MY PRESENTATION IS A LITTLE BIT DIFFERENT THAN ANYTHING YOU HAD BEFORE. I'M NOT A MEDICAL DOCTOR OR RESEARCHER, I'M A PATIENT. I HAVE BEEN A PATIENT FOR A LONG TIME, FOR 37 YEARS HERE. THEY WORKED ON ME BECAUSE I HAD MELANOMA, THYROID CANCER, AND PROSTATE ISSUES THAT THEY STILL CAN'T FIGURE OUT WHAT'S GOING ON. BUT I'M HERE REALLY ON BEHALF OF MY FELLOW PATIENTS TO SHARE OUR EXPERIENCES, OBLIGATIONS AND SUGGESTIONS WITH YOU WHO ARE INTERESTED IN -- MEDICAL RESEARCHERS, THE RESEARCH IS AN ACUMULATION OF EXPERIENCES AND SUGGESTIONS OF A NUMBER OF MY FELLOW NIH PATIENTS A HOT OF THIS MAY BE ORIENTED TO NIH BUT I THINK IT'S PROBABLY HOLDING TRUE FOR RESEARCHING OUTSIDE OF THE CLINICAL CENTER IN THE NIH. SO WHY DO PATIENTS PARTICIPATE IN CLINICAL TRIALS? THEY'RE REALLY BASICALLY TWO TYPES OF PATIENTS. THOSE WHO ARE HEALTHY, WHO WANT TO PARTICIPATE AND HELP OTHERS BY CONTRIBUTING TO MEDICAL RESEARCH AND ADVANCING SCIENCE, AND THOSE WHO ARE SICK, THOSE WHO ARE ILL WHO MAY HAVE BEEN REFERRED BY OUTSIDE PRIVATE PHYSICIANS OR WHO ARE SELF-REFERRED. THAT'S MORE AND MORE THE CASE THESE DAYS. IN MANYCACIES THEY'VE X HAWSED ALL OTHER OPTIONS TO TAKE ADVANTAGE. THEY'VE COME TO TAKE ADVANTAGE AND SOMETIMES THE EXPERIMENTAL AND SOMETIMES POTENTIALLY RISKY TREATMENTS, THAT ARE OFTEN INACCESSIBLE IN ANY OTHER WAY. AND MANY ARE LOOKING FORWARD, REALLY LOOKING FOR MEDICAL MIRACLES. MY THESIS IS THAT IT'S AN IMPORTANT AND BENEFICIAL FOR YOU AS RESEARCHERS TO FORM A PARTNERSHIP WITH YOUR PATIENT VOLUNTEERS. A PARTNERSHIP THAT'S BASED ON TRUST AND UNDERSTANDING, A PARTNERSHIP OF PALM BEACHES, ONE THAT -- PIERS, ONE THAT ADVANCES MEDICINE AND ALSO ULTIMATELY SAVES LIVES. TO BE SUCCESSFUL YOUR RESEARCH BEIN SOME MEASURE BE DEPENDENT ON THE COOPERATION OFF YOUR PATIENT VOLUNTEERS, THEIR CONFIDENCE ENYOU WILL HELP ESTABLISH A POSITIVE RELATIONSHIP, ONE THAT CAN BE EXTREMELY HELPFUL TO YOU AND FOR THE OUTCOME OF YOUR STUDY. AT THE HEART OF THIS PARTNERSHIP FOR PATIENT AND SCIENTISTS ALIKE IS THE BASIC OPTIMISM AND HOPE FOR A POSITIVE OUTCOME. SO I'VE CREATED AN ACRONYM THAT HOPEFULLY IS APPRECIATE AS WE DISCUSS THIS. AND I CALL THE -- THIS CUE. C IS FOR COMMUNICATION. U, UNDERSTANDING AND E, EMPATHY. COMMUNICATION. VERBAL AND NON VERBAL SKILLS. YOU ONLY HAVE ONE CHANCE TO MAKE AN INITIAL IMPRESSION. IT'S MY POSITION THAT THE PRINCIPLE INVESTIGATOR SHOULD BE PRESENT AND TAKE THE TIME FOR YOU AND THE INVESTIGATOR TO BE THOROUGH IN A VERY PRIVATE SETTING. YOU MUST EXPLAIN THE ROLE OF FELLOWS OR INVESTIGATORS AS THE CASE MAY BE, AND THAT YOU NOT PUSH FOR AN INITIAL DECISION FROM THE PATIENT TO MAKE A -- THAT DECISION TO CONTINUE TO PROCEED WITH THE PROJECT. YOU NEED TO HAVE A FULL EXPLANATION OF EVERY ASPECT OF HOW THE PROCESS WILL WORK, AND UNDERSTAND THAT PATIENTS MAY BE INTIMIDATED AND OVERWHELMED ESPECIALLY IN THEIR INITIAL MEETING, AND DO ENCOURAGE NOTE TAKING SO THAT THEY CAN HAVE A PRETTY GOOD RECALL OF WHAT WAS DISCUSSED AT THE MEETING. EXPLAIN THE RISK, POSSIBLE LIFE STYLE EFFECT CHANGES. WHILE UNDERGOING TREATMENT, WILL THEY BE ABLE TO WORK, WILL THEY TAKE CARE OF THEIR FAMILY? WHAT WILL BE THE DURATION OF THE TRIAL. TRANSPORTATION ISSUES AND POSSIBLE COST IF ANY, AND SHOULD THEY BRING A CAREGIVER. MAKE SURE THIS CONVERSATION DOESN'T TAKE PLACE IN HALLWAYS. OR IN THE MIDST OF A BUSY CLINIC. AND RESPECT BY ALL MEANS, RESPECT THEIR PRIVACY. SITTING WHEN YOU'RE TALKING TO YOUR PATIENT, CONVEYS A SENSE OF IMPORTANCE AND A CONVERSATION OF PEERS. MAKE EYE CONTACT. IT CONVEYS A SENSE OF DIRECT ENGAGEMENT AND THAT THEY HAVE YOUR COMPLETE ATTENTION AND FOCUS AND LISTEN INTENTLY, NO WRITING, NO TYPING. TODAY, IN THIS WORLD, IT SEEMS THAT SO MANY CLINICIANS, WHEN THEY'RE MEETING WITH A PATIENT, ARE ON THEIR DESKTOP TYPING AWAY OR LAPTOP, TIMING AWAY AND HARDLY MAKING -- TYPING AWAY AND HARDLY MAKING EYE CONTACT WITH THE PATIENT. I HAVE TO TELL YOU, FROM PERSONAL EXPERIENCE, THAT IS EXTREMELY OFF PUTTING. LISTEN INTENTLY AND TYPE AFTER THE VISIT. AND REVIEW YOUR PATIENTS FILE AND HISTORY BEFORE, NOT DURING THE MEETING. THINK THROUGH IN ADVANCE THE LIKELY QUESTIONS OR THOSE THAT SHOULD BE ASKED AND COVER THEM, EVEN IF THE PATIENT DOESN'T ASK. UNDERSTAND THAT THE EXPERIENCE CAN BE INTIMIDATING, OVERWHELMING, AND GIVE THEM TIME TO OR SO MUCH AND ENCOURAGE NOTE TAKING. BE TOTALLY ACCESSIBLE BETWEEN CLINICAL VISITS. YOU CAN BE ASSURED THAT PARTICULARLY IN THE FIRST VISIT, BUT PERHAPS ON ENSUING ADVICE AS WELL, THE PATIENT IS NOT GOING DO REALLY BE ABLE AT A ABSORB EVERYTHING THAT YOU SAY. THERE ARE GOING TO BE QUESTIONS THAT ARISE AFTER SHE OR HE LEAVES YOU. BE TOTALLY ACCESSIBLE BETWEEN CLINICAL VISITS. RETURN PHONE CALLS AND E-MAILS IN A TIMELY FASHION. BEING ABLE TO STAY IN CONTACT WITH THE RESEARCHER IS EXTREMELY IMPORTANT. AND IF YOU RESPOND QUICKLY IT DOES SHOW A SENSE YOUR REGARD FOR THIS PERSON AND INTEREST IN THEIR WELLBEING. IF THE SITUATION WARRANTS IT, KEEP OUTSIDE PRIMARY CARE PHYSICIANS REGULARLY APPRISED OF DEVELOPMENTS. UNDERSTANDING. LISTENING IS MORE THAN AN NINE LETTER WORD. YOU NEED TO ASSESS THE PATIENT VOLUNTEERS UNDERSTANDING. DO THEY REALLY GET IT? BE CAREFUL OF THE OVER-USE OF MEDICAL JARGON. TRANSLATE TECHNICAL TERMS. UNDERSTAND THAT MANY RETURNING PATIENTS HAVE BEEN COMING FOR YEARS. THEIR KNOWLEDGE AND UNDERSTANDING OF THEIR ILLNESS AND RESEARCH MAY POSSIBLY BE GREAT IRRELEVANT YOURS AS A NEW FELLOW OR RESEARCHER. IT'S AN INDICATION OF RESPECT FOR YOU TO RECOGNIZE AND ACKNOWLEDGE THIS. RESPECT AND ENCOURAGE PATIENT VOLUNTEERS OWN RESEARCH. I'M SURE YOU'RE AWARE THAT EVERYBODY IS ON THE INTERNET THESE DAYS, MORE THAN LIKELY THOSE PATIENTS WHO HAVE THAT DEGREE OF INTEREST AND AVAILABILITY OF COMPUTERS WILL BE ON THEIR GOOGLE SITE AND LOOKING FOR AS MUCH INFORMATION AS THEY CAN. SOME OF THIS RESEARCH IS NOT GOING TO BE ACCURATE BUT RESPECTFULLY, CORRECT THEIR MISINFORMATION AND DIRECT THEM TO RERYABLE SOURCES. BE HONESTLY OPTIMISTIC. NO FALSE HOPE. BUT ACKENIATE THE POSITIVE WITHOUT ELIMINATING THE GIVE. UNDERSTAND PATIENTS -- UNDERSTAND PATIENTS PREVIOUSLY TREATED IN THE PRIVATE SECTOR MAY FEEL THE CLINICAL RESEARCH ENVIRONMENT IS INTIMIDATING AND OFF PUTTING. BE NEGATIVE SENSITIVE -- BE SENSITIVE TO THAT. MAKE SURE PATIENTS UNDERSTAND THEY CAN DISCONTINUE PATIENTS -- CAN DISCONTINUE THE TRIAL AT ANY TIME WITHOUT NEGATIVE CONSEQUENCES OR MISTREATMENT. PLEASE, NEVER USE THE FACT THAT PATIENTS ARE RECEIVING FREE CARE. THIS CAN BE OFFENSIVE TO PATIENTS. SO RATHER ENFORCE THE IDEA THAT THEY ARE VERY -- A VERY COMPONENT TO THE OVERALL PROCESS OF CLINICAL RESEARCH. THIS PROCESS COULD NOT BE DONE WITHOUT THEM. REMEMBER THE SO-CALLED FREE CARE IS OFTEN EXPERIMENTAL, AND SOMETIMES COMES WITH POTENTIAL RISKS FOR THE PATIENT. EMPATHY. THE ACT OF SIMPLY COMING TO MOST LARGE MEDICAL FACILITIES IN THE ENTIRE INITIAL EXPERIENCE AND EVEN SUBSEQUENT VISITS CAN BE INTIMIDATING AND OVERWHELMING. ILL PATIENTS CAN BE EXERCISED, EMOTIONAL. REMEMBER, FOR SOME, YOU WILL REPRESENT THEIR LAST HOPE. SOME PATIENTS HAVE COMPLAINED THAT BEING TREATED LIKE GUINEA PIGS OR LAB RATS AND FEEL THAT THEY'RE ONLY VALUE IS TO PROVIDE DATA AND RESENT BEING MADE 250 FEEL THIS WAY. SO GO OUT OF YOUR WAY TO MAKE YOUR PATIENTS UNDERSTAND AND BELIEVE THAT YOU TRULY CARE ABOUT THEIR WELFARE. TIME MANAGEMENT. DON'T ACT RUSHED. THE WORST THING THAT CAN -- I THINK THAT CAN SET A PATIENT OFF IS FORA CLINICIAN TO COME IN TO DEEXAMINING ROOM, SAY I ONLY AFTER FEW MINUTES TO TALK TO YOU. LET'S GET ON WITH THIS. WHAT COULD BE MORE IMPORTANT AT THAT TECH MOMENT IN TIME THAN TO GO FACE TO FACE WITH YOUR PATIENT. BE ON TIME. LONG CLINIC WAITS ARE DISRESPECTFUL. AND OFF PUTTING. AND TO SICK AND ANXIOUS PATIENTS IT'S EXTREMELY OFF PUTTING. I CAN GIVE TESTIMONY THAT HAVING SAT IN SOME CLINICS, WAITED FOR AN EXTRAORDINARY LONG TIME FOR MY FELLOW DO COME JOIN ME. SO PLEASE, PUT THAT IN YOUR BOOK AND DO MAKE IT AN EXTREME EFFORT. DIFFICULT CONVERSATION. DELIVERING BAD NEWS. EVERY PATIENT IS A VERY REAL UNIQUE PERSPECTIVE WITH GENUINE FEARS AND HOPES AND NOT JUST AN EXPERIMENT IN YOUR LAB. A NEGATIVE DIAGNOSIS CAN INCLUDE THE PERCEPTION THAT LIFE HAS ONE HAS LIVED IT IS GONE FOREVER. THERE MAY BE LITTLE HOPE FOR THE FUTURE. IT MAY REQUIRE A STRETCH BUT I SUGGEST THAT YOU TRY TO STRETCH TO PUT YOURSELF IN THE PATIENT'S SHOES. IT'S CRITICAL FOR YOU TO BE UNDERSTANDING AT THIS POTENTIALLY VERY, VERY SENSITIVE MOMENT. PERHAPS THE REASON THAT THE TRIAL HAS TO BE CANCELED IS BECAUSE THE TREATMENT WAS NOT EFFECTIVE OR BECAUSE THE SEVERE DEBILITATING SIDE EFFECTS WERE OVERWHELMING. OR THE TEST THAT THE PATIENT HAS TAKEN IS -- HE IS NOT OR SHE IS NOT COMPLYING. WHATEVER DEREASON, CANCELLATION OF A TRIAL CAN BE DEVASTATING. SO FIND A PRIVATE SETTING. FIND SOMEPLACE REALLY OUT OF THE WAY, QUIET, WHERE VERY CONFIDENTIAL AND SENSITIVE