Department  of Health  and Human  Services 
OFFICE  OF 
INSPECTOR  GENERAL 
Institutional  Review  Boards: 
A  Time  for  Reform 
JUNE  GIBBS  BROWN 
Inspecior  General 
JUNE1998 
OEI-01-97-00193  EXECUTIVE  SUMMARY 
PURPOSE 
To summarize  the challenges facing  institutional  review  boards and to make 
recommendations  for Federal oversight. 
BACKGROUND 
Role  of Institutional  Review  Boards 
Institutional  review  boards (IRE3s) play  vital roles in protecting  human research subjects. 
They review  initial  research plans to make certain that the plans provide  subjects with 
adequate opportunity  to provide  informed  consent and do not expose subjects to 
unreasonable  risks.  They also conduct  continuing  review  of approved  research to ensure 
that human-subject  protections  remain  in force.  They carry out their  initial  and 
continuing  review  functions  in accord  with  Federal regulations  first established  in the 
1970s and applicable  to all research funded  by the U.S. Department  of Health and Human 
Services or carried out on products  regulated  by the Food and Drug  Administration. 
This  Summary  Report 
This is a synthesis report.  It draws  on our broad inquiry  of 1-s  and on findings  we 
presented in three parallel  reports.  Its overarching  conclusion  is that the long-established 
system for protecting  human research subjects has vulnerabilities  that threaten its 
effectiveness.  In the report we highlight  the major  elements leading  to this conclusion 
and offer recommendations  for improvement.  The recommendations  are especially 
important  in view  of current  Federal  plans to increase significantly  the numbers of human 
subjects participating  in clinical  trials,  and proposals  to give IRE& increased responsibility 
in the areas of genetics and confidentiality. 
With  this report,  we offer a warning  signal  and a framework  for a concerted response to 
it.  We do not document, nor do we suggest that widespread  harm is being done to human 
subjects.  We recognize the strengths  of the current  system and seek to build  on them to 
enhance human-subject  protections. 
Methodology 
Given  our focus on the overall  system of protections,  we did not carry  out audits of IRBs 
or investigations  of particular  cases.  To help us understand  the big picture,  we conducted 
an extensive  review  of Federal records  and pertinent  literature;  held interviews  and group 
discussions  with  many Federal officials  and with  representatives  of about 75 IRBs; 
visited  IRE3sat 6 academic health  centers where extensive  clinical  research is taking 
place; attended IRE3meetings;  and accompanied  FDA  inspectors  on IRB  site visits. 
i 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  FINDINGS 
The  Effectiveness  of IRBs  Is in Jeopardy. 
They  Face Major  Changes  in the Research  Environment.  The current  framework  of 
IRB  practices was shaped in the 1970s in an environment  where  research typically  was 
carried out by a single  investigator  working  under government  funding  with  a small 
cohort  of human  subjects in a university  teaching  hospital.  In recent years, that 
environment  has been changing  dramatically  as a result of the expansion  of managed 
care, the increased commercialization  of research, the proliferation  of multi-site  trials, 
new types of research, the increased number of research proposals,  and the rise of patient 
consumerism.  Each of these developments  has presented major  disruptions  and 
challenges  for IRBs.  Never  before,  concluded  one recent review,  has such a pressure-
cooker  atmosphere  prevailed  within  the IRB  system. 
They  Review  Too  Much,  Too  Quickly,  with  Too  Little  Expertise.  This is especially 
apparent in many  of the larger institutions.  Expanded  workloads,  resource constraints, 
and extensive Federal  mandates contribute  to a rushed atmosphere  where  sufficient 
deliberation  often  is not possible.  At the same time, the IRBs  frequently  are hardpressed 
to gain access to the scientific  expertise they need to reach informed  judgments  about the 
research taking  place under their jurisdiction. 
They  Conduct  Minimal  Continuing  Review  of Approved  Research.  In the 
environment  described  above, continuing  review  often loses out.  Even where there is the 
will,  there often is not the time to go beyond the perfunctory  obligations.  A lack of 
feedback from  other entities  that oversee multi-site  trials  contributes  to the problem.  The 
result is that IRBs  have all too little  information  about how  the informed  consent process 
really  works  and about how  well  the interests of subjects are being protected  during  the 
course of research. 
They  Face Conflicts  That  Threaten  Their  Independence.  Clinical  research provides 
revenue and prestige  to the institutions  to which  many IRBs  belong.  The institutions 
expect IRBs  to support  these interests at the same time that they protect  human subjects. 
The resulting  tension  can lessen the IRBs  focus on their  basic mission.  The minimal 
outside  representation  that typically  exists on IRBs  deprives  them of an important 
counterbalance  to the institutional  interests.  For independent  IRBs,  the dependence on 
revenue from  industry  sponsors exerts similar  possibilities  for conflict. 
They  Provide  Little  Training  for  Investigators  and  Board  Members.  The RI3  system 
depends heavily  on research investigators  commitment  to uphold  human-subject 
protections.  But  as that system now  operates, it offers little  educational  outreach to 
investigators  to help them become informed  and sensitized  about these protections. 
Similarly,  it provides  minimal  orientation  and continuing  education  for IRB  members--a 
deficiency  that is especially  detrimental  to nonscientific  and noninstitutional  members. 
-w 
ii  OEI-Ol-97-00193  IRBS:  A Time  For Reform  Neither  IRBs  Nor  HHS  Devote  Much  Attention  to Evaluating  IRB  Effectiveness. 

IRBs  rarely  conduct  inquiries  to determine  how  well  they are accomplishing  their 

mission;  their judgments  of effectiveness  rely  mainly  on the number  of protection  lapses 

or complaints  that are brought  to their  attention.  The HHS  agencies conducting  oversight 

seldom go any further.  The Offrce  for Protection  from  Research Risks,  in the National  1 

Institutes  of Health,  focuses almost entirely  on upfront  assurances.  The Food and Drug 

Administration  relies on compliance-focused  inspections. 

RECOMMENDATIONS 
With  the above findings,  we do not claim  that there are widespread  abuses of human 
research subjects.  The current  system of protections  is supported  by many  conscientious 
research investigators  committed  to protecting  human subjects and by many dedicated 
IRB  members and staff doing  their best under trying  circumstances.  A reviewer  of this 
system can not help but be impressed by the contributions  of these individuals,  and the 
important  function  that IRBs  have fulfilled  over the past quarter of a century. 
But our findings  present an important  warning  signal.  The capacity  of IRBs  to 
accomplish  all that is expected of them is strained.  In the years ahead, this difficult 
situation  could  become even worse  in view  of Federal plans to increase significantly  the 
numbers  of subjects in clinical  trials  and various  proposals  to give IRBs  added 
responsibility  in the areas of genetics and confidentiality.  It is time, we believe,  for 
reform. 
Our recommendations  offer  a framework  for such a response.  We direct  them jointly  to 
the two  HHS  agencies responsible  for IRB  oversight:  the Office  of Protection  from 
Research Risks  (OPRR),  which  is located within  the National  Institutes  of Health  (NIH), 
and the Food and Drug  Administration  (FDA).  These agencies oversee IRBs  with 
different  jurisdictions  and operational  approaches.  It is essential, therefore,  for them to 
collaborate  closely  if HHS  as a whole  is to respond  effectively  to the serious concerns 
that emerge from  our inquiry.  Below  we present our general recommendations  for the 
two  agencies.  In the text, we offer  more explicit  elaborations  directed,  as appropriate,  to 
the particular  agencies. 
Recast  Federal  IRB  Requirements  So That  They  Grant  IRBs  Greater  Flexibility  and  Hold 
Them  More  Accountable  for  Results. 
t Eliminate  or lessen some of the procedural  requirements  directed  to IRBs. 
t Require  that IRBs  undergo  regular  performance-focused  evaluations. 
Strengthen  Continuing  Protections  for  Human  Subjects-Participating  in Research. 
b Require  Data Safety Monitoring  Boards  for some multi-site  trials. 
. . . 

