WE ARE CERTAINLY HAPPY TO BE
HERE TODAY FOR OUR OCTOBER
SESSION OF THE OHSRP EDUCATION
SERIES WHICH FEATURES A
PRESENTATION ENTITLED
CONSIDERATIONS FOR INFORMED
CONSENT IN CELL AND GENE THERAPY
TRIALS.
BEFORE I INTRODUCE OUR I'LL
REMIND YOU THE PRESENTATION WILL
BE ARCHIVED IN THE PAST EVENTS
SECTION OF THE NIH VIVDEO SITE
AND POSTED ON THE OHSRP WEBSITE
APPROXIMATELY ONE TO TWO WEEKS
AFTER THE SECTION IN THE
PRESENTATION ARCHIVED SECTION OF
THE OHSRP EDUCATION AND TRAINING
WEB PAGE.
DURING THE SESSION WE ENCOURAGE
YOU TO SUBMIT QUESTIONS BY
CLICKING ON THE BOX ENTITLED
LIVE FEEDBACK LINK.
OUR GUEST SPEAKER IS DR. DANIEL
KAVANAGH ADVISER FOR GENE
THERAPY AND VACCINES AND
BIOLOGICS AS A LABORATORY LEAD
AND WORKS WITH SPONSORS AND CROs
AND INSTITUTIONS USING THE
INSTITUTIONAL BIO SAFETY
COMMITTEE OTHERWISE KNOWN AS AN
IBC AND OTHER CLINICAL TRIAL
SUPPORT SERVICES IN 16
COUNTRIES.
PRIOR HE WAS ASSISTANT PROFESSOR
OF MEDICINE AT HARVARD MEDICAL
SCHOOL AND VICE CHAIR OF THE
BRIGHAM IBC.
HE WAS ALSO A CO-CHAIR OF A
PHASE 1 HUMAN GENE TRANSFER
CLINICAL TRIAL AT NGH AND HOLDS
A REGULATORY AFFAIRS SOCIETY
CERTIFICATE AND SERVES ON THE
TECHNICAL AND REVIEW COMMITTEE
FOR THE ASSOCIATION FOR BIO
SAFETY AND BIO SECURITY
INTERNATIONAL AND THE BIO
INDUSTRY COMMITTEE FOR THE
AMERICAN SOCIETY OF GENE AND
CELL THERAPY.
DR. KAVANAGH, PLEASE GO AHEAD.
>> THANK YOU.
LET ME KNOW IF THE SLIDES APPEAR
CORRECTLY.
>> THEY LOOK GREAT.
>> THANK YOU TO OHSRP FOR
ARRANGING THE PRESENTATION.
IT'S BASED ON A PREVIOUS
PRESENTATION INTENDED FOR AN
AUDIENCE WITH MIXED BACKGROUND
IN MOLECULAR BIOLOGY OR GENE
THERAPY.
WE'LL TRY TO INTRODUCE SOME
BASIC CONCEPTS AND ALSO ADDRESS
SOME OF THE MORE COMPLEX ISSUES
FACING RESEARCH IN THIS AREA AND
INFORMED CONSENT.
I'M AN EMPLOYEE OF WC
G.
FOR TODAY'S AGENDA WE'LL SPEND
TIME DEFINING GENE THERAPY AND
GENE TRANSFER RESEARCH.
WE'LL LOOK AT SOME NIH HAD AND
FDA GUIDANCE FOR INFORMED
CONSENT IN THE SECTOR.
CONSIDER BEST PRACTICES FOR IRBs
AND FOR INSTITUTIONAL BIO SAFETY
COMMITTEES TO WORK TOGETHER ON
ICD REVIEW.
WE'LL LOOK AT THE MAJOR
CATEGORIES OF RISK WITH CELL
EDITING AND THERAPY RESEARCH AND
MOST IMPORTANT PART OF TODAY'S
PRESENTATION IS SOME INFORMATION
ABOUT PATIENT PERSPECTIVES ON
THE CLINICAL TRIALS AND AT THE
END I'LL BRING UP UNRESOLVED
ISSUES OR CONTINUING CHALLENGES.
I IMAGINE ALMOST EVERYBODY ON
TODAY'S CALL IS AWARE OF GENERAL
REQUIREMENTS FOR ICDs.
THERE HAS TO BE A DESCRIPTION OF
THE RESEARCH OF THE RISK AND
BENEFITS.
ALTERNATIVES TO PARTICIPATION,
CONFIDENTIALITY, COMPENSATION
AND WHO TO CONTACT.
VERY IMPORTANTLY THE RESEARCH IS
VOLUNTARY AND INFORMATION
GATHERED THAT'S IDENTIFIABLE AND
THAT'S ANYTHING REVIEWED AT
INSTITUTIONS.
WHEN IT COMES TO GENE TRANSFER
RESEARCH, WHAT WE'RE TALKING
ABOUT HERE ARE LESS ABOUT
REQUIREMENTS, MORE ABOUT WHAT
WE'RE CALLING CONSIDERATIONS OR
BEST PRACTICES THAT MAY APPLY
DIFFERENTLY TO DIFFERENT
STUDIES.
AS FAR AS I'M AWARE ANY SUCH
STUDY SHOULD INCLUDE AN
EXPLANATION THIS THAT THE
PRODUCT CONTAINS GENETICALLY
MODIFIED DNA OR RNA OR CAPABLE
OF MODIFYING THE DNA AND RNA
THROUGH SOME TYPE OF GENE
EDITING.
I CAN'T THINK OF EXCEPTIONS
WHERE THAT WOULD NOT BE
INCLUDED.
WHERE IT'S APPROPRIATE TO THE
RESEARCH UNDER REVIEW, THERE ARE
OTHER CONSIDERATIONS THAT APPLY.
RISK OF GENETIC MODIFICATIONS,
REPRODUCTIVE RISKS, VECTOR
EFFECTS.
TRANS GENE EFFECTS.
WE'LL LOOK AT THEM LATER IN THE
PRESENTATION AND EACH HAS TO BE
CONSIDERED IN THE CONTEXT OF A
PARTICULAR STUDY.
LET'S ARE -- REVIEW THE
TECHNOLOGY.
INFORMATION IS STORED IN DNA,
TRANSCRIBED IN RNA AND
TRANSLATED INTO PROTEINS AND
PROTEINS ARE DOING THE HEAVY
LIFTING FOR MACHINERY OF THE
CELL.
