KEYNOTE ADDRESS - PERSPECTIVES FROM THE FDA
STUART L. NIGHTINGALE, M.D.
ASSOCIATE COMMISSIONER FOR HEALTH AFFAIRS

PUBLIC RESPONSIBILITY IN MEDICINE & RESEARCH

ANNUAL CONFERENCE, NOVEMBER 1, 1994

Good MORNING. I AM PLEASED TO BE INVITED TO SPEAK AT THIS YEAR'S CONFERENCE, WHICH MARKS THE 20TH ANNIVERSARY OF PRIM&R'S FOUNDING. WE AT FDA APPRECIATE PRIM&R'S CONTINUOUS EFFORTS TO SEE THAT THE LEVEL OF HUMAN SUBJECT PROTECTION IN CLINICAL RESEARCH IN THIS COUNTRY IS AT THE HIGHEST LEVEL. FDA HAS BENEFITTED GREATLY OVER THE YEARS BY HAVING THE OPPORTUNITY TO COME TO YOUR MEETINGS, SHARE OUR PERSPECTIVES ON EVENTS IN THIS FIELD, AND LEARN FROM YOU. IT IS A FACT THAT MANY OF THE FDA IRB AND CLINICAL INVESTIGATOR INFORMATION SHEETS WERE DEVELOPED IN RESPONSE TO TOPICS AND QUESTIONS RAISED AT THESE CONFERENCES.

THE ANNUAL PRIM&R CONFERENCE PROVIDES A RARE OPPORTUNITY FOR INTELLECTUAL EXCHANGE--AMONG ACADEMICS, REGULATORS, AND THE PEOPLE ON THE FRONT LINES OF HUMAN SUBJECT PROTECTION, THE IRB MEMBERS. ONLY BY SHARING AND DISCUSSING IDEAS AND REAL-WORLD EXPERIENCES IN A FORUM SUCH AS THIS, CAN WE HOPE TO MEET THE NEW CHALLENGES THAT FACE US, AND FASHION SOLUTIONS THAT ARE BOTH REALISTIC AND CONSISTENT WITH THE ETHICAL PRINCIPLES THAT UNDERPIN OUR REGULATORY FRAMEWORK.

I ENDORSE GARY ELLIS' COMMENTS IN YESTERDAY'S KEYNOTE WHERE HE IDENTIFIED THE INCREASING EMPHASIS IN OUR COUNTRY BEING GIVEN TO PROTECTION OF HUMAN SUBJECTS IN CLINICAL RESEARCH. I WOULD ADD TO HIS LIST OF RECENT EVENTS THAT DEMONSTRATE THIS THE SEVERE TOXICITY AND DEATHS IN THE FIAU CLINICAL TRIALS AND THE INTERNATIONAL HARMONIZATION OF TECHNICAL, SCIENTIFIC AND ETHICAL GUIDELINES TO BE USED IN DRUG APPROVAL SUBMISSIONS IN THE U.S., JAPAN, AND THE EUROPEAN UNION.

THERE ARE A NUMBER OF SPECIAL GROWING CHALLENGES FOR THOSE INVOLVED IN HUMAN SUBJECT PROTECTION--THE IRB COMMUNITY, CLINICAL INVESTIGATORS, AND SPONSORS AND FOR THE FEDERAL REGULATORS--FDA AND OPRR. THE CHALLENGES FACING ALL OF US ARE BOTH SUBSTANTIVE AND ADMINISTRATIVE. EXAMPLES OF SOME OF THE SUBSTANTIVE ISSUES ARE WHETHER PARTICULAR RESEARCH PRACTICES CONFORM TO THE ETHICAL PRINCIPLES THAT WE HAVE ENDORSED, FOR EXAMPLE--ISSUES RELATING TO THE DEMARCATION BETWEEN RESEARCH AND TREATMENT, THE USE OF PLACEBO CONTROLLED TRIALS AND THE ISSUE OF INFORMED CONSENT IN EMERGENCY RESEARCH.

ADMINISTRATIVE ISSUES ARE LEGION. SOME RELATE TO PROCEDURES FOR DEALING WITH THE FIRST GROUP, E.G., HOW TO RESOLVE PROBLEMS WITH INFORMED CONSENT IN EMERGENCY RESEARCH. OTHER ADMINISTRATIVE ISSUES FOR THE IRB COMMUNITY INCLUDE SUCH ITEMS AS THE INCREASING RESPONSIBILITIES BEING PLACED ON IRBS AND HOW IRBS CAN REALISTICALLY CARRY THEM OUT, AND HOW TO DEAL WITH REAL AND APPARENT DIFFERENCES IN REGULATIONS BETWEEN FDA AND OPRR. CHALLENGES FOR THE FDA TO AN EXTENT MIRROR THESE AND INCLUDE MANY OTHERS. WE MUST DEAL WITH THE SUBSTANTIVE ISSUES IN THE PERSPECTIVE OF ETHICS, LAW, REGULATION, AND POLICY ARTICULATION. AMONG THE ADMINISTRATIVE ISSUES FACING US ARE HOW TO INFORM THE IRB AND CLINICAL INVESTIGATOR COMMUNITY OF NEW POLICIES, GUIDELINES, INTERPRETATIONS OF CURRENT REGULATIONS, AND HOW TO LET THE COMMUNITY KNOW OF OPPORTUNITIES TO COMMENT ON PROPOSALS THAT ARE SET OUT FOR COMMENT IN THE FEDERAL REGISTER--THE SOMEWHAT OBSCURE PUBLICATION WE USE TO OBTAIN COMMENT FROM THE PUBLIC AND TO NOTIFY THE PUBLIC OF FINAL REGULATIONS.

HAVING LISTED SOME OF THE CHALLENGES FOR THE IRB COMMUNITY AND REGULATORS, IT BECOMES QUITE CLEAR THAT WE FACE MOST OF THESE TOGETHER. UNLESS WE CAN HAVE A DIALOGUE ABOUT BOTH SUBSTANTIVE AND ADMINISTRATIVE CONCERNS, THESE CHALLENGES TO ALL OF US WILL NOT BE MET. WE NEED YOUR FEEDBACK. WE NEED CONFERENCES SUCH AS THIS, AND WE NEED YOUR VIEWS ON OUR PROPOSALS. I WILL NOW TURN TO SOME OF THE CHALLENGES THAT WE FACE AND SOME OF THE APPROACHES WE ARE TAKING TO MEET THEM.

EMERGENCY RESEARCH AND THE USE OF PLACEBO CONTROLS ARE TWO TOPICS CURRENTLY UNDER INTENSE DISCUSSION. I WILL BRIEFLY ADDRESS THE TOPICS AND PLANS FOR ADDRESSING THESE FURTHER.