111  OEI-Ol-9740193  IRBS:  A Time  For Reform 
 b Provide  IRESswith  feedback  on developments  concerning  multi-site  trials. 
b Routinely  provide  IRE&swith  feedback about FDA  actions against investigators. 
b Require  sponsors and investigators  to notify  IRBs  of prior  reviews  of research plans. 
b Call for increased IRE3 awareness of on-site research practices. 
Enact  Federal  Requirements  That  Help  Ensure  That  Investigators  and  IRB  Members  Are 
Adequately  Educated  About  and  Sensitized  to Human-Subject  Protections. 
b Require  that research institutions  have a program  for educating  its investigators  on 
human-subject  protections. 
. 	Require  that investigators  provide  a written  attestation  of their familiarity  with  and 
commitment  to human-subject  protections. 
b Require  that IRBs  have an educational  program  for board members. 
Help  Insulate  IRBs  from  Conflicts  That  Can  Compromise  Their  Mission  in Protecting 
Human  Subjects. 
b Require  more representation  on Irks  of nonscientific  and noninstitutional  members. 
b Reinforce  to IRE3 institutions  the importance  of IRBs  having  sufficient  independence. 
b Prohibit  IRE! equity  owners  from  participating  in the IRE3review  process. 
Recognize  the Seriousness  of the Workload  Pressures  That  Many  IRBs  Face and  Take 
Actions  That  Aim  to Moderate  Them. 
b Require  that IREJshave access to adequate resources. 
Reengineer  the Federal  Oversight  Process. 
b Revamp the NIWOPRR  assurance process. 
b Revamp the FDA  on-site  inspection  process. 
t Require  the registration  of 1-s. 
iv 
031-01-97-00193  IRRS:  A Time  For Reform  COMMENTS  ON THE  DRAFT  REPORTS 
Within  the Department  of Health  and Human  Services (HHS),  we received comments  on 
our four draft  reports from the National  Institutes  of Health  (NIH),  the Food and Drug 
Administration  (FDA),  and jointly  from the Assistant  Secretary for Planning  and 
Evaluation  (ASPE)  and the Assistant  Secretary for Health  (ASH).  We also solicited  and 
received  comments  from the following  external  organizations:  the Applied  Research 
Ethics National  Association  (ARENA),  the American  Association  of Medical  Colleges 
(AAMC),  the Consortium  of Independent  Review  Boards  (CIRB),  and Public  Citizens 
Health  Research Group.  We include  the detailed  text of their  comments  and our 
responses to them in appendix  D.  Below  we summarize  the major  thrust of both their 
comments  and our responses.  We made a number  of changes in the final  reports.  Most 
were technical  in nature.  Their  comments  sought to clarify  certain  findings  and a few 
involved  clarifications  and elaborations  concerning  the recommendations. 
NIH,  FDA,  and  ASPE/ASH  Comments 
The HHS  parties viewed  the reports as raising  important  issues and recommendations 
warranting  widespread  discussion.  They  suggested various  ways this could be 
accomplished.  The NIH  expressed particular  support  for our recommendation  calling  for 
the assurance process to be revamped  so that it rests essentially  on an institutional 
attestation  to conform  to IRB  requirements  and thereby  enables OPRR to focus more on 
performance  assessment and education.  The FDA  expressed reservations  about 
refocusing  its compliance-oriented  inspection  process, which  it regards as having  great 
value,  to one that is more performance-oriented.  The FDA  also raised concerns about 
the resource implications  of some of our recommendations. 
We will  support  efforts to engage broadly-based  dialogue  on our findings  and 
recommendations.  At the same time, we underscore  the importance  ofpractical  near-
term actions  that can be taken to address the vulnerabilities  we point  out.  We 
particularly  urge that FDA  and NIH  incorporate  into their  oversight  spectfic lines of 
inquiry  to determine  how well IRBs are actually  protecting  human subjects.  This would 
call for  examining  such matters as how the processes  of recruiting,  selecting,  and gaining 
informed  consent@om  human subj*ects actually  work.  It would  also call for addressing 
vertftcation  efforts to make sure that protocols  are in fact  submittedfor  review and that 
approvedprotocols  do not stray offcourse.  On the matter  of resources,  we agree that this 
is an important  issue warranting  serious  attention  in the research  andpolicy 
communities,  particularly  in view of added responsibilities  IRBs may well face  in the 
years  ahead. 
External  Organizations  Comments 
While  the external  parties supported  many of our findings  and recommendations,  they 
also raised some strong concerns.  Basically,  these involved  differences  of substance and 
objections  to the use of certain terms and language.  In regard to the former,  Public 
V  OEI-Ol-97-00193  IRBS:  A Time  For Reform  Citizen,  in expressing  considerable  alarm over our findings,  felt that we should have gone 
further  with  our investigations  and recommendations.  On the other hand, ARENA  and 
AAMC  had reservations  about our call for performance-focused  evaluations  and for more 
outside representation  on IRBs.  They were also concerned  that a more active IRB  role in 
conducting  continuing  review  could  undermine  the trust that has existed between IRBs 
and the research community.  With  respect to the language we used, ARENA,  AAMC, 
and CIRE3 called for a more precise use of a number  of terms.  The ARENA  indicated  that 
our use of the term IRE3 oversight  was particularly  misleading.  The ARENA  and 
AAMC  both indicated  that some of our wording  was unduly  alarmist  and more 
encompassing  than our methodology  warranted. 
To facilitate  a serious  examination  of the matters of substance  we raise,  we changed 
some of the language  we used in the draft  reports.  Most  notably,  instead of referring  to 
IRB  oversight,  we focused  on IRB responsibilities  and authorities  to conduct 
continuing  review,  as spectfied  in Federal  regulations.  But, this and various  other 
such textual  modifications  we made in no way lessen our assessment that the effectiveness 
of the IRB system is in jeopardy.  Our wide  ranging  and in-depth  inquiry  offers us ample 
basis to sound that warning.  With respect to concerns  raised  that focus  more strictly  on 
matters of substance, we must underscore  that if IRBs are to meet the significant 
challenges  they face  in the years  ahead  they must become more fully  accountable  to the 
public.  Trust in the investigators  performing  research  is vitally  important,  but in itself is 
insuf$cient.  The IRBs and Federal  oversight  agencies mustfind  more effective and open 
ways of verifying  that the consumer protection  mission  of IRBs is in fact  being 
accomplished.  This is especially  important  as the research  environment  in which  IRBs 
function  becomes increasingly  commercialized. 
vi 
OEI-Ol-9740193  IRRS:  A Time  For Reform  PAGE 
EXECUTIVE  SUMMARY 
INTRODUCTION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..l 
IRBs:THEBASICS............................................................3 
FINDINGS:  The Effectiveness  of IRBs  is in Jeopardy 
They  Face Major  Changes in the Research Environment  ........................  .4 
They Review  Too Much,  Too Quickly,  with  Too Little  Expertise  .................  .5 
They Conduct  Minimal  Continuing  Review  of Approved  Research  ................  .6 
They Face Conflicts  that Threaten  Their  Independence  .........................  .7 
They Provide  Little  Training  for Investigators  and Board  Members  .................  8 
Neither  They Nor  HHS  Devote  Much  Emphasis to Evaluating  Effectiveness  .........  8 
RECOMMENDATIONS.......................................................lO 
COMMENTS  ON THE  DRAFT  REPORT  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22 
APPENDICES 
A: Advertising  to Recruit  Human  Subjects  .................................  A-l 
B: Federal Requirements  on IRB  Continuing  Review  ..........................  B-l 
C: Federal Oversight  of IRBs  .............................................  C-l 
D: Comments  on the Draft  Reports  .......................................  D-l 
E:Endnotes  ........................................................  ..E- 1 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  INTRODUCTION 
PURPOSE 
To summarize  the challenges  facing  institutional  review  boards and to make 
recommendations  for Federal oversight. 
BACKGROUND 
On page three we offer  a primer  on IRBs:  why  they were established, what roles they 
perform,  how  they are organized,  where  they are located, and how they are overseen by 
the Department  of Health  and Human  Services. 
Prior  Inquiries 
For about a quarter of a century,  IRELshave been playing  an important  role in protecting 
human subjects enrolled  in research projects.  Almost  from the start, however,  prominent 
studies have drawn  attention  to some of their  limitations.  A  1983 Presidential 
commission  report raised concerns  about the adequacy  of the review procedures  of some 
Irks,  about how well  some of the members  of these boards understood  their  roles, and 
about the commitment  of some of the institutions  to their  1RBs.r  Twelve  years later, in 
1995, a Presidential  advisory  committee  raised even stronger  concerns about the 
adequacy of the IRB  review  process, especially  for research involving  greater than 
minimal  risks, and about the effectiveness  of Federal oversight  strategies.*  In the 
following  year, the General Accounting  Office  issued a report reinforcing  these points 
and identifying  numerous  factors inhibiting  IRB  performance.3 
In a recent inquiry  of our own,  we raised concerns  about the continuing  review  effort  of 
Irks.  In examining  clinical  trials  involving  four  investigational  medical  devices, we 
discovered  inadequacies  related to IRB  oversight  in each case. These inadequacies 
concerned  serious matters such as the implantation  of a device in three times the number 
of human subjects specified  in the IRB-approved  research protocol,  the initiation  of a 
research effort  without  the changes called  for in the informed  consent document,  and the 
continuation  of a research project  for six weeks beyond  when the IRB  had suspended it.4 
The concerns about human-subject  protections  become even more significant  in view  of 
current  developments.  These include  current  Federal plans to raise the level of funding 
for the National  Institutes  of Health  (NIH),  which  would  significantly  increase the 
number  of human subjects participating  in clinical  trials,  and proposals to give Irks 
increased responsibility  in the areas of genetic testing  and confidentiality. 
1 
OEMl-9740193  IRBS:  A Time  For Reform  This Inquiry  and Report 
This inquiry  builds  on the prior  reviews  and, we hope, will  contribute  to the deliberations 
of the currently  active Presidential  advisory  body examining  the protections  available  to 
human subjects.6  This report  is one of four that has resulted  from  our total inquiry.  It is a 
summary  report that draws  on our overall  review  and on findings  presented in the three 
companion  reports.  It presents a picture  of IRE& under considerable  stress. It houses our 
recommendations  for improving  the current  system of human-subject  protections. 
A second report, Institutional  Review Boards:  Their Role in Reviewing  Approved 
Research, finds that continuing  review  of approved  research is of vital  importance  but 
that IREJsare devoting  little  attention  to this part of their  mission.  It also identifies  key 
obstacles to effective  continuing  review.  A third  report, Institutional  Review Boards: 
Promising  Approaches,  presents innovative  strategies that IRE& have developed in six 
key areas of responsibility.  These include  promising  approaches to managing  the 
expanding  workload  and providing  education  to investigators  and members.  A fourth 
report, Institutional  Review Boards:  The Emergence  of Independent  Boards,  finds that 
independent  IRBs  are becoming  a significant  force and addresses the advantages and 
disadvantages they present. 
The inquiry  that supports  each of these reports draws on a rich variety  of sources.  These 
included  analyses of Federal records; reviews  of government  documents  and national 
commission  reports produced  over the past 25 years; articles  and books addressing 
human-subject  protections;  site visits to IRE& in 6 academic health  centers 7; additional 
IRE3 site visits accompanying  FDA  inspectors;  attendance at IRE3 meetings;  a survey on 
the electronic  e-mail  forum  for those associated with  IRE3s; and the systematic gathering 
of data from representatives  of about 75 IRE& of varying  sizes and auspices.8 At the 
academic health centers, which  are among the most heavily  funded  biomedical  research 
centers in the cour~try,~ we interviewed  not only  IRB  administrators  and members, but 
also many others in the parent institutions  who  had a bearing  on IRB  performance.  These 
included  medical  school  deans; hospital  vice presidents;  heads of pertinent  academic, 
administrative,  and clinical  committees  or departments;  attorneys;  ethicists;  and many 
others. 
The thrust of our information  gathering  for this and the other reports  was to gain a better 
understanding  of the big picture  involving  IRE3s. We focused on the IRB  system as a 
whole  and on the environment  in which  they function.  We did not conduct  an audit of 
their operations,  nor did we carry out an investigation  of specific  IRE& or of specific 
research plans reviewed  by IRE3.s. 
We conducted  this inspection  in accordance with  the Quality  Standards for Inspections 
issued by the Presidents  Council  on Integrity  and Efficiency. 
2 
OEI-Ol-97-00193  IRRS:  A Time  For Reform  INSTITUTIONAL  REVIEW  BOARDS:  THE  BASICS 
What Do They  Do? 
The responsibilities of IRBs fall into two main categories:initial review and continuing review of research 
involving human subjects. 
Initial  Review:  IRBs review and approve a researchplan before the researchis carried out. This review 
encompassesthe researchprotocol, the informed consent document to be signed by subjects,any 
advertisementsto be used in recruiting subjects,and other relevant documents. In carrying out this review, 
the boards seekto ensurethat any risks subjectsmay incur are warranted in relation to the anticipated 
benefits, that informed consentdocuments clearly convey the risks and the true nature of research,that 
advertisementsare not misleading, and that the selection of subjectsis equitable andjustified.  IRBs focus 
much attention on the informed consent document becauseit is the vehicle for providing information to 
potential researchsubjects. 
Continuing  Review:  The continuing review processis multifaceted and includes required reviews at an 
interval appropriate to the degreeof risk but not lessthan once per year.  In addition to this continuing 
review, study amendmentsand reports of unexpectedadverseexperiencesby subjectsare received 
periodically and reviewed to ensurethat the risk-benefit ratio of the researchhasnot changedandremains 
acceptable. 
Why  Were They  Established? 
As public awarenessand concern about the treatment of human subjectsin researchincreased,the needfor 
additional review mechanismswas evident. Theseconcerns grew from stories of the abuseof subjectsduring 
the World War II trials at Nuremberg, the promotional distribution of thalidomide resulting in numerous 
children born with birth defects,the administration of cancer cells to chronically ill and senile patientsat a 
hospital in New York, and others. A 1966 article by Henry Beecherbrought prominent attention to human 
researchabusesin medical schoolsand hospitals citing 22 casesinvolving  highly questionableethics. The 
formal requirements for the establishmentof IRBs were outlined in regulations stemming from the National 
ResearchAct of 1974 and in FDA regulations issued in 1981. 
Where  Are They  Located? 
An estimated3,000-5,000 IRBs can be found acrossthe country.  They are most commonly associatedwith 
hospitals and academiccenters. Boards also exist in managedcare organizations, government agencies(such 
asthe National Institutes of Health, the Centersfor DiseaseControl, and Stategovernments),or asfor-profit 
entities that are independentof the institutions in which the researchtakes place. 
How Are They  Organized? 
Federalregulations require that boardshave at least five memberswith varying backgrounds. At leastone 
membermust have primarily scientific interests,one must have primarily  nonscientific interests,and one must 
be otherwise unaffiliated with the institution in which the IREJresides. A quorum, with at leastonemember 
whose interestsare primarily nonscientific present, is neededfor voting. 
How Does the Department  of Health  and Human  Services  (HHS) Oversee  Them? 
Two agencieswithin HHS shareresponsibility for IRB oversight: the Office for Protection from Research 
Risks (OPRR) in NIH and the FDA.  The OPRRs main tool for oversight is the assurancedocument. Any 
institution that intends to conduct HHS-funded researchmust have an assuranceon file with OPRR. The 
assuranceis a written statementof an institutions requirements for its IRB and human-subjectprotections. 
Institutions consistently conducting multiple HHS-supported studies are eligible for a multiple project 
assurance(MPA) which can be renewed every five years. Institutions with smaller HHS-funded workloads, 
however, usea single project assurance(SPA) for each such project it conducts. The OPRRalso conductsa 
small number of site visits.  The FDAs main mechanism for IRB oversight is the inspection process. The 
FDA also inspectsresearchsponsorsand scientists (known as researchinvestigators). A more detailed 
t-explanation of the agencies oversight processescan be found in appendix C. 
3 
OEI-Ol-97-00193  IRRS:  A Time  For Reform  FINDINGS 
The Effectiveness  of IRBs  Is in Jeopardy. 
As they have for about 25 years, IRBs  continue  to provide  vital  protections  for human 
subjects.  But our inquiry  leads us to the troubling  central conclusion  that the system of 
protections,  that has been so carefully  developed  over the years, is in jeopardy.  A recent 
review,  published  in The Journal  of the American  Medical  Association,  offered a similar 
conclusion:  Never  before has such a pressure-cooker  atmosphere  prevailed  within  the 
IRB  system, leading  government  officials,  university  administrators,  research sponsors, 
and IRB  members to wonder  whether  the IRB  system will  crack or reform. 
This vulnerability  becomes especially  significant  in view  of emerging.budgetary 
developments  that could add significantly  to the number  of human  subjects taking  part in 
clinical  trials  and proposals  to give IRBs  increased responsibility  in the areas of genetic 
testing and confidentiality.  It is crucial,  therefore,  to understand  the major  factors that 
jeopardize  IRB  effectiveness  and then to take strong corrective  actions.  In our three other 
reports we identify  and explain  a number  of such factors.  Below,  we highlight  six that 
are particularly  compelling  and that buttress the case for reform  at a national  level. 
IRBs  Face Major  Changes  in the Research  Environment. 
Federal IRB  regulations  were formulated  during  the 1970s and early  1980s at a time when 
most research involving  human subjects took place under government  funding  in a 
university  teaching  hospital  with  established  research-related  controls.  Clinical  trials 
typically  involved  a small cohort  of subjects and were generally  conducted  by a single 
investigator  at a single institution.2  In the wake of the Tuskegee experiments  and other 
research abuses of human subjects, there was considerable  awareness of the risks that 
research could pose for human subjects.13 IRB  workloads  were, for the most part, limited 
enough to allow  IRBs  ample opportunity  to deliberate  about the research proposals before 
them.r4 
The environment  in which  IRBs  operate has changed significantly  in the past two 
decades.  The chart on the next page identifies  six major  developments  contributing  to 
this change and outlines  some of the key implications  for IRBs. 
One of the more visible  reflections  of this new environment  is the widespread  advertising 
that sponsors and investigators  often rely upon to recruit  human  subjects.  Such 
advertisements  are prominently  displayed  in buses and subways,  newspapers,  university 
bulletin  boards, and other places.  Typically,  they stress the personal  benefits  (including 
cash payments)  that one may receive by signing  up as a research subject and make no 
mention  of attendant risks (see appendix  A).  _ 
4 
031-01-97-00193  IRIS:  A Time  For Reform  A CHANGING  ENVIRONMENT  FOR IRBs 
CHANGE  EXPLANATION  KEY  IMPLICATIONSFOR IRBs 
Expansion of  Emphasison cost control  *Pressuresto accommodateresearchsponsorswho can 

