YOU ABOUT TODAY.
HE TALKED ABOUT CHARACTERIZATION
OF CHEMICALLY COMPLEX AND --
VARIABLE DIETARY SUPPLEMENTS
LIKE BOTANICAL PRODUCTS, AND
WHAT I WANT TO DO IS BUILD ON
THAT FOUNDATION THAT HE PROVIDED
AND TALK -- DIVE WAY MORE INTO
HOW YOU FIGURE OUT WHETHER THE
CHEMISTRY OF THE PRODUCT THAT
YOU'RE LOOKING AT IS GOING TO
GIVE YOU THE BIOLOGICAL EFFECT
THAT YOU ARE HOPING TO HAVE.
SO THE QUESTION THAT I ALWAYS
GET FROM PEOPLE IS TELL US WHICH
PLANT, WHICH SUPPLEMENTS WILL
WORK FOR WHICH CONDITIONS.
AND AS YOU CAN SEE FROM THIS
GRAPHIC HERE, I AM GOING TO
TOUCH VERY BRIEFLY ON
[INAUDIBLE] BUT HOW DO WE AN SER
THIS QUESTION?
BEFORE WE TURN TO A ANSWER IT IN
MORE DEPTH, ADAM TALKED ABOUT
HOW WE CHARACTERIZE THE
CHEMISTRY BUT NOT WHAT I'M GOING
TO TALK ABOUT, WHICH IS HOW WE
CONNECT THE CHEMISTRY TO THE
BIOLOGICAL EFFECTS IN THE
CONSUMER.
BUT WHY IS THIS IMPORTANT?
BECAUSE IT IS CHALLENGING, GIVEN
THE CHEMICAL CHALLENGES ADAM WAS
TELLING YOU ABOUT.
ONE WAS THAT AS DR. BAILEY TOLD
YOU YET, A LOT OF PEOPLE USE
DIETARY SUPPLEMENTS.
NOW A SMALLER PERCENTAGE USE THE
ONES THAT ARE NOT VITAMINS OR
MINERALS LIKE BOTANICALS, BUT
THAT'S STILL AT A MINIMUM 5% OF
THE U.S. POPULATION WHICH IS
50 MILLION PEOPLE WHICH IS
GETTING TO BE REAL NUMBERS.
THE OTHER REASON I THINK IT'S
IMPORTANT TO STUDY THIS IS THAT
THE -- COMPLEXITY, CHEMICALLY
COMPLEX AS THESE DIETARY
SUPPLEMENTS MAY BE, AND I'M
GOING TO SHOW YOU SOME EXAMPLES
OF WHAT I MEAN BY THAT, COMPLEX
AS THEY MAY BE, THEY'RE STILL
SIMPLER TO TRACK HUMAN EXPOSURE
TO AND SIMPLER TO TRACK ONCE
THEY'RE INSIDE THE BODY BECAUSE
THEY DON'T HAVE A UBIQUITOUS
BACKGROUND LIKE FLAVONOID, FOR
EXAMPLE, WHICH ARE IN MANY OF
THE FOODS ONE HOPES YOU ARE
EATING.
AND THEN YOU CAN TAKE THE
METHODS THAT YOU DEVELOPED,
EASIER TO TRACK CASES, BRING
THEM TO UNDERSTANDING WHICH MAY
BE BENEFICIAL FOR WHAT AND WHY.
SO HERE'S THE ROAD MAP THAT I'M
HOPING TO TAKE YOU THROUGH
TODAY.
I'M GOING TO START BY TELLING
YOU A LITTLE BIT ABOUT THE
CONSORTIUM EVENTS -- AND OTHER
NATURAL PRODUCTS WHICH I
CODIRECT AND WE'RE GOING TO
SPEND A LOT OF TIME CONTINUING
TO FOCUS ON PRODUCT BUT MORE
FROM THE POINT OF VIEW, DOES IT
HAVE THE DESIRED -- DR. KUSZAK
TOLD YOU A LOT ABOUT LOOKING AT
SAFETY, WHAT'S THE RIGHT
CHEMISTRY AND HOW DO YOU FIGURE
THAT OUT.
SOME EXTENT IS THAT SORT OF A
CHICKEN AND EGG QUESTION, AS
YOU'RE NOT SEEING THE DESIRED
EFFECTS BECAUSE YOU'RE LOOKING
AT THE WRONG -- THE RIGHT
CHEMISTRY SO YOU'RE WORKING BACK
AND FORTH BETWEEN THOSE.
I'LL THEN TALK A LITTLE ABOUT
WHETHER WHAT'S IN THE
SUPPLEMENT, HOW DID IT GET TO --
AND VERY LITTLE BIT ABOUT TIMING
AT CONSUMPTION.
OBVIOUSLY THAT'S REALLY
IMPORTANT, WHAT TIME OF DAY YOU
TAKE THINGS, WHETHER YOU TAKE IT
BEFORE, IF DO YOU TAKE IT EARO
PREVENT, FOR RECOVER AFTER YOU
ALREADY SEE SYMPTOMS, AND THEN
I'M GOING TO TAKE IT A BIT
BEYOND THE CHEMICAL COMPLEXITY
OF NATURAL PRODUCTS THAT ARE --
FOR THIS 30 MINUTES AND TALK A
LITTLE ABOUT SOME OF THE
CHALLENGES OF TAKING STUDIES ON
CHEMICALLY COMPLEX INHERENTLY
VARIABLE SUPPLEMENTS THAT PEOPLE
HAVE VERY STRONG BELIEFS ABOUT
IN MANY CASES.
FROM TAKING ANIMAL MODELS LIKE
MICE AND GOING FROM THOSE TO
HUMANS AND SOME OF THE
CHALLENGES THAT I DON'T THINK
YOU'RE GOING TO HEAR ABOUT
ELSEWHERE TODAY OR TOMORROW.
HERE'S THE OUTLINE.
THIS IS ONE OF THE PAPERS THAT I
PUT IN MY REFERENCE LIST OR LIST
OF REFERENCES AND RESOURCES, THE
PAPER THAT I READ, MANY, MANY
AUTHORS, BEGINNING OF 2020, AND
MANY OF THE THINGS I'M GOING TO
TALK ABOUT TODAY ARE EXPANDED ON
IN THAT PAPER IF YOU'RE
INTERESTED.
CHEMICAL CONSTITUENTS IN THE
PRODUCT, WE KNOW HERE YOU'RE
LOOKING AT MULTIPLE CONSTITUENTS
AND POTENTIALLY MULTIPLE
DIFFERENT TARGETS IN THE
CONSUMER.
AND THAT IS, I THINK, AN PORP
POINT AND ONE OF THE VERY
IMPORTANT REASONS WHY IT'S NOT
SUFFICIENT TO LOOK AT A SINGLE
COMPOUND IN A BOTANICAL LIKE
CURCUMIN, FOR EXAMPLE, AND I'LL
TRY TO CONVINCE YOU THAT IS A
REALLY IMPORTANT THING TO DO AND
IMPORTANT FOREIGN UNDERSTANDING
BIOLOGICAL EFFECTS BECAUSE
OBVIOUSLY IF YOU HAVE MULTIPLE
COMPONENTS IN A PRODUCT,
MULTIPLE CELLULAR TARGETS IN THE
CONSUMER, DIFFERENT WAYS OF --
DIFFERENT CHEMISTRIES, DIFFERENT
WAYS OF STANDARD USING THE
PRODUCT ARE GOING TO GIVE YOU
DIFFERENT OUTCOMES, AND SO
KNOWING WHICH CHEMISTRY HAS WHAT
OUTCOME IS GOING TO BE REALLY
IMPORTANT FOR COMPARING BETWEEN
DIFFERENT STUDY, DIFFERENT
OUTCOMES, DIFFERENT POPULATIONS,
PERHAPS, THAT POPULATIONS DIFFER
IN, FOR EXAMPLE, MICROBIOTA.
THE ODS WEBSITE HAS A NUMBER OF
PAGES ON THE CONSORTIUM.
YOU CAN FIND THEM AT THIS URL.
I AM NOT GOING TO TAKE YOU
THROUGH THE FIVE CURRENT
BOTANICAL -- FIVE CURRENT
CENTERS, RESEARCH CENTERS IN
DETAIL, BUT WHAT I AM GOING TO
DO IS, AS I GO THROUGH MY
DISCUSSION OF HOW YOU GET THE
RIGHT CHEMISTRY IN YOUR PRODUCT
FOR THE BIOLOGY, THE OUTCOME
THAT YOU'RE INTERESTED IN, HOW
YOU -- HOW THEY'VE CONTRIBUTED
TO THAT ARGUMENT, EXCITING WORK
THEY HAVE DONE.
THE ONE CENTER I'M NOT GOING TO
TALK ABOUT IS THE NATURAL
PRODUCTS MAGNETIC RESONANCE
DATABASE.
IF YOU ARE INTERESTED IN
CHEMISTRY OF NATURAL PRODUCTS, I
URGE YOU SO HAVE A LOOK AT IT
AND IF YOU GO TO THIS WEBPAGE
THAT WILL TAKE YOU TO THEIR
WEBSITE.
WE'VE TALKED ABOUT THE
CONSORTIUM.
LET'S TURN TO THE PRODUCT.
ADAM ALREADY TALKED TO YOU ABOUT
IT. URMERIC, CURCUMIN, AND
CURCUMINOIDS.
IN ADDITION TO CURCUMINNOIDS, --
PEOPLE USUALLY THINK CURCUMIN OR
PERHAPS CURCUMINNOIDS BUT
DR. JANET FUNK AT UNIVERSITY OF
ARIZONA HAS SOME EVIDENCE THAT,
IN FACT, EXOIN THE OILS MAY ALSO
CONTRIBUTE TO SOME BIOLOGICAL
ACTIVITIES OF TURMERIC ROOT.
ARGUMENT ONE, THE IMPORTANCE OF
LOOKING AT THE WHOLE PLANT, NOT
JUST THE CHARACTERISTIC
BIOACTIVE COMPOUNDS IN IT.
HERE'S ANOTHER REASON THAT IT'S
IMPORTANT TO LOOK AT MULTIPLE
COMPOUNDS.
AGAIN, THIS WAS SOMETHING -- A
STORY AT THE BOTANICAL RESEARCH
CENTER AT UNIVERSITY OF ILLINOIS
AT CHICAGO, THERE WERE 20-SOME
CASES OF ACUTE NON-VIRAL
HEPATITIS REPORTED AROUND
EUROPE, ALL IN ASSOCIATION
WITH -- TURMERIC PRODUCTS.
NOW WHEN YOU ARE -- SIMPLY BY
THE PRESENCE OF CURCUMIN, GIVEN
THAT IT'S RELATIVELY INEXPENSIVE
TO SYNTHESIZE CURCUMIN BUT MORE
EXPENSIVE TO ISOLATE
CURCUMINNOIDS FROM TURMERIC
ROOTS, ONE THING THAT SOMETIMES
HAPPENS IS THAT PEOPLE WILL TAKE
POWDER AND COLOR IT THAT LOVELY
ORANGE COLOR OF TURMERIC ROOT
USING OTHER -- LIKE CHROMATE
WHICH WOULD NOT SHOW UP ON A
TYPICAL ANALYSIS FOR
CURCUMINOIDS BECAUSE IT WOULDN'T
BE SOLUBLE IN THE SOLVENT THAT
YOU WOULD USE.
SO THIS GROUP GOT CALLED IN AND
THEY ANALYZED SOME OF THE
BATCHES OF SO-CALLED TURMERIC
THAT WERE ASSOCIATED WITH THIS
ACUTE NON-VIRAL HEPATITIS.
THE BATCHES A AND B SHOWN HERE.
AND INDEED, COMPARING THEM TO
GENUINE ISOLATED CURCUMIN, YOU
CAN SEE THAT THIS HAD CURCUMIN
IN IT, BUT IF IT WERE REALLY
ISOLATED FROM TURMERIC ROOT, IT
WOULD ALSO CONTAIN AT LEAST
TRACE AMOUNTS OF THE OTHER
CURCUMINOIDS ISOLATED PROTON NMR
OF THOSE CURCUMINOIDS SHOWN AT
THE BOTTOM, AND YOU CAN SEE
THESE ARE ABSENT FROM THESE TWO
PRODUCTS INDICATING THEY ARE
INDEED SYNTHETIC PRODUCTS AND
THAT IN ALL LIKELIHOOD, THE
CAUSE OF THE ACUTE HEPATITIS IN
THE PEOPLE WHO USED THESE
PRODUCTS WAS PROBABLY FROM ONE
OF THOSE SOLVENTS USED TO
SYNTHESIZE THE PRODUCT THAT WAS
NOT SUFFICIENTLY REMOVED.
GIVEN THE AMOUNT OF TIME I'VE
SPENT TALKING ABOUT TURMERIC AND
CURCUMINOIDS, OBVIOUSLY THERE
ARE MANY, MANY DIFFERENT HEALTH
CLAIMS FOR THEM.
AND THIS WEBSITE, I'M NOT GOING
TO TELL YOU WHAT IT WAS, GIVEN
WHAT I'M ABOUT TO SAY ABOUT IT.
THEY DID POINT OUT THAT THERE
ARE CASES WHERE INTEREST ARE
PROBLEMS WITH TURMERIC
SUPPLEMENTS THAT ARE ON THE
MARKET.
ALTHOUGH OF COURSE NOT THEIRS.
THEY ALSO POINT TO A GREAT MANY
DIFFERENT HEALTH OUTCOMES
THAT -- I'M NOT SURE WHETHER
THEY'RE TALKING ABOUT TURMERIC
OR CURCUMIN.
THEY DO SEEM TO HAVE SOME
PROBLEMS WITH -- THAT IT'S NOT
BOTH, AND THEY ALSO -- THE OTHER
THING THAT YOU SEE A LOT OF WITH
CURCUMIN, TURMERIC, IS INTEREST
IN WHETHER IT CAN HELP TO
PROTECT YOU FROM COVID-19.
I SEARCHED PUBMED LAST WEEK AND
FOUND 200 PAPERS THAT INCLUDED
THESE TERMS.
SO A LOT OF INTEREST THERE.
NOW, WHY SO MUCH INTEREST IN
TURMERIC?
I WOULD ARGUE THAT CERTAINLY
IT'S TRADITIONALLY USED AS A
MEDICINAL, I'LL COME BACK TO
THAT IN A MOMENT, BUT THE OTHER
THING IS THAT IN MANY CELL-BASED
OR IN VITRO ASSAYS, CURCUMIN
GIVES A POSITIVE RESULT.
OKAY.
NOW I'M GOING TO TELL YOU ABOUT
THE BOTANICAL TRADITIONAL USE
BASIS HERE, AND MY CAVEAT ABOUT
BUILDING A NON-CLINICAL TRIAL OR
MODERN USE WHERE YOU GO TO YOUR
SUPERMARKET OR HEALTH FOOD STORE
AND YOU BUY A PLASTIC BOTTLE
WITH CAPSULES IN IT, CONTRASTING
THAT FROM TRADITIONAL USE, YOU
NEED TO BE REALLY CAREFUL.
IN TRADITIONAL USE, THE
DIAGNOSTIC SYSTEM IS PROBABLY
DIFFERENT.
THIS IS A IS A SCENE FROM THH
AMERICA RAIN FOREST AND MY
COLLEAGUE AT THE FOOD AND DRUG
ADMINISTRATION.
YOU CAN IMAGINE THAT THE WAY
THEY GROW THEIR PLANTS, THAT
THEY'RE USING PERHAPS
MEDICINALLY IN THE WAY THEY
HARVEST AND PREPARE THEM, THEIR
ENVIRONMENTAL CONTEXT, WHAT THEY
EAT, STRESS THAT THEY'RE UNDER,
ARE ALL VERY, VERY DIFFERENT
FROM MODERN AMERICA.
AND I THINK JOE IS PUTTING
REGULATORY INFORMATION IN THE
CHAT.
I CAN'T SEE THE CHAT, JOE, I
DON'T THINK.
CAN I SEE THE CHAT?
I DON'T THINK I CAN WHILE I'M
SHARING, JOE.
>> NO, THOSE ARE ANSWERS TO THE
QUESTIONS FROM ADAM'S THING.
SO YOU CAN IGNORE THOSE.
>> OKAY.
SORRY.
THANKS.
OKAY.
SO THERE MAY CERTAINLY BE
DIFFERENCES BETWEEN THE EFFECTS
YOU WOULD SEE IN YOURSELF BUYING
SOMETHING AT YOUR LOCAL
SUPPLEMENT STORE AND THE RESULTS
THAT THESE PEOPLE SEE PERHAPS
SOMETHING IN A VIRTUAL CONTEXT,
THEY'RE PREPARING THEM
DIFFERENTLY, DIFFERENT DIE TET
ETS, DIFFERENT GUT MICROBIOTA.
THE OTHER TYPICAL MODERN USE IS
BASED ON ARE -- IN VITRO ASSAYS.
CURCUMIN IS ONE OF A NUMBER OF
COMPOUNDS THAT DRS. BAIL AND
WALTERS HAVE DUBBED IN THIS 2014
NATURE PAPER, THE PAN ASSAY
INTERFERENCE COMPOUND.
THESE ARE COMPOUNDS THAT ARE IN
MANY CASES HIGHLY CHEMICALLY
REACTIVE, IN MANY CASES THEY CAN
DISRUPT CELL MEMBRANES.
AMONG THESE COMPOUNDS IN
ADDITION TO KIRK MIN, ARE
RESVERITROL -- FROM GREEN TEA,
ALL OF WHICH YOU PROBABLY HAVE
HEARD OF AND SEEN AS DIETARY
SUPPLEMENTS.
SO WHEN YOU SEE POSITIVES WITH
THESE THINGS IN CELL-BASED DRUG
IN VITRO ASSAYS, IT DOESN'T
NECESSARILY MEAN THEY WORK THE
WAY THAT ASSAY INDICATES.
THEY HAVE I'M NOT SAYING THO
BIOLOGICAL EFFECT, I'M SIMPLY
SAYING USING THOSE ASSAYS AS A
GUIDE TO HOW THEY -- MAY BE
DECEPTIVE.
THE FACT THAT THEY'RE SO
CHEMICALLY ACTIVE AND WORK ON
CELL MEMBRANES SUGGEST TO ME
THEY MAY HAVE MANY BIOLOGICAL
EFFECTS, THEY MAY BE VERY
CONTEXT-DEPENDENT AND IT'S HARD
TO UNDERSTAND AND HARD TO
CONTROL.
SOME OF THE PROBLEMS WITH HOW WE
THINK ABOUT -- PROBLEMS WITH HOW
YOU THINK ABOUT CHEMICAL
CONSTITUENTS OR PHYTOCHEMICALS
FROM THESE CHEMICALLY COMPLEX
SOURCES ACT ON HUMAN BIOLOGY OR
CONTROL ANIMAL BIOLOGY.
WHAT ARE SOME OF THE
SOLUTIONS -- FIRST LET'S TAKE A
LOOK AT REALLY EXPLAINING WHAT I
MEAN WHEN I SAY THESE ARE
CHEMICALLY COMPLEX.
BECAUSE SO FAR YOU'VE LOOKED AT
TWO CURCUMINNOIDS AND OTHER
COMPOUNDS.
HERE'S ANOTHER EXAMPLE FROM THE
FOLKS FROM THE UNIVERSITY OF
ILLINOIS-CHICAGO.
YOU'RE LOOKING AT ABOUT THESE
TWO DOZEN BARS ABOUT TWO DOZEN
DIFFERENT BATCHES OF ONE OF THE
PLANTS THEY STUDIED COMMONLY
USED AROUND MENOPAUSE.
EACH DIFFERENT COLOR, THERE ARE
SIX DIFFERENT COLORS IN THESE
BARS, REPRESENTS A STANDARDIZED
AMOUNT OF EACH OF THESE VERIFIED
BATCHES EXACTLY THE SAME WAY AND
ANALYZED IN EXACTLY THE SAME WAY
WITH THE AMOUNT OF THESE SIX
DIFFERENT COMPOUNDS QUANTIFIED
EXACTLY THE SAME WAY.
SO THESE ARE ALL COMPARABLE,
THESE ARE ALL SET TO 100% OF
THESE SIX COMPOUNDS AND WHAT YOU
CAN SEE IS THAT THE RATIOS OF
THE COMPOUNDS BASED ON
ESTROGENIC ACTIVITY ARE ALL OVER
THE PLACE.
SO IF ONLY ONE -- THEN YOU COULD
STANDARDIZE TO THE AMOUNT OF
THAT COMPOUND, BUT THAT IS
MULTIPLE OF THESE COMPOUNDS,
THAT IS TWO OR THREE OF THEM,
CONTRIBUTE TO THE ESTROGENIC
ACTIVITY OF IT.
YOU JUST KEEP YOUR PRODUCT
STANDARD TO HAVE CONSISTENT
BIOLOGICAL ACTIVITY, YOU WOULD
NEED TO BE MIXING BATCHES
PROBABLY.
BECAUSE THIS IS HOW INHERENTLY
VARIABLE THE PLANT ITSELF IS.
TURNING TO HOW CHEMICALLY
COMPLEX THESE ARE, THIS IS A
PAPER FROM A DECADE AGO A
TYPICAL EXTRACT OF ST. JOHN'S
WORT COMMONLY USED FOR MOON
MODULATION.
THERE ARE 10 DIFFERENT BULLETS
HERE BUT EACH CORRESPONDS TO A
WHOLE FAMILY OF DIFFERENT
COMPOUNDS.
CHEMICALLY UNASSIGNED EXOWNTDZ
EXOWNDZ AT THE BOTTOM WHICH MAKE
UP 30 TO 40% OF WHAT'S IN THE
MAP OF YOUR TYPICAL EXTRACT.
UP AT THE TOP, THOUGHT TO BE
RESPONSIBLE FOR THE MOON
MODULATING -- OF ST. JOHN'S
WORT.
WE ALSO ARE CURRENTLY PARTNERING
WITH NATIONAL INSTITUTE ON
AGING.
DR. WEBER AND HER COLLEAGUES
WANT TO TEST WHETHER AN EXTRACT
OF ST. JOHN'S WORT WOULD IMPROVE
ADHD IN YOUNG PEOPLE WHEN THEY
STARTED IT THEIR HYPOTHESIS WAS
THAT THAT WAS THE ACTIVE
COMPOUND.
THERE IS NO DIFFERENCE IN ADHD
SYMPTOMS BETWEEN THEIR PLACEBO
AND THEIR CONTROL GROUP.
DOES THAT MEAN THAT ST. JOHN'S
WORT DIDN'T WORK, OR, GIVEN WHAT
WAS IN THEIR PRODUCT AT THE END
OF THE TRIAL WHICH WAS ONLY
.13%, DOES THAT MEAN ST. JOHN'S
WORT WASN'T SUFFICIENTLY THERE
TO HAVE THE EFFECT?
HARD TO KNOW.
DON'T KNOW WHY THEY DIDN'T TEST
TO MAKE SURE IT WAS .3% AT THE
BEGINNING OF THE STUDY, AND THEN
MONITOR THE STABILITY.
SO STABILITY IS A HUGE ISSUE AND
IF YOU'RE DOING A CLINICAL
TRIAL, YOU ABSOLUTELY DON'T WANT
TO BE IN THIS SITUATION.
THE OTHER SITUATION YOU DON'T
WANT TO BE IN IS THAT BY THE
TIME THEY FINISH THIS TRIAL, THE
THINKING WAS MORE THAT IT WAS
THE HYPERFORIN WAS RESPONSIBLE,
BUT IT WOULDN'T HAVE BEEN ENOUGH
EITHER ACCORDING TO THAT
HYPOTHESIS.
IT'S A REALLY GOOD IDEA FROM
YOUR STARTING DATA WHAT CONTENT
YOU NEED AND AT WHAT LEVELS, AND
HOW STABLE THEY'RE LIKELY TO BE
AND MONITOR THAT, BECAUSE YOU
GET TO THE END OF THE CLINICAL
TRIAL AND YOU DON'T KNOW WHETHER
THE PROBLEM WITH WAS YOUR PRR
THAT THE PRODUCT JUST COULDN'T
WORK EVEN IF YOU HAD ENOUGH,
EVEN IF YOU'RE NOT PLANNING TO
REPEAT THAT STUDY.
HERE IS ANOTHER EXAMPLE THAT I
LIKE.
FROM OUR BOTANICAL CENTER IN
OREGON, CHEMICAL ENHANCING --
AND AGING CENTER.
HERE THEY ARE LOOKING AT
COMPOUNDS IN CENTELLA ASIATICA,
TO IMPROVE MEMORY AND COGNITIVE
FUNCTION.
AND TRADITIONALLY, THE
TRITERPENES ARE THOUGHT TO BE
THE COMPOUNDS IMPORTANT FOR THAT
ACTIVITY.
THEY INCLUDE ASIATIC ACID, SHOWN
HERE AS AA, AND WHAT YOU'RE
LOOKING AT HERE IS IN THE YELLOW
BOXES, TRANSGENIC MICE
ENGINEERED TO HAVE AN AMYLOID
BETA GENE MUTATION THAT IS FOUND
IN HUMANS LINKED WITH
ALZHEIMER'S DISEASE, AND THE
AREA OF -- WHICH IS WHERE YOU
WOULD HAVE YOUR SYNAPSES IN THE
HIPPOCAMPUS, WHICH IS A PART OF
THE BRAIN ASSOCIATED WITH
MEMORY, ARE GREATER SO
PRESUMABLY BETTER MEMORY, IN THE
WILD TYPE MICE THEY'RE BEING
COMPARED TO THAN IN THE
TRANSGENIC MICE, AND IN THE
TRANSGENIC MICE THAT GET -- ACID
OR ITS -- THE WILD TYPE MICE.
THE PRINCIPAL INVESTIGATOR HAD
SHOWN EARLIER THAT THEY ALSO SAW
SOME ACTIVITY OF -- ACIDS IN
IMPROVING COGNITION AND MEMORY
IN OLDER MICE AND IN THESE MICE
THAT ARE ENGINEERED WITH THE
AMYLOID BETA MUTATION.
AND INDEED THEY ALSO SAW
IMPROVEMENT IN DENDRITIC
ARBORIZATION AREA.
INTERESTINGLY, A DIFFERENT --
ACID HAS SIGNIFICANT EFFECT ON
THE NUMB WE NUMBER OF -- PEF
DENDRITE.
SO PERHAPS THE DENSITY OF
SYNAPTIC CONNECTIONS IN MEMORY.
SO THE IDEA HERE IS THAT
DIFFERENT CHEMICALS IN AN
ABSTRACT -- PLANT MAY CONTRIBUTE
TO DIFFERENT MECHANISMS OF
ACTION THAT ALL CONTRIBUTE TO
THE SAME OUTCOME, MAINLY, BETTER
MEMORY IN THE CONTEXT OF THIS
DEMENTIA-ASSOCIATED GENE DEFECT.
THAT IS CONSISTENT WITH
TRADITIONAL THINKING ABOUT HOW
BOTANICAL EXTRACTS WORK.
INDEED IN TRADITIONAL ASIAN
MEDICAL SYSTEMS OFTEN DIFFERENT
PLANTS ARE COMBINED.
FOR A GIVEN
PRESCRIPTION FOR A PATIENT.
HERE WE ARE SEEING THAT
DIFFERENT AND OFTEN IN
TRADITIONAL MEDICAL SYSTEMS
THERE'S A BELIEF THAT THE WHOLE
PLANT CAN BE BETTER THAN A
SINGLE ISOLATED CHEMICAL.
SO IT'S NOT JUST THAT THERE CAN
BE -- FOR ECONOMIC ADULTERATION
IF YOU FOCUS ON A SINGLE
CHEMICAL BUT ALSO THAT YOU MIGHT
GET BETTER -- WITH A MIBG TOUR
OF CHEMICALS FROM THE SAME
PLANT.
BUT THAT DOES MAKE IT HARDER TO
FIGURE OUT WHICH CHEMICALS TO
USE AND WHICH ONES DO WHAT.
I JUST WANTED TO GIVE YOU A
NUMBER OF OTHER REFERENCES WHERE
PEOPLE HAVE QUITE RIGOROUSLY
SHOWN CONTRIBUTION FROM MULTIPLE
CHEMICALS IN A SINGLE PLANT
ABSTRACT TO AN ACTIVITY OF
INTEREST, THIS ONE FROM
BOTANICAL CENTERS AT UNIVERSITY
OF ILLINOIS CHICAGO IN
COLLABORATION WITH ONE --
LOOKING AT ABILITY TO MAINTAIN
BLOOD SUGAR LEVELS IN THE
CONTEXT OF -- AND SUGAR INTAKE
FOR ANTIMALARIAL THERAPY, WHERE
WHOLE PLANT -- THE SOURCE OF THE
WORLD HEALTH ORGANIZATION FRONT
LINE DRUG FOR MALARIA TREATMENT,
SHOULD BE USED IN COMBINATION
THERAPY FOR MALARIA.
SO THERE AGAIN PEOPLE USE
COMBINATIONS BUT THEY'RE USING
DRUG COMBINATIONS, BULL -- TE
PLANT CAN ACTUALLY BE MORE
EFFECTIVE AND ELICIT MORE
RESISTANCE BY THE -- THAN BY
USING -- OR ITS DERIVATIVE.
DR. CECH AND HER COLLEAGUES HAVE
SHOWN GOLDENSEAL AGAINST METH
METHICILLIN-RESISTANT
STAPHYLOCOCCUS US AUREUS -- AA
LOVELY PAPER IN 2019 WHERE THEY
TALK ABOUT METHODS, SO HERE YOU
START GETTING THE METHODS THAT
ALLOW YOU TO DO THIS, FINDING
EITHER SYNERGY OR ANTAGONISM IN
NATURAL PRODUCT EXTRACT.
AND NOW AN APPROACH TO ACTUALLY
DOING THIS SUFFICIENTLY, FINDING
WHICH CHEMICALS IN A CHEMICALLY
COMPLEX EXTRACT AS SHOWN HERE
CONTRIBUTE TO WHICH BIOLOGICAL
ACTIVITY.
THIS IS THE GOAL OF THE CARBON
CENTER, HIFAN CENTER.
AGAIN YOU CAN FIND OUT MORE
ABOUT THEM FROM THE ODS CARBON
WEBSITE VIA THEIR WEBSITE.
THE APPROACH THEY'RE TRYING TO
USE IS THAT YOU TAKE YOUR
CHEMICALLY COMPLEX NATURAL
PRODUCT, YOU FRAX ATE FRAC,
THEY HAVE REALLY DEVELOPED THE
METHOD OF USING MASS SPEC
ANALYSIS USING CHEMICALLY
COMPLEX -- AND ARE GOOD AND
FINDING OUT WHAT THE DIFFERENT
COMPOUNDS ARE IN THE MIXTURE.
AT THE SAME TIME, THEY ARE
TAKING THE SAME FRACTIONS THAT
THEY'RE ANALYZING CHEMICALLY AND
LOOKING AT THEIR EFFECTS ON CELL
PHENOTYPE AND GENE EXPRESSION IN
THE SAME CELLS.
THEY ORIGINALLY USED THIS METHOD
WITH CANCER CELLS BUT THEY CAN
NOW USE IT WITH IMMUNE CELLS SO
THIS IS STARTING TO GET VERY
INTERESTING.
OBVIOUSLY YOU CAN USE 21ST
CENTURY COMPUTATIONAL METHODS,
ISOLATE SPECIFIC COMPOUNDS THAT
YOU SEE IN ASSOCIATION WITH
CHANGES IN CELL PHENOTYPE OR
CHANGES IN GENE EXPRESSION THAT
THEY HAVE SHOWN IN SOME OF THEIR
PAPERS THAT IF YOU COMBINE TWO
DIFFERENT WAYS OF LOOKING AT
CHANGES IN CELLS, YOU GET
STRONGER AND MORE SPECIFIC
ABILITY TO PREDICT WHICH
COMPOUNDS ARE ACTING ON WHICH
CELLULAR SUBSTRATES TO GENERATE
POTENTIAL BIOLOGICAL EFFECT OF
INTEREST.
AND I THINK I HAVE SOME OF THEIR
PAPERS IN THE REFERENCE LIST.
WE'VE COVERED ALL OF THIS, LET'S
MOVE TO BIOLOGICAL AVAILABILITY
AND TIMING VERY BRIEFLY.
AND THEN HOW WE TAKE THIS FROM
THE CHEMISTRY AND THE CELLS INTO
HUMANS.
BIOLOGICAL AVAILABILITY, ADAM
MENTIONED THE IMPORTANCE OF
FORMULATION.
HERE'S AN EXAMPLE OF EGCG FROM
GREEN TEA, WITH COLLEAGUES, FROM
U.S. DEPARTMENT DEPARTMEN.
DR. KUSZAK IS A CO-AUTHOR ON IT.
THEY TOOK 11 DIFFERENT BATCHES
OF GREEN TEA CAPSULES AND THEY
TRIED TO SEE HOW WELL THOSE
DISSOLVED AND RELEASED THE ECGC,
WHICH IS OFTEN THOUGHT TO HAVE
BIOLOGICAL ACTIVITY THAT MAY BE
A FUNCTION OF ITS CHEMICAL
REACTIVITY AND ABILITY TO
INTERACT WITH CELL MEMBRANE, BUT
IT'S NOT GOING TO HAVE
BIOLOGICAL ACTIVITY IF IT
DOESN'T GET OUT OF THE CAPSULE
AND INTO THE CONSUMER.
THREE OF THESE BATCHES OF
CAPSULES, IN FACT, OVER TWO
HOURS AT 37 DEGREES NEVER DID
RELEASE MORE THAN ABOUT HALF OF
THE EGCG THAT WAS IN THEM.
SO IF YOU'RE THINKING ABOUT
CHEMICAL TRIALS, IF YOU'RE
LOOKING AT THE TRIAL THAT HAS
COME OUT NEGATIVE, YOU MAY WANT
TO THINK ABOUT WHETHER THE
CHEMISTRY THAT YOU NEED ACTUALLY
GOT OUT OF YOUR CAPSULE AS
FORMULATED.
VERY IMPORTANT.
AND THEN YOU DO WANT TO THINK
ABOUT HOW MUCH OF IT GETS TO
WHEREVER YOUR HIGH CONTENT ASSAY
SAYS IT NIEDZ NEEDS TO GO TOE
ACTIVE.
HERE WE'RE LOOKING AT CATACHIN
IN PARTICULAR, A GREAT
POLYPHENOL PRODUCT, IN
COLLABORATION WITH WHAT'S NOW A
CARBON CENTER AT MOUNT MOUNT.
THEY'RE LOOKING AT HOW MUCH OF
THE DIFFERENT PHENOLICS FROM THE
GREAT POLYPHENOL MIXTURE GETTINT
INTO THE PLASMA IN HUMANS,
LOOKING WITH PEOPLE AT EITHER
LOW OR HIGH BODY MASS INDICES.
YOU CAN SEE A LOT MORE GET IN TO
THE PLASMA OF PEOPLE WITH LOW
BMI, THE BEING TRIANGLE, BUTT
SEE IT AFTER ONE DAY, ONLY AFTER
11 DAYS.
SO THE IMPORTANT OF BACKGROUND
DIET AND HOW MUCH OF THESE
THINGS PEOPLE CAN ABSORB, AND
YOU CAN SEE HERE THAT IT VARIES
FOR DIFFERENT POLYPHENOLS, THE
CATACHIN I JUST SHOWED YOU GOT
FAIRLY SIMILAR RESULT FOR --
CATACHIN AS YOU MIGHT EXPECT.
WE SEE SOME DIFFERENCES IN
TIMING PERHAPS.
AT LEAST AT 11 DAYS DOSING AS
WELL AS THE INCREASED
BIOAVAILABILITY.
SO THERE ARE IMPORTANT CHANGES,
IMPORTANT CONSUMER-RELATED
EFFECT ON BIOAVAILABILITY.
IT'S NOT JUST -- BUT HERE AS WE
START TO TALK ABOUT THE
INTERFACE WITH HUMANS, THEY CAN
BE VARIABLE DEPENDING ON THEIR
HISTORIES AS WELL AS, FOR
EXAMPLE, THEIR GUT MICROBIOTA.
SO MOUSE MODELS ARE GREAT, THEY
ALLOW YOU TO MAKE IMPORTANT
PREDICTIONS ABOUT WHAT'S GOING
ON BECAUSE THEY ARE SO
HOMOGENEOUS, AND IT'S REALLY
IMPORTANT TO REMEMBER MODELS ARE
USEFUL BUT THEY'RE ALWAYS -- YOU
NEED TO THINK ABOUT THE WAYS IN
WHICH YOUR MOUSE MODEL IS
DIFFERENT FROM HUMANS, PROBABLY
MOST UNDERSTANDING OF YOUR
PRODUCT ON, PRESUMABLY ARE GOING
TO ADJUST TEMPERATURE IN MOST
CASES TO MAKE THEM FEEL
COMFORTABLE.
THE MICE CAN'T DO THAT.
-- SUBJECT TO DIFFERENT KINDS
OF STRESSES.
THE MICE UNLIKE HUMANS THAT
REQUIRE VITAMIN C, THEY CAN MAKE
THEIR OWN.
THERE ARE DIFFERENCES IN THEIR
IMMUNE SYSTEMS, DIFFERENCES IN
THEIR GUT MICROBIOTA, ESPECIALLY
IF LIKE MOST MICE THAT YOU DO
RESEARCH IN, THERE ARE SPECIFIC
PATHOGEN-FREE MICE, VERY
DIFFERENT FROM THOSE OF WILD
TYPE MICE.
IN THAT PAPER I TOLD YOU ABOUT
EARLIER, THERE'S MORE ON THAT.
I KEEP TALKING ABOUT MICROBIOTA
SO JUST VERY QUICKLY, I KNOW I'M
RUNNING OUT OF TIME HERE, THIS
IS ANOTHER STUDY FROM THE EYE TN
SCHOOL OF MEDICINE IN SUPPORT OF
THEIR APPLICATION TO BECOME A
CENTER.
WHAT YOU'RE LOOKING AT HERE --
AND THEY'RE INTERESTED IN THIS
GREAT PRODUCT TO IMPROVE
COGNITIVE FUNCTION IN THE
CONTEXT OF STRESS.
THIS IS AN EXPERIMENT IN MICE,
AND WHAT THEY'RE LOOKING AT IS
HOW MUCH TIME THE MOUSE SPENDS
IN DIFFERENT PARTS OF ITS CAGE
OR LOOKING DOWN ON ITS CAGE,
THERE'S A COMPARTMENT OVER HERE
THAT CAN CONTAIN A STRANGER
MOUSE, YOU CAN SEE IF THE MICE
HAVE NOT BEEN SUBJECT TO STRESS,
NO RSDS, NO SOCIAL STRESS, THEY
EXPLORE AROUND THAT COMPARTMENT
WHETHER THERE'S A MOUSE IN IT AS
SHOWN IN THE BOTTOM OR NOT, BUT
IF THEY'VE BEEN SUBJECT TO
STRESS, THE -- IF THERE'S NO
MOUSE IN IT, BUT IF THEY'VE HAD
BAD EXPERIENCES WITH STRANGER
MICE BEFORE, ONLY IF THEY'VE
TAKEN THIS POLLLY POLYPHENOL
SUPPLEMENT, IF THEY'VE BEEN FED
IT, DO THEY EXPLORE IF THERE'S A
NOVEL MOUSE THERE.
NOW WHAT HAPPENS IN THE CONTEXT
OF SLEEP DEPRIVATION STRESS AND
COGNITION WITH THIS SUPPLEMENT?
WHAT HAPPENS IS IF YOU -- AND
HERE WE'RE TESTING MEMORY OF THE
SHOCK, MICE FREEZE, IF YOU PUT
THEM BACK -- IF THEY'RE SLEEP
DEPRIVED, THEY SORT OF FORGET
WHAT HAPPENED THERE THE DAY
BEFORE, BUT THEY DON'T FORGET IF
YOU GIVE THEM THIS POLYPHENOL
SUPPLEMENT.
HOWEVER, MICE THAT HAVE BEEN
TREATED WITH ENOUGH ANTIBIOTIC
TO -- AT THEIR GUT MICROBIOTA
EVEN WITHOUT SLEEP DEPRIVATION
LIKE THE SLEEP DEPRIVED MICE
WITH NORMAL MICROBIOTA AND IN
THE CONTEXT OF SLEEP DEPRIVATION
AND KNOCKED OUT MICROBIOTA, THE
POLYPHENOLIC PREPARATIONS -- TO
BRING THEM BACK TO THE WILD
TYPE.
SO GUT MICROBIOTA IS SUPER
IMPORTANT, AND HUMANS MUCH MORE
VARIABLE THAN THEY'RE GOING TO
BE IN THE MICE.
SO I'VE TALKED ABOUT THE
IMPORTANCE OF THINKING ABOUT THE
CHEMISTRY OF THE PRODUCT, WHICH
CHEMICALS IN THE PRODUCT MAY ACT
ON WHICH SUBSTRATES AND THE
CONSUMER, AND I TALKED A LITTLE
BIT ABOUT VARIABILITY IN THE
CONSUMER.
