>>> GOOD AFTERNOON. MY NAME IS SARAH HULL. I'M PART OF THE BIOETHICS CORE
AND THE VICE-CHAIR OF THE NHGRI INTRAMILE-PER-HOUR IRB. AND I SHEAR A JOINT
APPOINTMENT — INTRAMURAL IRB — WITH THE
CLINICAL DEPARTMENT OF BIOETHICS. WHAT I HOPE TO ACCOMPLISH TODAY
IN THE NEXT HOUR IS TO GIVE YOU A VERY CLASSICAL PERSPECTIVE ON
THE ETHICAL AND IRB ISSUES ASSOCIATED WITH DOING WHOLE
EXOME SEQUENCING RESEARCH. I WANT TO NOTE AHEAD OF TIME
THAT I'M POSSIBLY GOING TO USE THE TERMS, NECKS GENERATION AND
WHOLE GENOME SEQUENCING INTERCHANGEABLY REALIZING THERE
ARE HUGE TECHNICAL DIFFERENCES BUT THE ETHICAL CONSIDERATIONS
MAY NOT BE QUITE SO MUCH.
SO IF MY USE OF TERMINOLOGY
SEEMS A LITTLE BIT LOOSE, I APOLOGIZE FOR THAT BUT THE
REASONS BEING PROTOCOLS THAT USE ALL OF THESE TECHNOLOGIES AND
THAT'S BEEN INFLUENCING OUR THINKING. THE OPINIONS I WILL BE SHARING
WITH YOU ARE MY OWN AND NOT THOSE OF ANY OFFICIAL
PERSPECTIVE OF THE AGENCIES THAT EMPLOY ME. —
MANY INTERACTIONS I'M PRIVILEGED TO HAVE BEING HERE IN THE
INTRAMURAL PROGRAM AT THE NIH. SO I WANT TO ACKNOWLEDGE UPFRONT
BECAUSIC THAT WILL HELP YOU TO UNDERSTAND THE EXPERIENCES MY
COMMENTS ARE GROUNDED AND BASED UPON.
FIRST I WANT TO ACKNOWLEDGE MY
COLLEAGUE, BEN BERK MAN WHO WITH ME RUNS THE NHGRI CORE AND THAT
INVOLVES PROVIDING RESEARCH ETHICS CONSULTATION TO OUR
INTRAMURAL SCIENTISTS AND HELPING TO RUN AND PROVIDE THE
INFRASTRUCTURE FOR OUR IRB. WE HAVE HAD THE OPPORTUNITY TO
DO DOZENS OF CONSULTS RELATED TO QUESTIONS RELATED ABOUT NEXT
GENERATION SEQUENCING RESULTS FROM THE EARLIEST DESIGN STAGE
TO DISSEMINATION AND PUBLICATION OR ATTEMPTED PUBLICATION.
TOO MANY OF THESE CONSULTATIONS
TO COUNT BUT THOSE ARE VERY MUCH INFLUENCING MY THINKING ABOUT
ALL OF THIS AND THE EVOLUTION OF MY THINKING OVER TIME. MY ROLE WITH THE NHGRI-IRB HAVE
BEEN VERY IMPORTANT. WE ARE A SPECIALIZED IRB. WE HAVE BEEN ADDRESSING ISSUES
RELATED TO GENETICS AND GENOMICS FOR ALMOST 13 YEARS THAT WE HAVE
NOW BEEN UP AND RUNNING. AND AS EARLY AS 2006, WE WERE
STARTING TO THINK IN AN ANTICIPATORY WAY ABOUT THE
QUESTIONS RELATED TO NEXT GEN SEQUENCING THANKS TO THE
CLIN-SEQUE PROTOCOL, ONE OF THE EARLIEST ONES THAT WERE TRYING
TO TRY OUT THESE TECHNIQUES AND WE SPENT THE LAST TWO ANNUAL
TRAINING RETREATS WE RUNG, WE RUN HALF DAY RETREATS AND WE
SPENT THE LAST TWO DEDICATED TO EXPLORING IN MORE DEPTH ISSUINGS
COMING UP ANOTHER NEXT GEN PROTOCOLS.
I ALSO WANT TO CALL TENSION TO
THE ETHICS CONSULTATION SERVICE WHICH IS ONE OF THE ROLES I'M
INVOLVED WITH AS PART OF MY FACULTY APPOINTMENT WITH THE
DEVELOPMENT OF BIOETHICS. ANYBODY WHO IS HERE PART OF THE
NIH CAN CALL-UP OUR PAGING OPERATOR AND REQUEST TO GET IN
TOUCH WITH THE BIOETHICS FELLOW ON CALL TO ASK FOR A CONSULT,
ETHICS CONSULT TO HELP WITH QUESTIONS THAT MIGHT COME UP AT
ANY STAGE IN THE CONDUCT OF THE RESEARCH. THIS IS A CLINICAL SERVICE
AVAILABLE TO YOU. A NUMBER OF CONSULTATIONS
SERVICES I BELIEVE INVOLVE WITH THROUGH THIS REFERRAL MECHANISM
DEALT WITH QUESTIONS AROUND THE ETHICS OF WHOLE EXOME AND WHOLE
GENOME SEQUENCING. I WANT TO CALL OUT ONE
ADDITIONAL PERSON WHO WAS HERE EARLIERER, PART OF THE PROGRAM
AND SHE ILLUSTRATES THAT THE SPIRIT OF CORPORATION AND
COLLABORATION BETWEEN THOSE WHO ARE WORKING ON THE ETHICAL AND
OVERSIGHT SIDE OF THINGS LIKE MYSELF AND THE SCIENTISTS WHO
ARE AT THE COMPUTER AND SEEING THE SUBJECT.
SHE HAS BECOME AN EXAMPLE OF A
VERY GOOD GATEKEEPER. SHE KNOWS WHEN TO REFER THEM TO
TALK TO US ABOUT THE ETHICAL OVERSIGHT AND REVIEW. SHE MAKES SURE EVERYTHING IS IN
PLACE BEFORE YOU GET TOO FAR DOWN THE PIPELINE. THAT'S A REALLY IMPORTANT ASPECT
OF OUR WORK. AND THERE ARE MANY INTERACTIONS
WITH THE OTHER IRBs HERE AT THE NIH AS WELL AS
COLLABORATORS. MY OWN RESEARCH PROGRAM IS IN
SPARED BY THE KINDS OF QUESTION THAT IS COME OUT OF THESE
CONSULTATIONS AND I LISTED ALL THE VARIOUS COLLABORATORS ON
PAPERS STARTING TO COME OUT ABOUT THESE REQUEST QUESTIONS
AND I'M GRATEFUL FOR THE OPPORTUNITY TO BE ABLE TO WORK
ON THEM. AND SO LET ME GET TO THE POINT. I THINK MANY OF YOU HERE ARE
HERE BECAUSE YOU HAVE A VERY BASIC QUESTION. YOU WANT TO KNOW HOW DO I GET MY
WHOLE EXOME SEQUENCING PROTOCOL THROUGH THE IRB? AND IF YOU DRAW ON DAVID'S
PRESENTATION EARLIER, RESEARCH IN GENERAL, PROTOCOLS IN GENERAL
ARE ON A CHARIOT RACE. EVERYBODY WANTS TO USE THIS
TECHNOLOGY, GET THROUGH THE PROCESS, DO THE SCIENCE, GET THE
PAPER OUT.
AND WE REALLY DON'T WANT THE IRB
PROCESS TO HOLD THINGS UP FOR SURE. THAT SAID, I'M GOING POLITELY
SUGGEST THAT THIS IS NOT THE RIGHT QUESTION TO START WITH. FIRST, THERE IS MORE THAN ONE
ETHICALLY APPROPRIATE WAY TO DO WHOLE EXOME SEQUENCING RESEARCH. SO ON THE NEXT FEW SLIDES, I'M
INCLUDING QUOTATIONS FROM A QUALITATIVE PROJECT I'M WORKING
ON WITH BEN BERK MAN AND OTHERS WHO JUST STARTED THE ANALYSIS. WE HAVE A FEW QUOTES FROM A
QUESTION WE CLOSED. THIS IS INTERVIEWS WITH IRB
CHAIRS AND STAFF AT THREE DIFFERENT SITES. THE NIH AND ACADEMIC MEDICAL
CENTRES IN THE BOSTON AREA AND IN THE SEATTLE AREA.
AND WE ASKED ABOUT POLICIES
THEIR IRB HAS ABOUT THE ETHICS OF WHOLE EXOME SEQUENCING
RESEARCH. AND THIS CASE, ONE ADMINISTRATOR
SAID — [READING]
SO HERE WE GET THE SENSE THERE IS NOT A ONE-SIZE-FITS-ALL
APPROACH FOR HANDLING THIS. ANOTHER ISSUE IS THAT IRBs AND
I'M PERFECTLY WILLING TO ADMIT THIS, WE ARE ALL STILL TOO IING
TO FIGURE THIS OUT — TRYING TO FIGURE THIS OUT. WE ARE STRUGGLING WITH THE
ETHICS AND REVIEWING THE PROTOCOLS. SO THIS QUOTE IS FROM AN IRB
CHAIR. WE DON'T HAVE A POLICY AND I
DON'T KNOW THAT WE REALLY HAVE COME TO A FIRM CONCLUSION.