Managed Care 	 and competition.  Squeeze  provide research-relatedrevenuesfor the parent institution. 

on researchsupport for  *Increaseddifficulty  in obtaining staff and other resources. 

academichealth centers.  *More pressureon staff physiciansto generateincome, 

with lesstime available for voluntary commitmentsto IRBs. 

Increased  Heightened industry role  l Institutional and sponsorpressuresfor quick reviews. 

Commercialization  in sponsoring research.  *Sponsorshopping for customer-focusedIRBs. 

of Research 	 Sponsoremphasison rapid  *Added complexity on issuesinvolving liability,  academic 

product development.  freedom, and patient disclosure. 

Proliferation of  Proliferation of trials  *Diminished influence of local review. 

Multi-Center  spreadacrosshundreds of  *Flood of adverse-eventreportsto review. 

Trials 	 sites, even acrossthe  *Lack of accessto significant information concerning the 

world.  statusof ongoing research. 

New Types of  Advances in biomedical  *Need for new, highly specializedareasof expertise. 

Research 	 researchin the areasof  *Emergenceof thorny ethical issuesinvolving  informed 

genetesting and gene  consentand appropriate research. 

therapy; increasedresearch  -Increased importance of having noninstitutional board 

on mental health issues.  members. 

IncreasedNumber  Intensified efforts to  *Significant increasein workloads. 

of Proposals 	 obtain government funding  *Without sufficient increasesin staff and/or efficiency, less 

and to develop new  time is available to review initial protocols and to conduct 

products.  continuing reviews of approvedresearch. 

Rise of Patient  Increasedconsumer  *Presentsmajor challengesin: 
Consumerism  demand for accessto  Ensuring equitable recruitment of subjects. 
research.  Ascertaining local attitudes and values. 
Maintaining distinctions betweentherapy and research. 
IRBs  Review  Too  Much,  Too  Quickly,  with  Too  Little  Expertise. 
IRBs  across the country  are inundated  with  protocols.  Our study sites reported  average 
increases of 42 percent in initial  reviews  during  the past 5 years, with  the result that some 
of them are now  reviewing  more than 2,000 protocols.  At the same time, these IRBs  are 
being deluged with  adverse-event  reports from  the multi-center  trials they oversee.  One 
IRB  we visited  had received  several boxes of adverse-event  reports within  the past few 
weeks.  Another  indicated  that it was receiving  an average of 200 such reports a month. 
Although  the large academic  health centers are hit hardest by mounting  workloads,  small 
IRE!s are suffering  as well.  Several small IRE3 representatives  told us that while  the 
number  of proposals  they review  is substantially  fewer than at the large institutions,  they 
--  often have only  one staff member who  is responsible  for coordinating  all IRE3 activities. 
5 
OEI-Ol-9740193  IRBS:  A Time  For Reform  Despite  the increase in workload,  staffing  levels and budgets have remained the same at 
many IRE3s. At the same time, 
managed care cost pressures have 
constrained  the time that IRE3members 
IRBs Under Pressure 
have to devote to reviewing  protocols. 
In an effort  to cope, many rely on pre- The agendasof the IRB review meetingsat 
academichealth centerswhere most of the HHS
assigned reviewers  to examine and 
sponsoredresearchoccurs arepacked, leaving 
summarize  research plans for the entire 
busy reviewers little time to reflect on and debate 
IRB.  In some IRBs,  unless one of the 
issuesraised by researchprotocols. As an 
assigned reviewers  raises a question  or  illustration, at the siteswe visited, their most 
concern  about the research, the IRE3  recent meetings typically lastedabout 2 % hours 
and included an averageof 18 initial reviews, 9 
engages in little  or no discussion  at its 
expedited reviews, 43 protocol amendments,and 
meeting.15  While  some IRE& have been 
2 1 adverse-eventreports. 
able to increase the length  of their 
meetings,  others squeeze more reviews 
into a fixed  block  of time.  With  limited  personnel  and few resources, IRBs  are hard 
pressed to give each review  sufficient  attention.  A  1996 GAO  report stated that some 
Irks  may spend only  one to two  minutes  of review  per study.16 
Many  IRBs  find that they lack sufficient  scientific  expertise  on their boards or staffs to 
adequately  assess protocols.  For example,  protocols  involving  advanced biomedical 
techniques--such  as gene testing--raise  scientific  issues, as well  as moral  and ethical 
questions,  that might  not be apparent to the untrained  eye.  From time to time, IRBs  will 
use consultants  to fill  the gap, but this can be costly  and can bog down  an already 
overburdened  review  process. 
IRBs  Conduct  Minimal  Continuing  Review  of Approved  Research. 
Continuing  review  has become a low  priority  at many IRBs,  often relegated to the last 
few minutes  of a meeting.  For example,  at one IRE3 meeting  we observed, several annual 
reviews  and amendments were approved  within  the last 15 minutes of the 2 %hour 
meeting.  At another site, several members were visibly  hurried  to end the almost 6 hour 
meeting  and the board relied mainly  on the assessment of the primary  reviewer  for the 
annual re-reviews.  One IRE3member told  us that he reviews  the continuing  review 
summaries  during  the board meeting  to see if a patient  has died.  If no patient  has died, 
then he generally  will  not raise questions. 
Continuing  review  is a paper-based activity  at many IRE3s. At the six academic medical 
centers we visited,  officials  reported  that during  the past year they seldom visited  the 
research site.  Five of the 11 independent  boards we interviewed  reported  that they have 
no routine  policy  for visiting  the research sites under their purview.  Although  many IRBs 
would  like to, very few oversee the consent process or solicit  feedback from  subjects. 
According  to one IRB  chair, the lack of resources has forced  IRE&sto rely  on the 
willingness  of investigators  to provide  timely,  accurate reports to the IRK  Many 
6 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  members are uncomfortable  with  this degree of reliance  on self-reported  data and would 
like to devote more attention  to continuing  review. 
Continuing  review  is further  limited  by the inadequate  information  IRBs receive from 
outside  sources.  There is little  communication  between  the Data Safety Monitoring 
Boards, which  are established by sponsors to oversee many  of the large-scale trials,  and 
the IRB.  The adverse-event reports that the IRBs receive  from  sponsors arrive without 
sufficient  contextual  information  to make them meaningful.  When FDA  issues a warning 
letter to a clinical  investigator,  it typically  does not inform  the IRB.7  And,  when a 
sponsor or investigator  submits a research plan to the IRB,  it may not inform  the RI3  of 
any prior  review  of that plan by another IRB. * 
In an effort  to improve  continuing  review,  the OPRR and FDA  have issued interpretations 
of Federal requirements  in the forms of Dear Colleague  letters and Information  Sheets.lg 
Many  of these are outlined  in appendix  B.  From the perspective  of the IRBs, some of 
these have served to reduce IRE3flexibility  and add to their  burdens.  Of particular  note is 
the OPRR issuance reinforcing  the Federal intent that IRBs  conduct  substantive and 
meaningful  annual reviews  of active protocols.  This issuance, some conclude, has had a 
particularly  disruptive  and demoralizing  effect on many IRBs.~ 
IRBs  Face Conflicts  that  Threaten  Their  Independence. 
Clinical  research is an important  revenue source for most academic  health centers.  For 
example, at one of our sites, about 25 percent of the operating  budget  (nearly $200 
million)  derives from research activities.  For decades, under the fee-for-service  system, 
research expenditures  were subsidized  by patient-care  revenues;  under managed care, 
however,  traditional  financial  support  for research activities  has been diminishing.  In the 
process, commercial  sponsorship  has become increasingly  important.  At the academic 
health centers we visited,  commercial  sponsorship  accounted  for as much as 50 percent of 
the research funding. 
Commercial  sponsorship  of research has heightened  the potential  for conflicts  of interest. 
We found  several examples of hospital  IRBs  that are housed  in offices  of grants and 
contracts or in clinical  research programs,  the very offices  geared to bringing  in research 
dollars.  Such organizational  placements,  while  not necessarily  representing  a conflict, 
certainly  can accentuate pressures on IRBs  to accommodate  institutional  financial 
interests.  Independent  IRBs,  which  primarily  review  commercially  sponsored research, 
are subject to similar  pressures.  This may be particularly  so for those independent  IRBs 
that are owned  by contract  research organizations:  and those that allow  equity owners  to 
participate  in the review  process.  The NIH  policy  for HHS-funded  research reviews  by 
for-profit  IRBs  is to prohibit  IRB  equity  owners  from participating  in the review  process, 
but there is no such policy  for industry-sponsored  studies submitted  to FDA. 
The phenomenon  of IRB  shopping,  in which  research sponsors  seek out the IRB  they 
..-
choose to work  with,  places considerable  pressure on IRBs  and their  institutions. 
7 
OEI-tIl-97-00193  IRBS:  A Time  For Reform  Commercial  sponsors seek quick  turnaround  reviews  for their protocols  and can be tough 
negotiators  on publication  rights,  liability  issues, and other matters.  Many  academic 
health centers are struggling  to respond to this new environment.  They find it especially 
difficult  to be as timely  in their reviews  as the independent,  typically  for-profit  IRBs that 
are a growing  presence.  While  they rarely  can conduct  initial  reviews  within  a month, the 
independent  IRBs  often do so in little  more than a week.22 
Federal regulations  calling  for at least one IRB  member whose  concerns are primarily  in 
nonscientific  areas and orie member who  is not otherwise  affiliated  with  the institution 
aim to provide  a counterbalance  to the kind  of pressures noted above.  But, we found few 
such outside  members on the boards.  Few IRBs  seem to seek or to be able, on a 
consistent  basis, to recruit  and maintain  lay and/or nonaffiliated  members who play an 
active, effective  role in helping  the IRBs  stay focused on their mission  of protecting 
human subjects.  It is not unusual  for an IRB  of 15 to 20 or more members to include  only 
one or two  noninstitutional  members. 
IRBs  and  Their  Institutions  Provide  Little  Training  for  Investigators  and  Board  Members. 
The IRB  officials  that we spoke with  fully  recognize  the significance  of educational 
outreach  to research investigators  and board members.  Many  have been active in holding 
seminars and/or providing  individualized  assistance to help investigators  become more 
informed  about and sensitized to human-subject  protections.  But nationally,  in the 
context  of the numbers of investigators  and the complexity  of the issues, such efforts are 
minimal.  Further,  they face significant  obstacles which  include  not only  insufficient 
resources, but the reluctance  of many investigators,  especially  experienced  ones, to 
participate. 
For new RI3  members, their  orientation  to the role is seldom much more than a stack of 
materials  to read and on-the-job  learning.  A  1995 survey of 172 university-based  IRBs 
found  that one-quarter  offered  no training  at all to their members.  At the vast majority  of 
institutions,  training  was limited  to less than four hours. 23 This limitation  is especially 
detrimental  to the outside  members who  tend to need grounding  not only  in the basics 
of the regulations  but also, in many cases, in the basic concepts,  approaches, and terms 
associated with  scientific  research.  The lack of such training  further  impedes their ability 
to serve as an effective  counterbalance  to institutional  and scientific  interests. 
Neither  IRBs  nor  HHS  Devote  Much  Emphasis  to Evaluating  IRB  Effectiveness. 
As we conducted  our inquiry,  we became increasingly  aware of a striking  reality:  IRBs 
have little  basis for knowing  how  well  they are accomplishing  their  mission  of protecting 
human  subjects.  The IRB  and institutional  officials  we spoke with  typically  felt that their 
IRBs  were quite successful.  But when  we asked them their  bases for that judgment,  they 
almost  invariably  pointed  to the lack of serious problems  or complaints  that have come to 
their  attention.  Such factors are, of course, relevant  to assessing effectiveness,  but in 
.. 