CONVERSATION CAN BE HAD. MAKE SURE THAT THE PROPER STAFF IS THERE. IN ALLOCATIONS IF AT ALL POSSIBLE, THE PRINCIPLE INVESTIGATOR SHOULD BE THERE. ANY ONE THAT YOU MAY FEEL IS IMPORTANT DO THE PATIENT TO -- TO THE PATIENT TO BE PRESENT AND PRESENT THE CASE TO HIM OR HER. ALLOW NECESSARY TIME. IT'S AWFULLY IMPORTANT AT THIS MOMENT PARTICULARLY AT THIS MOMENT THAT YOU GIVE ALL THE TIME NECESSARY TO GIVE THE PATIENT WHAT SHE OR HE NEEDS TO HEAR IN THE MOST POSITIVE, IF POSSIBLE, FASHION POSSIBLE. AND WHEN THIS -- WHEN BAD NEWS HAS TO BE GIVEN DO ADVISE THE PATIENT IN ADVANCE TO BRING SOMEBODY WITH THEM. PERHAPS A CAREGIVER, PERHAPS A RELATIVE. BUT TO BE THERE WITH THEM AT THIS VERY TRAUMATIC MOMENT. BE CAREFUL WITH YOUR CHOICE OF LANGUAGE A COMPLAINT THAT SOME CANCER SURVIVERS HAVE VOICED IS THE PHRASE THAT SOME PHYSICIAN AND MANY OTHERS MAY HAVE USED FROM TIME TO TIME, W YOU FAILED YOUR CHEMO. OR ANOTHER TREATMENT. AND -- BECAUSE BY MOST REASONABLE AMERICANERS THE FAILURE -- MEASURES, THE FAILURE OF THE TREATMENT IS THE TREATMENT, NOT THE PATIENT IS AT FAULT. HEARING THE PHRASE UTTERED CAN CONTRIBUTE MIGHTILY TO CONTINUING BAD NEWS EVEN WORSE. THIS TIME OF PEJORATIVE LANGUAGE SHOULD NEVER BE USED AN SHOULD BE FORBIDDEN. SO PLEASE, UNDERSTAND THAT. IT'S IMPORTANT ALSO TO HAVE AN ADVANCE PREPARED WHAT OTHER POSSIBLE OPTIONS ARE. IF THERE ARE OTHER STUDIES IN OTHER FACILITATES AROUND THE COUNTRY, MAKE SURE THAT THEY KNOW ABOUT THEM. IF THIS ARE OTHER DRUGS, ANY OTHER POSSIBILITIES, THIS IS THE TIME TO TALK TO THE PATIENT AND MAKE SURE THAT SHE OR HE UNDERSTANDS THAT THERE ARE OTHER OPTIONS. MAKE THE PATIENT AWARE THAT THERE IS SUPPORTIVE CARE. FOR EXAMPLE, PSYCHOLOGIST, SOCIAL WORKERS, SPIRITUAL PROFESSIONALS. ALL THIS NEEDS TO BE ARRANGED IN ADVANCE SO THAT YOU'RE PREPARED FOR WHATEVER EVENTUALITY, WHATEVER REACTION THIS PATIENT MAY HAVE. AND WHEN IT'S APPROPRIATE, MAKE SURE THAT THE PHYSICIAN AT HOME UNDERSTANDS WHAT THE SITUATION IS SO THAT SHE OR HE CAN BE PREPARED TO DEAL WITH A PATIENT WHEN THEY RETURN TO THEIR HOMES. BASICALLY, WHAT I'VE SAID HERE IS THAT WE TAKE MY CUE, AND THAT MAKE COMMUNICATION UNDERSTANDING AND EMPATHY CARDINAL ELEMENTS OF YOUR PARTNERSHIP RELATIONSHIP WITH YOUR PATIENT VOLUNTEER. AND NEVER FORGET, NEVER FORGET THAT IN ADDITION TO BEING YOUR PATIENT, AN PERHAPS JUST ONE ELEMENT IS YOUR RESEARCH THAT WE PATIENTS ARE HUMAN, VERY REAL, WITH SENSITIVITIES, CONCERNS, AND FEELINGS. WHEN WE WERE PRESENTING THIS -- I PRESENT THIS TO THE NEW FELLOWS HERE EVERY YEAR. AND WE HAVE PATIENTS WHO GATHER HERE TWICE A YEAR TO BE PART OF A GROUP CALLED A PATIENT ADVISORY GROUP. DR. GALLIN HAS ASKED WE PATIENTS COME TOGETHER AND DISCUSS WITH HIM WHAT ISSUES WE SEE AS WE GO THROUGH THE CLINICAL TRIALS HERE. AND I ASKED AT ONE OF THE MEETINGS IF ANY OF MY FELLOW PATIENTS HAD ANY COMMENTS THAT THEY WANTED ME TO CONVEY TO THE FELLOWS. AND I THINK IT'S APPROPRIATE FOR ME TO READ TO YOU THE LETTER THAT SHE WROTE TO ME AND ASKED TO BE PRESENTED TO HER FELLOWS. IT GOES LIKE THIS. DEAR FELLOWS. WE ARE HONORED TO BE UNDER YOUR CARE. WE SEE YOU AS INCREDIBLE CURIOUS PEOPLE, SOME ADVANTAGE TO BE NAMED A FELLOW AT THE NIH. WE WANT YOU TO KNOW WE PRESENTER YOUR INTELLECTUAL FORITUDE AND LACK OF SELFISHNESS. BUT WE ALSO WANT YOU TO UNDERSTAND THAT YOUR NOT OUR FIRST SHOPPING EXPERIENCE. WE HAVE BEEN POKED, PRODDED, TESTED BY OTHERS, YOUR COLLEAGUES, YOUR ELDERS, YOUR NURSES, NOW, HOWEVER, ARE NEW TO US. WE WANT YOU TO KNOW WE ARE NOT OUR DISEASE. YES, WE UNDERSTAND THAT YOU LOVE INVESTIGATING. INVESTIGATING THE DISEASE. AND HAVE AN URGENT SKY FOR INVESTIGATION. BUT WE ARE MORE THAN OUR DISEASE. WE ARE GRANDMOTHERS, WORRIED PARENTS, FRIGHTENED CHILDREN, WE HAVE HOPE, LOVE, AND COMPASSION. WE SUFFER. WE WORRY. WE WORRY A LOT. WE ALLOW YOU TO BE INTIMATE WITH OUR INNER WORKERS, AND DO IT OVER AND OVER AND OVER AGAIN. FOR THOSE OF US WHO HAVE COME TO THE NIH TIME AND TIME AGAIN, IF WE'RE LUCKY, WE GET TO REPEAT OUR STORY OVER AND OVER AGAIN. SO WHEN YOU'RE ABLE, MAKE THE TIME TO READ UP ON US. BE INFORMED. WE KNOW YOU LIKE TO BE INFORMED. YOU TOUCH THE PETE RIDISH OF OUR LIVES. WHY NOT READ ABOUT US FIRST? A PHYSICIAN ONCE WISELY TOLD ME, KAREN DIAGNOSES IS 90% HISTORY. I'VE NEVER FORGOTTEN THAT. WE'RE THE SUM OF OUR PARTS AND YOUR RECOGNITION OF OUR WHOLENESS MATCHES IN THE HEALING PROCESS, AS WELL AS THE SURING PROCESS. SO CARRY ON WITH HOPE, LOVE, AND COMPASSION, BRINGING THOSE QUALITIES TO THE EXAM ROOM WILL EPLIGHTEN AND ENRICH YOUR EXPERIENCE, TOO. SHE SIGNS THE LETTER KAREN. SISTER, SHE'S AN RN, BY THE WAY. MS. SISTER, MOTHER, GRANDMOTHER, FRIEND, NURSE, PATIENT, SURVIVOR. TO ME IT IS AT THIS THE MOST MEANINGFUL STATEMENT I COULD LEAVE YOU WITH TO UNDERSTAND HOW WE FEEL AND PATIENTS GOING UNDER YOUR CARE. AND BE PARTICIPATING WHICH IN YOUR TRIALS. SHEATHY VERY MUCH FOR LISTENING. AND -- THANK YOU VERY MUCH FOR LISTENING. I WISH YOU WELL. AND THANK YOU FOR YOUR INTEREST IN BECOMING INVESTIGATORS. ANY QUESTIONS? THANK YOU AGAIN. [APPLAUSE] GOOD EVENING. I AM KATE STONEY, A PROGRAM DIRECTOR AT THE NATIONAL HEART LUNG AND BLOOD INSTITUTE. AND AT THE NHLBI I OVERSEE A DIVERSE PORTFOLIO OF CLINICAL TRIALS THAT REALLY SPAN THE ENTIRE SPECTRUM OF THE RESEARCH SPECTRUM, THE TRANSLATIONAL SPECTRUM. AND I HAVE BEEN ASKED TO COME AND TALK TO YOU A LITTLE BIT TODAY ABOUT WHAT YOU NEED TO THINK ABOUT WHEN SELECTING PARTICIPANTS TO ENGAGE IN YOUR RESEARCH STUDIES. AND I'M REALLY DELIGHTED TO DO THAT. LET ME JUST START BY, I THINK -- JERRY HAS LEFT. BY I WANTED TO THANK HIM AND REALLY ENDORSE THE COMMENTS THAT HE MADE. I THINK THEY'RE REALLY HEARTFUL COMMENTS, SOMETHING THAT ALL OF US AS RESEARCHERS REALLY NEED 250 HEAR. AND LIVE AS WE GO FORTH WITH OUR RESEARCH PROGRAMS. AND IN THAT VAIN, I -- YOU MIGHT NOTICE IN MY SLIDES I REALLY DON'T REFER TO PATIENT BUT RATHER PARTICIPANTS BECAUSE I REALLY LIKE THIS NOTION THAT THE PEOPLE THAT PARTICIPATE IN OUR RESEARCH STUDIES ARE PARTNERSHIPS. RIGHT? THEY'RE PARTNERS WITH US AS RESEARCHERS, IDENTIFYING THEM AS PARTICIPANTS UNDERSCORES THAT PARTNERSHIP. SOMETIMES I MIGHT -- I MIGHT SLIP AND CALL THEM PATIENTS BUT I REALLY MEAN TO CALL THEM PARTICIPANTS. THAT IS HOW I SEE THEM. OKAY. NOW I'LL FIGURE OUT HOW TO DO THIS. OKAY. SO IT'S AN INTERESTING TOPIC TO THINK ABOUT. WHEN YOU ARE UNDERTAKING A RESEARCH PROGRAM, A STUDY THAT YOU WANT TO CONDUCT, AND YOU'RE THINKING BROUGHT RESEARCH PARTICIPANTS AND WHO YOU WANT TO SELECT, YOU MIGHT THINK RIGHT OFF THE BAT, THIS IS NOT A HARD THING TO DO. RIGHT? SO LET'S SAY YOU'RE INTERESTED IN DIABETES, SO YOUR GOING TO ENROLL IN YOUR STUDY -- THE PARTICIPANTS ARE GOING TO BE THOSE THAT HAVE DIABETES. THAT SEEMS TO BE OBVIOUS. BUT I'D LIKE TO KIND OF DEVELOP DEEPER TO GET TO SOME OF THE MORE INTRICATE ASPECTS OF PARTICIPANT SELECTION TO TALK ABOUT SOME OF THE CHARACTERISTICS TO REALLY FIGURE OUT WHAT ARE THE THINGS THAT WE NEED TO THINK ABOUT CAREFULLY WHEN WE'RE THINKING ABOUT WHO WE WANT TO PARTICIPATE IN OUR STUDIES. SO SOME OF THE THINGS THAT YOU MIGHT HAVE QUESTIONS ABOUT, IF YOU THINK A LITTLE BIT MORE DEEPLY, IS NOT ONLY HOW YOU DECIDE WHO TO PARTICIPATE IN YOUR -- WHO YOU WANT PARTICIPATING IN YOUR STUDY, BUT YOU NEED TO ONGOING ABOUT HOW GENERALIZABLE THE EFFECTS THAT YOU FIND IN YOUR STUDY, HOW GENERALIZABLE DO YOU WANT THEM TO BE TO A BROADER POPULATION? AND THE ANSWER TO THAT QUESTION IS NOT A SINGLE AMOUNTS. IT REALLY DEPENDS ON A LOT OF FACTORS. WE'LL TALK ABOUT THOSE BLOOD PRESSURE HOW DO YOU KNOW THAT YOUR STUDYING WHO YOU THINK YOU WANT TO STUDY? WE'LL TALK ABOUT SOME OF THOSE ISSUES. AND REALLY IMPORTANTLY, HOW DO I MATCH THE CHARACTERISTICS OF THE PARTICIPANTS THAT YOU ENROLL IN YOUR STUDIES TO THE OUTCOMES THAT YOU REALLY WANT TO MEASURE? THIS IS A CRITICAL FACTOR THAT I REALLY WANT TO UNDERSCORE AS WE WALK THROUGH THE STUDY. AND LET ME JUST SAY NOW THAT THERE IS AN ADDITIONAL LECT LECTURE THAT DEALS WITH PARTICIPANT CHARACTERISTICS IN TERMS OF INCLUSION OF UNDER-REPRESENTED MINORITIES IN WOMEN IN STUDIES. AND IT'S ARCHIVED ON THE IAPPCR ARCHIVES. BY DR. MIRIUM COALTY, I VERY STRONGLY ENCOURAGE YOU TO LISTEN TO THAT LECTURE. IT'S VERY GOOD. SHE'S AN EXPERT, EXTREMELY WELL VERSED IN NOT ONLY THE REGULATIONS BUT THE ETHICAL ASPECTS. SO I'M NOT GOING TO TOUCH ON THOSE, THOUGH ISSUES ARE DEALT WITH IN HER LECTURE. BUT I DO WANT TO TOUCH ON THESE OTHER ISSUES. SO WE'RE GOING TO START OFF TALKING ABOUT THE REASONS THAT YOU WANT TO THINK ABOUT CHARACTERISTICS OF YOUR PARTICIPANTS AND HOW TO SELECT THOSE CHARACTERISTICS. I WANT TO SPEND A LITTLE BIT OF TIME TALKING ABOUT THE TRANSLATIONAL SPECTRUM OF CLINICAL TRIALS. AND YOU KNOW SOME OF THIS ALREADY. JUST BY VIRTUE OF THE FACT THAT YOU'RE HERE. BUT I WANT TO TALK ABOUT THAT TRANSLATIONAL SPECTRUM SPECIFICALLY WITH REGARD TO HOW IT