I MEAN, IT GETS DISCUSSED EVERY
TIME AND THERE IS DISAGREEMENT EVERY TIME. BUT THIS SUGGESTS THAT WITHIN
THE IRB, PROTOCOL TO PROTOCOL, THERE ARE SOME DISAGREEMENTS AND
I'LL ALSO MENTION THAT FROM IRB TO IRB, EVEN HERE WITHIN THE
NIH, THERE ARE SOME DIFFERENCES OF OPINION AND DIFFERENT
OUTCOMES WE SEE. SO I CAN FEEL THE SENSE OF
FRUSTRATION WELLING UP IN SOME OF YOU WHO ARE HERE IN THE ROOM. ANOTHER IRB CHAIR SAID, WE DO
NOT HAVE AN INSTITUTIONAL POLICY. I THINK WE HAVE GONE THROUGH
SEVERAL DIFFERENT DISCUSSIONS IN OUR IRB FOR EACH SPECIFIC
PROTOCOL BUT I THINK WE ARE STILL AT THE STAGE WHERE WE HEAR
FROM INVESTIGATORS WHAT THEIR APPROACH IS AND THEN WE DECIDE
AT THE MEETING IF THIS SOUNDS REASONABLE. I INCLUDED THIS QUOTE BECAUSE I
HOPE IT GIVES YOU THE SENSE THAT THE PROCESS IS A LITTLE BIT MORE
CONSTRUCTIVE THAT IRBs ARE QUITE OPEN TO HEARING FROM
INVESTIGATORS WHAT A REASONABLE PLAN IS FOR THEIR SET OF
CIRCUMSTANCES AND SHOULD REVIEW IT ON A CASE-BY-CASE BASIS TO
COME WORK TOGETHER TO COME OUT WITH THE RIGHT SET OF ANSWERS
AND THE RIGHT PROTOCOLS AND SOLUTIONS TO THE ETHICALLY
WITHS.
—
ETHICAL QUESTIONS. WE DO VEY POLICY HERE AT THE NIH
IN THE INTRAMURAL RESEARCH PROGRAM THAT PERTAINS TO WHOLE
EXOME — THE ETHICAL REVIEW OF WHOLE
EXOME AND WHOLE GENOME SEQUENCING PROTOCOLS. IT'S NOT A VERY PRESCRIPTIVE
POLICY. IT TALKS ABOUT THE LEVEL OF
REVIEW THAT IS REQUIRED. SO THE POLICY STATES —
[READING] NOW OHSRP IS THE OFFICE OF HUMAN
SUBJECTS RESEARCH PROTECTION. IT'S AN OVERSITE OFFICE HERE AT
THE NIH. SO EXISTING PRO PROTOCOLS WILL
NEED TO BE AMENDED TO INCLUDE WHOLE EXOME SEQUENCING AND WHOLE
GENOME SEQUENCING. AND THIS WAS OR THIS IS A POLICY
THAT WAS ENDORSED BY A GROUP THAT SAY COLLECTION OF ALL THE
INTRAMURAL IRB CHAIRS AND HIGHER LEADERSHIP IN JULY OF 2010. SO YOU MIGHT BE THINKING TO
YOURSELF, WHAT IF I ALREADY HAVE CONSENT TO DO GENETIC RESEARCH
ON SPECIMENS THAT I COLLECTED FROM SUBJECTS IN MY PROTOCOLS? THIS WOULD STILL REQUIRE ETHICAL
REVIEW OVERSIGHT.
IT MIGHT BE AS SIMPLE AS AN
AMENDMENT TO ADD THE NEW ANALYSIS TO YOUR PROTOCOL BUT
THEY WOULD HAVE TO BE REVIEWED BY AN IRB. WHAT IF I'M ONLY USING CODED
SPECIMENS GIVEN TO ME FROM AN OUTSIDE EXTRAMURAL COLLABORATOR? THIS TOO WOULD MEAN SOME KIND OF
INSTITUTIONAL REVIEW. WHAT IF I'M NOT PLANNING TO
RETURN ANY INCIDENTAL RESEARCH FINDINGS? THAT WOULD SOLVE THE PROBLEM,
RIGHT? THAT MIGHT BE AN ACCEPTABLE
APPROACH DEPENDING ON CIRCUMSTANCES BUT AN APPROACH
THAT NEEDS TO BE REVIEWED EITHER BY AN IRB OR OHSRP. SO NOW YOU MIGHT BE GETTING THE
SENSE THAT WE ARE PROCEEDING VERY CAUTIOUSLY AND DELIBERATELY
WHEN IT COMES TO THE ETHICAL OVERSIGHT OF WHOLE EXOME
SEQUENCING RESEARCH. AND YOU WOULD BE CORRECT ABOUT
THAT AND THAT LEADS TO ANOTHER QUESTION, WHICH IS WHAT IS THE
BIG DEAL? WHAT IS SO DIFFERENT ABOUT WHOLE
EXOME SEQUENCING THAT EVERYBODY IS TAKING IT QUITE SO SERIOUSLY? GLAD YOU ASKED. HERE IS THE NOW SOMEWHAT
FAMILIAR CURVES THAT MAP OUT THE EXTRAORDINARY SPEED AT WHICH
SEQUENCING TECHNOLOGY IS ABLE TO GENERATE KILOBASES AND THE
EXTRAORDINARILY DECLINING COSTS THAT WE HAVE BEEN TALKING ABOUT. AND WHAT THIS MEANS IS THAT IT'S
MUCH MORE EFFICIENT, MUCH MORE ACCESSIBLE TO USE, NEXT
GENERATION SEQUENCING TECHNOLOGIES, INVESTIGATORS ARE
SCRAMBLING TO INCORPORATE THESE INTO THEIR PROTOCOLS AND WILL
RESULT IN MUCH, MUCH MORE.
EXPONENTIALLY MORE GENETIC AND
GENOMIC INFORMATION BEING GENERATED ABOUT INDIVIDUAL
RESEARCH SUBJECTS. IT'S THAT MAGNITUDE THAT PRESSES
ON THE ETHICAL QUESTIONS. SO IN GENERAL, MY COLLEAGUES AND
I HAVE ARGUED THAT THESE TECHNOLOGIES DON'T ACTUALLY
ALTER OR RAISE NEW ETHICAL CONCERNS. THE CONCERN IS THAT WE HAVE BEEN
TALKING ABOUT IN RELATION TO GENETIC RESEARCH, ISSUES AROUND
ADEQUATE AND CONFORMED CONSENT, HOW TO PROTECT CONFIDENTIALITY
AND MINIMIZE RISKS AND MAXIMIZE BENEFITS. THESE ARE ALL STILL STABLE AND
IN TACT AND STILL APPLIED TO WHOLE EXOME SEQUENCING RESEARCH. THE ISSUE IS THAT BECAUSE OF THE
MAGNITUDE OF INFORMATION THAT IS GOING TO BE GENERATED, THIS WILL
IN TURN MAGNIFY AND MAKE MORE CONCRETE MANY OF THE CONCERNS
THAT WERE RELATIVELY HYPOTHETICAL OR THEORETICAL
UNTIL THIS POINT AND IT'S THIS THAT HAS IMPLICATIONS FOR HOW WE
CONDUCT ETHICAL REVIEW OF WHOLE EXOME SEQUENCING RESEARCH. ESPECIALLY IN THE CONTEXT OF THE
REGULATORY FRAMEWORK THAT WE ARE WORKING WITHIN. SO I THINK THAT THESE, THE
ETHICAL ISSUES THAT EMERGE FROM THIS CONTEXT CAN BE SORTED OUT
INTO THREE GENERAL CATEGORIES. THERE IS ISSUES RELATED TO THE
MANAGEMENT OF ALL OF THIS INFORMATION AND SPECIFICALLY
WHAT WE DO WITH INDIVIDUAL RESEARCH RESULTS, ALSO THOSE
CONSIDERED TO BE PRIMARY OR RESEARCH-RELATED RESULTS, AS
WELL AS THOSE THAT WE HAVE BEEN CALLING SECONDARY OR OFTEN
PEOPLE REFER TO THESE AS INCIDENTALS.
IN OTHER WORDS, INCIDENTAL TO
THE CORE RESEARCH QUESTIONS BEING ASKED. THERE IS ALSO A LOT OF
INTERESTING AND CHALLENGING QUESTIONS AROUND ETHICS OF BROAD
DATA SHARING REQUIREMENTS AND HOW THAT WILL PLAY OUT IN THE
CONTEXT OF LARGE-SCALE GENOMIC SEQUENCING AND THEN IMPORTANT
QUESTIONS TO ASK ABOUT THE CONTENT OF INFORMED CONSENT AND
WHETHER IT IS ADEQUATE TO COVER ALL OF THESE PLANS AND ISSUES
AND IN SOME CASES, PERHAPS WHETHER WE CONTACT PEOPLE AND
GIVE THEM NEW INFORMATION MIGHT BE REQUIRED.