themselves provide  a weak  foundation.  Seldom,  we found,  do the IRBs  seek out 
8 
OEI-Ol-9740193  IRBS:  A Time  For Reform  feedback  from human subjects or their families,  examine the few complaints  that they do 

receive to determine  if they reflect  broader,  systemic problems,  or initiate  probing 

inquiries--for  example, to determine  how  the informed  consent process is actually 

working.  Even more seldom,  it appears, do independent,  outside parties conduct  such 

evaluations. 

Federal oversight  does not compensate  for these deficiencies  as it, too, is not geared to 

evaluating  effectiveness  (see appendix  C).  The OPRRs  oversight  is limited  almost 

entirely  to upfront  assurances aimed at obtaining  an institutions  commitment  to adhere to 

Federal requirements.24  The majority  of IRB  staff we spoke with  viewed  the assurance as 

a paperwork  process having  no impact  on RI3  functioning.  Only  in instances of alleged 

breakdowns  in RI3  protections  has the OPRR conducted  site visits.  Some of these 

reviews  represent the most probing  and results-focused  inquiries  we have found of IRB 

performance,  resulting  in strong recommendations  to the IRBs.  But because of resource 

shortages, they are infrequent.  Between  April  1997 and May  1998 only  one such visit 

was carried  out. 

The FDA  oversight  involves  a more frequent  on-site presence.  In 1997, they conducted  a 

little  under 200 site visits  (see appendix  C).  These visits  are carried out by FDA 

inspectors  who  often are also responsible  for inspections  focusing  on food products, 

research sponsors, and clinical  investigators.  They  focus almost entirely  on IRB 

compliance  with  the procedural  requirements  set forth  in Federal regulations--concerning 

matters such as attendance at review  meetings,  completeness  of minutes,  and a review  of 

the informed  consent document.  Such matters can be important  indicators  of 

performance,  but they offer  FDA  little  direct  feedback  on the actual effectiveness  of 

IRBs.  For instance, in an information  letter to IRBs,  FDA  calls for them to make certain 

that individuals  understand  what  they are consenting  to when they agree to participate  in a 

research effort.  Yet, FDAs  inspection  process does not extend beyond  determining  that 

informed  consent forms contain  all the appropriate  elements and that they have been 

reviewed  by the IRB.  For example,  the FDA  inspectors  do not review  the adequacy of 

the IRBs  own bases for determining  subject understanding. 

9 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  The stress that so many IRBs  now  face compromises  the protections  that IRBs  seek to 
provide  to human research subjects.  Federal leadership  can be instrumental  in addressing t 
this vulnerability  and in shoring  up the system of protections  that is vital to the continued 
progress of biomedical  and behavioral  research.  It is toward  this end that we present our 
recommendations.  We call for some strong and inevitably  controversial  actions.  But, the 
recommendations  also seek to minimize  unnecessary  Federal regulation.  They reflect  a 
respect for the largely  collegial  manner in which  IRBs  operate and aim to nourish  the 
volunteer  contributions  that have provided  the underpinning  of IRB  reviews.  They also 
take into account the increasingly  important  role being played by independent  IRBs. 
We direct  most of our recommendations  jointly  to the Office  of Protection  from Research 
Risks (OPRR)  which  is located within  the National  Institutes  of Health  (N1I-I)~ and to 
the Food and Drug  Administration  (FDA),  since they are the two  focal points for IRB 
oversight  in the Department  of Health  and Human  Services (HHS).  In those instances 
where we direct  a recommendation  to one of the agencies, we specify the agency. 
In presenting  our recommendations  jointly  to NIWOPRR  and FDA,  we fully  recognize 
that they have different  jurisdictions,  mandates, and operational  approaches.  Yet they are 
bound by a common  intent to protect  human  subjects and by what is, for the most part, a 
common  set of regulations.  If they are to respond effectively  to the very serious warning 
signal that our findings  present, then it is essential that they collaborate  closely  among 
themselves  and with  other pertinent  HHS  components.  In that context, they might  also 
address how  the Departments  responsibilities  for overseeing  IRBs  could  be organized  in 
a manner that is most effective  and allows  for the clearest possible Federal leadership. 
In their deliberations  on how to enhance human-subject  protections,  we also urge 
NIWOPRR  and FDA  to take the lead in finding  ways to involve  other non-HHS  parties. 
This should  include  representatives  of the research community,  the institutions  in which 
IRBs  are located, and most of all IRBs  themselves.  Many  of these individuals  bring 
valuable  front-line  perspectives  on how  best to protect  human subjects and can offer 
valuable  insights  into how the Federal government  can provide  effective  leadership. 
Finally,  we must emphasize that emerging  developments  add a sense of urgency  to the 
reforms  we propose.  Most  notably,  these include  Federal plans to increase substantially 
the Federal  investment  in cancer and other biomedical  research.  This expanded research 
holds forth  great potential  benefit to society  and perhaps even to subjects participating  in 
clinical  trials,  but at the same time it will  add to the review  burden of IRBs.  So too, if 
enacted, could  recent proposals  to expand IRB  responsibilities  in overseeing  genetic 
testing  and in ensuring  patient  confidentiality.  In considering  these developments,  it is 
particularly  vital  that sufficient  financial  provisions  be made to buttress IRB  and Federal 
efforts  that aim to provide  essential protections  for research subjects. 
10 
OEI-Ol-97-00193  IRRS:  A Time  For Reform  1.  Recast Federal  IRB  Requirements  so that  They  Grant  IRBs 
Greater  Flexibility  and Hold  Them  More  Accountable  for  Results. 
Such a redirection  is an essential starting  point.  We have found  that RI3  members and 
staff tend to be strongly  committed  to human-subject  protections  and have many ideas 
about how  to improve  performance.  Our report  on promising  approaches reveals many of 
the innovative  efforts they are undertaking,  even under current  restraints?6  The 
NII-I/OPRR  and FDA  could help unleash further  innovation  by giving  IRBs  more 
flexibility  in how they carry out their  responsibilities.  But,  in doing  so, a necessary quid 
pro quo, we believe,  would  be a greater accountability  for results. 
What we call for here is in accordance  with  what is occurring  generally  in the field of 
health care quality  assurance.  For instance,  in recently  announcing  major  reforms  in 
Federal conditions  for hospitals  participation  in Medicare,  HHS  Secretary  Shalala noted: 
We  are doing  away with  old requirements  that focused on process rather than results, 
and instead were  telling  hospitals  that they must monitor  the quality  of care they provide, 
improve  that quality,  and document  that improvement.27 
1 a.  Eliminate  or Lessen  Some of the Procedural  Requirements  that  Federal  Regulations 
Impose  on IRBs. 
The aim here should be to enable IRBs  to be more strategic  in how  they use their limited 

time and resources and, in that context,  to concentrate  their  attention  on those research 

practices posing  the greatest risks to human  subjects.  Too much of their  attention  now 

focuses on perfunctory  review  responsibilities  yielding  little  protective  value. 