AND HUMAN GENE TRANSFER RESEARCH
SAY DEFINITION CONTAINED IN THE
NIH GUIDELINE FOR RESEARCH
INVOLVING RECOMBINANT MOLECULES
RELATED TO THE CONCEPT OF GENE
THERAPY AND WE'LL GO BACK AND
FORTH BETWEEN THE CONCEPTS IN
TODAY'S PRESENTATION.
IN GENERAL UNDER THE NIH
GUIDELINES HUMAN GENE TRANSFER
INVOLVES ADMINISTRATION TO A
HUMAN SUBJECT AND RNA PRODUCTS
OR OLICO NUCLEOTIDES THAT DON'T
PRODUCE LASTING CHANGES IN THE
CELL AND GUIDELINES NEEDS TO BE
APPROVED BY AN INSTITUTIONAL BIO
SAFETY COMMITTEE APPROVED BY THE
NIH OR INSTITUTION AND WITHIN
THIS CATEGORY THERE IS FDA
MARKETING APPROVAL FOR A GROWING
NUMBER OF PRODUCTS INCLUDING
VECTORED GENE THERAPIES FOR
INHERITED DISEASE, EX VIVO
ENGINEERED CELLULAR THERAPIES
FOR THE TREATMENT OF CANCER OR
INHERITED DISEASES.
WE SEE ONCOLYTIC VIRUSES AND
mRNA GENE THERAPY.
WE SEE PRODUCTS THAT ARE
DELIVERING DNA OR RNA SUCH AS AN
RNA VECTOR AND RNA PRODUCTS
PRODUCE TYPICALLY TRANSIENT
CHANGES IN THE GENETIC CONTENT
OF THE CELL.
AND SOME AS CLASSIFIED AS GENE
THERAPY IF THEY'RE NOT
CLASSIFIED AS VACCINES.
WHEN DNA IS ADDED TO THE CELL,
SOME OR BUT NOT ALL PRODUCTS
MAKE PERMANENT CHANGES TO DNA IN
THE CHROMOSOME.
SOME OF THESE MAY BE DERIVED
FROM RETROVIRUSES OR TRANSPOSONS
THAT PROVIDE DNA INTEGRATED IN
THE CHROMOSOME.
THE CAPACITY FOR INTEGRATION
INTRODUCES SAFETY CONSIDERATIONS
NEED TO BE CONSIDERED AS PART OF
THE RISK ASSESSMENT.
THIS ENTIRE CATEGORY OF HUMAN
GENE TRANSFER PRODUCTS INCLUDES
A REALLY BROAD AND GROWING
VARIETY OF MODALITIES.
WE SEE CAR T CELLS AND OTHER
GENETICALLY MODIFIED EFFECTERS.
NON-REPLICATING VIRAL VECTORS,
mRNA VACCINES AND GENE
THERAPIES.
OTHER PRODUCTS SUCH AS LIVE O
ONOLYTIC VIRUSES AND GENETICALLY
MODIFIED ANIMALS ARE ALL BEING
USED IN CLINICAL TRIALS IN ONE
WAY OR ANOTHER.
WE WON'T ADDRESS ALL TODAY
BECAUSE WE'RE FOCUSSING ON
TRADITIONAL CONCEPTS OF GENE
THERAPY AND GENE EDITING.
WHEN IT COMES TO DELIVERY OF
THESE PRODUCTS IN CLINICAL
DOSING THERE'S TWO PRIMARY
TYPES.
IN VIVO GENE DELIVERY WITH THE
DNA AND RNA IS INTRODUCED BY
INJECTION OR INFUSION AND LEADS
TO A GENETICALLY MODIFIED CELLS
AND LIPID AND NANO PARTICLES MAY
CONTAIN mRNA AS PART OF A
VACCINE FOR GENE THERAPY OR FOR
VACCINES OR GENE THERAPY.
THERE ARE REPLICATING AND
NON-REPLICATING VECTORS THAT
ACCOMPLISH THAT IN VIVO.
EX VIVO IS A SEPARATE FORM OF
DELIVERY WHERE PRODUCTS ARE
REMOVED FROM HUMAN DONOR,
GENETICALLY MODIFIED IN THE LAB
UNDER CONTROLLED CONDITIONS AND
INFUSED INTO A SUBJECT IN THE
CASE OF OTOLOGOUS SELLS AND HAVE
DIFFERENT TYPES OF RISK THAT
NEED TO BE EXPLAINED IN INFORMED
CONSENT.
SO WHEN THESE TRIALS COME TO AN
INSTITUTION NEAR YOU, WHAT IS
INVOLVED IN INSTITUTIONAL REVIEW
OF INFORMED CONSENT FOR SUBJECTS
CONSIDERING PARTICIPATION?
INTERESTING HISTORY TO REVIEW IS
THAT INVOLVED INSTITUTIONAL BIO
SAFETY COMMITTEES AND IRBs.
SO THE CHANGING ROLES OF THESE
TWO ROLES HAS GONE THROUGH A
NUMBER OF PHASES IN RECENT
YEARS.
PRIOR TO 2016, THE NIH REQUIRED
UNDER THE NIH GUIDELINES
INSTITUTIONAL BIO SAFETY
COMMITTEES TO REVIEW THE
DOCUMENTS AND NIH LISTED POINTS
TO CONSIDER AND ADVISED BY THE
COMMITTEE AT NIH AND THE NIH
GUIDELINES INCLUDED AN APPENDIX
X REQUIRING IBC REVIEW OF
SUBJECT SAFETY ISSUES SUCH AS
SERIOUS ADVERSE EVENTS.
AFTER THE AMENDMENT TO 2016 AND
UP TO 2019, THERE WAS CONTINUING
REQUIREMENT FOR THE
INSTITUTIONAL BIO SAFETY
COMMITTEES TO REVIEW THE CONCEPT
DOCUMENTS.
THE ACTUAL POINTS TO CONSIDER
WERE LESS SPECIFIC THE IBC WERE
TO PERFORM A TYPE OF ASSESSMENT.
DURING THIS PERIOD THERE WERE
FEW PROTOCOLS REVIEWED BY THE
RAC.
AFTER THE MOST RECENT AMENDMENT
TO THE GUIDELINES IN 2019, IBC
REVIEW OF INFORMED CONSENT
DOCUMENTS IS NO LONGER REQUIRED.