ONE MORE THING I WANT TO TALK
ABOUT VERY BRIEFLY THAT'S
TYPICAL OF HUMANS BUT NOT OTHER
ANIMAL MODELS IS PLACEBO
RESPONSE.
SUPER IMPORTANT.
HERE LOOKING AT ST. JOHN'S WORT
AGAIN, COMPARING TO A POSITIVE
CONTROL ANTIDEPRESSANT IN A
DEPRESSION TRIAL FROM 20 YEARS
AGO.
JUST COMPARING ST. JOHN'S WORT
AND ANTIDEPRESSANT, LOOKS LIKE
IT'S JUST AS GOOD AS THE
POSITIVE CONTROL BUT BECAUSE THE
PLACEBO RESPONSE IN THIS TRIAL
WAS SO STRONG, THE TRIAL AS A
WHOLE WAS UNINFORMATIVE BECAUSE
NEITHER OF THE ANTIDEPRESSANT
NOR THE ST. JOHN'S WORT WERE AS
GOOD AS THE PLACEBO, ALLEVIATING
DEPRESSION IN THIS TRIAL.
SO I THINK TO CONTROL FOR AND
MINIMIZE THE INFORMATION
DEPLETING EFFECT OF PLACEBO
RESPONSE IN TRIALS, IT'S REALLY
IMPORTANT TO DO A NUMBER OF
THINGS.
THIS IS FROM A PAPER FROM 10
YEARS AGO LOOKING AT ECHINACEA
FOR THE COMMON COLD, AND WHAT
THEY FOUND, THEY DID A NO TELL
GROUP AND THEY FOUND THAT IN
PARTICIPANTS WHO GOT NO PILLS,
THEY ALL HAD LONGER AND MORE
SEVERE ILLNESSES THAN THOSE WHO
RECEIVED PILLS.
WHETHER THOSE PILLS WERE
ECHINACEA OR PLACEBO.
AND PEOPLE WHO AT BASELINE TOLD
THEM THEY EXPECTED THE ECHINACEA
WOULD HELP THEM HAVE SHORTER AND
LESS SEVERE COLDS REGARDLESS OF
WHETHER THEIR PILLS CONTAINED
ECHINACEA OR PLACEBO.
SO I THINK IT'S REALLY USEFUL IN
DOING CLINICAL TRIALS OF ANY
SORT TO ASK AT BASELINE WHAT
PARTICIPANTS' EXPECTATIONS ARE
AND THE OTHER THING THAT REALLY
HELPS IF YOU ASK AT THE END OF
THE TRIAL WHICH GROUP THEY THINK
THEY WERE ASSIGNED TO SO THEY
CAN TELL YOU WHETHER THEY -- SO
THAT YOU CAN FIND OUT WHETHER --
BECAUSE IF YOUR BLINDING DIDN'T
WORK, YOUR TRIAL IS GOING TO BE
CONTAMINATED BY THEIR BASELINE
EXPECTATION.
REALLY NICE PAPER FROM HARVARD
MAGAZINE FROM 2013, IF YOU WANT
TO LEARN MORE ABOUT THE
FASCINATING COMPLEXITIES OF
PLACEBO EFFECT.
SO I'VE TOLD YOU SOME OF THE
THINGS THAT I THINK WE CAN DO TO
GET MORE REPLICABLE RESULTS
ADDED TO OUR CLINICAL TRIALS OF
NATURAL PRODUCTS TO MOVE FROM A
DIFFERENT RESULT EVERY TIME WE
DO A NEW TRIAL TO INFORMATION
THAT WE ACTUALLY FEEL
COMFORTABLE USING.
MORE THINGS HERE ABOUT THINGS TO
LOOK AT BEFORE YOU BELIEVE
WHAT'S IN THE LITERATURE AND USE
IT AND BUILD ON IT THAT I AM
RUNNING SHORT ON TIME, SO WITH
THAT PARTING WORD, I AM OPEN TO
YOUR QUESTIONS.
>> THANK YOU, DR. SOL SORKIN.
IS THERE ANYTHING IN PLACE FOR
NIH GRANTS USING DIETARY
SUPPLEMENTS THAT REALLY COVERS
ALL THE PRODUCT CHARACTERIZATION
ISSUES YOU BRING UP IN YOUR FINE
TALK?
>> THANKS FOR THAT GREAT
QUESTION, JOHANNA.
I'M NOT SURE WHAT YOU MEAN ABOUT
ALL OF THE CHARACTERIZATION
ISSUES.
I THINK ONE IS THE REASON THAT
WE FUND THAT THE OFFICE IN
COLLABORATION WITH NCCIH FUNDS
BOTANICAL RESEARCH CENTERS, IS
THAT THE CENTER FOR MATT ALLOWS
US TO BRING IN BOTH A RANGE OF
PEOPLE WITH DIFFERENT KINDS OF
PHYTOCHEMICAL EXPERTISE.
PEOPLE WITH COMPUTATIONAL
EXPERTISE, AS WELL AS PEOPLE
WITH CLINICAL EXPERTISE AND
EXPERTISE IN THE -- IN DIET, FOR
EXAMPLE.
SO IT ALLOWS US TO BRING
TOGETHER MANY DIFFERENT KINDS OF
EXPERTISE AND HAVE THEM WORKING
ON A DAY-TO-DAY BASIS BACK AND
FORTH SO THAT EACH EXPERTISE CAN
INFORM THE OTHER.
DOES THAT -- NOW THAT I HAVE
ACCESS TO THE CHAT AGAIN, OR DO
I -- THAT I'M NOT -- IN Q & A.
THAT DOESN'T ANSWER YOUR
QUESTION BUT CERTAINLY WE HAVE
THOSE -- AND WE ENCOURAGE OUR
CARBON CENTERS TO COLLABORATE
WITH EACH OTHER IF ONE CENTER
HAS EXPERTISE THAT ANOTHER COULD
USE.
WE DO TRY TO KEEP THEM TALKING
TO EACH OTHER AND AWARE OF EACH
OTHER'S CAPACITIES AND INTEREST
SO THAT THEY CAN COLLABORATE AND
I SHOWED YOU AT LEAST ONE PAPER
WHERE, IN FACT, ONE OF THOSE
COLLABORATIONS ARE SUCCESSFUL
AND PUBLISHED, AND WE'VE SEEN
THAT CAN REALLY ADD SYNERGY
WITHIN THE CARBON PROGRAM
ITSELF.
>> SO FROM JOHANNA, SH MEANS
EFFICACY AND ALSO EXPERTISE IN
PLACEBOS' EFFECTS, ET CETERA.
>> YES, YES, SO THAT'S WHAT THE
CENTER -- IT'S REALLY DIFFICULT
TO FUND ALL OF THAT IN A TYPICAL
NIH R01.
YOU CAN GET SOME GOOD PIECES OF
THAT, AND NCCIH, FOR EXAMPLE,
FUNDS SOME LOVELY WORK ON
CHEMICAL CHARACTERIZATION AS IT
RELATES TO BIOLOGY, BUT IT'S
REALLY HARD TO GET THE BREADTH
THAT YOU CAN GET WITH A CENTER
APPROACH WITHOUT THAT KIND OF
FUNDING THAT ALLOWS YOU TO BRING
IN THAT LARGE A TEAM UNDER
PRINCIPAL INVESTIGATORS WITH
DIFFERENT EXPERTISE.
AND OF COURSE THE CENTER FOR
MATT ALSO ALLOWS YOU TO GIVE THE
POSTDOCTORAL FELLOWS AND OTHER
STUDENTS FROM THE CENTERS THAT
TRANS DISCIPLINARY EXPERIENCE
AND LEARN HOW TO WORK THAT WAY.
BECAUSE SOMETIMES IT'S HARD TO
COMMUNICATE ACROSS DIFFERENT
EXPERTISE.
>> THANK YOU.
ANOTHER QUESTION.
RECENTLY, MANY PRODUCTS THAT ARE
NOT VERY BIOAVAILABLE ALONE HAVE
ADDED BLACK PEPPER EXTRACT TO
INCREASE BIOAVAILABILITY OF THE
PRINCIPAL AGENT.
HOW EFFICIENT IS THIS
COMBINATION?
DO YOU HAVE ANY COMMENTS ON
THIS?
>> LET ME REPEAT THE QUESTION TO
MAKE SURE I UNDERSTAND.
THE QUESTION IS ABOUT ADDING
CAPSAICIN OR PEPPER TO OTHER --
>> BLACK PEPPER, BUT
SPECIFICALLY WITH CURCUMIN
BECAUSE IT'S USUALLY USED FOR
THAT.
>> I KNOW THAT IS A COMMON
PRACTICE, ALSO USING
NANOCURCUMIN, MAKING IT INTO
NANOPARTICLES.
AND I CAN'T SAY THAT I'VE REALLY
SEEN DATA ON HOW THAT AFFECTS
BIOAVAILABILITY.
THAT MIGHT BE AN INTERESTING
STUDY TO DO IF IT HASN'T BEEN
DONE, BUT I HAVE NOT SEARCHED
RECENTLY TO SEE WHETHER THERE
ARE DATA THAT, IN FACT, SHOW
INCREASED BIOAVAILABILITY.
CERTAINLY I, TOO, HAVE HEARD
THAT THE PEPPER INCREASES THE
BIOAVAILABILITY AND THAT THAT'S
WHY TRADITIONALLY YOU USE -- YOU
INCLUDE IT WHEN YOU'RE MAKING A
CURRY.
>> THANK YOU.
AS WE'VE LEARNED FROM COVID IN
CHINA AND COMBINATIONS OF
BOTANICALS IN TERMS OF HOW TO DO
CLINICAL STUDIES.
TRADITIONAL MEDICINE OFTEN USES
COMBINATIONS IN PATIENT
CENTER -- THE STUDY
APPROPRIATELY.
>> I THINK THAT THERE'S A GOOD
POINT THERE, THAT'S AN
INTERESTING QUESTION.
I DON'T SEE WHY YOU COULD NOT
TAKE TWO DIFFERENT EXTRACTS AND
CHARACTERIZE THEIR POTENTIAL
BIOLOGICAL ACTIVITY AS OUR HIFAN
CENTER IS DOING.
IT TESTS YOUR CHEMICAL
COMPLEXITY SOMEWHAT AND THEY ARE
JUST PIONEERING THIS METHOD,
THIS APPROACH, BUT CERTAINLY
THERE'S NO REASON WHY IT
COULDN'T BE EXTENDED TO MIXTURES
OF BOTANICALS.
WE ARE FINDING THAT EVEN WITHIN
A SINGLE BOTANICAL, THERE ARE
CHEMICAL CONSTITUENTS THAT HAVE
DIFFERENT ACTIVITIES OR APPEAR
TO HAVE DIFFERENT ACTIVITIES IN
ANIMAL MODELS AND IN VITRO.
AND MY TEMPTATION IS ALWAYS TO
BE REDUCTIONIST AND TO START
THERE BECAUSE YOU WANT TO SEE
WHETHER YOUR METHODS ACTUALLY
WORK AND ARE REP -- BUT ABSOLY
MULTIPLE BOTANICALS COULD GIVE
YOU MORE BIOLOGICAL ACTIVITIES
THAT COULD CONTRIBUTE TO AN
OUTCOME.
I DO THINK THAT WE ARE GOING TO
SEE OVER THE NEXT YEAR OR SO
WITH ALL THE FOCUS ON RESEARCH
ON BOTANICALS AND OTHER -- AND
DRUGS, AND THAT MAY BE USED TO
REDUCE ILLNESS FROM COVID, THAT
WE WILL SEE THINGS, MY GUESS IS
FROM BOTANICALS AS WELL AS FROM
MORE TRADITIONAL DRUG-BASED
APPROACHES.
>> THANK YOU.
SO I HAVE A QUESTION RELATED
WITH THE PLANTS FOR THEIR
TRADITIONAL USE THAT YOU
MENTIONED IN YOUR PRESENTATION
THAT COULD BE DIFFERENT FROM THE
PLANTS THAT ARE USED IN MODERN
TIMES.
SO IN SOME COUNTRIES AROUND THE
WORLD, SOME REGULATIONS DEPEND
ON THE LONG TERM USAGE OF
TRADITIONAL MEDICINE.
CAN WE -- COUNT ON THEIR LONG
TERM USAGE FOR THEIR SAFETY?
DO YOU HAVE ANY COMMENTS ON
THAT?
>> SO ARE THERE DIFFERENCES IN
SAFETY BETWEEN LONG TERM USAGE
AND ACHIEVEMENTS?
>> SO IF A PLANT EXTRACT HAS
BEEN USED FOR SEVERAL YEARS,
MORE THAN 15 YEARS, IT CAN BE
LIKE ACCEPTED AS SAFE IN SOME
COUNTRIES FOR THE REGULATIONS OF
THESE COMPOUNDS.
DO YOU HAVE ANY COMMENTS ON
THIS?
>> I AM --IO
INSTITUTES OF HEALTH DOES
RESEARCH ON MANY THINGS AND WE
HOPE IT IS USEFUL TO OUR
COLLEAGUES AT THE FOOD AND DRUG
ADMINISTRATION THAT ARE
RESPONSIBLE FOR THE REGULATIONS,
BUT I THINK I'M GOING TO STAY
WITHIN MY UNIT AND NOT COMMENT
ON REGULATION.
>> OKAY.
IS THERE ANY ONLINE RESOURCE
FOR -- AND HERBAL DIETARY --
>> YES, THERE ARE A NUMBER OF
RESOURCES.
ONE THAT IMMEDIATELY COMES TO
MIND IS OUR COLLEAGUES AT NCCIH,
AND I THINK THIS WAS MENTIONED
YESTERDAY, THE CENTER ON
HERB-DRUG INTERACTIONS BASED AT
UNIVERSITY OF WASHINGTON.
UNDER DR. -- THE PRINCIPAL
INVESTIGATOR IS OR WAS DR. MARY
PAINE.
BUT THERE ARE ALSO -- THERE IS
DATABASES THAT HAVE SOME
INFORMATION ON HERB-DRUG
INTERACTION.
THE CENTER AT THE NCCIH FUNDED
OR DRUG INTERACTION CENTER IS
WORKING MUCH MORE SYSTEMATICALLY
AND CONDUCTING SOME CLINICAL
TRIALS TO ACTUAL LITTLE VERIFY
THESE INTERACTIONS.
MOST OF THE ONES YOU'LL FIND IN
THE ONLINE DATABASES ARE BASED
ON IN VITRO ASSAYS ON ADMISSION
OF CYTOCHROME P450, FOR EXAMPLE,
OR ON ANECDOTAL REPORTS OF
INTERACTIONS.
FOR OBVIOUS REASON, THERE'S NOT
BEEN A LOT OF RESEARCH LOOKING
FOR POTENTIAL ADVERSE
INTERACTIONS OF BOTANICALS AND
DRUGS IN HUMANS, BUT THEY TRYING
TO BE MORE SYSTEMATIC ABOUT
THAT.
THE UNIVERSITY OF
ILLINOIS-CHICAGO HAS TWO STUDIES
LOOKING FOR POTENTIAL FOR DRUG
INTERACTIONS.
I DON'T REMEMBER WHETHER THEY
REPORTED ON COHOSH.
>> THANK YOU SO MUCH.
I CAN'T SEE ANY MORE QUESTIONS
COMING UP, SO I WOULD LIKE TO
THANK ALL OUR SPEAKER,
DR. KUSZAK, DR. SORKIN AND
DR. BETZ FOR JOINING US FOR THE
SESSION.
THANK YOU, I'LL LEAVE TO
DR. GAHCHE.
>> THANK YOU.
OKAY.
THAT WAS GREAT.
WE'RE GOING TO TAKE A LITTLE
BREAK
THIS IS SESSION 5, DR. LAVERNE
BROWN WILL MODERATE.
DR. BROWN IS PROGRAM DIRECTOR AT
OFFICE OF DIETARY SUPPLEMENTS,
INTERESTED IN RESEARCH THAT
EXPLORES IMPACT OF DIETARY
SUPPLEMENT USE ON RESILIENCE AND
HEALTH IN DIVERSE POPULATIONS.
SHE WILL BE GIVING A
PRESENTATION LATER TODAY AT
3:15, RESILIENCE RESEARCH AT
NIH.
PLEASE STICK AROUND FOR THAT.
THANK YOU, DR. BROWN.
WE WILL INVITE DR. HOWARD SESSO
TO THE PODIUM, VIRTUAL PODIUM.
DR. SESSO IS ASSOCIATE
EPIDEMIOLOGIST AT DIVISION OF
PREVENTIVE MEDICINE AND AGING AT
BRIGHAM AND YOUNG WOMEN'S
HOSPITAL, ASSOCIATE PROFESSOR OF
MEDICINE AT HARVARD MEDICAL
SCHOOL, ASSOCIATE PROFESSOR IN
EPIDEMIOLOGY AT HARVARD T H CHAN
SCHOOL OF PUBLIC HEALTH, LEADS
DESIGN METHODOLOGY AND CONDUCT
OF RANDOMIZED CLINICAL TRIALS IN
EPIDEMIOLOGIC STUDIES FOCUSING
ON VITAMIN AND MINERAL
SUPPLEMENTS AND LIFESTYLE
FACTORS IN PREVENTION OF
CARDIOVASCULAR DISEASE,
HYPERTENSION, OBESITY, CANCER,
AND OTHER AGING-RELATED
OUTCOMES.
TODAY DR. SESSO'S PRESENTATION
IS EFFICACY AND EFFECTIVENESS,
LINES OF EVIDENCE IN SUPPLEMENT
RESEARCH.
TAKE IT AWAY, DR. SESSO.
>> NECESSARY PART OF THE
PROCESS.
CAN EVERYONE HEAR ME?
AND I'LL SWITCH TO FULL SCREEN
MODE.
>> COMING THROUGH CLEARLY.
>> GREAT.
SO APPRECIATE EVERYONE'S
FLEXIBILITY, WHETHER IN PERSON
OR VIRTUAL.
THESE THINGS HAPPEN.
NEVERTHELESS WHAT I'M HERE TO
SPEAK ABOUT FOR THE NEXT HALF
HOUR OR SO IS ISSUE OF EFFICACY
AND/OR EFFECTIVENESS ESPECIALLY
IN CONTEXT OF DIETARY SUPPLEMENT
RESEARCH.
WHERE I'M COMING FROM, BY
TRAINING BOTH AN
EPIDEMIOLOGIST AND TRIALIST.
WE COME IN FROM DIFFERENT ANGLES
RESEARCHING DIETARY SUPPLEMENTS,
BUT JUST AS A DISCLOSURE MY
INTEREST IN DIET HAS GONE FAR
BACK IN TIME, THIS IS FROM FOUR
DECADES AGO.
I REALIZED QUICKLY I WAS MUCH
LESS OF AN ARTIST, MORE
INTERESTED IN ROLES OF DIET AND
NUTRITION.
WHAT I LOVE ABOUT THIS PRACTICE.
WE'RE BRINGING EXPERTS FROM
DIFFERENT ANGLES IN THE
DISCUSSION, IMPORTANT HOW WE
APPROACH RESEARCH, THIS IS WHERE
THE ODS HAS BEEN A HUGE
SUPPORTER OF UNDERSTANDING THE
INTERDISCIPLINARY ASPECTS, NO
DIFFERENT THAN THE CONTEXT OF
CLINICAL TRIALS AND EFFICACY AND
EFFECTIVENESS, UNDERSTANDING
WHAT EACH REPRESENTS.
SO, FOR STARTERS, I JUST WANT TO
START WITH A BROAD CONCEPT.
IT'S WHAT I CONSIDER TO BE
TERMED DIETARY REDUCTIONISM THAT
TAKES PLACE IN THE UNITED STATES
AND AROUND THE WORLD.
TYPICALLY WHEN WE THINK OF
NUTRITION AND NUTRITIONAL
EPIDEMIOLOGY WE'VE IDENTIFIED
FOODS, DIETARY PATTERNS,
SPECIFIC NUTRIENTS, AND SOME OF
THESE AT LEAST IN THE
OBSERVATIONAL STUDIES THROUGH
EPIDEMIOLOGY HAVE BEEN SHOWN TO
FOLKSILY REDUCE MAJOR MORBIDITY
AND MORTALITY AND DIFFERENT
BIOMARKER CHANGES.
WE BELIEVE THESE BENEFITS ARE
DRIVEN BY SPECIFIC VITAMINS,
MINERALS, NUTRIENTS, BIOACTIVE
OR HERBAL COMPONENTS BUT DIETARY
SUPPLEMENTS, WHETHER A
PARTICULAR ONE CAN CAPTURE
BENEFITS IN FOODS TO
MEANINGFULLY IMPROVE HEALTH.
WHAT WE ALSO KNOW IS THAT THE
STUDIES COME OUT AND DIETARY
SUPPLEMENT USE OFTEN INCREASES
MARKEDLY BEFORE SOME DEFINITIVE
RANDOMIZED CLINICAL TRIAL IS
GOING TO GET PUBLISHED THAT
DEMONSTRATES TO SOME EXTENT
EITHER EFFICACY OR
EFFECTIVENESS.
I'M JUST USING A STRAWBERRY HAS
AN EXAMPLE.
A CHALLENGE IS WE LOOK AT A
STRAWBERRY, IS IT THE FOOD, IS
IT THE FOOD MATRIX, SOMEBODY
ABOUT THE STRAWBERRY THAT HAS
FIBER, VITAMIN C, OTHER
NUTRIENTS?
IS IT THE STRAWBERRY IN
COMBINATION WITH OTHER FOODS?
IS IT ABOUT DIETARY PATTERN?
OR IS IT A FUNCTION SIMPLY OF
NON-DIETARY FACTORS,
CONFOUNDING, USUALLY THE BANE OF
AN EPIDEMIOLOGIST'S EXISTENCE OR
ONE OR MORE NUTRIENT WHERE WE
THINK ABOUT SUPPLEMENTS ON THE
BASIS OF SPECIFIC NUTRIENTS OR
FOOD-BASED SUPPLEMENTS DEVELOPED
AS WELL.
WHEN WE'RE THINKING ABOUT
CONCEPTS OF EFFICACY OR
EFFECTIVENESS WHICH I'LL
INTRODUCE IN A MOMENT, IN THE
CONTEXT OF DIETARY SUPPLEMENTS
WE AT LEAST TRADITIONALLY THINK
OF THIS HIERARCHY OF DESIGN OF
STUDIES THAT PUT US IN THE
POSITION OF BEING MORE VALID.
NOW, THE MECHANISTIC STUDIES IN
FOOD SCIENCE ARE KEY FOUNDATION
UPON WHICH ALL THESE OTHER
STUDIES ARE DONE.
THAT TAKES NOTHING AWAY FROM THE
IMPORTANCE OF THOSE.
THOSE SHAPE THE WAIT WE APPROACH
THE OBSERVATIONAL STUDIES AND
CLINICAL TRIALS.
AT THE SAME TIME I WOULD SUBMIT
TO YOU JUST BECAUSE THE CLINICAL
TRIAL IS VERY LONG AND LARGE,
THAT DOESN'T -- IF IT'S DONE
POORLY THAT DOESN'T GIVE IT THAT
MUCH WEIGHT RELATIVE TO A COHORT
STUDY DONE QUITE WELL.
SO, IT'S NOT JUST THE STUDY
DESIGN BUT ALSO HOW WELL -- THE
QUALITY OF THE STUDY THAT
MATTERS TOO.
SO, WHEN WE THINK ABOUT THE
CONCEPTS OF EFFICACY VERSUS --
OR EFFECTIVENESS, YOU HAVE TO
REMEMBER THAT CLINICAL TRIALS
ESPECIALLY WHEN -- SO THE DANGER
HERE IS WE THINK ABOUT CONTEXT
OF DIETARY SUPPLEMENTS WE MIGHT
VIEW IT ONE WAY, MORE BROADLY
WHEN WE THINK ABOUT
PHARMACOLOGIC INTERVENTIONS,
STATINS, ANTI-HYPERTENSIVE
MEDICATIONS AS THOSE ARE BEING
DEVELOPED WE'RE TRYING TO
DESCRIBE THE RESULTS OF A
CLINICAL TRIAL FOR THAT
INTERVENTION, WHAT WE DEEM IDEAL
OR REAL WORLD SITUATIONS,
EITHER/OR.
EFFICACY REFLECTS WHETHER OR NOT
A TREATMENT INCLUDING DIETARY
SUPPLEMENTS MIGHT WORK UNDER
IDEAL CIRCUMSTANCES.
AS YOU'LL SEE THIS HAS THE
HIGHEST DEGREE OF INTERNAL -- --
INTERNAL VALIDITY, WORKING IN
IDEAL CIRCUMSTANCES BUT WHAT
ABOUT ACTUAL PRACTICE WHAT
HAPPENS?
WHAT AFFECTS ARE THINGS LIKE
COMPLIANCE, WHO ARE PATIENTS,
HOW PRACTICAL, SIDE EFFECTS,
WHAT ARE COSTS? WITH
EFFECTIVENESS YOU START TO GET
MORE OF A REAL WORLD
INTERPRETATION OF YOUR CLINICAL
TRIAL OR STUDY OF THE DIETARY
SUPPLEMENT, AND THAT HELPS TO
INCREASE YOUR GENERALIZABILITY
BUT COMES AT A COST OF THE
INTERNAL VALIDITY, AS YOU'LL
SEE.
LET'S LOOK AT THIS IN MORE
DETAIL.
SO, AGAIN, FOR THIS QUESTION OF
WHAT IS AN EFFICACY TRIAL, WHAT
IS EFFICACY, THIS ASKS THE
QUESTION WHETHER OR NOT A
TREATMENT, AKA DIETARY
SUPPLEMENT, WHATEVER YOU'RE
TESTING, CAN HELP UNDER IDEAL
CIRCUMSTANCES.
NOW, TRIALS, CLINICAL TRIALS
THAT ARE DEEMED OR TREATED AS
EFFICACY TRIALS, HAVE SPECIFIC
CHARACTERISTICS THAT ARE
IMPORTANT TO CONSIDER.
FIRST, THINK ABOUT IT, RIGHT?
I'VE BEEN RANDOMIZED INTO A
TRIAL, AND I'VE BEEN ASSIGNED TO
TAKE A DIETARY SUPPLEMENT, I'M
TOLD TOE TAKE IT.
I DON'T KNOW WHAT IT IS, MAYBE,
DEPENDING ON THE BLINDING.
I HAVE TO ACCEPT THAT
INTERVENTION IS OFFERED.
THAT'S HOW I'M TREATED.
I FOLLOW THE INSTRUCTIONS TO THE
TRIAL FAITHFULLY.
I HAVE TO HOPEFULLY GET THE BEST
POSSIBLE CARE AND HOPEFULLY NOT
HAVE TO CARE FOR ANY OTHER
CONDITIONS OR DISEASES OR SIDE
EFFECTS THAT MIGHT EMERGE.
AND MOST TRIALS ARE DESIGNED
THIS WAY, RIGHT?
SEWS, IF WE'RE GOING TO TEST THE
ROLE OF A LYCOPENE SUPPLEMENT ON
PSA LEVELS WE HOPE THEY TAKE AT
THIS TIME AS ASKED, AND THOSE
GIVEN PLACEBO WOULD TAKE IT AS
WE'VE ASKED THEM TO, THROUGHOUT
THE STUDY, SO WE CAN ANALYZE
DATA APPROPRIATELY FOR OUTCOME.
WHEN WE ANALYZED THESE DATA FOR
EFFICACY, IN A CLINICAL TRIAL,
THESE ARE CALLED INTENTION TO
TREAT ANALYSES.
AND THE BEAUTY OF A CLINICAL
TRIAL INHERENTLY, NO MATTER HOW
SMALL OR LARGE IT MIGHT BE, IS
THROUGH THE POWER OF
RANDOMIZATION, AND THROUGH AN
INTENTION TO TREAT ANALYSIS,
WHERE YOU'RE BASICALLY ASSUMING
ONCE RANDOMIZED ALWAYS ANALYZED.
IT ELIMINATES CONFOUNDING WHICH
AS I SAID BEFORE IS REALLY WHAT
DOGS OBSERVATIONAL STUDIES.
SO, THAT'S THE PERFECT
SITUATION.
ON THE OTHER HAND, WE HAVE THIS
ISSUE OF EFFECTIVENESS.
EFFECTIVENESS ALSO GIVES
INFORMATION.
THIS TELLS US WHETHER A DIETARY
SUPPLEMENT MIGHT HELP UNDER
ORDINARY OR REAL WORLD
CIRCUMSTANCES.
HERE, NOW WE'RE TRYING TO
INCORPORATE WHAT REALLY HAPPENS
IN PRACTICE.
IT'S THE USUAL ELEMENTS OF
PATIENT CARE OR WHAT HAPPENS
WHEN YOU ASK SOMEONE TO TAKE
SOMETHING IF YOU'RE SEEING THEM
IN THE DOCTOR'S OFFICE, OR IN
SOME OTHER SITUATION, AND WHAT
THEY ACTUALLY DO WHEN THEY
LEAVE.
SO, SUBJECTS MIGHT NOT TAKE WHAT
YOU'RE ASSIGNING THEM TO TAKE
BASED ON RANDOMIZATION, MIGHT
DROP OUT, MIGHT FIND WAYS TO
TAKE TREATMENT THEY WEREN'T
ASSIGNED, THINK THEY ARE TAKING
A PLACEBO AND WILL FIND A WAY TO
TAKE A VITAMIN OR HERBAL
SUPPLEMENT AND IT ACCOUNTS FOR
THE FACT ALL DOCTORS AND
FACILITIES AND TREATMENT
CENTERS, THERE'S VARIATION.
HOW DOCTORS TREAT PATIENTS WILL
VARY.
WHAT'S NICE ABOUT EFFECTIVENESS
TRIAL THIS DESCRIBES THE RESULT
MIDDLE -- MOST EXPERIENCE WOULD
EXPERIENCE THEM, COMPLIANCE
BASED MORE BROADLY FOR
EFFECTIVENESS TRIALS OR DEEMED
AS YOU'LL SEE IN A MOMENT PER
PROTOCOL OR AS-TREATED.
WHILE THIS DOES HELP TO ADDRESS
THE QUESTION OF WHAT A DIETARY
SUPPLEMENT MIGHT DO IN THE REAL
WORLD, IT DOES INTRODUCE
CONFOUNDING WHICH IS WHY WE
TYPICALLY DO RANDOMIZED TRIALS
IN THE FIRST PLACE.
SO YOU GAIN MORE CREDIBILITY AS
FAR AS HOW YOU CAN INTERPRET
THOSE DATA, DIRECTLY TO YOUR
INTERVENTION, BUT AT THE EXPENSE
OF POTENTIAL CONFOUNDING THAT'S
BEEN INTRODUCED.
JUST A LITTLE BIT MORE ON
APPROACHES TO ANALYZE CLINICAL
TRIALS TO DIETARY SUPPLEMENTS,
INTENTION TO TREAT ANALYSES
MEASURES EFFECT OF ASSIGNING
PARTICIPANTS TO A PARTICULAR
TREATMENT OTHER SUPPLEMENT,
INCLUDES ALL RANDOMIZED
PARTICIPANTS, INCORPORATION THE
FOLLOW-UP TIME THAT USUALLY
LEANS TO AN ENDPOINT, INCIDENT
OUTCOME, CHANGE IN BIOMARKER,
BUT THE IDEA IS TREATMENT
ASSIGNMENT NEVER CHANGES.
THAT'S THE KEY COMPONENT.
IF I'VE BEEN ASSIGNED TO
PLACEBO, I'M ALWAYS ANALYZED AS
IF I'M TAKING PLACEBO, EVEN IF I
DON'T.
ON THE OTHER HAND,
COMPLIANCE-BASED ANALYSIS
ESTIMATES EFFECTIVE RECEIVING A
TREATMENT, NOT WHAT I WAS
ASSIGNED THROUGH A FLIP OF A
COIN BUT WHETHER BASED ON WHAT I
RECEIVED AND WHAT I DID.
THERE'S TWO TYPES OF
COMPLIANCE-BASED ANALYSES.
ONE IS PER PROTOCOL ANALYSIS,
THIS MEANS THAT BASED ON THE
PROTOCOL YOU'VE WRITTEN UP FOR
YOUR STUDY, YOU'RE ONLY GOING TO
ANALYZE THE DATA FROM
PARTICIPANTS WHO FOLLOWED THAT
PROTOCOL.
EVERY CON STARTS -- EVERYONE
STARTS WITH WHAT YOU'RE
RANDOMIZED TOO BUT AS THEY
BECOME NON-COMPLIANT DURING THE
STUDY YOU EXCLUDE ANY DATA AFTER
THEY HAVE BECOME NON-COMPLIANT.
IF I'M TAKING A SUPPLEMENT, FOR
WHATEVER I STOP, MAYBE MY
STOMACH IS UPSET, REACTING IN
SOME WAY, THE DAY I STOP TAKING
THE PILLS IS THE DAY THAT I NO
LONGER CONTRIBUTE DATA IN A PER
PROTOCOL ANALYSIS.
SIMILARLY, IN AN AS-TREATED
ANALYSIS, ANOTHER TYPE OF
COMPLIANT BASED ANALYSIS THIS IS
MORE FLEXIBLE.
THIS ANALYZES DATA FOR
PARTICIPANTS BASED ON TREATMENTS
THEY TAKE WITHOUT REGARD TO
RANDOMIZED TREATMENT ASSIGNMENT.
IF YOU TAKE ME AS AN EXAMPLE
AGAIN I MIGHT INITIALLY BE
RANDOMIZED TO TAKE A PARTICULAR
DIETARY SUPPLEMENT, SO I AM
BEING ANALYZED AS IF I WAS -- TO
WHAT I WAS RANDOMIZED BUT IF YOU
STOP TAKING IT AND DECIDE TO
STAY OFF, IT'S LIKE A TIME
VARYING ANALYSIS, WHERE THE
MOMENT I STOP AND THEN I SWITCH
TO PLACEBO, NO TREATMENT AT ALL,
I'M STILL BEING FOLLOWED.
THE CHALLENGE AGAIN WITH THESE
COMPLIANCE BASED ANALYSES IT
INTRODUCES CONFOUNDING, THE
REASONS PEOPLE STOP TAKING
DIETARY SUPPLEMENT OR PLACEBO OR
WHATEVER YOU'RE TESTING COULD BE
RELATED TO PARTICULAR FACTORS
THAT WE DON'T NECESSARILY KNOW
OR CAN MEASURE VERY EASILY.
AND THE CHALLENGE THAT WE HAVE
IN CLINICAL TRIALS WHEN WE THINK
ABOUT EFFICACY AND EFFECTIVENESS
IS TO UNDERSTAND WHICH ONE IS
RIGHT, HOW DO YOU DECIDE, AND
WE'LL DIVE INTO THAT WITH
EXAMPLES TOWARD THE END.
SO, THIS DIFFERENCE WE SEE
BETWEEN EFFICACY AND
EFFECTIVENESS IS THE
IMPLEMENTATION GAP.
IT'S A GAP BETWEEN IDEAL CARE
AND ACTUAL TYPICAL CARE YOU
MIGHT HAVE FOR A PATIENT.
AND IT'S IMPORTANT TO CONSIDER
THIS GAP FOR NOT JUST DIETARY
SUPPLEMENTS BUT COMPARING
AGAINST DIFFERENT INTERVENTIONS.
HOW WE MIGHT INTERPRET IT IN
NUTRITION AND FOOD AND DIETARY
SUPPLEMENTS MIGHT DIFFER VERSUS
SOME NOVEL NEW DRUG.
BUT IT'S IMPORTANT TO NOTE THAT
EFFICACY TRIALS TYPICALLY
PRECEDE EFFECTIVENESS TRIALS.
IF A SUPPLEMENT UNDER BEST
CIRCUMSTANCES, MOST CONTROL
DOESN'T IMPACT YOUR OUTCOME,
EFFECTIVENESS MIGHT BE UNLIKELY
UNDER ORDINARY CIRCUMSTANCES.
IF HE EFFECTIVENESS TRIAL WERE
DONE FIRST AND SHOWED NO EFFECT
THAT RESULT MIGHT HAVE BEEN
BECAUSE SUPPLEMENT MIGHT HAVE
NOT WORKED OR WAS EFFECTIVE BUT
THERE WERE LIMITATIONS THAT
MIGHT HAVE MITIGATED EFFECTS IN
THE FIRST PLACE.
IT'S A TRICKY BALANCE BETWEEN
THE TWO.
WHAT NICE ABOUT DIETARY
SUPPLEMENTS THEY ARE NICELY
SUITED TO EVALUATE EFFICACY.
TYPICALLY, NOT ALL THE TIME, YOU
CAN USE PLACEBO CONTROL.
YOU HAVE A SIMPLE INTERVENTION
FOR DIETARY SUPPLEMENT.
AS YOU CAN IMAGINE IF IT'S A
DIETARY PATTERN, LOW FAT DIET
OTHER MEDITERRANEAN DIET, IT'S
MUCH HARDER TO REALLY TEASE OUT
AND HAVE CLEAR DISTINCTIONS
BETWEEN YOUR INTERVENTION GROUP
AND PLACEBO GROUP.
WHAT'S NICE ABOUT DIETARY
SUPPLEMENTS THESE ISSUES OF
EFFICACY CAN BE APPLIED TO LARGE
AND SMALL SCALE CLINICAL TRIALS
BUT IT'S DIFFICULT TO ACHIEVE
IDEAL EFFICACY.
ESPECIALLY WHEN THE TRIALS ARE
LONGER, LARGER, MORE
COMPLICATED, SIDE EFFECTS.
WE CAN'T EXPECT EVERY
INTERVENTION TO HAVE 100%
COMPLIANCE OR FOR LONGER TRIALS
CAN'T EXPECT FOLLOW-UP TO BE
100% EITHER.
THERE'S A SLIPPERY SLOPE BETWEEN
EFFICACY AND EFFECTIVENESS, THIS
IMPLEMENTATION GAP.
THE OTHER FACTOR IS IMPACT OF
GENERALIZABILITY.
THIS IS AN EXAMPLE FROM A TRIAL
I HELPED OVERSEE OVER WHO
DECADES, PHYSICIAN HEALTH STUDY,
UNDERSTANDING IT'S NOT JUST WHO
IS IN THE TRIAL FOR LOOKING AT
THE ISSUES OF EFFICACY AND
EFFECTIVENESS, BUT YOU CAN'T
FORGET THE ISSUE OF
GENERALIZABILITY FOR WHO ENROLLS
INTO A TRIAL.
THIS EXAMPLE, THIS RANDOMIZED
22,000 MALE PHYSICIANS.
WE STARTED WITH HALF A MILLION
QUESTIONNAIRES THAT WENT OUT TO
RESPONDENTS, SOME RESPOND, SOME
DON'T.
SOME PEOPLE ARE WILLING TO
ENROLL, SOME PEOPLE DON'T.
ULTIMATELY PEOPLE ARE ELIGIBLE
OR INELIGIBLE.
WE ULTIMATELY RANDOMIZED PEOPLE.
THIS IS TYPICAL FOR ANY STUDY,
LARGE OR SMALL.
BUT EVEN FOR SOMETHING AS SIMPLE
AND SUBTLE AS WHAT DIFFERENCES
ARE, I LIKE TO JOKE WITH
COLLEAGUES AND PARTICIPANTS,
GENTLY, THAT JUST BEING WILLING
TO RESPOND TO AN INVITATION TO
BE IN A TRIAL, BEING WILLING, AS
YOU SEE, THESE BARS GET LOWER
AND LOWER, AND THAT REFLECTS THE
FACT THE MORTALITY RATES FOR
THOSE WHO ARE ULTIMATELY
RANDOMIZED INTO A TRIAL ARE
BETTER, A LOT BETTER, MUCH LOWER
HERE THAN YOU SEE FOR TOTAL
CARDIOVASCULAR AND CANCER
MORTALITY, VERSUS THOSE WHO
NEVER RESPONDED IN THE FIRST
PLACE.
SO, WHILE EFFICACY AND
EFFECTIVENESS ARE EXTREMELY
IMPORTANT, DON'T DISCOUNT THE
ROLE OF GENERALIZABILITY AND WHO
YOU RECRUIT INTO A STUDY, LARGE
OR SMALL.
I'M GOING TO PIVOT.
ONE THING THAT'S WORTH NOTING IS
WHEN WE LOOK AT THE U.S.
PREVENTIVE SERVICES TASK FORCE
AND GUIDELINES THEY SET FORTH
NOW ABOUT 8 YEARS AGO ON
SUPPLEMENT USE FOR PREVENTING AT
LEAST CARDIOVASCULAR DISEASE AND
CANCER, LARGELY EQUIVOCAL
STATEMENTS THAT CAME OUT OF
THIS.