SO THIS IS GOING TO —
I'M GOING TO USE THIS FRAMEWORK TO ORGANIZE THE REMAINDER OF MY
COMMENTS THIS AFTERNOON. AND I'M GOING TO FOCUS ON MOSTLY
AROUND QUESTIONS AROUND INCIDENTAL RESEARCH FINDINGS AND
GENOMIC RESEARCH FINDINGS AND WHETHER OR NOT THEY SHOULD BE
DISCLOSED TO PARTICIPANTS BECAUSE THIS IS REALLY WHERE
SOME OF THE MOST CHALLENGING QUESTIONS HAVE BEEN COMING UP
FOR US AND WHERE WE HAVE BEEN SPENDING A LOT OF TIME AND
EFFORT IN OUR WORK WITH INVESTIGATORS. SO, JUST A COUPLE OF CONCEPTUAL
CLARIFICATIONS. IN THE WORLD THAT WE HAVE SEEN
SHIFT IN THE LAST 13 YEARS FROM A CANDIDATE GENE TARGETED
APPROACH TO GENETIC RESEARCH TO NOW NEXT GENERATION SEQUENCING,
A COUPLE OF OUR ASSUMPTIONS CHANGED. SO AN EXISTING ASSUMPTION IS
AROUND TRADITIONAL GENETIC RESEARCH IS THAT IT WILL PRODUCE
RELATIVELY FEW CLINICALLY SIGNIFICANT INCIDENTAL FINDINGS. IT WOULD BE RELATIVELY RARE TO
SEE THESE IN THE CONTEXT OF RESEARCH. AND OUR REVISED ASSUMPTION THAT
IT'S NOT SO MUCH A QUESTION OF WHETHER WE ARE GOING TO SEE
CLINICALLY RELEVANT RESULTS EMERGING FROM RESEARCH, BUT HOW
MANY AND OF WHAT CHARACTER THEY WILL BE IN AN INDIVIDUAL
PARTICIPANT? A SECOND ASSUMPTION THAT I WANT
TO PUT OUT THERE IS IT IS REALLY EASY TO DISTINGUISH BETWEEN
SO-CALLED INCIDENTAL OR SECONDARY FINDINGS AND THOSE
THAT ARE EXPLICITLY RELATED TO THE ORIGINAL STUDY HYPOTHESES OR
DISEASE THE FOCUS.
AS RESEARCH EVOLVES OVER TIME
AND AS WE GET FOCUSED ON BROADER MODELS OF GENOMIC MEDICINE, I
THINK IT'S ARGUABLE THAT RESEARCH THAT USES NEXT
GENERATION SEQUENCING IS GOING TO BLUR THE DISTINCTION BETWEEN
WHAT COUNTS AS INCIDENTAL AND WHAT COUNTS AS RELATED TO THE
RESEARCH. IT'S ALL GOING TO BE THERE AND
RELATE THE TO THE RESEARCH IN SOME WAY AND THIS DISTINCTION
MIGHT BECOME LESS MEANINGFUL OVER TIME.
A THIRD ASSUMPTION IS ONE THAT I
HAVE — AND MY COLLEAGUES INFORMALLY
REFER TO AS DON'T LOOK, DON'T TELL. I UNDERSTAND THAT PHRASE IS
AVAILABLE T REFERS TO RESEARCHERS —
THE IDEA THAT RESEARCHERS DON'T HAVE AN OBLIGATION TO BE
CLINICIANS AND TO AFFIRMATIVELY SEARCH FOR INCIDENTAL FINDINGS
IN THEIR DATA. THIS WAS PUT OUT BY SUZANNE WOLF
AND HERE COLLEAGUE AND SOME OF THE IMPORTANT PAPERS THEY WROTE
ABOUT INCIDENTAL FINDINGS. THE REVISED ASSUMPTION IS THE
NATURE OF THIS TECHNOLOGY IS THE ACTIVE LOOKING BECOMES MUCH MORE
PRACTICAL. A MORE FUNDAMENTAL COMPONENT OF
THE ANALYTIC APPROACH T WILL BE HARDER TO TELL PEOPLE YOU CAN
AVOID AND NOT SEAT INCIDENTAL FINDINGS THERE IN THE COMPUTER
BEFORE YOU. SO THIS LEADS TO INTERESTING
QUESTIONS. THE FUNDAMENTAL QUESTION IS
WHETHER THIS NEW TECHNOLOGY CHANGES THE SCOPE OF THE
OBLIGATION THAT INVESTIGATORS HAVE HAVE TO DISCLOSE RESEARCH
FINDINGS.
THERE IS A CONSENSUS THAT THERE
IS AN OBLIGATION TO BE DELIBERATELY DISCLOSING
INCIDENTAL FINDINGS OF GENOMIC RESEARCH AT LEAST IN CERTAIN
CONSPECS THAT SEEMS TO BE A TREND I'M SEEING HERE ACROSS THE
NIH AND BIOETHICS COLLEAGUES ARE TALKING ABOUT. SO THIS REPRESENTS A PARADIGM
SHIFT IN HOW WE THINK ABOUT INCIDENTAL FINDINGS. SO GIVEN THESE NEW TECHNOLOGIES,
WHAT DOES THIS MEAN FOR IRBs AND HOW WE REVIEW INVESTIGATORS
AND THEIR APPROACH? WHAT I'D LIKE TO DO IS PRESENT
YOU WITH A CASE TO CHEW ON. THIS IS A COMPOSITE OF A FEW
INVESTIGATORS WHO HAVE COME BEFORE OUR IRB BUT IT'S VERY
REALISTIC AND GROUNDED IN THEIR EXPERIENCE. I'M GOING TO PRESENT YOU WITH
HOW THEY APPROACH THEIR PROTOCOL AND THEN I'M GOING TO PRESENT
YOU WITH THE SPECIFIC CONCERNS THE IRB RAISED IN RESPONSE TO
THE PROPOSAL AND HOPEFULLY THAT WILL ILLUSTRATE TO YOU HOW THIS
IS PLAYING OUT.
SO OUR INVESTIGATOR, AND I CALL
HER WELL INTENDED BUT I WANT TO EMPHASIZE THAT EVERYBODY THAT I
HAVE BEEN TALKING TO IS VERY WELL INTENDED AND WANTS TO DO
THE RIGHT THING EVEN WHY WHILE THEY ARE ENTHUSIASTIC ABOUT
INCORPORATING INTO THEIR RESEARCH. SO I DON'T NEED TO SINGLE THAT
OUT JUST TO HIGHLIGHT IT. SO BENCH SCIENTISTS, A Ph.D.
SCIENTIST WHO STUDIES THE COMMON COMPLEX DISORDER AND COULD BE
CARDIOVASCULAR DISEASE, DIABETES, THAT'S NOT QUITE SO
IMPORTANT BUT TO UNDERSTAND IT'S MORE COMMON MIGHT BE HELPFUL.
THIS INVESTIGATOR WANTS TO
COLLECT SAMPLES AND USE WHOLE EXOME SEQUENCING ANALYSIS TO
HELP TO PINPOINT THE VARIATIONS THEY ARE INTERESTED IN. THE PROTOCOL THAT SHE PUTS
TOGETHER INVOLVES A ONE TIME BLOOD DRAW HERE AT THE CLINICAL
CENTER AND THE INTENTION IS THERE IS NOT GOING TO BE ANING
ON GO CLINICAL RELATIONSHIP OR A RESEARCH RELATIONSHIP BETWEEN
THE SUBJECTS AND THE RESEARCHER TEAM. AND ALTHOUGH, THE RESEARCHER HAS
DONE A GOOD JOB WITH PARTNERING WITH CLINICAL INVESTIGATORS AND
CERTAINLY IS WORKING WITHIN THE CLINICAL CENTER, NOBODY IS ON
HER TEAM WHO IS A CLINICIAN AND VERY RELEVANTLY, NO GENETIC
COUNSELOR SHE HAS ACCESS TO OR COUNSELING RESOURCES IMMEDIATELY
AT HAND AS PART OF THIS PROTOCOL.
NOR ANY FUNDING TO BE ABLE TO
BRING ONE ONBOARD. SHE WANTS TO DO THE RIGHT THING
BUT IT IS CONFLICTED AND A LITTLE BIT AMBIVALENT ABOUT WHAT
THIS MEANS IN PRACTICE. SHE DOES HER BEST TO PUT
TOGETHER A PROTOCOL THAT TRIES TO STRADDLE THIS BALANCE BETWEEN
DISCLOSING RESULTS AND DOING IT IN A WAY THAT IS PRACTICALLY
FEASIBLE. SO THIS IS SUBMITTED TO THE IRB
AND IT RETURNS WITH A COUPLE OF COMMENTS. THE IRB FELT, PICKED UP ON THE
FACT THAT THE PROTOCOL DIDN'T CLEARLY AND CONSISTENTLY ADDRESS
THE STUDY PROCEDURES AND MOST IMPORTANTLY, THE PLAN FOR
PROVIDING GENETIC FUNDING TO SUBJECTS. WHAT THEY WERE PICKING UP ON
HERE IS THE CONSENT FORM AND PROTOCOL WEREN'T CONSISTENT WITH
EACH OTHER.