The NIH/OPRR  and FDA  should work  with  IRBs  and others in identifying  the specific 

Federal requirements  to be eliminated  or modified.  One especially  strong candidate is the 

requirement  that IRBs  conduct  full,  annual reviews  of approved  protocols.  On the basis 

of our review,  this mandate generates substantial  burdens on IRBs  and does not have the 

intended  effect.  It compels IRBs  to devote too much effort  to routine,  paperwork  reviews 

at a time when the quantity  of that paperwork  is mounting.  It impedes them from taking  a 

more strategic  approach--one  that would  enable them to concentrate  on research 

involving  substantial  risks to human  subjects, to conduct  periodic  reviews,  and to visit 

research sites to determine  how the informed  consent process is actually  working. 

Another  candidate  for consideration  would  be what some call the unfunded  mandate, 

whereby  IRBs  must conduct complete  reviews  of Federal funding  applications  prior  to the 

funding  decisions.  Other candidates would  be those Federal requirements  that limit  what 

IRBs  can accomplish  in conducting  protocol  reviews  outside  of convened  board 

meetings.28 

11 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  1 b.  Require  that  All  IRBs  Under  the Purview  of NIH/OPRR  and  FDA  Undergo  Regular 
Performance-Focused  Evaluations  that  are Carried  Out  in Accord  with  Federal  Guidelines. 
This is the direction  called  for by the Advisory  Committee  on Human  Radiation 
Experiments.  In its 1995 report,  it concluded  (as we have) that the Federal system for   
overseeing  IRE& is inadequate.  An adequate system, it indicated,  would  require that  the 
system be subjected to regular,  periodic  evaluations  that are based on an examination  of 
outcomes  and performance  and that include  the perspective  and experiences  of research 
as well  as the research community.2g 
Federal guidelines  for IRB  evaluations  should call for the evaluation  results to be 
available  to the public  (to foster accountability).  The guidelines  should  be minimal  and 
should  stress assessments of IRB  effectiveness.  In this regard, they should be attuned to 
the Institute  of Medicines  recent recommendation  that IRE3 systems be examined to 
determine  how  well  they are functioning.  Among  the basic questions  posed by the IOM 
that we believe warrant  particular  attention  are the following:  1)  Are IRE& successfully 
representing  the interests of human subjects in research and not merely  those of the 
sponsoring  institution?  and 2) Do IRE3sgenerally  fulfill  their  goals?3o We suggest that 
NIWOPRR  and FDA  convene symposia with  IRE3sto discuss the type of performance 
measures and evaluations  that would  foster a system of accountability  based more fully 
on results.31 
The federally  mandated  evaluations  could be self-evaluations  or, better yet, ones 
conducted  by independent,  outside parties.  Their  frequency  should  depend on the 
quantity  of protocols  being  reviewed  by an IRl3, but probably  no less than every 5 years. 
To reinforce  their  importance,  NIWOPRR  could include  an evaluation  requirement  as a 
component  of the assurances it obtains from research institutions. 
2. 	 Strengthen  Continuing  Protections  for  Human  Subjects 
Participating  in Research. 
In a prior  study focusing  on investigational  medical  devices, we found  significant 
deviations  from  IRB-approved  protocols  and raised concerns  about the adequacy of IRB 
oversight  of such protocols.32  In this study, which  was more broadly  based, we found 
little  basis for easing those concerns;  in fact, they have been intensified. 
It is essential, we believe,  for NIWOPRR  and FDA  to ensure more rigorous  and 
accountable  oversight  of research approved  by IRBs.  As we have noted, the current 
regulatory  infrastructure  was established at a time when  research was typically  conducted 
by a principal  investigator,  working  at one institution,  with  a local  cohort  of subjects?3 
Now,  a significant  portion  of IRE3approved  research is part of multi-site  trials involving 
many investigators  and subjects at sites across the nation  and even the world?4  The 
Federal regulations  should  be updated to account more fully  for these changed 
circumstances. 
12  031-01-97-00193  IRBS:  A Time  For Reform  2 a.  Require  Data  Safety  Monitoring  Boards  for  Multi-Site  Trials  that  are Under 
NIWOPRR  and  FDA  Purview  and  that  Meet  Specified  Conditions  Warranting  Such a 
Safeguard. 
Data Safety Monitoring  Boards  (DSMBs)  are independent  review  bodies that review 
ongoing  research to assess the efficacy  of the data, the adherence of the research to the 
approved  protocols,  and the continued  safety of the subjects.  These boards include 
medical,  scientific,  and other expertise that typically  is not available  on IRBs.  The NIH 
institutes  do require  DSMBs  for many of the cooperative  group projects  they fund.  But, 
there are no Federal regulations  calling  for the routine  establishment  of DSMBs?5  The 
NIWOPRR  and FDA  should take the lead in seeing that DSMBs  become more firmly 
established  as oversight  mechanisms  and be made more clearly  accountable  in that 
regard. Among  their designated  responsibilities  should be those of assessing, 
summarizing,  and determining  when  and how  to follow  up on adverse-event reports 
submitted  by sponsors/investigators. 
The NIWOPRR  and FDA  should  define the types of trials  for which  DSMBs  would  be 
required.  These could  include  trials that involve  many subjects, that include  control 
groups not having  access to the research interventions,  and/or that involve  new drugs, 
devices or procedures  that present significant  risks to human subjects.  In addition,  the 
NIWOPRR  and FDA  should  set forth  requirements  for the composition  of DSMBs. 
2 b.  Provide  IRBs  with  Regular  Feedback  on Developments  Concerning  Multi-Site  Trials. 
As we have noted, a substantial  portion  of the research that many IRBs  now  oversee 

involves  local research investigators  and local  subjects participating  in national  or 

international  multi-site  trials  bound  by a common  research protocol.  To provide  adequate 

continuing  review  in these situations,  IRBs  must be informed  about key developments 

concerning  the trial  as a whole.  For instance, if an IRB  receives a report about an 

unexpected  adverse outcome  experienced  by a local subject, it will  be hard pressed to 

assess the significance  of that information  unless it knows  how many such outcomes have 

occurred  for the overall  trial.  During  the course of our inquiry,  we identified  two  key 

sources of information  of this kind  that should regularly  be shared with  IRBs. 

First, and probably  most important,  is information  from DSMBs.  Instead of receiving 

large quantities  of individual  adverse-event  reports  submitted  by sponsors and 

investigators,  IRBs  should  receive compilations  and assessments of those reports 

prepared  by DSMBs.  At present, most IRBs  receive little  if any feedback from  DSMBS?~ 

Routine,  substantive  feedback  from  DSMBs  would  allow  the IRB  to concentrate  its time 

and resources on reviewing  that which  it knows  best--the  continued  suitability  of the local 

environment  to the research project  in question.  Regular  feedback from the DSMB  will 

serve to increase the effectiveness  and thoroughness  of IRB  reviews,  as well  as its 

efficiency. 