THERE ARE UPDATED GUIDELINES
FORTHCOMING LATER THIS YEAR I
BELIEVE, BUT IT DOES RACE THE
QUESTION OF OVERRELIANCE ON
CLINICAL TRIALS
WHAT ABOUT OBSERVATIONAL
STUDIES? YOU CAN HAVE A LOUSY
POORLY DESIGNED CLINICAL TRIAL
VERSUS A WELL-DESIGNED
OBSERVATIONAL STUDY.
SO WHY CAN'T A WELL-CONDUCTED
OBSERVATIONAL STUDY POTENTIALLY
DEMONSTRATE EFFICACY?
JUST BECAUSE A COHORT STUDY IS
LARGER, THAT DOESN'T NECESSARILY
CONSTITUTED EFFECTIVENESS
BECAUSE OF THE ISSUE OF
CONFOUNDING.
CONFOUNDING GETS IN THE WAY OF
DETERMINING WHETHER THERE'S
TRULY A SUPPLEMENT MIGHT BE
EFFICACIOUS.
WE KNOW FROM LOTS OF STUDIES,
YOU HEARD ABOUT THIS IN THE
PRESENTATIONS, THAT THOSE TAKING
DIETARY SUPPLEMENTS DO TEND TO
BE ON AVERAGE OLDER, TEND TO BE
WOMEN, TEND TO HAVE MEANS TO
PURCHASE DIETARY SUPPLEMENTS.
AND THEY HAVE A HEALTHIER DIET,
EXERCISE MORE, CONVERSELY TEND
TO BE DIAGNOSED WITH CHRONIC
CONDITIONS.
A LOT OF TIMES PEOPLE SAY I WAS
TOLD I HAVE HIGH BLOOD PRESSURE
AND I WANTED TO THINK ABOUT WHAT
I SHOULD TAKE TO ADDRESS THAT.
MAYBE THINGS I CAN TAKE AHEAD OF
PERHAPS SOME OF THE
PHARMACOLOGIC INTERVENTIONS.
AND JUST AS EXAMPLE, THIS IS,
AGAIN, AN EXAMPLE OF DATA FROM
THE PHYSICIANS' HEALTH STUDY.
WHEN WE COMPARED PEOPLE USING
ONLY MULTI-VITAMINS TO THOSE
USING BOTH MULTI-VITAMINS AND
OTHER TYPES OF VITAMIN AND
MINERAL SUPPLEMENTS COMPARED
WITH THE THIRDS COLUMN ON THE
RIGHT, OTHER SUPPLEMENTS BESIDES
A MULTI-VITAMIN INTERESTING
PATTERNS EMERGE.
WE SEE WITH AGE PEOPLE ARE MORE
LIKELY TO TAKE SUPPLEMENTS,
PEOPLE WHO ARE HEAVIER HAVE
HIGHER BMI, ARE LESS LIKELY TO
TAKE SUPPLEMENTS.
SMOKING STATUS, VIGOROUS
EXERCISE, ASPIRIN USE, ALL
THESE.
IF YOU'RE CONSUMING FRUITS AND
VEGETABLES YOU'RE MORE LIKELY TO
BE TAKING SUPPLEMENTS ON
AVERAGE.
THINKING ABOUT WHO IS USING IT,
THE ISSUE OF GENERALIZABILITY IS
AN IMPORTANT COMPONENT THAT
SHOULD BE INCORPORATED INTO THE
ISSUES OF EFFICACY AND
EFFECTIVENESS WHEN THINKING
ABOUT DIETARY SUPPLEMENTS AND
RESEARCH YOU'RE READING OR ARE
INVOLVED IN.
JUST AS ANOTHER EXAMPLE,
SOMETHING THAT COMES OUT ALL THE
TIME, WITHOUT TRYING TO BE
CRITICAL, THERE ARE LOTS OF MET
A ANALYSES PUBLISHED SEEMS LIKE
EVERY OTHER WEEK THAT ARE TAKING
OBSERVATIONAL STUDIES AND
COMBINING THOSE DATA TOGETHER TO
ADDRESS SPECIFIC QUESTIONS.
THE BEAUTY IS IT HELPS BY
PULLING DATA TOGETHER, HELPS TO
GIVE A MORE PRECISE ANSWER TO A
QUESTION THAT OTHERWISE MIGHT
HAVE UNCERTAIN.
THIS IS LOOKING AT RELATIONSHIP
BETWEEN CIRCULATING LEVELS, NOT
DIETARY SUPPLEMENTS BUT
CIRCULATING HYDROXY D, RELATED
TO VITAMIN D.
THE BEAUTY OF THE META-ANALYSIS,
EVERY UNIT INCREASE, ONE
STANDARD DEVIATION DECREASE YOU
HAVE A BETTER CHANCE OF
DEVELOPING CVD.
THIS DOESN'T GET YOU CLOSER.
BECAUSE THERE'S CONFOUNDING THAT
GETS IN THE WAY UNDERSTANDING
WHETHER THERE'S EFFICACY THAT'S
COMING INTO PLAY, CAN WE MAKE
THAT LINKAGE ON A CAUSAL BASIS.
I'D LIKE TO WALK YOU THROUGH THE
WAY WE THINK THROUGH TYPICAL
DIETARY SUPPLEMENT TRIALS.
I SAY TYPICAL IN A BROAD SENSE
OF THE TERM.
A LOT OF THE TRIALS DONE, YOU
MIGHT HAVE, SAY, FOUR, EIGHT, 16
WEEKS OF TREATMENT AND
FOLLOW-UP, MIGHT TEST AND
HOPEFULLY RANDOMIZED DOUBLE
BLIND PERHAPS PLACEBO CONTROLLED
TRIAL TESTING, AND THIS EXAMPLE
MIGHT BE A SEVERAL DOZEN MEN AND
WOMEN COMING IN WITH ELEVATE
BLOOD PRESSURED AND YOU'RE
INTERESTED IN BRACHIAL ARTERY
STIFFNESS, BIOMARKER ALSO.
WHAT ABOUT TRIALS LIKE THIS?
DOES IT HAVE TO APPLY TO
CLINICAL OUTCOMES?
NO, NOT NECESSARILY.
CAN THIS TRIAL ON ITS OWN GET
US THERE?
THE ONE THING THAT'S ALWAYS
IMPORTANT, AGAIN, WHEN WE THINK
ABOUT, AGAIN, WHETHER IT'S A
SMALL TRIAL OR LARGE TRIAL, TO
WHAT EXTENT WE CAN DRAW
CONCLUSIONS FROM THESE
RELATIVELY SMALL OR SHORTER
TRIALS OF DIETARY SUPPLEMENTS IS
IT STILL A FUNCTION OF HOW GOOD
THAT METHODOLOGY IS, QUALITY OF
STUDY MATTERS.
IT'S ALSO EQUALLY IMPORTANT TO
UNDERSTAND THERE'S A CLEAR
MECHANISM OF EFFECT BEING
DEMONSTRATED WHETHER FOR A
BIOMARKER OR CLINICAL MEASURE OR
CLINICAL ENDPOINT.
EVEN CLINICAL ENDPOINTS CAN BE
MESSY WITH THE WAY THEY ARE
CAPTURED OR CONFIRMED.
OF COURSE IN A SMALLER STUDY YOU
HAVE CONCERNS OF REPRODUCIBILITY
BUT THAT CAN BE DETERMINED,
THAT'S WHERE THE META-ANALYSES
CAN COME INTO PLAY.
LACK OF HARD CLINICAL OUTCOMES
DOES LIMIT THE WAY YOU CAN
INTERPRET, JUST BECAUSE A
PARTICULAR SUPPLEMENT MIGHT
LOWER BLOOD PRESSURE WE DON'T
KNOW NECESSARILY WHETHER THAT
EXTENDS TO REDUCING RISK OF
STROKE OR OTHER VASCULAR
OUTCOMES THAT MIGHT BE A
SEQUELAE OF THOSE REDUCTIONS,
HOPEFULLY IN BLOOD PRESSURE.
AGAIN, THE ISSUE OF
GENERALIZABILITY SHOULD ALWAYS
BE FACTORED INTO PLAY TOO.
THIS IS LOOKING AT MAGNESIUM AND
SYSTOLIC BLOOD PRESSURE, THERE'S
A LOT OF NOISE PERHAPS, RIGHT?
YOU HAVE SOME EFFECTS THAT SOME
MAGNESIUM SUPPLEMENTS MIGHT
INCREASE, SOME MIGHT DECREASE.
THIS SHOWED YOU COMBINE DATA
TOGETHER, THERE'S A SUGGESTION
OF A MODEST BUT PERHAPS MODEST
AND SIGNIFICANT REDUCTION IN
SYSTOLIC BLOOD PRESSURE.
BUT THIS IS THE CHALLENGE,
AGAIN, OF TAKING THE SMALLER
TRIALS AND ADDING THEM UP INTO A
SINGLE UNIT MEASURE, SUMMARY
MEASURE YOU WILL GET IN A
META-ANALYSIS.
AND JUST BY WAY OF NOTE, SOME OF
YOU MAY BE AWARE.
EARLIER THIS YEAR THERE WAS A
QUALIFIED HEALTH CLAIM
APPLICATION FOR MAGNESIUM AND
BLOOD PRESSURE THAT WAS APPROVED
BY THE FDA, THE LANGUAGE IS
QUITE CONSERVATIVE AND NOT
EXACTLY SWEEPING IN TERMS OF
SUPPORT BUT THESE ARE THE TYPES
OF QUESTIONS THAT COME UP WHEN
YOU'RE THINKING ABOUT HEALTH
CLAIMS AS WELL.
HOW DO WE PUT THESE SMALLER
TRIALS TOGETHER TO HELP
FORMULATE WHETHER THERE IS OR IS
NOT AN ARGUMENT THAT CAN BE MADE
FOR POTENTIAL EFFICACY OR
EFFECTIVENESS, NOT JUST FOR
MAGNESIUM SUPPLEMENTATION AND
BLOOD PRESSURE BUT EXTENDS TO
MANY OTHER PRODUCTS WITHIN THE
STATION.
IT'S AN IMPORTANT QUESTION.
I'LL DO ANOTHER PIVOT TO WALK
THROUGH SOME EXAMPLES OF A FEW
CLINICAL TRIALS AND HOW WE
APPROACH THEM AND QUESTIONS OF
EFFICACY AND EFFECTIVENESS.
AND FOR THE FIRST EXAMPLE, AS
I'VE MENTIONED BEFORE, THE
PHYSICIANS' HEALTH STUDY II
COMPLETED A WHILE BACK,
MAIL-BASED, 15,000 U.S. MALE
PHYSICIANS, THIS WAS MALE-BASED.
11 YEARS OF FOLLOW-UP.
LONG TRIAL, PRIMARY ENDPOINTS
CARDIOVASCULAR EVENTS, CANCER,
FOCUSED ON CLINICAL OUTCOMES
WITH SEVERAL INDIVIDUAL
CARDIOVASCULAR AND SITE-SPECIFIC
CANCER ENDPOINTS FOR SECONDARY
OUTCOMES ALONG WITH EYE DISEASE
AND COGNITIVE FUNCTION.
ONE ISSUE YOU THINK ABOUT IN THE
CONTEXT OF EFFICACY VERSUS
EFFECTIVENESS IS ISSUE OF
COMPLIANCE.
IF WE LOOK AT RESULTS FOR THE
RANDOMIZED MULTI-VITAMIN
COMPONENT, AT FOUR YEARS
COMPLIANCE WAS 77%.
AT EIGHT YEARS 72%.
AND BY THE END OF THE TRIAL, 11
YEARS, 67%.
NOW, I WOULD ARGUE I'M BIASED AS
ONE OF THE CO-P.I.s OF THE
PROJECT THAT COMPLIANCE WAS
PRETTY GOOD FOR THE MALE
PHYSICIAN PARTICIPANTS TO TAKE
THESE PILLS AS ASKED FOR AS LONG
AS THEY HAVE, IT'S NOT 100% BUT
WAS QUITE GOOD.
HOWEVER, RAISES THE QUESTION OF
WHEN WE ANALYZE OUR DATA HOW ARE
WE ANALYZING AND HOW DO WE
INTERPRET THAT?
WHAT YOU HEAR IS CLASSIC -- YOU
SEE THE CLASSIC INTENTION TO
TREAT ANALYSIS.
I'M NOT GOING TO WALK THROUGH
ALL RESULTS FOR PURPOSES OF TIME
BUT THE IDEA HERE IS THAT
TRADITIONALLY AT LEAST FOR THE
LARGER SCALE LONGER TERM TRIALS
DONE WITH DIETARY SUPPLEMENTS
WE'VE ALWAYS RELIED ON INTENTION
TO TREAT ANALYSES.
I THINK A LOT IS STEEPED IN THE
CLASSIC THOUGHT PROCESS OF ARE
WE DOING A PHARMACOLOGIC
INTERVENTION OR IS THIS A DIE
TEAR -- DIETARY INTERVENTION
AND YOU CAN MAKE MERITS ON BOTH
SIDES.
THESE ARE NOT PHARMACOLOGIC
INTERVENTIONS BUT THE DESIGN IS
SIMILAR TO WHAT IT MILD BE IF IT
WERE -- MIGHT BE A BLOOD
PRESSURE DRUG WE WERE TESTING.
FOR MAJOR CARDIOVASCULAR EVENTS,
ONE PRIMARY OUTCOMES, RATIO OF
1.01, NO EFFECT.
SECONDARY, KNOCK -- NOTHING IS
GOING ON BUT THIS WAS AN
INTENTION TO TREAT ANNUAL --
ANALYSIS.
COMPLIANCE WAS REASONABLE, DID
NOT COMPEL US AT THE TIME TO
CONSIDER WHAT THE
COMPLIANCE-BASED ANALYSES MIGHT
LOOK LIKE.
NOW, WHEN WE ALSO LOOKED AT
OTHER PRIMARY OUTCOME FOR TOTAL
CANCER, HERE WE DID SEE A
SUGGESTION, BORDERLINE
SIGNIFICANT SUGGESTION, THAT
THOSE RANDOMIZED TO
MULTI-VITAMIN HAD 8% REDUCTION
VERSUS PLACEBO, AND
SITE-SPECIFIC CANCERS IN THE
RIGHT DIRECTION FOR OLDER MEN,
SEEMED TO BE A STRONGER EFFECT,
POTENTIALLY INTERACTION WITH AGE
WAS NOT SIGNIFICANT BUT WITH
INTENTION TO TREAT ANALYSIS, OUR
BELIEF WAS WE DON'T WORRY ABOUT
COMPLIANCE-BASED BECAUSE WE HANG
OUR HAT FOR CLINICAL OUTCOMES
WITH INTENTION TO TREAT
ANALYSES.
WE TREAT AS IF THIS IS EFFICACY.
ONCE RANDOMIZED TO A
MULTI-VITAMIN, THAT'S HOW YOU'RE
ALWAYS ANALYZED.
REGARDLESS OF WHAT HAPPENS.
SO FOR THE ONE-THIRD OR SO OF
PARTICIPANTS THAT STOPPED TAKING
THE MULTI-VITAMIN BY THE END OF
TRIAL WE'RE STILL ANALYZING AS
IF THEY WERE STILL TAKING THE
MULTI-VITAMIN EVEN THOUGH THEY
WEREN'T.
THERE'S A LITTLE BIT OF PARITY
THAT GETS INTRODUCED.
IT ANSWERS A FEW QUESTIONS AND
CREATES NEW QUESTIONS LIKE ANY
GOOD TRIAL.
SUBSEQUENTLY, WE PUBLISHED
RESULTS A FOLLOW-UP TRIAL, A
COCO SUPPLEMENT CALLED COSMOS,
21,000 OLDER U.S. MEN AND WOMEN,
TAKING COCOA FLAVANOL, PRIMARY
OUTCOMES FOR PURPOSES OF
EFFICACY AND EFFECTIVENESS MAJOR
CARDIOVASCULAR EVENTS AND TOTAL
INVASIVE CANCER.
JUST ON THE TOPIC OF COMPLIANCE,
AN IMPORTANT CONSIDERATION WHEN
THINKING ABOUT THE DISTINCTION
BETWEEN EFFICACY AND
EFFECTIVENESS, ONE GREAT THING
ABOUT THE TRIAL DESIGN, WHETHER
YOU'RE USING THESE CALENDAR
PACKS, ALL TOOLED TO INCREASE
COMPLIANCE.
WE WANT TO MAKE SURE THAT OUR
ANALYSES, WHETHER INTENTION TO
TREAT OR OTHERWISE, ARE GOING TO
REFLECT HOPEFULLY WHAT WE THINK
IS EFFICACY, AND OR
EFFECTIVENESS AS YOU'LL SEE.
AND IN FACT IF WE JUST FOCUS
EVEN ON THE MULTI-VITAMIN PART
OF THIS CHART ON THE RIGHT WE
SEE FIRST OF ALL OUR COMPLIANCE
WAS QUITE HIGH DEPENDING ON HOW
YOU DEFINED IT.
BY THE END WE HAD 80% TAKING
EITHER OR BOTH INTERVENTIONS.
AND AT THE SAME TIME IF YOU
DEFINE TOTAL COMPLIANCE ON BASIS
OF NOT TAKING OUT OF STUDY
PILLS, YOU CAN IMAGINE A LOT OF
PEOPLE RANDOMIZED TO TAKE
MULTI-VITAMIN DURING THE TRIAL
SAID, OH, I THINK I SHOULD BE,
I'M NOT SURE IF I AM.
AND THAT REFLECTS SLIGHTLY LOWER
TOTAL COMPLIANCE THAT YOU SEE AT
THE BOTTOM AT 24 AND 36 MONTHS.
BUT NEVERTHELESS WHAT WE DID FOR
COSMOS, A DEPARTURE THAN WHAT
WE'VE USUALLY DONE LOOK AT
RESULTS TWO WAYS.
WHAT I'M PRESENTING IS FIRST FOR
RESULTS OF MULTI-VITAMIN, ON
PRIMARY ENDPOINT OF TOTAL
INVASIVE CANCER, WHAT I WOULD
DEEM TRADITIONAL OR TYPICAL
INTENTION TO TREAT ANALYSES.
HOW YOU'RE RANDOMIZED IS HOW
YOU'RE GOING TO BE ANALYZED.
FOR THE MULTI-VITAMIN INVASIVE
CANCER OVERALL NO EFFECT.
PROMISING EFFECT IN PHYSICIANS
HEALTH STUDY II DID NOT
REPLICATE IN COSMOS, EXTENDED TO
SECONDARY OUTCOMES EXCEPT FOR
INVASIVE LUNG CANCER, INTRIGUING
38% REDUCTION FOR THOSE TAKING
MULTI-VITAMIN VERSUS PLACEBO.
THIS ASSUMES THAT WHEN YOU'RE
RANDOMIZED INTO THE TRIAL THAT'S
HOW YOUR ANALYZED.
WE ALSO WERE CURIOUS TO SEE WHAT
IF WE DID COMPLIANCE-BASED
ANALYSES, PER PROTOCOL ANALYSES.
THE RESULTS ARE BASICALLY THE
SAME.
I'LL FLIP-FLOP AND GO BACK FOR A
MOMENT.
PRIMARY OUTCOME OF TOTAL
INVASIVE CANCER, .97.
WHEN WE GO TO PROTOCOL ANALYSES,
STILL .97.
I'LL FLIP ONE MORE TIME.
YOU'LL NOTICE FOR THE INTENTION
TO TREAT ANALYSES, INCORPORATING
ALL OF THE DATA, WE HAVE MORE
THAN A THOUSAND PEOPLE WHO
DEVELOPED INVASIVE CANCER OVER
THE COURSE OF THE STUDY.
BECAUSE IN THE PER-PROTOCOL
ANALYSIS ONCE YOU BECOME
NON-COMPLIANCE WE STOP YOU FROM
BEING FOLLOWED UP ANYMORE, THE
NUMBER OF EVENTS HAS GONE DOWN.
ONE OF THE OTHER CONSIDERATIONS
FOR A PER-PROTOCOL ANALYSIS,
YOUR ENDPOINT COUNTS WILL BE
LESS BECAUSE WE'RE EXCLUDING YOU
ONCE YOU BECOME NON-COMPLIANT.
NOT ONLY ARE YOU INTRODUCING A
LITTLE BIT OF CONFOUNDING BUT
YOU'RE ALSO -- YOUR STUDY POWER
IS IMPACTED AS WELL.
WE FEEL IT'S IMPORTANT TO
COMPARE AN CONTRAST RESULTS, FOR
THE MULTI-VITAMIN IN COSMOS
REGARDLESS OF WHETHER YOU'RE
LOOKING AT FROM THE PERSPECTIVE
OF EFFICACY OR EFFECTIVENESS FOR
TOTAL INVASIVE CANCER THERE'S
SIMILAR LACK OF EFFECT.
ON THE OTHER HAND FOR OUR COCOA
FLAVANOL INTERVENTION PRIMARY
OUTCOME WAS, TOTAL
CARDIOVASCULAR EVENTS, INTENTION
TO TREAT ANALYSIS WE SAW NO
SIGNIFICANT REDUCTION IN TOTAL
CARDIOVASCULAR DISEASE BUT THERE
WAS AT LEAST A SUGGESTION,
PROMISING SIGNAL, A ALBEIT NOT
SIGNIFICANT, 10% REDUCTION FOR
THOSE TAKING THE COCOA EXTRACT
VERSUS PLACEBO, FOR THE COSMOS
TRIAL WE LOOK ALONG EACH
INDIVIDUAL RATIO, GENERAL
PATTERNS ARE POINTING IN THE
RIGHT DIRECTION.
WE WERE EQUALLY CURIOUS IF WE
LOOK AT THIS, FROM THE INTENTION
TO TREAT PERSPECTIVE, WHAT IF WE
LOOK FROM COMPLIANCE PERSPECTIVE
AND INCLUDE THOSE TAKING THE
COCOA EXTRACT CARING AGAINST
THOSE ONLY TAKING THE PLACEBO
WITH NO NOISE INTRODUCED?
SURE ENOUGH WHEN WE DO THE
PER-PROTOCOL ANALYSIS NUMBER OF
EVENTS GO DOWN, FEWER EVENTS,
YET THE STRENGTH OF THE EFFECT
NOT STATISTICALLY SIGNIFICANT IN
OUR INTENTION-TO-TREAT ANALYSES
BECAME STATISTICALLY
SIGNIFICANT, NOW 15% REDUCTION.
THERE WAS STRENGTHENING OF
EFFECT FOR SECONDARY OUTCOMES
RAISING THE QUESTION WHICH IS
RIGHT?
WHAT WE DECIDED I THINK THE BEST
WAY TO GO, DEPENDING ON YOUR
TRIAL AND DESIGN FOR YOUR
DIETARY SUPPLEMENT I WOULD
RATHER SEE MORE ANALYSES
PRESENTING BOTH SETS OF ANALYSES
TO MORE FULLY REFLECT WHAT WORKS
FOR DIETARY SUPPLEMENT, UNDER
EITHER IDEAL CIRCUMSTANCES OR
USUAL CIRCUMSTANCES.
SO JUST A FEW OTHER QUICK
THOUGHTS.
I THINK ANY TYPE OF TRIAL YOU
DO, WHETHER LARGE SCALE, SMALL
SCALE, IT'S ALWAYS HARD TO
DECLARE EFFICACY.
I THINK THAT'S AN IMPORTANT
THING TO REMEMBER.
EFFICACY IS IDEAL, RIGHT?
YOU'VE GOT A PERFECTLY DESIGNED
STUDY, NO ISSUES WITH FOLLOW-UP
COMPLIANCE, ET CETERA.
REGARDLESS, NO MATTER RESULTS
YOU'RE IN A CATCH-22.
IF YOU GET RESULTS PEOPLE THINK
THEY WANT TO HEAR THEY WILL
PRE-CLAIM YOU DID EVERYTHING
RIGHT.
TESTED THE RIGHT SUPPLEMENT,
REMOVED CONFOUNDING, MAYBE IT
WAS INTENTION-TO-TREAT, HAD THE
RIGHT ENDPOINTS BUT STILL ASK
YOURSELF WHAT ANALYSES DO WE
CONSIDER?
DID YOU INCORPORATE ALL THESE
ANALYSES?
NO DIFFERENTLY THAN A RESULT
PEOPLE DON'T LIKE OR AGREE WITH,
THEY WILL SAY HIGHLIGHTS THE
TRIALS AND WEAKNESSES AND
EPISTUDIES DON'T CONNECT WELL,
WRONG SUPPLEMENT, WRONG PATIENT
POPULATION, GENERALIZABILITY IS
AN ISSUE.
YOU CAN'T WIN.
IT'S IMPORTANT TO CONSIDER
INTENTION-TO-TREAT AND
INTENTION-BASED ANALYSIS.
LOOKING FORWARD SHORT-TERM
TRIALS WILL CONTINUE BUT WE WANT
TO THINK ABOUT IT BOTH IN TERMS
OF EFFICACY AND EFFECTIVENESS.
IT STARTS WITH A WELL-DESIGNED
CLINICAL TRIAL.
I CAN'T EMPHASIZE THAT ENOUGH.
YES, RESULTS MATTER, BUT IF IT'S
NOT A WELL-DESIGNED TRIAL IT'S
GARBAGE IN, GARBAGE OUT.
SELECT YOUR SUPPLEMENTS
CAREFULLY, CONSIDER MULTIPLE
DOSES, DIFFERENT FORMULATIONS,
HAVE THE RIGHT POPULATION
REPRESENTED.
AND MORE AND MORE NO MATTER HOW
SHORT OR LONG THE TRIAL IS IT'S
IMPORTANT TO CONSIDER TRIALS
WHERE YOU MIGHT HAVE I WOULD SAY
DOESN'T HAVE TO BE A HARD
CLINICAL OUTCOME LIKE
CARDIOVASCULAR DISEASE BUT
PRIMARY ENDPOINT, THINK THE
ABOUT MECHANISMS OF EFFECT THAT
UNDERLIE OUTCOMES YOU'RE
TESTING.
IT'S IMPORTANT TO THINK ABOUT
THAT.
IT REQUIRES THOUGHTFUL
COLLABORATION ACROSS MANY
SECTORS.
GOVERNMENT, INDUSTRY, ACADEMIA.
SO WITH THAT, THANK YOU FOR YOUR
ATTENTION, I'D BE HAPPY TO TAKE
QUESTIONS YOU MIGHT HAVE.
>> THANK YOU, DR. SESSO.
LET'S JUMP INTO THE QUESTIONS.
YOU HAVE A FEW.
NOT A LOT OF TIME.
FIRST QUESTION, IS CONFOUNDING
ELIMINATED IN SECONDARY OR
STRATIFIED ANALYSES IN EFFICACY
TRIALS?
>> YEAH, SO THAT'S A GOOD
QUESTION.
IF YOU'RE ANALYZING THE DATA AS
IF IT WERE INTENTION TO TREAT,
THEN IF YOU'RE LOOKING AT
SUBGROUP ANALYSES, AND THOSE
OUGHT TO BE PRE-SELECTED BEFORE
YOU DO YOUR STUDY INSTEAD OF
POST HOC, SUBGROUP ANALYSES
WOULD STILL BE APPROPRIATE IN
THE CONTEXT OF EFFICACY.
HOWEVER, IF YOU'RE DOING
PER-PROTOCOL ANALYSES YOU HAVE
TO BE MINDFUL -- AS-TREAT
ANALYSES YOU DO LOSE THAT
ABILITY.
>> ANOTHER QUESTION, HOW ABOUT
USING CLUSTER RANDOMIZED
PLATFORM TRIALS LIKE RECOVERY
AND SOLIDARITY?
A LOT OF WHAT YOU TALKED ABOUT
APPLIES TO DRUGS AS WELL, ALSO
BAYESIAN ANALYSES VERSUS
FREQUENT -- LET'S SEE WHAT YOU
CAN MAKE OF THAT.
>> THERE'S A BUNCH OF QUESTIONS
IN THAT, VALID POINTS RAISED BY
MR. CARTER, THAT THE -- SO MY
VIEW, I THINK WE NEED TO BE -- I
THINK THE POINT HERE IS AN
IMPORTANT ONE WE NEED TO BE NOR
INNOVATIVE WITH THE WAY WE
APPROACH THE DESIGN OF TRIALS,
NOT JUST FOR DIETARY SUPPLEMENTS
BUT FOR DRUG TRIALS TOO.
THERE ARE METHODS, WHETHER
IT'S -- SO THE BAYESIAN ANALYSES
AND FREQUENCY APPROACHES ARE ONE
WAY BUT IT STILL DOESN'T TAKE
AWAY FROM THE BASIC TENETS OF
CLINICAL TRIALS WHICH APPLY TO
DIETARY SUPPLEMENTS.
AT THE END OF THE DAY YOU NEED A
WELL-DESIGNED TRIAL REGARDLESS
OF METHODOLOGY IN WHICH YOU WANT
TO MAXIMIZE COMPLIANCE, MINIMIZE
LOSS TO FOLLOW-UP, CAPTURE THOSE
THINGS WELL SO YOU CAN
QUANTITATE IT, AND THEN AT THE
SAME TIME APPROACH THE ANALYSES
FROM DIFFERENT PERSPECTIVES TO
GIVE THE READER AND RESEARCH
COMMUNITY I THINK A MORE
COMPLETE PICTURE AS TO ROLE OF
DIET IS, WHAT THE DIETARY
SUPPLEMENT MIGHT BE ON A
PARTICULAR OUTCOME YOU'RE
TESTING.
>> THE NUTRITIONAL GENOMICS
TESTING FOR SNPs SEEMS TO
INDIVIDUALITY, INFLUENCED BY
ENVIRONMENTAL FACTORS AND
INTAKE.
DOES THIS MAKE META-ANALYSIS
INVALID FOR INDIVIDUAL
SUPPLEMENT EFFICACY?
>> GREAT QUESTION.
THIS IS ONE OF THE CHALLENGES
THAT WE HAVE WITH NUTRITION
RESEARCH MORE BROADLY, WHETHER
DIETARY SUPPLEMENTS, FOODS,
FUNCTIONAL FOODS OR DIETARY
PATTERNS FOR THAT MATTER, WE
KNOW NEUTRIGENOMICS OR HOWEVER
YOU WANT TO TERM IT, WE KNOW
INDIVIDUAL RESPONSES TO WHETHER
IT BE DIETARY SUPPLEMENTS,
WHETHER IT BE FUNCTIONAL FOODS,
OR WHETHER THEY BE DIETARY
PATTERNS DIFFERS.
SO THERE'S ALWAYS GOING TO BE
ENVIRONMENTAL FACTORS AND/OR
GENOMIC COMPONENTS THAT ARE
GOING TO DETERMINE WHETHER I
MIGHT RESPOND DIFFERENTLY TO A
MAGNESIUM SUPPLEMENT THAN DR.
BROWN MIGHT.
AND SO THE DANGER OF THIS OF
COURSE IS THAT A STUDY HAS TO BE
BIG ENOUGH AND DESIGNED
APPROPRIATELY ENOUGH TO TEASE
THOSE THINGS OUT.
SMALLER TRIALS, UNLESS YOU HAVE
A HYPOTHESIS FOR A SPECIFIC SNP
THAT YOU BELIEVE MIGHT MAKE ME
MORE OR LESS RESPONSIVE TO A
PARTICULAR SUPPLEMENT OR HAVE
SERUM LEVELS OF A BIOMARKER
CHANGE, THOSE ARE IMPORTANT BUT
YOU HAVE TO BE CAREFUL NOT TO
LET THAT BOG DOWN THE BASIC
QUESTION OF A DESIGNED TRIAL IN
THE FIRST PLACE TO ADDRESS THE
QUESTION OF EITHER EFFICACY OR
EFFECTIVENESS IN THE FIRST
PLACE.
IT'S AN IMPORTANT CONSIDERATION.
>> THANK YOU.
ANOTHER ONE, HOW MANY BLOOD
PRESSURE DRUG TRIALS GO ON FOR
11 YEARS?
>> NOT TOO MANY.
THE TRIAL I WAS ALLUDING TO WAS
A DIETARY SUPPLEMENT SUPPLEMENT
TRIAL OF A FEW SUPPLEMENTS, TWO
BY TWO BY TWO FACTORIAL TRIAL,
YOU CAN IMAGINE THE CALENDAR
PATH, THIS IS ONE FROM THE
COSMOS TRIAL, THIS HAD A LOT OF
PILLS IN IT BUT FOR DIETARY
SUPPLEMENT TRIALS ESPECIALLY FOR
CLINICAL OUTCOMES, NOT AS MUCH
FOR CARDIOVASCULAR, UP TO FIVE
YEARS OF FOLLOW-UP IS ENOUGH BUT
FOR CHEMOPREVENTION TRIALS,
ESPECIALLY FOR NUTRITION AND
CANCER, IT TAKES TIME FOR
EFFECTS TO EMERGE.
COLORECTAL CANCER, WITH
DIFFERENT NUTRITIONAL
INTERVENTIONS, EVEN AFTER
INTERVENTION STOPS IT'S
IMPORTANT FOR THE FOLLOW-UP TO
CONTINUE BECAUSE THERE'S ISSUES
OF LATENCY.
IT'S HARD TO DO.
BUT IT'S IMPORTANT TO HAVE
SUFFICIENT FOLLOW-UP TO TEASE
OUT THOSE EFFECTS.
>> THANK YOU.
I THINK WE DO HAVE TIME FOR ONE
MORE QUESTION.
MAYBE TWO MORE.
SUGGESTED COMBINES OBSERVATIONAL
STUDIES WITH RANDOMIZED CLINICAL
TRIALS, COULD YOU ELABORATE ON
THIS TYPE OF ANALYSIS?
>> YEAH, I APPRECIATE DR.
DWYER'S QUESTION.
I'VE HEARD THIS QUESTION A LOT.
I TAKE APPEARSALLY, IT
INTRODUCES DANGERS.
THE BEAUTY OF A CLINICAL TRIAL
DONE AS INTENTION, WHERE YOU CAN
ELIMINATE CONFOUNDING, NOT JUST
FOR WHAT YOU CAN MEASURE BUT YOU
CAN'T MEASURE.
OR NEW RISK FACTORS THAT HAVE
NOT YET EMERGED, IT BOILS DOWN
TO A SIMPLE TWO BY TWO TABLE,
TAKE A SUPPLEMENT, OR YOU DON'T,
WHATEVER THE CONTROL.
YOU HAVE AN OUTCOME.
OR YOU DON'T.
OBSERVATIONAL DATA WELL
CONDUCTED OBSERVATIONAL STUDY
CARRIES WEIGHT.
THERE'S ALSO WAYS TO TAKE
OBSERVATIONAL DATA THROUGH
MARGINAL STRUCTURAL MODELING AND
OTHER TECHNIQUES OUT THERE THAT
YOU CAN START TO APPROXIMATE
WHAT THE TRIAL RESULT MIGHT LOOK
LIKE FOR AN OBSERVATIONAL STUDY
BUT THAT BEING SAID I WOULD NOT
PUT THOSE TOGETHER PERSONALLY.
>> FOR DOCTORAL STUDENTS, DO YOU
HAVE SUGGESTIONS FOR STUDENTS,
WHAT ARE THINGS WE NEED TO BE
CAREFUL ABOUT?
>> IT'S A GREAT QUESTION.
I THINK THE SIMPLE ANSWER IS
TWO-FOLD.
ONE IS KNOW YOUR DATASET.
IT'S UNFAIR TO ASSUME ONLY
CLINICAL TRIALS ARE GOOD.
YOU HEARD ABOUT NHANES, THESE
ARE WONDERFUL RESOURCES WE ALL
OUGHT TO TAKE ADVANTAGE OF.
AT THE SAME TIME IT'S IMPORTANT
TO UNDERSTAND NOT JUST THE
NATURE OF THE OBSERVATIONAL
STUDY AND WHO IT RECOMMENDS BUT
HOW DATA WERE COLLECTED AS WELL
AS OUTCOMES AND QUESTIONS THAT
YOU'RE ASKING.
APPRECIATING THE ROLES OF BIAS
AND ERROR IN CONFOUNDING, HOW
THIS ROLLS INTO HOW YOU ANALYZE
DATA AND INTERPRET IT.
AT THE SAME TIME WHEN YOU'RE
DOING SECONDARY ANALYSES OF
EXISTING COHORTS EMBRACE THE
OPPORTUNITY.
KNOW WHAT YOUR LIMITATIONS ARE.
DON'T OVERINTERPRET YOUR
RESULTS, DON'T UNDERESTIMATE
WHAT RESULTS MEAN.
EMBRACE THE OPPORTUNITY.
>> THANK YOU.
>> MY PLEASURE.
IF ANYONE HAS QUESTIONS, DON'T
HESITATE TO REACH OUT TO ME, IF
YOU HAVE QUESTIONS ABOUT
RESEARCH AND DIETARY SUPPLEMENTS
IN GENERAL.
THANK YOU.
>> BACK TO DR. HARDY, IF SHE'S
READY.
DR. HARDY, ARE YOU READY?
I DON'T SEE DR. HARDY.
>> I'M HERE.
>> GREAT.
DR. HARDY WILL TAKE THE PODIUM
AND PRESENT ON THE CONCEPT OF
SAFETY, ITS MEASUREMENT, AND
REPORTING.
TAKE IT AWAY.
>> THANK YOU.
>> NOW WE DO.
>> OKAY.
LET ME GO BACK TO THE BEGINNING.
AGAIN, THIS IS AN ADVERSE EVENT,
SO WE'RE GOING TO HAVE TO THINK
ABOUT THIS AS THE SAFETY OF NOT
SIGNING ON FOR YOUR THING AN
HOUR EARLY.
THANK YOU, EVERYBODY.
I'M VERY GRATEFUL TO BE HERE AND
GRATEFUL TO OFFICE OF DIETARY
SUPPLEMENTS.
I WANT TO START THINKING ABOUT
THE CONCEPT OF SAFETY WITH YOU.
THIS IS USUALLY DISCUSSED AS AN
ON/OFF SWITCH.
I THINK IT'S REALLY -- WE HAVE
TO THINK BIT AS A MORE NUANCED
CONCEPT, AND AS DR. SESSO TALKED
ABOUT WHERE IS YOUR INFORMATION
COMING FROM AND WHAT DOES THAT
MEAN?
I TRAINED FIRST AS A CLINICIAN
SO I'M REALLY GOVERNING MYSELF
AND MY PRACTICE AND ANALYSIS AND
HOW I LOOK AT THINGS BY FIRST DO
NO HARM, BUT IS SAFETY ONLY THE
ABSENCE OF HARM OR IS THERE
SOMEBODY MORE PRO-ACTIVE WILL
SAFETY WE WOULD THINK ABOUT?
I THINK YOU CAN MAKE A CASE FOR
THE PRO-ACTIVE PUBLIC HEALTH
ISSUES OF SAFETY AT THE VERY
LEAST.
THIS IS WHAT THE ANALYSIS LOOKS
LIKE, THINKING ABOUT RISK,
RELATED TO SAFETY, VERSUS
BENEFIT.
CAN YOU PUT PATIENT CHOICE ON
TOP OF THAT, CAUSALITY, OR
POPULATION ISSUES, AND THEN
DECIDE OFTEN GIVEN THE AMOUNT OF
BENEFIT HOW MUCH RISK YOU'RE
WILLING TO ACCEPT.
SO, SAFETY IS OFTEN NOT AN
ABSOLUTE -- DISCUSSED IN
ABSOLUTE TERMS.
THERE ARE MULTIPLE SOURCES OF
SAFETY INFORMATION.
EACH OF THEM ARE USEFUL BUT EACH
OF THEM ARE LIMITED.
IN THE DIETARY SUPPLEMENT REALM
FOR HERBAL MEDICINE PEOPLE GO
STRAIGHT TO HISTORICAL USE IN
HUMANS, USED FOR THOUSANDS OF
YEARS, THEREFORE IT'S SAFE.
WE'LL LOOK AT THAT MORE CLOSELY
BECAUSE THERE'S SIGNIFICANT
LIMITATIONS.
PHARMACOLOGICAL AND MECHANISTIC
ACTIVITY IS USEFUL, IT MIGHT
SUPPORT YOU TO THINK ABOUT WHERE
THE SITUATION MIGHT BE OF HIGHER
RISK OR MIGHT BE BIOLOGICAL
PLAUSIBILITY.
IN SILICO ANALYSIS WHEN WE CAN'T
TEST THINKS IN VITRO OR IN VIVO
WHICH WE PREFER TO LOOK AT
SOMETHING, HERB-DRUG ANALYSIS IS
CLASSIC.
IN SILICO MAY GIVE US A HINT
BECAUSE WE FOUND OFTEN LOOKING
AT THIS STUFF SPECIFICALLY FROM
CELL SCREENING OR SOMETHING LIKE
THAT ISN'T ALWAYS PREDICTIVE,
NEITHER IS ANIMAL DATA OFTEN
PREDICTIVE OR ISOLATED SIP
ANALYSIS PREDICTIVE OF WHAT'S
GOING TO HAPPEN WHEN WE LOOK AT
A HUMAN WHO TAKES IT AS A FULL
PHARMACOLOGICAL STUDY.