THEY WERE CONCERNED IT WASN'T A
COHERENT AND INTERNALLY CONSISTENT PLAN. IT'S THE DECISION OF THE
INVESTIGATOR TO DETERMINE WHICH FINDINGS WILL BE RETURNED. TO FIGURE OUT WHAT IT IS THEY
WILL FOCUS IN ON AND NEEDS TO COME BACK WITH A REASONABLE
PLAN. THERE IS NO SET LIST AND IT WAS
UP TO HER TO COME UP WITH A PLAN. INVESTIGATOR HAS A DUTY TO
INFORM SUBJECTS CLEARLY DURING THE CONSENT PROCESS ABOUT THE
POSSIBILITY THAT USING THESE TECHNIQUES, THE STUDY ITSELF,
MAY IDENTIFY GENETIC VARIANCE THAT COULD BE OF RELEVANCE TO
SUBJECTS BUT ONLY SOME OF WHICH WOULD BE OF KNOWN CLINICAL
SIGNIFICANTS.
SO YOU NEED TO PUT OUT THERE AND
INFORM PEOPLE THAT STUFF IS GOING TO BE LEARNED THROUGH
THESE TECHNIQUES AND THE CONSENT FORM WOULD ALSO HAVE TO ADDRESS
WHETHER OR NOT THE SUBJECTS WOULD BE PROVIDED WITH ANY OF
THESE RESULTS OR IF THEY WOULD BE GIVEN A CHOICE ABOUT WHETHER
OR NOT THEY WANTED TO BE RECONTACTED AND RECEIVE THESE
RESULTS. AND THEN SOME OTHER ISSUES AS
WELL. IF A DECISION IS MADE TO RETURN
RESULTS, THEY WOULD HAVE TO BE CONFIRMED IN A CERTIFIED LAB AND
HAVE TO BE DISCLOSED WITH APPROPRIATE COUNSELING AVAILABLE
TO THE SUBJECTS AND THE IRB SUGGESTED TO THE INVESTIGATORS
THEY LOOK INTO WHETHER THEIR INSTITUTE, HOME INSTITUTION, AND
OR THE CLINICAL CENTER MIGHT BE ABLE TO PROVIDE SOME SUPPORT IN
THE AREA OF GENETIC COUNSELING CONSULTATION. SO, THIS CAME TO THE
INVESTIGATOR IN THE FORM OF A SERIES OF RECOMMENDATIONS. THE ORIGINAL PROTOCOL WAS TABLED
AND THIS DOES HAPPEN AND THE IDEA IS THE INVESTIGATOR CAN GO
BACK AND INCORPORATE THOSE SUGGESTIONS AND COME BACK TO THE
IRB AND RECEIVE A FULL REVIEW.
SO THE INVESTIGATOR DID THAT,
CONSULTED WITH THE BIOETHICS DEPARTMENT FOR DISCLOSING
INCIDENTAL FINDINGS AND PROVIDED SOME CRITERIA ABOUT WHAT
CLINICALLY RELEVANT MIGHT LOOK LIKE. AND THE PROTOCOL MADE CLEAR IT
WAS EXPECTED THE NUMBER OF VARIANTS THAT WOULD BE
IDENTIFIED WERE QUITE SMALL. AND THIS WAS REFLECTED IN THE
CONSENT FORM IN A CONSISTENT WAY AS WELL. SO THIS TIME THE PROTOCOL WAS
APPROVED WAY SERIES OF STIPULATIONS THAT WERE ATTACHED
TO IT. THE IRB WANTED MORE SPECIFICITY
ABOUT THE PROCESS THAT WOULD BE USED TO REVIEW INCIDENTAL
FINDINGS TO DETERMINE WHICH ONES WERE CLINICALLY SIGNIFICANT. AND BASED ON THE IRB'S REVIEW OF
OTHER WHOLE EXOME SEQUENCING, IT MADE A RECOMMENDATION THAT THE
INVESTIGATOR MIGHT WANT TO CONSIDER PUTTING TOGETHER A
MULTIDISCIPLINARY COMMITTEE AND THIS COMMITTEE WOULD BE USED TO
REVIEW THE VARIANTS THAT EMERGED IN THE ANALYSIS AND HELP TO
DETERMINE WHICH ONES WERE ACTIONABLE AND WOULD RISE THE
LEVEL OF SOMETHING THAT OUGHT TO BE DISCLOSED TO A SUBJECT. THE COMMITTEE SHOULD INCLUDE A
BROAD RANGE OF EXPERTISE, INCLUDING MEDICAL GENETICS,
GENETIC COUNSELING, FX AND THE IRB PERSPECTIVE AND IT ALSO
POINTED OUT THIS THE SHOULD BE REOCCURRING BEFORE DECISIONS ARE
MADE WHICH VARIANTS SHOULD BE CONFIRMED PRIOR TO DISCLOSURE.
WE HAD A SENSE THE LIST WAS
GOING TO BE LONGER THAN THE INVESTIGATOR WAS ASSUMING. THE IRB FELT IT WOULD BE
BENEFICIAL FOR THE INVESTIGATOR TO TALK TO OTHERS WHO WERE
INVOLVED IN THIS RESEARCH. PEOPLE WHO ARE DEALING WITH THIS
CONDITION AND HOW TO INTERROGATE THE DATA THAT THEY ARE
GENERATING FOR A CLINICALLY SIGNIFICANT VARIANT. AND COMMENTED THEIR EXPERIENCE
OF THESE OTHER PROTOCOLS IS SUCH THAT PROBABLY A LARGER NUMBER OF
INCIDENTAL VARIANTS WILL BE IDENTIFIED. IT'S INTERESTING. MAYBE AS AN IRB, OUR OWN HAS
SHIFTED SOMEWHAT IN A — AND IS THINKING ABOUT THIS ISSUE
OVER TIME.
IT'S CLEAR TO US NOW THE NUMBER
OF INCIDENTAL OR SECONDARY VARIANTS GENERATED DEPENDS ON
HOW HARD YOU'RE LOOKING AND I THINK JENNIFER'S PRESENTATION
BEFORE GAVE US A SENSE OF HOW POSSIBLE IT IS TO FIND
INCIDENTAL VARIANCE AND ALSO HOW COMPLICATE TODAY IS AT THE SAME
TIME. AND I THINK THE IRB DEVELOPED A
NEW MORE NUANCED PERSPECTIVE ON THIS QUESTION SINCE THESE
COMMENTS WERE MADE SUGGESTS THAT WE ARE NOT SURE IN DIFFERENT
STUDIES, WE THINK DIFFERENT AMOUNTS OF LOOKING MIGHT BE
HAPPENING, MIGHT BE INDICATED AND SO WE HAVE SEEN MORE
VARIATION IN HOW INVESTIGATORS ARE NOW PROPOSING TO HANDLE THE
HOW HARD SHOULD WE LOOK QUESTION.
SO I HOPE THAT GIVES YOU A
LITTLE BIT OF A SENSE OF WHAT ARE COMING UP AT THE IRB. WHAT ARE THE QUESTIONS WE ARE
ASKING? I HIGHLIGHTED THE EXAMPLE OF A
Ph.D. SCIENTIST TO SHOW THAT NOT EVERYBODY DOING THIS IS
TRAINED IN THE FIELD OF MEDICAL GENETICS. AND MAYBE CELL TO TO DRAW ON THE
EXPERTISE OF OTHERS. SOME OF THE QUESTIONS I RAISED
WILL APPLY TO OTHER STUDIES AS WELL. WHAT I'D LIKE TO DO IS LOOK MORE
DEEPLY INTO WHAT IS BEHIND SOME OF THESE IRB CONCERNS WHAT
ETHICAL PRINCIPALS ARE AT STEAKS AND WHY IS THE IIB CONCERNED? WHY IS THIS COMPLICATED? THERE IS GOOD SOUND ETHICAL
ARGUMENTS IN FAVOR OF INCIDENTAL FINDINGS AND ARGUING AGAINST
SUCH DISCLOSURE AND THAT'S THE NATURE OF BIOETHICS. THE TRUE DILEM A MY COLLEAGUE,
FRANK MILLER, A FACULTY MEMBER IN THE DEPARTMENT OF BIOETHICS
AND OUR PAST FELLOWS, ARGUED THAT A PRINCIPAL OR OBLIGATION
TO RETURN FINDINGS IS GROUNDED IN THE PRINCIPLE OF RESPECT FOR
PERSONS. THEY SAID IT WOULD BE DISRESPECT
TO TREAT RESEARCH VOLUNTEERS AS CONNED WITS FOR GENERATING
SCIENTIFIC DATA WITHOUT GIVING DUE CONSIDERATION IN THEIR
INTERESTS RECEIVING INFORMATION ABOUT THEMSELVES DERIVED FROM
THEIR PARTICIPATION AND RESEARCH.