THE PRIMARY RESPONSIBILITY FOR
PARTICIPANT SAFETY AND CONSENT
REVIEW IS PLACED ON THE
SHOULDERS OF THE IRB.
THE OLD APPENDIX M WAS DELETED
AND THE RAC WAS REPURPOSED AND
RENAMED SO THERE WAS NO LONGER A
PRE-REVIEW STEP BEFORE IT LANDS
ON THE DESK OF THE IRB WHO IS
REQUIRED TO CONDUCT THESE
REVIEWS OF THE INFORMED CONSENT
AND OTHER ASPECTS OF ENROLLMENT.
SO THERE'S NOW A DIVISION OF
LABOR WHEN IT COMES TO MINIMAL
REQUIREMENTS OF INFORMED CONSENT
REVIEW DOCUMENTS.
THE IRB IS THERE TO REVIEW
CLINICAL TRIALS WITH OR WITHOUT
GENE THERAPY FOCUSSING ON THE
PROTECTION OF THE STUDY
PARTICIPANTS LOOKING AT THE
RISK, BENEFIT, CONSENT,
COMPENSATION AND THE OTHER
ISSUES WE DISCUSSED.
THE IBC IS REQUIRED TO REVIEW
THE TRIALS BUT THE FOCUS OF THE
IBC IS NOT PROTECTING STUDY
PARTICIPANTS AS A MINIMAL
MANDATE BUT TO PROTECT STAFF,
AND THE PUBLIC FOCUSSING ON
DISINFECTING AND ACCIDENTAL
EXPOSURES AND OCCUPATIONAL
HEALTH.
THOSE ARE ALL REQUIRED
CONSIDERATIONS OF IS THE IBC A
USEFUL DIVISION OF LABOR.
HOWEVER, THESE COMMITTEES AND
THE SERVICE OF THEIR
INSTITUTIONS DON'T HAVE TO BE
COMPLETELY SEPARATED IN THE
WORKS THEY DO.
IRBs MAY OR MAY NOT HAVE EXPERT
MEMBERS FAMILIAR WITH ALL
ASPECTS OF GENETIC ENGINEERING
AND MOLECULAR BIOLOGY.
ADVERSELY, IBC OFTEN HAVE
MEMBERS WITH STRONG INTEREST IN
HUMAN BIO PROTECTION AND ETHICS.
WHEN ONE OF THESE PROTOCOLS
COMES TO AN INSTITUTION THE
INSTITUTIONS MAY REQUEST IBC
REVIEW OF THE ICD AND
PUBLIC-FACING DOCUMENTS.
IRBs CAN REQUEST A CONSULT AND
THEY CAN ATTEND IBC MEETINGS.
WHAT WE DO IN MY DIVISION WE
SOMETIMES HAVE JOURNAL CLUBS AND
SEMINARS AND SHARE KNOWLEDGE ON
NEW TECHNOLOGY AND PUBLICATIONS.
ALONG WITH THE PREVIOUS
REQUIREMENT OF INFORMED CONSENT
REVIEW FROM THE NIH THERE WAS A
LIST OF POINTS TO CONSIDER AND
THESE ARE STILL USEFUL TODAY
WHEN YOU'RE OPENING NEW ICD AND
THINGS TO THINK ABOUT.
IS THE INVESTIGATIONAL NATURE OF
THE PRODUCT PROPERLY DESCRIBED.
IS LONG-TERM FOLLOW-UP
CONSIDERATION DESCRIBED.
ARE THERE REPRODUCTIVE ISSUES.
IS THERE REQUEST FOR AUTOPSY.
WE SEE THAT SOMETIMES.
DEPENDING ON WHICH WAY THE MEDIA
IS GO THERE MAY BE INTEREST IN
MEDIA OF THE PROJECT.
THESE CAN SERVE AS GUIDE POSTS
WHEN REVIEWING THE DUMES.
-- DOCUMENTS.
THE SECOND POINT WAS LONG-TERM
FOLLOW-UP.
FDA HAS ISSUED GUIDANCE FOR
INDUSTRY AND GENE THERAPY.
THE REQUIREMENT FOR INTEGRATION
OF LONG-TERM FOLLOW-UP DEPENDS
ON THE NATURE OF THE PRODUCT.
AND SPECIFICALLY DEPENDENT ON
EXPECTED POTENTIAL RISK OF
DELAYED ADVERSE EVENTS
ASSOCIATED WITH A PARTICULAR
INVESTIGATIONAL PRODUCT.
A 15 YEAR LTFU MAY BE
RECOMMENDED DEPENDING ON RISK
AND DELAYED ADVERSE VNTZ OF A
PARTICULAR CONCERN AND MAY
MODIFY THE CHROMOSOME SUCH AS
GENETIC CONSTRUCTS KNOWN OR GENE
EDITING MODALITIES.
FOR THESE TYPE OF PRODUCT AS A
PRIMARY CONCERN IS MALIGNANT
TRANSFORMATION MEANING A CHANGE
IN THE CHROMOSOME COULD LEAD TO
ACTIVATION OF AN ONO GEEB GENE
AND COULD TRANSFORM CELLS TO
MALIGNANT TRANSFORMATION.
THIS COULD APPEAR LONG AFTER
DOSING AND CONTINUOUS MONITORING
FOR THIS IS OFTEN RECOMMENDED.
THERE ARE ALSO OTHER POTENTIAL
DELAYED ADVERSE EVENTS THAT
COULD EFFECT IMMUNOLOGY OR OTHER
TOXICITIES THAT MAY APPEAR AND
REQUIRE CONSIDERATION DEPENDING
ON THE NATURE OF THE PRODUCT
OVER TIME.
IT MUST HAVE OBSERVATIONS AND
TIME INTERVALS AND STUDY VISIT
CONTACTS AND DETAILS AS TO WHAT
THE CONTACTS WILL INVOLVE.
IT NICE TO BE THOUGHT OF IN
ADVANCE AND EXPLAINED AT THE
TIME OF CONSENT.
IN AGAIN YOU MUST REVISE
INFORMED CONSENT DOCUMENTS NEW
EVENTS WITH THE PRODUCT OR
PROCEDURES THAT CREATES
INTERESTING RESPONSIBILITIES
OVER A 15-YEAR FOLLOW-UP PERIOD
IN TERMS OF REVISING INFORMED
CONSENT AND CONTAINING
INFORMATION TO THE ENROLLED
SUBJECTS.
SO WHAT SHOULD WE CONSIDER IN
LOOKING AT THE CATEGORIES OF
GENE RESEARCH.