13  OELOI-97-00193  IRRS:  A Time  For Reform  A second important,  external  source of information  is that which  federally  funded 
cooperative  research groups obtain  from their monitoring  visits to research sites that are 
part of a single protocol.37  This is valuable  information  collected  and analyzed by 
individuals  expert in the research being conducted.  The reports incorporating  this 
information  are sent to the research investigators,  but rarely  are shared with  the NBS!* 
The IRBs  should receive these reports routinely  and thus have the opportunity  to draw 
upon them as a complement  to their own reviews. 
2 c.  Routinely  Provide  IRBs  with  Feedback  on FDA  Actions  Taken  Against  Investigators 
Under  their  Jurisdiction. 
The FDA  inspections  of research investigators  can result in a variety  of actions, from 
warning  letters to a disqualification  from participating  in pre-market  research.  Officials 
at FDA  indicate  that legal restrictions  under the Privacy  Act  preclude  FDA  from 
disclosing  all investigator-related  correspondence  to Irks  and sponsors on a routine 
basis.  Certain  information,  however,  is available  to the public  on an FDA  web site or 
through  the Freedom of Information  Act.  But many IRBs  do not have the time to 
regularly  scan the FDA  website  and might  not know  when  to request information  from 
the FDA  about one of their  investigators.  The FDA  is in the process of seeking approval 
to modify  the relevant Privacy  Act  systems notice  so that the sharing of this information 
with  IRBs  and sponsors will  be made easier.  We think  this is important  as the lack of 
information  sharing puts IRBs  in an untenable  position  if they are to be held accountable 
for protecting  the interests of human subjects. 
2 d.  Require  Sponsors  and  Investigators  to Notify  IRBs  of any  Prior  IRB  Review  of a 
Research  Plan. 
We heard of a few situations  where sponsors and/or  research investigators  who were 
unhappy  with  one IRBs  reviews  switched  to another without  the new IRB  being aware of 
the others  prior  involvement.  This kind  of IRB  shopping  deprives the new IRB  of 
information  that it should  have and that can be important  in protecting  human subjects. 
The ground  rules should be changed so that the sponsors and investigators  have the clear 
obligation  to inform  an IRB  of any prior  reviews. 3g The obligation  should be applied  to 
all those conducting  research funded  by HHS  or carried  out on FDA-regulated  products. 
It will  have particular  importance  for those sponsors and investigators  working  with 
independent  IRBs. 
2 e.  Call  for  Increased  IRB  Awareness  of On-Site  Research  Practices  Involving  Human 
Subjects. 
To some readers, this recommendation  might  represent a violation  of the long established 
ethic of trust that has guided  IRBs  relationships  with  the research community.  It might 
be interpreted  as surveillance  and policing  that could  compromise  the research 
enterprise.  But given the scope and type of research now  under the purview  of IRBs,  the 
-- 
risks that much of this research presents to human  subjects, the widespread  blurring  of 
14 
OEI-OI-9740193  IRBS:  A Time  For Reform  research and therapy,  and, the kinds  of violations  we identified  in our previous  OIG 
report,  trust alone does not provide  sufficient  continuing  protection.  The credibility  of the 
IRB  process in protecting  human subjects requires  more.  While  trust must remain an 
important  part of the system, it should  be accompanied  by a greater readiness to verify 
that IRE3sare accomplishing  their  consumer  protection  mission.  Such verification  is 
allowable  under current  Federal regulations  and, in fact, consistent  with  the intent of the 
National  Commission  that laid the groundwork  for those regulations!o 
Increased awareness of actual practice  is consistent  with  our earlier  call for a greater 
focus on results and can be carried  out, we believe,  in a manner that does not shatter the 
foundation  of trust.  For projects that are particulary  sensitive and/or risky,  the increased 
awareness we call for can involve  observers,  intermediaries,  or counselors  who are 
available  to make sure that the informed  consent process functions  in the interests of the 
human  subjects.  It can involve  periodic,  announced  or unannounced,  random visits by 
IRE3representatives,  both to review  pertinent  records and to observe the informed  consent 
process.  It can involve  surveys of and/or  focus groups with  human subjects.  As 
illustrated  in our report  on promising  approaches,  several IRBs  have begun implementing 
these techniques.4  However  it is done, the aim should be to provide  IRE& with  greater 
assurance that stated intentions  involving  human subjects are, in fact, being fulfilled. 
3. 	 Enact  Federal  Requirements  that  Help  Ensure  that  Investigators 
and IRB  Members  are Adequately  Educated  About  and Sensitized 
to Human-Subject  Protections. 
In the final  analysis,  the most important  continuing  protection  for human subjects is the 
presence of well-trained  and sensitized  investigators.  Such investigators  can also serve to 
minimize  the need for regulatory  intervention,  be it by the Federal government  or by IlU3s 
themselves.  Accordingly,  our recommendation  calls for strong Federal action concerning 
education.  It is in accord with  the Presidents  May  1997 statement of apology  for the 
ethical  transgressions  of the Tuskegee  syphilis  study.  In that statement, the President 
announced  a commitment  to  strengthen  researchers  training  in bioethics  as a means of 
ensuring  that human subjects  rights  and dignity  will  be respected as new drugs, 
treatments,  and therapies are tested and used.*2 
The NIH  is well  positioned  to assume a leading  role here since it funds a significant 
portion  of the biomedical  and behavioral  research in the country.  It can help convey to 
researchers that along with  the considerable  independence  that they enjoy  in the research 
process there exists a significant  responsibility  to ensure that human  subjects are 
protected  in accord with  established principles  and Federal law.  It can assist IRBs  and 
their  institutions  by developing  generic  educational  materials  and model  curricula.  The 
NIH  may want  to consider working  with  the FDA,  and with  groups  such as PRIM&R  and 
ARENA,  to develop  these materials. 
15 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  3 a.  Require  that  Institutions  Receiving  Funding  Under  the Public  Health  Service  Act  for 
Research  Involving  Human  Subjects  Have  a Program  for  Educating  its Investigators  on 
Human-Subject  Protections. 
This is similar  to and an extension  of a current NIH  requirement  calling  for institutional   
recipients  of research training  grants to have acceptable plans for instructing  trainees in 
the responsible  conduct  of research.43 It parallels  a recommendation  offered  in 1995 by 
the Commission  on Research Integrity44 and is the kind  of recommendation  that 
NIWOPRR  sometimes  directs to an institution  after it has investigated  a lapse in the 
institutions  system of human-subject  protections.  Such a requirement  is currently  in 
place for research involving  animals. 
The education  we call for could  be provided  through  various  modalities  such as seminars, 
individual  instruction,  videos, or on-line  tutorials.  A number  of the IRE& we interviewed 
have, of their  own  accord, developed  innovative  educational  programs  along the lines we 
call for.  The NIWOPRR  could promote  these efforts and our recommendation  generally 
by calling  for an educational  assurance as part of its multiple  project  assurance (MPA) 
with  health care institutions.  This assurance would  more clearly  commit  the institutions 
to seeing that its investigators  have appropriate  training  in human-subject  protections. 
Further,  since institutions  with  MPAs  typically  apply the IRE3requirements  to all research 
conducted  by affiliated  researchers whether  or not they are funded  by NIH,  such an 
educational  assurance could help to reach a larger universe of investigators  than just those 
funded under Public  Health  Service Act  programs. 
3 b.  Require  that  Investigators  Receiving  Funding  Under  the Public  Health  Service Act  for 
Research  Involving  Human  Subjects  Provide  a Written  Attestation  that  They  Are  Familiar 
With  and Will  Uphold  Federal  Policies  Concerning  Human-Subject  Protections. 
This recommendation,  which  again parallels  one that the Commission  on Research 
Integrity  set forth  with  respect to the the  responsible  conduct  of research,  asks that the 
investigators  acknowledge  their  awareness of the pertinent  policies  and procedures.  It 
aims to heighten  their  awareness of their  responsibilities  as investigators  and their interest 
in participating  in educational  programs  addressing human-subject  protections.  The 
FDA,  it is important  to note, already  requires  a similar  attestation  for investigators 
submitting  an investigational  new drug  application  or investigational  device exemption  to 
the agency!  Further,  some of the institutions  we contacted  already  require  that 
investigators  sign statements assuring  the IRR that they are familiar  with  and will  adhere 
to the human-subject  protection  requirements. 
Even with  such an attestation,  we recognize  that its effectiveness  is likely  to depend 
heavily  on high-quality  educational  offerings  being readily  available  to investigators.  The 
prior  recommendation  calling  for institutions  to provide  educational  offerings  responds to 
this need.  The NIWOPRR  and FDA  could  also help meet it by conducting  more 
educational  outreach  of their own.  This  could  involve  the convening  of conferences, as 
W 	
they have periodically,  as well  as preparing  and disseminating  self-study  materials.46 
16 
OEI-Ol-97-00193  IRRS:  A Time  For Reform  3 c.  Require  that  Each  IRB  Under  the Purview  of NIIWOPRR  or FDA  Have  an Orientation 
Program  for  New  IRB  Members  and  a Continuing  Education  Program  for  All  Members. 
The core content of these education  programs  should cover not only  the basic 
requirements  spelled out in Federal law, but also a broader review  of ethical principles 
governing  human-subject  protections  and of ways in which  IRBs  can address those 
principles.  For noninstitutional  and nonscientific  board members, the educational 
programs  should also serve as a primer  on scientific  and research issues, with  the intent  of 
helping  the members gain a better appreciation  of key concepts, terms, and context.  Here, 
again, a prescription  that NIH/OPRR  sometimes offers as a corrective  action in response 
to an adverse event involving  human subjects should be incorporated  on the front  end as a 
required  preventive  measure and could be included  as part of multiple  project  assurances. 
4.  Help  Insulate  IRBs  from  Conflicts  that  Can Compromise  Their 
Mission  in Protecting  Human  Subjects. 
Two  long-time  analysts of IRBs  have described  IRB  regulations  as a permeable  shield, 
with  no strong framework  to ensure that the subjects  interests take precedence over 
institutional  ones.  They  added that in balancing  risks and benefits,  an IRB  that 
consistently  makes the calculus  in favor of research will  hardly  ever be identified.d7 
While  many Federal and IRB  officials  are likely  to object to this assessment, the minimal 
information  they have on the effectiveness  of IRBs makes it difficult  for them to rebut it. 
Even more troubling,  in an environment  where IRBs  are expected to be responsive to the 
financial  pressures facing  their parent institutions  and/or the sponsors, some IRBs  are 
finding  it difficult  to maintain  sufficient  focus on their core mission;  thus the above 
recommendation. 
Our point  is not that IRBs  can or should be completely  independent  entities impervious  to 
developments  in an increasingly  market-based  health care system.  Rather, it is that they 
and the Federal government  must be alert to pressures that might  lead some IRBs  to 
become overly  accommodating  to the significant  financial  pressures that surround  them. 
One of the most important  roles that NIWOPRR  and FDA  can play is to help prevent 
such accommodations. 
4 a.  Require  More  Extensive  Representation  on IRBs  of Nonscientific  and Noninstitutional 
Members. 
This is a vital matter that responds to a commitment  that the President made in his May 
1997 Tuskegee statement.48 Individuals  not associated with  the institution  or with  the 
research enterprise  can provide  a valuable  counterbalance  to pressures that threaten IRB 
independence.  But to do so, it is important  not only that they be well-trained,  but also 
that there be enough  of them on a board so that their-voices  are more likely  to be heard 
W 	
and their  sense of belonging  more likely  to be enhanced.  The current requirement  that 
there be one noninstitutional  and one nonscientific  member on a board (this requirement 
17 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  can be satisfied by the selection  of a single individual)  is clearly  inadequate in this regard. 
In its 1978 report the National  Commission  recommended  that at least one third  but no 
more than two thirds of IRE3 members be scientists  as a way assure the IRE3s access to 
[scientific]  expertise, yet guard against self-interest  influencing  or appearing  to influence 
IRE3 determination.  The case remains strong both for increasing  the number  of   
noninstitutional  and nonscientific  members and for requiring  that at least one 
noninstitutional  member be present at any board meeting  where research plans are 
reviewed.  It may well  be desirable,  we would  note, to include  scientists among the 
noninstitutional  members considered  for IRBs. 
4 b.  Reinforce  to IRBs  and Their  Parent  Institutions  the Importance  of IRBs  Maintaining 
Sufficient  Independence  in Their  Mission  to Protect  Human  Subjects. 
We suggest that an IRB  with  sufficient  independence  is one that is not under any 
institutional  or ownership  pressure whatsoever  to approve protocols  and related 
documents;  bases it reviews  on the merits of a proposal  and the attendant risk/benefit 
ratio,  without  regard for business concerns;  does not report directly  to the part of the 
institution  responsible  for bringing  in research funds;  is not compensated based on the 
outcome  of a review;  and has recourse, should  it feel subject to any pressure. 
Through  Dear  Colleague  and informational  letters, NIH/OPRR  and FDA  could  draw 
greater attention  to the danger signs that inhibit  IRE3sfrom  operating  with  sufficient 
independence  and to the kind  of preventive  measures that they and parent institutions 
might  take to ensure a proper  focus on their  core mission.  The FDA,  in its compliance 
site visits,  could give special attention  to the emergence of any of these signs and could 
bring  them to the attention  of the IRE3 and its parent institution.  The NIWOPRR  could 
reinforce  the issue by including  in its multiple  project  assurances a clause that institutions 
will  afford  their IRBs  sufficient  independence  in their mission  of protecting  human 
subjects.  Although  the immediate,  practical  effect of such a commitment  is uncertain,  it 
could  serve to generate additional  consideration  to this important  matter. 
4 c.  Prohibit  IRB  equity  owners  from  participating  in the IRB  review  process. 
Such participation,  in itself,  does not necessarily  inhibit  the independence  of the review 
process, but it creates a situation  that can be conducive  to ownership  influence  in that 
process and, certainly,  it undermines  a perception  of impartiality.  The OPRR practice  of 
prohibiting  such participation  should  be formalized.  The FDA  should follow  suit and 
prohibit  ownership  participation  in IRB  reviews  for industry-sponsored  research on 
products  to be submitted  to FDA  for approval. 
5.  Recognize the Seriousness of the Workload  Pressures that  Many 
IRBs 	 Face and Take Actions  that  Aim  to Moderate  Them. 
vu 
18 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  Federal actions along the lines we have called for in our previous  recommendations 
would  help reduce IRB  workload  pressures.  IRBs  would  be freed of a number of 
procedural  requirements  that are of questionable  value and of the torrent  of adverse-event 
reports they now receive.  Further,  if greater educational  outreach  led to investigators 
becoming  better informed  about the purpose and particulars  of regulations  to protect 
human subjects, IRBs  quite likely  would  find that research applications  submitted  by 
these investigators  would  require  fewer  changes (thus saving IRE3s time). 
Yet, even with  such changes, the adequacy of the resources available  to IFU3swould 
remain a significant  issue of concern.  If the external  pressures we have described in this 
report continue  (as seems likely)  and if IRBs  do more continuing  reviews  and evaluation 
(as we call for), IRBs  could  still be struggling  to maintain  a sufficient  level of human and 
other resources (such as computer  equipment  and office  space). 
5 a.  Require  That  IRBs  Have  Access to Sufficient  Resources  to Enable  Them  to Carry  out 
Their  Responsibilities  as Intended  in Federal  Law. 
The resources we refer to are, above all, the human resources represented by staff and 
board members, but also space, computers,  and other elements essential to an efficient 
and effective  IRE3. We recognize  that the term sufficient  is a general one, not easily 
measured.  Yet, the centrality  of the resource issue and the clear shortages that many 
IRBs  now  face, call for enhanced Federal attention  to it.  One direction  that NIWOPRR 
and FDA  could take toward  that end could  be the development  of indicators  of minimally 
adequate resource levels, below  which  IRBs  are likely  to find themselves in a danger 
zone.  For instance, these could  involve  measures of numbers  of staff and board members 
to the number  of active protocols,  or the number  of protocols  reviewed  per meeting.  As a 
starting point,  the NIWOPRR  and FDA  could  survey IRBs  about their  current resource 
levels. 
The NIWOPRR  Multiple  Project Assurance  currently  requires  institutions  to provide 
meeting  space and sufficient  staff  When negotiating  an MPA,  the NIWOPRR  could 
reinforce  the importance  of resource adequacy by bringing  the same scrutiny  to it when 
negotiating  those assurances as it does when  conducting  an investigation  of an IRBs 
lapse in protecting  human  subjects.51 Similarly,  the FDA  could  modify  its site visit 
protocol  to identify  signs of inadequate resource levels to use that information  to present 
recommendations,  or if serious enough,  warning  letters to the IRE& involved. 
6.  Reengineer  the Federal  Oversight  Process. 
As it now  functions,  the Federal oversight  of IRE& is not equipped  to respond effectively 
to the warning  signal we present in this report.  -l-heFDA  conducts just  under 200 IRB 
site inspections  a year, but its procedural,  compliance-focused  reviews  reveal little  about 
IRB  effectiveness  in protecting  human  subjects.  The NIWOPRR,  on the rare occasions 
19 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  when  it visits  IRBs,  gets closer to assessing IRB  performance  but its emphasis on upfront 
assurances is of questionable  value.  Further,  while  there is some sharing of information 
between  the two  agencies, they operate in very different  domains,  rooted  in separate 
statutory  bases and organizational  cultures. 
It is time, we believe,  for a fundamental  reexamination  and reengineering  of the HHS 
oversight  process, viewed  as a whole.  The principal  aims of this ambitious  effort  should 
be twofold:  (1) to develop  more streamlined,  coordinated,  and probing  means of assessing 
IRB  performance  and (2) to enhance the Federal  capacity  to identify  and respond to 
emerging  problems  before they result in serious transgressions. 
6 a.  Revamp  the NIIWOPRR  Assurance  Process 
We suggest reorienting  the assurance process so that it rests essentially  on an institutional 
attestation  to conform  to the IRB  requirements  set forth  in Federal regulations.52  This 
attestation  could  be provided  in a brief  statement referencing  the pertinent  regulations. 
As a result, the scarce NIWOPRR  resources that are now  devoted to reviewing  and 
negotiating  assurances could be freed up to conduct  periodic  performance-based  reviews 
along the lines we have been noting  and to provide  education  to help investigators  and 
IRB  members become knowledgeable  about and sensitized to human-subject  protections. 
Along  this line, we also suggest that NIWOPRR  consider providing  some incentive  for 
smaller IRBs  to tie in with  larger ones (both  hospital-based  and independent)  that can 
bring  more experience  to the job.  This  is important  in view  of the increased complexity, 
sensitivity,  and scale of so much of the research taking  place.  It is also important  because 
it could  help concentrate  Federal oversight  resources more effectively,  moving  in the 
directions  we call for in the prior  recommendations. 
6 b.  Revamp  the FDA  On-site  Inspection  Process. 
This is especially  important  under current  conditions  whereby  FDA  is the only  HHS 