INFORMED CONSENT IN EMERGENCY RESEARCH

AS MOST OF YOU KNOW, OVER THE PAST SEVERAL YEARS, FDA HAS BEEN CONFRONTED WITH A NUMBER OF STUDIES--INVOLVING BOTH DRUGS AND DEVICES--IN WHICH THE STUDY DESIGN CALLED FOR THE TEST ARTICLE TO BE ADMINISTERED TO AN UNCONSCIOUS OR OTHERWISE INCAPACITATED PATIENT. AT LEAST ONE OF THESE STUDIES--THE SO- CALLED "PEG-SOD (POLY ETHYLENE GLYCOL-CONJUGATED SUPER OXIDE DISMUTASE) STUDY" INVOLVING A DRUG AIMED AT LIMITING NEUROLOGICAL DAMAGE FOLLOWING HEAD TRAUMA--WAS THE SUBJECT OF MUCH DISCUSSION AT LAST YEAR'S PRIM&R CONFERENCE AND HAS BEEN DISCUSSED IN THE HUMAN SUBJECT PROTECTION LITERATURE. ANOTHER STUDY RAISING THIS ISSUE INVOLVED THE "AMBU CARDIOPUMP". THIS DEVICE WAS BEING INVESTIGATED FOR USE IN CARDIOPULMONARY RESUSCITATION, A SITUATION THAT--AT LEAST WHEN USED BY PARAMEDICS IN THE FIELD--DOES NOT LEND ITSELF TO PRIOR INFORMED CONSENT. THIS WAS THE SUBJECT OF AN ARTICLE IN THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, BUT WITH A FOCUS MORE ON THE SCIENTIFIC ISSUES THAN HUMAN SUBJECT PROTECTION.

THE 1976 MEDICAL DEVICE AMENDMENTS TO THE FD&C ACT SET A STATUTORY STANDARD FOR DEVICES MORE RESTRICTIVE THAN THAT WHICH EXISTED FOR DRUGS RELATIVE TO POSSIBLE EXEMPTIONS FROM INFORMED CONSENT REQUIREMENTS. WHEREAS THE STATUTORY LANGUAGE WITH RESPECT TO INVESTIGATIONAL DRUGS DEPENDS SOLELY UPON A PHYSICIAN'S DETERMINATION THAT PROVIDING INFORMED CONSENT IS EITHER "NOT FEASIBLE" OR "CONTRARY TO THE BEST INTEREST" OF THE PATIENT, THE EXCEPTION TO INFORMED CONSENT FOR THE USE OF INVESTIGATIONAL DEVICES COMBINES THE REQUIREMENT OF NON- FEASIBILITY WITH AN EXPLICIT REQUIREMENT THAT THE PATIENT BE FACING A "LIFE-THREATENING" SITUATION. MOREOVER, THE POSSIBLE BENEFITS OF USING THE DEVICE MUST SUPPORT A CONCLUSION THAT THE SITUATION "NECESSITATES THE USE" OF THE DEVICE.

IN 1981, WHEN FDA PROMULGATED ITS IRB AND INFORMED CONSENT REGULATIONS CONCURRENT WITH NIH/HHS PUBLISHING ITS REGULATIONS, THE AGENCY APPLIED TO ALL REGULATED PRODUCTS THE STRICT PROTECTIONS CONSISTENT WITH THE STATUTORY LANGUAGE IN OUR MEDICAL DEVICE AMENDMENT AND REQUIREMENTS, NAMELY, THAT A DETERMINATION MUST BE MADE THAT NO ALTERNATIVE METHOD OF THERAPY IS AVAILABLE THAT WOULD PROVIDE AN EQUAL OR GREATER LIKELIHOOD OF SAVING THE PATIENT'S LIFE. THUS, FDA'S CURRENT REGULATIONS GOVERNING WHEN AN EXCEPTION TO THE INFORMED CONSENT REQUIREMENT MAY BE INVOKED CONTAIN FOUR CRITERIA (21 CFR  50.23):

1. THE SUBJECT MUST BE CONFRONTED BY A LIFE-THREATENING SITUATION THAT NECESSITATES THE USE OF THE INVESTIGATIONAL DRUG OR DEVICE;
2. INFORMED CONSENT CANNOT BE OBTAINED FROM THE SUBJECT BECAUSE OF THE SUBJECT'S INABILITY TO COMMUNICATE, OR TO GIVE LEGALLY EFFECTIVE CONSENT;
3. TIME IS NOT SUFFICIENT TO OBTAIN CONSENT FROM THE SUBJECT'S LEGAL REPRESENTATIVE (AND NOTE THAT FDA DEFERS TO STATE LAW ON THE QUESTION OF WHO MAY BE A "LEGAL REPRESENTATIVE"); AND
4. THERE IS NO ALTERNATIVE METHOD OF APPROVED OR GENERALLY RECOGNIZED THERAPY THAT PROVIDES AN EQUAL OR GREATER LIKELIHOOD OF SAVING THE LIFE OF THE SUBJECT.

FDA'S EXCEPTION TO INFORMED CONSENT HAS EVOLVED CONSIDERABLY FROM THE ORIGINAL DRUG STATUTORY PROVISION SIMPLY REQUIRING A FINDING THAT IT IS "NOT FEASIBLE" TO OBTAIN CONSENT OR THAT OBTAINING CONSENT IS "CONTRARY TO THE PATIENT'S BEST INTERESTS." WHILE MOST WOULD AGREE THAT THESE STRICTER REQUIREMENTS HAVE EFFECTIVELY DISCOURAGED ABUSE OF THIS EXCEPTION BY OVER-ZEALOUS (THOUGH GENERALLY WELL-INTENTIONED) INVESTIGATORS, EXPERIENCE WITH RECENT STUDIES SUGGESTS THAT THE CURRENT REGULATIONS MAY NOT BE SERVING THEIR INTENDED PURPOSE. IN ADDITION, THE FACT THAT MUCH IMPORTANT RESEARCH OCCURS AT HOSPITALS HAVING "MULTIPLE PROJECT ASSURANCES" WITH THE DEPARTMENT OF HEALTH AND HUMAN SERVICES THROUGH OPRR MEANS THAT INVESTIGATORS MUST COMPLY WITH THE DEPARTMENT'S HUMAN SUBJECT PROTECTION REGULATIONS, AS WELL AS FDA'S IRB AND INFORMED CONSENT REGULATIONS. IN CONTRAST TO FDA'S REGULATIONS IN THIS AREA, THE DEPARTMENTAL REGULATIONS ONLY PERMIT WAIVER OF INFORMED CONSENT WHERE THE RESEARCH INVOLVES "NO MORE THAN MINIMAL RISK TO THE PATIENTS." SOME CONCLUDE THAT "MINIMAL RISK" IN THIS CONTEXT REFERS ONLY TO THE RELATIVE INCREMENT OF RISK FACED BY THE PATIENT. HOWEVER, THE REGULATORY EXAMPLES OF MINIMAL RISK WHERE THE RISKS OF HARM OR DISCOMFORT ARE NO GREATER THAN THOSE ORDINARILY ENCOUNTERED IN DAILY LIFE OR DURING THE PERFORMANCE OF ROUTINE PHYSICAL OR PSYCHOLOGICAL TESTS SUGGEST TO MANY THAT OTHER CONTEXTS WERE CONSIDERED IN DRAFTING THE REGULATIONS. I AM PLEASED THAT THIS TOPIC WILL BE ADDRESSED FURTHER TODAY IN THE WORKSHOPS.