IMPACTS YOUR PARTICIPANTS SELECTION CRITERIA. WE'RE GOING TO TOUCH ON INDENVERSES EXTERNAL VALIDITY. AND YOU WILL HEAR THIS AGAIN IN THIS COURSE. AND YOU'LL HEAR IT SPECIFICALLY WHEN YOU TALK ABOUT SIGNIFICANCE TESTING, WHEN YOU TALK ABOUT ANALYTIC STRATEGIES, AND OTHER DESIGN ISSUES. I'M NOT GOING TO TALK ABOUT THE ANALYTIC PART HERE. I REALLY WANT TO TALK ABOUT CONCEPTUALLY WHAT WE MEAN BY INTERNAL AND EXTERNAL VALIDITY, AND HOW THAT IMPACTS OUR DECISIONS REGARDING WHO WE ENROLL IN OUR STUDIES. I WANT TO TALK THROUGH SOME OF THE FACTORS TO THINK ABOUT, THE CHARACTERISTICS TO THINK ABOUT. AND HOW TO THINK ABOUT THOSE IN RELATIONSHIP TO YOUR TRIALS. I'M GOING TO GIVE YOU AN EXAMPLE FROM A REALLY INTERESTING STUDY THAT IS GOING TO ILLUSTRATE MANY OF THE FACTORS THAT WE'RE LOOKING AT. SO LET'S GET STARTED. SO SOME OF THE REASONS TO THINK ABOUT PARTICIPANTS SELECTION. ONE IS THAT IT'S GOING TO -- IF YOU THINK ABOUT IT CAREFULLY, IT WILL HELP YOU CLARIFY THE QUESTION THAT YOU WANT TO ASK. AND THE STUDY DESIGN THAT'S MOST APPROPRIATE FOR THAT QUESTION. AND THE WAY THIS WILL HAPPEN IS BY UNDERSTANDING WHERE YOUR SCIENCE, THE QUESTION THAT YOU'RE ADDRESSING, FITS ON WHAT'S CALLED THIS RESEARCH CONTINUUM, OR YOU MIGHT REFER TO IT AS A TRANSLATIONAL SPECTRUM. BUT THIS IS THE COURSE OF SCIENCE. HOW CLINICAL TRIALS MOVE. NOT A SINGLE TRIAL BUT THE SCIENCE BEHIND A SINGLE QUESTION. IN TERMS OF THE TRIALS THAT ARE RUN. FOR EXAMPLE, WE START IN TELEPHONING ANY KIND OF TRIALS, WE START WITH PHASE ONE TRIALS. AND PHASE ONE TRIALS ARE REALLY EARLY STAGE RESEARCH THEY'RE DEALING WITH. SAFETY ISSUES, DEALING DOSE RANGING QUESTIONS. THESE PHASE ONE TRIALS ARE VERY, VERY SMALL. BECAUSE THEY'RE DEALING WITH ISSUES THAT YOU DON'T NEED A LOT OF PARTICIPANTS TO DEAL WITH. YOU REALLY WANT TO KNOW WHAT THE SAFETY CHARACTERISTICS ARE OF YOUR INTERVENTION. SO THEY'RE SMALL TRIALS. AND THEY SOMETIMES, OFTEN TIMES, ARE HEALTHY INDIVIDUALS. IF YOU'RE TEARGAS, IF YOU'RE JUST STARTING TO DEVELOP -- IF YOU'RE AT THE PHASE AND JUST STARTING TO DEVELOP AN INTERVENTION, YOU DON'T KNOW IF IT'S SAFE, YOU DON'T KNOW THE DOSE, HOW MUCH OF THE INTERVENTION YOU NEED DO DELIVER IN ORDER TO HAVE THE OUTCOME YOU'RE LOOKING FOR, IF YOU'RE IN THAT PHASE, THE CHARACTERISTICS OF YOUR PATIENT POPULATION ARE GOING TO BE SPECIFIC TO THAT AND VERY DIFFERENT THAN THEY WOULD BE IN, SAY, A PHASE 2 TRIAL. FACE 2 TRYING EFFICACY TRYING. THESE ARE TRAILS WHERE YOU'RE REALLY ASK THE QUESTION UNDER VERY HIGHLY CONTROLLED CONDITIONS. DOES MY INTERVENTION THAT I HAVE DEVELOPED, DOES MY INTERVENTION DO ANYTHING? IS THERE A SIGNAL ANYWHERE? AND LET ME SORT OF SPECIFY WHAT I MEAN BY HIGHLY CONTROLLED SITUATIONS. WHAT I MEAN BY THAT IS THAT YOU HAVE REAL CLARITY AND -- AS AN EXPERIMENTER, A RESEARCHER, YOU'RE IMPOSING A LOT OF CLARITY AND CONTROL ON THE CHARACTERISTICS OF YOUR PATIENT -- OF YOUR PARTICIPANT POPULATION. OF THE ENVIRONMENT IN WHICH YOUR INTERVENTION IS BEING DELIVERED. THE PEOPLE WHO DELIVER THE INTERVENTION. YOU'RE REINING THAT CONTROL IN. WHAT YOU WANT DO KNOW IS UNDER THESE VERY TIGHTLY CONTROLLED SITUATIONS, IS THERE A SIGNAL? IS THERE SOME INDICATION THAT YOUR INTERVENTION IS DOING SOMETHING. >> IN SHOWS SITUATIONS THE PATIENT CHARACTERISTICS ARE GOING TO BE VERY WELL DESCRIBED. AND YOUR PATIENTS -- AREN'T GOING TO LOOK -- THERE COULD CAN BE A LOT OF VARIABILITY. YOU WANT TO DECREASE THE VARIABILITY SO YOU CAN TELL WHETHER THERE IS A SIGNAL. DOES THROUGH MAKE SENSE? YES, GO? OKAY. AS YOU MOVE FORWARD, LET'S SAY YOU GOT A SIGNAL. AND UNDER A PHASE 2 EFFICACY TRIAL, YOU HAVE SOME INDICATION THAT YOUR INTERVENTION IS EFFICACIOUS. YOU, THEN, MIGHT MOVE GORD TO A PHASE 3 TRIAL WHICH IS AN EFFECTIVENESS TRIAL. AND EFFECTIVENESS TRIALS ARE THOSE WHERE YOU TAKE WHAT WORKS UNDER HIGHLY CONTROLLED SITUATIONS AND YOU TEST IT IN A BROADER CONTEXT. SO YOU MIGHT, INSTEAD OF TESTING IT IN YOUR -- IN YOUR ACADEMIC MEDICAL CENTER, IN THE CRC, YOU MIGHT GO BEYOND THAT AND TEST IT IN SOME COMMUNITIES HEALTH CENTERS. MAYBE YOU'LL DESIT IN THE -- A MUNCH OF PCP OFFICES. IT COULD BE IN ANY NUMBER OF SITUATIONS BUT YOU'RE BROADENING IT TO SEE IF WHAT WORKS IN HIGHLY CONTROLLED SETTINGS WORKS IN MORE REAL WORLD SETTINGS. OF COURSE THAT'S WHERE WE WANT TO TAKE OUR INTERVENTIONS. WE WANT THEM TO WORK IN THE REAL WORLD. WHERE WE REALLY DON'T, AS RESEARCHERS, WE REALLY DON'T HAVE CONTROL. WE DON'T KNOW WHO IS GOING TO BE DELIVERING THE INTERVENTION. WE DON'T KNOW THE CONDITIONS UNDER WHICH THOSE INTERVENTIONS ARE BEING DELIVERED. AND WE KNOW THAT PATIENTS ARE GOING TO BE EXTREMELY VARIABLE IN TERMS OF THE -- THEIR INDIVIDUAL CHARACTERISTICS. SO PHASE 3 TRIALS ARE MORE LIKELY TO MIMIC THOSE REAL WORLD SITUATIONS. SO BY NECESSITY IF YOU'RE DOING A PHASE 3 TRIAL, THEN YOU'RE GOING TO LOOSEN THE CONTROL THAT YOU HAVE SO YOU'RE GOING TO LOOSEN UP THE PATIENT CHARACTERISTICS. THAT IS YOU'RE MORE LIKELY TO TAKE MORE INDIVIDUALS THAT VARY WITH REGARD TO A WHOLE NUMBER OF FACTORS. THEN THERE ARE PHASE 4 STUDIES AS WELL THAT ARE EVEN BROADER. THESE ARE COMMUNITY BASED STUDIES WHERE YOU GO OUT INTO THE COMMUNITY. AS A RESEARCHER, YOU HAVE VERY LITTLE CONTROL. YOU MAY HEAR THIS -- THESE PHASES REFERRED TO AS INSTEAD OF PHASE ONE, PHASE TWO, AS T1, T2 TRANSLATION 1, TRANSLATION 2. THERE IS SOME SMALL DIFFERENCES BETWEEN PHASE 1 AND PHASE 2, TRANSLATION 1, TRANSLATION 2. BUT THEY REALLY DO PARALLEL EACH OTHER. SO IF YOU HEAR TRANSLATION 2, THAT MEANS SOMETHING SIMILAR TO AN EFFICACY TRIAL. OKAY. SO WHAT I'M HOPING IS THAT IF UNDERSTANDING THIS SORT OF RESEARCH CONTINUIAN, YOU GET THE MESSAGE THAT THE KIND OF CHARACTERISTICS OF YOUR PATIENT POPULATION AND HOW CLEARLY YOU OUTLINE WHAT THOSE CHARACTERISTICS ARE IS GOING TO BE DEPENDENT, IN PART, ON WHERE YOUR PARTICULAR SCIENCE FITS ON THIS TRANSLATIONAL SPECTRUM. IN ORDER TO KNOW THAT, YOU HAVE TO REALLY KNOW THE SCIENCE. YOU HAVE TO KNOW THE LITERATURE, YOU HAVE TO UNDERSTAND WHAT'S BEEN DONE BEFORE YOU. AND YOU HAVE TO UNDERSTAND WHERE YOU WANT TO BE GOING. OTHER REASONS TO THINK ABOUT PARTICIPANT SELECTION, THE CHARACTERISTICS OF YOUR STUDY PARTICIPANTS ARE GOING TO DETERMINE HOW GENERALIZABLE YOUR FINDINGS ARE. WE KIND OF GOT A PEAK OF THAT IN THE LAST SLIDE WHEN WE TALKED ABOUT THE CONTINUUM, AND THE FACT THAT WE'RE MOVING MORE AND MORE TO A MORE GENERALIZABILITY AS YOU MOVE THROUGH THE TRANSLATIONAL SPECTRUM. LET ME OFFER ANOTHER WAY OF THINKING ABOUT THIS. AND THAT WAY IS TO THINK ABOUT INTERNAL INVESTORS VERSES EXTERNAL VALIDITY. I WANT TO THINK ABOUT THIS AND TALK ABOUT THIS IN VERY CONCEPTUAL TERMS. THERE ARE SOME ANALYTIC ANALOGS TO THIS. AND YOU'LL TALK ABOUT THOUGH AND FIGURE OUT WHEN YOU GET TO THAT POINT IN THE SERIES HERE, YOU'LL UNDERSTAND MORE HOW YOU MAKE THAT ANALYTIC BALANCE. I WANT TO REALLY THINK OF IT AS A HIGHER LEVEL RIGHT NOW. AND THINK OF IT IN TERMS OF CONCEPTUAL UNDERSTANDING. SO INTERNAL AND EXTERNAL VALIDITY ARE A BALANCE. IF YOU HAVE HIGH INTERNAL VALIDITY, YOU HAVE LOWER EXTERNAL VALIDITY, AND VICE VERSA. SO IT'S A BALANCE. YOU HAVE TO CHOOSE HOW MUCH OF EACH YOU'RE WILLING TO LIVE WITH FOR THE PARTICULAR STUDY THAT YOU ARE CARING OUT. OKAY? ALL RIGHT. SO HERE IS A LITTLE BIT MORE WHAT THEY ARE. SO EXTERNAL VALIDITY REALLY REFERS TO THE EXTENT TO WHICH YOU CAN GENERALIZE YOUR FINDINGS, BEYOND THE SITUATION THAT YOU -- THE RESEARCH STUDY THAT YOU JUST CONDUCTED. SO IF YOU HAVE HIGH EXTERNAL VALIDITY, THAT MEANS THAT YOU CAN MORE EASILY GENERALIZE ACROSS PARTICIPANTS, ACROSS SITUATIONS, ACROSS PROVIDERS, ACROSS TIME, A PLACE. IT'S MORE GENERALIZABLE GLOBABLY. YOU MIGHT THINK, THAT SOUNDS G WHY DON'T WE ALWAYS JUST HAVE REAL HIGH EXTERNAL VALIDITY? THAT SOUNDS LIKE WHAT WE'RE REALLY AIMING FOR IN THE END. WE WANT TO BE ABLE TO GENERALIZE ACROSS A LARGE GROUP OF INDIVIDUALS IN SITUATIONS. THE PROBLEM WITH THAT IS THAT THERE IS ALWAYS A RISK. ALWAYS A RISK FOR EITHER HIGH EXTERNAL OR HIGH INTERNAL VALIDITY. IF YOU HAVE HIGH EXTERNAL VALIDITY, THE RISK IS THAT YOU'RE GOING TO MAKE AN ERROR IN YOUR ANALYSIS. AND THE ERROR THAT YOU'RE GOING TO MAKE WITH HIGH EXTERNAL VALIDITY, IS THAT YOU'RE GOING TO THINK YOU SEE AN EFFECT THAT'S NOT REALLY THERE. YOU'RE GOING TO HAVE A FALSE POSITIVE. SO THE HIGHER YOUR EXTERNAL VALIDITY, THE HIGHER THE LIKELIHOOD IS THAT YOU'LL MAKE THAT ERROR. OKAY? ANALYTICALLY YOU'LL UNDERSTAND THIS LATER. RIGHT NOW, CONCEPTUALLY I WANT YOU TO UNDERSTAND IT. SO ON THE OTHER END OF THE STICK TREMENDOUS, ON THE BALANCE IS INTERNAL VALIDITY. WE TALK ABOUT INTERNAL VALIDITY, BEING ABLE TO MAXIMIZE THE AMOUNT OF CONTROL THAT YOU HAVE. THIS IS CONTROL OVER ALL KINDS OF THINGS. CONTROL OVER YOUR PARTICIPANTS, COLE OVER HOW INTERVENTION IS DELIVERED, CONTROL UNDER THE SITUATION IN WHICH AN INTERVENTION IS DELIVERED. IT ENABLES YOU TO CONTROL MANY