OBSERVATIONAL DATA WE'VE HEARD
FROM DR. SESSO ABOUT THAT
ALREADY.
PHARMACOVIGILANCE IS VOLUNTARY
FOR THE PUBLIC, AND MANDATED FOR
REPORTERS, BUT IT'S WOEFULLY
UNDERREPORTED.
WE SEE A LOT OF DECISIONS MADE
BASED AROUND ADVERSE EVENTS AND
THIS HAS LIMITATIONS.
TRADITIONAL USE VARIES FOR
MODERN USE, WHAT LIMITS ABILITY
TO USE TRADITIONAL SAFETY.
SO, IF WE SAY WE WANT TO TAKE A
CERTAIN HERB FOR CARDIOVASCULAR
DISEASE, AND WE'RE THINKING
ABOUT CHOLESTEROL LOWERING, OR
BLOOD PRESSURE MEASUREMENT, IN A
TRADITIONAL SYSTEM THIS KIND OF
DIAGNOSTIC USE IS NOT REALLY
PRESENT IN THAT TRADITIONAL USE.
LIKEWISE, HERBS MAY BE MODIFIED,
GINKO HAS BEEN MODIFIED, IT'S A
PROPERTY STRUCTURED TO TAKE OUT
CERTAIN ADVERSE CONSTITUENTS,
BLEND IN THINGS THAT ARE THOUGHT
TO BE THE ACTIVE CONSTITUENTS,
AND SO THE PRODUCT THAT WE USE
AS A MODERN PHYTO MEDICINE,
GINGKO, HAS VERY LITTLE USE I
SUBMIT TO THE TRADITIONAL
CHINESE USE, SO WHEN DISEASES
AREN'T SAME, PATIENT POPULATIONS
AREN'T THE SAME YOU HAVE TROUBLE
INTEGRATING THIS, WE KNOW THAT
FOR ACUTE TOXICITY DATA
TRADITIONAL USE CAN BE HELPFUL.
THINGS THAT ARE TRADITIONALLY
TOXIC BUT GET THE LABEL OF
POISONS BECOME HISTORICALLY
IMPORTANT AS AGENTS OF
GOVERNMENTAL CHANGE IN A
DIFFERENT KIND OF SOCIETY, LET'S
SAY.
BUT WE DO HAVE SOME PRECEDENT IN
GOVERNMENTAL AGENCIES, LARGER
REGULATORY SCHEMA.
SO WHEN WE LOOK AT THIS DIETARY
SUPPLEMENT FOR SAFETY WE'RE
BALANCING BETWEEN TWO BASIC
THINGS.
WE'RE LOOKING AT SORT OF THE
ISSUE OF PATIENT AND CONSUMER
ISSUES, THINGS ABOUT THE
INDIVIDUAL PERSON, OR CONTEXT OF
USE, VERSES RELIABILITY OF THE
PRODUCT, QUALITY OF THE PRODUCT,
AND THOSE TWO INTERACTIONS OFTEN
RAISE SAFETY ISSUES.
WHEN WE'RE THINKING ABOUT SAFETY
ISSUES FOR THE PATIENT, WE'RE
LOOKING AT STAGE OF LIFE, VERY
YOUNG PEOPLE, VERY OLD PEOPLE,
IF THEY HAVE A MEDICAL CONDITION
OF HYPERTENSION WHICH
PREDISPOSES TO THE ADVERSE EVENT
WE'RE INTERESTED IN LET'S SAY
STROKE, THEN FINDING A STROKE IN
A PERSON WHO TOOK A DIETARY
SUPPLEMENT BUT HAS OTHER RISK
FACTORS BECOMES A LESS CLEAN
INDICATION OF NON-SAFETY OF THAT
PRODUCT, LET'S SAY.
AND THEN WHAT YOUR STATE OF
HYDRATION IS, STATE OF EXERTION,
AND ANY OTHER MEDICATION
SUPPLEMENTS, ET CETERA, ALL
PATIENT ISSUES RELEVANT AND CAN
BE SIGNIFICANTLY OF AN ISSUE.
WE HAD GUIDANCE IN THE PAST FROM
OUR WONDERFUL COLLEAGUE NORM WHO
IS NO LONGER WITH IS, HIS ADAGE
IF WHAT'S IN THE BOTTLE IS ON
THE LABEL, IF THEY ARE
CONCURRENT, IF THE PRODUCT HAS
BEEN PREPARED PROPERLY, SAFETY
IS NOT A COMMON EVENT, RARELY
ENCOUNTERED.
TOXICITY IS RARELY ENCOUNTERED.
LET'S LOOK AT WHY THAT'S SO.
THERE ARE DIFFERENT ISSUES ABOUT
QUALITY CONTROL THAT AFFECT
DIRECTLY ON SAFETY.
SOMETHING'S MISLABELED, IF IT'S
NOT -- IF PRODUCT IN THE BOTTLE
IS NOT WHAT THE LABEL SAYS IT
IS, IF THE PRODUCT'S BEEN
SUBSTITUTED OR MISIDENTIFIED, OR
IF IT'S THE RIGHT AGENT BUT
THERE'S TOXIC CONSTITUENTS
EITHER OVERCONCENTRATED OR NOT
ACCOUNTED FOR.
FOR EXAMPLE, IF YOU HAVE A
PRODUCT THAT'S TRADITIONALLY
USED AS A WATER-BASED HERBAL TEA
THAT'S TAKEN AS A WEAK
CONCOCTION, IN SMALL AMOUNTS,
YOU THEN EXTRACT THAT HERB WITH
AN ALCOHOL WATER EXTRACT, THE
CHANCE OF SEQUESTERING TOXIC
CONSTITUENTS IS GOOD.
IN ETHNIC PHARMACOPEIA PRODUCTS,
CONTAMINANTS HAPPEN ALL THE
TIME, IN THE WATER, MATERIAL, IF
WE MAKE OYSTER -- CALCIUM WITH
OYSTER SHELLS, CAN BE
CONTAMINATED BY LEAD.
IMPROPERLY MADE SUPPLEMENT WHEN
TOO MUCH OF THE OTHERWISE SAFE
INGREDIENT IS ADDED, WE SAW WITH
A THAT SELENIUM TOXICITY EVENT.
HOW IS MODERN REGULATION?
THIS IS THE PURVIEW OF THE
OFFICE OF FDA.
AND THERE ARE REGULATIONS ABOUT
HOW PLANTS ARE GROWN, COLLECTED,
HOW INGREDIENT IS HANDLED, WHAT
HAPPENS TO IT IN THE SUPPLY
CHAIN, AND THOSE ARE ALL
NECESSARY CONSTITUENTS THAT HAVE
SIGNIFICANT REGULATIONS ATTACHED
TO THEM NOW.
THE BETTER COMPANIES, MORE
RIGOROUS ABOUT UNDERSTANDING
THEIR MATERIALS REALLY GO ABOVE
AND BEYOND THESE REGULATIONS.
ONE OF THE ISSUES NOT
NECESSARILY TOXICITY BUT CAN
MAKE THIS COMPLICATED WITH
HERBAL PRODUCTS, THEY ARE
VARIABLE.
NOT INHERENTLY A BAD THING.
IT HAPPENS WHEN YOU GROW
SOMETHING.
YOU ARE JUST HAVE TO DRINK A
BOTTLE OF WINE AND YOU CAN GET A
WHITE WINE OR RED WINE OR
CHAMPAGNE, BASICALLY THE SAME
PLANT BUT THE WAY IT'S HANDLED
MAKES A DIFFERENCE.
THE WAY IT'S GROWN MAKES A
DIFFERENCE.
THAT SHOWS UP IN HERBAL PRODUCTS
AS WELL.
AND IT MAKES THIS ISSUE A BIT
MORE COMPLICATED.
VARIABILITY CAN MAKE IT
DIFFICULT, MAY CONTRIBUTE TO
TOXICITY DEPENDING ON ISSUES
THAT ARE THE NATURE OF THE
PLANT, WHERE IT'S GROWN.
AND WE ALSO LABEL UNEXPECTED
VARIABILITY BECAUSE WE KNOW
RTAIN AMOUNT OF VARIABILITY IS
TOLERATED, EXPECTED, WE ALL THAT
ADULT ADULTERATION, IF WE SEE
CHEAP TO BUY AND PUT BACK INTO
THE PRODUCT, ASCORBIC'S ACID,
FOR EXAMPLE, THE PRODUCT HAS
BEEN ARTIFICIALLY ENHANCED OR
ADULTERATED.
CONTAMINATION IS DIFFERENT THAN
ADULTERATION.
THIS IS AN EXAMPLE LOOKING AT
PRODUCTS BOUGHT OFF THE SHELF IN
BOSTON, LOOKING FOR HEAVY
METALS.
IT'S COMPLICATED.
IN THE ETHNOBOTANY OF PRODUCTS,
HEAVY METALS WOULD BE INCLUDED,
HANDLED BY PRECIPITATING AND
RESUSPENDING, ET CETERA.
SO, TO FIND THESE IN HERE IN
SMALL AMOUNTS MAY MIGHT OR MAY
NOT BE PART OF THE NATURE OF
THESE MATERIALS BUT WHAT WAS
FOUND WAS REALLY QUITE ALARMING
BECAUSE OF THE 70 PRODUCTS
IDENTIFIED AND ANALYZEDs, 14
BOUGHT OFF THE SHELF AVAILABLE
TO THE GENERAL SHELF HAD AT
LEAST ONE HEAVY METAL IN EXCESS,
THE RANGE WAS BROAD.
AND QUITE VARIABLE.
WHAT WAS SO -- ANOTHER FORM OF
CONTAMINATION IS IF THE PLANT
THAT'S USED IS MISIDENTIFIED,
THIS IS AN EXAMPLE OF A TOXIC
SUBSTITUTION, LOOKING FOR THIS
PLANT, PLANTAIN, BROAD LEAVES,
THIS IS THE INFLUORESCENCE,
IDENTIFYING IN THE WILD SHOULD
BE A STRAIGHT FORWARD EVENT.
BUT IF YOU JUST HAVE THE FLOWER,
A MISTAKE WAS MADE.
A RELATIVE OF FOXGLOVE WHERE THE
LEAF LOOKED LIKE THE PLANTAIN
WAS COLLECTED DURING A TIME WHEN
NO FLOWERS INFLUORESCENCE WAS
PRESENT, THE MISTAKE WAS MADE.
THIS IS AN EXAMPLE OF
UNINTENTIONAL ADULTERATION WITH
SIGNIFICANT CONSEQUENCES.
THIS IS A DIFFERENT EXAMPLE,
BLACK COHOSH, STARTING FROM THE
POINT OF VIEW OF KNOWN PROBLEM,
ADVERSE EVENTS, A CLUSTER FOUND
OF ADVERSE EVENTS SUBMITTED TO
THE NATURAL HEALTH PRODUCT
DIRECTORY OF CANADA.
WE WERE ASKED TO LOOK AT THIS
SERIES.
THE FIRST THING THAT THOSE OF US
WHO HAVE HAD EXPERIENCE FIRST
THING WE DID WAS FIND A BOTTLE
OF THE STUFF THAT ALLEGEDLY
CAUSED THE PROBLEM AND FIND OUT
WHAT'S IN THE BOTTLE.
AGAIN, THAT'S THE GUIDANCE OF
DR. FARNSWORTH, MAKE SURE WHAT'S
IN THE BOTTLE IS WHAT YOU THINK
YOU'VE GOT.
TURNED OUT THAT WASN'T THE CASE.
THESE PRODUCTS WERE ADULTERATED
WITH A DIFFERENT SPECIES, A
SEDATIVE FROM CANADA, WITH
DIFFERENT CONSTITUENT BASE,
DIFFERENT PHYTOCHEMICAL BASE
THAN THE NORTH AMERICAN BLACK
COHOSH, AND BECAUSE NORTH
AMERICAN BLACK COHOSH CAN BE
QUITE EXPENSIVE THIS WAS AN
ECONOMIC ADULTERATION, ONCE
ASSUMES IT WAS INTENTIONAL.
NOW A LOT OF ATTENTION PUT ON
ADVERSE EVENTS,
ATTENTION-GETTING THINGS,
TAINTED PRODUCTS SOLD, A
PITCHER DIED AFTER INGESTING
EFED RIN COMPOUND.
THEY ROUSE UP A LOT OF PUBLIC
FEELING SO THE ISSUE IS HOW TO
WEIGHT SAFETY ISSUES
APPROPRIATELY.
SO, HERE IS HOW ADVERSE EVENTS
CAN HAPPEN.
THERE'S A LOT OF THINGS I'VE
ALREADY TOLD YOU, ADULTERATION,
INHERENT TOXICITY.
PHARMACOLOGIC EFFECTS OF AN
INDIVIDUAL PRODUCT, FOR EXAMPLE,
IF IT'S SOMETHING THAT LOWERS
BLOOD SUGAR IN A SENSITIVE
INDIVIDUAL, YOU COULD HAVE A
SIGNIFICANT LOWERING OF BLOOD
PRESSURE, ISSUE OF INTERACTIONS
IS POSSIBLE, I THINK
OVEREXAGGERATED, AND BILL GURLEY
WILL GIVE YOU A DISCUSSION OF
THAT TODAY.
ABUSE AND MISUSE, YOU HAVE
PEOPLE USING THESE THINGS, DON'T
ALWAYS MAKE SENSIBLE CHOICES.
AND THEN AS ALWAYS THERE ARE
THINGS WE CALL IDIOSYNCRATIC
REACTIONS, SOME MAY BE EXPLAINED
BY THE ISSUE OF THE INDIVIDUAL
GENOMICS WE'RE BEGINNING TO GET
A HANDLE ON.
ADVERSE EVENTS ARE HARD TO FIND
REPORTS OF.
AND THERE ARE TWO SYSTEMS.
THERE'S GOVERNMENTAL SYSTEM BUT
WE ALSO AS A SCHOLAR LOOK BACK
AT PubMed.
THERE'S OFTEN MORE TIME TO
ANALYZE THESE EVENTS, REPORT
THEM MORE COMPLETELY, SO WE WANT
TO SEE CAN WE FIND THESE EVENTS
IN PubMed.
MeSH TERMS, A WAY THAT DATA IS
FOUND IN PubMed, AND OTHER
ACADEMIC TYPES OF SEARCHING
SYSTEMS, THEY ARE VERY --
SENSITIVITY IS VERY POOR.
IF YOU SAY ADVERSE, YOU DON'T
GET MUCH.
ADVERSE EFFECTS, 86% BUT DON'T
ALWAYS GET WHAT YOU'RE LOOKING
FOR.
THAT CONTAINS A LOT OF THINGS
THAT AREN'T EXACTLY THE ISSUE
THAT YOU'RE LOOKING FOR.
COMPLICATIONS GIVES YOU A CHUNK,
POISONING GIVES YOU A CHUNK.
IF YOU ADD FOUR TERMS TOGETHER
YOU OFTEN GET EVERYTHING WHICH
YOU THEN HAVE TO SORT THROUGH TO
FIND THE RELEVANT DATA FOR WHAT
YOU'RE INTERESTED IN.
OKAY.
SO, NOW, FIRST OF ALL WE SHOULD
BE CLEAR, MINOR EVENTS HAPPEN A
LOT, SELF-LIMITING, OFTEN DON'T
STOP USE OF A PRODUCT, DRUG OR
SUPPLEMENT ESPECIALLY IF THE
PERSON IS COMMITTED TO USE.
ADVERSE EVENTS RESULT IN SERIOUS
OUTCOME THAT OFTEN REQUIRES
MEDICAL ATTENTION, IF IT'S
ULTIMATE, IT'S DEATH.
CAN REQUIRE A VISIT TO THE
EMERGENCY ROOM, MAY OR MAY NOT
IN RESULT IN HOSPITALIZATION.
BIRTH DEFECTS ARE DIFFICULT TO
PROVE.
BUT IT'S BASICALLY AN IMPORTANT
MEDICAL EVENT THAT REQUIRES
MEDICAL OR SURGICAL INTERVENTION
TO PREVENT A SERIOUS OUTCOME IF
ONE HASN'T ALREADY OCCURRED.
FOR THE PURPOSE OF REPORTING
EVENTS, THE PATIENT ALSO GETS TO
DECIDE FOR THEMSELVES WHAT'S A
SERIOUS OUTCOME, MAY BE
DIFFERENT THAN OUR SERIOUS
MEDICAL INTERVENTION.
IN FACT I'LL TELL YOU ABOUT THAT
WHEN HE LOOK AT ADVERSE EVENT
DATA BIT LATER ON.
THERE'S A LOT OF UNCERTAINTY AND
VARIABILITY IN THIS REPORTED
INFORMATION, MISSING INFORMATION
IS VERY, VERY COMMON.
WE OFTEN DON'T KNOW THE PRODUCT,
WHICH IS BAD, BECAUSE ONLY 50%
OF DIETARY SUPPLEMENTS SOLD IN
THE UNITED STATES ARE SOLD AS
SINGLE AGENT PRODUCTS.
MANY OF THEM ARE MULTIPLE
FORMULAS, AND THEREFORE YOU
CAN'T ATTRIBUTE RISK SOLELY TO
ONE ENTITY IF IT'S IN A
MULTIPLE-ENTITY PRODUCT.
AGAIN, WE HAVE ALL THIS
VARIABILITY WITH PATIENTS AND
POPULATIONS AND CONDITIONS OF
USE, WHICH WITHOUT ADEQUATE
REPORTING MAKE IT VERY DIFFICULT
FOR US TO PUT ADVERSE EVENT IN
CONTEXT.
HAPPILY, AS DR. SESSO TOLD US, A
WELL-DESIGNED CLINICAL TRIAL
WHICH ELIMINATES A LOT OF
VARIABILITY AND SOURCES OF
EFFECT THAT WE DO OR DON'T KNOW
ABOUT AS HE SAID CAN BE GOOD
PLACES TO SELECT ADVERSE EVENT
DATA.
A LOT OF STUDIES DO REPORT SIDE
EFFECTS OR ADVERSE EFFECTS IN
THE PROCESS OF DESIGNING AND
REPORTING A TRIAL, BUT, AGAIN,
CAUSALITY CAN STILL BE AN ISSUE,
AND IN AS YOU ASK THE QUESTION
AFFECTS WHAT YOU GET.
SO IF YOU JUST SAY ANY PROBLEMS,
AND THAT MAY BE TOO CASUAL, IF
YOU SPECIFICALLY ASK FOR ISSUES
YOU'RE INTERESTED IN, YOU MAY
GET OVERREPORTING OF THOSE
ISSUES, AND LESS REPORTING OF
ISSUES THAT YOU DON'T
PARTICULARLY KNOW ABOUT, ET
CETERA.
AND THE ISSUE ALWAYS NEEDS TO BE
MAKE SURE YOU KNOW WHAT YOUR
MATERIAL IS, EITHER THE
OFFENDING MATERIAL OR MATERIAL
YOU'RE STUDDING IN A CLINICAL
TRIAL.
THIS IS A BIT TRICKY, IT'S NOT
THE SAME AS INTAKE LIMIT
ANALYSIS IN TOXICOLOGY.
IT'S NOT THE SAME THING AS
TOXICOLOGY ASSESSMENT.
YOU CAN GET A WELL ROUNDED
PICTURE OF WHAT THIS IS.
IT'S INFORMED BY PHARMACOLOGY.
WHAT KIND OF TIME FRAME WOULD BE
APPROPRIATE TO SEE AN ADVERSE
EVENT, WOULD BE BASED ON
PHARMACOLOGY OF THE MATERIAL
THAT'S BEING TAKEN.
IF ADVERSE EVENT IS TOO QUICKLY,
OR SEPARATED IN TIME, THE EVENT
HAS LESS OF A LIKELIHOOD OF
BEING A CLEAR DEMONSTRATION OF
TOXICITY.
TOXICOLOGY ALSO EXPOSURE, ET
CETERA.
THE THINGS THAT MAKE THIS
ANALYSIS IMPORTANT IS IF YOU CAN
TIE THEM BACK TO CAUSALITY, AND
THAT'S TRICKY.
SO RANDOMIZED CONTROLLED TRIALS
YOU CAN ATTRIBUTE CAUSALITY,
SUCCESSFULLY RANDOMIZED TRIAL
ANYTHING THAT HAPPENS IN THE
GROUP THAT GOT THE MATERIAL
VERSUS PLACEBO GROUP OR CONTROL
GROUP THAT DIDN'T GET THE
MATERIAL AS A BROAD STATEMENT IF
YOU'VE DONE YOUR RANDOMIZATION
PROPERLY AND HAVE SHOWN A
DIFFERENCE IN OUTCOME THAT
OUTCOME COULD BE CALLED -- COULD
BE ATTRIBUTED TO MATERIAL TAKEN.
THE COHORT DEPENDING HOW
STRUCTURED MIGHT BE ABLE TO
ATTRIBUTE CAUSALITY.
CASE SERIES OR LARGE NUMBERS,
UNABLE TO ATTRIBUTE CAUSALITY
UNLESS THE PATIENT IS
RECHALLENGED.
NOW, THIS IS A TRICKY PIECE OF
BUSINESS BECAUSE LET'S SAY YOU
TOOK SOMETHING AND HAVE SERIOUS
MEDICAL ADVERSE EVENT, CERTAINLY
IF YOU DIED THAT ABILITY TO
RECHALLENGE THAT IS NOT
POSSIBLE.
AND SO DECHALLENGING, TAKE THE
MATERIAL AWAY, ADVERSE EVENT
GOES AWAY.
WELL, IF IT'S A HARD ENDPOINT
ADVERSE EVENT LIKE STROKE, THE
STROKE ISN'T GOING AWAY BUT YOU
MIGHT SEE RESOLUTION OF SYMPTOMS
FOR ANXIETY, BLOOD PRESSURE,
TACHYCARDIA, ET CETERA, YOU CAN
SEE ADVERSE EVENT GO AWAY, TAKE
THE MEDICATION AWAY.
TAKE THE CAUSATIVE AGENT AWAY,
AND RETURN IF YOU'RE
RECHALLENGES.
I'VE SEEN THAT IN AN INTEGRATIVE
ONCOLOGY CASE, WHERE A PATIENT
WAS GIVEN A BIOLOGICAL RESPONSE
MODIFIER DRUG ON THEIR CANCER,
WERE HAVING A CERTAIN EFFECT,
STARTED DRINKING GREEN TEA,
EFFECT REDUCED ON TUMOR, STOPPED
THE GREEN TEA, TUMOR RESPONSE
CAME BACK TO NORMAL, READDED
GREEN TEE AND REPLICATED SAME
RESPONSE, THAT'S SUCCESSFUL
DECHALLENGE/RECHALLENGE BUT MOST
PEOPLE WON'T RISK SERIOUS
ADVERSE EVENT.
AND THERE ARE LOTS OF OTHER
KINDS OF STUDIES BUT NONE ON THE
FACE AS A SINGLE ENTITY, A PIECE
OF DATA WOULD BE ABLE TO
ATTRIBUTE CAUSALITY.
NOW, CLINICAL STUDIES HAVE THE
STRONGEST ABILITY TO GIVE US A
SENSE OF ADVERSE EVENT, ALSO
HAVE LIMITATIONS.
THEY ARE USUALLY NOT LARGE
ENOUGH TO SHOW US RARE EVENTS.
SO, LOOK AT THIS.
IF AN EVENT HAPPENS ONE TIME IN
A THOUSAND THE RULE OF THUMB IS
YOU NEED TO ENROLL THREE TIMES
OF THE NUMBER OF PREVALENCE OF
EVENT TO BE ABLE TO CLEARLY SAY
THAT YOU SHOULD SEE IT OR NOT
SEE IT.
SO IF SOMETHING HAPPENS ONCE IN
A THOUSAND, WHICH ON PUBLIC
HEALTH LEVELS IS NOT ALL THAT
UNUSUAL, YOU NEED A TRIAL WITH
THREE THOUSAND SUBJECTS AT
MINIMUM.
WE DON'T USUALLY SEE THAT IN
RANDOMIZED CONTROLLED TRIAL,
CERTAIN CERTAINLY NOT FOR WHAT
YEAR LOOKING AT.
ALSO IT TAKES A LONG TIME TO
SHOW ADVERSE EVENT.
IT'S A SELECTIVE POPULATION.
YOU DON'T GET ALL COMERS.
PEOPLE WHO MIGHT HAVE ISSUES
THAT WOULD MAKE THEM MORE LIKELY
TO HAVE AN ADVERSE EVENT MIGHT
NOT SHOW UP.
OBJECTS SERVERS AND SUBJECTS
OFTEN UNDERREPORT.
METHOD OF ASKING THE QUESTION AS
WE SAID EARLIER COULD BIAS
REPORTING, AND VERY FEW TRIALS
ARE RUN IN SAFETY STUDIES BUT
ONES THAT WILL CAN BE INCREDIBLY
USEFUL.
OKAY.
NOW, WE TALKED ABOUT THESE
ADVERSE EVENT LIMITATIONS
BEFORE.
JUST THEY ARE THERE AGAIN SO YOU
CAN SEE THEM.
AND JUST AS AN ADDITIONAL PIECE
OF REMINDER THIS MAY BE THE ONLY
WAY POST MARKET REPORTING MAY BE
THE ONLY WAY TO ACTUALLY FIND
UNEXPECTED RARE BUT SERIOUS
ADVERSE EVENTS, WE'VE SEEN THAT
WITH DRUGS AS WELL AS
POTENTIALLY DIETARY SUPPLEMENTS.
ONE ISSUE THAT'S PARTICULARLY
STICKY WHEN TRYING TO ATTRIBUTE
CAUSALITY TO ADVERSE EVENT OR
CLUSTER OF ADVERSE EVENTS IS
ELIMINATION OF OTHER CAUSAL
FACTORS.
THE MORE THAT YOU CAN ELIMINATE
OTHER CAUSAL FACTORS AND HAVE
CONCORDANCE IN OTHER REPORTED
THINGS LIKE THE RIGHT
PHARMACOLOGY, EXPOSURE IS
CORRECT, YOU KNOW THE PERSON
BOUGHT AND HAD THE MATERIAL
YOU'RE INTERESTED IN THEIR HAND,
YOU SAW THE BOTTLE, ET CETERA.
THIS IS MUCH TRICKIER BECAUSE
THIS IS LARGELY A CLINICAL
DECISION.
YOU TRY TO TAKE AWAY ANY
CONDITIONS THAT MIGHT HAVE
CORRECTED TO THE OUTCOME YOU'RE
LOOKING AT.
IF YOU'RE LOOKING AT A
CARDIOVASCULAR EVENT YOU WANT TO
RULE OUT HYPERTENSION, HIGH
CHOLESTEROL, REALLY ADVERSE
FAMILY HISTORY, SHORT T2
INTERVAL.
MOST CLINICAL TRIALS ARE NOT --
MOST ADVERSE EVENTS REPORTS,
EXCUSE ME, ARE NOT INVESTIGATED
ENOUGH, NOT EXPLICIT OR COMPLETE
ENOUGH TO MAKE THIS ASSESSMENT,
AND I CAN SAY THIS WITH SOME
DEGREE OF AUTHORITY BECAUSE I
READ ALL THE ADVERSE EVENT
REPORTS, WHEN WE DID OUR -- WE
DID THE ADVERSE EVENT ANALYSIS
FOR EPHEDRA.
WITH FDA INVESTIGATING IN
DEMENTIA A -- DEPTH, THERE WAS
NOT ENOUGH DATA TO MAKE A
CLEAR-CUT ASSESSMENT.
HERE IS A LOOK AT SAFETY STUDIES
SO YOU CAN SEE THEY EXIST.
THIS IS EPHEDRA CASE ANALYSIS
FROM WHAT I WAS SPEAKING ABOUT.
WE TOOK RANDOMIZED CONTROLLED
STYLES USING EPHEDRA,
EPHEDRA-CONTAINING PRODUCTS, DID
EPHEDRA AND EPHEDRINE, TWO
REVIEWERS, CHECKING FOR
ANALYSIS, PUT THEM IN CATEGORIES
WHERE THEY WERE THOUGHT TO BE
SENTINEL EVENTS THAT WE COULDN'T
OTHERWISE EXPLAIN, POSSIBLE
SENTINEL EVENTS WITH OTHER
CAUSAL FACTORS BUT THERE WAS A
CLUSTER OF THESE CASE, SEPARATED
BY AGE, SEPARATED BY THE CAUSE.
I WILL SAY IN OUR DEATH ANALYSIS
WE WERE INCREDIBLY STRICT, THERE
HAD TO HAVE BEEN AN AUTOPSY
AFTER THE EVENT FOR US TO EVEN
CONSIDER THIS AS A SENTINEL
EVENT, FOR EXAMPLE.
AND YOU CAN SEE HERE THAT IF WE
GO DOWN IN THE YOUNG AGE GROUP,
WE ACTUALLY HAVE EVENTS THAT
WERE OCCURRING IN VERY YOUNG
PATIENTS WITHOUT OTHER POSSIBLE
SENTINEL EVENTS.
THAT WAS VERY COMMON.
THE POSSIBLE SENTINEL EVENTS
OCCURRED WHEN THE PATIENTS
CHANGED THEIR EXTERNAL
ENVIRONMENT TO MAKE IT MORE
LIKELY TO HAVE CAUSED THE
OUTCOME.
HEAT STROKE, CARDIOVASCULAR
COLLAPSE, DEATH.
SO, THIS REQUIRED A GREAT DEAL
OF EFFORTS TO FIND THE DATA AND
ANNUAL IT.
NOW, LOOKING AT THE CLINICAL
TRIALS WE HAD A DIFFERENT KIND
OF ADVERSE EVENT DATA TO LOOK
AT.
THIS IS DATA THAT WE FOUND IN
LOOKING AT CLINICAL TRIALS,
TOLERABILITY SECTION, ADVERSE
EVENT REPORTED, WE HAD A NUMBER
OF STUDIES THAT REPORTED THESE
EVENTS.
YOU CAN SEE THE ONES I'VE
HIGHLIGHTED IN PINK ODDS RATIO
GREATER THAN 1 TO SUGGEST
DIFFERENCE BETWEEN PLACEBO AND
INTERVENTION WAS STATISTICALLY
SIGNIFICANT AND COULD BE
ATTRIBUTED TO EFFECTS.
TAKING EPHEDRA, JITTERY AND
NERVOUS INSIDE LOOKED CAUSAL.
EPHEDRA WAS NOT OFTEN GIVEN AS
SINGLE ENTITY, IT WAS IN
COMBINATION WITH OTHER PRODUCTS
WHICH COULD HAVE AFFECTED
ADVERSE EFFECT PROFILE BUT
EPHEDRA WAS A CAUSAL AGENT IF
NOT THE CAUSAL AGENT.
I WANTED TO TALK ABOUT THIS, AN
OPEN LABEL STUDY FOR 12 MONTHS,
LOOKED AT POST MENOPAUSAL
SYMPTOMATIC WOMEN, TAKING A
WELL-CHARACTERIZED GERMAN BLACK
COHOSH EXTRACT, DOSE IS THERE.
AND THIS WAS TO LOOK TO SEE,
THERE'S A LOT OF CONFUSION IN
LITERATURE ABOUT WHETHER BLACK
COHOSH WAS A PHYTOESTROGEN, A
PATIENT POPULATION WITH BREAST
CANCER THAT WAS ESTROGEN
SENSITIVE, DESIGNED TO LOOK AND
SEE IF YOU COULD SEE ESTROGEN
EFFECT, WHETHER THAT WAS OR
WASN'T AN ADVERSE EVENT, LIKE
BLEEDING, FOR EXAMPLE, COULD YOU
SEE AN ESTROGEN EFFECT, IT WAS
LOOKED AT ENDOMETRIAL SAFETY.
A VERY DETAILED STUDY.
WOMEN WITHOUT ADVERSE PATHOLOGY
AGREED TO HAVE A BIOPSY IF THEY
ARE ENDOMETRIAL LINING
THICKENED, AND DENSE BREASTS ARE
AT HIGHER RISK FOR DEVELOPING
BREAST CANCER, LIVER FUNCTION
TEST, ET CETERA, LIPIDS, BONE,
ET CETERA.
I WON'T SHOW ALL THE DATA FROM
THIS TRIAL BECAUSE OF TIME BUT
ISOFORMS SHOW HIGHER EFFECT AT
BEGINNING, GREAT NUMBER OF
PATIENTS, THAT THE SAFETY,
DISTRIBUTION WAS HIGH EFFECT
HERE, LOW EFFECT HERE,
DISTRIBUTION DID FAVOR POST
MENOPAUSAL WOMEN WITH LOW
EFFECT, ONCE GIVEN MATERIAL
AFTER VISIT 7, MAJORITY SHOWED
LOWER EFFECT, AGAIN THE BIOPSY
AGAIN SHOWED THAT AS WELL.
THIS IS LOOKING AT THE SAFETY
DATA FOR REGULAR MONITORED
LABORATORY VALUES.
A SLIGHT INCREASE IN CHOLESTEROL
BUT PROBABLY NOT CLINICALLY
SIGNIFICANT.
THE ISSUE OF LIVER FUNCTION TEST
WAS HIGHLY RELEVANT BECAUSE
THERE HAD BEEN CASE REPORTS OF
ADVERSE REPORTS OF LIVER
DIFFICULTY CAN BLACK COHOSH.
I SHOWED THAT REPORTS, GIVEN TO
THE NATURAL HEALTH PRODUCT DRUG
OF CANADA, WHAT WOULD THIS LOOK
LIKE AT A YEAR, EVIDENCE OF
SIGNIFICANT DISTURBANCE IN LIVER
FUNCTION?
THERE WAS SLIGHT ELEVATIONS
TAKEN IN THIS GROUP.
A FAIRLY LARGE GROUP OF WOMEN SO
THINGS COULD BE STATISTICALLY
SIGNIFICANT WITHOUT BEING
CLINICALLY SIGNIFICANT.
INCREASES WERE SMALL AND I WENT
BACK AND ASKED THE STUDY AUTHORS
TO GIVE ME THEIR FULL DATA AND
LOOKED AT EACH INDIVIDUAL
PATIENT DATA, NONE OF THESE
ELEVATIONS WERE SUSTAINED.
SO THIS DID NOT SHOW EVIDENCE
EVIDENCE OF SUSTAINED LIVER
FUNCTION STAGE.
MANDATORY REPORTING STARTED IN
DECEMBER 2007 FOR HERBAL AND
OVER THE COUNTER PRODUCTS,
ANYTHING REPORTED BY PATIENTS
DEEMED A SERIOUS ADVERSE EVENT
HAS TO BE REPORTED.
MANY PEOPLE JUST REPORTED
EVERYTHING, SO AS NOT TO BE
CAUGHT IN THE ISSUE WHETHER IT
IS OR ISN'T A SIGNIFICANT EVENT.
NOW, I DID ANALYSIS WITH THE
AMERICAN HERBAL PRODUCTS
ASSOCIATION, MERLE ZIMMERMAN
WILL PRESENT TOMORROW, MY
PARTNER IN DOING THIS DATA
ANALYSIS.
MANDATORY REPORTERS WERE
REPORTED, MUCH SMALLER, LIMITS .
BUT ONE THING, WE DID FIND ONE
DETECTED, THAT ALSO DETECTED BY
THE FDA, ACTED ON WHEN A BODY
BUILDING SUPPLEMENT WAS TAKEN
OFF THE MARKET.
SO, THE PILLS WERE TOO LARGE,
THAT GAVE AN INTERESTING VIEW ON
THE DIFFERENCE BETWEEN WHAT WE
AND THE PATIENT CONSIDER
ADVERSE.
THERE WAS A SIGNAL, SENTINEL
EVENT, NO OTHER APPARENT CAUSE,
LIKELY CAUSE, CLUSTER OF
SENTINEL EVENTS IS A SIGNAL.
RISK ASSESSMENT NEEDS TO BE
DONE, USUALLY BY A FEDERAL
AGENCY OR PUBLIC HEALTH AGENCY,
TO DECIDE WHETHER THIS MATERIAL
IS RISKY ENOUGH THAT IT SHOULD
BE TAKEN -- ACCESS BY THE PUBLIC
TO THIS MATERIAL SHOULD BE
LIMITED.
AND AGAIN ANALYSIS WITH
POTENTIAL SIGNALS IS LIKELY, IS
THERE EVIDENCE FOR MECHANISM,
ANALYSIS OF PROPER MATERIAL, IS
THE CLUSTER LARGE ENOUGH AND
DIFFERENT ENOUGH FROM BACKGROUND
REPORTING TO ADD A DEGREE OF
SURGERY TO TAKING ACTION ON
THAT.
SO THANK YOU VERY MUCH.
I WILL STOP MY SHARING AND
ANSWER QUESTIONS.
>> THANK YOU, DR. HARDY.
THERE'S ALREADY ONE QUESTION IN
THE CHAT.
FROM GEORGE CARTER, DIFFERENCE
BETWEEN (INDISCERNIBLE) GROWING
CONDITIONS.
>> REPEAT THAT AGAIN.
>> IT SAYS, I DON'T KNOW IF I'M
PRONOUNCING IT CORRECTLY,
DIFFERENCE BETWEEN
(INDISCERNIBLE) VERSUS HIGH
CHROMIUM OR LIGHT FROM GROWING
CONDITIONS.
>> SO, I DON'T QUITE UNDERSTAND
THE QUESTION BUT I CAN COMMENT
ABOUT THE ISSUE OF GROWING
CONDITIONS.
YOU DO THEN -- PLANTS CAN HAVE
DIFFERENT VARIANTS, DIFFERENT --
CAN BE GENETICALLY DIFFERENT, IN
THE SAME CLONE, AND THEREFORE
THE RESULTS WOULD BE EXPECTED TO
BE SIMILAR BASED ON SIMILAR
ENVIRONMENT AFFECTING SIMILAR
SETS .
ALL THE PRODUCTS ARE SECONDARY
METABOLITES OF THE PLANT'S
METABOLISM WHICH IT MAKES FOR
ITS OWN USE.
IF I UNDERSTOOD THE QUESTION
THAT MIGHT GET CLOSE TO IT, IF
NOT, GEORGE COULD ASK IT AGAIN.
>> GEORGE HAS ELABORATED.
PREPARATION OF HEAVY METALS.
>> OH YES.
ABSOLUTELY.
AND THIS WE SEE NOT JUST IN
MEDICINAL PLANTS BUT IN FOOD
PLANTS, WE COULD ASK DR. SESSO.
THE WATER THAT YOU GROW RICE IN
AFFECTS HOW MUCH ARSENIC IS IN
RICE.
THAT'S A COMMON CONTAMINANT TO
FIND IN RICE.
IT'S NEVER A MATTER OF NO EXPOSE
WHY YOU BUT MINIMAL EXPOSURE.
I WAS ASSOCIATE DIRECTOR OF
BOTANICAL RESEARCH GROUP AT
UCLA, SOURCING PLANT MATERIALS
IN CHINA, THE FIRST THING WE DID
TO VALIDATE OUR MATERIALS WAS TO
DO A HEAVY METAL SCREEN.
IF THE FIELD THAT WE GOT OUR
PLANTS FROM SHOWED EVIDENCE OF
HEAVY METAL WE WENT TO A
DIFFERENT COLLECTING SITE
BECAUSE THAT INVALIDATED THE
MATERIAL.
YOU MIGHT HAVE TOXICITY YOU'RE
ATTRIBUTING TO THE PLANT WHEN IT
MIGHT BE A RESULT OF HEAVY MET
METALS, AND EXTRACTION
TECHNIQUES COULD ENHANCE OR
INCREASE.
POLLUTION IS A PROBLEM, CERTAIN
GROWING GROUNDS NOW BECOME
INTOLERABLE BECAUSE OF CLIMATE
CHANGE OR INHOSPITABLE BUT
POLLUTION PUTS TOXINS INTO THE
WATER AND SOIL WHICH IS
SEQUESTERED IN PLANTS, OR LIKE
IN THE CASE OF CALCIUM SOURCES
IF THE CALCIUM SOURCE OYSTER
SHELL GROWS IN POLLUTED WATER
SEQUESTERS HEAVY METAL CAN BE
PASSED ALONG THE CHAIN OF
DEVELOPMENT IN A PRODUCT FOR
HUMANS TO TAKE.
>> AND A NOD TO TRADITIONAL
MEDICINE PREPARATION,
TRADITIONAL PREPARATION, HE'S
STATING IF PREPARED CORRECTLY
ACCORDING TO SOME DATA FROM
COLLEAGUE IT DOES NOT INDUCE
TOXICITY.
>> I'VE HEARD THAT BEFORE WITH
SHANGMI, CHINESE PLANTS IN
PARTICULAR, I ALLUDED TO THAT
WITH AYUREDIC PREPARATION, IN
PREPARATION AS DESCRIBED THEY
ASSERT THAT MEANS HEAVY METALS
ARE NOT AVAILABLE TO BE
METABOLICALLY ACTIVE, THEREFORE
AREN'T TOXIC.
BUT THERE'S A LOT OF SLIP
BETWEEN CUP AND LIP, AS WE SAY.