I THINK OF HUMAN PRODUCTS BEING
COMPRISED OF TWO COMPONENTS.
ONE IS A TRANS GENE WHICH IS
GENETICALLY ENGINEERED DNA OR
RNA AND ENCODING SOME KIND OF
THERAPEUTIC GENE PRODUCT
PROTEIN.
THE OTHER COMPONENT WOULD BE THE
DELIVERY METHOD OR VEHICLE SUCH
AS THE EX VIVO MANUFACTURER LIKE
A CAR T CELL.
COULD BE A VIRAL VECTOR OR NANO
PARTICLE AND IN THINKING ABOUT
CATEGORIES OF RISK THEY MAY
APPLY TO THE TRANS GENES.
THERE'S A VARIETY OF RISKS THAT
COULD APPLY.
ENCODED PROTEINS MAY INDUCE DOSE
LIMITING TOXICITIES.
WHEN YOU'RE EXPRESSING A
CLOTTING FACTOR TO TREAT
HEMOPHILIA THERE IS GOING TO BE
A THERAPEUTIC WINDOW AND
EXPRESSION BEYOND THAT POINT HAS
POTENTIAL RISK TO LEAD TO ADE
VERSE EVENTS SUCH AS THROMB
THROMBOSIS-.
THERE'S POTENTIAL FOR OTHER
ISSUES SO THAT HAS TO BE
CONSIDERED.
WHEN THE ENCODED PROTEIN IS
CAPABLE OF MODIFYING THE
CHROMOSOME THEN THERE'S OBVIOUS
RISKS TO THIS AND INHERITED
DISEASES AN ESSENTIAL PROTEIN IS
NOT EXPRESSED BECAUSE OF A
GENETIC DEAL EFFECT.
INTRODUCING THAT PROTEIN AS A
NOVEL GENE PRODUCT POSES RISK AS
IDENTIFYING IT TO NON-SELF
LEADING TO IMMUNE REACTION THAT
CAN INTERFERE WITH FUTURE
TREATMENTS.
I NOT BE AN IMPORTANT RISK.
IT INVOLVES MOLECULAR ANALYSIS
OF THE TRANS GENE AND DATA IN
RELEVANT MODELS AND PRIOR
EXPERIENCE WITH THE MOST SIMILAR
PRODUCTS AVAILABLE.
THE OTHER COMPONENT IS THE
DELIVERY METHOD AND VECTOR AND
THOSE MAY HAVE THEIR OWN RISK.
IF THE VECTOR IS AN IMMUNE
EFFECTER CELL IN VIVO THEY'RE
ASSOCIATED WITH CYTOKINE RELEASE
SYNDROME AND NEURO TOXICITY
SYNDROME.
OTHER WELL DESCRIBED POTENTIAL
ADVERSE EVENTS THAT ARE OFTEN
DESCRIBED AS KNOWN RISKS FOR
THESE INTERVENTIONS.
WHEN CELLS ARE MODIFIED EX VIVO
THE CELLS COULD BE MALIGNANT OR
SUBJECT TO TRANSFORMATION
BECAUSE OF GROWTH IN VITRO AND
THAT NEEDS TO BE CONSIDERED AS A
POTENTIAL RISK.
WHEN THE VEHICLE'S AN NANO
PARTICLE DEPENDING ON CLINICAL
EXPERIENCE WITH THAT CART
PARTICLE THE COMPONENTS COULD BE
TOXIC OR IMMUNOGENIC.
THERE'S NEW METHODS OF
DEVELOPING PARTICLES AND
EXCITING NEW TECHNOLOGY BUT THEY
HAVE TO BE EXAMINED FOR
POTENTIAL RISKS.
WHEN THE VICTORY CLASS CAN
MODIFY THE CHROMOSOME THERE'S
ADDITIONAL MUTAGENESIS AND WE
DISCUSSED SOME OF THOSE ASPECTS
ALREADY.
ANOTHER KNOWN CATEGORY IS THE
IMMUNE RESPONSE TO THE VECTOR.
WE SEE GENE THERAPY FOR RARE
INHERITED DISEASE USING THESE
VECTORS WITH A LOT OF PROMISING
ASPECTS BUT ALSO INDUCE IMMUNE
RESPONSES.
AFTER DOSING WHEN AN IMMUNE
RESPONSE DEVELOPS TO THE VECTOR,
THAT CAN INTERFERE WITH
OTHERWISE DESIRABLE APPROACHES
TO RESEARCH SUCH AS A DOSE
ESCALATION STUDY WHERE REPEATED
DOSING IN THIS CASE IS NOT
POSSIBLE.
THAT MAKES IT MORE DIFFICULT TO
ANTICIPATE TOLERATED DOSES AND
IN YOUR INFORMED CONSENT FORM
YOU HAVE TO EXPLAIN WHAT THE
LIMITATIONS ARE AND WHETHER IT'S
INFORMATIVE AND UNDERSTANDABLE
TO THE READING AUDIENCE.
IMPORTANTLY, AFTER DOSING WITH A
PARTICULAR SUBJECT WHO THAT
IMMUNE RESPONSE IS EXPECTED TO
BE REFRACTORY TO SUBSEQUENT
DOSING WITH A SIMILAR PRODUCT.
A LOT OF RESEARCH IS TRYING TO
ADDRESS THESE ISSUES AND MAKE
THEM LESS OF A PROBLEM BUT THE
INABILITY TO REDOSE WITH THE
ITEMS DUE TO IMMUNE RESPONSES.
THERE'S BEEN NICE AND
INFORMATIVE SEMINARS SPONSORED
BY DIFFERENT AGENCIES ADDRESSING
POTENTIAL ADVERSE EFFECTS.
USUALLY ASSOCIATED WITH HIGH
DOSES THAT ARE USED FOR CERTAIN
INDICATIONS.
AND THESE TOXICITIES INCLUDE
HEPATOTOXICITIES AND THE DOSE
AND RISKS HAVE TO BE CONSIDERED
AND EXPLAINED CAREFULLY.
SO THOSE NOW QUALIFY AS THE
OLDER TECHNOLOGIES.
WE NOW HAVE NEW CATEGORIES AND
MODALITIES COMING ONLINE AND
APPEARING IN THE CLINIC AND
POSSIBLY BEING CONSIDERED FOR
FDA APPROVAL.
THESE ARE CRISPR AND RELATED
GENE EDITING PROJECTS.