TO EXPLORE THESE ISSUES FULLY, FDA AND THE NATIONAL INSTITUTES OF HEALTH WILL BE CO-SPONSORING A PUBLIC FORUM FOCUSED ON THE ETHICAL AND PRACTICAL PROBLEMS OF INFORMED CONSENT IN EMERGENCY RESEARCH. THE MEETING WILL BE HELD SOMETIME IN EARLY 1995. THE MEETING WILL CONSIST OF A SERIES OF PRESENTATIONS AND PANEL DISCUSSIONS OF THE ETHICAL, SCIENTIFIC AND REGULATORY ISSUES ASSOCIATED WITH THIS TYPE OF RESEARCH, AS WELL AS PRESENTATIONS BY SOME OF THE LEADING RESEARCHERS IN EMERGENCY MEDICINE. THERE WILL BE AN OPPORTUNITY FOR THE PUBLIC TO PARTICIPATE IN THE DISCUSSIONS AND TO SUBMIT WRITTEN COMMENTS TO THE RECORD. FDA WILL USE THE INFORMATION AND VIEWS GATHERED AT THIS FORUM IN CONSIDERING WHETHER OR NOT THE AGENCY'S CURRENT INFORMED CONSENT REGULATIONS ARE SATISFACTORY AND, IF APPROPRIATE, WHAT POSSIBLE MODIFICATIONS TO THE REGULATIONS AND/OR GUIDANCE DOCUMENTS MERIT CONSIDERATION.

THE FACT THAT FDA AND NIH ARE JOINTLY HOLDING A PUBLIC FORUM ON THIS TOPIC DEMONSTRATES THAT THIS IS A MAJOR PROBLEM AREA-- ONE REQUIRING PUBLIC DEBATE AND DISCUSSIONS WITH EXPERT CONSULTANTS. THIS IS THE FIRST TIME SINCE THE 1981 REGULATIONS WENT INTO EFFECT THAT THE TWO AGENCIES HAVE SPONSORED A SINGLE-TOPIC, MAJOR NATIONAL SYMPOSIUM TO SEEK POLICY AND TECHNICAL ADVICE. WE WILL MAKE SURE THAT YOU KNOW ABOUT THE CONFERENCE AND HAVE AN OPPORTUNITY TO PARTICIPATE. THE MOST SENIOR LEVELS AT NIH AND FDA ARE COMMITTED TO HAVING THIS CONFERENCE SOON.

PLACEBO CONTROLLED RESEARCH

THE ETHICS OF PLACEBO-CONTROLLED RESEARCH IS AN ISSUE THAT IS PERIODICALLY REAWAKENED IN THE MEDICAL AND BIOMEDICAL LITERATURE--AND REGULARLY CONFRONTED BY IRBS IN THEIR DELIBERATIONS. THERE IS A MAJOR SERIES OF ARTICLES ON PLACEBOS CURRENTLY APPEARING IN THE LANCET AND THE ISSUE WAS RECENTLY ADDRESSED IN AN ARTICLE BY ROTHMAN AND MICHELS IN THE NEW ENGLAND JOURNAL OF MEDICINE. THE AUTHORS QUESTION THE CONTINUED USE OF PLACEBO CONTROLS IN STUDIES OF VARIOUS DISEASES AND CONDITIONS FOR WHICH RELATIVELY EFFECTIVE MEDICINES ARE AVAILABLE, SUCH AS HYPERTENSION, CHEMOTHERAPY- INDUCED EMESIS, DEPRESSION, AND CONGESTIVE HEART FAILURE. THE AUTHORS CONTEND THAT DETAILED INFORMED CONSENT DOES NOT VITIATE THE ETHICAL DEFECTS OF THESE STUDIES. THE AUTHORS ALSO ARGUE THAT FDA'S REQUIREMENTS FOR PLACEBO-CONTROLLED TRIALS IS, IN MANY INSTANCES, NOT SCIENTIFICALLY JUSTIFIED. SINCE ONE OF THE AUTHORS OF THIS COMMENTARY WILL BE OUR LUNCHEON SPEAKER, I WILL NOT DISCUSS THEIR VIEWS FURTHER.

FDA'S POSITION REGARDING THE IMPORTANCE OF PLACEBO-CONTROLLED TRIALS IS ELUCIDATED IN AN FDA CLINICAL INVESTIGATOR INFORMATION SHEET ENTITLED, "PLACEBO-CONTROLLED AND ACTIVE CONTROLLED DRUG STUDY DESIGNS" ALONG WITH AN APPENDIX THAT INCLUDES TWO ARTICLES ON THIS TOPIC BY DR. ROBERT TEMPLE. IT IS MY VIEW THAT THE INFORMATION SHEET AND THE ARTICLES DEAL VERY DIRECTLY WITH THE ISSUES RAISED. LET ME BRIEFLY SUMMARIZE, HOWEVER, SOME OF THE MAIN POINTS THAT FDA VIEWS AS IMPORTANT IN RESPONDING TO THE TYPES OF CHALLENGES BEING MADE.