SOME OF WHAT IS BEHIND THIS IS
THE IDEA THAT THERE IS SOME QUESTION GENETIC INFORMATION
THAT IS QUITE IMPORTANT AND RELEVANT AND IF SOMEBODY HAD IT
IN THEIR POSSESSION, IT MIGHT ENDANCE THEIR DECISION-MAKING. IT WOULD ENHANCE THEIR ABILITY
TO MAKE DECISIONS ABOUT THEIR HEALTH, AND OTHER LIFE
CONSIDERATIONS. AND ALSO WHAT IS EMBEDDED IN
THIS ARGUMENT IS AN IDEA THAT RETURNING RESULTS ALSO
RECOGNIZES AND REPAYS THE PARPARTICIPANT'S CONTRIBUTION TO
RESEARCH. THERE ARE A NUMBER OF OTHER
ARGUMENTS MADE IN SUPPORT OF AN OBLIGATION TO RETURN GENETIC
RESEARCH RESULTS. IS THE GENERAL IDEA OF DOING
GOOD, DOING SOMETHING BENEFICIAL OR RAISING THE PROSPECTIVE
BENEFIT TO PARTICIPATE IN A STUDY. THE NOTION OF RECIPROCITY, THE
IDEA THAT IS RELATED TO THE POINT ON THE LEFT BY ABOUT
GIVING PARTICIPANTS SOMETHING THAT IS RECOGNIZING THEIR
CONTRIBUTION AND REALIZING IT IS FAIR TO GIVE SOMETHING BACK IF
YOU CAN. THE PRINCIPLE OF JUSTICE, IT'S
MORE THAN OF A NUANCE POINT BUT IT HAS TO DO WITH THE IDEA THAT
SOME OF OUR PARTICIPANTS WILL BE IN CATEGORIES THAT ARE
CONSIDERED MORE VULNERABLE. THEY MAY HAVE LESS ACCESS TO
HEALTH CARE RESOURCES AND IF THEY ARE IN A STUDY WHERE IT MAY
BE THEIR ONLY ACCESS TO CERTAIN KINDS OF SERVICES AND CERTAIN
KINDS OF INFORMATION, THAT MIGHT HIGHTEN THE OBLIGATION FOR US TO
DISCLOSE WHAT WE KNOW BECAUSE WE CAN'T REASONABLY EXPECT THEM TO
BE ABLE TO FIND OUT THIS INFORMATION SOMEWHERE ELSE.
SO, A PRINCIPLE OF FAIRNESS
WOULD SAY WE MIGHT TREAT CERTAIN POPULATIONS IN A PARTICULAR WAY
AND GIVE THEM CERTAIN KINDS OF INFORMATION AS A RESULT. THE PRINCIPLE OR ISSUES AROUND
INVESTIGATOR INTEGRITY AND PROFESSIONAL RESPONSIBILITY, I
THINK OF THESE AS HAVING TO DO WITH WHAT SOME MEDICAL
GENETICS — GENETICISTS DESCRIBED TO ME AS
THE FEELING OF WANTING TO BE ABLE TO SLEEP AT NIGHT. THE IDEA THAT IF THEY ARE
ENGAGED IN THIS RESEARCH AND THEY KNOW ENOUGH TO KNOW THAT
WHAT IS SITTING ON THEIR COMPUTER IS ACTUALLY RELEVANT TO
SOMEBODY'S HEALTH CARE, THEY THINK IT'S A MATTER OF
PROFESSIONAL RESPONSIBILITY TO MAKE THIS INFORMATION AVAILABLE.
PROFESSION AND A RESEARCH ASPECT
BUT THE CLINICAL AFFECT KEEPS THEM UP AT NIGHT AND THIS DRIVES
THEIR SENSE OF OBLIGATION TO RETURN FINDINGS. SO SOME ARGUMENTS AGAINST AN
OBLIGATION TO RETURN INCIDENTAL FINDINGS. THERE ARE SOMETHING WHO DISPUTE
THESE PRINCIPLES WHO DESCRIBED, RECIPROCITY AND JUSTICE ARE
VIOLATED BY A FAILURE TO DISCLOSE OR A LACK OF
DISCLOSURE. THEY WILL EMPHASIZE THE CORE
PURPOSE OF RESEARCH IS TO GENERATE GENERALIZABLE
KNOWLEDGE. RESEARCH IS DIFFERENT THAN
CLINICAL CARE AND WE SHOULDN'T BE IN THE BUSINESS OF
RE-CREATING A CLINICAL SETTING AND IS THERE IS RISKS OF DOING
SO THAT RESEARCH IN CLINICAL CARE COULD DO THINGS LIKE LEAD
TO THERAPEUTIC MISCONCESSIONS WHERE PEOPLE START TO EXPECT
MORE FROM THE RESEARCH ENVIRONMENT THAN PERHAPS THEY
SHOULD. WE PERHAPSALCY DON'T WANT TO
OVER ESTIMATE THE VALUE OF THESE RESULTS TO INDIVIDUALS OR WE
WANT TO BE REALLY SURE THAT THEY ARE OF THE SORT THAT ARE
CLINICALLY RELEVANT, ACTIONABLE AND MEET CERTAIN CRITERIA AND
MANY RESULTS WILL NOT. DIFFERENT ARGUMENTS ARE MADE
AROUND RESOURCE LIMITATIONS. IT IS VERY RESOURCE INTENSIVE TO
BE THE SOURCE OF ANALYSISES AND DISCLOSURE THAT YOU HEARD
DESCRIBED HERE.
IT REQUIRES LOTS OF TECHNICAL
EXPERTISE AND BIOINFORMATICS TOOLS, CHAISES TO COUNSELING
RESOURCES. THE ABILITY TO PAY FOR
VALIDATION AND WE ALL KNOW THAT WE ARE OPERATING IN ENVIRONMENT
WITHOUT OVERFLOWINGLY ABUNDANT RESOURCES. WE ARE LIVING UNDER RESOURCE
CONSTRAINTS. SO THERE MIGHT BE SOME PRACTICAL
CONSIDERATIONS THAT WAY AGAINST OUR OBLIGATIONS TO DISCLOSE
INCIDENTAL FINDINGS THAT WE HAVE TO TAKE INTO ACCOUNT, AT THE
VERY LEAST ACKNOWLEDGE MORE RESOURCES ARE NEEDED TO BE ABLE
TO DO THIS WELL ACROSS-THE-BOARD TO BE ABLE TO BELIEVE ETRAP LATE
FROM THE IDEAL MODELS THAT WE ARE HEARING DESCRIBED. SO, MANY HAVE ATTEMPTED TO
DEVELOP GUIDANCE AND TO ASSIMILATE THESE COMPETING
VALUES INTO A SET OF PRINCIPLES THAT WILL HELP US FIGURE OUT
WHAT DO WE DO WITH ALL OF THESE DIFFERENT COMMITMENTS AND
OBLIGATIONS AND AS YOU CAN SEE, THERE IS QUITE A FEW GUIDELINES
OUT THERE.
THERE IS THE NHLBI GUIDELINES
THAT ARE COMMONLY SITED AND REFERRED TO EARLIER. BUT A LOT OF OTHER APPROACHES
OUT THERE AS WELL. AND WHEN YOU LOOK ACROSS ALL OF
THESE APPROACHES, THEY DO HAVE SOME COMMON FEATURES. SO THEY DO COME UP WITH A
GENERALLY CONSISTENT SET OF FACTORS THAT SHOULD BE APPLIED
TO FIGURE OUT WHICH KIND OF RESULT OF THIS SORT THAT
GENERATE AN OBLIGATION FOR DISCLOSURE.
SO VALIDITY. WE WANT TO MAKE SURE IT'S
ACCURATE. IT SHOULD BE RELATED TO
SOMETHING IMPORTANT AND RELEVANT TO HEALTH AND HEALTH CARE. ACTION ABILITY, THE IDEA THAT
THERE IS SOMETHING THAT CAN BE DONE TO ALTER THE COURSE OF A
NEGATIVE OUTCOME, THERAPEUTIC INTERVENTION, SCREENING
PROCEDURES, PERHAPS A DIFFERENT REPRODUCTIVE DECISION DEPENDING
ON WHAT KIND OF A RESULT YOU'RE TALKING ABOUT. AND A FOURTH FEATURE OF THE
GUIDELINES IS THAT A RESULT SHOULD BE DESIRED THAT
INDIVIDUALS SHOULD BE ASKED ABOUT THE DECISIONS AND THEIR
DECISIONS SHOULD BE RESPECTED.