I THINK HE'S RIGHT.
SOMETIMES TRADITIONAL MEDICINE
PREPARATIONS BECAUSE THEY ARE SO
FAMILIAR WITH THE PLANT AND
AGAIN I GO BACK TO CHAPPARAL
ISSUE, I HAD A NATIVE AMERICAN
CHIEFTAIN GIVE THIS MATERIAL TO
A WHOM BEING TREATED BUT GAVE --
WOMAN BEING TREATED IN CUP FORM,
WE AGREED ON LIMITATION OF
AMOUNT AND HOW WEAK THE TEA
WOULD BE, WERE ABLE TO REDUCE
RISK BUT STILL ALLOW HER TO
PARTICIPATE WITH TRADITIONAL
MEDICINE TRADITIONS.
EVERY BIT OF INFORMATION IS
GOOD, YOU HAVE TO PUT IT IN
CONTEXT.
>> THANK YOU, WE'RE BACK ON
SCHEDULE.
>> MY APOLOGIES FOR WHATEVER
HAPPENED.
THANK YOU FOR YOUR FLEXIBILITY
AND KUDOS TO DR. SESSO.
>> THANK YOU.
WE'RE READY FOR DR. BILL
GURLEY'S PRESENTATION.
PRINCIPAL SCIENTIST, DIRECTOR OF
CLINICAL RESEARCH FACILITY
NATIONAL CENTER FOR NATURAL
PRODUCTS RESEARCH, MISSISSIPPI
SCHOOL OF PHARMACY, MEMBER OF
THE AMERICAN ASSOCIATION OF
PHARMACEUTICAL SCIENTISTS,
AMERICAN SOCIETY OF CLINICAL
PHARMACOLOGY AND THERAPEUTICS,
USP EXPERT PANEL ON DIETARY
SUPPLEMENTS.
RESEARCH INTERESTS INCLUDE
MECHANISM ALSO OF HERB-DRUG
INTERACTION, PHYTOCHEMICAL
MODULATION OF HUMAN DRUG
METABOLIZING ENZYMES AND DRUG
TRANSPORT PROTEINS,
PHARMACOKINETICS, USE IN SPECIAL
POPULATIONS, PRESENTATION FOR
TODAY IS "INTERACTIONS BETWEEN
SUPPLEMENTS AND DRUGS."
TAKE IT AWAY, DR. GURLEY.
>> THANK YOU, LAVERNE.
IT'S A PLEASURE TO SPEAK AT THE
OFFICE OF DIETARY SUPPLEMENTS
RESEARCH PRACTICUM AGAIN.
I'VE BEEN DOING THIS FOR QUITE
SOME TIME.
I'M GOING TO CUT TO THE CHASE.
LET ME SHARE THINGS WITH YOU AND
MAKE SURE THINGS ARE SQUARED
AWAY.
CAN YOU SEE MY SLIDES OKAY?
>> LOOKS GREAT.
>> VERY GOOD.
I WANTED TO -- WE'RE SLAVES TO
TECHNOLOGY, I WANTED TO MAKE
SURE.
SO I'M GOING TO CUT STRAIGHT TO
THE CHASE AND LET EVERYBODY KNOW
I THINK WHAT WE ALREADY KNOW,
PLANTS HAVE BEEN A SOURCE OF
DRUGS SINCE TIME IMMEMORIAL BUT
THE ISSUE OF HERB-DRUG
INTERACTION CAME TO THE
FOREFRONT AFTER THE SECOND WORLD
WAR WHEN MOVING TO PURIFIED
SYNTHETIC COMPOUNDS.
IT'S OBVIOUS PHYTOCHEMICALS HAVE
BEEN RECOGNIZED FOR ABILITY TO
MODULATE THE ACTIVITY OF
CONVENTIONAL DRUGS FOR MANY
DECADES.
INTERACTION IS DESCRIBED AS
ABILITY OF PHYTOCHEMICALS
PRESENT IN CRUCIFEROUS
VEGETABLES, TO MODULATE ENZYMES
AND AFFECT PHARMACOKINETICS,
THAT WAS IT FOR A LONG TIME.
THEN CONCERN FOR HERB-DRUG
INTERACTION WAS MINIMAL UNTIL
1991, THAT YEAR GREAT FRUIT
JUICE WAS FOUND TO INCREASE ORAL
ABSORPTION OF DRUGS AND THE ACT
WAS PASSED AND PLETHORA OF
UNIQUE PHYTOCHEMICALS BECAME
AVAILABLE FOR CONSUMPTION IN THE
UNITED STATES IN THE FORM OF
BOTANICAL DIETARY SUPPLEMENTS.
NOW, SEVERAL FACTORS CAN
CONTRIBUTE TO HERB-DRUG
INTERACTIONS, THE MORE ONE IS
EXPOSED TO THE GREATER THE
INTERACTION RISK.
SUPPLEMENTS ARE COMPLEX MIXTURES
OF MULTIPLE PHYTOCHEMICALS.
MULTI-INGREDIENTS ARE
COMPLICATED.
THEY ARE ACTUALLY POWDERED PLANT
MATERIAL THAT'S EXTRACTED WITH
AQUEOUS OR NON-AQUEOUS SOLVENTS
AND TRIED TO CONCENTRATE
PHYTOCHEMICALS.
THE DRIED EXTRACTS INCREASE
PHYTOCHEMICAL EXPOSURE.
WE KNOW VERY LITTLE, LET ALONE
COMPLEX MIXTURES.
PANAX GINSENG IS GOOD EXAMPLE.
500 PHYTOCHEMICALS HAVE BEEN
IDENTIFIED.
YOU CAN GET A PICTURE OF JUST
HOW COMPLICATED THE SITUATION
CAN GET.
NOW, TO ILLUSTRATE COMPLEXITY
THERE'S A PARTIAL LISTING OF
SOME OF THE KNOWN PHYTO
CONSTITUENTS IN ST. JOHN'S WART
EXTRACT.
ON THE RIGHT FLAVANOIDS AND
ESSENTIAL OILS ARE FOUND IN MANY
PLANTS.
THOSE ON THE RIGHT ARE MORE
SPECIFIC TO ST. JOHN'S WORT.
I'VE GOT ONE HIGHLIGHTED IN RED,
HYPERFORIN, PLAYING AN IMPORTANT
ROLE IN INTERACTIONS, AS WE'LL
SEE LATER IN THE TALK.
SEVERAL SURVEYS HINT AT OTHER
FACTORS THAT CAN CONTRIBUTE TO
THE RISK OF HERB-DRUG
INTERACTION, FROM 30 TO 60% OF
HOSPITAL PATIENTS USE THE
BOTANICAL DIETARY SUPPLEMENTS ON
A REGULAR BASIS.
SURVEYS INDICATE BETWEEN 25 AND
30% OF PRESCRIPTION DRUG USER
INGEST SUPPLEMENTS WITH
PRESCRIPTION MEDICATIONS.
ONE STATISTIC THAT HELD STEADY,
LESS THAN 40% OF PATIENTS REVEAL
THE FACT THAT THEY INGEST
SUPPLEMENT TO HEALTH CARE
PROVIDER.
SO EVEN IF PATIENTS DID REVEAL
THEIR SUPPLEMENT USAGE TO HEALTH
CARE PROVIDERS, SADLY NURSES AND
PHARMACIESES AND PHYSICIANS KNOW
VERY LITTLE ABOUT SUPPLEMENTS TO
BEGIN WITH.
HOW DO YOU INITIALLY RECOGNIZE
POTENTIAL HERB-DRUG INTERACTION?
OFTENTIMES CASE REPORTS
APPEARING IN THE PEER REVIEWED
MEDICAL LITERATURE ARE GOOD
INDICATORS ESPECIALLY IF THERE'S
SEVERAL CASE REPORTS THAT
DESCRIBE THE SAME TYPE OF
INTERACTION.
THAT CASE REPORT CANNOT
ESTABLISH CAUSATION BUT THEY CAN
HELP GENERATE HYPOTHESES FOR
POSSIBLE MECHANISMS OF ACTION.
NOW, ADVERSE EVENT REPORTS ARE
QUITE HELPFUL ESPECIALLY THOSE
REPORTED THROUGH THE FDA
MEDWATCH PROGRAM, AS WELL AS
CENTER FOR FOOD SAFETY AND
APPLIED NUTRITION'S ADVERSE
EVENT REPORTING DATABASE AS WELL
AS REPORTS THAT ARE SUBMITTED TO
STATE AND REGIONAL POISON
CONTROL CENTERS.
SCIENTIFIC LITERATURE IS ALSO
AWASH IN IN VITRO STUDIES AIMED
AT PREDICTING HERB OF HERB-DRUG
INTERACTIONS, AND THE REASON
THESE ARE USED IS BECAUSE THEY
ARE COST EFFECTIVE.
MANY IN VITRO STUDIES EXPOSE THE
WHOLE MECHANISM IS THAT THESE
STUDIES EXPOSE PURIFIED DRUG
METABOLIZING ENZYMES OR CELL
LINES, OR EVEN HUMAN LIVER CELLS
THAT EXPOSE CONCENTRATED
SOLUTIONS, IF HIGH ENOUGH YOU'LL
OBSERVE EFFECT.
OFTENTIMES THEY RARELY TRANSLATE
TO THE IN VIVO CONDITION.
SO THE GOLD STAND ARD IS
PROSPECTIVE CLINICAL STUDIES IN
HUMAN BEINGS.
RATE LIMITING ASPECTS HOWEVER IS
EXPENSE AND THEY CAN BE QUITE
EXPENSIVE.
OUR GROUP HAS BEEN CONDUCTING
SUCH STUDIES FOR 25 YEARS, SO
I'M GOING TO SHARE A FEW
EXAMPLES FROM OUR EXPERIENCE IN
THIS PARTICULAR PRESENTATION TO
ILLUSTRATE EXACTLY WHAT IT IS
WE'RE TALKING ABOUT TIMES OF
HERB-DRUG INTERACTIONS.
THERE ARE TWO CATEGORIES, FIRST
IS PHARMACODYNAMIC.
THE PHARMACODYNAMIC INTERACTION
ARISES WHEN THE BOTANICAL HAS
PHARMACOLOGICAL PROPERTIES,
EITHER SIMILAR TO OR HAS
PHARMACOLOGICAL PRODUCTS THE
OPPOSITE OF CONVENTIONAL
MEDICATION.
BOTANICAL MIGHT COMPOUND OR
EXACERBATE THE ACTIVITY OF
CONVENTIONAL OR MIGHT COUNTERACT
THE EFFECTS OF THAT MEDICATION.
FOR THE SAKE OF TIME I'LL
ILLUSTRATE THE EPHEDRA-FREE
SUPPLEMENTS.
I'LL TOUCH TO THOSE AGAIN.
THE EPHEDRA-FREE ARE A NICE
EXAMPLE OF PHARMACODYNAMIC
HERB-DRUG INTERACTION.
MANY OF YOU MAY REMEMBER THE
SUPPLEMENTS THAT CAUSED QUITE A
STIR FROM 1994 UNTIL REMOVAL
FROM THE MARKET IN 2004.
THIS WAS A PERIOD I CALL EPHEDRA
WARS, BECAUSE I WAS A TESTED
VETERAN IN THAT CONFLICT.
BASICALLY THE SUPPLEMENTS WERE
MULTI-INGREDIENT FORMULATIONS
CONTAINING NATURAL SOURCES OF
ALLOYS BUT ALSO CONTAINED OTHER
NATURAL STIMULANTS, PRIMARILY
CAFFEINE, A HOST OF OTHERS WE'LL
TALK ABOUT SHORTLY.
THREE OF THE MOST POPULAR
PRODUCTS ARE SHOWN HERE, BACK IN
THE DAY.
SO RIPPED FUEL, METABO LIFE AND
XENADRIN SWAYED THE MARKET,
MARKETED AS WEIGHT LOSS AIDS,
ENERGY BOOSTERS, EXERCISE
PERFORMANCE ENHANCERS.
PRIOR TO THESE PRODUCTS COMING
ON THE MARKET, IN THE LATE
1980s SYNTHETIC COMBINATIONS
OF THESE DRUGS HAVE COME ON THE
MARKET AND HAD SHOWN TO PRODUCE
SERIOUS ADVERSE HEALTH EFFECTS
LIKE HEART ATTACKS, STROKES,
SEIZURES, PSYCHOTIC EVENTS.
SO, NOT SURPRISINGLY, THESE
NATURAL ALTERNATIVES WERE ALSO
LINKED TO SOME OF THE SAME TYPES
OF ADVERSE EVENTS.
SALES, AS YOU SEE WITH THE
GRAPH, SALES PEAKED AROUND 2001,
EXCEEDED OVER A BILLION DOLLARS
IN SALES PER YEAR.
AND MUCH OF THOSE SALES WERE
ATTRIBUTED TO METABO-LIFE.
DEATHS OF SEVERAL COLLEGE AND
PROFESSIONAL ATHLETES AS WELL AS
MANY NON-ATHLETES WERE LINKED TO
THESE PRODUCTS.
AND ACCORDINGLY THERE WAS A
RESULTANT MEDIA FRENZY AND
LITIGATIONS AIMED AT THESE
PRODUCTS, INCLUDING THOSE BY THE
FDA CAUSED THE EPHEDRA SALES TO
PLUMMET AS YOU CAN SEE WITH THE
ORANGE CURVE IF YOU FOLLOW FROM
1998 UNTIL 2000, PEAKED AND
DROPPED PRECIPITOUSLY.
SO, THE COMPANIES, THEY SOLVED
THAT PROBLEM BY TAKING THE
EPHEDRA OUT OF THE FORMULATIONS.
AND QUICKLY EPHEDRA-FREE
PRODUCTS SURFACED THEIR
PROBLEMATIC PREDECESSORS.
NOW THE QUESTION IS, OR WAS, ARE
THESE PRODUCTS ANY SAFER?
SO TODAY NATURAL CAFFEINE
SOURCES ARE THE MOST FREQUENTLY
USED SUBSTITUTES FOR EPHEDRA.
THIS INCLUDES PLANT SOURCES FOR
CAFFEINE LIKE QUARINA, GREEN
TEA, COLA NUT, YERBA MATTE AND
SYNTHETIC CAFFEINE, CAN CONTAIN
3 TO 6 CUPS OR MORE, ARE THEY
ANY SAFER?
AND WHEN HIGH DOSE CAFFEINE
SOURCES ARE COMBINED WITH OTHER
NATURAL STIMULANTS, AND OTHER
NATURAL STIMULANTS, ARE THEY ANY
SAFER THAN THEIR
EPHEDRA-CONTAINING PREDECESSORS?
CASE REPORTS BEGAN APPEARING
DOCUMENTS ADVERSE EVENTS EERILY
SIMILAR TO THE
EPHEDRA-CONTAINING PRODUCTS.
AND SO CLEARLY, THIS DIDN'T BODE
WELL FOR THE EPHEDRA
SUPPLEMENTS, SAME TYPES OF STUFF
WE WERE SEEING WITH EPHEDRA WERE
BEING LINKED WITH EPHEDRA-FREE
SUPPLEMENTS.
SO, SINCE THAT WAS -- WE WERE
INTIMATELY INVOLVED IN EPHEDRA
WARS, WE DECIDED TO TAKE PART IN
THE EPHEDRA-FREE WARS.
IN 2012 CONDUCTED A SMALL
CLINICAL TRIAL LOOKING AT THREE
POPULAR EPHEDRA-FREE PRODUCTS AS
WELL AS COMMON INGREDIENT IN ALL
OF THEM, GUARANA, A NATURAL
SOURCE OF CAFFEINE.
SO YOU CAN SEE UNDER THE
PRODUCTS IN YELLOW, UNDER EACH
TRADE NAME IS LIST OF
INGREDIENTS IN THE PRODUCT.
YOU CAN SEE ALL MULTI-INGREDIENT
PRODUCTS WITH EXCEPTION OF
GUARANA, A MAIN STAY.
YOU'LL NOTICE THERE'S NUMBERS
HIGHLIGHTED IN RED.
FIRST NUMBER IS AMOUNT OF
CAFFEINE THAT WOULD HAVE BEEN IN
AN INDIVIDUAL DOSAGE FORM.
AND THEN NEXT NUMBER IS AMOUNT
OF CAFFEINE THAT AN INDIVIDUAL
WOULD HAVE CONSUMED IF THEY
FOLLOWED THE LABEL DIRECTIONS.
AND SO YOU CAN SEE THAT THE
CAFFEINE DOSES WENT FROM HALF A
GRAM TO ALMOST OVER A GRAM OF
CAFFEINE PER DAY, AND DEPENDING
UPON YOUR INDIVIDUAL
SENSITIVITY, A GRAM OF CAFFEINE
CAN HAVE SIGNIFICANT
PHARMACOLOGICAL EFFECTS.
SO BASICALLY WE TOOK 12 HEALTHY
MALE VOLUNTEERS, RANDOMIZED TO
TAKE EACH OF THESE PRODUCTS,
RANDOMIZED FOR SEQUENCE, ACTIVE
PHASES, IN BETWEEN EACH ACTIVE
PHASE THERE WAS A WASH OUT
PHASE.
TWO CAPSULES THREE TIMES A DAY
FOR THREE DAYS, WE MONITORED
SUBJECTS FOR BLOOD PRESSURE,
HEART RATE, EKG ACTIVITY USING A
HOLTER MONITOR.
AND SO NOT TOO SURPRISINGLY
DURING THE ACTIVE PHASES OF THE
STUDY WE SAW SIGNIFICANT
INCREASES IN SYSTOLIC AND
DIASTOLIC BLOOD PRESSURE, HEART
RATE, AND MORE ABNORMAL EKGs
THAN IN WASHOUT PHASE.
WE ASKED OURSELVES SIGNIFICANT
NAUSEA AND VOMITING, WITH THIS
MUCH CAFFEINE, INSOMNIA AND
ANXIETY WERE COMMON SIDE EFFECTS
TOO.
WE WERE NOT TOO SURPRISED BY THE
FACT THAT WE SAW SOME INSOMNIA,
CHANGES IN HEART RATE, BLOOD
PRESSURE, BECAUSE IN THE
CAFFEINE DOSE IS HIGH BUT ALSO
COMPLEXITY OF FORMULATIONS
PROBABLY CONTRIBUTED TO EFFECTS
AS WELL.
ONE OF THE THINGS WE ANALYZED
FOR CAFFEINE CONTENT, WE FOUND
TWO PRODUCTS RAN US OUT OF THE
LAB BECAUSE THEY SMELLED SO BAD,
MY TECHNICIANS SAID I THINK WE
MAY HAVE A BACTERIAL
CONTAMINATION.
SURE ENOUGH WE SENT THE PRODUCTS
DOWN TO THE NATIONAL CENTER FOR
TOXICOLOGIC RESEARCH AND TWO
PRODUCTS CAME BACK AS BEING
HEAVILY CONTAMINATED WITH
BACILLUS SPECIES, ONE WAS
BACILLUS SIRIUS, WELL RECOGNIZED
HUMAN PATHOGEN.
I FELT BAD ABOUT EXPOSED MY
SUBJECTS TO THESE CONTAMINATED
PRODUCTS, CERTAINLY COULD
ATTRIBUTE TO NAUSEA AND
VOMITING.
HEY, THERE WAS NO LISTING FOR,
AS YOU CAN NOTICE ON LIST OF
INGREDIENTS, NO LIST LABEL CLAIM
FOR BACILLUS SPECIES.
BOTTOM LINE IS EVEN THOUGH THESE
PRODUCTS MAY BE EPHEDRA FREE
THEY ARE NOT NECESSARILY TROUBLE
FREE.
WITH REGARDS TO CARDIOVASCULAR
EFFECT, NEXT POINT, IF AN
INDIVIDUAL IS TAKING SOME OF
THESE PRODUCTS PRIMARILY TO LOSE
WEIGHT OR WHATEVER AND YOU'RE ON
AN ANTI-HYPERTENSIVE MEDICATION
DON'T BE SURPRISED IF YOUR
MEDICATION DOESN'T WORK VERY
WELL AND YOUR BLOOD PRESSURE IS
NOT CONTROLLED WELL.
PRE-WORKOUT SUPPLEMENTS ARE
POPULAR TODAY, IT'S SURPRISING
HOW MANY YOUNG ATHLETES WITH
TAKING ADHD MEDICATIONS
CONCOMITANTLY.
THIS PRODUCT HERE CALLED STIM
LORD IS A PRE-WORKOUT
SUPPLEMENT.
YOU NOTICE I'VE GOT SOME
INGREDIENTS HIGHLIGHTED IN
YELLOW.
THESE ARE ALL CAFFEINE SOURCES.
ALSO SOURCES OF OTHER
STIMULANTS.
AND THE COMPOUND IN RED OCCURS
IN CERTAIN PLANTS, IT'S AN OLD
DRUG, ONCE USED AS A MAINSTAY TO
TREAT ASTHMA AND PULMONARY
DISEASE, THE NARROW THERAPEUTIC
INDEX, IT DOESN'T TAKE MUCH TO
BECOME TOXIC.
IF YOU HAVE AN INDIVIDUAL YOUNG
ATHLETES TAKING ADHD MED LIKE
AMPHETAMINE, EXERCISING IN A HOT
HUMID ENVIRONMENT DON'T BE
SURPRISED IF YOU EXPERIENCE
UNTOWARD CARDIOVASCULAR EFFECT.
SOMEONE IS OVERWEIGHT, ALSO ON
HYPERTENSIVE MEDS, BLOOD
PRESSURE WON'T BE WELL
CONTROLLED.
PRODUCTS LIKE THIS ARE BASICALLY
PHARMACODYNAMIC HERB-DRUG
INTERACTIONS WAITING TO HAPPEN.
YOU MAY RECOGNIZE PABLO ESCOBAR,
THAT GIVES YOU AN IDEA HOW THE
MARKETERS OF SOME PRODUCTS, YOU
KNOW, HOW THEY THINK ABOUT THIS.
THAT SPEAKS VOLUMES ABOUT THE
PRODUCTS.
I WANTS TO SHIFT GEARS AND TALK
ABOUT THE NEXT MAJOR CATEGORY
WITH PHARMACOKINETIC MECHANISM.
THE HERB-DRUG, BOTANICAL ALTERS
ABSORPTION, DISTRIBUTION,
METABOLISM, AND/OR EXCRETION OF
A CO-ADMINISTERED MEDICATION.
THIS USUALLY COMES ABOUT THROUGH
PHYTO CHEMICAL MODULATION OF
ENZYMES FOUND IN THE SMALL
INTESTINE AND LIVER.
AND THESE ARE PRIMARILY ENZYMES,
TRANSFERATIONS, SULFATASE
A HOSE OF -- HOST OF ENZYMES
THAT CAN BE AFFECTED AND CAN BE
THE RESULT OF PHYTOCHEMICAL
MODULATION, FOUND IN THE
BLOOD-BRAIN BARRIER.
AN EFFLUX PUMP PREVENTS DRUGS
FROM GETTING INTO CELLS, ON THE
OTHER HAND YOU CAN HAVE UPTAKE
TRANSPORTERS, PROTEINS THAT
LITERALLY PULL DRUGS OR
TRANSPORT DRUGS INTO CELLS.
YOU CAN HAVE DEPENDING ON THE
TYPE OF TRANSPORTER CAN WORK AT
CROSS-PURPOSES.
NOW, ENZYMES THAT ARE MOST
INVOLVED ARE CYTOKINE P450s,
THIS ILLUSTRATES THE ENZYMES
PRESENT IN THE LIVER AND SMALL
INTESTINE.
OF THESE THE MOST IMPORTANT IS
WHAT'S CALLED CYP 3A4, IT'S
INVOLVED IN METABOLISM OF ALMOST
HALF OF ALL CONVENTIONAL
MEDICATIONS TO SOME EXTEND.
SECOND MOST IMPORTANT ONE IS CYP
2D 6, 20% OF DRUG METABOLISM,
AND THEN SEVERAL OTHERS KIND OF
ROUND OUT THE LIST.
THIS PARTICULAR CARTOON
DEMONSTRATES SPECTRUM OF
POSSIBLE PHARMACOKINETIC
HERB-DRUG INTERACTION.
AT THE TOP WE SEE THIS RED
CIRCLE WHICH IS A DOSE
FEDODAPINE, IN THE SMALL
INTESTINE IT'S EXPOSED TO
ENZYMES, NAMELY CYP 384, THAT
METABOLIZES SUCH THAT ONLY ABOUT
30% OF THE ORIGINAL DOSE REACHES
PORTAL CIRCULATION UNCHANGED,
AND THEN GOES TO THE LIVER,
EXPOSED TO EVEN MORE CYTOCHROME
P450 METABOLISM, 15% OF ORIGINAL
DOSE REACHS THE SYSTEMIC
CIRCULATION, WHERE IT CAN THEN
ACT ON CALCIUM CHANNELS IN THE
HEART TO LOWER BLOOD PRESSURE.
NOW, AN N SAID ON THE LEFT, THE
GREEN CIRCLE RECOMMENDS
GRAPEFRUIT JUICE THAT CONTAINS
AN INHIBITOR OF CYP 384 IN THE
GUT.
IF FELODAPINE IS TAKEN WITH
GREAT FRUIT JUICE,
BIOAVAILABILITY CAN BE INCREASED
TO AS MUCH AS 45%, VIRTUALLY
TRIPLING OF THE DOSE, AND SO
THAT CAN LEAD TO SIGNIFICANT
HYPOTENSION DUE TO GRAPEFRUIT
JUICE EFFECT ON INHIBITING
METABOLISM OF FELODAPINE.
IT MIGHT RENDER A DRUG MORE
TOXIC, IN THIS CASE.
ON THE OTHER HAND, IF WE HAVE A
PHYTOCHEMICAL THAT INDUCES
EXPRESSION OF DRUG METABOLIZING
ENZYMES IN GUT OR LIFE
BIOAVAILABILITY OF FELODAPINE
MIGHT BE REDUCED TO SAY 5%, TO
THE POINT THAT IT RENDERS THE
DRUG INEFFECTIVE.
SO THOSE ARE POSSIBILITIES, YOU
COULD HAVE IN TERMS OF TOXICITY.
LET'S LOOK AT THIS INDUCTION OR
INHIBITION ON STEADY STATE BLOOD
LEVELS.
SO, WE ADMINISTER DRUGS AT DOSES
AND DOSING INTERVALS TO ACHIEVE
STEADY STATE BLOOD LEVEL THAT
FALLS WITHIN A DESIRED
THERAPEUTIC RANGE.
DOTTED LINE HERE DEPICTS
THERAPEUTIC RANGE BOUNDED BY
THEORETICAL MAXIMUM SAFE
CONCENTRATION AND MINIMUM
EFFECTIVE CONCENTRATION.
IT'S THE ACTIVITY OF THESE
VARIOUS ENZYMES AND TRANSPORTERS
THAT DICTATE WHETHER THE STEADY
STATE BLOOD LEVELS WILL FALL
WITHIN OR OUTSIDE OF THIS
THERAPEUTIC RANGE.
SO THE YELLOW LINE DEPICTS IDEAL
DOSING SCHEDULE.
GREEN LINE DEPICTS WHAT HAPPENS
WHEN THE ENZYMES OR EFFLUX
TRANSPORTERS ARE INDUCED.
LESS DRUG GETS ABSORBED, WHAT
DOES GET ABSORBED GETS
METABOLIZED QUICKLY, THEREFORE
THE HALF-LIFE IS MUCH SHORTER
AND LESS OF THE DRUG
ACCUMULATES.
AND IT RENDERS THE DOSING
REGIMEN IN EFFECTIVE.
YOU CAN SEE BELOW MINIMUM
EFFECTIVE CONCENTRATION.
PURPLE LINE ON THE OTHER HAND
DEPICTS WHATS WHEN ENZYMES OR
TRANSPORTSERS ARE INHIBITS, MORE
DRUG GETS ABSORBED, IT'S NOT AS
METABOLIZED AS READILY,
HALF-LIFE GETS LONGER, MORE DRUG
ACCUMULATES.
THERE BY EXCEEDING MAXIMUM SAFE
CONCENTRATION AND POSSIBLY
INDUCING TOXICITY.
THIS IS THE SPECTRUM OF
HERB-DRUG INTERACTION
POSSIBILITY WITH PHARMACOKINETIC
MECHANISM.
LET'S LOOK AT EXAMPLES.
YOU ALREADY KNOW THIS BUT THE
MOST PROBLEMATIC BOTANICAL WITH
REGARD TO NUMBER OF CLINICALLY
RELEVANT INTERACTIONS IS ST.
JOHN'S WART USED TO RELIEF MILD
TO MODERATE DEPRESSION.
EFFICACY IS QUITE GOOD, IF YOU
HAVE HIGH QUALITY ST. JOHN'S
WORT BEING USED.
IN FACT ST. JOHN'S WORT AHERE'S
APPEARS TO BE BETTER, BUT
CARRIES A RISK BECAUSE IT CAN
RENDER MOST MEDICATIONS
INEFFECTIVE.
WHAT IT DOES IS INDUCES
EXPRESSION OF SEVERAL KEY P450
ENZYMES, AND MY GROUP IN THE
LATE 1990s WAS THE FIRST TO
IDENTIFY PENCHANT FOR INDUCING
CYP 3A4 IN HUMANS.
WE'RE CONDUCTING A CLINICAL
ASSESSMENT, ABILITY TO MODERATE
ACTIVITY, IT WAS AMONG THE FIRST
WE EVALUATED.
WHAT THESE TWO SLIDES
DEMONSTRATE IS WHAT HAPPENS TO
CYP 3 A 4 ACTIVITY, BLUE BARS
ARE PHENOTYPE BEFORE AND AFTER A
COURSE.
RED CIRCLE IS MEAN VALUES.
IN BOTH YOUNG AND ELDERLY
COHORTS ACTIVITY WAS INCREASED
BY APPROXIMATELY 100%, YOU MIGHT
SAY THAT'S ALL WELL AND GOOD,
BUT IS THAT EFFECT CLINICAL
RELEVANT?
WELL, LET'S FIND OUT.
ABOUT TWO WEEKS AFTER I
GENERATED THAT DATA
AGAIN DATA IN THE PREVIOUS SLIDE
I GOT A PHONE CALL FROM THE
CHIEF TRANSPLANT SURGERY AT MY
PREVIOUS INSTITUTION, UNIVERSITY
OF ARKANSAS FOR MEDICAL
SCIENCES.
AND THE TRANSPLANT SURGEON WHO
WAS A GOOD FRIEND CALLS ME AND
SAYS, I KNOW YOU WORK WITH THAT
HERBAL CRAP, HE USED A HARSHER
EXPLETIVE, SAME NUMBER OF
LETTERS.
HE ASKED IF ST. JOHN'S WART
WOULD INTERFERE WITH
CYCLOSPORIN.
I SAID DO YOU HAVE TRANSPLANT
PATIENTS TAKING ST. JOHN'S WORT
WITH CYCLOSPORIN?
YEAH, WE DO.
I SAID I'LL BET THE CYCLOSPORIN
LEVELS ARE REALLY LOW, AREN'T
THEY?
THERE WAS A LONG PAUSE ON THE
PHONE.
HE'S LIKE, YEAH, HOW DID YOU
KNOW THAT?
SO WHAT THIS FIGURE DEPICTS IS
CYCLOSPORIN TROUGH CONCENTRATION
PROFILE IN 28-YEAR-OLD WHITE
FEMALE FIVE YEARS POST
TRANSPLANT.
IT REVOLUTIONIZED SOLID ORGAN
TRANSPLANT BUT HAS A NARROW
THERAPEUTIC INDEX, SUBSTRATE FOR
CYP 3A4, YOU CAN REJECT YOUR
KIDNEY IF LEVELS ARE TOO LOW, IF
TOO HIGH CAN BE TOXIC.
LEVELS HAVE TO BE CLOSELY
MONITORED.
FOR A LONG TIME THIS PARTICULAR
INDIVIDUAL THINGS WERE JUST
FINE.
AROUND CHRISTMAS TIME OF 1999
HER LEVELS STARTED TO PLUMMET.
IN ORDER TO ADJUST, THE DOSE WAS
ALMOST DOUBLED, FROM 100
MILLIGRAMS TWICE A DAY TO 175
MILLIGRAMS TWICE A DAY.
EVEN AFTER THAT DOUBLING OF THE
DOSE LEVELS KEPT GOING DOWN,
DOWN, DOWN, EVERYBODY WAS
STARTING TO GET IN A BIT OF
CONCERN, THE TRANSPLANT TIME,
SHOWING SIGNS OF ACUTE
REJECTION.
SHE WAS BEING COMPLIANT AND
WASN'T TAKING ANY OTHER
MEDICATIONS.
AND SO IT JUST SO HAPPENED AN
OFFHAND COMMENT SHE MENTIONED TO
THE DIETITIAN ON THE TEAM, I'VE
BEEN FEELING DEPRESSED, HAVE
BEEN TAKING ST. JOHN'S WORT,
THAT'S ABOUT THE ONLY THING I
CAN RECALL THAT MIGHT BE
DIFFERENT.
THAT'S WHAT PROMPTED THE PHONE
CALL.
SO, ONCE THEY GOT HER OFF ST.
JOHN'S WORT THE EFFECT WENT
AWAY, BUT WITH HIGH DOSES OF
CYCLOSPORIN, LEVELS STARTED TO
SKYROCKET, THERE WAS A RISK OF
KIDNEY DAMAGE.
THEY REDUCED HER DOSE, GOT HER
LEVELS BACK UNDER CONTROL, BUT
UNFORTUNATELY HERE ACUTE
REJECTION, DEVOLVED INTO CHRONIC
REJECTION, SHE LOST THE GRAFT
AND HAD TO GO BACK ON DIALYSIS,
BACK ON THE TRANS TRANSPLANT
LIST, ONE OF FOUR CASES IN OUR
TRANSPLANT CENTER AT ABOUT THAT
TIME.
SO, SOON AFTER WE PUBLISHED OUR
RESULTS, TRANSPLANT CENTERS
AROUND THE WORLD BEGAN
DESCRIBING CASES OF REJECTION IN
HEART, LIVER, KIDNEY TRANSPLANT
RECIPIENTS, TAKING ST. JOHN'S
WART, SO THE INTERACTION WAS
EXTREMELY CLINICALLY RELEVANT.
THE REASON IT'S SO PROBLEMATIC
IT INDUCES THE EXPRESSION OF
SEVERAL KEY CYTOCHROME P450
ENZYMES AND EFFLUX TRANSPORTERS.
PRIMARILY P-GLYCOPROTEIN.
TOGETHER WHEN INDUCED, THEY
MARKEDLY REDUCE BIOAVAILABILITY
OF MANY ORALLY ADMINISTERED
MEDICATIONS.
IT SO HAPPENS A UNIQUE CHEMICAL
IN ST. JOHN'S WART IS THE
CULPRIT, WE POINTED OUT
HYPERFORIN EARLIER, IT BINDS TO
HUMAN PXR, AND WE WON'T GET INTO
THAT, BUT NEVERTHELESS WHAT IT
DOES WHEN IT'S ACTIVATED, IT
TURNS ON THE GENES FOR THESE
VARIOUS ENZYMES AND TRANSPORTERS
AND CAUSES THEM TO BE
OVEREXPRESSED IN THE GUT AND
LIVER.
IN FACT, HYPERFORIN IS THE MOST
POTENT LIGAND.
BUT HYPERFORIN RUNS CIRCLES IN
TERMS OF POTENCY.
WHAT MAKES IT SO PROBLEMATIC,
TOGETHER CYP3A4 ARE RESPONSIBLE
IN HALF OF CONVENTIONAL
MEDICATIONS.
HYPERICIN IS EASY TO MEASURE BUT
DOESN'T AFFECT P450, IT TOLD YOU
NOTHING ABOUT THE HYPERFORIN
CONTENT.
TODAY MOST SUPPLEMENTS ARE
STANDARDIZED TO HYPERFORIN,
THERE'S A WARNING ABOUT
POTENTIAL DRUG INTERACTIONS ON
THE LABEL, BUT TO GO FURTHER, I
WANT TO ILLUSTRATE WHY
STANDARDIZING TO ONE
PHYTOCHEMICAL COMPOUND DOESN'T
TELL MUCH ABOUT THE CONTENT OF
THE OTHERS.
WE'VE ANALYZED CONSENT OF SIX
BRANDS OF SAINT JOHN'S WORTH,
STANDARDIZED TO HYPERICIN, THE
CONTENT IS CONSISTENT ACROSS ALL
THE BRANDS, BUT LOOK AT THE
HYPERFORIN INNED MEL.
IT'S ALL -- IN THE MIDDLE, IT'S
ALL OVER THE MAP, WHEN THE
CONTENT GETS ABOVE 7 MILLIGRAMS
PER GRAM YOU HAVE SIGNIFICANT IN
INDUCTION OF P450.
PRODUCT A IS TWO LOTS OF THE
SAME BRAND.
THE CONTENT BETWEEN LOTS DIFFERS
BY ALMOST A FACTOR OF FOUR, SO
CLEARLY ONE LOT IS GOING TO POSE
GREAT GREATER RISK, AND SUCH
DISCREPANCIES ARE NOT ALL THAT
UNCOMMON WHEN IT COMES TO
DIETARY SUPPLEMENT WORLD,
REGARDLESS OF BOTANICAL.
NOT AS BAD AS IT USED TO BE BUT
YOU SEE A LOT OF VARIABILITY
SOMETIMES BETWEEN LOTS TO LOT.
ALL RIGHT.
SO TO SUMMARIZE IT INDUCES HOST
OF P450 ENZYMES AND EFFLUX
TRANSPORTERS.
HERE ARE A FEW OF THE DRUGS
KNOWN TO BE ADVERSELY AFFECTED
BY ST. JOHN'S WORT, WE SAW
CYCLOSPORIN, AFFECTS DRUGS LIKE
DIGOXIN, WARFARIN AND CANCER
CHEMOTHERAPEUTIC, AND MIRACLE
BABIES WITH WOMEN TAKING ORAL
CONTRACEPTIVES, IF YOU ARE
TAKING IT WITH ST. JOHN'S WORT
YOU DON'T HAVE GOOD
CONTRACEPTION.
IN SHORT, THE CONSEQUENCES ARE
NUMEROUS, AS ST. JOHN'S WART
RENDERS MOST MEDICATIONS
INEFFECTIVE.
SHIFTING GEARS TO THE OPPOSITE
EFFECT IN TERMS OF CYTOKINE P450
ENZYMES, GOLDENSEAL, TO WARD OFF
COLDS AND LOWER BLOOD GLUCOSE
AND MASK URINE DRUG SCREEN
RESULTS.
IF YOU PLAN ON USING GOLDENSEAL
TO MASK A URINE DRUG SCREEN YOU
BETTER KNOW HOW DRUG OF ABUSE IS
METABOLIZED, IT CAN MAKE CERTAIN
ONES EASIER TO DETECT.
I WON'T TELL WHICH ONES.
EFFICACY IS DEBATABLE BUT ITS
HERB-DRUG INTERACTION POTENTIAL
IS HIGH BECAUSE IT INHIBITS
ACTIVITIES MANY P450 ENZYMES.
WE CAN SEE 30-DAY ON CYP3A4 IN
HEALTHY VOLUNTEERS, THE ACTIVITY
OF BOTH ENZYMES WAS REDUCED BY
40%, CLINICAL RELEVANT OUTCOME.
JUST THIS PAST YEAR OUR FINDINGS
WERE BORNE OUT BY CLINICAL
STUDIES BY A COLLEAGUE, DR. MARY
PAINE, CURRENT DIRECTOR OF
NCCIH-SPONSORED CENTER FOR
NATURAL PRODUCT-DRUG
INTERACTIONS, IT'S NICE TO HAVE
YOUR RESEARCH INDEPENDENTLY
VERIFIED.
SO WHAT MAKES GOLDENSEAL
PROBLEMATIC IS THAT THE
INHIBITORY EFFECTS ARE CLINICAL
RELEVANT AND THESE TWO ENZYMES,
IT PRIMARILY EFFECTS ARE
RESPONSIBLE FOR METABOLISM OF
75% OF ALL MEDICATIONS, IT'S
CLINICAL RELEVANT OUTCOME.
AND THE RESPONSIBLE ARE
ALKALOIDS
MECHANISM BASED OR TIME
DEPENDENT, EFFECT IS PRONOUNCED
AND TAKES SEVERAL DAYS FOR THE
ENZYME ACTIVITY TO RECOVER ONCE
GOLDENSEAL HAS BEEN STOPPED.
SO WHEN YOU HAVE A
MECHANISM-BASED INHIBITION,
TIME-DEPEND OR IRREVERSE ABLE,
IT'S MORE PROBLEMATIC THAN
STANDARD REVERSIBLE INHIBITION.
HERE ARE STRUCTURES THAT ARE THE
CULPRITS IN GOLDENSEAL.
THE BROKEN CIRCLE OF THE
MOLECULE HIGHLIGHTS A MOIETY,
INTERACTS CAN P450 ENZYME,
METABOLIZED BINDS TO ENZYME AND
SHUTS IT DOWN, COMPLETELY LOCKS
UP THE ENZYME.