THE ETHICAL PRINCIPLE ON WHICH ROTHMAN AND MICHELS REST THEIR OBJECTION TO PLACEBO CONTROLLED TRIALS IS CONTAINED IN THE DECLARATION OF HELSINKI. UNDER THIS PRINCIPLE, ALL PARTICIPANTS IN A TRIAL, INCLUDING THOSE IN A CONTROL GROUP, MUST BE ASSURED OF THE BEST PROVEN THERAPEUTIC AND DIAGNOSTIC METHODS. FDA BELIEVES THAT THE AUTHORS' INTERPRETATION OF THIS PRINCIPLE IS OVERLY NARROW AND IGNORES SOME IMPORTANT ISSUES. ONE SUCH ISSUE IS, HOW IT IS POSSIBLE TO CONDUCT ANY CLINICAL RESEARCH AT ALL ONCE ONE THERAPY HAS BEEN PROVEN EFFECTIVE. IF ALL PATIENTS MUST RECEIVE THE BEST PROVEN METHOD, IT IS NOT CLEAR HOW SUBSTITUTING ACTIVE CONTROLS FOR PLACEBO CONTROLS HELPS AT ALL, SINCE THE EXPERIMENTAL TREATMENT BEING TESTED IS BY DEFINITION UNPROVEN. PERHAPS THERE IS A PROBLEM WITH THE TERMINOLOGY OF THE DECLARATION OF HELSINKI REVISIONS. THE WORLD MEDICAL ASSOCIATION IS THE BODY RESPONSIBLE FOR THIS AND THE AMERICAN MEDICAL ASSOCIATION IS THE U.S. REPRESENTATIVE TO THAT BODY. PERHAPS WE SHOULD BECOME MORE INVOLVED IN REVISIONS TO SEE THAT REVISIONS TAKE CURRENT REALITIES INTO ACCOUNT. ALTERNATIVELY, PERHAPS OUR REGULATION SHOULD LOOK TO AND CITE WORLDWIDE ETHICAL PRINCIPLES ENUNCIATED BY CIOMS/WHO AND RECENTLY REVISED AND PUBLISHED IN 1993 THAT DEAL MORE APPROPRIATELY WITH INFORMED CONSENT AND MODERN CLINICAL RESEARCH.

WHILE FDA HAS ALWAYS AGREED THAT IT IS ETHICALLY UNACCEPTABLE TO EMPLOY A PLACEBO WHEN THE STUDY INVOLVES SERIOUS, IRREVERSIBLE, OR LIFE-THREATENING DISEASES OR CONDITIONS, A DISTINCTION CAN AND SHOULD BE MADE FOR LESS SERIOUS OR SELF- LIMITING CONDITIONS--SO LONG AS IRBS HAVE CAREFULLY REVIEWED THE PROTOCOL AND INFORMED CONSENT, AND BELIEVE IT IS APPROPRIATE TO PROCEED. THE KEY ISSUE IS THE NEED FOR SUBJECTS TO BE FULLY INFORMED VIA THE CONSENT PROCESS. THE DIFFICULTIES OF ASSESSING THERAPEUTIC EFFICACY WHEN ACTIVE CONTROLS RATHER THAN PLACEBO CONTROLS ARE USED SHOULD NOT BE UNDERSTATED. IN CONDITIONS WHERE DRUG EFFECTS TEND TO BE SMALL AND PLACEBO EFFECTS ARE NONTRIVIAL, ACTIVE CONTROL TRIALS CAN BE VERY DIFFICULT TO INTERPRET. JUST AS WE SOMETIMES HAVE TO SETTLE FOR OBSERVATIONAL DATA WHEN RANDOMIZED TRIALS CANNOT BE DONE, WE SOMETIMES HAVE TO SETTLE FOR ACTIVE CONTROL TRIALS WHEN PLACEBO-CONTROLLED TRIALS ARE INAPPROPRIATE--BUT WE MUST UNDERSTAND THE ANSWERS WE GET ARE LESS PRECISE AND RELIABLE.

FDA PLANS TO RESPOND TO THE RECENT ARTICLE IN THE NEW ENGLAND JOURNAL OF MEDICINE THROUGH THE MEDICAL LITERATURE.

FINANCIAL DISCLOSURE IN CLINICAL INVESTIGATION

ANOTHER LONG-STANDING ISSUE IN THE WORLD OF CLINICAL RESEARCH IS THAT OF CLINICAL INVESTIGATORS HAVING A FINANCIAL STAKE IN THE SUBJECT OF THEIR RESEARCH. BECAUSE THE PRIMARY FOCUS OF FDA'S STATUTORY RESPONSIBILITIES IS THE SAFETY AND EFFICACY OF PRODUCTS, THE AGENCY'S INTEREST IN THE ISSUE OF INVESTIGATORS' FINANCIAL HOLDINGS HAS BEEN FROM THE PERSPECTIVE OF WHETHER THESE MIGHT COMPROMISE THE INTEGRITY OR RELIABILITY OF DATA SUBMITTED TO FDA IN SUPPORT OF A MARKETING APPLICATION FOR A DRUG OR DEVICE. OVER THE YEARS, FDA HAS RELIED ON ITS BIORESEARCH MONITORING PROGRAM, THE GROUP THAT PERFORMS, AMONG OTHER THINGS, ON-SITE AUDITS OF CLINICAL INVESTIGATORS AND IRBS, AS ITS PRIMARY SAFEGUARD. NEW INFORMATION, INCLUDING INFORMATION ON SUBSTANTIAL FINANCIAL INTERESTS HELD BY CLINICAL INVESTIGATORS WHO CONDUCTED THE CLINICAL TRIALS THAT WERE USED FOR PREMARKET APPROVAL APPLICATION SUBMISSIONS TO FDA, FORCED US TO CAREFULLY REEVALUATE THIS ISSUE. AFTER THIS REVIEW, FDA PUBLISHED IN THE FEDERAL REGISTER ON SEPTEMBER 22, 1994, A NOTICE OF PROPOSED RULEMAKING THAT ADDRESSES THIS ISSUE.

IN DRAFTING THIS PROPOSED REGULATION, FDA CONSULTED WITH MANY INTERESTED PARTIES, INCLUDING CLINICAL INVESTIGATORS, HEALTH PROFESSIONAL ORGANIZATIONS, DRUG AND DEVICE MANUFACTURERS, CONSUMER ADVOCATES, AND OTHERS. THE AGENCY CONCLUDED THAT AN OUTRIGHT PROHIBITION ON SPECIFIC HOLDINGS WAS UNNECESSARY AND POTENTIALLY DAMAGING TO THE DEVELOPMENT OF NEW PRODUCTS.

CONSEQUENTLY, THE PROPOSED REGULATION DOES NOT PROHIBIT ANY PARTICULAR FINANCIAL ARRANGEMENTS BETWEEN INVESTIGATORS AND STUDY SPONSORS. IT SIMPLY REQUIRES THAT CERTAIN TYPES OF ARRANGEMENTS BE DISCLOSED TO THE AGENCY. MOREOVER, RECOGNIZING THAT THE VAST MAJORITY OF STUDIES CONDUCTED UNDER AN IND OR IDE DO NOT GENERATE DATA THAT WOULD SUPPORT A MARKETING APPLICATION (AND HENCE ARE IRRELEVANT TO THE ISSUE OF PRIMARY CONCERN TO FDA, NAMELY, DATA INTEGRITY IN THE APPROVAL PROCESS), FDA HAS CHOSEN TO LIMIT DISCLOSURE TO THOSE STUDIES THAT ARE IN FACT SUBMITTED WITH A DRUG OR DEVICE MARKETING APPLICATION. THE VAST MAJORITY OF FINANCIAL ARRANGEMENTS BETWEEN SPONSORS AND INVESTIGATORS WILL NOT REQUIRE DISCLOSURE TO FDA. CASH PAYMENTS FOR SERVICES PERFORMED IN CONNECTION WITH A STUDY ARE NOT COVERED BY THE PROPOSED REGULATION, NOR IS COMPENSATION IN ANY FORM TO AN INVESTIGATOR WHO IS A FULL-TIME EMPLOYEE OF THE SPONSOR--SINCE IN THESE INSTANCES THE PRESENCE OF A POTENTIAL CONFLICT OF INTEREST IS UNDERSTOOD.