SOURCES OF BIAS, MANY EXPERIMENTER AND -- AND MEASUREMENT EFFECTS. SO THIS IS THAT HIGH CONTROL END OF THINGS. WELL, THAT SOUNDS PRETTY GOOD, TOO. BUT WHEN YOU HAVE HIGH INTERNAL VALIDITY, THE RISK IS THAT YOU'RE GOING TO MAKE THE ERROR OF A DIFFERENT SORT WITH HIGH INDENVALIDTY, THE RISK IS YOU'RE MORE LIKELY TO MAKE A FALSE NEGATIVE ERROR. THAT IS NOT SEEING AN EFFECT THAT REALLY IS THERE. SO YOU CAN SEE NOW YOU NEED TO BALANCE HIGH EXTERNAL WITH HIGH INTERNAL VALIDITY. AND THAT BALANCE IS GOING TO LOOK DIFFERENT, DEPENDING ON THE QUESTION THAT YOU'RE ASKING, AND WHERE THAT QUESTION SITS ON THAT TRANSLATIONAL SPECTRUM. SO YOU MIGHT GUESS THAT EARLY IN THAT TRANSLATIONAL PHASE, YOU MIGHT WANT HIGHER INTERNAL VALIDITY. THAT'S WHERE YOU WANT A LOT OF CONTROL. AND YOU'RE WILLING TO LIVE WITH FALSE NEGATIVES. YOU'RE WILLING TO NOT SEE AN EFFECT THAT'S REALLY THERE. AS LONG AS YOU HAVE A LOT OF CONTROL. AS YOU MOVE ALONG THE TRANSLATIONAL SPECTRUM, THOUGH, THE BALANCE TIPS IN THE OTHER WAY. AND YOU'RE INCREASINGLY MORE WILLING TO INCREASE YOUR EXTERNAL VALIDITY SO THAT YOU CAN GENERALIZE ACROSS PARTICIPANTS, ACROSS SITUATIONS AROUND PROVIDERS, THERE YOU'RE MORE WILLING TO LIVE WITH THE FALSE POSITIVE. SO YOU MAKE THAT DECISION BASED ON YOUR INDIVIDUAL QUESTION THAT YOU'RE ASKING. SO YOU HAVE TO THINK REALLY CAREFULLY ABOUT WHERE IS MY QUESTION SITTING? WHAT DO WE KNOW. WHAT'S MOST IMPORTANT TO ME? WHEN YOU MAKE THAT DETERMINATION, YOU'RE REALLY TRYING TO STRIKE THE RIGHT BALANCE FOR YOUR PARTICULAR QUESTION. AND I LIKE TO THINK ABOUT THIS IN TERMS OF WHAT DO I WORRY ABOUT THE MOST? DO I WORRY ABOUT FALSE NEGATIVES OR POSITIVES? FOR THE QUESTION I'M ASKING, FOR THE PATIENT, PARTICIPANTS, WHAT DO I WORRY ABOUT MOST. THAT GUIDES YOU NOT ONLY WHERE YOU ARE ON THE TRANSLATIONAL SPECTRUM BUT WHICH KIND OF VALIDITY YOU'RE MORE WILLING TO LIVE WITH. THE TYPE OF VALIDITY THAT YOU'RE MORE WILLING TO LIVE WITH IS GOING TO HELP DETERMINE HOW TIGHTLY CONTROLLED YOU WANT TO -- NOT ONLY HAVE ALL ASPECTS OF YOUR STUDY, BUT HOW TIGHTLY CONTROLLED YOU WANT YOUR PARTICIPANT SELECTION FACTORS TO BE. OKAY. FEASIBILITY. THE PARTICIPANT SELECTION FACTORS ARE GOING TO IMPACT YOUR FEASIBILITY. NOW, YOU WANT TO SELECT PARTICIPANTS AND MAKE THE DETERMINATION ABOUT WHAT FACTORS ARE IMPORTANT BASED ON SCIENCE. BUT THE REALITY IS THAT YOU HAVE A BEAUTIFUL SCIENTIFIC AWARD WINNING QUESTION. IF IT'S NOT FEASIBILITY, IF YOU CAN'T IMPLEMENT IT, THEN IT'S NOT HELPFUL. SO YOU DO NEED TO THINK ABOUT FEASIBILITY WHEN YOU THINK ABOUT THESE KINDS OF ISSUES. FEASIBILITY REALLY MEANS DIFFERENT THINGS. FIRST OF ALL, DO YOU HAVE ACCESS TO THE PARTICIPANTS WITH THE KIND OF CRITERIA YOU'RE LOOKING FOR, WHETHER THEY'RE DEMOGRAPHIC OR CLINICAL. DO YOU HAVE ACCESS TO THAT POPULATION? IN ADDITION, YOU HAVE TO THINK ABOUT THE PARTICIPANTS THEMSELVES. AND BASED ON THE SELECTION CRITERIA THAT YOU OF DETERMINED -- YOU HAVE DETERMINED, ARE YOU GOING TO BE ABLE AND ARE THEY GOING TO BE -- ARE THE RESPONSIBILITIES GOING TO BE ABLE AND WILLING TO PARTICIPATE IN YOUR STUDY? ARE THEY GOING TO BE ABLE AND WILLING TO ADHERE TO YOUR TREATMENT PROTOCOL? THOSE QUESTIONS ARE GOING TO BE DETERMINED IN MANY RESPECTS BY THE CHARACTERISTICS THAT YOU SET OUT. RIGHT? SO IF YOU WANT TO DO -- IF YOU WANT TO UNDERTAKE A STUDY THAT REQUIRES LOTS OF ACTIVE PARTICIPATION BY YOUR PARTICIPANTS, THEY HAVE TO COME TO THE CRC WEEKLY IN ORDER TO GET SOME KIND OF TESTING DONE, AND YOU ARE TARGETING PARTICIPANTS WHO ARE PHYSICALLY DISABLED, THAT IS GOING TO BE AIRSTREAM THAT MAY NOT WORK FOR YOU. -- A STRATEGY THAT MAY NOT WORK. IT'S A FEASIBILITY ISSUE. YOU DO NEED TO THINK ABOUT ETHICAL QUESTIONS, OF COURSE, IN ALL OF THESE CASES. YOU NEED TO THINK ABOUT ETHICAL QUESTIONS WITH REGARD TO WHETHER YOU CAN RANDOMIZE IDEAS TO PLACEBO, WHAT 2 ADVERSE EVENT RATES. AND WHAT I WANT TO UNDERSCORE HERE IS THAT WHEN YOU THINK ABOUT THESE KINDS OF CONSIDERATIONS, YOU NEED TO THINK ABOUT THEM FOR ALL OF THE ARMS OF YOUR STUDY. NOT JUST THE ACTIVE INTERVENTIONAL ARM. ALL CLINICAL TRIALS HAVE SOME KIND OF COMPARISON ARM. YOU'LL AFTER PLACEBO, OR USUAL CARE, OR MAYBE ANOTHER TYPE OF INTERVENTION THAT YOU'RE COMPARING YOUR ACTIVE INTERVENTION WITH. AND WHEN YOU THINK ABOUT ETHICAL ISSUES, YOU NEED TO THINK ABOUT NOT ONLY IS IT ETHICAL TO RANDOMIZE THIS -- MY PARTICIPANTS DO AN ACTIVE INTERVENTION ARM, BUT IS IT ETHICAL FOR THE CHARACTERISTICS OF THAT POPULATION TO RANDOMIZE THEM TO A CONTROL ARM, TO A MR. OBAMA ARM, TO A -- PLACEBO ARM, DO A USUAL CARE ARM. SOMETIMES WE FORGET ABOUT THAT AND FOCUS ON THE INTERVENTION GROUP. TIMING OF THE INTERVENTION IS GOING TO BE CRITICAL WHEN YOU WANT TO CAPTURE THE PARTICIPANTS. WHAT I MEAN BY THAT IS THAT IN SOME CASES WE WANT PARTICIPANTS WHO HAVE JUST HAD AN EVENT. THOSE ARE THE PARTICIPANTS WE WANT 250 STUDY. AND IT MAY BE VERY DIFFICULT FOR YOU FEASIBLY DIFFICULT, TO YOU, ACCESS THE PARTICIPANTS IN THAT TO EVENT IS VERY SMALL. IF YOU'RE DOING A STUDY OF INDIVIDUALS WHO HAVE RECENTLY COME TO AN EMERGENCY DEPARTMENT BECAUSE OF AN ELICIT DRUG, POTENTIAL OVERDOSE, AND YOU WANT TO ENROLL THEM INTO A STUDY THAT ASKS THE QUESTION OF WHAT SATINED OF OUTCOME IS WITHIN 30 MINUTES OF ARRIVING OUGHT AN EMERGENCY DEPARTMENT, THAT IS GOING TO BE VERY DIFFICULT. SO THE TIMING OF YOUR INTERVENTION, IT MIGHT MAKE PERFECT SCIENTIFIC SENSE BUT IT MAY NOT BE FEASIBLE. WHEN YOU THINK ABOUT WHO YOU WANT TO BE IN YOUR STUDY, YOU NEED TO THINK ABOUT THAT IN RELATIONSHIP TO THE OUTCOMES THAT YOU WANT TO TARGET FOR MEASURING. NOW, OUTCOMES ARE WHAT WE LOVE, RIGHT? THAT'S WHAT WE'RE INTERESTED IN. WHAT THOSE OUTCOMES ARE. BUT YOU HAVE TO THINK ABOUT THOSE OUTCOMES IN RELATIONSHIP TO THE PARTICIPANTS THAT YOU'RE INCLUDING. SO OUTCOMES CAN BE LOTS OF THINGS. YOU CAN HAVE EVENT OUTCOMES WHICH WE THINK OF AS HARD OUTCOMES. THINGS LIKE MORTALITY, THAT'S A VERY HARD ENDPOINT. OR VARIOUS TYPES OF MORBIDITY. SO FROM THE NATIONAL HEART LUNG AND BLOOD INSTITUTE, I HAVE A LOT OF EXAMPLES THAT ARE CARDIOVASCULAR IN NATURE. THAT'S WHAT I NEED TO TELL YOU, BECAUSE THAT'S WHAT I LIVE WITH. SO A MORTALITY -- MORBIDITY OUTCOME MIGHT BE SOMETHING LIKE A HEART ATTACK. BUT IN A LOT OF STUDIES WE REALLY DON'T HAVE THE LUXURY OF MEASURING THESE KINDS OF EVENT OUTCOMES. EITHER EVENTS DON'T HAPPEN FREQUENTLY, OR SAMPLE SIZES ARE SMALL, OR IT TAKES A LONG TIME FOR EVENTS TO OCCUR. SO IF YOU WANT TO STUDY CHILDREN, YOU DON'T WANT TO HAVE A MORTALITY ENDPOINT. IT TAKE ADDS LONG TIME IN MOST CASES FOR CHILDREN TO REACH THAT ENDPOINT. SO WHAT WE DO IS THAT WE SOMETIMES WILL USE SURROGATE BIOMARKER OUTCOMES. YOU PUT A STAR HERE, BECAUSE THERE IS A DEFINITION OF A SURROGATE MEASURE. IT'S A BIOMARKER THAT IS A SUBSTITUTE, AND IMPERFECT SUBSTITUTE FOR A CLINICAL ENDPOINT. SO EXAMPLES OF SURROGATE MEASURES ARE SOMETHING LIKE, AGAIN, FROM THE NHHBI, SOMETHING LIKE REVASCULARIZATION FOR SOMEONE WHO HAS HEART DISEASE, IF THEY HAVE A CORONARY BYPASS. THAT'S A SURROGATE MEASURE FOR UNDERLYING CARDIOVASCULAR DISEASE. CHOLESTEROL IS A VERY COMMON SURROGATE MEASURE FOR UPDATE LYING CARDIOVASCULAR DISEASE. THERE ARE MANY OTHERS, DEPENDING ON WHAT YOUR PARTICULAR AREA IS. AND THESE ARE VERY COMMON OUTCOMES BECAUSE THEY'RE ACCESSIBLE, AND THEY'RE MORE READILY AVAILABLE TO US RATHER THAN EVENT RELATED OUTCOMES. THEY'RE ALSO PATIENT SPECIFIC OUTCOMES. AND THESE ARE REFERRED TO AS PROs, AND THESE PATIENT SPECIFIC OUTCOMES ARE REALLY IMPORTANT. FOR SOME TRIALS, THEY REALLY WILL BE THE PRIMARY ENDPOINT, THE PRIMARY OUTCOME THAT YOU'RE INTERESTED IN. THESE ARE THINGS THAT ONLY THE PARTICIPANT, IN THIS CASE, THE PATIENTS CAN REPORT ON. THINGS LIKE PAIN, OTHER KINDS OF SYMPTOMS. THEY'RE QUALITY OF LIFE. REALLY GOOD WAYS OF MEASURING THESE OUTCOMES. THE NIH PUT A LOT OF EFFORT INTO ESTABLISHING VALID AND RELIABLE MEASURES OF PROs. IF YOU HAVE QUESTIONS I'D BE HAPPY TO ANSWER THEM FOR YOU. BUT WHEN YOU HAVE THESE PATIENTS SPECIFICALLY OUTCOMES, YOU WANT TO THINK VERY CAREFULLY ABOUT THE MEANING OF THOSE OUTCOMES IN RELATIONSHIP TO THE PATIENT CHARACTERISTICS YOU'RE LOOKING AT. THEM THERE ARE COMPOSITE OUTCOMES, THAT DOESN'T HAVE MUCH RELEVANCE TO THIS CONVERSATION. THOSE ARE THE TYPES OF OUTCOMES THAT WE'RE INTERESTED IN. WHAT DOES THIS HAVE TO DO WITH PATIENT FACTORS? ARE THE OUTCOMES THAT YOU WANT TO INCLUDE, MAYBE YOUR PRIMARY OR SECONDARY OUTCOME IN YOUR TRIAL, A FEASIBLE TO MEASURE, GIVEN THE CHARACTERISTICS OF THE PARTICIPANTS THAT YOU ARE TARGETING? WHAT I MEAN BY THAT, WHAT YOU REALLY WANT FOR AN OUTCOME IS A HARD CARDIOVASCULAR EVENT, LIKE MYOCARDIAL INFARCTION, HEART ATTACK. THAT'S THE MEASURE YOU'RE LOOKING FOR. IF YOU CHOOSE TO ENROLL IN THIS EXAMPLE 50 YEAR OLD ESSENTIALLY HEALTHY WOMEN, YOU'RE NOT GOING TO SEE TOO MANY OF THOSE OUTCOMES IN YOUR 5 YEAR TRIAL FEEL IT'S NOT