AS A SIGN OF THE TIMES WE SAW AN
ANNOUNCEMENT IN THE FEDERAL
REGISTER ABOUT PROPOSED CHANGING
TO THE NIH GUIDELINES.
MOST ARE NOT RELATED TO
COLLABORATES AND INFORMED
CONSENT AND THERE'S A POPULATION
TO CHANGE HUMAN GENE RESEARCH TO
HAVE TECHNIQUES NOT USUALLY
COVERED.
THIS REFLECTS THE GROWING
REALITY OF SEEING THESE IN THE
CLINIC.
GENE EDITING IS A CATEGORY OF
INTERVENTION THAT REWRITES THE
GENETIC CODE.
MOST FAMOUSLY THAT MEANS CRISPR
AND RELATED TECHNOLOGIES.
THEY HAVE THE TO PRECISELY ADD
AND DELETE GENETIC INFORMATION
FROM THE CHROMOSOME.
AS MENTIONED, CERTAIN APPROACHES
DO NOT QUALIFY UNDER THE CURRENT
NIH GUIDELINES BUT IF THE
PROPOSED CHANGES ARE IMPLEMENT
ED AND WHEN WE TALK ABOUT THE
CONCEPT WE HAVE TO MENTION
SOMATIC CELL EDITING MEANS
MODIFYING CELLS FOR THERAPEUTIC
PURPOSES IN A HUMAN SUBJECT NOT
ENGAGING IN INTENTIONAL
MODIFICATION OF GERM LINE CELLS
THAT WOULD LEAD TO INTENTIONAL
HERITABLE MODIFICATIONS PASSED
ON TO HUMAN GENERATIONS.
THAT'S NOT HAPPENING IN ANY
CLINICAL TRIALS AND WE'RE NOT
GOING TO TALK ABOUT IT HERE BUT
IT'S THE FOCUS OF A LOT OF
OPINION.
SO WHEN WE LOOK AT THIS CATEGORY
OF INTERVENTION, IT WOULD
INCLUDE THE INTERVENTIONS THAT
MODIFY THE DNA BASED ON PRIME
EDITORS RISKS WOULD INCLUDE
ERRORS THAT RESULT IN OFF-TARGET
EDITING MEANING CHANGING THE
GENETIC CODE IN A PLACE OUTSIDE
OF WHERE YOU WANTED TO DO IT.
UNWANTED DELETIONS AND POTENTIAL
TRANS LOCATIONS OF CHROMOSOMAL
DNA.
WE CURRENTLY HAVE VERY GOOD
METHODS FOR DETECTING ERRORS BUT
THE LIMIT OF SENSITIVITY ARE
SOMETIMES DIFFICULT TO DEFINE IN
THE CONTEXT OF A CLINICAL TRIAL
AND WHAT THE CLINICALLY
ACCEPTABLE ERROR RATE IS
DIFFICULT TO DEFINE.
THERE'S UNDETERMINED AREA
BETWEEN WHAT IS ACCEPTABLE AND
DEFINITIVELY DETECTABLE.
THE DIFFERENT TYPES OF APPROACH
IN VIVO AND EX VIVO WHEN THE EX
VIVO APPLICATION IS USED, CELLS
ARE MODIFIED IN THE LABORATORY,
PETRI DISH UNDER THE CONTROLLED
CONDITIONS IT'S EASIER TO
IDENTIFY ERRORS.
THERE'S A POTENTIAL CONCERN
THERE COULD BE EXPANSION OF
CELLS WITH INAPPROPRIATE
REPLICATION BECAUSE OF SOME ONYO
GENIC EVENT.
THAT HAS TO BE CONSIDERED AS A
POTENTIAL RISK.
GENE EDITING MAY ALSO BE
PERFORMED IN VIVO WHERE THE
MACHINERY IS INTRODUCED TO THE
NANO PARTICLE.
IT'S MORE DIFFICULT TO TRACK THE
SPECIFIC ERRORS THAT MAY BE
OCCURRING IN VIVO.
SO THIS GREATER UNCERTAINTY IN
THAT CASE AND THERE WON'T BE
INTENTIONAL MODIFICATION AND THE
POTENTIAL IN VIVO DELIVERY FOR
GERM LINE MODIFICATION THROUGH A
VARIETY OF TECHNIQUES,
THEORETICAL APPROACHES NEEDS TO
BE CONSIDERED.
OF COURSE, PRECLINICAL DESIGN OF
THESE CLINICAL TRIALS IS MEANT
TO ADEQUATELY ADDRESS THESE
POINTS BUT IT'S SOMETHING THAT
THE IRB'S NEED TO TAKE INTO
CONSIDERATION.
IT SHOULD BE PART OF INFORMED
CONSENT WHEN APPROPRIATE.
IN DRAFT GUIDANCE FROM FDA, WE
SEE PRIOR TO ENROLLING SUBJECTS
SHOULD BE ASKED TO PROVIDE
VOLUNTARY INFORMED CONSENT TO
LONG-TERM FOLLOW-UP.
SO IF THERE'S A DOSING PROTOCOL
AND LONG-TERM FOLLOW-UP PROTOCOL
AND CONSENT TO THE LONG-TERM
FOLLOW-UP SHOULD PROCEED
ENROLLMENT, THERE'S LOGISTICAL
QUESTIONS TO CONSIDER ABOUT HOW
YOU DO YOUR INFORMED CONSENT
PROCESS TO COVER ALL YOUR BASES
IN ADVANCE.
THERE'S A LOT OF ACCEPTABLE
APPROACHES BUT SOMETHING TO
THINK ABOUT WHILE PLANNING YOUR
INFORMED CONSENT.
WE CAN SEE PATIENT PERSPECTIVES
ARE REALLY IMPORTANT.
THERE'S PATIENT ADVOCACY GROUPS
AND PEOPLE ENROLLED PROVIDING
INPUT AND IT'S A VALUABLE SOURCE
OF INFORMATION.
I'VE HAD THE PRIVILEGE OF
SPEAKING TO PATIENT ADVOCATES
AND CLINICAL TRIAL PARTICIPANTS
AND ROUNDTABLES AND DIFFERENT
CONFERENCES AND IT'S ALWAYS
VALUABLE SOURCE OF END POINT.