AND SO A WHOLE HOST OF PLANTS
BESIDES GOLDENSEAL PRODUCE PHYTO
CHEMICALS WITH THESE MOIETIES,
AND THE REASON THEY DO THAT IS
BECAUSE THEY ARE ACTUALLY PRETTY
DECENT INSECTICIDES.
SO, PLANTS ARE MOTHER NATURE'S
QUINTESSENTIAL ORGANIC CHEMISTS.
WHEN BUGS START NIBBLING ON THEM
IN ORDER TO GET RID OF THE
INSECTS THEY MAKE SOME
INTERESTING PHYTOCHEMICALS THAT
CAN BE HAZARDOUS TO THE INSECT
BUT IN OUR CASE WHEN A HUMAN
BEING INGESTS THESE THEY CAN
HAVE OTHER INTERESTING EFFECTS,
LIKE INHIBITING P450.
PIPER IS ANOTHER PLANT THAT
CONTAINS THESE MOIETIES,
PIPERANINES, WE CONSUME BLACK
PEPPER, ON A DAILY BASIS, I'M A
HUGE BLACK PEPPER AFICIONADO,
BUT THE QUANTITY PRESENT IN
BLACK PEPPER IS NOT ENOUGH TO
CAUSE HERB-DRUG INTERACTION IN
FOOD.
NOT AT ALL.
CONCENTRATED BLACK PEPPER
EXTRACT HOWEVER IS FORMULATED IN
MANY MULTI-INGREDIENT
SUPPLEMENTS, AND THE REASON THEY
ADD BLACK PEPPER EXTRACT IS THAT
BY INHIBITING THESE ENZYMES IN
THE GUT AND LIVER, YOU CAN
IMPROVE BIOAVAILABILITY OF OTHER
PHYTOCHEMICALS THAT MIGHT
NORMALLY UNDERGO EXTENSIVE
PRE-SYSTEMIC METABOLISM.
THE OPEN CIRCLES ARE LEVELS
BEFORE, CLOSED CIRCLES ARE
CONCENTRATIONS AFTER COURSE OF
PIPERINE.
BECAUSE IT HAS A NARROW
THERAPEUTIC WINDOW AND NASTY
SIDE EFFECT PROFILE, YOU CAN SEE
PIPARINE INCREASES BLOOD LEVELS
OF NEVIRAPINE.
I WANTED TO ILLUSTRATE THIS
EFFECT ON NEVIRAPINE.
ANOTHER EMERGING BOTANICAL FOUND
IN MANY SUPPLEMENTS IS HOST TO A
NUMBER OF PHYTOCHEMICALS,
SCISANDRA, AND POSES ARE RISK
FOR INTERACTION, ON THE
IMMUNOSUPPRESSIVE DRUG TAKEN
OVER FOR CYCLOSPORIN,
IMMUNOSUPPRESSANT USED FOR SOLID
ORGAN TRANSPLANT RECIPIENTS TO
KEEP THEM FROM REJECTING THE
ORGAN, HAS A NARROW THERAPEUTIC
INDEX, SO YOU CAN SEE IF TAKEN
WITH SCISANDRA, BLOOD LEVELS ARE
MARKEDLY INCREASED.
HERE AGAIN WE HAVE AN EXAMPLE OF
A CLINICAL RELEVANT HERB-DRUG
INTERACTION CAUSED BY A
PHYTOCHEMICAL THAT INHIBITS
METABOLISM, INHIBIT ACTIVITY OF
DRUG METABOLIZING ENZYMES.
ONE FINAL EXAMPLE INVOLVES GREEN
TEA.
IN THE FIGURE TO THE LEFT, GREEN
TEA WHEN TAKEN CONCOMITANTLY
WITH ANTI-HYPERTENSIVE DRUG
NADOLOL INCREASES
CONCENTRATIONS.
YOU MIGHT THINK, IT LOOKS LIKE
GREEN TEA IS INDUCING
METABOLISM.
IT IS NOT METABOLIZED.
OKAY.
SO WHAT'S GOING ON HERE?
NOT ONLY DOES IT REDUCE BLOOD
LEVELS WILL YOU AFFECTS
NADOLOL'S ANTI-HYPERTENSIVE
ACTIVITY AND PRECLUDES
APPEARANCE IN URINE, ON THE
RIGHT-HAND SIDE.
WHAT'S GOING ON?
WELL, WHAT'S HAPPENING IS THAT A
GROUP OF CHEMICALS IN GREEN TEA,
YOU MAY HAVE HEARD OF EGCG, ONE
OF THE MORE PREVALENT
PHYTOCHEMICALS, WHAT THEY DO IS
INHIBIT SPECIFIC UPTAKE
TRANSPORTERS IN THE GUT.
AND SO THESE ARE UPTAKE
TRANSPORTERS LIKE OATP, ORGANIC
ANTI-ION TRANSPORTING
POLYPEPTIDE.
SO, BECAUSE NADOLOL USES UPTAKE
TRANSPORTERS TO BE ABSORBED,
INOF RENDERS THE DRUG LESS
EFFECTIVE.
THIS INTERACTION IS QUITE
IMPORTANT GIVEN GREEN TEA IS ONE
OF THE MOST POPULAR BEVERAGES,
PRESENT IN A HOST OF WEIGHT LOSS
SUPPLEMENTS.
FROM THE PREVIOUS EXAMPLES, ONE
MIGHT THINK ALL BOTANICALS POSE
A SERIOUS RISK BUT THAT'S NOT
THE CASE.
MANY POPULAR BOTANICAL
SUPPLEMENTS POSE LITTLE TO NO
RISK FOR CLINICAL RELEVANT
INTERACTIONS, HOWEVER THE VAST
MAJORITY OF OF HAVEN'T BEEN
STUDIED ADEQUATELY IN CLINICAL
SETTING.
THERE ARE SEVERAL REASONS WHY
THIS IS THE CASE.
AND ONE EXPLANATION INVOLVES
POOR DOSAGE FORM PERFORMANCE DUE
TO POOR WATER SOLUBILITY, IF IT
CAN'T GO INTO SOLUTION IN.
GOOD
THE-- IN THE G.I. TRACT IT CAN'T
BE ABSORBED.
MANY UNDERGO EXTENSIVE
PRE-SYSTEM SYSTEM METABOLISM.
THE PLANT MIGHT NOT HAVE ANY
PHYTOCHEMICALS THAT CAN CAUSE AN
INTERACTION.
TO CONCLUDE, MANY POPULAR
BOTANICALS APPEAR TO POSE NO
RISK WE HAVEN'T EVALUATED IN A
CLINICAL SETTING.
IF YOU'RE NOT SURE ABOUT RISK
FOR A PARTICULAR BOTANICAL MY
ADVICE IS JUST TO AVOID TAKING
THEM CONCURRENTLY WITH YOUR
CONVENTIONAL MEDICATIONS.
SO WITH THAT, I WILL END AND BE
HAPPY TO ANSWER ANY QIONS
YOU MIGHT HAVE.
SO I WILL SEE IF WE CAN GET BACK
TO THE --
>> THANK YOU VERY MUCH.
WE DO HAVE A FEW QUESTIONS IN
THE CHAT.
SINCE WE'RE UP AGAINST THE BREAK
WE'VE BEEN GIVEN PERMISSION TO
GO A LITTLE BIT OVER.
HERE IS A QUESTION.
IN YOUR STUDIES WHY DID YOUR
GROUP USE ONLY MALE SUBJECTS, NO
FEMALES?
>> THAT'S JUST ONE OF THOSE
THINGS.
WE TRY TO GET FEMALES BUT THEY
JUST DIDN'T SHOW UP AND WE
COULDN'T WAIT FOR FOREVER.
SO THERE YOU GO.
THAT'S JUST A PRACTICAL ASPECT
OF DOING CLINICAL TRIALS
SOMETIMES.
NOW, WRITE -- IDEALLY WOULD
HAVE LIKED FEMALES BUT THAT'S
THE WAY IT CAME OUT.
WE WENT WITH IT.
>> DR. DWYER HAS A QUESTION, A
COMMENT AND QUESTION.
SHE'S ALWAYS WONDERED WHY DURING
THE EPHEDRA YEARS NOBODY DID A
SMALL CLINICAL TRIAL ON THE
EPHEDRA-FREE PRODUCTS EXCEPT YOU
DID IN 2012.
>> YES.
>> WHY DO YOU THINK THAT WAS THE
CASE?
>> YOU KNOW, I'M NOT REALLY
SURE.
I MEAN, IN FACT WHEN THAT PAPER
WAS PUBLISHED IN CLINICAL
PHARMACOLOGY AND THERAPEUTICS IN
2012, THERE WAS AN EDITORIAL
ASSOCIATED WITH IT.
PEOPLE WERE ASKING WHY IS THIS
RESEARCH EVEN NECESSARY, BUT
WHEN THE REASON IT'S NECESSARY
IS BECAUSE PEOPLE JUST DIDN'T
REALIZE HOW PROBLEMATIC THESE
THINGS COULD BE, SO THEY JUST
ASSUMED THAT TAKING EPHEDRA OUT
OF THE EPHEDRA-CONTAINING
SUPPLEMENTS WAS THE SOLUTION,
BUT THAT WASN'T THE CASE.
I'VE BEEN A PROPONENT IT WAS
NEVER THE PROBLEM, IT WAS THE
MILIEU THAT WAS THE ISSUE.
AND SO I'LL BE HONEST WITH YOU
AGAIN, ANOTHER REASON PEOPLE
HAVEN'T DONE IT, IT'S HARD TO
GET FUNDING, YOU'RE NOT GOING TO
GET DIETARY SUPPLEMENT INDUSTRY
TO FUND IT.
AND SO WE JUST DECIDED TO FOOT
OUR OWN BILL AND DO THAT BECAUSE
WE THOUGHT IT WAS NECESSARY,
NEEDED TO BE DONE.
AND IT ILLUSTRATES A HOST OF
POINTS.
THERE ARE PHARMACODYNAMIC
INTERACTIONS, ALSO ILLUSTRATED
PROBLEMS WHEN YOU COMBINE
MULTIPLE STIMULANTS, ALSO
ILLUSTRATED THE WHOLE ISSUE OF
CONTAMINATION ISSUE THAT DR.
HARDY BROUGHT UP TOO.
THE STUDY WAS HIGHLY CITED, I
DON'T KNOW IF IT'S THE BE-ALL,
END-ALL, AND THERE MAY BE OTHER
STUDIES OUT THERE SINCE, BUT
I'VE NOT SEEN THEM.
THAT'S MY TAKE ON IT.
>> WE HAVE A QUESTION FROM MARY
LEE, WONDERING ABOUT
VERIFICATIONS OF THE COMPONENTS
OR INGREDIENTS IN SUPPLEMENTS
YOU'RE TESTING IN YOUR STUDIES.
>> WE ALWAYS HAVE OUR PRODUCTS
INDEPENDENTLY VERIFIED FOR
PHYTOCHEMICAL CONTENT, SINCE DAY
1.
WE WOULD SEND OUR PRODUCTS, THE
ONES WE WERE GOING TO UTILIZE
FOR CLINICAL STUDY, WOULD SEND
THEM TO UNIVERSITY OF
MISSISSIPPI AT THE NATIONAL
CENTER FOR NATURAL PRODUCTS
RESEARCH, AND HAVE THEM WELL
CHARACTERIZED AND THAT WAS WHEN
I WAS AT THE UNIVERSITY OF
ARKANSAS.
NOW I'M AT THE NATIONAL CENTER
FOR NATURAL PRODUCTS RESEARCH,
AND SO FOR ANYBODY THAT DOES ANY
TYPE OF CLINICAL RESEARCH,
WHETHER IT'S EFFICACY STUDIES OR
WHETHER IT'S SAFETY OR HERB-DRUG
INTERACTION STUDIES YOU JUST
CAN'T TAKE -- YOU JUST CAN'T
TAKE -- A LOT OF PEOPLE TAKE FOR
GRANTED THAT LABEL CLAIM
ACTUALLY REPRESENTS WHAT'S IN
THE PRODUCT.
YOU CAN'T ASSUME THAT.
YOU HAVE TO HAVE IT
INDEPENDENTLY VERIFIED,
SURPRISED HOW OFTEN THE LABEL
CLAIM DOESN'T REPRESENT WHAT'S
IN THE PRODUCT.
WE'VE BEEN DOING THAT FOR MANY
YEARS, AND IF YOU DON'T DO THAT,
YOU NEED TO FIND ANOTHER AREA OF
RESEARCH TO GET INTO.
>> WE HAVE TWO QUESTIONS BUT
THEY ARE ALONG THE SAME LINES SO
WE'LL WRAP IT AFTER THESE
QUESTIONS.
THE QUESTION IS INSTEAD OF
LOOKING AT THE PHARMACOKINETIC
OR PHARMACODYNAMIC EFFECTS, DRUG
INTERACTION, THESE BOTANICALS
HAVE ON THE DRUGS, AS PROBLEMS,
HAS ANYBODY CONSIDERED THEM AS
POTENTIAL BENEFITS?
>> SURE.
OF COURSE, IN FACT THE CLASSIC
EXAMPLE WITH GRAPEFRUIT JUICE,
PEOPLE WOULD GIVE IT WITH
CERTAIN MEDICATIONS TO IMPROVE
BIOAVAILABILITY.
HAVE YOU TO BE CAREFUL WHICH
DRUGS AND PHYTOCHEMICALS YOU'RE
ADMIXING, AS LONG AS YOU
UNDERSTAND THE BOTANICAL YOU'RE
DEALING WITH AS WELL AS THE
PHARMACOLOGY OF BOTH
PHYTOCHEMICAL AND CONVENTIONAL
MEDICATION YOU'RE COMBINING,
DOESN'T MEAN THERE ARE HORRIBLE
THINGS.
THEY CAN BE USED ADVANTAGEOUSLY,
IN THE PROPER CONTEXT AND MAKE
SURE THINGS ARE MONITORED
PROPERLY.
THAT'S ALL.
>> THANK YOU, DR. GURLEY.
I'LL GIVE THE PLATFORM TO JAIME
TO TAKE US TO THE BREAK.
>> THANK YOU, DR. BROWN.
WE LOOK FORWARD TO SEEING YOU
NEXT SESSION AT 3:15, TALKING
ABOUT RESILIENCE STUDIES AT NIH
AND WE HAVE DR. HAGGERTY TALKING
ABOUT NIH SUPPORT FOR RESEARCH
AND TRAINING ON NUTRITION AND
DIETARY SUPPLEMENTS.
TWO GREAT PRESENTATIONS, WE'LL
BE STARTING THEN AT 3:15.
THANK YOU.
>>THIS IS SESSION 6, MODERATED
BY DR. BECKY COSTELLO, WITH THE
OFFICE ALMOST SINCE ITS
INCEPTION SINCE 1999.
THANK YOU, BECKY.
>> WELCOME.
THIS IS SESSION 6, SPECIAL
TOPICS.
THIS AFTERNOON'S SESSION WE'LL
HEAR FROM DR. BROWN AND DR.
HAGGERTY, INTRODUCING YOU TO
SOME ADDITIONAL PROGRAMS HERE AT
THE ODS, AND DESCRIBE HOW THEIR
PROGRAMS ARE CARRYING OUT THE
MISSION OF THE OFFERS OF DIETARY
SUPPLEMENTS.
OUR FIRST SPEAKER WILL BE DR.
BROWN, AND TO REMIND YOU BEFORE
I INTRODUCE HER TO USE THE Q&A
BOX FOR YOUR QUESTIONS, CHAT BOX
FOR TECHNICAL ISSUES.
DR. BROWN IS AT THE ODS
EXPLORING IMPACT OF DIETARY
SUPPLEMENT IS UP USE ON
RESILIENCE AND HEALTH IN DIVERSE
POPULATIONS, TRAINING IN ORGANIC
AND NATURAL PRODUCTS CHEMISTRY.
I WILL LET DR. BROWN BEGIN HER .
THANK YOU.
>> IT'S MY PLEASURE TO JOIN YOU
FOR THE 2022 OFFICE OF DIETARY
SUPPLEMENT PRACTICUM, I'M A
PROGRAM DIRECTOR AT THE OFFICE
OF DIETARY SUPPLEMENTS, FOUNDER
OF THE RESILIENCE WORKING GROUP.
THE PRESENTATION WILL FOCUS ON
PROCESS TO HARMONIZE RESEARCH
ACROSS MULTIPLE NIH INSTITUTES,
CENTERS, OFFICE, AS WELL AS
DOMAINS.
I WILL DISCUSS BEST PRACTICES IN
A DESIGN OF RESEARCH STUDY.
WHY RESILIENCE RESEARCH?
AS YOU KNOW, SUPPLEMENTS ARE NOT
INTENDED TO TREAT, CURE,
MITIGATE, OR PREVENT ANY
DISEASE.
WHILE DIETARY SUPPLEMENT LABELS
USUALLY DO NOT MAKE CLAIMS, THEY
DO CLAIM TO ENHANCE OR
STRENGTHEN RESILIENCE.
SHOWN ARE EXAMPLES, OBTAINED
FROM THE OFFICE OF DIETARY
SUPPLEMENT LABEL DATABASE.
NOTICE THAT THE WORD RESILIENT
OR SIMILAR TERMS ARE FREQUENTLY
USED IN NAMES OR CLAIMS
STATEMENTS OF DIETARY SUPPLEMENT
PRODUCTS.
HOW BEST TO ADDRESS KNOWLEDGE
GAPS ENTERTAINING TO BENEFITS OF
PRODUCT SUCH AS THESE?
INCREASED RIGOR AND
HARMONIZATION OF DATA.
AND THE OFFICE OF DIETARY
SUPPLEMENTS IS SUITED TO TAKE ON
THIS ROLE, COORDINATION AND
HARMONIZATION ACROSS NIH.
RESILIENCE RESEARCH STUDIES
RELEVANT TO TYPE OF SCIENCE WE
DO HERE AT NIH IS NOT A NEW
CONCEPT.
IN FACT, APPLIES TO BIOMEDICAL
SCIENCES DATING BACK TO THE
1800s, THERE HAS BEEN
SIGNIFICANT UPTICK IN RECENT
YEARS AS EVIDENCED BY THIS
PubMed SEARCH SHOWING 42,000
FULL TEXT ARTICLES BETWEEN 2012
AND 2022 HAVING THE TERM
RESILIENCE IN THE TITLE.
BROADER SEARCH GAVE 1.6 MILLION
RESULTS WITH THE TERM RESILIENCE
IN THE TITLE.
WHAT'S EVEN MORE INTERESTING
ABOUT THESE SEARCH RESULTS IS
THE FACT THE TOP FEW MANUSCRIPTS
ARE FOCUSED ON DEFINING
RESILIENCE, AND THEY HAVE A
CUMULATIVE TOTAL OF 3,000
CITATIONS.
CLEARLY THERE'S AN IMPORTANT GAP
THAT NEEDS ADDRESSING, AND
SCIENTISTS ARE EAGER FOR
SOLUTIONS.
I'D LIKE TO SUGGEST ONE SOLUTION
COULD BE THE DEVELOPMENT OF AN
OPERATIONALIZED DEFINITION OF
RESILIENCE OR SCIENTIFIC
RESEARCH.
IN 2019 THE RESEARCH WORKING
GROUP WAS ESTABLISHED TO
CONTRIBUTE TO DEVELOPMENT OF
OPERATIONALIZED DEFINITION OF
RESILIENCE.
UPON CONVENING MEMBERS AGREED
SCIENCE OF RESILIENCE ALIGNS
WITH MISSION OF NIH, SEEK
FUNDAMENTAL KNOWLEDGE ABOUT
NATURE AND BEHAVIOR OF LIVING
SYSTEMS AND APPLICATION OF THAT
KNOWLEDGE TO ENHANCE HEALTH,
LENGTHEN LIFE, REDUCE ILLNESS
AND DISABILITY.
IN FACT, NIH FUNDED RESILIENCE
RESEARCH STUDIES WERE EVIDENT
ACROSS INSTITUTES, CENTERS, AND
OFFICES, SPANNING MULTIPLE
DOMAINS INCLUDING INDIVIDUALS
SUCH AS MOLECULAR, PHYSIOLOGIC
AND PSYCHOSOCIAL, BEHAVIOR,
COMMUNITY, ENVIRONMENTAL
RESILIENCE.
FINALLY THE FOUNDATION OF THE
GROUP WAS BUILT ON A NOTION THAT
UNDERSTANDING OF RESILIENCE
WITHIN CONTEXT OF HUMAN HEALTH
AND BIOMEDICAL SCIENCES MIGHT
PROVIDE INSIGHT TOWARD
IMPROVEMENT OF HEALTH AND
MAINTENANCE WITH COMPLEMENTING
PERSPECTIVES.
REALIZING OPPORTUNITY TO HELP
ADVANCE SCIENCE, TRANS-NIH
RESILIENCE WORKING GROUP HOSTED
A FORUM TO DEVELOP NIH-WIDE
OPERATIONAL DEFINITION OF
RESILIENCE, PARTICIPANTS
INCLUDED REPRESENTATIVES FROM
NATIONAL CANCER INSTITUTE,
NATIONAL HEART, LUNG AND BLOOD
INSTITUTE,NA NAT INSTITUTE ON
AGING, NATIONAL INSTITUTE ON
MINORITY HEALTH AND HEALTH
DISPARITIES, NATIONAL INSTITUTE
ON NURSING RESEARCH, NATIONAL
CENTER FOR COMPLEMENTARY AND
INTEGRATIVE HEALTH, OFFICE OF
BEHAVIOR AND SOCIAL SCIENCES
RESEARCH, NATIONAL INSTITUTE ON
MENTAL HEALTH, OF COURSE THE
OFFICE OF DIETARY SUPPLEMENTS.
FOLLOWING PRESENTATIONS OF
EXAMPLES OF RESILIENCE RESEARCH
TWO BREAKOUT SESSIONS AND SERIES
OF DELIBERATIONS, PARTICIPANTS
SUGGESTED CRITERIA FOR
CONSIDERATION OF NIH-WIDE
DEFINITION OF RESILIENCE.
THOSE CRITERIA WERE BROAD ENOUGH
TO ENCOMPASS ALL THE HEALTH
DISEASE OUTCOMES, RANGE OF
STRESSORS AND CHALLENGES DUE TO
NORMAL PHYSIOLOGIC PROCESSES
SUCH AS AGING, NUMBER TWO
DEFINITION SHOULD ENSURE
APPLICABILITY AT THE POPULATION
LEVEL, INDIVIDUAL BIOLOGICAL
LEVEL, PSYCHOLOGICAL LEVEL.
NUMBER THREE, NIH WIDE
DEFINITION SHOULD ALIGN WITH THE
MISSION OF THE NIH.
WITH THESE CRITERIA AND
ACKNOWLEDGMENT OF KEY RESILIENCE
CONSENTS UTILIZED IN LITERATURE,
NIH DEFINITION OF RESILIENCE WAS
DEVELOPED.
IT STATES RESILIENCE CAN BE
DEFINED AS SYSTEM'S CAPACITY TO
RESIST, RECOVER, RECOVER BETTER,
GROW, OR ADAPT IN RESPONSE TO A
CHALLENGE OR STRESSOR.
THEN TO FULLY CAPTURE THE
FUNCTIONAL ASPECT, TRANS-NIH
RESILIENCE DEVELOPED A GRAPHIC,
OVER TIME A SYSTEM'S RESPONSE TO
CHALLENGE MIGHT SHOW VARYING
DEGREES OF REACTION THAT
FLUBBING FLUCTUATE, GRAPHIC
SHOWS A SYSTEM CAN BE
REPRESENTED BY VARIOUS DEMAINS,
FACTORS OR PROCESSES THAT IMPACT
HUMAN HEALTH, INCLUDING BUT NOT
LIMITED TO ENVIRONMENTAL OR
COMMUNITY FACTORS, AS WELL AS
INDIVIDUAL PSYCHOLOGICAL,
PHYSIOLOGICAL, MOLECULAR
CAPACITY.
IT PROVIDES EXAMPLES OF REACTION
TO STRESSOR.
FOR EXAMPLE, WHEN A SYSTEM IS
EXPOSED TO A CHALLENGE OR
STRESSOR RESULTS IN NO
DISRUPTION, SYSTEM RESPONDED BY
RESISTING THE CHALLENGE.
RESISTING THE STRESSOR.
IF THE SYSTEM IS INITIALLY
DISTURBED AND THEN RECOVERS, BUT
RECOVER STATE IS IMPROVEMENT
COMPARED WITH BASELINE THE
SYSTEM SHOWED GROWTH OR
RECOVERED BETTER.
HOWEVER, IF A SYSTEM SHOWS
UNANTICIPATED CHANGES THAT
INFLUENCE SYSTEM'S ABILITY TO
THRIVE, EXPERIENCE CAN BE
CHARACTERIZED AS ADAPTIVE
RESPONSE.
AND IF A SYSTEM SHOWS INITIAL
DISRUPTION THAT IS ULTIMATELY
RESTORED TO BASELINE STATUS,
SYSTEM'S RESPONSE IS
CHARACTERIZED AS RECOVERY.
EACH ARE RELEVANT TO THE
RESILIENCE OUTCOMES.
ON THE OTHER HAND, REACTIONS NOT
CONSISTENT RESILIENCE OUTCOMES
OCCUR WHEN IT RESULTS IN A
WORSENED CONDITION,
CHARACTERIZED AS DIMINISHED OR
MALADAPTIVE RESPONSE.
IF IT FAILS TO RECOVER, IT IS
LOST OR HAS COLLAPSE.
THE GOAL IS NOT TO SUGGEST ONE
FRAMEWORK IS PREFERRED OVER THE
OTHER.
RESILIENCE, RISK REDUCTION,
PREVENTION AND EVEN DISEASE
TREATMENT ARE ALL BENEFICIAL
FRAMEWORKS FOR WHICH THE DESIGN
STUDIES OR ASK QUESTIONS OF THE
DATA.
EACH OF THE FRAMEWORKS MIGHT
LEAD TO IMPROVE HEALTH OUTCOMES.
I'M SUGGESTING A NICE BALANCE
REPRESENTING EACH OF THE
FRAMEWORKS IN THE LITERATURE
WHICH I DON'T THINK IS CURRENTLY
THE CASE FOR RESILIENCE
FRAMEWORKS, BUT IF THERE WERE A
NICE BALANCE INCLUDING
RESILIENCE FRAMEWORKS, IT MIGHT
OPEN OUR EYES TO QUESTIONS AND
KNOWLEDGE GAPS CURRENTLY
OVERLOOKED OR UNDERAPPRECIATED.
LET'S CONSIDER AS EXAMPLE THE
STATUS OF POPULATION
DISTRIBUTION DATA SHOWN HERE.
WE SEE FROM DATA THAT IN
POPULATION D, THE LEVELS RANGE
FROM 10 TO 80 NANOGRAMS PER MIL.
TAKE A LOOK AT POPULATION A
CURVE.
THE NUTRIENT X STATUS LEVELS IN
POPULATION A RANGE FROM 2
NANOGRAMS TO 40 NANOGRAMS PER
MIL, AND MEAN STATUS LEFT IN
POPULATION A IS ABOUT 15
NANOGRAMS PER MIL.
NOW, DEPENDING UPON YOUR
PERSPECTIVE, OR LENS BY WHICH
YOU VIEW THIS DATA YOUR IDEAS ON
HOW BEST TO RESPOND TO THE DATA
OR YOUR APPROACH TO TREATMENT
PARADIGM OR THOUGHTS ON HOW BEST
TO ADDRESS POTENTIAL KNOWLEDGE
GAPS COULD ALL BE VERY
DIFFERENT.
FOR EXAMPLE, YOU COULD LOOK AT
THIS DATA AND SAY, HMM, LET'S
DEVELOP A DRUG OR SUPPLEMENT TO
MAKE LEVELS OF NUTRIENT X IN
POPULATIONS A, B,C LOOK MORE
LIKE THOSE IN POPULATION D.
OR DEPENDENTING UPON YOUR
PERSPECTIVE YOU COULD LOOK AT
THIS DATA AND THINK LET'S
IDENTIFY FACTORS THAT ALLOW OR
CAUSE POPULATIONS A, B, C, TO BE
AT GREATER RISK FOR HAVING LOWER
LEVELS OF NUTRIENT X.
PERHAPS YOU LOOK AT THIS DATA
AND THINK, LET'S DEVELOP
POLICIES TO PREVENT POPULATIONS
A, B, AND C FROM EXPOSURE TO
THOSE RISK FACTORS THAT MIGHT
LEAD TO LOWER LEVELS OF NUTRIENT
X.
MAYBE YOU LOOK AND SAY LET'S
STUDY SUCCESS STORIES IN
POPULATION A AND IDENTIFY
PROTECTIVE FACTORS ASSOCIATED
WITH LOWER LEVELS OF NUTRIENT X.
PERHAPS YOU'LL LOOK AND SAY
LET'S IDENTIFY POTENTIAL
BENEFITS ASSOCIATED WITH HAVING
LOWER LEVELS OF NUTRIENT X IN
POPULATION A.
EACH IS IMPORTANT.
HOWEVER, I'D LIKE TO SUGGEST THE
LOWER TWO PERSPECTIVES WHICH
WERE DESIGNED OTHER CONSIDERED
IN RESILIENCE ARE APPLIED LESS
OFTEN.
IN OTHER WORDS, PERSPECTIVE OR
FRAMEWORK CAN DETERMINE NOT ONLY
TYPES OF QUESTIONS THAT ARE
ASKED IN YOUR STUDY BUT CAN ALSO
DETERMINE HOW YOU RESPOND TO THE
DATA.
FOR EXAMPLE, IF YOUR STUDY IS
DESIGNED WITHIN THE RISK
REDUCTION OR PREVENTION
FRAMEWORK, IT'S LIKELY YOUR
STUDY IS FOCUSED ON
UNDERSTANDING RISK FACTORS,
RIGHT?
UNDERSTANDING OR IDENTIFYING
THOSE FACTORS THAT ARE
ASSOCIATED WITH INCREASED
LIKELIHOOD OF ADVERSE OUTCOMES.
BUT IF YOUR STUDY IS DESIGNED IN
RESILIENCE FRAMEWORK IT'S LIKELY
THAT THE FOCUS IS TO BETTER
UNDERSTAND THE PROTECTIVE
FACTORS, OR TO IDENTIFY THOSE
FACTORS THAT ARE ASSOCIATED WITH
POSITIVE RESPONSE UPON EXPOSURE
TO ADVERSITY, STRESSES,
CHALLENGES.
RISK REDUCTION AND PREVENTION
OPINION BASED FRAMEWORKS TEND TO
EMPHASIZE OR PLACE EMPHASIS ON
EXPOSING VULNERABILITIES,
WHEREASES ARE FRAMEWORKS PLACE
EMPHASIS ON UTILIZATION OF
ASSETS OR STRENGTH IN A SYSTEM.
RISK REDUCTION AND PREVENTION
FRAMEWORKS TEND TO HAVE
INTERVENTIONS THAT TEND TOWARDS
PREVENTING OR REDUCING RISK.
RESILIENCE FRAMEWORKS HAVE
INTERVENTIONS THAT TEND TOWARDS
EMPOWERING OR STRENGTHENING TO
BETTER RESPOND TO THOSE RISKS OR
STRESSORS OR CHALLENGES.
IF YOU'RE DESIGNING A STUDY IT'S
LIKELY IT WILL BE DESIGNED TO
TARGET OR MANIPULATE RISK OR
VULNERABILITIES.
ON THE OTHER HAND, IF YOUR STUDY
IS DESIGNED TO INVESTIGATE
PROTECTION FACTORS, OR
RESILIENCE OUTCOMES, YOUR STUDY
WILL BE DESIGNED TO FOCUS ON THE
SYSTEM, MORE SPECIFICALLY
RESILIENCE-BASED STUDIES WILL BE
DESIGNED TO STRENGTHEN A
SYSTEM'S RESPONSE TO THE RISK.
HOW CAN YOU APPLY THE RESILIENCE
FRAMEWORK TO THE DESIGN OF YOUR
NEXT RESILIENCE STUDY?
YOU CAN CONSIDER FIRST WHETHER
OR NOT ONE OF THE FOLLOWING KEY
TERMS OR SIMILAR TERMS ARE ISSUE
REPLACEABLE IN DESCRIBING YOUR
STUDY DESIGN.
FOR EXAMPLE, DO YOU HAVE TERMS
LIKE RESILIENCE?
OR RESTORATION?
OR ADAPTIVE RESPONSE?
OR PROTECTIVE FACTORS IN YOUR
STUDY?
NOW, OF COURSE, INCLUSION OF
THESE TERMS ALONE IN YOUR STUDY
DESIGN IS NOT SUFFICIENT.
YOU SHOULD ALSO ASK YOURSELF,
DOES THE RESEARCH DESIGN INCLUDE
STRESSOR OR CHALLENGE?
THE LITERATURE SUPPORTS THE
NOTION WE CANNOT PERCEIVE
RESILIENCE OR MEASURE RESILIENCE
UNLESS THE SYSTEM IS EXPOSED
FIRST TO A STRESSOR OR
CHALLENGE.
SO ANY STUDY DESIGN TO ADVANCE
SCIENCE OF RESILIENCE SHOULD
HAVE WELL CHARACTERIZED DETAILS
DESCRIBING MAGNITUDE OF THE
STRESSOR, TIMING OF THE
STRESSOR, IS IT AN ACUTE OR
CHRONIC STRESSOR, WHAT LIFE
STAGE OR CYCLE DOES THE STRESSOR
IMPACT THE SYSTEM?
ALL OF THESE ARE FEATURES THAT
SHOULD BE CONSIDERED IN YOUR
RESILIENCE STUDY DESIGN.
YOU SHOULD ASK YOURSELF DO THE
MEASUREMENTS AND/OR OUTCOMES
TARGET HEALTH MAINTENANCE
SURVIVORSHIP OR PROTECTIVE
PATHWAYS OR ANOTHER WAY TO THINK
ABOUT IT, DO YOUR METRICS
CAPTURE CHANGE THAT STRENGTHENS
THE SYSTEM TOWARDS RESISTANCE,
ADAPTIVE RESPONSE, GROWTH,
RECOVERY FROM A STRESS OR
CHALLENGE?
IN OTHER WORDS, DO THE METRICS
CAPTURE CHANGE TOWARD A MORE
POSITIVE RESPONSE WHEN EXPOSED
TO A STRESSOR?
YOU SHOULD ALSO ASK, IS THERE AN
INTERVENTION OR PROTECTIVE
FACTOR IDENTIFIED OR SOUGHT FOR
DISCOVERY IN YOUR STUDY?
IF AN INTERVENTION IS
IDENTIFIED, DOES THE
INTERVENTION TRAIN THE SYSTEM TO
REACT DIFFERENTLY OR MORE
POSITIVELY TOWARDS THE STRESSOR
OR CHALLENGE?
ASK YOURSELF DOES THE
INTERVENTION HAVE MULTIPLE
DIVERSE EFFECTS WITHIN A SYSTEM
OR ACROSS SYSTEMS, DOES IT SHOW
POTENTIAL TO STRENGTHEN THE
SYSTEM, VIA MULTIPLE PATHWAYS
THAT ARE DISTINCT FROM TARGETED
APPROACH THAT IS DESIGNED TO
MITIGATE SOME RISK OR DISEASE
PATHWAY?
LET'S CONSIDER A FEW EXAMPLES.
SHOWN IS A HANDFUL OF EXAMPLES
OF RESEARCH STUDIES THAT WERE
CO-FUNDED BY THE OFFICE DIETARY
SUPPLEMENTS BETWEEN 2018 AND
2020.
NOTICE THE WIDE RANGE OF SYSTEMS
INVESTIGATED IN THIS LIST OF
EXAMPLES, YOU HAVE PHYSIOLOGIC
NEUROVASCULAR, BIOLOGICAL AND
BEHAVIOR SYSTEMS.
IN EACH STUDY SYSTEMS ARE
EXPOSED TO A CHALLENGE OR
STRESSORS.
MEASUREMENTS TARGET HEALTH
MAINTENANCE OR POTENTIAL
PROTECTIVE PATHWAYS, AND
INTERVENTIONS IN THIS CASE ALL
ARE DIETARY SUPPLEMENTS BELIEVED
TO HAVE DIVERSE EFFECTS ACROSS
MULTIPLE SYSTEMS.
HERE'S AN EXCERPT OF A STUDY
THAT WAS CO-FUNDED BY THE OFFICE
OF DIETARY SUPPLEMENTS.
I MODIFIED THE TITLE SLIGHTLY TO
PROTECT THE INVESTIGATORS AND
RESEARCH INTEGRITY.
THIS IS STUDY WHICH I'VE TITLED
MECHANISMS AND ACTIVE COMPOUNDS
IN BOTANICAL WATER EXTRACT, BWE,
SERVES AS GOOD EXAMPLE OF
RESILIENCE STUDIES ADDRESSING
KEY CRITERIA.
FOR EXAMPLE, ONE OR MORE OF THE
KEY WORD TERMS, IN THIS CASE
ENHANCE OR REVERSE ARE
IRREPLACEABLE IN DESCRIBING THE
STUDY DESIGN.
ALSO, WE SEE THE INVESTIGATORS
USE AN AGED MICE MODEL WITH HIGH
BETA AMYLOID PLAQUE BURDEN IN
THE STUDY DESIGN.
THIS MODEL OF ALZHEIMER'S
DISEASE SERVES AS STRESSOR OR
CHALLENGE IN THIS STUDY.
AND THEN WHEN CONSIDERING
WHETHER MEASUREMENTS OR OUTCOMES
TARGET HEALTH MAINTENANCE,
SURVIVORSHIP OR PROTECTIVE
PATHWAYS WE SEE THE
INVESTIGATORS USE BOTH TARGETED
AND UNBIASED APPROACHES TO
EXPLORE THE INTERVENTION OR
BWEs PROTECTIVE EFFECTS
AGAINST MECHANISMS OF BETA
AMYLOID PLAQUE TOXICITY AND
WHETHER OR NOT MEASURES CAPTURE
CHANGE TO STRENGTHEN TOWARDS A
POSITIVE RESPONSE UPON EXPOSURE
TO STRESSOR, WE SEE THE
INVESTIGATORS HAVE SHOWN THAT
THE INTERVENTION BWE CAN
ATTENUATE BETA AMYLOID
NEUROTOXICITY WITHOUT ALTERING
ITS FORMATION OR DEPOSITION.
IN OTHER WORDS, DESPITE
CONTINUED EXPOSURE TO THE
STRESSOR, THE INTERVENTION
APPEARS TO STRENGTHEN SYSTEM
TOWARD ABILITY TO RESIS
PERTURBATION FROM STRESSOR.
THEN WE ASK, IS THERE AN
INTERVENTION OR PROTECTIVE
FACTOR IDENTIFIED?
JUST IN THIS STUDY WE HAVE
INDICATED INTERVENTION IS
BOTANICAL WATER EXTRACT OR BWE,
BUT THEN WE ASK DOES THE
INTERVENTION TRAIN THE SYSTEM TO
REACT DIFFERENTLY OR MORE
POSITIVELY TOWARDS STRESSOR OR
CHALLENGE?
WE SEE HERE THAT THE
INTERVENTION IS ABLE TO REVERSE
LEARNING DEFICITS THAT ARE
CAUSED BY HIGH BETA AMYLOID
PLAQUE BURDEN WITHOUT ALTERING
THE BRAIN BETA AMYLOID PLAQUE
LEVELS SUGGESTING DESPITE
CONTINUED EXPOSURE TO STRESSOR,
WITHOUT ALTERING THE HIGH LEVELS
OF THE STRESSOR, THE
INTERVENTION IN THIS CASE IS
ABLE TO REVERSE THE LEARNING
DEFICITS, REVERSE THE NEGATIVE
IMPACT.
THEN WE ASK OURSELVES, DOES THE
INTERVENTION HAVE MULTIPLE
DIVERSE EFFECTS WITHIN A SYSTEM
OR ACROSS MULTIPLE SYSTEMS.
WE SEE HERE THAT THE
INVESTIGATORS HAVE INDICATED
THAT THEIR STUDY WILL FOCUS ON
NEURONAL HEALTH AND COGNITION IN
GENERAL, AND THE STUDY DESIGN IS
NOT LIMITED TO THOSE IMPACTS OR
EFFECTS ASSOCIATED SOLELY WITH
THE BETA AMYLOID TOXICITY.
THEY ALSO HYPOTHESIZE THE BETA
AMYLOID MODULATING EFFECTS ARE
MEDIATED BY NON-TRITERPENE
COMPOUNDS RELEVANT TO NEURONAL
HEALTH.
I'VE WALKED YOU THROUGH ONE
EXAMPLE.
I'VE OFFERED A FEW QUESTIONS TO
CONSIDER WHEN REPORTING ON OR
DESIGNING YOUR NEXT RESILIENCE
STUDY BUT REALLY THE KEY TO
UTILIZING THE RESILIENCE
FRAMEWORK IS HAVING A CLEAR
UNDERSTANDING WHAT RESILIENCE IS
AND WHAT IT IS NOT.