GOING TO HAPPEN. IF THEY'RE ESSENTIALLY HEALTHY WOMEN, MIDDLE-AGED WOMEN. SO YOU NEED TO MATCH THE CHARACTERISTICS OF YOUR PARTICIPANTS THAT YOU NEED TO LOOK AT. IN THIS SITUATION YOU HAVE TO CHANGE THE CHARACTERISTICS OR CHANGE YOUR OUTCOME. YOU ALSO WANT TO THINK ABOUT WHETHER YOUR OUTCOMES CAN CHANGE WITHIN THE PARAMETERS OF YOUR TRIAL, THE LENGTH OF YOUR TRIAL. AND THE FOLLOW-UP PERIOD THAT YOU HAVE DESIGNED FOR YOUR TRIAL. GIVEN THE PATIENT CHARACTERISTICS. SO, FOR EXAMPLE, AGAIN, IF YOU HAVE -- LET'S SAY YOU'RE DOING A TRIAL OF -- LET'S SAY YOU WANT TO LOOK AT CORODED IMT, BLOCKING IN THE CORODED ARTERY OVER THE COURSE OF YOUR TRIAL AND FOLLOW-UP PERIOD OF 6 MONTHS AND YOU'RE LOOKING AT ESSENTIALLY HEALTHY PEOPLE. THAT'S NOT GOING TO HAPPEN. YOU HAVE TO CHANGE YOUR OUTCOME OR YOUR PARTICIPANT CHARACTERISTICS. IF YOUR FOCUS OF YOUR OUTCOME IS GOING TO BE ON PATIENT REPORTED OUTCOMES, PROs, THEN YOU NEED TO THINK ABOUT THE CHARACTERISTICS OF YOUR PARTICIPANTS, WHETHER THEY WILL BE ABLE TO GIVE YOU THOSE KINDS OF OUTCOMES. SO, FOR EXAMPLE, THE EXAMPLE I HAVE HERE IS IF YOU ARE HOOKING AT PAIN IN CHIRP, IF YOU'RE ENROLLING 2-YEAR OLD CHIRP TO REPORT ON THEIR PAIN SYMPTOMS, YOU WILL GET AN OUTCOME BUT IT MAY NOT BE VERY RELIABLE. NOW, I WILL PREFACE THIS BY SAYING THAT WE CAN GET GOOD RELIABLE PATIENT REPORTED OUTCOMES FROM CHILDREN IF YOU USE THE RIGHT MEASURES. BUT YOU HAVE TO THINK ABOUT THAT. IN THE CONTEXT OF YOUR TRIAL. THE BOTTOM LINE WITH ALL THESE THINGS IS THAT DECISIONS THAT YOU MAKE REGARDING THE CHARACTERISTICS OF THE PARTICIPANTS THAT YOU STUDY ARE GOING TO INFLUENCE THE CAUSAL INFERENCES THAT YOU CAN MAKE. AND THE BOTTOM LINE WITH ALL OUR TRIALS, WHAT WE WANT TO DO IS MAKE CAUSAL INFLUENCE -- INFERENCES. YOU WANT TO BE ABLE TO SAY THE REASON I FOUND THIS OUTCOME IS BECAUSE I EMPLOYED THIS INTERVENTION. THAT'S A CAUSAL INFERENCE. YOU WANT TO BE ABLE TO DO THAT. YOU WANT THAT INFERENCE TO BE HIGH. SO YOU WANT TO MAKE THESE DECISIONS VERY CAREFULLY. SO I WANT TO MOVE NOW -- ANY QUESTIONS? OKAY. I WANT TO MOVE NOW TO TALKING ABOUT SOME OF THE THINGS TO THINK ABOUT IN OUTLINING YOUR PARTICIPANT CHARACTERISTICS. WE'LL TALK ABOUT ENTRY CRITERIA, CONTEXTUAL FACTORS, ACCESS, ADHERENCE, AND RECRUITMENT RETENTION. LET'S START OFF WITH ENTRY CRITERIA. WHEN YOU ARE STARTING A STUDY -- BEFORE YOU START A STUDY YOU WANT TO ESTABLISH WHAT YOUR CRITERIA ARE FOR ENTRY. YOU'RE GOING TO ESTABLISH BOTH YOUR INCLUSIONARY CRITERIA AS WELL AS YOUR EXCLUSIONARY CRITERIA. AND BY THE WAY, YOU ALSO -- AND I HAVE NOTE HERE THAT YOU WANT TO IDENTIFY WHAT THE TARGET OF THE INTERVENTION IS. MOST OF THE TIME IT'S GOING TO BE AN INDIVIDUAL PATIENT OR PARTICIPANT IN YOUR STUDY. BUT SOMETIMES IT COULD BE A DIAD, A FAMILY, SOMETIMES IT CAN BE A PROVIDER OR HEALTHCARE DELIVERY SYSTEM. IT'S IMPORTANT TO IDENTIFY THAT STRAIGHT UP. SO LET'S TALK ABOUT ENTRY CRITERIA. INTERESTINGLY, DEMAIN PURPOSE OF INCLUSIONARY CRITERIA IS DIFFERENT THAN THE MAIN PURPOSE OF EXCLUSIONARY CRITERIA. OKAY? SO WITH INCLUSIONARY CRITERIA, THE MAIN PURPOSE IS TRYING TO IDENTIFY THE PARTICIPANTS WHO ARE GOING TO BE MOST RELEVANT TO THE OUTCOMES OF YOUR STUDY. THAT'S THE MAIN PURPOSE. YOU ALSO NEED TO ENROLL -- TO THINK ABOUT INCLUSIONARY CRITERIA, BECAUSE YOU NEED TO REPORT ON IT. YOU NEED TO REPORT IN YOUR CONSORT STATEMENT WHAT YOUR INCLUSIONARY AND EXCLUSIONARY -- BOTH CRITERIA, AND NEED TO BE ABLE TO IDENTIFY INDIVIDUALS THAT YOU'VE IDENTIFIED THAT ARE FITTING YOUR INCLUSIONARY CRITERIA. AND THEN YOU NEED TO BALANCE BETWEEN PARTICIPANT VARIABILITY. SO WHAT DO I MEAN BY BALANCING BETWEEN PARTICIPANT VARIANCE? SO YOUR PARTICIPANTS ARE GOING TO BE -- HAVE LOTS OF DIFFERENT CHARACTERISTICS. AND WHEN YOU INCLUDE PARTICIPANTS, WHEN YOU SET OUT WHAT YOUR INCLUSIONARY CRITERIA ARE, YOU HAVE TO BE HOW LOOSE YOU WANT THEM TO BE. SO IF YOU SAY YOU'RE INCLUSIONARY CRITERIA ARE ANYONE BETWEEN THE AGES OF 18 AND 70, THAT'S A WIDE, WIDE OPEN CRITERIA. AND THAT'S FINE. BUT IT'S GOING TO HAVE LOTS OF VARIABILITY IN IT. FOR SOME STUDIES THAT'S GOING TO BE APPROPRIATE BUT FOR MANY IT WON'T BE. THE VARIANCE WILL BE TOO WIDE. WHAT ARE THE EXAMPLES -- ONE OF THE EXAMPLES I GIVE, LET'S SAY YOU'RE DOING A STUDY OF MIGRAINE, YOU HAVE A NEW TREATMENT FOR MIGRAINE. SO YOU HAVE TO SET OUT INCLUSIONARY CRITERIA. MAYBE YOU'LL SAY I'M GOING TO IDENTIFY THE TYPE OF MIGRAINES, IDENTIFY THE DURATION THAT THE MIGRAINES IN ANY INDIVIDUAL PARTICIPANT OCAN YOU FOR. AND THE FREQUENCY OF THOSE ATTACKS. AND I'M GOING TO SPECIFY WHAT OTHER MEDICATIONS PARTICIPANTS CAN USE WHEN THEY'RE ENROLLED IN THE STUDY. THOSE ARE INCLUSIONARY CRITERIA. THOSE YOU REPORT OUT ON. THOSE ARE GOING TO TARGET FORTH THIS QUESTION SPECIFIC CHARACTERISTICS THAT ARE RELEVANT. NOW, CONTRAST THAT WITH EXCLUSIONARY CRITERIA. THE MAIN PURPOSE OF EXCLUESRY CRITERIA IS FOR FEASIBILITY. HEN YOU SET OUT THE CRITERIA BY WHICH YOU'RE NOT GOING TO ALLOW SOMEONE TO PARTICIPATE IN THE STUDY, THE MOST IMPORTANT REASON TO NOT ALLOW SOMEONE TO BE IN YOUR STUDY IS FOR SAFETY REASONS. IF THE STUDY IS GOING TO BE TOO HIGH RISK FOR THAT TECH CHARACTERISTIC OF A PARTICIPANT, YOU DON'T WANT THEM IN YOUR STUDY. IT'S GOING TO BE TOO RISKY. IF YOU'RE NOT SURE ABOUT THE SAFETY ISSUE, YOU MAY USE -- YOU MAY USE SOME OF THE CRITERIA AS EXCLUSIONARY CRITERIA. THERE MAY BE THINGS THAT PARTICIPANTS CHARACTERISTICS BRING WITH THEN THAT MIGHT CONFOUND YOUR FINDINGS. LET'S SAY YOU ARE TRYING TO TEST A NEW DRUG. AND YOU WANT TO MAKE SURE THAT THE AFFECTS OF THAT DRUG ARE CLEAR. YOU MAY NOT WANT TO ALLOW OTHER MEDICATIONS TO BE USED. THEY WOULD CONFOUND THE EFFECTS THAT YOU'RE LOOKING AT FOR YOUR INTERVENTION. AND THEN FEASIBILITY WHICH WE'VE TALKED ABOUT BEFORE. SO THE EXAMPLE I GIVE HERE, LET'S STAKE YOU'RE TESTING A DO MEDICATION FOR HIGH BLOOD PRESSURE. YOU MAY WANT TO EXCLUDE PEOPLE WITH HEART FAILURE FOR SAFETY REASONS. PEOPLE WITH HEART FAILURE ARE COMPLEX AND DIFFICULT TO TREAT AND SO WE MAY NOT WANT TO INCLUDE THEM IN A TRIAL OF A NEW MEDICATION. YOU MAY ESCLUDE PEOPLE WITH DIABETES. BUT THERE MAY BE CONFOUNDING FACTORICS. SO YOU MAY DECIDE TO EXCLUDE THOSE PARTICIPANTS. AND FEASIBILITY ISSUES, IF YOU HAVE TO DO LOTS OF TESTING, YOU MAY NOT WANT TO INCLUDE INDIVIDUALS WHO ARE BEDRIDDEN, FOR EXAMPLE, BECAUSE IT WOULDN'T BE FEASIBLE FOR THEM TO COME TO THE CLINIC FREQUENTLY FOR TESTING. SO THE REASON FOR EXCLUDING PARTICIPANTS IS VERY DIFFERENT THAN THE REASON FOR INCLUDING PARTICIPANTS. NOW, ONE OF THE QUESTIONS I GET ALL THE TIME IS WHEN DO I ESTABLISH INCLUSIONARY AND EXCLUSIONARY CRITERIA ARE? THE ANSWER IS VERY, VERY EARLY. WE WANT TO ESTABLISH THIS BEFORE YOU START YOUR STUDY OBVIOUSLY, NEED TO ESTABLISH IT BEFORE YOU GO TO YOUR IRB FOR APPROVAL. YOU NEED TO ESTABLISH IT BEFORE YOU GET FUNDING BECAUSE IT'S GOING TO BE SO CRITICAL TO THE SUCCESS OF YOUR STUDY. SO YOU DO IT VERY, VERY EARLY ON. THE REASON THESE CRITERIA ARE SO IMPORTANT IS BECAUSE THIS IS A EASY WAY FOR UNINTENTIONAL BIAS TO CREEP INTO YOUR STUDY DESIGN. IF YOU'RE NOT CLEAR AND I MEAN CRYSTAL CLEAR WHAT YOUR INCLUSIONARY AND EXCLUSIONARY CRITERIA ARE, NOT ONLY FOR YOU, AS A PI, BUT ALSO FOR ANY STAFF THAT YOU HAVE WHO ARE GOING TO BE RECRUITING PARTICIPANTS. IF YOU DON'T HAVE CRYSTAL CLEAR CRITERIA, IT'S POSSIBLE THAT YOU MAY END UP WITH A BIAS SAMPLE. YOU MAY -- YOUR OWN BIAS IN WANTING TO ENROLL PARTICULAR PARTICIPANT INTO YOUR STUDY MAY CREEP IN, UNLESS YOU HAVE REALLY CLEAR REASONS TO INCLUDE THEM OR EXCLUDE THEM. SO I ENCOURAGE YOU TO DO THIS EARLY, TO BE VERY, VERY SPECIFIC. TO WRITE IT ALL DOWN. AND TO MAKE SURE THAT EVERY ONE ON YOUR STAFF UNDERSTANDS WHAT THESE CRITERIA ARE. SO THE NEXT QUESTION THAT I GET IS WELL, CAN I CHANGE THEM? NOW, WHY DO PEOPLE WANT TO CHANGE THEIR ENTRY CRITERIA? THE MOST DIFFICULT PART OF DOING A CLINICAL TRIAL IS WHAT? RECRUITMENT! EVERY ONE KNOWS THAT. SO IF YOU START A TRIAL, YOU HAVE ENTRY CRITERIA THAT'S CLEARLY LAID OUT. YOU CAN'T ENROLL ADEQUATELY. YOU'RE NOT MEETING YOUR MILE ZONES. ONE OF THE THINGS THAT PEOPLE WANT TO DO IS CHANGE THEIR ENTRY CRITERIA. YOU CAN DO THAT. BUT YOU PAY A PRICE. SO THE PRICE YOU PAY IS THE PRICE THAT YOU MAY ACTUALLY ALLOW SOME OF THAT BIAS TO CREEP IN. SO IF YOU'RE GOING TO GO -- IF YOU'RE GOING DOWN THIS ROAD AND CHANGE YOUR ENTRY CRITERIA, YOU WANT TO MAKE SURE THAT YOU DO IT AS UNBIASED A WAY AS POSSIBLE. YOU DON'T CHANGE YOUR ENTRY CRITERIA WHEN YOU'RE ACROSS FROM SOMEONE THAT YOU REALLY WANT TO ENROLL IN YOUR STUDY, THEY'RE REALLY PERFECT. THERE IS ONE LITTLE INCLUSIONARY CRITERIA THEY DON'T QUITE MEET. BUT THEY'RE CLOSE. AND YOU NEED TO MEET YOUR MILESTONE THIS MONTH. THAT'S NOT THE TIME AND WAY YOU CHANGE YOUR ENTRY CRITERIA. IF YOU IMMEDIATE TO CHANGE IT YOU GO TO YOUR DSMB, YOUR IRB, DO IT IN AN IN BIASED WAY AS POSSIBLE AND EXTREMELY