THE PURPOSE OF OBTAINING THIS INFORMATION FROM SPONSORS IS NOT TO REJECT CATEGORICALLY STUDIES THAT WERE CONDUCTED IN WHOLE OR IN PART BY AN INVESTIGATOR WITH A FINANCIAL INTEREST IN THE OUTCOME OF THE RESEARCH. RATHER, FDA WILL USE THIS INFORMATION AS A BASIS FOR EVALUATING WHETHER ADEQUATE MEASURES WERE TAKEN TO MINIMIZE THE RISK OF BIAS. IF THE AGENCY DETERMINES THAT THE STUDY WAS ADEQUATELY BLINDED OR THAT SUFFICIENT CHECKS ON THE ACCURACY OF THE DATA WERE IN PLACE, THE PRESENCE OF THE FINANCIAL INTEREST WILL NOT ADVERSELY IMPACT UPON THE TEST ARTICLE'S APPROVAL PROSPECTS.

IRBS DO NOT HAVE AN EXPLICIT ROLE IN IMPLEMENTING FDA'S PROPOSAL FOR MANAGING POTENTIAL FINANCIAL CONFLICTS OF INTEREST IN CLINICAL INVESTIGATIONS. HOWEVER, IRBS RETAIN THE AUTHORITY TO REQUIRE--AS THEY SEE FIT--DISCLOSURE TO SUBJECTS OF ANY FINANCIAL INTERESTS THAT THEY BELIEVE A PROSPECTIVE SUBJECT IN A STUDY WOULD WANT TO KNOW PRIOR TO CONSENTING TO PARTICIPATION.

DO IRBS HAVE THE INFORMATION THEY NEED TO DO THIS? SHOULD IRBS BE MORE INVOLVED IN THIS PROCESS? ARE YOU SATISFIED WITH THE DIFFERING PUBLIC HEALTH SERVICE, NATIONAL SCIENCE FOUNDATION, AND FDA APPROACHES TO THIS TOPIC? WHAT DO THE VARIOUS COMPONENTS OF THE HUMAN SUBJECT PROTECTION COMMUNITY THINK ABOUT THIS? LET US HEAR FROM YOU. WE WELCOME COMMENTS ON THE PROPOSED REGULATIONS. THEY MUST BE SUBMITTED TO THE AGENCY BY DECEMBER 21.

MEDICAL DEVICES: SIGNIFICANT VS. NON-SIGNIFICANT RISK

THE DISTINCTION BETWEEN SIGNIFICANT RISK AND NON-SIGNIFICANT RISK DEVICES, THE RELEVANCE OF THIS DISTINCTION, AND THE CENTRAL ROLE THAT IRBS PLAY IN SEPARATING THE TWO AT TIME IS CONFUSING TO IRBS.

IN AN ARTICLE BY SHERERTZ AND STREED IN THE SEPTEMBER 28, 1994 ISSUE OF JAMA, THE AUTHORS RECOUNTED AN EXPERIENCE AT THEIR INSTITUTION WHICH "DEMONSTRATES A PITFALL THAT AWAITS ESSENTIALLY ANY HOSPITAL IN THIS COUNTRY IF ITS [IRB] IS NOT CAREFUL TO DISTINGUISH BETWEEN [AN SR/NSR DEVICE] STUDY." THE AUTHORS REPORTED THAT A STUDY SPONSOR ADVISED THEIR IRB THAT AN ANTI-INFECTIVE COATED URINARY CATHETER WHICH IT WISHED TO STUDY WAS NSR. UNAWARE OF FDA'S REQUIREMENTS IN THIS AREA, THE IRB WAS INCLINED TO RELY UPON THE SPONSOR'S REPRESENTATIONS. THE RESULT OF THE CONCLUSION THAT THE CATHETER STUDY WAS NSR IS THAT THE SPONSOR DID NOT NEED TO FILE AN INVESTIGATIONAL DEVICE EXEMPTION (IDE) WITH FDA PRIOR TO COMMENCING THE STUDY. VERY LATE IN THE PROCESS, HOWEVER, THE IRB CHAIRMAN LEARNED FROM A COLLEAGUE THAT THE CATHETER MIGHT WELL BE SR. THE IRB REPRESENTATIVE WAS THEN TOLD BY STAFF OF THE APPROPRIATE DIVISION IN FDA'S CENTER FOR DEVICES AND RADIOLOGICAL HEALTH THAT ALL URINARY CATHETERS ARE DEEMED SIGNIFICANT RISK DEVICES, AND THEREFORE THAT THE SPONSOR'S FILING OF AN IDE WITH FDA WAS REQUIRED. WHEN AN IRB DETERMINES THAT AN INVESTIGATION INVOLVES AN SR DEVICE, IT IS ONLY RESPONSIBLE FOR NOTIFYING THE INVESTIGATOR AND, WHERE APPROPRIATE, THE SPONSOR, OF THIS DETERMINATION. THE RESPONSIBILITY FOR TAKING THE NEXT STEP--NAMELY, FILING AN IDE--RESTS ENTIRELY WITH THE SPONSOR.

THE LESSONS WHICH THE AUTHORS DREW FROM THEIR EXPERIENCE ARE TWOFOLD: FIRST, THAT TOO MANY IRBS ARE UNFAMILIAR WITH THE DISTINCTION BETWEEN SIGNIFICANT AND NONSIGNIFICANT DEVICE STUDIES. AND SECOND, THAT UNDER THE CURRENT REGULATORY SCHEME, IRBS ARE SUSCEPTIBLE TO MANIPULATION BY DEVICE MANUFACTURERS EAGER TO EXPLOIT IRBS' NAIVETE IN THIS AREA. THE AUTHORS PROPOSED SOLUTION TO THIS PROBLEM IS FOR FDA TO REQUIRE SPONSORS TO PROVIDE ACCURATE INFORMATION (PERHAPS USING AN FDA-APPROVED DOCUMENT) TO IRBS ABOUT THEIR RESPONSIBILITIES IN MAKING SR/NSR DETERMINATIONS.