RESILIENCE IS ABOUT STRENGTHEN
THE SYSTEM.
IT IS NOT ABOUT MITIGATING THE
RISK.
RESILIENCE IS ABOUT LEARNING OR
BUILDING RESPONSE DIVERSITY, IT
IS NOT ABOUT MAINTAINING PERFECT
CONTROL OF THE STRESSORS OR
SYSTEM FOR THAT MATTER.
RESILIENCE IS ABOUT
ACKNOWLEDGING SOME EXPOSURE TO
SOCIAL, ENVIRONMENTAL, AND
BIOLOGICAL STRESSORS ARE
EXPECTED.
IT MAY EVEN STRENGTHEN THE
SYSTEM.
RESILIENCE IS NOT ABOUT
AVOIDANCE OF ALL CHALLENGES.
WITH THAT I'D LIKE TO CLOSE BUT
IN CLOSING I'D LIKE TO FIRST
ACKNOWLEDGE A FEW OF THE
DETERMINED BRAVE INDIVIDUALS
WHOSE FULL DATE OF DELIBERATION,
ONE DAY BEFORE WE WERE IN
ISOLATION DUE A PANDEMIC, THOSE
DELIBERATIONS LED TO THE
DEVELOPMENT OF OUR RESILIENCE
DEFINITION AND CONCEPTUAL MODEL.
PLEASE SHARE YOUR FEEDBACK.
TELL US ABOUT YOUR NEXT
RESILIENCE STUDY DESIGN.
YOU CAN E-MAIL US AT TRANS-NIH
RESILIENCE PROGRAM@OD.NIH.GOV OR
IF YOU WOULD LIKE MORE
INFORMATION ABOUT SOME
ACTIVITIES OF THE TRANSNIH
WORKING GROUP REVIEW OUR WEB
PAGE ON THE ODS WEBSITE.
THANK YOU FOR YOUR INTEREST IN
OUR EFFORTS TO ADVANCE THE
SCIENCE OF RESILIENCE.
ENJOY THE REST OF YOUR DAY.
>> THANK YOU VERY MUCH, DR.
BROWN.
THAT WAS A WONDERFUL OVERVIEW OF
THE RESISTANCE PROGRAM.
AND WHILE WE'RE WAITING FOR SOME
QUESTIONS TO COME IN THE Q&A
BOX, LET ME ASK YOU, CAN A STUDY
THAT'S INITIALLY DESIGNED TO
LOOK AT PREVENTION ALSO
INCORPORATE RESILIENCE FEATURES
WITHIN IT?
SO COULD YOU LOOK AT BOTH SIDES
OF THE COIN IN THE SAME STUDY
DESIGN?
>> OF COURSE.
IN FACT I THINK IN SOME WAYS
THAT'S WHAT WE'RE HOPING FOR,
RIGHT?
WE'RE HOPING THAT THE STUDIES
THAT ARE OUT THERE NOW CAN
CONSIDER MULTIPLE PERSPECTIVES.
WE LOOK AT DATA THAT HAS BEEN
CONTRIBUTED TO THE STUDIES THAT
HAVE ALREADY BEEN CONDUCTED,
MAYBE WE GO BACK AND CONSIDER
THAT DATA WITH DIFFERENT
QUESTIONS.
MAYBE THOSE QUESTIONS WILL COME
FROM A DIFFERENT PERSPECTIVE OR
DIFFERENT LENS.
AND SO MOST DEFINITELY ANY STUDY
CAN BE VIEWED FROM WHICH EVER
PERSPECTIVE, RIGHT?
AND ALL WE'RE SUGGESTING IS THAT
DEPENDING UPON YOUR PERSPECTIVE
YOUR NEXT STEP OR HOW YOU DECIDE
TO TREAT A GROUP OF INDIVIDUALS
OR HOW YOU INTERPRETED DATA ARE
ALL DEPENDENT UPON THE LENS BY
WHICH YOU'RE LOOKING AT DATA.
SO, YOU KNOW, THERE'S NO WAY
THAT ONE PARTICULAR FRAMEWORK
SHOULD BE PREFERRED OR THAT WE
SHOULD EVEN STOP AT ONE
PARTICULAR FRAMEWORK WHEN WE'RE
LOOKING AT THESE STUDIES OR
DATA.
>> GREAT.
GREAT.
MAYBE YOU COULD GIVE US AN IDEA
OF THE LENS OF SOME OF THE OTHER
I.C.s THAT ARE PARTICIPATING
IN THE RESILIENCE PROGRAM.
FOR EXAMPLE, MAYBE THE INSTITUTE
OF AGING, DO THEY HAVE A LITTLE
BIT DIFFERENT LENS OF LOOKING AT
RESILIENCE THAN THE ODS MIGHT
HAVE?
>> IT'S INTERESTING THAT WITH
THAT QUESTION, I MIGHT ARGUE
YOU'RE COMING FROM A DIFFERENT
PERSPECTIVE F .
IF I LOOK FOR DIFFERENCES, I'M
GOING TO INDIAN FOO IT.
IF I LOOK FOR SIMILARITIES, I
CAN FIND THAT TOO.
TWO I NOTICE IS THAT THERE ARE
QUITE A BIT OF SIMILARITIES HOW
INSTITUTES AND CENTERS APPLY
RESILIENCE BUT OUTSIDE THE NIH
AS WELL.
WE'VE SEEN FROM ANOTHER GROUP I
WORK WITH, WE'VE SEEN HOW
SIMILARITIES ACROSS FEDERAL
AGENCIES, EVEN IF DO YOU A
GOOGLE SEARCH, HOW RESILIENCE IS
DEFINED IN GOOGLE, OF COURSE
YOU'RE GOING TO SEE SOME
DIFFERENCE IN THE TEXT BUT IF
YOU THINK ABOUT WHAT IT MEANS TO
MEASURE RESILIENCE GIVEN THOSE
DEFINITIONS AND WHAT THOSE
DEFINITIONS ARE TRYING TO
APPLIER THERE FAR MORE
SIMILARITIES THAN DIFFERENCES.
>> THAT'S GOOD TO KNOW.
WE HAVE A QUESTION IN THE BOX
HERE.
THERE'S AN INTEREST IN
OPTIMIZING HEALTH THROUGH
DIETARY SUPPLEMENTS WHAT ROLE
DOES RESILIENCY PLAY IN
OPTIMIZING HEALTH?
>> AGAIN, RESILIENCE IS A
FRAMEWORK.
UP TO THIS DATE I DON'T KNOW
WHAT YOU FEEL BUT I KNOW THAT
WHENEVER I LOOK AT SOME BENEFITS
OR TRY TO UNDERSTAND BENEFITS OR
RISK OF A DIETARY SUPPLEMENT,
THERE'S ALWAYS THIS LINE THAT
SAYS MORE INFORMATION IS NEEDED.
MORE STUDIES ARE NEEDED.
AND WHAT I SUGGEST, MAYBE WE'RE
JUST APPROACHING DIETARY
SUPPLEMENT OR STUDY OF DIETARY
SUPPLEMENTS, MAYBE WE CAN
CONSIDER APPROACHING FROM A
DIFFERENT LENS, MAYBE FROM A
RESILIENCE FRAMEWORK, MAYBE IF
WE CAN HAVE THE BALANCE OF
DISEASE PERSPECTIVE OR
PREVENTION PERSPECTIVE, MAYBE WE
CAN COMMENT DEFINITIVE RESULTS,
BETTER INTERPRETATIONS OF DATA
THAT COULD LEAD US TO UNDERSTAND
ARE THERE TRULY BENEFITS OF SOME
OF THESE DIETARY SUPPLEMENTS, SO
THE GOAL HERE IS NOT TO SUGGEST
THAT THIS ONE INTERVENTION IS
MORE RESILIENT OR ONE POPULATION
IS MORE RESILIENT BUT DEPENDING
UPON YOUR PERSPECTIVE, WHAT YOU
LOOK FOR, YOU'LL FIND.
IF YOU'RE LOOKING FOR
RESILIENCE, OR PROTECTIVE
FACTORS, YOU CAN FIND THEM,
RIGHT?
WHAT I SUGGEST IS LOOKING --
WE'VE BEEN FOCUSING MORE OFTEN
THAN NOT ON THE RISK OR THE
DISEASE PATHWAYS, SO OF COURSE
THAT'S WHAT WE'VE BEEN FINDING.
>> AND I THINK WE CAN DO ONE
LAST QUESTION HERE.
CAN YOU PROVIDE SOME EXAMPLES OF
PHYSIOLOGICAL AND MENTAL
STRESSORS APPLIED TO A STUDY
DESIGN TO CAPTURE RESILIENCE?
>> SO, OKAY.
SO, WE THINK THE WAY WE APPROACH
IT, AGAIN, IS JUST A FRAMEWORK.
WE UNDERSTAND THAT WE ACCEPT THE
FACT AND ACKNOWLEDGE THE FACT
WE'RE ALWAYS EXPOSED TO
STRESSORS, RIGHT?
SO, MENTAL STRESSOR COULD BE --
HMM.
THERE ARE SO MANY OF THEM.
I DON'T KNOW, IT COULD BE
(INDISCERNIBLE).
>> THANK YOU, BECKY.
YOU KNOW, YOU CAN COME UP WITH
ANY TYPE OF STRESSOR, YOU NAME
IT.
IF IT'S SOMETHING THAT DISRUPTS
THE SYSTEM OR DISTURBS THE
SYSTEM, THEN WE CAN CONSIDER IT
A STRESSOR.
IN FACT, EVEN IF IT DOESN'T
DISRUPT ONE SYSTEM BUT DOES
DISRUPT A SECOND SYSTEM, WE
COULD CONSIDER THAT A STRESSOR,
FROM ANY DOMAIN, FROM THE MENTAL
HEALTH DOMAIN, PHYSIOLOGIC
DOMAIN, AND IT'S ALL, AGAIN --
LET ME TAKE, FOR EXAMPLE, THE
PHYSIOLOGIC DOMAIN.
I'VE SEEN FOR INSTANCE EXERCISE.
EXERCISE HAS BEEN APPLIED AS
BOTH A STRESSOR IN SOME OF THESE
RESILIENCE STUDIES AS WELL AS AN
INTERVENTION OR POTENTIAL
PROTECTIVE FACTOR.
BUT NONETHELESS WE STILL
CONSIDER THOSE THINGS RESILIENCE
STUDIES BECAUSE OF THE TYPE OF
QUESTIONS THEY WERE ASKING, AND
BECAUSE OF THE LENS BY WHICH
THEY APPROACH THE STUDY.
>> GREAT.
GREAT.
WELL, THANK YOU SO MUCH FOR YOUR
PRESENTATION TODAY.
I'M SURE IT GIVES EVERYBODY A
LOT OF FOOD FOR THOUGHT ON A NEW
PARADIGM.
AND THEY CAN CONTACT YOU WITH
YOUR INFORMATION.
>> GREAT.
THANK YOU, BECKY.
>> THANK YOU.
AND NOW OUR NEXT SPEAKER, OUR
LAST SPEAKER FOR THE SESSION
TODAY, DR. PATRICIA HAGGERTY.
SHE'S CURRENTLY THE DIRECTOR OF
GRANTS AND EXTRAMURAL ACTIVITIES
AT THE OFFICE OF DIETARY
SUPPLEMENTS, IN THIS CAPACITY
ENGAGES OTHER NIH INSTITUTES AND
CENTERS TO FACILITATE FUNDING OF
GRANTS OF HIGH RELEVANCE TO THE
ODS MISSION.
AND GOALS.
DR. HAGGERTY'S ACADEMIC TRAINING
IS IN HUMAN NUTRITION AND SHE
HAS WORKED AND TRAVELED
EXTENSIVELY GLOBAL NUTRITION
PROGRAMS.
I'M GOING TO TURN THE FLOOR OVER
TO DR. HAGGERTY NOW.
>> THANK YOU, BECKY.
CAN YOU HEAR ME ALL RIGHT?
>> OKAY.
>> YES, CAN YOU HEAR ME?
>> YES, WE CAN HEAR YOU.
>> OKAY, GREAT.
>> YEAH, VERY CLEAR.
>> I'LL SHARE MY SCREEN.
OKAY.
I'M GOING TO --
OKAY.
CAN YOU SEE FULL SCREEN
PRESENTATION MODE?
>> THAT LOOKS GREAT.
>> OKAY, GREAT.
THANK YOU.
GOOD AFTERNOON, EVERYONE.
I'M VERY HAPPY TO BE HERE.
THIS IS THE FUN PART.
THIS IS WHAT YOU ALL HAVE BEEN
WAITING FOR.
NUTS AND BOLTS OF WHAT NEEDS TO
BE DONE, WHAT YOU NEED TO KNOW,
HOW YOU DO IT, TO GET FUNDED
THROUGH THE NIH EXTRAMURAL
RESEARCH SYSTEM.
I HOPE YOU STAY AWAKE FOR THIS
ONE BECAUSE THIS HAS A LOT OF
GOOD INFORMATION FOR YOU.
I DO WANT TO FIRST OF ALL SAY
THAT IN DISCLOSURE THIS
PRESENTATION HAS BEEN GIVEN IN
PREVIOUS YEARS BY MY GOOD FRIEND
AND COLLEAGUE, DR. (
INDISCERNIBLE) STILL WITH THE
ODS, RETIRED CONTRACTOR, MOST OF
THIS IS IS FROM HER
PRESENTATION.
I'M NOT GOING TO GIVE IT WITH
THE SAME WIT AND CHARM BUT
HOPEFULLY I CAN REMAIN TRUE TO
THE CONTENT.
THE PRESENTATION IS GOING TO
LOOK AT THE EXTRAMURAL SYSTEM AT
NIH, I'M GOING TO TALK ABOUT
THAT AND THE TOPICS FALL INTO
THREE MAIN BUCKETS.
FIRST, AN OVERVIEW OF THE NIH
AGENCY.
THEN WE'LL TALK ABOUT THE
SUPPORT OF NUTRITION
[AUDIO DISTORTION]
AND THEN FINALLY ABOUT HOW YOU
AS A RESEARCHER ARE LIKELY TO BE
INTERACTING WITH THE NIH
EXTRAMURAL SYSTEM.
SO, WHERE DOES THE NIH FIT IN
THE ENTIRE FEDERAL GOVERNMENT
SYSTEM?
ABBY WOULD SAY THIS IS YOUR
LESSON IN CIVICS.
THE NIH IS -- I'LL TURN MY LASER
ON HERE.
THE NIH IN THE MIDDLE IS A
SUBAGENCY OF THE DEPARTMENT OF
HEALTH AND HUMAN SERVICES, OR
DHHS.
WE ALL WORK UNDER THE AUTHORITY
OF THE PUBLIC HEALTH SERVICES
ACT.
AND THE JARGON TECHNICALLY IS
DHHS IS THE DEPARTMENT AND NIH
IS ONE OF THE AGENCIES IN THE
DEPARTMENT.
WITHIN THE DEPARTMENT WE HAVE
SISTER AGENCIES THAT YOU
CERTAINLY HEARD ABOUT,
ESPECIALLY THE CENTERS FOR
DISEASE CONTROL AND PREVENTION,
AND FOOD AND DRUG
ADMINISTRATION.
THERE ARE A NUMBER OF OTHER
AGENCIES WITHIN THE DEPARTMENT,
MOST OF THEM SOMEWHAT SMALLER.
BUT WE WORK CLOSELY WITH ALL OF
THESE OTHER AGENCIES, EACH ONE
HAS A SPECIALTY.
WE TRY TO AVOID OVERLAP AS WELL
AS COORDINATE PROGRAMS, AND
BASICALLY WE AIM FOR EFFICIENCY
AND GOOD STEWARDSHIP OF THE
PUBLIC'S DOLLAR.
SO A LITTLE BIT AT HIGH LEVEL
ABOUT THE NATIONAL INSTITUTES OF
HEALTH, OR NIH.
THE NIH HAS AN ARRAY OF
ACTIVITIES.
I'LL TALK A LOT ABOUT JARGON
TODAY.
HOPEFULLY SOME WILL BECOME
CLEARER TO YOU BY THE END OF
THIS PRESENTATION.
SO, NIH HAS A MAIN CAMPUS, MUCH
LIKE A UNIVERSITY CAMPUS OR
ACADEMIC RESEARCH CENTER CAMPUS
WITH LABORATORIES, AND CLINICAL
RESEARCH CENTER.
THE CLINICAL RESEARCH CENTER IS
ALSO THE NIH HOSPITAL, WHICH IS
PROBABLY THE BIGGEST BUILDING
I'VE EVER SEEN IN MY LIFE.
IT IS HUGE, BUT IT'S ALSO
RENOWNED.
THE NIH HAS SEVERAL SATELLITE
CENTERS, BOTH HERE IN THE D.C.
AREA AS WELL AS ELSEWHERE IN THE
U.S.
NIH CONDUCTS RESEARCH IN ITS OWN
LABORATORIES, AND THIS IS CALLED
INTRAMURAL PROGRAM.
INTRAMURAL FOR WITHIN THE WALLS.
NIH ALSO SUPPORTS RESEARCH
CONDUCTED BY NON-FEDERAL
SCIENTISTS AT ACADEMIC RESEARCH
INSTITUTIONS, RESEARCH
HOSPITALS, INDEPENDENT RESEARCH
ORGANIZATIONS.
AND THIS IS CALLED THE
EXTRAMURAL PROGRAM, OR OUTSIDE
THE WALLS.
NIH SUPPORTS TRAINING OF
RESEARCHERS, EITHER DIRECTLY,
THROUGH TRAINING PROGRAMS, SUCH
AS WHAT WE'RE DOING RIGHT NOW,
SABBATICALS, AND OTHER TRAINING
PROGRAMS ON CAMPUS, AS WELL AS
INDIRECTLY THROUGH THE SUPPORT
OF TRAINING GRANTS.
NIH ALSO FOSTERS COMMUNICATION
OF HEALTH INFORMATION AND
RESEARCH FINDINGS TO THE PUBLIC.
IT DEVELOPS SCIENCE BASE FOR
TRANSLATING BASIC RESEARCH,
BASIC SCIENCE RESEARCH FINDINGS
INTO CLINICAL GUIDELINES AND
COMMUNITY PROGRAMS.
AS FOR THE BUDGET, HOW MANY OF
YOU KNOW WHAT THE CURRENT NIH
BUDGET IS?
WRITE IT DOWN.
I'M GOING TO TELL YOU.
IT'S AN HONOR SYSTEM.
SEE IF YOU GET IT RIGHT.
FISCAL YEAR 2022, CONGRESS
INCREASED NIH'S BASE BY $2,000,
$2 BILLION -- $2 BILLION,
RECURRENT BUDGET IS $45 BILLION,
BILLION WITH A B, A LOT OF
MONEY.
THE AGENCY THAT CONGRESS ALMOST
ALWAYS LIKES, BOTH SIDES OF THE
AISLE, SO WE'RE FORTUNATE TO BE
IN THAT POSITION.
ABOUT 10% OF THE BUDGET COVERS
OVERHEAD, INCLUDES MAINTENANCE
OF THE BUILDINGS, FACILITIES,
PAYS SALARIES OF THE EMPLOYEES
THAT WORK WITHIN, PROVIDES OUR
SUPPLIES AND MATERIALS AND SO
ON.
BUT 10% OF IT COVERS THE
INTRAMURAL PROGRAM, RESEARCH
DONE BY THE INTRAMURAL
SCIENTISTS.
AND BELIEVE IT OR NOT 80% OR
MORE OF THE BUDGET ACTUALLY GOES
OUT THE DOOR.
THEN 80% OF THE BUDGET IS USED
TO SUPPORT BIOMEDICAL RESEARCH
CONDUCTED OUTSIDE OF THE NIH, IN
THOSE ACADEMIC RESEARCH CENTERS,
HOSPITALS, AND INDEPENDENT
RESEARCH ORGANIZATIONS.
NOW, AT THE NIH, IT'S A VERY BIG
PLACE, THERE ARE FIRST OF ALL
THE URL HERE WILL GIVE YOU THE
LIST OF ALL OF THE INSTITUTES
AND CENTERS THAT COMPRISE THE
NIH.
THERE ARE 28 INSTITUTES,
CENTERS, AND OFFICES.
JARGON ALERT, INSTITUTES AND
CENTERS WE OFTEN CALL I.C.s.
YOU HEAR THE TERM I.C.s.
WE'RE TALKING ABOUT INSTITUTES
AND CENTERS.
WE HAVE OFFICES WHICH I'LL
DESCRIBE LATER.
SOMETIMES WE SAY I.C.Os, WE'RE
TALKING ABOUT INSTITUTE CENTERS
AND OFFICES.
THERE ARE THREE SERVICE UNITS
INCLUDING THE CLINICAL CENTER,
THAT IS THE HOSPITAL I
MENTIONED.
THE CENTER FOR INFORMATION
TECHNOLOGY, THEY TAKE CARE OF
ALL COMPUTER, DIGITAL, DATABASE
NEEDS, AS WELL AS PRIVACY AND SO
ON AND SECURITY.
CENTER FOR SCIENTIFIC REVIEW OR
CSR, AND THAT CENTER IS
RESPONSIBLE FOR CONDUCTING THE
MAJORITY OF THE PEER REVIEW
MEETINGS FOR THE GRANT
APPLICATIONS.
WE HAVE WITHIN THE NIH OFFICE OF
THE DIRECTOR THERE ARE A NUMBER
OF NUTRITION-RELEVANT OFFICES.
THE NIH OFFICE OF DIRECTOR HAS
A HUGE BUNCH OF OFFICES.
MOST OF THEM ARE UNDER AN
UMBRELLA DIVISION CALLED DPCPSI,
AND THAT STANDS FOR DIVISION OF
PROGRAM COORDINATION PLANNING
AND STRATEGIC INITIATIVE.
I KNEW THAT.
WITHIN THE UMBRELLA OF DPCPSI,
THERE ARE ABOUT 12 OR 13
OFFICES, AND ONES ON THE SLIDE
I'VE LISTED ARE THE ONES THAT
HAVE SOME RELEVANCE OR OVERLAP
OR INTEGRATION WITH NUTRITION
AND DIETARY SUPPLEMENT RESEARCH.
I ALSO SHOULD MENTION THAT THEY
TEND TO HAVE SPECIALTY AREAS OR
TRANS-NIH FUNCTIONS OR OTHER
NICHE KINDS OF FUNCTIONS, I WILL
COME BACK TO SOME OF THOSE
LATER.
SO LET'S START WITH INFORMATION
ABOUT THE NIH OFFICE OF
NUTRITION RESEARCH, ONR.
AGAIN, THE WEBSITE OF THIS
OFFICE IS AT THE TOP OF THE
SLIDE.
I HAVE TAKEN SOME OF THE
LANGUAGE DIRECTLY FROM THEIR
WEBSITE AS WELL AS ON THE
PICTURES, BECAUSE THEY DESCRIBE
THE OFFICEES THE B
PRIMARILY, THE OFFICE OF
NUTRITION RESEARCH HAS A
COORDINATION FUNCTION.
SO, THE OFFICE COORDINATES
NUTRITION RESEARCH NOT ONLY
ACROSS THE NIH ICOS BUT ALSO
ACROSS OTHER HHS AGENCIES,
INCLUDING THE FDA AND CDC, AND
EVEN OTHER DEPARTMENTS SUCH AS
DEFENSE AND AGRICULTURE.
I WOULD SAY THAT PROBABLY THE
BIGGEST, THE MOST PRIMARY ROLE,
IS THE IMPLEMENTATION,
COORDINATION AND IMPLEMENTATION,
OF THE STRATEGIC PLAN FOR NIH
NUTRITION RESEARCH.
I BELIEVE THAT THE DEVELOPMENT
OF THE STRATEGIC PLAN IS A GREAT
ACCOMPLISHMENT OF THIS OFFICE
BECAUSE NIH HAS NEVER HAD A
STRATEGIC PLAN FOR NUTRITION
RESEARCH BEFORE.
SO, IT IS A WONDERFUL
ACCOMPLISHMENT AND WE ARE
FOLLOWING THAT STRATEGIC PLAN
NOW TO THE BEST OF OUR ABILITY.
ONR ALSO IDENTIFIES RESEARCH
PROJECTS THAT DESERVE EXPANDED
EFFORT AND SUPPORT BY THE ICOS.
DEVELOPS, LEADS, MANAGES
TRANS-NIH NUTRITION PROJECTS
WITH THE ICOS.
YOU'VE HEARD OF THE DEVELOPMENT
OF THE NUTRITION FOR PRECISION
HEALTH INITIATIVE.
NOW THAT IS MANAGED BY THE
OFFICE OF THE COMMON FUND,
THERE'S ALSO INTEGRATED INTO THE
NIH "ALL OF US" RESEARCH
PROGRAM.
BUT THE DEVELOP RELATIVE
HUMIDITY OF THE NUTRITION
PRECISION HEALTH WAS INDEED
ORIGINATED FROM THE OFFICE OF
NUTRITION RESEARCH.
THE OFFICE ALSO REPRESENTS THE
NIH ACROSS THE FEDERAL
GOVERNMENT, ON COMMITTEES
RELEVANT TO NUTRITION AND
NUTRITION RESEARCH, LAST BUT NOT
LEAST ADVISES THE NIH LEADERSHIP
AND OTHER KEY OFFICIALS ON
NUTRITION-RELATED MATTERS.
I WANT TO SHOW YOU A LITTLE BIT
OF DATA ABOUT THE NIH NUTRITION
RESEARCH PORTFOLIO.
THE GRAPH HERE, TWO GRAPHS HERE,
REPRESENT THE NIH NUTRITION
RESEARCH PORTFOLIO FROM FISCAL
YEAR 2008 THROUGH 2020.
THIS ANALYSIS WAS DONE BY THE
OFFICE OF PORTFOLIO ANALYSES.
ON THE LEFT YOU SEE IT SHOWS ON
THE HORIZONTAL AXIS ALL OF THE
NIH ICOS, AND ON THE VERTICAL
AXIS IS THE AMOUNT OF DOLLARS
INVESTED IN BILLIONS, THAT'S THE
INVESTMENT IN NUTRITION
RESEARCH, SPECIFICALLY IN TYPE I
AND TYPE II AWARDS.
I WILL GET INTO THOSE
DEFINITIONS LATER BUT BASICALLY
FOR NOW THOSE ARE NEW AND
RENEWAL RESEARCH PROJECTS, AND
THIS IS THE LEVEL OF -- SHOWS
INVESTMENT LEVEL OF ALL OF THE
ICOS.
ON THE RIGHT IT HAS THE SAME
HORIZONTAL AXIS, VERTICAL AXIS
IS NUMBER OF AWARDS, MAXIMUM UP
HERE IS 4,000.
IT IS SMALL BUT I'LL READ
RELEVANT DATA.
SO THE LARGEST NUTRITION
PORTFOLIOS IN TERMS OF DOLLARS
ARE IN THE ORDER (INDISCERNIBLE)
NATIONAL INSTITUTE THE DIABETES
AND DIGESTIVE AND KIDNEY
DISEASE, NIDDK, AT $2.1 BILLION
OVER THAT FIVE-YEAR -- OVER
THAT, SORRY, 12- YEAR PERIOD
FOLLOWED BY NHLBI AT
$0.8 BILLION, FOLLOWED BY NCI,
CANCER, $0.5 BILLION, FOLLOWED
BY NATIONAL INSTITUTES OF AGING,
$0.5 BILLION, AND THEN THE
NICHD, CHILD HEALTH AND
DEVELOPMENT, $0.4 BILLION.
IN TERMS OF NUMBER OF AWARDS,
PATTERN IS PRETTY MUCH THE SAME.
AND THAT IS THAT -- MY LASER IS
HAVING A MIND OF ITS OWN HERE.
I'M GOING TO TURN IT OFF.
SORRY.
THERE WE GO.
IN TERMS OF NUMBER OF AWARDS,
FOR THE SAME PERIOD, THE ICOS
WITH THE MOST AWARDS WERE NIDDK,
DIABETES AND DIGESTIVE AND
KIDNEY DISEASE, AT ALMOST 4,000,
NHLBI CLOSE TO 1400 AWARDS,
CANCER CLOSE TO 1300 AWARDS,
CHILD HEALTH HAD CLOSE TO 900
AWARDS, AND NATIONAL INSTITUTE
OF AGING HAD APPROXIMATELY 850
AWARDS.
SO, NUTRITION IN MANY WAYS IS A
VERY SUBSTANTIAL PART OF THE NIH
PORTFOLIO.
THIS IS ONE MORE DATA SLIDE.
THIS IS A FUN ONE.
THIS SLIDE ALSO DONE BY THE
OFFICE OF PORTFOLIO ANALYSIS
SHOWS THE DOLLAR INVESTMENT AND
NUMBER OF AWARDS.
IN TERMS OF TOPIC AREAS, THIS IS
A CLUSTER ANALYSIS.
THE SCALE FOR THE DOLLARS IS
OVER HERE.
THE MORE RED INDICATES HIGHER
DOLLAR INVESTMENT.
THE CIRCLES, SIZE OF THE
CIRCLES, REPRESENTS THE NUMBER
OF AWARDS.
SO AS THE CIRCLES GET LARGE
ISSUE -- LARGER, THE NUMBER OF
AWARDS GET LARGER.
I THINK I GOT RID OF THAT LASER.
THE LARGEST CLUSTERS IN TERMS OF
DOLLAR INVESTMENTS WERE OBESITY
PREVENTION.
I GOT IT UNDER CONTROL.
OBESITY PREVENTION, FOLLOWED BY
BMI ACTIVITY AND CARDIOVASCULAR
DISEASE.
FOLLOWED BY METABOLIC
MECHANISMS, FOLLOWED BY TYPE 2
DIABETES.
AND THE NUMBER OF AWARDS FOLLOWS
A SIMILAR PATTERN, THE LARGEST
NUMBER OF AWARDS IN THE AREA OF
OBESITY PREVENTION, AND
METABOLIC MECHANISMS, AND THEN
BMI ACTIVITY AND CARDIOVASCULAR
DISEASE.
I DON'T THINK IT'S TOO MUCH OF A
SURPRISE TO THIS AUDIENCE.
BUT IT DOES SERVE TO REMIND US
THAT OBESITY RESEARCH IS STILL A
VERY LARGE PORTION OF THE NIH
NUTRITION RESEARCH PORTFOLIO.
FOR YOUR INFORMATION, OBESITY
RESEARCH IS CARRIED OUT,
COORDINATED BY THE NIH OBESITY
RESEARCH TASK FORCE.
THEY HAVE A WEB PAGE, AND THAT
IS OBESITYRESEARCH.NIH.GOV.
YOU CAN LEARN MORE ABOUT THAT.
OKAY.
SO WHAT ABOUT THE ODS?
NOW, THE TOP OF THE SLIDE HAS
OUR URL FOR OUR WEBSITE.
ODS IS AN OFFICE, AND IT
SPONSORS AND SUPPORTS MANY
DIETARY SUPPLEMENT RESEARCH AND
RESEARCH-RELATED ACTIVITIES
COVERING NOT ONLY THE NUTRITION
SIDE BUT ALSO THE BOTANICAL
SIDE.
THIS SLIDE IS FROM THE LANDING
PAGE, PART OF THE LANDING PAGE
OF OUR WEBSITE.
I TOOK A SNIP OF THE LANDING
PAGE.
I LIKE THIS PART BECAUSE YOU
CAN -- YOU CAN CLICK ON ANY ONE
OF THESE IMAGES, IT WILL TAKE
YOU TO A DEEPER DISCUSSION OF
THE INDIVIDUAL PROGRAMS, WHAT'S
BEEN FUNDED, WHAT THE RESEARCH
IS, WHAT'S THE TOPICS ARE, AND
SO ON.
I ENCOURAGE YOU TO GO TO THIS
WEBSITE, ONE OF THE BEST
WEBSITES AT THE NIH.
I SAY THAT WITH CONFIDENCE
BECAUSE I'M BEEN AT THE NIH FOR
20 YEARS AND HAVE SEEN A LOT OF
WEBSITES.
IT IS A MILE WIDE AND SEVERAL
MILES DEEP.
NOW, IF YOU AGAIN, WHEN YOU
CLICK ON THESE AREAS, YOU'RE
ALSO GOING TO SEE THAT A
SUBSTANTIAL PART OF OUR SUPPORT
IS NOT EXTRAMURAL BUT IN
ADDITION TO EXTRAMURAL IT IS
SOME INTERAGENCY AGREEMENTS,
SOME RESEARCH CONTRACTS, EVEN
SOME INTRAMURAL RESEARCH
PROGRAMS.
I WANT TO POINT OUT THE PROGRAM
IN THE BOTTOM RIGHT CORNER,
EDUCATION AND TRAINING.
IF YOU CLICK ON THAT, YOU'RE
GOING TO BE TAKEN TO A SECTION
THAT TELLS YOU MORE ABOUT SOME
NON-EXTRAMURAL PROGRAMS
INCLUDING THE ODS SEMINAR
SERIES, WHICH IS AN EXCELLENT
SERIES THAT RUNS APPROXIMATELY
THE ACADEMIC YEAR, AS WELL AS
THIS PRACTICUM THAT WE'RE IN
RIGHT NOW, AS WELL AS ODS
RESEARCH SCHOLARS PROGRAM.
THE LATTER, WHICH I MENTIONED TO
YOU A COUPLE OF ADDITIONAL
POINTS RESEARCH SCHOLARS PROGRAM
PROVIDES SUPPORT TO EARLY CAREER
SCIENTISTS WITH MENTORS IN THE
INTRAMURAL LABS WHO WISH TO DO
RESEARCH ON DIETARY SUPPLEMENTS.
ODS PROVIDES ONE-YEAR SUPPORT,
$100,000, AN APPLICATION PROCESS
IS INVOLVED AND INTERNAL
EVALUATION IS CONDUCTED.
IF YOU'RE INTERESTED REACH UP ON
THE-- REACH OUT AND CONTACT ME
FOR DETAILS.
YESTERDAY YOU HEARD ABOUT DAD
BASE, TODAY ABOUT THE CARBON AND
BOTANICAL PROGRAM, YOU JUST
HEARD ABOUT THE RESILIENCE
PROGRAM, AND NOW I'M GOING TO
TAKE YOU TO THE WORLD OF GRANTS
AND FUNDING AND TALK ABOUT
EXTRAMURAL GRANTS.
SO THIS IS THE PAGE FROM OUR
WEBSITE THAT DEALS WITH GRANTS
AND FUNDING OPPORTUNITIES.
THE URL IS HERE, YOUR
INFORMATION.
I WANT TO CALL YOUR ATTENTION TO
THREE HIGH LEVEL POINTS THAT YOU
SHOULD BEAR IN MIND.
FIRST OF ALL, AS AN OFFICE, LIKE
OTHER O.D. OFFICE, ODS IS NOT A
PRIMARY FUNDER OF EXTRAMURAL
GRANTS.
SO, WE DON'T HAVE GRANT-MAKING
AUTHORITY IN THE SAME WAY THAT
NIH RESEARCH INSTITUTES DO.
SO, WE CANNOT AWARD OR
ADMINISTER GRANTS THE SAME WAY
THEY CAN.
HOWEVER, THERE ARE TWO OTHER
WAYS THAT WE DO OR CAN AND WE DO
SUPPORT EXTRAMURAL GRANTS.
ONE IS THROUGH CO-FUNDING.
SO WE CAN CO-FUND GRANTS
ASSIGNED TO OTHER NIH
INSTITUTES.
WHAT DOES CO-FUNDING MEAN?
JUST AS THE TERM SUGGESTS, IT IS
A SHARING OF COSTS OF A
COMPETING RESEARCH PROJECT.
SO CO-FUND IS A FINANCIAL
AGREEMENT BETWEEN TWO OR MORE
ICOS.
IT IS AGREEMENT BETWEEN THE
ICOS, AFTER THE APPLICATION HAS
COME IN THE DOOR, AND HAS GONE
THROUGH PEER REVIEW, BUT BEFORE
THE PROJECT IS FUNDED.
SO THAT'S IMPORTANT.
THE CO-FUND IS AN AGREEMENT
BETWEEN TWO OR MORE ICOS, TO
SHARE THE COST OF A RESEARCH
PROJECT, AFTER THAT APPLICATION
HAS BEEN RECEIVED, GONE THROUGH
PEER REVIEW, BUT BEFORE ANY
FUNDING DECISION HAS BEEN MADE.
ODS CO-FUNDS NEW AND RENEWAL
GRANT WITH PARTNER ICOS.
NOW, THE APPLICANT HAS NO ROLE.
THIS IS AN INTERNAL
BEHIND-THE-SCENES PROCESS, THE
APPLICANT CANNOT ARRANGE A
CO-FUND AGREEMENT BETWEEN
INSTITUTES.
THE CO-FUND IS MADE, YOU KNOW,
WITH CERTAIN REQUIREMENTS,
ACONDITIONS GIVEN, MET BY THE
PROGRAM.
THE PROJECT MUST HAVE RELEVANCE
TO OUR MISSION AND TO ONE OR
MORE OF OUR STRATEGIC
OBJECTIVES.
OFTEN, ODS PARTICIPATE IN
DEVELOPMENT OF THE FUNDING
INITIATIVE THAT AN APPLICATION
HAS RESPONDED TO.
AND IN FACT WE HAVE INTEREST IN
MANY TRANS-NIH INITIATIVES AND
THAT OPENS UP A NUMBER OF
POSSIBILITIES FOR CO-FUNDING.
SO THE OTHER WAY WE SUPPORT
GRANTS THROUGH ADMINISTRATIVE
SUPPLEMENTS.
SO ODS CAN FOUND ADMINISTRATIVE
SUPPLEMENTS TO EXISTING GRANTS.
THE PROJECT THAT'S ALREADY
EXISTING, ALREADY FUNDED, THIS
IS ADMINISTRATIVE SUPPLEMENTS
ESSENTIALLY ADD-ONS, TO THE
EXISTING PROJECT.
SO, IN THIS CASE, FOR ODS,
SUPPORT AND ADMINISTRATIVE
SUPPLEMENT, WITH ADDITION OF A
DIETARY SUPPLEMENT RESEARCH
COMPONENT, AND MAY BE A NEW
SPECIFIC AIM BUT USUALLY IT'S
NOT.
COULD BE JUST SOME ADDITIONAL
COMPONENT.
AS LONG AS IT IS WITHIN THE
SCOPE OF THE ORIGINAL PARENT
GRANT.
NOW, WE HEARD YESTERDAY THE
DEFINITION OF DIETARY SUPPLEMENT
RESEARCH BUT I'M GOING TO REMIND
YOU AGAIN ANYWAY BECAUSE THERE'S
A LOT OF TALKS THAT HAVE
OCCURRED IN BETWEEN THEN.
SO, DIETARY SUPPLEMENT RESEARCH
INCLUDES RESEARCH ON VITAMINS,
MINERALS, HERBS, OTHER
BOTANICALS, AMINO ACIDS, OTHER
DIETARY SUPPLEMENT OR BIOACTIVE
SUBSTANCES, AS WELL AS EXTRACTS,
CONCENTRATES, METABOLITES,
CONSTITUENTS THAT ARE AVAILABLE
WITHOUT PRESCRIPTION, THAT ARE
INTENDED TO BE TAKEN BY MOUTH,
CONSUMED, IN ADDITION TO REGULAR
DIET, TO PROMOTE HEALTH AND
PREVENT DISEASE.
ON THE RIGHT SIDE OF THE SLIDE
HERE IS A PICTURE FROM THE WEB
PAGE, AND I HAVE CIRCLED IN RED
SOME COMPONENT, SOME PARTS OF
THIS THAT I STRONGLY URGE YOU TO
GO TO AND READ FOR MORE
INFORMATION.
HERE ODS RESEARCH PORTFOLIO,
CLICK ON THIS, YOU'LL BE TAKEN
TO A LIST OF ALL OF THE
EXTRAMURAL GRANTS THAT ODS HAS
FUNDED, IN THE PAST MANY FISCAL
YEARS SO YOU WILL GET A FLAVOR
OF THE TYPES OF PROJECTS THAT WE
FUND.
HERE IF YOU CLICK ON THIS,
YOU'LL BE TAKEN TO AN
ANNOUNCEMENT FOR FUNDING
OPPORTUNITY FOR ADMINISTRATIVE
SUPPLEMENTS FOR RESEARCH ON
DIETARY SUPPLEMENTS, THE NUMBER
HAPPENS TO BE PA 20-227, IT IS
CURRENTLY ACTIVE.
HERE, PRODUCT INTEGRITY
INFORMATION, CLICK ON THIS
SECTION, IT'S GOING TO TAKE YOU
TO MORE INFORMATION, MORE
IN-DEPTH INFORMATION, DETAIL AND
RESOURCES ABOUT WHAT I MEANS TO
PROVIDE PRODUCT INTEGRITY
INFORMATION, AND THIS IS
IMPORTANT IF YOUR RESEARCH
PROJECT INVOLVES TESTING A
DIETARY SUPPLEMENT OR
INTERVENING WITH A NEW DIETARY
SUPPLEMENT.