COLLATING SOME OF THE ADVICE
FROM THE GROUPS WE HEAR INFORMED
CONSENT THERAPY IS TOO LONG AND
IT'S AN ONGOING ISSUE WHEN
THERE'S A LONG BENEFITING AND
HOW DO WE ADDRESS WHAT NEEDS TO
BE ADDRESSED IN A MANAGEABLE
SCOPE.
THE SCIENCE OF GENE TRANSFER IS
DIFFICULT TO UNDERSTAND AND
DIFFICULT FOR ALL OF US TO KEEP
UP WITH IT WHEN WE'RE
PROFESSIONALS AND EXPLAINING IT
TO A LAY AUDIENCE IS AN ART OF
INTERPRETATION THAT REQUIRES A
LOT OF ATTENTION AND IS A SOURCE
OF CONCERN FOR PARTICIPANTS.
WHEN IT COMES TO NON-EXPERTS
THEY EXPRESS DIFFICULTY
ASSESSING AND IN AN ERROR WHERE
THERE'S AMOUNT OF DISTRUST IN
MEDICINE AND IRBs CAN PLAY AN
IMPORTANT ROLE IN MAINTAINING
CONFIDENCE IN THE PROCESS AND
LISTENING TO CONCERNS.
ALONG THIS LINE I WAS INTERESTED
TO READ THIS PARTICULAR PAPER
CALLED IMPROVING PATIENT
INFORMED CONSENT FOR HEMOPHILIA
GENE THERAPY CASE FOR CHANGE BY
PHYSICIAN PATIENT ADVOCATES AND
IDENTIFYING POINTS OF CONCERN
AND ALSO CONSTRUCTIVE ADVICE.
SO IT'S WORTH LOOKING UP FOR
THOSE INTERESTED.
AND IDENTIFY INFORMATION OVER
LOAD.
IT'S A RISK WHEN SOMEONE LIKE
MYSELF GETS INTERESTED IN
READING ALL ASPECTS OF MOLECULAR
INTERVENTION AND HAS MORE
INFORMATION THAN IS USEFUL.
WE NEED TO THINK ABOUT AVOIDING
THAT PROBLEM.
FOR GENE THERAPY THERE MAY BE
MISCONCEPTION AND DIFFICULTY
DRAWING THE LINE BETWEEN
RESEARCH AND TREATMENT AND WITH
THE BEST OF INTENTIONS IT'S AN
ONGOING TENSION AND IDENTIFIED
IN THE PAPER AS POTENTIAL POINT
OF CONFUSION FOR SUBJECTS
CONSIDERING ENROLLMENT.
THERAPEUTIC OPTIMISM AND HYPE
AND WE WANT INTERVENTIONS TO
SUCCEED AND ARE WE PROVIDING
REALISTIC ASSESSMENTS OF
POTENTIAL BENEFITS AND RISKS.
I QUOTED THIS PARTICULAR
STATEMENT BECAUSE I LIKE THE
WORDING.
PATIENTS DESIRE FOR IMPROVEMENT
AND HEALTH-RELATED QUALITY OF
LIFE IN FEASIBLY DESPERATE
MEDICALLY CIRCUMSTANCES CAN
UNDERMINE THEIR DECISIONAL
CAPACITY.
IN OTHER WORDS, WHAT QUALITY OF
LIFE IS SO BAD IS DECISION
IMPAIRED AND HOW DO IRB'S
ACCOUNT FOR THAT AS PART OF THE
INFORMED CONSENT PROCESS.
IT'S IN IMPORTANT QUESTION AND
MORE VISUAL AIDS AS PART OF THE
INFORMED CONSENT DOCUMENTATION.
SOME TYPE OF FREQUENTLY ASKED
QUESTION LIST FOR PATIENT
QUESTIONS AND CONCERNS AND
DEVELOPMENT OF STANDARDIZED
LEXICONS FOR PREFERRED
TERMINOLOGY THEY'RE PROBABLY
DIFFERENT FOR DIFFERENT
POPULATIONS BUT USEFUL FOR THE
FIELD IN GENERAL.
SO WHEN WE THINK ABOUT
INFORMATION OVERLOAD, HOW DO YOU
SEPARATE SIGNAL FROM NOISE.
WHEN WE TALK ABOUT DETAILED
SPECULATIVE RISK ASSESSMENT,
TECHNICAL, MOLECULAR INFORMATION
I DOVE INTO THE FIRST LEVEL OF
THAT BUT THERE'S MANY MORE
LAYERS YOU COULD GET INTO
COMPREHENSIVE MEDICAL ANALYSIS
OR ALL PARTS OF DUE DILIGENCE.
THE IBC REGULATORS AND AUTHORS
THIS SHOULD BE PART OF THEIR
DISCUSSION DURING PREPARATION.
WHEN IT COMES TO THE INFORMED
CONSENT PROCESS WE NEED A FILTER
TO AVOID THE INFORMATION
OVERLOAD.
THERE SHOULD BE A FOCUS ON PLAIN
LANGUAGE AND INFORMATION THAT IS
LIKELY TO AFFECT WILLINGNESS TO
PARTICIPATE.
WE CAN STILL HAVE TECHNICAL
INFORMATION AVAILABLE FOR
SUBJECTS WHO ASK AND SOME IN
RARE DISEASE THE SUBJECTS ARE
SOMETIMES EXPERTS THEMSELVES AND
THAT'S WONDERFUL BUT THE PROCESS
HAS TO ALLOW FOR SUBJECTS WHO
ARE LESS WELL INFORMED AND NOT
NECESSARILY IN A POSITION TO
READ AND NEXT IS CONSIDERATION
OF WHAT MANY OF US CONSIDER TO
BE UNSOLVED PROBLEMS IN THIS
AREA.
SO THESE ARE ISSUES RELATED TO
SHEDDING AND COMMUNITY RISK.
FOR SOME THE MODIFIED OBJECTS
ARE EXPECTED TO BE SHED FROM
INJECTION SITES OR BODY FLUIDS.
SO CURRENT FDA GUIDANCE
CONSIDERING RISK OF TRANSMISSION
TO OTHER PEOPLE AND NON
PARTICIPANTS IS OFTEN EXTREMELY
LOW PROBABILITY AND A TRADE-OFF
AGAIN RISK AND INFLAMMATION.
EXPOSURE TO INTIMATE CONTACT OF
THE PUBLIC COULD IMPLY HARM TO
THE GROUPS.