THERE ARE DISAGREEMENTS ACROSS
THE DIFFERENT GUIDELINES AS WELL. ONE AREA OF DISAGREEMENT IS THE
LEVEL OF CLINICAL RELEVANCE THAT —
WHAT IS THE THRESHOLD WHERE IS THE CUT OFF BETWEEN CLINICALLY
RELEVANT AND NOT? AND DIFFERENT WAYS THAT THIS
GETS DEFINED AND DEBATED IN ALL OF THESE GUIDELINES. IF THERE IS A QUESTION OF DESIRE
ABILITY, WHETHER WE WANT INDIVIDUAL SUBJECTS TO ACTIVELY
CONSENT TO RECEIVE ALL KINDS OF RESULTS, THERE MAY BE SOME
PEOPLE ARGUE, CERTAIN TYPES OF RESULTS THAT ARE SO IMPORTANT
THAT YOU — IT WOULDN'T BE REASONABLE FOR
SOMEBODY TO SAY THEY WOULDN'T WOULDN'T WANT THEM IF IT'S A
LIFE ALTERING KIND OF RESULT.
AND EASY INTERVENTION THAT WOULD
CHANGE THE COURSE OF THEIR HEALTH OUTCOMES AND WE MIGHT
OVER RIGHT THEIR RIGHT NOT TO KNOW OR OVERRIDE THEIR INTEREST
IN MAKING A DECISION AND SAY NO, YOU HAVE A DUTY TO DISCLOSE
THAT. THERETO IS A LOT OF DEBATE ABOUT
THAT QUESTION AT THE MOMENT IN THE BIOETHICS FIELD. ALSO ABOUT ANALYTIC VALIDITY. SOME PEOPLE QUESTION WHETHER THE
CERTIFICATION OR CLINICAL VALIDATION IS A CERTIFIED SLAB
REQUIRED. IT WOULD BE IRRESPONSIBLE OF ME
TO SUGGEST THAT IS A VALID QUESTION TO ASK HERE AT THE NIH. IT IS OUR POLICY, IT IS SAY
POLICY OUT THERE THAT WE FOLLOW HERE THAT YES, IF YOU'RE
PLANNING TO DISCLOSE ANY KIND OF GENETIC RESULT TO A RESEARCH,
ANY KIND OF CLINICAL RESULT, IT DOES HAVE TO BE CONFIRMED IN A
VALIDATED LAB FIRST.
BUT THIS IS AN AREA OF DEBATE
THAT IS OUT THERE AND WHETHER THIS IS AN APPROPRIATELY GOOD
ENOUGH STANDARD IN SOME CIRCLES. UP UNTIL NOW I HAVE BEEN TALKING
ABOUT THE ETHICAL ARGUMENTS AND GUIDELINES ABOUT THE KINDS OF
INFORMATION, THE KINDS OF GENOMIC INFORMATION THAT MIGHT
GENERATE AN OBLIGATION FOR DISCLOSURE. THERE IS SOME ADDITIONAL LAYERS
I WANT TO THROW OUT THERE AND ENCOURAGE YOU TO THINK ABOUT
THAT HAVE TO DO WITH CONTESTUAL FAGGORS ABOUT THE STUDY
CHARACTERISTICS OR POPULATION CHARACTERISTICS THAT MIGHT ALTER
OUR OBLIGATIONS TO DISCLOSE INCIDENTAL FINDINGS.
HOPE AND EXPECTATION FOR
BENEFITS. IS IT A NATURAL HISTORY STUDY? IS IT A BASIC SCIENCE PROTOCOL? AND DO THESE PURPOSES HAVE SOME
INFLUENCE ON EXPECTATIONS? STUDY RESOURCES. WARESOURCES ARE AVAILABLE? ARE THERE ADEQUATE RESOURCES FOR
COUNSELING AND CONFIRMATION? WHAT INVESTIGATOR EXPERTISE TO
BE ABLE TO DO THE RIGHT KINDS OF ANALYSIS? WHAT ARE THE AIMS OF A PROTOCOL
AND WHAT COUNTS OF — COUNTS AS INCIDENTAL? HOW LONG HAS IT BEEN SINCE WE
HAVE BEEN IN TOUCH WITH THESE SUBJECTS? DO WE HAVE CURRENT INFORMATION
IF WE WANT TO FOLLOW-UP WITH THEM? [READING]
ANOTHER INTERESTING QUESTION, WHAT IS THE DEPTH OF THE
RELATIONSHIP BETWEEN THE SUBJECT AND INVESTIGATOR? IS THIS A LONG TERM STUDY WHERE
THERE ARE ROUTINE FOLLOW UPS AND MULTIPLE OPPORTUNITIES TO TALK
ABOUT SOME OF THESE ISSUES OR IS IT A ONE TIME INTERACTION? IS IT SOMEBODY KNOWN TO THEM OR
SOMEBODY WHO IS A STRANGER TO THEM? IS IT A DOWNSTREAM SECONDARY AND
TERTIARY USER OF THE DATA AS IT HAS BEEN OR SAMPLED AS THEY HAVE
BEEN DRAWN OUT OF REPOSITORY.
AND HOW DOES THAT BEAR ON THE
ABILITY AND OBLIGATIONS TO DISCLOSE? SO I WANT TO GO BACK TO A
QUESTION THAT I RAISED EARLIER. THE QUESTION OF WHAT, IF I'M
USING CODED SPECIMENS GIVEN TO ME BY AN EXTRAMURAL
COLLABORATOR. AND I HAVE A DIFFERENT CASE
STUDY I DEVELOPED AROUND THIS. YOU'RE THE INVESTIGATOR AND
IDENTIFIED A SOURCE OF CLINICAL SAMPLES FROM PATIENTS WITH A
RARE:ARE BEING SEEN AT UNIVERSITY X. SAMPLES WERE COLLECTED UNDER
UNIVERSITY IRB AND THEY WERE COLLECTED WITH INFORMED CONCEPT
THAT IRB APPROVED. THEY ARE PLANNING TO CODE
THIS — CODE THE SAMPLES AND BE
IDENTIFIED TO YOU. YOU WON'T HAVE ACCESS TO PATIENT
INFORMATION OR ANY OTHER PATIENT NAMES OR OTHER IDENTIFIERS. AND YOU WANT TO PROCEED AND SAY
YOU SET UP YOUR PLANNING MEETING WITH MISC AND THEY ASK YOU DO
HAVE A APPROPRIATE INSTITUTIONAL APPROVAL FROM AN NIHIRB OR
OHSRP? GOOD QUESTION.
SO, IF YOU ARE USING CODED
DEIDENTIFIED SAMPLES, IT'S TRUE THAT YOU MIGHT NOT SNEED IRB
APPROVAL FROM YOUR OWN INSTITUTION. AND THIS IS BECAUSE UNDER
CURRENT REGULATORY GUIDANCE, CURRENT INTERPRETATIONS OF THE
COMMON RULE, WHICH IS A SET OF RULES THAT GOVERNS THE CONDUCT
OF HUMAN SUBJECTS IN THIS COUNTRY, THE USE OF DATA
CONSIDERED TO BE DEIDENTIFIED AND IS NOT CONSIDERED TO BE
HUMAN SUBJECTS RESEARCH UNDER CERTAIN CIRCUMSTANCES. AND BECAUSE OF THAT, IT'S NOT
SUBJECT TO IRB REVIEW AND OTHER OVERSIGHT REQUIREMENTS. HOWEVER, YOU DON'T GET TO THE
MAKE THIS DETERMINATION AS AN INVESTIGATOR. THIS DETERMINATION HAS TO BE
MADE BY THE NIH FROM OFFICE OF HUMAN SUBJECTS RESEARCH
PROTECTION. SOME OF YOU MIGHT BE FAMILIAR
WITH AN ACRONYM, OHSR. IT'S THE SAME OFFICE THEY
RECENTLY ADDED THE P FOR PROTECTION TO THEIR NAME SO WHEN
YOU SEE THESE ACRONYMS, THEY ARE INTERCHANGEABLE AND MEAN THE
SAME THING.
AND YOU SUBMIT A REQUEST FOR
REVIEW TO THEM THROUGH A FORM THEY HAVE AVAILABLE ON THEIR
WEBSITE WHICH I MADE AVAILABLE HERE. AND THIS CONNECTS TO A SECOND
PART OF THE NIH INTRAMURAL POLICY THEY MENTIONED EARLIER. THIS POLICY STATES THAT
INVESTIGATORS REQUESTING OHSRP REVIEW OF WHOLE EXOME SEQUENCING
RESEARCH ACTIVITIES WILL BE ASKED TO ANSWER A SET OF
SUPPLEMENTAL QUESTIONS TO ALLOW FOR ENHANCED OHRP REVIEW. THEY WERE CONCERNED THAT IT
WOULD BE INAPPROPRIATE TO QUICKLY APPROVE UNDER CURRENT
REGULATORY GUIDANCE THE USE OF WHOLE EXOME SEQUENCING
TECHNOLOGY IN PROTOCOLS HERE WITHOUT LOOKING CLOSELY AT SOME
OF THE ETHICAL CONSIDERATIONS THAT I HAVE BEEN TALKING ABOUT.