YOU WILL NEED TO PROVIDE THAT
INFORMATION IN YOUR APPLICATION.
IN THIS SECTION, THIS IS ALL
ABOUT ODS FUNDING OF GRANTS AND
ADMINISTRATIVE SUPPLEMENTS.
AND THE FREQUENTLY ASKED
QUESTIONS AND ANSWERS WHICH IS
VERY USEFUL.
AND THIS SECTION HERE IS ABOUT
ADMINISTRATIVE SUPPLEMENTS FOR
VALIDATION STUDIES OF ANALYTICAL
METHODS, WHICH TIES TO THE
PROGRAM THAT DR. KUZAK WAS
TALKING ABOUT EARLIER.
THIS PARTICULAR ANNOUNCEMENT HAS
JUST EXPIRED, BUT WE ARE
CURRENTLY WORKING TO REISSUE IT.
AND IT WILL BE REISSUED IN TIME
FOR THE NEXT RECEIPT DATE, WHICH
IS OCTOBER 15.
SO LAST BUT NOT LEAST ON THE
RIGHT SIDE OF THE PAGE, UNDER
ANNOUNCEMENTS, IS A LIST WITH
LINKS TO ACTIVE FUNDING
ANNOUNCEMENTS OUT THERE
AVAILABLE TO YOU.
OKAY.
OOPS.
GO BACK.
THERE WE GO.
SO, NOW I WANT TO TALK A LITTLE
BIT MORE ABOUT THE NIH
EXTRAMURAL SYSTEMS, REALLY THE
MACHINERY OF THE EXTRAMURAL
PROGRAM.
I ENCOURAGE YOU TO VISIT THE
WEBSITE, THE OFFICE OF
EXTRAMURAL RESEARCH, HERE'S URL.
PLENTY OF INFORMATION BEHIND
THAT URL.
A VERY HIGH LEVEL, IF YOU'RE
ENTERING INTO THIS WORLD, YOU
SHOULD UNDERSTAND THAT THERE ARE
ORGANIZATIONAL COMPONENTS AND
FUNCTIONS OF THOSE COMPONENTS.
THE ORGANIZATIONAL COMPONENTS
WITHIN -- ARE WITHIN EACH I.C.
AND CONSIST OF PROGRAM OFFICES,
PROGRAM OFFICES ARE DIVISIONS,
OR BRANCHES, THAT HAVE SPECIFIC
SCIENTIFIC FOCUS OR PRIORITY.
THERE ARE ALSO MANAGEMENT
OFFICES, INCLUDING BRANCH
MANAGEMENTS, USUALLY A BUDGET
OFFICE, AND ACQUISITION OFFICE,
NOT ALWAYS WITH SOME SMALLER
I.C.s, BUT ACQUISITIONS WILL
BE OVERSEEING RESEARCH
CONTRACTS.
AND THEN MANY OF THE INSTITUTES
HAVE THEIR OWN PEER REVIEW
UNITS.
AND THEN YOU HAVE PROGRAM
OFFICIALS.
SO THESE ARE THE PEOPLE WITHIN
THE OFFICES THAT YOU WILL LIKELY
BE INTERACTING WITH, AND THEY
HAVE A NUMBER OF DUTIES AND
FUNCTIONS TOO LONG TO LIST HERE.
BUT IN GENERAL PROVIDE GUIDANCE
TO APPLICANTS AND AWARDEES, THEY
DEVELOP AND MANAGE PORTFOLIOS
AND THEY MONITOR THE AWARDS OF
THE BRANCH WITHIN THEIR
PORTFOLIOS.
ALL OF THESE COMPONENTS HAVE
CHARTERED RESPONSIBILITIES THAT
REVOLVE AROUND THE MISSION AREAS
OF THEIR INDIVIDUAL --
SCIENTIFIC MISSION AREAS AROUND
THEIR INDIVIDUAL I.C.s.
THEY ALL PROVIDE GUIDANCE AND
SERVICE, SERVICES TO THE
APPLICANTS AND AWARDEES.
THEY PROVIDE SCIENTIFIC FISCAL
ETHICAL AND LEGAL OVERSIGHT,
POLICIES AND COMPLIANCE,
RECOMMEND FUNDING, IN
COORDINATION WITH OVERSIGHT
COMMITTEES.
AND PORTFOLIOS ARE DEVELOPED
THROUGH WORKSHOPS, CONFERENCES,
AND RESEARCH SOLICITATIONS,
THERE ARE PROGRAMS DESIGNED TO
DEVELOP INDIVIDUAL AND INSTITUTE
RESEARCH CAPACITY FOR
CONSTITUENTS THROUGH TRAINING
AND INFRASTRUCTURE SUPPORT.
OKAY.
NOW, WHAT ARE THE NIH
MECHANISMS?
MORE JARGON, ALERT, ALERT!
MECHANISMS, THIS IS A TERM YOU
HEAR A LOT.
IT IS AN UMBRELLA TERM.
AND IT REFERS TO THE WAY THE NIH
SUPPORTS GRANTS.
AND THE NIH DISTINGUISHES GRANTS
BY VARIOUS CHARACTERISTICS, SUCH
AS THE PURPOSE, TYPE OF THE
RECIPIENT, THE AMOUNT OF MONEY
AVAILABLE, OTHER
CHARACTERISTICS.
THE MAIN FUNDING MECHANISM THAT
YOU'VE LIKE LIKELY HEARD OF
GRANTS, COOPERATIVE AGREEMENTS,
CONTRACTS.
THERE ARE OTHERS, BUT MAIN ONES
ARE THESE.
AND THE ONCE WE'RE GOING TO
FOCUS ON IN -- ONES WE'RE GOING
TO FOCUS ON IN THIS PRESENTATION
ARE GRANTS.
ONE WAY THAT THE NIH
DIFFERENTIATES THIS WIDE VARIETY
OF RESEARCH PROGRAMS IS THROUGH
ACTIVITY CODES.
ACTIVITY CODES ARE THREE
CHARACTER CODES THAT INDICATE
THE CATEGORY AND SPECIFIC FORM
OF SUPPORT.
FOR EXAMPLE, R01, U01.
FOR A FULL LIST OF THOSE
ACTIVITY CODES, HERE'S THE URL.
AGAIN, I ENCOURAGE YOU TO GO TO
THAT WEBSITE, YOU KNOW, IF
YOU'RE BEGINNING TO ENTER THIS
WORLD AND SEEKING SUPPORT.
HOPING TO MAKE THIS A CAREER.
I DO WANT TO POINT OUT TO YOU
THOUGH THAT NIH I.C.s MAY VARY
IN THE WAY THEY USE SPECIFIC
ACTIVITY CODES, A COUPLE
EXAMPLES ARE R21 AND R56, THEY
ARE USED SLIGHTLY DIFFERENTLY
AMONGST THE I.C.s.
AND THEN NOT ALL I.C. ACCEPTS
APPLICATION FOR ALL ACTIVITY
CODES.
THAT WOULD BE TOO MUCH.
IN TERMS OF GRANT TYPES, WE
HAVE -- THESE ARE CATEGORIES,
RIGHT?
GRANT TYPES AGAIN IS A KIND OF
UMBRELLA TERM.
BUT THE SAKE OF THIS DISCUSSION,
ONE WAY TO CHARACTERIZE GRANT
TYPES IS THROUGH CATEGORIES.
ACTUALLY BUDGET CATEGORIES.
ONE CATEGORY IS RESEARCH PROJECT
GRANTS, AND THAT ARE SUCH THINGS
AS R01, R21, R03, LARGE CENTER
GRANTS BEGIN WITH P ACTIVITY
CODES SOMETIMES USED.
THERE ARE TRAINING MECHANISMS,
MOST OF THESE BEGIN WITH
ACTIVITY CODES F, T, OR Ks.
SMALL BUSINESS AND TECHNOLOGY
TRANSFER AWARDS, SBIR, STTR, AND
THERE'S RESEARCH RESOURCES AND
INFRASTRUCTURE AWARDS, THERE ARE
OTHER CATEGORIES BUT THOSE ARE
THE MOST COMMON THAT YOU'LL RUN
INTO.
AGAIN, THIS IS A URL THAT WILL
TAKE YOU TO A LIST OF THESE
DIFFERENT GRANT TYPES.
BY FAR AND LARGE THE ONE THAT IS
MOST WELL KNOWN IS THE R01
RESEARCH PROJECT GRANT.
THAT IS I BELIEVE STILL
CONSIDERED TO BE THE GOLD
STANDARD OF NIH RESEARCH
SUPPORT.
IT IS I THINK A PREVAILING
BELIEF THAT ONCE YOU HAVE AN R01
YOU ARE ON YOUR WAY BECAUSE IT'S
A BIG -- QUITE A BIG
ACCOMPLISHMENT TO GET THAT FIRST
R01.
OKAY.
AND I ADDED THIS SLIDE BECAUSE I
THINK IT IS IMPORTANT, AND I'M
OFTEN SURPRISED AT HOW MANY
PEOPLE DON'T KNOW WHAT
APPLICATION TYPES ARE.
NOW, THIS IS JARGON THAT'S NOT
FOR THE FAINT HEARTED.
ALERT.
THIS IS ALSO SOME JARGON THAT'S
PROBABLY MORE IMPORTANT TO KNOW
ONCE YOU HAVE RECEIVED AN NIH
AWARD.
FOR EXAMPLE, IF YOU'RE READING
UP ON NIH POLICY NOTICES, OR
YOU'RE ON AN I.C. WEBSITE, AND
READING A PAGE, YOU MIGHT BE
LOOKING UP PAY LINES OR MAY BE
SPEAKING TO A PROGRAM OFFICIAL,
THESE ARE -- I'VE LISTED A FEW
OF THE TYPES.
THERE ARE OTHERS.
BUT THESE ARE THE MOST IMPORTANT
ONES.
A TYPE 1 MEANS THAT THIS IS A
NEW RESEARCH PROJECT THAT HAS
NEVER HAD PRIOR NIH FUNDING.
IT IS COMPETING, IT HAS TO GO
THROUGH PEER REVIEW.
TYPE 2 IS A RENEWAL.
SO, IT HAD -- THIS IS A RESEARCH
PROJECT WITH PRIOR FUNDING, THAT
FUNDING ENDED.
NOW THE APPLICATION IS COMING
IN.
IT IS COMPETING APPLICATION FOR
CONTINUATION OF SUPPORT.
AND EASY EXAMPLE IS AN R01
FUNDED FOR FIVE YEARS, COMES TO
THE END OF THAT FIVE YEARS, AND
NOW THE P.I. SUBMITS A ANOTHER
COMPETING APPLICATION FOR
ANOTHER FIVE YEARS OF SUPPORT.
YEARS SIX THROUGH TEN.
THAT'S TYPE 2.
A DATA SLIDES I SHOWED TYPE 2
AND TYPE 2 ON THE SLIDE.
TYPE 3 IS A SUPPLEMENT TO AN
EXISTING GRANT.
AND TO MAKE THINGS REALLY
INTERESTING, NIH HAS BOTH
COMPETITIVE AND NON-COMPETITIVE
ADMINISTRATIVE -- COMPETITIVE
SUPPLEMENTS.
ADMINISTRATIVE SUPPLEMENTS ARE
NON-COMPETITIVE BY DEFINITION.
A COMPETITIVE SUPPLEMENT MUST GO
THROUGH PEER REVIEW.
TYPE 5 IS A NON-COMPETING
CONTINUATION, THIS IS AN EASY
ONE.
THIS IS THE OUTYEAR.
YOU GET YOUR R01, YEAR 1 IS
COMPETING YEAR, HAS TO GO
THROUGH PEER REVIEW, YEARS 2, 3,
4 AND 5 DON'T HAVE TO GO THROUGH
PEER REVIEW EACH OF THOSE YEARS.
THOSE ARE THE OUTYEARS, EACH
CALLED TYPE 5s.
AGAIN FOR A LIST OF APPLICATION
TYPES, HERE IS THE URL.
OKAY.
SO, WHAT IS A FUNDING
OPPORTUNITY ANNOUNCEMENT?
IT IS, I QUOTE, A PUBLICLY
AVAILABLE DOCUMENT IN WHICH THE
FEDERAL AGENCY MAKES KNOWN ITS
INTENTIONS TO AWARD, USUALLY AS
A RESULT OF COMPETITION FOR
FUNDS, THAT'S STRAIGHT FROM THE
NIH GRANTS MANUAL.
WE CALL THEM FOAs, FUNDING
OPPORTUNITY ANNOUNCEMENTS.
FOA IS THE ACRONYM.
NIH FOAs PRIMARILY FALL INTO
THE CATEGORIES OF PROGRAM
ANNOUNCEMENTS, REQUESTS FOR
APPLICATIONS, PARENT
ANNOUNCEMENT.
PROGRAM ANNOUNCEMENTS ARE
ANNOUNCEMENTS OF A NEW OR
ONGOING EXTRAMURAL ACTIVITY,
PROGRAM, MAY SERVE AS REMINDER
OF CONTINUING INTEREST IN
RESEARCH AREA, OR DESCRIBE
MODIFICATION OF AN ACTIVITY OR
PROGRAM, USUALLY ALWAYS INVITE
APPLICATIONS.
RFA SOLICITS GRANT OR
COOPERATIVE AGREEMENT
APPLICATIONS IN A WELL-DEFINED
SCIENTIFIC AREA TO ACCOMPLISH
SPECIFIC PROGRAM OBJECTIVES.
AND A PARENT ANNOUNCEMENT, VERY
GENERIC, THESE ARE OMNIBUS OR
PARENT ANNOUNCEMENTS PROVIDED TO
APPLICANTS BECAUSE EVERY
APPLICATION MUST BE SUBMITTED
ELECTRONICALLY UNDER SOME FOA,
UNDER THE GUISE OR UMBRELLA OF
AN ANNOUNCEMENT.
AND THE PROJECT SUBMITTED UNDER
PARENT ANNOUNCEMENTS ARE NOT
TARGETED TO ANY SPECIFIC
INITIATIVE BUT THEY ARE FUNNELED
TO THE CORRECT -- MOST FITTING
INSTITUTES ONCE THEY COME IN THE
DOOR.
REQUEST FOR PROPOSALS, RFPs,
SOLICITATIONS FOR CONTRACTS,
RESEARCH CONTRACTS.
WE'RE NOT GOING TO TALK ABOUT
THOSE TODAY BECAUSE THEY ARE
VERY, VERY DIFFERENT.
THEY ARE NOT AS FREQUENT.
SO, NIH ALSO HAS AN EXTENSIVE
TRAINING AND CAREER DEVELOPMENT
PROGRAM.
THIS IS FROM THE WEBSITE FOR
TRAINING AND CAREER DEVELOPMENT.
AGAIN, THE URL IS HERE.
I LOVE THIS WEBSITE.
IT IS EXTREMELY THOROUGH, IT'S
BEEN HERE FOR A LONG TIME.
THEY REALLY BUILT IT UP AND MADE
IT A BEAUTIFUL WEBSITE.
IT'S EASY TO USE.
VERY COMPREHENSIVE.
AT THE TOP YOU HAVE THE
TRAJECTORY, GENERIC TRAJECTORY
OF RESEARCH CAREER.
CLICK ON ANY BOX, IT WILL TAKE
YOU TO MORE INFORMATION ABOUT
THAT STAGE OF THE RESEARCH
CAREER.
MOST OF THE TRAINING AND CAREER
DEVELOPMENT GRANTS FALL INTO
THREE GROUPS, ONE IS THE
INSTITUTIONAL AND INDIVIDUAL
TRAINING GRANTS, THEY BEGIN WITH
Ts FOR THE MOST PART.
ANOTHER GROUP ARE THE INDIVIDUAL
FELLOWSHIPS WHICH BEGIN WITH
Fs.
AND THEN THE OTHER GROUP IS
CAREER DEVELOPMENT AWARDS WHICH
BEGIN WITH Ks FOR THE MOST
PART.
THE MIDDLE OF THE PAGE YOU SEE
KIOSKS.
WHEN YOU'RE ON THE SITE, IF YOU
CLICK ON ANY OF THESE KIOSKS IT
WILL TAKE YOU TO MUCH MORE
INFORMATION ABOUT EACH OF THOSE
AREAS.
IN THE CAREER DEVELOPMENT KIOSK
YOU'LL SEE 15 DIFFERENT TYPES OF
K GRANTS.
RESEARCH TRAINING KIOSK THERE'S
SEVEN DIFFERENT TYPES OF
PROGRAMS.
IN THE FELLOWSHIP KIOSK THERE
ARE ALSO SEVEN DIFFERENT TYPES
OF FELLOWSHIPS, FELLOWSHIP
GRANTS.
THE OTHER TRAINING-RELATED
KIOSK, DP 2, DP 5, R35, LRP LOAN
REPAYMENT PROGRAM AND
ADMINISTRATIVE SUPPLEMENTS TO
PROMOTE DIVERSITY AND
HEALTH-RELATED RESEARCH AND
REENTRY INTO THE BIOMEDICAL WORK
FORCE FOR THOSE WITH
INTERRUPTIONS IN THEIR CAREERS.
NOT ALL I.C.s HAVE ALL OF
THESE GRANT MECHANISMS TO OFFER.
THAT WOULD BE TOO MUCH.
BUT ON THE WEBSITE THERE'S A
VERY NICE LINK THAT WILL TAKE
YOU TO A TABLE, THAT TABLE WILL
TAKE YOU TO EACH OF THE I.C.s,
WHICH EVER ONE YOU'RE INTERESTED
IN, TO THEIR TRAINING PAGE WHERE
THEY WILL DESCRIBE THE TRAINING
PROGRAMS THEY OFFER.
I ALSO SHOULD POINT OUT THIS
ONE, EXTRAMURAL DIVERSITY KIOSK,
CLICK ON THAT KIOSK AND IT
BRINGS YOU ALMOST TO AN ENTIRELY
NEW WEBSITE, IT SEEMS.
IT'S VERY EXTENSIVE.
THIS KIOSK COVERS ALL OF THE --
IT'S A WEALTH OF INFORMATION
ABOUT HOW NIH PROMOTES
SCIENTIFIC -- DIVERSE SCIENTIFIC
RESEARCH WORKFORCE AND DOES
INCLUDE FUNDING OPPORTUNITIES AS
WELL.
OKAY.
NOW, WE'RE GOING TO TALK ABOUT
HOW YOU INTERACT WITH THIS
SYSTEM AND THE PEOPLE.
HOW CAN I IDENTIFY TOPICS,
FUNDING MECHANISMS, FUNDING
OPPORTUNITIES?
YOU NEED TO BECOME FAMILIAR WITH
NIH-WIDE AND I.C. WEBSITES.
I KNOW IT SOUNDS TRITE BUT IT IS
REALLY TRUE.
IT IS SO HELPFUL AND SO MUCH
MORE PRODUCTIVE IF YOU'RE DONE
YOUR HOMEWORK BY LOOKING THROUGH
SOME OF THESE WEBSITES, THAT'S
THE REASON I GAVE YOU SO MANY
URLs IN THE PREVIOUS SLIDES.
BEFORE YOU CONTACT A PROGRAM
OFFICIAL.
BECAUSE YOU'LL BE INFORMED.
SOMEWHAT INFORMED.
ALSO, BECOME FAMILIAR WITH THE
NIH GUIDE FOR GRANTS AND
CONTRACTS, AND I'LL SHOW YOU
MORE IN JUST A MINUTE.
WHEN YOU ATTEND SCIENTIFIC
MEETINGS, CORNER AN NIH
OFFICIAL.
NIH PROGRAM OFFICIALS LOVE TO
ANSWER QUESTIONS.
LOVE TO FEEL LIKE THEY ARE
HELPING YOU.
CONTACT AN OFFICIAL FOR GUIDANCE
ON WHETHER CERTAIN FUNDING
MECHANISMS ARE SUITABLE FOR YOU
OR WHAT FUNDING ANNOUNCEMENTS
ARE OUT THERE.
SCIENTIFIC TOPIC THAT YOU HAVE
AND ARE DEVELOPING, TYPE OF
PROJECT, ALSO TO ASK ABOUT
WHAT'S AVAILABLE FOR YOUR CAREER
STAGE AND YOUR PRIOR RESEARCH
EXPERIENCE.
THERE ARE MANY GOOD PROGRAMS AND
POLICIES AVAILABLE FOR
EARLY-STAGE INVESTIGATORS, THAT
PROVIDE VERY ADVANTAGEOUS
CLIMATES FOR YOUR APPLICATION.
AND DO FOLLOW UP.
>> DR. HAGGERTY, WE'RE AT TIME.
A FEW MORE MINUTES TO WRAP UP.
>> SURE.
I'M GOING TO JUST SKIP THAT ONE.
AND SHOW YOU THE GUIDE.
THIS IS A PAGE FROM THE NIH
GUIDE.
THAT IS WHERE YOU WILL FIND
PROGRAM ANNOUNCEMENTS.
[AUDIO DISTORTION]
IN THE MIDDLE YOU CAN PUT A
SEARCH TERM IN.
[AUDIO DISTORTION]
THIS IS RECENT.
>> WE'RE GETTING SOME FEEDBACK
WITH YOUR MICROPHONE.
>> IS THAT BETTER?
>> YES, MUCH BETTER.
>> OKAY.
SO THAT'S WHAT YOU'LL SEE.
I ENCOURAGE YOU NOT TO LIMIT
YOURSELF TO THE WORD
"NUTRITION."
HOW CAN I IDENTIFY?
AGAIN, MORE ON THIS TOPIC, NIH
REPORTER IS ANOTHER BEAUTIFUL
WEBSITE.
I THINK IT'S PROBABLY THE BEST
RESOURCE THAT THE NIH HAS.
IN ADDITION TO REPORTER, YOU
ALSO HAVE CLINICALTRIALS.GOV, A
WORLDWIDE DATABASE, PRIVATELY
AND PUBLICLY FUNDED CLINICAL
TRIALS STUDIES AND REGISTRATION
IS REQUIRED NOW BEFORE JOURNALS
WILL PUBLISH YOUR PAPERS.
I'M PUTTING THIS IN HERE BECAUSE
I JUST FOUND OUT, I RECENTLY
JUST LEARNED THAT THE FEDERAL
REPORTER, WHICH SOME OF YOU KNOW
ABOUT, HAS BEEN PUT TO SLEEP.
AND IS NOW REPLACED BY ANOTHER
SITE CALLED U.S. SPENDING,
USSPENDING.GOV, THERE FOR YOUR
INFORMATION.
AND THE NIH REPORTER IS A
WONDERFUL RESOURCE, HERE IS THE
WEBSITE.
THIS IS ACTUALLY THE MODERNIZED
VERSION OF THE REPORTER WEBSITE.
IT WAS JUST RELEASED TO THE
PUBLIC IN OCTOBER OF 2020.
IT HAS A GUIDED TOUR FOR YOU UP
HERE.
IT ALSO HAS A QUICK SEARCH BAR.
YOU CAN PUT IN A TERM LIKE A
P.I. NAME, OR A PROJECT NUMBER,
OR A FISCAL YEAR.
I WOULD NOT ENCOURAGE YOU TO
JUST PUT IN A FISCAL YEAR
BECAUSE YOU'LL GET A LONG LIST
BUT WILL PULL UP EVERYTHING
FUNDED BASED ON YOUR SEARCH
TERM.
THE REPORTER, NIH REPORTER, IS A
DATABASE THAT CONTAINS FUNDED --
INFORMATION ON FUND RESEARCH
PROJECTS, DOES NOT CONTAIN
INFORMATION ON APPLICATIONS THAT
WERE NOT FUNDED.
IN REPORTER YOU CAN DO MANY
DIFFERENT THINGS.
YOU CAN USE AN ADVANCED SEARCH
FEATURE WHICH HAS MULTIPLE
DIFFERENT FILTERS, THAT YOU CAN
SET TO NARROW DOWN THE SEARCH
THAT YOU WANT TO FIND FUNDED
RESEARCH THAT IS GOING TO INFORM
WHAT YOU ARE TRYING TO DO.
AND IT ALSO HAS A VERY COOL
TOOL, I'M GOING TO MENTION THE
MATCHMAKER, FOR ONE.
MATCHMAKER IS A NEW FUNCTION IN
REPORTER.
AND THIS IS -- YOU CAN ENTER
ANYTHING HERE, ENTER UP TO
15,000 CHARACTERS, CAN YOU ENTER
EXTRACTS, MATCHMAKER WILL
RETURN SIMILAR PROJECTS
ASSOCIATED WITH THOSE PROJECTS.
SO THIS IS ONE WAY TO FIND
PROGRAM OFFICIALS THAT ARE
MATCHED TO YOUR AREA OF SCIENCE.
I WOULD ENCOURAGE YOU TO PLAY
WITH THIS, TRY IT OUT.
YOU CAN ALSO LOOK AT THE ONR AND
ODS WEBSITES.
WE HAVE VARIOUS COMMITTEES,
WORKING GROUPS, WITH LISTS OF
MEMBERS AND YOU CAN FIND I.C.
REPRESENTATIVES ON THOSE LISTS.
AND LAST BUT NOT LEAST OF COURSE
LOOK AT THE INDIVIDUAL I.C.
WEBSITES AS I MENTIONED BEFORE.
SO, IN CLOSING, LAST SLIDE IS
THIS.
THERE ARE A NUMBER OF EXCELLENT
GRANTSMANSHIP WEBSITES DEVELOPED
BY NIAID.
AND THIS WAS IN HERE LAST YEAR
BEFORE I WAS HERE AT ODS, SO
IT'S NOT JUST BECAUSE I WAS AT
NIAID FOR 13 YEARS, IT'S IN
HERE.
ALL OF THE I.C.s LIKE TO USE
NIAID'S WEBSITE, PARTICULARLY
THESE RESOURCES.
THEY HAVE EXCELLENT SECTIONS FOR
GRANTS, GRANTS PROCESS, AND
APPLICATION STRATEGIES, FOR SBIR
AND STTR PROGRAMS, APPLICATIONS,
STRATEGIES.
THEY EVEN HAVE SOME SIMPLE
APPLICATIONS AND SUMMARY
STATEMENTS THAT SOME P.I.s
WERE WILLING TO HAVE POSTED ON
THE WEBSITE FOR OTHERS TO LEARN
FROM.
SO, WITH THAT, I WILL CLOSE AND
THANK YOU FOR YOUR ATTENTION .
IF I HAVE ANY QUESTIONS PLEASE
FOLLOW UP, CALL ME OR E-MAIL.
GLAD TO HELP YOU.
THANKS.
>> THANK YOU SO MUCH, DR.
HAGGERTY.
THAT'S A WEALTH OF INFORMATION
AND WEBSITES FOR US TO GO BACK
TO.
I'LL CHECK WITH THE CHAIRMAN
HERE TO SEE IF WE HAVE SOME TIME
FOR QUESTIONS OR IF SHE WANTS TO
CLOSE UP ON THE THE SESSION.
>> NO, LET'S DO A FEW QUESTIONS.
>> OKAY.
GREAT.
SO, THIS IS ONE OF THE
CHALLENGES IN DIETARY
SUPPLEMENTS SPACE, LACK OF
QUALITY RESEARCH STUDIES ON
MARKETED PRODUCTS.
ARE THERE RFPs SPECIFIC FOR
INDUSTRY IN ADDITION TO SBIRs
TO HELP SUPPORT FUNDING OF
RESEARCH ON DIETARY SUPPLEMENTS?
SO ASKING SPECIFICALLY ABOUT
RFPs WITH INDUSTRY.
>> SO, I DON'T HAVE A LOT OF
FAMILIARITY WITH RFPs.
I MENTIONED THOSE ARE FOR
CONTRACTS, SOLICITATIONS, THE
QUESTION IS SPECIFIC TO
INDUSTRY, PERHAPS JOE, IF HE'S
ON THE LINE, MIGHT HAVE SOME
INSIGHTS ABOUT THAT.
BUT OFF THE TOP OF MY HEAD, YOU
KNOW, I JUST -- I DON'T KNOW.
I WOULD SAY TO THE PERSON WHO
ASKED, GO TO THE SITE WHERE IT
USED TO BE FEDBIZOPS WHERE THEY
HAVE RFPs LISTED AND ENTER
SEARCH TERMS.
THAT'S NOT A GREAT ANSWER BUT
THAT'S THE BEST I HAVE.
>> YEAH, THIS IS JOE.
I'LL WEIGH IN A LITTLE BIT.
THERE ARE SOME SPECIFIC GRANTS
THAT ARE ACTUALLY CONGRESSIONAL
SET-ASIDES, NOT JUST FOR NIH BUT
ACROSS THE FEDERAL GOVERNMENT
THAT ARE SBIR, SMALL BUSINESS
INNOVATION RESEARCH, OR STTR,
THOSE ARE TECHNOLOGY RESEARCH
GRANTS.
THOSE ARE TYPICALLY FUNDED IN
TWO PHASES, ONE IS TO HELP
DEVELOP THE SCIENCE FOR THE
CREATION, BASIC SCIENCE CREATION
OF COMMERCIAL PRODUCT, AND
SECOND PHASE I BELIEVE IS
REVIEWED FOR BUSINESS PLAN, TO
TAKE, TO COMMERCIALIZE THE NEW
TECHNOLOGY.
THOSE ARE PEER REVIEWED THE SAME
AS ANY OTHER GRANT.
I DON'T KNOW IF YOU CALL THOSE
RFAs.
THERE'S A STANDING RFA IN THE
GRANTS.GOV WEBSITE WHERE YOU CAN
FIND -- I'M SORRY, NIH GRANTS
WEBSITE, WHERE YOU CAN FIND
INFORMATION ABOUT THE STANDING
RFA FOR THESE BUSINESS GRANTS.
SOME PLACES, THE GRANTS ARE VERY
COMPETITIVE.
SOME PLACES NOT SO MUCH.
SO NSF, NIST, FDA, I SAID,
EPA, NIH, ARE ALL REQUIRED TO
SUPPORT THESE PROGRAMS, THESE
GRANT PROGRAMS FOR BUSINESS.
SOME PLACES GET FEWER OF THESE
APPLICATIONS THAN OTHERS.
AND SO THEY WILL BE LESS
COMPETITIVE.
I CAN'T TELL YOU WHICH ONES
THOSE WOULD BE.
SORRY.
I DON'T HAVE THAT DEPTH OF
KNOWLEDGE.
BUT THEY ARE INDUSTRY SPECIFIC
AND THE IDEA IS TO DEVELOP
COMMERCIALIZABLE PRODUCTS FROM
THE GOVERNMENT RESEARCH
ENTERPRISE.
>> THANKS, JOE.
YEAH, AND SO THE -- FOR GRANTS
THERE ARE THE OMNIBUS
SOLICITATIONS FOR SMALL BUSINESS
AND SBIR AND STTR PROGRAM,S CAN
GO TO THE SMALL BUSINESS
ADMINISTRATION WEBSITE TO FIND
THOSE BUT NIH HAS A LOT OF
THOSE.
I UNDERSTOOD THE QUESTION TO
SORT OF ALSO BE ASKED ABOUT
RFPs OR CONTRACTS.
THERE ARE SUCH THINGS.
I KNOW NIAID HAS SOME BUSINESS
CONTRACT SOLICITATIONS SO I
WOULD ENCOURAGE YOU TO GO TO THE
I.C.s THAT DO HAVE -- MOST OF
THE I.C.s HAVE SMALL BUSINESS
COMPONENTS, SMALL BUSINESS
PROGRAMS, AND THEN CONTACT THE
PEOPLE WITHIN THOSE PROGRAMS TO
ASK THAT KIND OF A QUESTION.
NIAID DOES HAVE BOTH GRANT AND
CONTRACT SMALL BUSINESS
SOLICITATIONS.
I DON'T KNOW AS MUCH ABOUT THE
OTHER I.C.s.
I KNOW THAT NICHD, CHILD HEALTH
HAS SMALL BUSINESS SECTION, BUT
NOT TOO MUCH DETAIL ABOUT IT.
>> OKAY.
GOOD.
NEXT QUESTION, QUITE A FEW
COMPANIES ARE WILLING TO PROVIDE
OR DONATE RESEARCH MATERIAL FOR
PRE-CLINICAL AND CLINICAL
STUDIES.
DOES ODS PROVIDE A DATABASE OR
INFORMATION OF SUCH COMPANIES
AND MATERIALS THEY PROVIDE,
OBVIOUSLY SOME DONATIONS COULD
HELP OFFSET COST OF RESEARCH.
>> AGAIN, I'M GOING TO MAYBE
DEFER TO ADAM, IF HE'S ON THE
LINE.
IN TERMS OF DONATION OF RESEARCH
MATERIAL FOR PRE-CLINICAL AND
CLINICAL STUDIES, I DON'T
BELIEVE ODS HAS THAT KIND OF
FUNCTION.
OR DATABASE.
SOMEONE CAN CORRECT ME IF I'M
WRONG BUT I DON'T THINK THAT'S
ONE OF OUR DATABASES.
>> THAT WOULD PROBABLY BE LEFT
UP TO INDIVIDUAL INVESTIGATE
COURT -- INVESTIGATORS TO SEEK
THEIR OWN RESEARCH THEY DO.
ANOTHER QUESTION YOU TOUCHED ON,
ARE THERE CURRENT -- ANY CURRENT
R01s, R21s, OR RFAs
SPECIFICALLY TARGETED FOR
DIETARY SUPPLEMENT RESEARCH?
>> SO, I WOULD -- THAT'S A
LITTLE BIT OF A TRICKY QUESTION.
I WOULD ENCOURAGE YOU TO GO TO
THE NIH GUIDE WITH THOSE KEY
WORDS, DIETARY SUPPLEMENT, IN
YOUR SEARCH TERMS.
AND USE THE ADVANCED SEARCH
TERM, USE THE ADVANCED SEARCH
FEATURE WHICH WILL SEARCH NOT
ONLY THE TITLE BUT ALSO THE
ABSTRACT AND THE SPECIFIC AIMS
OF THE INITIATIVE OR FUNDING
OPPORTUNITY.
OF TO PULL UP ANY.
ODS HAS THE FUNDING
ANNOUNCEMENTS THAT I MENTIONED,
ONE IS FOR ADMINISTRATIVE
SUPPLEMENTS, FOR RESEARCH ON AN
EXISTING PARENT GRANT.
AS I SAID, WE CO-FUND GRANTS, SO
OTHER I.C.s ARE THE PRIMARY
ADMINISTERS OF THOSE GRANTS, AND
DIETARY SUPPLEMENTS MAY BE
RELATED TO TOPIC OF THOSE
INITIATIVES THE OTHER I.C.s
SPONSOR, BUT ODS DOESN'T HAVE A
PRIMARY INITIATIVE OUT THERE,
JUST ON THAT.
AGAIN, IT'S SUCH A BIG QUESTION
THAT IT'S A LITTLE BIT HARD TO
ANSWER.
MANY NUTRITION STUDIES AND
INITIATIVES WILL HAVE RELEVANCE
TO DIETARY SUPPLEMENTS.
THERE ARE INITIATIVES IN
DEVELOPMENT OR OUT THERE ON FOOD
AND NUTRITION SECURITY, ABOUT
MATERNAL MORTALITY, AND
CHARACTERISTICS INVOLVED IN
THAT.
THERE'S MANY DIFFERENT
INITIATIVES THAT TOUCH ON
NUTRITION AND DIETARY INTAKE,
RIGHT?
BUT -- AND SO THERE'S A
PERIPHERAL POTENTIAL
RELATIONSHIP BETWEEN DIETARY
SUPPLEMENTS AND FOR THOSE WE
SOMETIMES RECEIVE -- WE
SOMETIMES CO-FUND.
BUT MY BEST ADVICE WOULD BE GO
TO THE NIH GUIDE AND DO A SEARCH
WITH THOSE KEY WORD TERMS.
>> GREAT.
THANK YOU.
I'LL TAKE THE PREROGATIVE FOR
THE LAST QUESTION.
YOU SHOWED US THAT THE NIH
NUTRITION PORTFOLIO IS LARGELY
PREDOMINANTLY FOCUSED ON OBESITY
RESEARCH.
SO, FOR THE ODS, DIETARY
SUPPLEMENT SUPPLEMENT RESRCH,
OTHER THAN OUR BOTANICAL CENTERS
PROGRAM OR CARBON PROGRAM, DOES
ODS HAVE A SPECIFIC FOCUS FOR
THE GRANT PORTFOLIO OR WHAT WE
FUND?
>> SO, I'M TRYING TO FIND THAT
QUESTION IN THE Q&A, BECKY.
I THOUGHT YOU WERE GOING TO SAY
YOU WERE GOING TO ANSWER IT.
>> OH, NO, I'M ASKING IT.
>> SO, THE QUESTION AGAIN,
SUMMARIZE FOR ME PLEASE.
>> OTHER THAN THE BOTANICAL
RESEARCH CENTERS, CARBON
PROGRAM, WHAT DOES THE ODS
PORTFOLIO LOOK LIKE GENERALLY?
DO WE FUND, YOU KNOW, VITAMINS,
MINERALS, AMINO ACIDS?
>> ALL OF THE ABOVE.
WE FUND A WIDE VARIETY OF
RESEARCH PROJECTS THAT HAVE
RELEVANCE TO DIETARY SUPPLEMENT
RESEARCH, AND I PUT THE
DEFINITION, I MENTIONED
DEFINITION OF DIETARY SUPPLEMENT
RESEARCH, ONE OF THE SLIDES.
SO, JUST FOR THAT REASON, TO
SHOW HOW WIDE, YEAH, HOW MANY
DIFFERENT TYPES OF TERMS ARE
ENCOMPASSED IN THAT.
WE HAVE -- I THINK THE
QUESTIONER IS ASKING IF WE HAVE
SPECIFIC IDENTIFIED RESEARCH
PRIORITIES FOR NON-MANDATED
PROGRAMS, SO THE GRANTS PROGRAMS
THAT ARE COMPLETELY INVESTIGATOR
INITIATED, AND I WOULD SAY WE DO
NOT, AT THE MOMENT.
BUT WE DO TEND TO -- WE ARE
SUPPORTIVE OF OTHER NUTRITION
RESEARCH, PRIORITIES OF OTHER
PARTS OF THE NIH, LIKE THE ONR,
OFFICE OF DIETARY DISEASE
PREVENTION HAS MANY INITIATIVES
THAT RELATE TO DIETARY
SUPPLEMENT RESEARCH.
SO WE'RE PRETTY BROADLY BASED.
I WOULD ENCOURAGE THE INDIVIDUAL
TO GO TO THE GRANTS AND FUNDING
WEB PAGE I SHOWED AND CLICK ON
ODS RESEARCH PROJECTS TO SEE A
LIST OF WHAT WE HAVE FUNDED IN
THE PAST.
IT'S ALL OF THE ABOVE.
BOTANICALS, MINERALS, VITAMINS,
ALL THE MICRONUTRIENTS AS WELL
AS CONSTITUENTS OF THOSE WHICH
OFTEN ARE THE FOCUS OF THE BASIC
SCIENCE RESEARCH WE SUPPORT.
WE SUPPORT BASIC SCIENCE,
CLINICAL SCIENCE, TRANSLATIONAL,
THE WHOLE GAMUT.
>> GREAT.
THANK YOU SO MUCH.
WONDERFUL PRESENTATION.
AND I THANK ALL THE ATTENDEES
FOR QUESTIONS AND RETURN THE
FLOOR TO DR. GHACHE.
>> THIS CONCLUDES THE SECOND DAY
OF THE PRACTICUM.
A BIG THANKS TO MODERATORS AND
SPEAKERS.
TOMORROW WE'RE GOING TO CONTINUE
OUR SESSION 6, AND DR. COSTELLO
WILL STILL BE MODERATED.
WE HAVE A PRESENTATION ON
DIETARY SUPPLEMENT USE IN THE
MILITARY AND DIETARY SUPPLEMENTS
AND IMMUNITY, LESSONS LEARNED
FROM COVID-19, SO TWO REALLY
INTERESTING TALKS.
WE HAVE A SPECIAL SESSION,
DIFFERENT THAN WHAT WE HAVE SO
FAR.
WE'LL HAVE SHORT PRESENTATIONS
FOLLOWED BY SEVERAL PANEL
DISCUSSIONS, WITH FOLKS FROM
DIETARY SUPPLEMENT TRADE GROUPS,
CONSUMER ADVOCACY GROUP, SOMEONE
FROM THE MEDIA.
SO THEY ARE GOING TO TALK ABOUT
DIFFERENT TOPICS RELATED TO
DIETARY SUPPLEMENTS.
WE'LL START AT 11:00 EASTERN
TIME.
PLEASE HAVE A GREAT EVENING.
THANK YOU ALL FOR ATTENDING.
AND SUBMITTING GREAT QUESTIONS.
AND PLEASE KEEP THAT UP FOR
TOMORROW.
THANK YOU.