REGARDLESS OF ANY FUTURE PROPOSALS OR MODIFICATIONS TO FDA REQUIREMENTS, IRBS NEED A CERTAIN BASIC KNOWLEDGE AND NEED TO KNOW WHERE TO TURN TO SEEK ADDITIONAL DEFINITIVE INFORMATION. FIRST, IRBS SHOULD KNOW THAT CERTAIN CATEGORIES OF DEVICES HAVE BEEN CONCLUSIVELY DETERMINED BY FDA TO FALL INTO EITHER THE SR OR NSR CLASS. IF YOU KNOW THAT THE DEVICE FALLS INTO ONE OF THESE TWO CLASSES, THEN THE IRB NEED NOT CONSIDER THE QUESTION AT ALL. YOU NEED ONLY NOTIFY THE INVESTIGATOR THAT AN IDE MUST BE FILED IF IT IS SR. IT IS PERFECTLY APPROPRIATE IN THESE INSTANCES, THOUGH NOT EXPLICITLY REQUIRED, FOR THE IRB TO REQUEST PROOF FROM THE INVESTIGATOR OR SPONSOR THAT THE IDE HAS BEEN FILED. RECENTLY FDA'S CENTER FOR DEVICES AND RADIOLOGICAL HEALTH HAS UPDATED THE LIST OF DEVICES THAT ARE CATEGORICALLY CONSIDERED TO BE SR OR NSR. COPIES OF THIS UPDATED LIST ARE CONTAINED IN THE REVISED (OCTOBER 1994) IRB INFORMATION SHEETS. I WILL NOT GO INTO FURTHER DETAIL HERE BUT WOULD BE PLEASED TO DISCUSS THIS AT OUR WORKSHOP. I STRONGLY SUGGEST THAT YOU CAREFULLY REVIEW THE JAMA ARTICLE AND THE ACCOMPANYING EDITORIAL.

IN THE EVENT THAT THE DEVICE TO BE EVALUATED HAS NOT BEEN CLASSIFIED BY FDA, THE IRB MUST MAKE ITS OWN DETERMINATION REGARDING WHETHER THE DEVICE--AS USED IN THE STUDY--IS SR OR NSR. THIS STARTS WITH THE DEFINITION OF AN SR DEVICE: AN INVESTIGATIONAL DEVICE (THAT IS, ANY DEVICE USED IN AN INVESTIGATION--EVEN IF IT HAS ALREADY BEEN APPROVED FOR MARKETING) THAT PRESENTS A POTENTIAL FOR SERIOUS RISK TO THE HEALTH, SAFETY, OR WELFARE OF A SUBJECT AND THAT IS EITHER: (1) AN IMPLANT, (2) FOR USE IN SUPPORTING OR SUSTAINING HUMAN LIFE, OR (3) SUBSTANTIALLY IMPORTANT IN DIAGNOSING, CURING, MITIGATING, OR TREATING DISEASE, OR IN PREVENTING IMPAIRMENT OF HUMAN HEALTH. A STUDY WITH "POTENTIAL FOR SERIOUS RISK" IS ONE THAT PRESENTS A POTENTIAL FOR SERIOUS HARM. AN IRB MUST CONSIDER THE NATURE OF THE HARM THAT MAY RESULT FROM USE OF THE DEVICE. IF THE DEVICE BEING INVESTIGATED MIGHT CAUSE SIGNIFICANT HARM TO ANY OF THE SUBJECTS, THE STUDY SHOULD BE CONSIDERED SR. ALSO, IF THE SUBJECT MUST UNDERGO A PROCEDURE AS PART OF THE INVESTIGATIONAL STUDY (SUCH AS A SURGICAL PROCEDURE), THE IRB SHOULD CONSIDER THE POTENTIAL HARM THAT COULD BE CAUSED BY THE PROCEDURE ITSELF, AS WELL AS THE POTENTIAL HARM THAT THE DEVICE MIGHT CAUSE.

THE INITIAL ASSESSMENT OF WHETHER A DEVICE STUDY PRESENTS A SIGNIFICANT RISK TO THE HEALTH, SAFETY, OR WELFARE OF THE PATIENT IS MADE BY THE SPONSOR. IF THE SPONSOR BELIEVES THAT A STUDY IS NSR, THE SPONSOR SHOULD PROVIDE THE IRB WITH THE STUDY PROPOSAL, AN EXPLANATION OF WHY THE STUDY IS NSR, AND OTHER SUPPORTING INFORMATION. THE SPONSOR SHOULD ALSO INFORM THE IRB IF THE FDA OR ANY OTHER IRB HAS DETERMINED THAT THE STUDY IS SR OR NSR, AND PROVIDE ANY OTHER INFORMATION REQUESTED BY THE IRB. THE IRB MAY AGREE OR DISAGREE WITH THE SPONSOR'S INITIAL NSR DETERMINATION. IF THE IRB AGREES THAT THE STUDY IS NSR, THE INVESTIGATION MAY BEGIN WITHOUT THE SPONSOR'S FILING AN IDE APPLICATION TO FDA AND, THEREFORE, WITHOUT FDA KNOWLEDGE OR REVIEW OF THE STUDY. (THE IRB MUST THEN DECIDE THE INDEPENDENT QUESTION OF WHETHER THE STUDY SHOULD BE APPROVED UNDER THE USUAL CRITERIA THAT ARE APPLIED TO ANY STUDY BY AN IRB--NAMELY, THAT THE RISKS TO SUBJECTS ARE MINIMIZED AND ARE REASONABLE IN RELATION TO ANTICIPATED BENEFITS, KNOWLEDGE TO BE GAINED, ETC.) IF THE IRB DISAGREES WITH THE SPONSOR'S DETERMINATION AND CONCLUDES THAT THE STUDY IS SR, THEN THE SPONSOR MUST FILE AN IDE (OR IT CAN LEGALLY GO TO ANOTHER IRB, BUT MUST INFORM IT OF THE EARLIER IRB'S DECISION).

IF A DEVICE STUDY IS PRESENTED TO YOUR IRB AND INFORMED CONSENT IS PROPOSED TO BE WAIVED OR AN EXCEPTION PERMITTED, THE AGENCY, BY DEFINITION, CONSIDERS THESE STUDIES TO BE SR AND AN IDE IS NEEDED. IF YOUR IRB REGULARLY REVIEWS STUDIES INVOLVING MEDICAL DEVICES, THEN I URGE YOU TO OBTAIN FDA'S "IDE MANUAL" AND OUR INFORMATION SHEETS. I HAVE SPENT SOME TIME ON THIS PROCESS, BECAUSE IT IS CONFUSING TO IRBS. SOME HAVE ASKED WHY FDA HAS PLACED THESE ADDITIONAL RESPONSIBILITIES ON IRBS REVIEWING MEDICAL DEVICE STUDIES AND WHY FDA CANNOT TREAT ALL MEDICAL DEVICES THE SAME, REQUIRING IDES FOR ALL DEVICES UNDERGOING CLINICAL TESTING. THIS IS AN ISSUE WORTHY OF INFORMED DISCUSSION.