WHEN ONE SIBLING RECEIVES A GENE
THERAPY WITH AN AAV VECTOR AND
MAY BE SHEDDING AND MAY POSSIBLY
EXPOSE HOUSEHOLD MEMBERS TO THE
SHED VECTOR, IS THERE A RISK IS
THAT A SIBLING MAY BE EXPOSED
AND THEN BE INELIGIBLE FOR
TREATMENT IN THE FUTURE?
THERE HAS TO BE A REALISTIC RISK
ASSESSMENT AND ADVICE GIVEN TO
SUBJECTS.
THERE'S OTHER THEORETICAL RISK
WITH EXPOSURE TO MATERIALS AND
THEY SOMETIMES PROVIDE
INSTRUCTIONS FOR PARTICIPANTS.
THOSE ARE PARTICIPANT-FACING
DOCUMENTS.
THEY MAY BE REVIEWED BY THE IRB
BUT ALSO LOOK LIKE HAZARD REVIEW
DOCUMENTS SO MAY BE REVIEWED BY
THE IBC.
THE REVIEW MAY NOT BE MANDATED
DEPENDING ON HOW YOU READ
CERTAIN GUIDANCES BUT LIKELY
THEY HAVE COMPLIMENTARY VIEW
POINTS ON THE DOCUMENTS IN TERMS
OF DUE DILIGENCE BOTH COMMITTEES
MAY BE INVOLVED IN REVIEW.
THE SECRETARY'S ADVISORY
COMMITTEE ON HUMAN RESEARCH
PROTECTION, SACHRP HAS ADVISE.
THEY ADVISE IRBs MAY CONSIDER
RISK TO NON SUBJECT AS
THIRD-PARTY RISK.
ALSO WHILE EMPHASIZING A NEED TO
AVOID UNNECESSARY OR DUPLICATIVE
REVIEWS OF SAFETY
CONSIDERATIONS.
THIS ADVISE HIGHLIGHTS
PARTICULAR CONSIDERATIONS
RELATED TO THE RISK SUCH AS THE
PROBABILITY AND FORESEEABILITY
AND MAGNITUDE OF A RISK.
THOSE CATEGORIES ARE REALLY
USING IN GENERAL WHEN WE TALK
ABOUT ALL THESE RISK ASSESSMENTS
BECAUSE EACH OF THESE FACTORS
PLAYS A ROLE IN WHETHER OR NOT
WE SHOULD SPEND TIME DURING THE
CONSENT PROCESS IN ADDRESSING
THE ISSUES.
OTHER ISSUE THAT MAY BE
CONSIDERED UNRESOLVED IS CONSENT
AND LONG-TERM FOLLOW-UP.
WHEN SUBJECTS ARE UNDER AGE
CHILDREN MAY BE ENROLLED UP
CLINICAL TRIALS WITH PLANNED
FOLLOW-UP.
IF A CHILD IS OLD ENOUGH TO
UNDERSTAND THE PROCESS THEN
ASSENT MAY BE REQUIRED BUT AT
WHEN THEY'RE YOUNG IT WON'T
HAPPEN AT THE TIME OF DOSING.
HOWEVER THEY'RE ENROLLED IN A
LONG-TERM FOLLOW-UP FOR 15
YEARS.
AT WHAT AGE ARE ASSENT AND
REASCENT BE RECOMMENDED SHOULD
IT BE WHEN A CHILD REACH A
CERTAIN AGE OR PARTICIPATE IN
THE LONG-TERM FOLLOW-UP OR FOR
SOME TYPES OF INTERVENTIONS FOR
REDOSING.
OVER AN EXTENDED TIME PERIOD IS
IT RECOMMENDED TO HAVE RE-ASSENT
BE NEEDED AND HOW THEY SHOULD BE
INFORMED OF NEW INFORMATION OVER
LONG-TERM FOLLOW-UP AS BEING A
REQUIREMENT OF THE PROTOCOL AND
HOW ARE THEY EXPRESSED IN AN
AGE-APPROPRIATE MANNER.
WE DISCUSS THESE QUESTIONS FOR
ADULT PARTICIPANTS WHEN HAVE YOU
SUBJECT ARE CHILDREN,
COMMUNICATION IS ADVISABLE OR
REQUIRED BUT INTERPRETATION AND
AGE APPROPRIATE LEVEL IS
REQUIRED WITH SPECIAL EXPERTISE
AND THERE'S A RIGHT TO WITHDRAW
PRESUMABLY INCLUDE THE LONG-TERM
FOLLOW-UP STUDIES CHILDREN GOING
THROUGH DIFFERENT STAGES OF
CHILDHOOD AND ADOLESCENTS ARE
GOING TO HAVE DIFFERENT
ATTITUDES TOWARDS COMPLIANCE AND
PARTICIPATION AND MAINTENANCE OF
ASSENT AND UNDERSTANDING OF
THEIR RIGHTS AS AN ONGOING ISSUE
THAT NEEDS TO BE CONSIDERED BY
IRBs BY PARENTS AND GUARDIANS
AND PARTICIPANTS THEMSELVES.
ANOTHER ASPECT OF ASSENT IS
ADULTS WITH VARYING COMPETENTS
AND A NEW AREA OF GENE TRANSFER
RESEARCH INVOLVES BEHAVIORAL
INTERVENTIONS OR GENE THERAPY
INTENDED TO ADDRESS BEHAVIORAL
HEALTH AND WE'LL ALSO SEE ASSENT
ISSUES BECOMING PROMINENT IN
THOSE AREAS OF THOSE CLINICAL
TRIALS MOVING FORWARD.
IN SUMMARY FOR TODAY'S
PRESENTATION, CELL AND GENE
THERAPY CAN ENCOMPASS A WIDE
RANGE OF INVESTIGATIONAL
PRODUCT.
EACH WITH SPECIFIC RISKS AND
CONCERNS FOR HUMAN SUBJECT
PROTECTION.
VARIOUS THERAPIES INVOLVE CLASS
RISK COMMON TO THE VECTOR OR
MODALITY.
EACH GENE THERAPY INVOLVE TRANS
GENES THAT REQUIRES CAREFUL
EVALUATION BASED ON KNOWN
BIOLOGY OF THOSE INTERVENTIONS.
PREPARING AN ICD TO ADDRESS ALL
THE COMPLEX BIOLOGY IS
CHALLENGING AND LIKELY TO
REQUIRE SEVERAL INTERVENTIONS
AND THE INPUT OF A LOT OF
DIFFERENT EXPERT VOICES.