INFREQUENTLY. SO IF YOU'RE GOING TO DO IT BECAUSE OF RECRUITMENT ISSUES, DO IT ONCE. DON'T KEEP COMING BACK TIGHT. YOU DO NOT WANT TO BIAS YOUR SAMPLE. COP TEXT. THERE ARE LOTS OF CONTEXTUAL FACTORS. AND I'M NOT GOING TO GO THROUGH ALL THE FACTORS THAT ARE POTENTIALLY FACTORS TO THINK ABOUT WHEN YOU'RE THINKING ABOUT WHO TO INCLUDE IN YOUR STUDIES. BUT CONTEXT IS REALLY IMPORTANT. AND JUST HIKE JERRY WAS SAYING EARLIER, WHEN YOU'RE A RESEARCHER, AND YOU ARE ENGAGING WITH A PARTICIPANT IN YOUR STUDY, YOU HAVE A RELATIONSHIP -- THAT IS A RELATIONSHIP. AND THAT RELATIONSHIP HAS CONTEXT. AND NOW ONLY THAT, PARTICIPATANTS WHO COME INTO YOUR STUDY HAVE A WHOLE WORLD OF CONTEXT. ALMOST NONE OF WHICH YOU'RE AWARE OF. SOME OF WHICH YOU MAYBE. BUT ALMOST NONE OF WHAT YOU'RE AWARE. BY CONTEXT WHAT I MEAN ARE THINGS LIKE PERSONAL EXPERIENCES. BACKGROUND MOVE CULTURE. SOCIAL ENVIRONMENT. HOW A PARTICIPANT FEEL ON THAT PARTICULAR DAY. THE RELATIONSHIP THAT YOU AS AN EXPERIMENTER OR RESEARCHER. ALL OF THESE ARE CONTEXTUAL FACTORS AND THEY MAKE A DIFFERENCE. I'M GOING TO PROVE TO YOU THAT THEY MAKE A DIFFERENCE. I HAVE A COUPLE STUDIES TO SHOW YOU. SO THESE ARE THE FINDINGS FROM A STUDY CALLED SWAN WHICH IS A STUDY -- A LONGITUDINAL STUDY. NOT A TRIAL. A LONGITUDINAL STUDY FOR MIDDLE-AGED WOMEN. AND THE PURPOSE OF SWAN WAS TO LOOK AT WOMEN LONGITUDINALLY AS THEY GO THROUGH -- AS THEY AGE. AND TO LOOK AT A VARIETY OF HEALTH OUTCOMES. ONE OF THE OUTCOMES THAT THEY'RE PARTICULARLY INTERESTED IN WAS METABOLIC SYNDROME. BUT THEY TOOK A LOT OF MEASURES. AS OFTEN WE ALL DO AS RESEARCHERS. WE TAKE A LOT OF MEASURES. ONE OF THE MEASURES THAT THEY HAPPEN TO TAKE WERE MEASURES ON EARLY CHILDHOOD TRAUMA. AND THE INVESTIGATORS HAD SOME MEASURES OF MET BOTIC SYNDROME AT TWO DIFFERENT TIME POINTS. WHEN THEY HOOKED TO SEE HOW METABOLIC SYNDROME WAS PROGRESSING IN THIS LARGE COHORT OF WOMEN, SOMEBODY HAD THE VERY CLEVER IDEA TO LOOK AT THE PROGRESSION OF METABOLIC SYNDROME IN RELATIONSHIP TO EARLY CHILDHOOD PHYSICAL ABUSE. THERE IS A LITERATURE THAT SUGGESTIONS THAT MIGHT BE SOMETHING INTERESTING TO LOOK AT. WHAT THEY FOUND WAS THAT THE PERCENTAGE OF WOMEN WHO ACTUALLY WERE MORE LIKELY TO DEVELOP METABOLIC SYNDROME WAS MUCH, MUCH HIGHER, TWICE AS HIGH IN WOMEN WHO HAD EXPERIENCED EARLY CHILDHOOD PHYSICAL ABUSE. THE EXPERIENCE OF HAVING EARLY CHILDHOOD TRAUMA IS A CONTEXTUAL FACTOR. AND I'M NOT SUGGESTING THAT YOU GO OUT NO MATTER WHAT YOUR QUESTION IS AND ASK EVERY ONE ABOUT EARLY CHILDHOOD TRAUMA BUT I AM SUGGESTING THAT YOU LOOK AT THE LITERATURE CAREFULLY IN TERMS OF THESE CONTEXTUAL FACTORS, AND THINK CAREFULLY ABOUT WHO MEASURES YOU NEED TO BE TAKING IN ADDITION TO YOUR PRIMARY OUTCOMES. BECAUSE CONTEXT IS IMPORTANT HAVE AND I HAVE ANOTHER EXAMPLE IN CASE THIS INCIDENT SWAY YOU. THIS IS A FINDING THAT PEOPLE KNOW ABOUT. IT'S VERY FAMILIAR. BUT IT'S INTERESTING TO POINT OUT. THIS IS A STUDY LOOKING AT AMBULATORY BLACKBERRY. HOOKING AT CARDIAC EVENTS. I'M FROM THE NATIONAL HEART LUNG BLOOD INSTITUTES. THAT'S WHAT I TALK ABOUT. THEY FOLLOWED UP INDIVIDUALS WHO WERE HYPERTENSIONIVE AND TAKING HYPERTENSIONIVE MEDICATION, AND FOLLOWED UP TO FIND OUT WHAT THE -- WHAT T HE SURVIVAL WAS. AND -- IN THESE PATIENTS. WHAT THEY FOUND WAS THAT -- I DIDN'T SHOW YOU THE FIRST CURVE, WHICH WAS SOMETHING LIKE A CURVE IN BETWEEN HERE. WHAT THEY FOUND, THOUGH, WAS THAT IF YOU SEPARATED OUT PATIENTS THAT TOOK AT LEAST ONE OF THEIR BLOOD PRESSURE BED MEDICATIONS BEFORE BED FROM THOSE THAT TOOK THEM ALL IN THE MORNING, YOU FIND VERY DIFFERENT SURVIVAL CURVES. AND AS I SAY, IT'S BETTER TO TAKE IT -- BETTER TO TAKE IT BEFORE YOU GO TO BED, BY THE WAY. AS I SAY THIS IS A FAMILIAR FINDING TO US NOW. WE KNOW THAT THE TIMING OF MEDICATION IS IMPORTANT. FOR BLOOD PRESSURE MEDICATION IT'S IMPORTANT TO TAKE AT LEAST ONE OF YOUR MEDICATIONS AT NIGHT. BUT WHAT I'D SUGGEST TO YOU IS THAT THE TIME AT WHICH OUR PARTICIPANT TAKES MEDICATION IS A CONTEXTUAL FACTOR. SO AGAIN YOU WOULDN'T KNOW THAT UNLESS YOU READ THE LITERATURE, AND IT IS A BIG LITERATURE NOW. INCREASING LITERATURE. BUT IT'S CONFEDEXIAL. SO CONTEXT IS IMPORTANT. THAT DOESN'T MEAN THAT YOU NEED TO MEASURE EVERYTHING BECAUSE YOU CAN'T. BUT YOU NEED TO THINK ABOUT CONTEXT WHEN YOU ARE THINKING ABOUT YOUR PARTICIPANT CHARACTERISTICS. AND YOUR OUTCOMES SO ACCESS ANOTHER FEASIBILITY ISSUE. CAN YOU ACCESS THE PARTICULAR PARTICIPANTS WITH A PARTICULAR CHARACTERISTICS THAT YOU'RE HOOKING FOR. YOU NEED TO THINK ABOUT THIS EARLY. YOU CAN HAVE A FANTASTIC STUDY, CAN BE THE BEST SCIENCE IN THE WORLD. IF YOU CAN'T GET PARTICIPANTS INTO YOUR STUDY BECAUSE THEY DON'T LIVE IN YOUR GEOGRAPHIC AREA OR DON'T COME TO YOUR CLINIC, OR YOU -- IN ANY OTHER WAY DON'T HAVE ACCESS, YOU CAN'T CARRY OUT THE STUDY. AND ONE WAY OF INCREASING ACCESS TO THE PARTICIPANTS THAT YOU WOULD LIKE TO STUDY, IS TO BUILD AN INTERDISCIPLINARY TEAM. THIS ARE LOTS OF GOOD REASONS TO BUILD A INTERDISCIPLINARY TEAM. ONE, IT HELPS ENHANCE ACCESS TO PARTICIPANTS THAT YOU MIGHT NOT HAVE ACCESS TO BUT SOMEONE ON YOUR TEAM MIGHT. AND AS YOU BUILD THIS INTERDISCIPLINARY TEAM AND AS YOU HAVE, YOU KNOW, ACCESS ISSUES YOU MAY NEED TO HAVE MANY SITES IN YOUR TRIAL. THAT'S OKAY. IT HAS ITS, YOU KNOW, DOWN SIDES BUT THAT'S OKAY. BUT, AGAIN, THINKING ABOUT THESE IN THE CONTEXT OF THE PATIENT CHARACTERISTICS THAT YOU ARE IDENTIFYING. I'D LIKE TO MAKE A PLEA TO NOT INCLUDE YOUR OWN PATIENTS OR PRACTICE IN YOUR RESEARCH. SEPARATION HELPS YOU MAINTAIN ECHO POISE, AND DELIVER GOOD CLINICAL CARE. WE'LL TALK A LITTLE BIT ABOUT RECRUITMENT AND RETENTION, BECAUSE IT'S SUCH A CRITICAL ISSUE YOU THINK E IN RUNNING A TRIAL. AND I ACTUALLY DO A WHOLE COUPLE OF LECTURES ON RECRUITMENT INTENTION. BECAUSE IT IS SO IMPORTANT AND BECAUSE IT'S COMPLEX. IT DOESN'T SEEM THAT WAY. WE ALL START OUR TRIALS SAYING OKAY WE'RE GOING TO RECRUIT PEOPLE AND THEY'RE GOING TO STAY BECAUSE THEY LOVE US BUT IT'S HARD, REALLY HARD WORK. IT'S GOOD TO THINK ABOUT IN ALL PHASES OF YOUR TRIAL. MOST OF THE TRIALS THAT DON'T COMPLETE, FAILED TRIALS IS A TRIAL THAT DECENT COMPLETE. MOST FAILED TRIALS DON'T COMPLETE BECAUSE OF RECRUITMENT ISSUES, SOMETIMES RETENTION BUT MOSTLY RECRUITMENT. WHAT DO YOU NEED TO THINK ABOUT IN TERMS OF BOTH RECRUITMENT AND RETENTION? PROBABLY THE NUMBER ONE THING IS THE BURDEN THAT YOU IN YOUR PROTOCOL ARE PUTTING ON THE PARTICIPANTS, THE PARTICIPANTS THAT YOU'RE SELECTING. TO BE IN YOUR STUDY. AND THAT BURDEN IS PART OF YOUR -- THE ASSESSMENTS THAT YOU DO, THE MEASUREMENTS THAT YOU DO. AS WELL AS THE COMPLEXITY AND THE DURATION OF THE TREATMENTS, IF YOU'RE PLANNING A FIVE YEAR TRIAL THAT REQUIRES FOUR YEARS OF FOLLOW-UP FROM YOUR PARTICIPANTS, THAT'S A HEAVY BURDEN. IF YOU'RE REQUIRING PARTICIPATANTS TO COME INTO YOUR CLINIC EVERY DAY FOR A COUPLE OF WEEKS THAT'S A HEAVY BURDEN. AND THE HIGHER THAT BURDEN, THE MOTHER DIFFICULT IT WILL BE TO GET PARTICIPATANTS INTO YOUR STUDY, FO MATTER WHO THEY ARE AND TO RETAIN THEM. IT WILL BE MORE IMPORTANT DEPENDING ON THE CHARACTERISTICS OF YOUR PARTICIPANTS, THINGS LIKE HOW HEALTHY YOUR PARTICIPANTS ARE, HOW SICK, WHAT ARE THEIR NEEDS. AND REMEMBER, THOSE NEEDS EXTEND BEYOND THEIR OWN PERSONAL NEEDS. TO THEIR FAMILY NEEDS AS WELL. SO IF YOU WANT TO TO A STUDY OF CHILD BEARING WOMEN, FOR EXAMPLE, IT'S GREAT TO IDENTIFY THAT POPULATION FOR STUDY. BY THEY MAY HAVE CHILD BEARING ISSUES. YOU MAY NEED TO PROVIDE CHILDCARE FOR THEM. OTHER PARTICIPANTS MAY HAVE -- OTHER KINDS OFF LOGISTICS ISSUES, LIKE TRANSPORTATION ISSUES. EVERY ONE HAS PARKING ISSUES BECAUSE IT'S DIFFICULT TO PARK, SO THOSE KINDS OF THINGS ARE THINGS THAT YOU WANT TO THINK ABOUT AND TRY TO DO SOMETHING ABOUT. TO REDUCE THE BURDEN. I HAVE HERE THIS NOTION THAT INTENTION TO TREAT IS THE ANALYSIS THAT YOU WILL DO AND INTENT 250 TREAT ANALYSIS MEANS THAT YOU WILL THAT WOULD EVERY ONE THAT YOU'RE RANDOMIZED INTO YOUR TRIAL. YOU WILL ALL DO INTENT TO TREAT ANALYSIS. THAT MEANS AS SOON AS YOU RANDOMIZE SOMEONE INTO YOUR TRIAL THEY'RE YOURS. THEY ARE YOURS. THAT MEANS THAT YOU WILL CARRY THEM THROUGHOUT THE DURATION OF THE TRIAL. THEY MAY NOT GIVE YOU ANYMORE DATA BEYOND THE FIRST VISIT, BUT YOU MUST INCLUDE THEM. INYOUR ANALYSIS. IN YOUR PRIMARY ANALYSIS. WHAT THAT MEANS -- YOU'LL TALK ABOUT IN THIS THE ANALYTIC SECTION. THAT MEANS THAT YOU WANT TO BE REALLY CAREFUL ABOUT WHO YOU RANDOMIZE INTO YOUR STUDY. SO I KNOW THAT A LOT OF YOU HAVE HAD EXPERIENCE IN TRYING TO ENHANCE RECRUITMENT AND YOU DO A LOT OF THINGS. WE'LL TALK WITHOUT WHAT SOME OF THOSE THINGS MIGHT BE. AND WHAT YOU WANT IS TO ENCOURAGE PEOPLE TO SIGN UP FOR YOUR TRIAL. THAT'S WHAT YOU TRY TO DO WHEN YOU MAKE THESE ACTIVE AND REALLY INTENSE RECRUITMENT EFFORTS. THAT'S A GOOD IDEA. BUT I WOULD SUGGEST TO YOU THAT WHEN YOU ARE DOING YOUR RECRUITMENT EFFORTS, WHAT