WOMEN IN CLINICAL TRIALS

FDA'S RECENT INITIATIVE REGARDING THE PARTICIPATION OF WOMEN IN CLINICAL TRIALS PROVIDES ANOTHER EXAMPLE OF FDA ACTIONS AND HOW WE INFORM THE COMMUNITY ABOUT IMPORTANT EMERGING RESEARCH ISSUES. IN JULY 1993, FDA ISSUED A DOCUMENT ENTITLED, "GUIDELINE FOR THE STUDY AND EVALUATION OF GENDER DIFFERENCES IN THE CLINICAL EVALUATION OF DRUGS." ALTHOUGH THIS GUIDELINE DOES NOT FORMALLY AMEND ANY FDA REGULATIONS--INCLUDING FDA'S INFORMED CONSENT AND IRB REGULATIONS, IT DOES MERIT SERIOUS CONSIDERATION BY IRBS. ON THE DAY OF PUBLICATION OF THE GUIDELINE, AN FDA-AUTHORED ARTICLE WAS PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDICINE. MY OFFICE RECENTLY MAILED TO ALL IRBS (FOR WHICH WE HAVE ADDRESSES) A COPY OF THE 1993 GUIDELINE TOGETHER WITH A LETTER SIGNED BY THE INTERIM DEPUTY COMMISSIONER FOR OPERATIONS AT FDA, MS. LINDA SUYDAM. THIS LETTER WAS DEVELOPED TO RESPOND TO SOME OF THE QUESTIONS FDA HAD RECEIVED FROM CLINICAL RESEARCHERS, IRBS, ADVOCACY GROUPS, AND OTHERS SINCE THE GUIDELINE WAS PUBLISHED. BECAUSE OF ITS IMPORTANCE AND IN LINE WITH THE CONFERENCE THEME, I WOULD LIKE TO HIGHLIGHT FOR YOU SOME OF THE MAJOR POINTS OF THE GUIDELINE AND WHAT WE SEE AS THE IMPLICATIONS FOR IRBS.

THE 1993 GUIDELINE ADDRESSED TWO MAJOR POINTS: FIRST, IT "LIFTED" FDA'S 1977 PERCEIVED RESTRICTION ON THE PARTICIPATION BY MOST WOMEN OF CHILDBEARING POTENTIAL FROM ENTERING PHASE I AND EARLY PHASE II TRIALS. THE NEW GUIDELINE ENCOURAGES THE PARTICIPATION OF WOMEN IN THESE EARLY DRUG TRIALS SO LONG AS PREGNANCY MONITORING AS WELL AS PRECAUTIONS AGAINST PREGNANCY ARE EFFECTIVELY IMPLEMENTED. SECOND, THE NEW GUIDELINE NOTIFIES SPONSORS THAT THEY SHOULD COLLECT GENDER-RELATED DATA DURING DRUG RESEARCH AND DEVELOPMENT, AND SHOULD ANALYZE THE DATA FOR GENDER EFFECTS. A CHARACTERIZATION OF DRUG EFFECTS BY GENDER MUST NOW BE PART OF ALL NEW DRUG APPLICATIONS, AND THE AGENCY MAY REFUSE TO FILE AN APPLICATION THAT DOES NOT INCLUDE THESE DATA. THIS GUIDELINE SETS OUT FDA'S EXPECTATION THAT THERE WILL BE A FAIR REPRESENTATION OF BOTH GENDERS AS PARTICIPANTS IN CLINICAL TRIALS SO THAT CLINICALLY SIGNIFICANT GENDER-RELATED DIFFERENCES IN DRUG RESPONSE CAN BE DETECTED. FDA URGES IRBS TO EXAMINE CAREFULLY THE STUDY PROTOCOLS UNDER THEIR AEGIS TO SEE WHETHER ENTRY CRITERIA NEEDLESSLY EXCLUDE WOMEN OR OTHER GROUPS IN THE TARGET POPULATION OF THE DRUGS, OR UTILIZE ENTRY CRITERIA THAT ARE NEEDLESSLY DIFFICULT FOR WOMEN TO MEET.

WE PLAN TO "CONVERT" ELEMENTS IN THE GUIDELINE AND THE LETTER INTO A NEW IRB INFORMATION SHEET IN OUR SERIES SO THAT IT WILL BE MORE READILY DISSEMINATED AND ROUTINELY AVAILABLE AS A MORE PERMANENT RESOURCE.

ON A RELATED ITEM, NEXT WEEK (ON NOVEMBER 7 AND 8), FDA WILL BE SPONSORING A CONFERENCE ENTITLED "FDA REGULATED PRODUCTS AND PREGNANT WOMEN." THE PROGRAM WILL FOCUS ON A DISCUSSION OF THE SCOPE AND NEED FOR MEDICAL INTERVENTIONS IN PREGNANCY, AND WILL PROVIDE BACKGROUND ON THE EXTENT TO WHICH PHYSIOLOGIC CHANGES DURING PREGNANCY ALTER THE PHARMACOKINETICS, METABOLISM, AND PHARMACODYNAMICS OF DRUGS IN PREGNANT WOMEN.

INFORMATION DISSEMINATION

WHILE I HAVE FOCUSED MANY OF MY REMARKS ON INFORMATION DISSEMINATION AS IT RELATED TO SPECIFIC TOPICS, LET ME SAY A FEW WORDS ABOUT DISSEMINATION OF INFORMATION BY FDA IN GENERAL AND ABOUT OBTAINING INFORMATION FROM US. WE HAVE MATERIALS AND EXPERTS THAT CAN BE OF ASSISTANCE TO YOU IN DISCHARGING YOUR RESPONSIBILITIES. FDA OPERATES UNDER CERTAIN LIMITATIONS IN ROUTINELY DISSEMINATING INFORMATION TO IRBS. UNLIKE OPRR, FDA DOES NOT HAVE MULTIPLE PROJECT ASSURANCES OR ANY OTHER SYSTEM WHERE IRBS REGISTER WITH THE AGENCY. THE NAMES AND ADDRESSES OF IRBS ARE INCLUDED WHEN SPONSORS FILE INVESTIGATIONAL NEW DRUG APPLICATIONS AND INVESTIGATIONAL DEVICE EXEMPTIONS, AND WE TRY TO ENSURE THEIR INCLUSION, ALONG WITH OPPR'S LIST THEY PROVIDE TO US, IN OUR INFORMATIONAL MAILINGS. WE ARE NOW DEVELOPING A DATABASE FOR MAILINGS THAT, BY ITS NATURE (BEYOND OPRR'S LISTINGS), WILL BE IMPRECISE, BUT IS INCREASINGLY NECESSARY. IN LARGE MEASURE, WE RELY UPON IRBS TO CONTACT US--AND HERE I MEAN THE OFFICE OF HEALTH AFFAIRS--TO LET US KNOW OF YOUR EXISTENCE. IF YOU DID NOT RECEIVE OUR RECENT MAILING ON WOMEN IN CLINICAL TRIALS OR HAVE ANY DOUBTS AT ALL ABOUT WHETHER YOUR IRB IS INCLUDED IN OUR DATABASE, PLEASE FAX YOUR IRB'S ADDRESS INFORMATION TO MY OFFICE AT 301-443-0232 OR WRITE TO US. SHOULD FDA ATTEMPT TO ESTABLISH A REGULAR NEWSLETTER OR MAILING LIKE OPRR DOES? PERHAPS WE CAN HAVE YOUR VIEWS IN OUR WORKSHOP SESSION LATER THIS MORNING.