agency conducting  IRB  site visits with  any degree of regularity.  We recognize  that there 

is some value to the compliance  checks that are the core of FDA  inspections.  But we 

suggest that FDA  search for ways of revamping  its inspections  so that they focus less on 

narrow  compliance  matters and more on performance  issues.  Such reviews  would  probe 

deeper and wider  and would  pay particular  attention  to how  individuals  are actually  being 

approached  about participating  as human  subjects and to how  IRBs  are making 

continuing  assessments of risk-benefit  trade-offs. 

We suggest further  that FDA  and NIWOPRR  collaborate  on ways in which  they could 

focus more directly  on front-line  practices  that have particular  bearing  on human 

subjects.  For instance, they might  probe  on how  often potential  subjects actually  turn 

down  requests to participate  in research or on how  much time they are given to deliberate 

about participation.  They might  also examine  the marketing  approaches being used to

*-
20 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  entice the participation  of subjects, paying  particular  attention  to whether  too much 
emphasis is given to potential  personal  benefits and not enough to risks. 
Both  FDA  and NIWOPRR  could  enhance a performance  focus by finding  ways in which 
experienced  IRB  members and staff could  play some on-site role in reviewing  IRB 
performance.s3  The Federal agencies could  include  such a peer review  element as part of 
some of its own reviews  and/or  offer  some kind  of incentive  for IRBs  to include  it as part 
of a continuous  quality  improvement  effort.  In either case, it would  represent a way of 
incorporating  greater outside  expertise  into site reviews  focusing  on performance. 
6 c.  Require  That  All  IRBs  Register  with  the Federal  Government  and  on a Regular  Basis 
Report  Minimal  Descriptive  Information. 
Uncertainty  as to the number  of IRBs  subject to regulatory  oversight  by FDA  and 
NIH/OPRR  is a major hindrance  to effective  oversight  by these agencies.  We recognize 
the concerns about Federal intrusions  that could add unnecessary burdens to the research 
process.  We suggest that a requirement  that all IRBs  register with  the Federal 
government  need not be much of an intrusion.  It could  involve  a simple registration 
process in which  IRBs  regularly  update the Federal government  on minimal  descriptive 
information.  This information,  for example, could  include  their location,  contact 
information,  and the number  of protocols  and human subjects under their jurisdiction. 
Such a requirement  would  help NIWOPRR  and FDA  to target their  oversight,  to 
communicate  more effectively  and fully  with  IRBs,  and, in the final  analysis, offer 
improved  protections  to human  subjects. 
21 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  COMMENTS  ON  THE  DRAFT  REPORTS 
Within  the Department  of Health  and Human  Services (HHS),  we received comments on 

our four draft reports from the National  Institutes  of Health  (NIH),  the Food and Drug  1 

Administration  (FDA),  and, jointly,  from the Assistant  Secretary for Planning  and 

Evaluation  (ASPE)  and the Assistant  Secretary for Health  (ASH),  who  is also the 

Surgeon General.  We also solicited  and received  comments  from the following  external 

organizations:  the Applied  Research Ethics National  Association  (ARENA),  the 

American  Association  of Medical  Colleges  (AAMC),  the Consortium  of Independent 

Review  Boards (CIRB),  and Public  Citizens  Health  Research Group.  We include  the 

complete  text of the detailed  comments  in appendix  D.  Below  we summarize the major 

comments  and, in italics,  offer our responses. 

NIH,  FDA,  and ASPE/ASH  Comments 
The HHS  parties responded  in generally  positive  terms.  They viewed the reports as 
raising  important  issues and recommendations  warranting  serious and widespread 
attention.  The NIH  urged that the final  reports be sent to all  16 Federal agencies adhering 
to the common  Federal regulations  on human-subject  protections;  indicated  that it will 
take our recommendations  to the National  Science and Technology  Council,  which  is 
responsible  for uniform  implementation  of the common  Federal regulations;  and 
suggested that our recommendations  will  be addressed at the FDAs  March  1999 National 
Forum  on Human  Subject Protections.  The FDA  expressed its intention  to place some of 
the issues posed in the report  on the agenda of the Forum.  And  ASPE/ASH  suggested 
that all the reports be placed on the HHS  website. 
Both NIH  and FDA  also offered  comments  on our specific  recommendations  calling  for a 
revamping  of NIH  and FDA  practices of overseeing  IRBs.  The NIH  responded that our 
call for reorienting  the assurance process so that it rests essentially  on an institutional 
attestation  to conform  to IRB  requirements  was well-taken.  It added that the OPRR has 
been seriously  considering  a redirection  of its intensive  assurance effort toward 
performance-based  reviews  of IRBs.  The FDA,  which  has a long-established  system of 
conducting  compliance-oriented  inspections  of IRBs,  responded  with  some caution  to our 
call that the inspections  focus less on narrow  compliance  matters and more on 
performance  issues.  The FDA  indicated  that it regarded  the current inspection  program  as 
having  great  value,  and that developing  performance  measures would  be a major 
challenge. 
Finally,  the FDA,  as well  as some of the subsequent  commenters,  pointed  out that some 
of our recommendations,  if enacted, could be resource  intensive  for IRBs  and as a 
result could  add to the stress on the IRB  system.  Such impact,  it suggested, must be 
carefully  considered. 
22 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  We appreciate  the interest  in using our reports  to stimulate  widespread  discussion  on 
how the IRB system can be reformed  to further  human-subject protections.  We will 
cooperate fully  in such efforts.  At the same time, we urge immediate  attention  to the 
spectjic  recommendations,  such as those concerning  information  sharing,  education,  and 
training,  which  can have important  near-term  effects in improving  protections.  We ought 
not allow  the needfor  discussion  to obscure  the importance  ofpractical  actions  that can 
be taken immediately  to address the vulnerabilities  we present  in our reports. 
On the matter of revamping  NI.OPRR  and FDA  oversight  practices,  we strongly  urge 
that both agencies give a priority  to identtjying  spectfic  ways of conducting  more 
extensive and eflective performance  assessments as part  of their  on-site reviews.  We 
recognize  that for FDA  this will  involve a major  departure  porn  a well-established 
compliance  approach  that does help assure conformance  with processes  calledfor  in 
Federal  regulations.  But given the scope and signtficance  of IRB responsibilities,  it is 
imperative,  as the Institute  of Medicine  has indicated,  to gain  a better understanding  of 
how well  IRBs are fulfilling  their goals  to represent  the interests  of human subjects.  Over 
time, this performance  assessment could  involve developing  specific  quantitative 
measures that could be helpful  in comparing  the performance  of different  IRBs and of 
individual  IRBs over time. But the move to performance  assessment should  not await 
such measures.  Many practical  steps can be taken in the near-term  to help assess or 
veriJL that IRBs are having  their  intended  impact. 
We would  be happy to workfurther  with  FDA  and/or  NIH  to examine specific  ways in 
which  their  on-site reviews might focus  more closely  and effectively  on results.  Among 
the key questions that should  be addressed  in any such effort  would  be the following: 
How  do we know that the informed  consent process  is carried  out in a manner that 
minimizes  the possibility  of coercion  or undue influence?  How  do we know that the 
process  of recruiting  and selecting  human subjects  is being  carried  out in an equitable 
manner?  How  do we know  tfprotocols  that should  be submittedfor  review  are not 
submitted?  Or ifapprovedprotocols  stray  in ways that are not identtjied  in paperwork 
submitted  to the IRB?  These vital  questions  call for  some kind of vertfication  by Federal 
parties  as well as IRBs themselves.  We ought not allow  the quest to develop quantitative 
performance  measures delay practical  steps that can be taken immediately. 
Finally,  FDA s point  about  the resource  implications  of our recommendations  is a very 
important  one, warranting  further  deliberation.  We suggest that some of our 
recommendations,  such as those that relieve IRBs of some Federal  procedural 
requirements  and of some of the burden  of adverse action  reviews,  would  help free  up 
resources.  But we recognize  that the  trust  but verify  thrust  we call for  is likely  to add 
to resource  needs as are other forces  now being exerted.  Most  especially,  theseforces 
include  a potentially  sign&ant  increase  in Federal funding  for research  on cancer and 
other serious diseases.  They also include policy  proposals  to enhance IRB 
responsibilities  to protect  individuals  participating  in genetic  tests and to ensure 
conzdentially  of information  obtained  on human subjects.  Thejeopardy  that we suggest 
exists now could well be exacerbated  tfIRBs  are not provided  with  sufficient  resources  to 
23  OEI-Ol-9740193  IRBS:  A Time  For Reform  carry  out the vital functions  being entrusted  to them.  This matter,  we believe, warrants 
serious  attention  in both the research  and policy  communities. 
External  Organizations  Comments 
To varying  degrees, the external parties supported  many of our findings  and 

recommendations.  But, overall,  they reflected  a number  of strong concerns.  Generally, 

these concerns involved  differences  of substance and objections  to our use of certain 

language. 