BECAUSE THERE IS STILL A LOT OF
INFORMATION THAT THEORETICALLY COULD BE CONNECTED BACK TO
ORIGINAL RESEARCH SUBJECTS. THEY WANTED TO LOOK AT THIS MORE
CLOSELY. SO HERE IS A SAMPLING OF SOME OF
THE QUESTIONS THAT OHRS INTERESTED IN. THEY WANT TO KNOW WHETHER AN IRB
OR AN ETHICS COMMITTEE SOMEWHERE HAS LOOKED AT THIS PROPOSAL AND
HAS APPROVED THE CONDUCT OF WHOLE EXOME SEQUENCING RESEARCH
FOR EXAMPLE WITH A SET OF SAMPLES SO IF ANOTHER
INSTITUTION HAD DONE THIS AND SIGNED OFF, THEY WILL BE
REASSURED THAT SOMEBODY IS PAYING ATTENTION. THEY WANT TO KNOW WHETHER IT IS
POSSIBLE THAT RESULTS FROM THE PROPOSED ANALYSIS WILL BE
RETURNED BACK TO SUBJECTS AT THAT INSTITUTION. AND THIS BOILS DOWN TO, THEY
WANT TO MAKE SURE YOU AND YOUR COLLABORATORS HAVE A CLEAR PLACE
FOR INCIDENTAL FINDINGS. THEY WANT TO HEAR ABOUT PLANS TO
DEPOSIT SEQUENCING DATA INTO BROAD DATABASE —
DATA SHARING PERHAPSES SUCH AS IN DB GAP. AND INTERESTED IN KNOWING WHAT
KIND OF CONSENSUS GIVES IN. BASED ON YOUR ANSWERS TO THE
QUESTIONS ON THEIR CHECK LIST, THEY MIGHT ASK YOU TO GO BACK TO
AN INSTITUTION AND GET MORE INFORMATION.
THEY MIGHT APPROVE IT BASED ON
WHAT YOU HAVE SUBMITTED AND SAY YOU DON'T NEED ANY FURTHER
REVIEW HERE. OR THEY MIGHT DECIDE TO SEND YOU
ON TO AN NIHIRB TO HAVE THIS LOOKED AT MORE CLOSELY AND
REVIEWED THAN THEY ARE ABLE TO DO. THAT PROVIDES A NICE SEGUE OUT
OF QUESTIONS AROUND I THINK SO DENTAL FINDINGS AND INTO ANOTHER
TOPIC THAT I'D LIKE TO COVER, WHICH IS WHETHER NIH DATA
SHARING POLICIES APPLY TO EXOME SEQUENCE DATA. THE ANSWER IS, POSSIBLY. IF I HAD MORE TIME TO WORK ON MY
SLIDES, I WOULD HAVE REVISED THIS AND SAID PROBABLY. SOME OF YOU MIGHT BE FAMILIAR
WITH THE NIHGWAS. GENOME-WIDE ASSOCIATION STUDY
DATA SHARING POLICY.
THIS IS A DATA SHARING
REQUIREMENT FOR ALL NIH-FUNDED GWAS DATA THAT SAYS THERE IS AN
EXPECTATION THESE DATA WILL BE DEPOSITED IN A REPOSITORY LIKE
DB GAP OR THAT INVESTIGATORS HAVE TO COME UP WITH AN
ALTERNATIVE DATA SHARING PLAN. THESE ARE A DIFFERENT KIND OF
DATABASE OR OTHER PROCEDURE FOR BEING ABLE TO COLLABORATE WITH
OTHER INVESTIGATORS AND SHARE PUBLICLY FUNDED RESOURCES TO
HELP PROMOTE RESEARCH. WE HEARD IN A LOT OF TALKS
EARLIER IN THE DAY, THE VALUE OF THIS AND THE COMPARISON THAT
COMES OUT OF THINGS THAT ARE AVAILABLE IN DATABASES LIKE
THIS. THIS IS A VERY IMPORTANT
PRINCIPLE. IT PROMOTES GOOD ETHICAL
STEWARDSHIP OF RESOURCES AND EFFORTS TO EXPAND THIS POLICY TO
APPLY TO BROADER GENOMIC DATA TYPES THAT ARE UNDERWAY. A COMMITTEE LOOKING AT HOW THIS
OUGHT TO BE APPLIED TO DATA SHARING. THERE IS NOT YET AN
ACROSS-THE-BOARD REQUIREMENT THAT NIH-FUNDED SEQUENCING DATA
HAS TO BE DEPOSITED INTO SOMETHING LIKE DB GAP.
IT IS ALREADY HAPPENING AND THEN
YOU PROGRAM AS A REQUIREMENT OF INDIVIDUAL STUDIES. MANY INVESTIGATORS ARE STARTING
TO THINK THROUGH WHAT A REQUIREMENT WOULD LOOK LIKE AND
HOW IT WOULD PLAY OUT IN PROTOCOLS. I THINK THIS IS A VERY GOOD
THING. WE SHOULD BE ANTICIPATING THE
PROBABILITY THAT THERE WILL BE SOME EXPANDED DATA SHARING
REQUIREMENTS APPLYING TO GWAS DATA. WHEN AN INVESTIGATOR REALIZES
THAT HE OR SHE IS INTERESTED OR REQUIRED TO DEPOSIT THEIR GWAS
DATA INTO DB GAP, THE IRB IS ASKED TO CERTIFY THAT THE
PROTOCOL AND THE CONSENT FORM HAVE TAKEN SEVERAL ISSUES INTO
ACCOUNT. THEY WANT THE IRB TO CERTIFY THE
CONSENT PROCESS COVERS THE IDEA OF BROAD DATA SHARING AND THAT
RESEARCH SUBJECTS ARE AWARE THAT THIS IS HAPPENING AND HAVE GIVEN
THEIR APPROVAL.
THEY ALSO WANT THE IRB AND THE
INSTITUTION TO CERTIFY THAT APPROPRIATE CONFIDENTIALITY
MEASURES ARE BEING TAKEN TO DEIDENTIFY THE DATA THAT ARE
BEING DEPOSITED. AS WELL AS THE CONSIDERATION HAS
BEEN GIVEN TO MINIMIZE RISKS IN GENERAL TO INDIVIDUALS, FAMILIES
AND TO COMMUNITIES. AND COMMUNITIES AS A WHOLE. THERE ANOTHER INTERESTED AND
COMPLICATED QUESTION ABOUT HOW WE THINK ABOUT THE MANAGEMENT OF
INCIDENTAL FINDINGS THAT MIGHT BE GENERATED THROUGH SECONDARY
USERS OF THE DATA AND WHETHER THERE IS AN OBLIGATION TO
COMMUNICATE BACK TO THE PRIMARY RESEARCHER SO THEY CAN SOMETIMES
MAYBE ON VERY IMPORTANT CASES BE SUBJECTS. MY ADVICE OR ENCOURAGEMENT IS
WHAT I WOULD SAY IS THAT THIS PROCESS OF CERTIFYING DATA FOR
DEPOSITIONS TO DB GAP WORKS BEST WHEN INVESTIGATORS AND IRBs
HAVE ALREADY ANTICIPATED THIS IS A POSSIBILITY.
—
SO THEY DON'T HAVE TO RECOM TACT SUBJECTS AND GET THEIR RECONSENT
AROUND THAT CRASH. AND THAT THE PROTOCOL
ANTICIPATED IT. THAT AN APPROPRIATE LEVEL OF
ENGAGEMENT HAS TAKEN PLACE MANY STEPS BEFOREHAND TO CERTAIN
POPULATIONS AND CERTAIN COMMUNITIES WILL HAVE THE STRONG
OPINIONS ONE WAY OR ANOTHER IN FAVOR OF OR AGAINST THE IDEA OF
BROAD DATA SHARING AND FIGURING THIS OUT AHEAD OF TIME IS VERY
USEFUL AND SO, I WANT TO ENCOURAGE INVESTIGATORS TO START
THINKING ABOUT THESE QUESTIONS IN RELATION TO WHOLE EXOME
SEQUENCING TO MOVE ON FROM THE CONTEXT OF THE GENOME-WIDE
ASSOCIATION STUDIES. AND IT MAY BE THE CASE THERE ARE
NOVEL ISSUES THAT COME UP. IT MIGHT BE HARDER FOR EXAMPLE,
TO SAY, I GOT MY FILE. IT —
[OFF MIC] JUST A FEW COMMENTS ABOUT
APPROACHES TO AND FROM CONSENT. WE ARE ABOUT TO HAVE A TALK —
[OFF MIC] I WANT TO GIVE A COUPLE OF
COMMENTS ABOUT HOW IRB WITH AN EARLIER POINT IN TIME —
[LOW AUDIO] A FEW ELEMENTS OF INFORMED
CONSENT CAN BE HIGHLIGHTED TO WHOLE EXESOME SEQUENCING.