YOU ACTUALLY DO IS MAKE IT HARD. MAKE IT HARD FOR PARTICIPANTS TO SIGN UP FOR YOUR STUDY. AND THE REASON FOR THAT -- I DON'T MEAN MAKE IT HARD IN THE FEASIBLE SENSE. BUT I THINK YOU WANT TO BE REALLY, REALLY BRUTALLY HONEST WITH PARTICIPANTS IN TERMS OF WHAT IT WILL TAKE TO BE IN YOUR TRIAL. WHAT THEY WILL HAVE TO DO. I RECOMMEND THAT IF YOU HAVE A GROUP RECRUITMENT EFFORT, THAT IS, YOU HIRE A ROOM -- YOU HAVE A ROOM LIKE THIS AND HAVE A BUNCH OF PEOPLE COME TO LISTEN TO YOUR PITCH ABOUT BEING IN THE STUDY, YOU HAVE DISCUSSIONS ABOUT WHAT THE DOWN SIDES OF BEING IN YOUR STUDY IS. HAVE THE DISCUSSIONS OUT RIGHT. I CAN GUARANTY YOU THAT PARTICIPANTS ARE GOING THROUGH THOSE THINGS IN THEIR HEADS SO YOU MIGHT AS WELL GET IT ON TABLE. YOU MAY GET A FEW FEWER PEOPLE TO RECRUIT -- TO ACTUALLY ENROLL IN YOUR STUDY OR SAY THAT THEY'RE INTERESTED IN ENROLLING IN YOUR STUDY BUT YOU WILL GET PEOPLE WHO ARE MORE LIKELY TO BE REORDAINED IN YOUR STUDY. LIKELY TO BE RETAINED. IT IS MORE IMPORTANT TO GET PEOPLE TO BE RETAINED IN THE STUDY THAN 250 GET -- A LOT OF PEOPLE ENROLLED, THEN DROP OUT. THAT HURTS YOUR POWER, HURTS YOUR ABILITY, MAKES CAUSAL INFERENCES. MUCH MORE IMPORTANT TO RETAIN PARTICIPANTS. AS YOU'RE DOING RECRUITMENT EFFORTS WITH ALL THE CRITERIA THAT YOU HAVE LAID OUT IN TERMS OF WHO YOU WANT TO ENROLL AND WHO YOU NEED TO EXCLUDE, BE REALLY CRITICALLY HONEST BOW WHAT IT WILL TAKE FOR PARTICIPANTS TO BE IN YOUR TRIAL. SO OFTEN TIMES PEOPLE WANT TO KNOW -- I'VE TRIED EVERYTHING. WHAT MORE CAN I DO? SO I WANT TO WALK THROUGH A FEW THINGS. WE'RE A LITTLE BIT -- IT'S RELATED TO WHAT WE'RE TALKING ABOUT BUT IT'S IMPORTANT, I THINK. SO WHAT ARE SOME OF THE THINGS THAT YOU CAN DO TO ENHANCE RECRUITMENT? AND ONE OF THE THEM IS TO USE THIS LAYERED APPROACH. WHICH IS ANOTHER WAY OF SAYING MULTIPRONGED APPROACH. DO NOT REPLY ON ONE APPROACH. IT'S PROBABLY NOT GOING TO DO IT FOR YOU. SO IF YOUR IRB WILL ALLOW IT, USE SOCIAL MEDIA. IT'S VERY EFFECTIVE. YOU NEED TO GO TO YOUR IRB TO MAKE SURE IT'S ALLOWABLE. IF IT'S NOT YOU CAN USE COMMUNITY BASED KINDS OF STRATEGIES AND EVEN THOUGH YOU WOULDN'T GO THROUGH SOCIAL MARKETING STRATEGIES YOU MAY HAVE COMMUNITY BASED OUTREACH PROGRAMS THAT YOU CAN PIGGYBACK ON TO. THE OLD FASHION WAY IS TO DO TARGETED DISTRIBUTIONS OF MAILINGS. IT'S OLD FASHIONED BUT IT WORKS. YOU GET ABOUT 1%. AND THAT'S OKAY. BECAUSE THIS IS PRETTY CHEAP. BUT IT IS AN EFFECTIVE STRATEGY BUT YOU HAVE TO HAVE A LOT OF PEOPLE AVAILABLE TO SEND OUT YOUR MAILINGS TO IN ORDER FOR IT TO WORK FOR YOUR PARTICULAR STUDY. A LOT OF PEOPLE DO PRESENTATIONS AT HEALTH FAIRS OR COMMUNITY SETTINGS. THAT'S A GREAT IDEA. ENCOURAGE YOU TO DO IT. NONE OF THESE WILL GIVE YOU HALF OF YOUR SAMPLE. THEY'RE ALL GOING TO BE THIS LAYERED APPROACH THAT YOU TAKE. ONE THING THAT I DON'T SEE AS FREQUENTLY BUT RECOMMEND IT TO YOU IS TO PAIR UP WITH ONE OR TWO OTHERS WHO WERE DOING RESEARCH IN A DIFFERENT AREA. BUT MAYBE HAVE SORT OF SIMILAR CRITERIA, ENTRY CRITERIA, THAT YOU DO BUT DIFFERENT EXCLUSIONARY CRITERIA. BECAUSE WHAT MIGHT HAPPEN -- I'VE SEEN THIS DONE VERY SUCCESSFULLY, WHAT CAN HAPPEN IS THAT SOMEBODY WHO IS NOT ELIGIBLE FOR YOUR STUDY MAY BE ELIGIBLE FOR THE STUDY NEXT DOOR AND VICE VERSA. AND IF YOU CAN PURPOSE WITH OTHER RESEARCHERS -- PARTNER WITH OTHER RESEARCHERS, AND YOU MUST DO THIS WITH THE PERMISSION OF POTENTIAL RESPONSIBILITIES. IT CAN BE VERY EFFECTIVE. YOU HAVE SOMEBODY ALREADINISTED IN RESEARCH. THEY ALREADY WANT TO CONTRIBUTE. AND SO ONCE YOU HAVE THAT PERSON, EVEN IF THEY'RE NOT ELIGIBLE FOR YOUR STUDY, THEY MAY BE ELIGIBLE FOR ANOTHER STUDY. SO THINK ABOUT THAT EARLY -- REFERRAL PROCESS. SET YOUR MILESTONE GOALS REASONABLY. YOUR RECRUITMENT MILE STOPS. MAKE SURE THAT YOU ARE -- STONES. MAKE SURE YOU'RE BEING REALISTIC. IN SOME CASES YOU CAN EMPLOY A RUN-IN STRATEGY. THIS IS NOT UNIVERSE SIMPLY APPLICABLE FOR ALL STUDIES. YOU HAVE TO THINK ABOUT WHETHER IT IS APPROPRIATE FOR YOUR STUDY. THIS IS WHEN YOU HAVE POTENTIAL PARTICIPANTS BEFORE YOU RANDOMIZE THEM. CONSENT THEM BUT BEFORE YOU RANDOMIZE THEM, YOU HAVE THEM DO SOMETHING. YOU HAVE THEM DO SOMETHING SIMILAR TO WHAT THEY WOULD DO IN THE STUDY BUT IT'S SOMETHING THAT BOTH ARMS WOULD DO, OR ALL THREE ARMS. HOWEVER, MANY YOU HAVE. IF YOU HAVE PEOPLE THAT YOU WANT TO RECORD IN A DIARY, SEND THEM HOME FOR TWO WEEKS. ASK THEM TO RECORD WHATEVER YOU WANT THEM TO RECORD IN A DIARY. AND THAT RUN-IN PERIOD CAN HELP YOU IDENTIFY WHO WILL BE ADHERING AND WHO WILL NOT BE ADHERENT. IT'S A MUCH MORE SELF-SELECTED POPULATION THAT YOU END UP WITH, IF YOU GO THROUGH THIS STRATEGY. SO IF YOU'RE LOOKING TO DO SOMETHING ON THE EFFECTIVENESS END OF THE TECHRAM, IT MAY NOT BE THE RIGHT STRATEGY. IF YOU'RE LOOKING TO DO SOMETHING ON THE EFFICACY END OF THE SPECTRUM, IT MAY WORK FOR YOU. AND, OF COURSE, YOU ALWAYS WANT TO EMPLOY STRATEGIES TO MAKE SURE YOU HAVE A REPRESENTATIVE SAMPLE. RETENTION IS AS IMPORTANT, MAYBE MORE IMPORTANT THAN RECRUITMENT. IF YOU CAN GET PEOPLE INTO YOUR STUDY BUT YOU CAN'T KEEP THEM THERE, THAT'S A PROBLEM. SO HOW DO YOU IMPROVE RETENTION? AND THERE ARE LOTS OF THINGS YOU CAN DO. PROBABLY THE MOST IMPORTANT IS TO THINK ABOUT BURDEN AND THINK ABOUT HOW YOU CAN REDUCE BURDEN. THE OTHER THING TO THINK ABOUT IS -- AND BY REDUCING BURDEN WHAT I MEAN IS SHORTEN YOUR STUDY DURATION, SHORTEN THE AMOUNT OF QUESTIONNAIRES PEOPLE HAVE TO FILL OUT. SHORTEN THE NUMBER OF VISITS THEY HAVE TO DO. OR MAKE IT EASIER FOR THEM TO DO THOSE THINGS. PROVIDE VOUCHERS, GO TO THEIR HOMES SOMETIMES. GO TO A MORE CENTRAL LOCATION. THIS ARE LOTS OF THINGS THAT YOU CAN DO DEPENDING ON YOUR PARTICULAR STUDY. BUT MAKE YOUR INTERVENTION AS SIMPLE AS YOU CAN. COMPLEX INTERVENTIONS ARE A REASON THAT PARTICIPANTS DO NOT ADHERE AND EVENTUALLY WHY THEY DROP OUT. IF YOU CAN OPTIMIZE THE VISITS, I KNOW THEY'RE COMING TO THE CRC FOR A MEDICAL VISIT, MAKE SURE THAT'S ALWAYS A STUDY VISIT AS WELL. THAT HELPS. REDUCING BARRIERS, WE'VE TALKED ABOUT THAT. PROVIDING INCENTIVES. INCENTIVES DON'T HAVE TO BE COSTLY BUT THEY HAVE TO BE MEANINGFUL A REFRIGERATOR MAG IN THE, PENCIL, MAYBE NOT. BUT SOMETHING THAT REALLY MEANS SOMETHING. TO PARENTS. IF YOU'RE GETTING PARTICIPANTS A MEDICATION THAT, FOR EXAMPLE, REALLY INCREASES DRY MOUTH, THAT'S A BURDEN FOR PARTICIPANTS. NOBODY LIKES THAT. SO MAYBE YOU GIVE THEM A WATER BOT THAT WILL HAS YOUR LOGO ON IT. THAT'S MEANINGFUL BECAUSE IT TELLS PARTICIPANTS THAT YOU UNDERSTAND WHAT SOME OF THESE SIDE EFFECTS ARE AND YOU'RE TRYING TO HELP THEM OUT. MAKE YOUR VISITS -- SET UP YOUR VISITS EARLY IN THE PROCESS. IF YOU SET EACH VISIT AT A TIME WHEN YOU HAVE A CURRENT VISIT, THEN YOU -- WHAT AM I TRYING TO SAY? SET UP THE FOLLOW-UP VISITS EARLY ON. SET THEM ALL UP AT THE SAME TIME. SODA PARTICIPANTS WHAT THEY'RE GETTING INTO AND KNOW WHEN THEY'RE GOING TO COME BACK. IF YOU DO THAT THEY'RE MORE LIKELY TO BE ABLE TO MAKE THOSE VISITS. SO ADHERENCE. THE ONLY THING I REALLY HAVE TO SAY IS ADHERENCE, YOU NEED TO MEASURE IT. AND IT'S A HARD THING TO MEASURE. YOU NEED TO AS MUCH AS YOU CAN, ENHANCE IT. AND BE ADHERENCE, I MEAN PARTICIPANT ADHERENCE, OBVIOUSLY. BUT ALSO PROVIDER ADHERENCE. WHOEVER IS DELIVERING YOUR INTERVENTION, YOU WANT TO -- THAT PERSON TO BE AS ADHERENT AS POSSIBLE AS WELL. AND WE TALKED ABOUT USING A RUN-IN PHASE IN ORDER TO INCREASE ADHERENCE. THIS IS AN EXAMPLE THAT MANY PEOPLE ACTUALLY USE. IF YOU'RE DOING A STUDY OF OBSTRUCTIVE SLEEP APNEA, THEN THE TREATMENT OF CHOICE FOR MOST PATIENTS WITH OBSTRUCTIVE SLEEP APNEA IS TO USE CPAP, USE CONTINUOUS POSITIVE AIR PRESSURE FOR THEM. BUT IT'S VERY, VERY BURDENSOME, BECAUSE IT'S THE MASKS THAT PEOPLE HAVE TO WEAR, AT NIGHT. NOBODY LIKES IT. EVEN IF YOU'RE NOT RUNNING A STUDY PATIENTS WHO USE IT DON'T LIKE IT. BUT SOME PEOPLE WILL DO IT AND SOME PEOPLE ABSOLUTELY WON'T. SO HOW DO YOU KNOW WHO THOSE PEOPLE ARE BEFOREHAND? BECAUSE NOBODY IS GOING TO WEAR THE CPAP, THEN YOU'RE NOT GOING TO BE ABLE TO FIND OUT THE ANSWER TO YOUR QUESTION. THAT'S PART OF THE INTERVENTION. IN THAT CASE WHAT YOU MIGHT WANT TO DO IS HAVE A [INDISCERNIBLE] WITH YOU HAVE PEOPLE WEAR A CPAP. YOU DON'T DELIVER ANYTHING. NO POSITIVE -- BUT THEY WEAR THE MASK. PEOPLE THAT CAN'T ADHERE TO THAT LIKELY WON'T ADHERE TO THE INTERVENTION. SO THAT'S AN IDEA OF HOW YOU CAN DO THESE. THERE ARE WAYS TO OPTIMIZE ADHERENCE. I RECOMMEND YOU FET SOMEONE ON YOUR TEAM WHO KNOWS HOW TO DO THIS. THERE IS A SCIENCE TO ADHERENCE. ONE OF THE STRATEGIES THAT CAN BE USED IS CALLED MOTIVATIONAL INTERVIEWING. CAN BE USED WITH PARTICIPANTS AND WITH BROADERS. IT IS A WAY TO INCREASE ENGAGEMENT OF YOUR PARTICIPANTS IN YOUR STUDY. AND PROVIDERS. BUT YOU CAN'T LEARN HOW TO DO IT THERE A BOOK. YOU NEED TO BE TRAINED IN IT. SO IF YOU WANT TO EMPLOY THIS STRATEGY, IF YOU HAVE A LARGE TRIAL, AND WANT TO -- BURDENSOME, WANT DO EMPLOY THIS IT'S A GOOD IDEA TO THINK ABOUT FINDING SOMEBODY THAT CAN DO IT. THIS ORIENTATION SESSION IS SOMETHING THAT I WAS ALLUDING TO BEFORE. WHEN YOU HAVE A GROUP OF PEOPLE AND YOU'RE TELLING THEM ABOUT THE STUDY TO SEE IF THEY WANT TO PARTICIPATE. THIS IS BEFORE YOU ACTUALLY ENROLL ANYONE, BEFORE YOU RANDOMIZE ANYONE. YOU'RE LAYING OUT YOUR CASE FOR WHY THEY MAY WANT TO PARTICIPATE. THIS IS A GREAT OPPORTUNITY FOR YOU TO PROVIDE INFORMATION. AND TO DEVELOP THIS RELATIONSHIP WITH POTENTIAL PARTICIPANTS. I REALLY LIKE -- IT'S NOT APPROPRIATE FOR YOU'LL STUDIES BUT IF I SAID APPROPRIATE FOR YOUR STUDY I REALLY THINK THIS IS A FANTASTIC STRATEGY. IT EASTBOUND ABLEST YOU TO ANSWER QUESTIONS, ENABLES YOU TO GET FAIRLY ADHERENT PEOPLE. THEY'VE ALREADY COME TO AN ORIENTATION SESSION. PEOPLE INTERESTED IN THE STUDY. AND ENABLES YOU TO GIVE THEM THE CASE WHY THEY SHOULDN'T ENROLL. ALL THE REASONS THEY SHOULDN'T. YOU'RE ALSO GOING TO TALK ABOUT WHY THEY SHOULD ENROLL IN THE STUDY. BUT IT REALLY GIVES YOU ABOPPORTUNITY TO GET PEOPLE INTO YOUR STUDY WHO MAY BE -- YOU MAY BE ABLE TO RETAIN INTO THE STUDY. CONTACT BACKUPS. THESE ARE FAMILY MEMBERS, IF YOU CAN GET THOSE. THAT'S A GOOD IDEA IF YOU'RE DOING A LONGITUDE TECHNOLOGY STUDY. PEOPLE MOVE AND SOMETIMES THEY FORGET TO TELL YOU. SO IT'S A GOOD IDEA TO HAVE A BACKUP. AND AGAIN YOU GET THAT FROM THE PARTICIPANTS WITH THEIR CONSENT ON THE CONSENT FORM. IF YOU CAN MAINTAIN CONTACT AGAIN WITH TRIALS THAT ARE LONGITUDINAL, MAINTAIN CONTACT WITH PARTICIPANTS, ONE WAY TO DO IS IT TO PHONE THEM. IF THAT'S PART OF YOUR INTERVENTION. BUT IT'S NICE TO SEND BIRTH AT THAT CARDS. DOESN'T COST HAVE. PEOPLE REALLY APPRECIATE IT. AGAIN I RECOLLECT PART OF THIS RELATIONSHIP -- AGAINST IT'S PART OF THIS RELATIONSHIP THAT YOU'RE BUILDING. NEWS LETTERS ARE ALSO VERY EFFECTIVE. THEY TAKE TIME BUT VER VERY EFFECTIVE. SO I WANT TO END WITH AN EXAMPLE OF A STUDY THAT KIND OF HIGHLIGHTS SOME OF THE POINTS THAT I'VE TRIED TO LAY OUT FOR YOU. AND THIS IS A STUDY CALLED ENRICHED, DONE A COUPLE YEARS AGO. IT'S OVER NOW, CALLED ENHANCING RORY IN CORONARY HEART DISEASE PATIENTS. THE BASIC PREMISE COMES FROM DATA LIKE THESE. THIS IS NOT THE ENRICH DATA. THESE ARE FROM AN EARLIER STUDY. AND IT'S A PHENOMENON THAT WE KNOW VERY WELL. AND THE PHENOMENON IS THIS. THAT AFTER SOMEBODY HAS A HEART ATTACK, IF THEY'RE DEPRESSED THEY'RE MUCH MORE LIKELY TO DIE THAN IF THEY'RE NOT DEPRESSED. SO WHAT YOU CAN SEE, THIS IS A MONTH POST MI, POST HEART ATTACK. AND WITHIN TWO MONTHS POST MI, AS YOU CAN SEE HERE, WE SEE A DIVIRGINS, PARTICIPANTS WHO BECOME DEPRESSED VERSES THOSE THAT DO NOT. THE MORE TALLDY RATES JUST GO UP. A PHENOMENON THAT -- IT'S VERY REAL. SO THE EVAN RICHED TRIAL SAID WE NEED TO DO SOMETHING ABOUT THIS. LET'S SEE WHAT HAPPENS IF WE TREAT THE DEPRESSION. LET'S TRY THAT. SO THAT'S WHAT THE ENRICHED TRIAL WAS. AND THEY ALSO KNEW THAT DEPRESSION WAS VERY STRONGLY LINKED TO SOCIAL SUPPORT. SO THEY ACTUALLY HAD AN INTERVENTION, A DUAL INTERVENTION TO TARGET LOW SOCIAL SUPPORT AND HIGH DEPRESSION. AND SO THE HYPOTHESIS WAS THAT THEY THEY WANTED TO TEST WHETHER TREATING DEPRESSION AND LOW SOCIAL SUPPORT RIGHT AFTER A HEART ATTACK WAS GOING TO REDUCE DEATH RATES, AND NON FATAL RECURRENT HEART ATTACKS. SIMPLE STUDY, RIGHT? IT WAS NOT SIMPLE. SO ULTIMATELY, THEY ENROLLED ALMOST 2500 POST HEART ATTACK PARTICIPANTS THAT EITHER PRESENTED WITH DEPRESSION OR LOW SOCIAL SUPPORT OR BOTH. COMMONLY BOTH. AND THEY RANDOMIZED INTO A GROUP THAT GOT USUAL CARE. VERSUS ONE THAT GOT A PSYCHO SOCIAL INTERVENTION TO TREAT THE -- TO TRE AT THE SOCIAL SUPPORT AND DEPRESSION. AND THEIR ENDPOINTS WERE CARDIAC MORTALITY, AND RECURRENT HEART ATTACK. AND THEY FOLLOWED THEM FOR ALMOST 3-YEARS -- 3 AND A HALF YEARS, DETERMINE TOTALLY MOVINGED. SO HERE IS WHAT I WANT YOU -- THIS IS NOT WHAT -- THEIR INCLUSIONARY CRITERIA WERE THAT THEY WERE GOING TO ENROLL PEOPLE WIN 28 DAYS OF HAVING A HEART ATTACK. NOW, THEY WANTED TO ENROLL THEM QUICKER. THEY WANTED TO GET THEM MORE QUICKLY THAN THAT. BECAUSE YOU SAW IN THAT GRAPH THE DIVIRGINS HAPPENED AT TWO MONTHS. THEY NEW IT WOULD NOT BE FEASIBLE TO ENROLL THEM MORE QUICKLY THAN THIS. WHY IS THAT? WELL, YOU HAVE A PATIENT, JUST HAD A HEART ATTACK, IN THE HOSPITAL. THEIR FAMILY IS INVOLVED. THEY HAVE OTHER THINGS DO THINK ABOUT BESIDES YOUR STUDY. SO THEY SETTLED ON RECRUITING THEM WITHIN ABOUT A MONTH AFTER A HEART ATTACK. AND THEY HAD A BUNCH OF CRITERIA -- THEY H AD -- THEY HAD INCLUSIONARY CRITERIA THAT COULD SUNSTONIATE THE FACT THAT THEY HAD A HEART ATTACK. THEY HOOKED AT ENZYMATIC INCREASES, THEN IDENTIFIED WHETHER THEY WERE DEPRESSED OR HAD LOW SOCIAL SUPPORT AND THERE WERE GOOD MEASURES TO DO THAT. THIS IS WHAT I WANT TO SHOW YOU. THIS IS THE CONCERT DIAGRAM. THEY SCREENED HEADLINE 34,000 -- ALMOST 34,000 PEOPLE. 34,000 PEOPLE. TO GET 2,481. SO THEY SCREENED THIS NUMBER, SOME DIDN'T MEET CRITERIA FOR HAVING HAD A HEART ATTACK. RIGHT? BUT NOT THAT MANY. THEN SOME OF THEM, FAIR NUMBER, 7,000 ALMOST, WEREN'T DEPRESSED OR HAD LOW SOCIAL SUPPORT. LOOK AT THIS. 23,000 DIDN'T MEET THEIR MEDICAL ELIGIBILITY. GIVEN WHAT WE'VE JUST TALKED ABOUT WHAT DOES THAT MEAN? TH THEY TOOK SOMETHING WRONGTH EXCLUSIONARY CRITERIA? THESE ARE THE BEST RESEARCHERS AROUND. IT'S NOT WRONG BUT WHEN YOU STEP BACK AND LOOK AT IT, THIS IS WHERE THEY HAD THE PROBLEM. THIS IS WHERE IT HAPPENED. IT WASN'T THAT IT WAS WRONG BUT THEY HAD DO SCREEN SO MANY PEOPLE IN ORDER TO GET 2500 PEOPLE BECAUSE OF THESE ELIGIBILITY CRITERIA. SCIENTIFICALLY, IT WAS THE RIGHT THING TO DO BUT IT MADE FOR A VERY DIFFICULT STUDY. TO OPERATIONALIZE THIS MORE CLEARLY FOR YOU, WHAT THIS MEANS IS THAT FOR EVERY 100 PARTICIPANTS THAT THEY SCREENED, THESE WEREN'T PEOPLE THAT CALLED UP AND SAID I WANT TO SPATE. THESE ARE 100 PARTICIPANTS THAT THEY SCREENED. ONLY 7 WERE ACTUALLY ENROLLED AND RANDOMIZED INTO THE TRIAL. THAT'S A LOT OF WORK. ANOTHER WAY OF THINKING ABOUT IT, IN ORDER TO GET 1 THEY HAD TO SCREEN 14. AND, OF COURSE, THEY HAD A LOT OF FIGHTS. AND NONE OF THE SITES WERE ABLE TO ADEQUATELY ENROLL PARTICIPANTS. WHEN YOU HAVE A MULTISITE TRIAL YOU WILL FIND THAT SITES RECRUIT AT DIFFERENT RATES. THERE MAY BE REASONS TO KEEP SITES THAT HAVE LOW RECRUITMENT, BECAUSE THEY'RE RECRUITING PARTICULAR CHARACTERISTICS OF THE PATIENT POPULATION THAT YOU'RE INTERESTED IN. BUT IT IS A PHENOMENON THAT OCCURS FAIRLY FREQUENTLY. THERE HAS BEEN A LOT OF TALK AMONG THE INVESTIGATORS WHY THERE ARE DIFFERENCES -- PROBLEMS WITH RECRUITMENT AND RETENTION. AND SOME OF THEM HAD TO DO WITH AXIS. SOME OF -- ACCESS. SOME HAD TO DO WITH THE EXACT THEY WERE RECRUITING AT VERY RESEARCH HEAVY SITES. SO THERE WAS A LOT OF RESEARCH GOING ON. AND YOU HAVE TO THINK ABOUT THAT. IS THERE A LOT OF STUFF GOING ON IN THIS AREA? WHERE YOU'RE GOING TO BE RECRUITING. THEY DIDN'T HAVE ADEQUATE COLLABORATIVE TEAMS. AND SO THAT REDUCED THEIR ABILITY TO RECRUIT. THEIR BURDEN WAS HIGH. SO THESE PARTICIPANTS HAD TO COME IN AND PARTICIPATE IN A PSYCHO SOCIAL INTERVENTION, WHICH ALWAYS IS A LITTLE BIT MORE BURDENSOME THAN TAKING PHARMACOLOGIC PILL. AND THEY HAD A LOT OF ASSESSMENTS. THIS STUDY WENT ON FOR 3 AND A HALF YEARS. SO THIS WAS A VERY BURDENSOME STUDY. THEY -- BUT THE REAL KEY IS HERE THEY HAD REALLY RESTRICTIVE ELIGIBILITY CRITERIA. AS YOU CAN SEE FROM THE EXCLUSION. THE HIGH NUMBER OF PATIENTS THAT WERE EXCLUDED. SO LET ME WALK THROUGH A COUPLE OF OVERALL CONCLUSIONS. KNOW YOUR LITERATURE. KNOW THE HISTORY OF YOUR LITERATURE. KNOW WHERE THINGS FIT. BE ABLE TO IDENTIFY CONTEXTUAL FACTORS. KNOW WHERE YOUR QUESTION LIES. ON THAT RESEARCH CONTINUUM. THAT'S REALLY CRITICAL. MAKE SURE YOU'RE DESIGNING THE RIGHT STUDY FOR THE RIGHT TIME. FOR THAT LITERATURE. MAKE SURE YOU HAVE CLARITY ON YOUR QUESTION. THIS SOUNDS KIND OF SILLY, OF COURSE I HAVE CLARITY. I WANT TO KNOW IF THIS DOES THIS. UNDERSTANDING THE COMPLEXITY OF YOUR QUESTION REALLY MEANS THAT YOU HAVE TO DIVE DEEP INTO SOME OF THE ISSUES THAT WE'RE TALKING ABOUT AND MORE AS WELL. TO UNDERSTAND WHAT YOUR -- ALL OF THE COMPLEXITIES OF YOUR QUESTION. HAVE A REALLY GOOD, VERY SPECIFIC TARGETED UNDERSTANDING OF THE PATIENT CHARACTERISTICS THAT YOU WANT DO TARGET. MAKE SURE THE PARTICIPANTS MATCH THE OUTCOMES. YOUR PRIMARY OUTCOMES. MAKE SURE IT'S A GOOD MATCH, FEASIBLE MATCH. AND MAKE SURE THAT YOU'RE ASKING THE RIGHT QUESTIONS AT THE RIGHT DIME. GOING BACK TO INTERNAL VERSES EXTERNAL VALIDITY, FIGURE OUT IN THE CONTEXT OF YOUR QUESTION WHAT'S MOST IMPORTANT OR, IN OTHER WORDS, THINKING ABOUT WHAT WE WORRY ABOUT THE MOST. FALSE NEGATIVES OR FALSE POSITIVES. AND THAT'S ALL I HAVE. ARE THERE ANY QUESTIONS? IF AS YOU'RE READING THROUGH YOUR MATERIAL, IF YOU HAVE QUESTIONS FEEL FREE TO SUBMIT THEM TO ME. I'D BE HAPPY TO ANSWER THEM FOR YOU. THANK YOU.