I WOULD ALSO LIKE TO GIVE YOU A SENSE OF SOME INFORMATION THAT IS AVAILABLE FROM THE AGENCY THAT SHOULD BE USEFUL IN DISCHARGING YOUR RESPONSIBILITIES. FIRST, COPIES OF PERTINENT REGULATIONS, THE IRB INFORMATION SHEETS, AND THE CLINICAL INVESTIGATOR INFORMATION SHEETS CAN BE OBTAINED FROM MY OFFICE. NAMES OF CLINICAL INVESTIGATORS WHOSE PRIVILEGE TO CONDUCT RESEARCH WITH INVESTIGATIONAL DRUGS HAS BEEN REVOKED BY FDA CAN BE OBTAINED BY MAKING A REQUEST TO THE FREEDOM OF INFORMATION OFFICE. YOU MAY ALSO OBTAIN FROM THE FOI OFFICE COPIES OF INSPECTION REPORTS AND WARNING LETTERS THAT HAVE BEEN SENT TO IRBS. THESE MAY BE OF USE IN ASSISTING YOU IN UNDERSTANDING THE TYPES OF VIOLATIONS THAT ARE OCCURRING AND WHAT FDA IS DOING ABOUT THEM. THEY ALSO WOULD BE USEFUL IF YOU ARE CONSIDERING ENTERING INTO A COOPERATIVE RESEARCH ARRANGEMENT WITH ANOTHER INSTITUTION. THE "IDE MANUAL"--A VERY COMPLETE COMPILATION AND DESCRIPTION OF THE REGULATIONS COVERING RESEARCH WITH MEDICAL DEVICES--MENTIONED IN THE JAMA ARTICLES IS A VALUABLE RESOURCE.

A MAJOR CHALLENGE TO IRBS IS TO KEEP UP WITH THE WIDE ARRAY OF MATERIALS THAT ARE NOT ROUTINELY DISTRIBUTED TO YOU, BUT APPEAR IN THE MEDICAL LITERATURE. FOR EXAMPLE, EARLIER I MENTIONED A NUMBER OF ARTICLES IN THE MEDICAL LITERATURE--MANY AUTHORED BY FDA OFFICIALS WHO HAVE POLICY RESPONSIBILITIES FOR AREAS COVERED IN REGULATIONS AND GUIDELINES. SOME RELATE TO EXTANT TOPICS, OTHERS ARE MEANT TO SERVE AS PUBLIC ANNOUNCEMENTS OF NEW POLICIES AND REGULATIONS. MANY OF THESE NEW ITEMS ARE COVERED CONCURRENTLY IN THE LAY PRESS. THIS CAN SERVE AS AN ALERT FOR YOU TO REQUEST THE ORIGINAL DOCUMENT FROM US. MANY OF YOU PROBABLY SAW THE ANNOUNCEMENT IN THE NEWSPAPERS LATE LAST WEEK ABOUT FDA'S NEW PRPOSALS ABOUT ADVERSE EXPERIENCE REPORTING. THESE HAVE VERY IMPORTANT IMPLICATIONS FOR IRBS AND HUMAN SUBJECT PROTECTION, NATIONALLY AND INTERNATIONALLY. ALTHOUGH THE TERM "IRB" IS NOT MENTIONED IN THE PROPOSED REGULATIONS, THE IRB COMMUNITY NEEDS TO BE AWARE OF THE PROPOSAL AND TO COMMENT ON THESE. WE ALWAYS TRY TO USE OUR MONTHLY COLUMN IN JAMA, "FROM THE FDA," TO DESCRIBE NEW TOPICS OF INTEREST TO IRBS AND CLINICAL INVESTIGATORS. WE HAVE A CHALLENGE TO GET INFORMATION ABOUT OUR ACTIONS TO YOU. YOU HAVE A CHALLENGE TO BE ALERT TO NEW INFORMATION THAT WILL HELP YOU IN YOUR DUTIES. PARTICIPATE IN CONFERENCES AND SYMPOSIA AND GIVE US YOUR COMMENTS ON OUR PROPOSALS, INFORMATION SHEETS, OR ANY OF THE TOPICS. YOU ARE DEALING WITH MULTIPLE FEDERAL, STATE, AND LOCAL AGENCIES, AS WELL AS WITH YOUR OWN INSTITUTIONS, AND WITH LAWS, REGULATIONS, GUIDELINES, AND POLICIES. YOU ARE ON THE FRONT LINE PUTTING ALL THESE INTO OPERATION. WE NEED TO KNOW WHERE THE PROBLEMS ARE. WE DO NOT WANT TO BE AN IMPEDIMENT TO THE SMOOTH FUNCTIONING OF THE SYSTEM THAT HAS BEEN ESTABLISHED.

ALTHOUGH THE COPIES OF THE IRB INFORMATION SHEETS THAT ARE AVAILABLE HERE AT THE CONFERENCE WITH AN OCTOBER 1994 DATE HAVE BEEN UPDATED IN A NUMBER OF RESPECTS, WE ARE CURRENTLY IN THE PROCESS OF GATHERING SUGGESTED CHANGES AND COMMENTS FOR A POSSIBLE MAJOR RE-WRITE OF MANY OF THE SHEETS. WE WELCOME ANY COMMENTS THAT YOU MAY HAVE.

CONCLUSION

THANK YOU FOR GIVING ME THE OPPORTUNITY TO PRESENT SOME OF THE CHALLENGES THAT WE FACE AND IN OFFERING A PERSPECTIVE ON HOW FDA IS ADDRESSING THESE WITH YOUR ASSISTANCE.

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(Hypertext updated by jch 1998-MAY-14)