IN GENERAL THE BROAD SCOPE OF
THE ANALYSIS AND RESULTS THAT — [OFF MIC]
THIS IS SOMETHING THAT HASN'T BEEN TRADITIONALLY COVERED IF
CONSENT FORMS THAT MAY BE RELATIVE TO INDIVIDUALS AND
MAYBE SOMETHING THEY WANT TO KNOW AS PART OF THE CONSENT
PROCESS. MORE SPECIFICALLY, THEY ALMOST
CERTAINLY INTERESTED IN KNOWING WHETHER RESULTS WILL BE
DISCLOSED TO THEM WHETHER THEY ARE RELATED TO THE RESEARCH
QUESTION BEING STUDIED OR INCIDENTAL TO THAT QUESTION TOOT
EXTENT THAT CAN BE DISTINGUISHED. AND WHETHER OR NOT THEY ARE
GOING TO BE PRESENTED WITH CHOICES AND HOW TO NAVIGATE
THOSE CHOICES — [LOW AUDIO]
AND THEN THE ISSUE I WAS TALKING ABOUT, PLANS FOR DATA SHARING OF
THIS SYSTEMS DATA AND WHAT THE IMPLICATIONS OF THAT ARE TO THE
SUBJECTS. AND THERE ARE INTERESTING
QUESTIONS ABOUT PREVIOUSLY COLLECTED SAMPLES.
SO IF SOMEBODY IS ENROLLED ON A
GENETIC PROTOCOL, THEY HAVE BEEN GIVEN SOME AMOUNT OF INFORMATION
ABOUT GENETIC RESEARCH AND DISCLOSURE AND SO ON. IS THERE A TIME AND WHEN IS THAT
TIME THAT THEY ARE GOING TO NEED MORE INFORMATION AND GIVE
UPDATED INFORMATION TO PARTICIPATE IN THE STANDARD
AMOUNTS. A COUPLE EVER THINGS I'LL SAY
ABOUT THAT, I HAVE BEEN SEEING A LOT OF RECONSENT GOING ON. IRBs ARE ASKING INVESTIGATORS
TO GET CONCEPT AND MANY INVESTIGATORS WANT TO DO IT. THEY WANT AN OPPORTUNITY TO TALK
TO SUBJECTS AGAIN AND ANTICIPATE THESE KIND OF ISSUES. I THINK THIS IS ESPECIALLY TRUE
WHEN THERE ARE MORE PLANS FOR INCIDENTAL FINDINGS AND ALSO SAY
THIS COMES UP EVEN IN PROTOCOLS WHERE THERE IS A PLAN NOT TO
DISCLOSE FINDINGS.
THEY WANT —
[LOW AUDIO] AGAIN CHOICES ABOUT BROAD DATA
SHARING IS ANOTHER RELATIVELY NEW ASPECT IS THAT MANY PEOPLE
ARE NOW ANTICIPATING AND GETTING CONSENT FOR IT. WHAT I HAVE BEEN SEEING, I THINK
THERE IS REALLY 3 EMERGING MODELS, THREE DIFFERENT KINDS OF
PROTOCOLS THAT ARE BEING APPROVED HERE. I CAN'T SPEAK TO THOSE SET
OUTSIDE THE INTRAMURAL CONTEXT. SOME STUDIES HAVE BEEN APPROVED
WHERE A CLEAR PLAN IS ARTICULATED NOT TO DISCLOSE
INCIDENTAL GENOMIC FINDINGS IN INDIVIDUAL SUBJECTS.
AND THE CONSENT PROCESS CAPTURED
THIS. WHERE I'M TENDING TO SEE A
CLUSTER, THE MOST STUDIES THAT ARE BEING APPROVED RIGHT NOW IS
SOMETHING A LITTLE BIT IN THE MIDDLE, A MIDDLE GROUND APPROACH
WHERE THERE IS SOME LIMITED COMMITMENT TO PROVIDING —
UNDER CAREFULLY SPECIFIED AND RELATIVELY RARE CIRCUMSTANCES. AND THEN WE ARE ALSO FAMILIAR
WITH APPROVING VERY ROBUST PLANS FOR THE DISCLOSURE OF FINDINGS. I APOLOGIZE IF SOME OF THAT
WASN'T AUDIBLE. THE THIRD KIND OF PROTOCOL THAT
WE ARE SEEING THAT WE ARE COMFORTABLE WITH AND THAT WE
HAVE SEEN APPROVED FEATURES A VERY ROBUST PLAN FOR THE
DISCLOSURE OF FINDINGS AND VERY DETAILED AND OFTEN MULTIPLE TIME
POINTS ASSOCIATED WITH THE INFORMED CONSENT PROCESS AND A
DESCRIPTION OF HOW SUBJECT PREFERENCES WILL BE SOLICITED
OVER TIME. SO, AS I WAS SAYING, WHAT I'M
SEEING MORE OF IS THE MIGRATION TOWARDS SOMETHING IN THE MIDDLE,
EMERGING AND LIMITED OBLIGATION OR SENSE OF OBLIGATION AND PLANS
SURROUNDING THIS FOR THE DISCLOSURE OF INCIDENTAL
FINDINGS.
AND SO, I'M GOING TO LEAVE YOU
WITH TWO MAIN TAKEHOME MESSAGE IS. IF YOU JUST TUNED IN NOW, THE
TWO MOST IMPORTANT THINGS FOR YOU TO KNOW IN ANSWER TO THE
QUESTION, CAN I GO AHEAD WITH WHOLE EXOME SEQUENCING BASED ON
PROTOCOLS AND CONSENT FORMS I ALREADY HAVE IN PLACE? AND SWEETHEART IS NO. NOT UNTIL YOU RECEIVE SOME LEVEL
OF INSTITUTIONAL APPROVAL FROM EITHER AN IRB OR OHSRP, BUT IN
ADDITION TO INSTITUTIONAL APPROVALS, YOU SHOULD ALSO BE
FAMILIAR WITH THE MANY RESOURCES FOR CONSULTATION YOU'RE ABLE TO
DRAW ON BEYOND THIS COURSE ETHICS CONSULTATION, YOUR
COLLEAGUES WHO YOU HEARD FROM WHO ARE EXTREMELY GENEROUS ABOUT
SHARING WHAT THEY KNOW. IT'S USEFUL TO DRAW ON THE
RESOURCES WE HAVE AROUND US AS YOU PUT PLANS TOGETHER AND
SUBMIT THEM FOR APPROVAL.
SECOND TAKE HOME MESSAGE. WHAT ARE THE KEY THINGS AN IRB
OR ENTITY LIKE OHSRP IS GOING TO BE LOOKING FOR? AND THE ANSWERS ARE THREE FOLD,
I THINK. YOU AND YOUR COLLABORATORS HAVE
GIVEN THOUGHT TO A PLAN FOR MANAGING INCIDENTAL FINDINGS
THAT COHERENCE INTERNALLY CONSISTENT TAKES INTO ACCOUNT
YOUR EXPERTISE YOU HAVE AVAILABLE TO YOU, RESOURCES AND
SUBJECT EXPECTATIONS KEEP IN MIND THE IRB IS OPEN TO HEARING
WHAT WORKS IN YOUR CIRCUMSTANCES AND IN WORKING WITH YOU TO
FIGURE OUT WHAT THE MOST ETHICALLY SOUND APPROACH TO YOUR
STUDY IS. A SECOND THING THAT THEY ARE
LOOKING FOR IS THAT YOU'RE STARTING TO THINK ABOUT DATA
SHARING PLANS AND WHAT IMPLICATION THAT IS HAS FOR YOUR
STUDY AND THIRD, WE WANT TO MAKE SURE THAT THE INFORMED CONSENT
PROCESS, EITHER WAS IN PLACE OR THAT NEEDS TO BE IN PLACE
REFLECTS THESE VARIOUS PLANS THAT YOU DEVELOPED IN THE
CONTEXT OF A WHOLE EXOME SEQUENCING PROTOCOL.
THE BOTTOM LINE, MOSTLY HAS TO
DO WITH EXPECTATION MANAGEMENT. WE WANT NOBODY TO BE SURPRISED. WE DON'T WANT AN INVESTIGATOR
WHO END UP WITH A RESULT THEY WEREN'T EXPECTING AND IS
MOVING — LOOKING AT WHAT TO DO WITH IT
WITHOUT HAVING HAD THE BENEFIT OF THINKING THIS THROUGH AHEAD
OF TIME. WE DON'T WANT SUBJECTS GETTING
COLD CALLS ACCESSING THEIR SO-CALLED DEIDENTIFIED DATA
HEARING ABOUT RESULTS THAT THEY WEREN'T ANTICIPATING. WE WANT EVERYBODY TO GO FORWARD
WITH AS MUCH ADVANCED PREPARATION AND I GUARANTEE YOU
THERE WILL BE QUESTION THAT IS COME UP ALONG THE WAY. THAT'S WHY WE HAVE AN ETHICS
CONSULTATION SERVICE AND WE'LL CONTINUE WORKING WITH YOU ON HOW
TO MANAGE THESE QUESTIONS. BUT WE HOPE THAT WE CAN HELP
ANTICIPATE SOME OF THESE PROBLEMS AND COME UP WITH
ETHICALLY SOUND FRAMEWORKS FOR DOING WHOLE EXOME SEQUENCING
WHICH STARTS TO ANTICIPATE SOME OF THESE CHALLENGES AHEAD OF
TIME. THANK YOU..