USEFUL GUIDANCE HAS BEEN
PUBLISHED BY THE FDA AND NIH BY
PROFESSIONAL ORGANIZATIONS AND
BY PATIENT ADVOCACY GROUPS.
AND IRBs AND IBCs CAN WORK
TOGETHER TO OPTIMIZE INFORMED
CONSENT DOCUMENT REVIEWED.
-- REVIEWS.
SO I'VE SET ASIDE SOME TIME FOR
QUESTIONS I MAY HAVE QUESTIONS
COMING IN AND MAY BE AVAILABLE
FOR FURTHER DISCUSSION IF
ANYONE'S INTERESTED.
THANK YOU VERY MUCH.
ONE QUESTION THAT CAME UP
RELATED TO A POINT YOU MADE
OBVIOUSLY THIS IS INCREDIBLY
COMPLEX TOPIC HARD FOR EVEN SOME
OF US IN THE FIELD TO UNDERSTAND
HAS THERE BEEN ANY DATA
COLLECTED REGARDING THE REAL
LEVEL OF COMPREHENSION OF
POTENTIAL SUBJECTS?
>> SO A GREAT QUESTION, I DO NOT
HAVE DATA TOP OF MIND BUT IT'S
SOMETHING THAT OBVIOUSLY SHOULD
BE INVESTIGATED ON AN ONGOING
BASIS AND SOMETHING THAT SHOULD
BE DONE.
I'VE SEEN SOME DATA AT
CONFERENCES AND POSTERS BUT I
CAN'T CITE THAT TODAY.
>> YOU MENTIONED ASSENT AND SOME
THERAPIES PROVIDED TO CHILDREN.
HAVE THERE BEEN LONG-TERM
FOLLOW-UP IN TERMS OF THEIR
LEVEL OF UNDERSTANDING OVER
TIME?
OBVIOUS SOME ARE VERY YOUNG
PROBABLY AT AN AGE WHEN ASSENT
CAN BE OBTAINED AND IS THERE
CONCERN OF THE FOLLOW-UP
OBVIOUSLY NEEDED.
>> I HEAR HOW TO DO THE
FOLLOW-UP AND MAINTAIN THESE
ISSUES.
AS ALWAYS DATA WOULD BE
WONDERFUL AND I DO NOT HAVE DATA
OTHER THAN REMEMBERING SEEING
POSTERS AT ASGCT BUT WORTH
PURSUING.
>> OBVIOUSLY THE DEVIL IS IN THE
DETAILS AND THE FORMS ARE TOO
LONG.
THERE'S POTENTIAL RISKS INVOLVED
HERE.
ARE ANY TIPS IN TERMS OF RBIs
YOU MENTIONED CONSIDERATIONS.
IS THERE VARIABLE BETWEEN IRBs
IN TERMS OF WHAT THEY THINK IS
ESSENTIAL?
TRYING TO OF COURSE WEIGH WHAT
SUBJECTS NEED TO UNDERSTAND TO
MAKE AN EDUCATED DECISION AS TO
WHETHER THIS IS APPROPRIATE FOR
THEM OR NOT VERSUS THERE BEING
TOO MUCH OR NOT ENOUGH.
>> I'M SURE THERE IS FOR BETTER
OR WORSE AND SOME REVIEWS ARE
PERFORMED BY LOCAL INSTITUTIONAL
IRBs AND SOME BY CENTRAL IRBs
WHO HAVE DIFFERENT EXPERIENCES
WITH A BROAD RANGE OF THESE
PROTOCOLS.
A
AND INFORM WHAT THEY THINK IS
IMPORTANT AND COULD BE WHAT
THEY'VE BEEN READING RECENTLY
AND THAT'S WHY A GROUP
CONSIDERATION OF WHAT'S TRULY
GOING TO BE REALLY EFFECTING
SUBJECT'S DECISION TO
PARTICIPATE OR NOT IN AN
INFORMED WAY IS THE MOST
IMPORTANT QUESTION.
THERE'S NO SIMPLE SOLUTION
BECAUSE WE DON'T KNOW IN ADVANCE
WHAT'S GOING TO HAPPEN.
WE HAVE TO MAKE A BEST GUESS TO
WHAT IS GOING TO BE IMPORTANT.
>> YOU SPOKE OF EX VIVO MODIFIED
CELLS BECOMING MALIGNANT PRIOR
TO ADMINISTRATION.
HOW COULD THAT POSSIBLY BE
EVALUATED AHEAD OF TIME?
OBVIOUSLY IT CAN'T OR YOU
WOULDN'T HAVE MENTIONED IT
BUT --
>> IT'S A RARE RISK BUT
SOMETHING DEPENDING ON THE
SOURCE OF THE CELLS.
CERTAIN WAYS OF ACQUIRING CELLS
FOR EX VIVO MODIFICATION CAN
BRING IN A MALIGNANT CELL A RARE
EVENT BUT FOR TUMORS SOMETIMES
IT MAY HAPPEN.
IT COULD BE CAUGHT IN MOST
CASES.
AND WHEN YOU CHANGE CHROMOSOME
THERE'S ALWAYS A RISK YOU'LL
ACTIVATE AN ONCOGENE AND IF
YOU'RE EXPANDING YOURSELVES EX
VIVO DURING THAT PROCESS THERE
COULD BE OVER GROWTH OF
TRANSFORMED CELLS.
THERE ARE PROTECTIVE MEASURES IN
PLACE DURING MANUFACTURING TO
AVOID THOSE AFFECTS AND IT'S NOT
BEEN A MAJOR CONCERN IN CLINICAL
TRIALS SO FAR BUT IT'S A
CONSIDERATION THAT COULD APPEAR
ESPECIALLY AS MORE AND MORE
TRIALS ARE EXECUTED USING THOSE
TECHNOLOGIES.
>> LET ME SEE IF OTHER QUESTIONS
HAVE COME IN?
I DON'T SEE ANY BUT IF WE HAVE
ANY THAT COME IN I WILL FORWARD
THOSE TO YOU.
I'M SURE PEOPLE -- THIS HAS BEEN
VERY THOUGHT PROVOKE.
THERE'S MORE TO THIS THAN SOME
OF US HAVE UNDERSTOOD IN TERMS
OF THE RISK AND HOW TO CONVEY
AND WHAT TO CONVEY.
LOTS TO THINK ABOUT.
THANK YOU FOR JOINING US TODAY.
THANK YOU VERY MUCH.
WE APPRECIATE IT.
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