Overall,  the substantive  differences  were wide  ranging.  Public  Citizen  found many of our 

findings  to be alarming  and expressed concern  that we failed  to go far enough with  our 

investigations  or recommendations.  Among  other things,  it called for more funding  of 

IRBs,  greater representation  on IRBs  of disinterested  parties (including  scientists) from 

outside the institution,  and  FDA  regulation  of advertising  seeking human subjects for 

clinical  trials.  On the other hand, the ARENA  and AAMC  both expressed reservations 

about our call for performance-focused  evaluations  and for more outside representation 

on IRBs.  Both  also noted concern that a more active IRB  role in conducting  continuing 

review  could undermine  the trust and collegiality  that is key to the success of an IRB. 

The AAMC  added that our intent to insulate  IRBs  from  conflicts  with  their parent 

institutions  was  improperly  framed  because nothing  could  be more in the institutional 

interest than protecting  the subjects of research. 

The concerns about our use of certain terms and language,  expressed by ARENA, 

AAMC,  and CIRB,  were almost as strong as the ones about substance.  The ARENA,  in 

particular,  found  our use of the term IRB  oversight  to be misleading  because it 

suggested IRB  responsibilities  greater than those the IRBs  are mandated to carry out. 

Further,  both ARENA  and AAMC  raised concerns  that some of our wording  was 

inappropriately  alarmist  and more encompassing  than our methodology  warranted. 

In response to these concerns,  we changed some of the terms and language  we used in the 

draft  reports.  Most  notably,  instead of referring  to IRB  oversight,   we referred  to IRB 

responsibilities  and authorities  to conduct  continuing  review.  We also modtjied some 

statements in ways that we hope more clearly  andprecisely  express our findings  and 

concerns.  We made these changes because we seek to focus  attention  and dialogue  on 

the important  substantive  matters revealed  by our  inquiry  and on the needfor  reform  Cfor 

which  we believe there is widespread  support).  Our modtjications  in no way lessen our 

very real  concern  that the effectiveness of the IRB system, which  has performed  a 

valuable protective  function  for  many years,  is now  in jeopardy.  Our wide-ranging  data 

gathering  involving  in-depth  discussions  and reviews  in many different  settings provides 

us with  a sound basis to present  this warning. 

On the substantive  matters, we must underscore  that tfIRBs  are to meet the significant 

challenges facing  them in the years ahead, they must become more fully  accountable  to 

24 
OEI-Ol-9740193  IRBS:  A Time  For Reform  the public.  For  the system to be effective, trust  in those conducting  research  must remain 
an important  part  of the system.  But, it must be accompanied  by a greater  readiness  to 
verify that IRBs are accomplishing  their  consumer protection  mission.  Such verification 
is allowable  under current  Federal  regulations  and, in fact, consistentwith  the intent of 
the national  commission  in the 1970s that laid  the groundworkfor  those regulations.  We 
must also emphasize that in an increasingly  commercialized  research  environment  that is 
much different  than that which  existed when the regulations  were first  established, 
guarding  against  conflicts  that in subtle ways could  compromise  the IRBs  role  in 
protecting  human subjects is a matter  of increasing  urgency. 
25  OEI-Ol-9740193  IRBS:  A Time  For Reform  APPENDIX  A 

Advertisiw  to Recruit  Human  Subiects 
When Federal human-subject  protections  were established  in the 197Os, a key principle 
was that there should be clear distinctions  between research and therapy.  Subjects should 
participate  in research out of a desire to contribute  to generalizable  knowledge  and they 
should understand  that any personal benefits  were secondary.  Central  to their 
participation  was an assurance that they understood  the risks inherently  involved  in 
research; their  signature  on the informed  consent document  was meant to convey this 
understanding. 
Over the past two  decades this distinction  has increasingly  blurred  due to changes in 
subjects  and the investigators  perceptions.  Many  potential  subjects have begun to view 
access to research as their  best hope for effective  therapy  and do not want regulators 
inhibiting  such access out of a desire to protect  them.  At the same time, the growth  of 
multi-site  trials  increased the importance  of recruiting  large numbers  of research subjects. 
This,  in turn, created increased attention  to marketing  approaches to attract these potential 
subjects as researchers and their  sponsors began to emphasize the personal benefits that 
human subjects could  gain from participation  in research.  An effect of these changes has 
been that the line between  research and therapy has become increasingly  blurred.  As the 
Advisory  Committee  on Human  Radiation  Experiments  noted:  there is reason to worry 
that participants  in research may have unrealistic  expectations  both about the possibility 
that they will  personally  benefit  from  participation  and about the discomfort,  pain, and 
suffering  that sometimes accompany  some research.  The committee  further  stated that 
it is important  that in the informed  consent process, it is clearly  communicated  to the 
potential  subject . . .that the primary  intent  of research  is to advance medical  knowledge 
and not to advance the welfare  of particular  subjects. 
During  the course of our inquiry,  we identified  and collected  many advertisements 
seeking individuals  to participate  as human research subjects.  These advertisements  are 
readily  accessible to potential  subjects, being found  in newspapers  and on public 
transportation.  In a few of these advertisements,  even though  the studys  experimental 
nature is mentioned,  the accompanying  language strongly  implies  that the procedure  is 
treatment.*  Even when  this is not the case, the mention  of research is either placed at the 
end of a long list of benefits  or is embedded  in language so enticing  that the inevitable 
  Advisory  Committee  on Human  Radiation  Experiments,  Final  Report,  Washington  DC: 
U.S. Government  Printing  Office,  Chapter  18, Section 2 (1995). 
* It is important  to note that research advertisements-are  not substitutes  for the informed 
consent process.  Participants  must still  sign an informed  consent document  after they contact the 
researchers and agree to participate. 
A-l 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  risks of research are easily overlooked.  The advertisements  cite an overwhelming  array 
of these benefits  (see accompanying  box and photos  at the end of this appendix).  In only 
one study did the advertisers 
stress the voluntary  nature 
Examples of Marketing  Efforts  Aimed at Recruiting 
and not personal  gain. 
Human  Subjects 
Much  more commonly,  the 
advertisements  supported 
the view  that participation  in  DO YOU  HAVE  ASTHMA? 
research was an opportunity 
for the subject.  If you qualifjr for any of our asthma studies, you can: 
- Learn to care for your asthma! 
The danger of these  - Receive free medications! 
- Receive up to $1,730! 
advertisements  is that 
subjects may come to a 
research study with 
Women:  Receive $2710! 
misconceptions.  For 
example,  a person may enter 
Healthy,  non-smoking/drug-free  women (20-40) needed 
into research believing  it 
for USDA  research study.  Live-in  24 hrs/day for 78 days 
will  treat his or her 
depression,  panic disorder, 
diabetes, etc.  The allure  of  Speed or Cocaine? 
freedom  from  such an 
ailment  is likely  to be highly  Need help getting clean? 
motivating.  Persons may  Free Treatment  & Medication. 
also become attracted to  Repeat Callers Welcome! ! !  Get Paid $$$ 
research participation  by the 
promise  of alleviation  from 
Women With  PMS 
financial  as well  as physical 
distress.  They may be 
If you are between the ages of 18 and 40 and suffer from 

motivated  by the promise  of 
PMS (Premenstrual  Syndrome),  you may qualify  to 

free treatment,  free 
participate  in a research study using an investigational 

screening,  or extra money. 
drug for the treatment  of PMS. 

It is essential, therefore,  that 
both the informed  consent  If you qualify  to participate  you will  receive: 

document  and the individual  Free Medical  Exams  Free Pap Smears 

involved  in the recruitment  Free Labwork  Study Medications 

of subjects are vigilant  in  Up to $455 for Time  and Travel 
making  sure the risks 
involved  in research are 
clear.  But as we have noted in this report, IRBs  devote little  attention  to how the consent 
process works,  focusing  all too often solely on the documents  language. 
A-2  OEI-Ol-97-00193  IRBS:  A Time  For Reform  The following  two  photos were taken on a Philadelphia  subway  car in January  1998. 
Photoscourtesy of the OIG Office of Evaluation and Inspections, Philadelphia Regional Office 
A-3 
OEI-OI-97-00193  IRBS:  A Time  For Reform  APPENDIX  B 

Federal  Requirements  on IRB  Continuing  Review 
Institutional  review  boards  role in protecting  human subjects does not end after the 
completion  of an initial  review.  An  IRB  is responsible  for reviewing,  and has the 
authority  to monitor,  a research protocol  from the time of approval  onward--until  the 
close of the study.  The Department  of Health  and Human  Services, through  the auspices 
of both OPRR  and FDA,  has specific  requirements  concerning  how  this review  should be 
conducted.  These are specified  in the regulations  and elaborated  on in various agency 
issuances such as OPRRs  Dear  Colleague  letters and FDAs  information  sheets. The 
regulations  are intended  to be used as minimum  requirements  and IRBs  are encouraged to 
impose greater protections  as they see fit. 
The continuing  review  process is multifaceted  and involves  both an annual review  by the 
IRB  and the ongoing  review  of amendments,  modifications,  and adverse event reports as 
they are received.  What follows  is a brief  description  of the elements of this process. 
Continuing  Review 
A continuing  review  must be completed  at intervals  appropriate  to the degree of risk, but 

not less than once per year.*  This interval  has been interpreted  as no less than 12 months 

from the date of initial  review.3  The review  must be completed  by a convened board 

unless the protocol  qualifies  for an expedited  review  process.  The review  should include 

an assessment of the protocol  and any amendments/modifications.  A status report from 

the investigator  containing  such information  as the number  of subjects accrued, 

descriptions  of any adverse events or withdrawals  of subjects, new information  pertaining 

to the study and the current  informed  consent document  should  also be reviewed!  In 

particular,  attention  should be focused on determining  whether  the risk-benefit  ratio 

remains adequate based on the new information  and/or risks that were discovered. 

 45 C.F.R.,  sec. 46 (HHS/OPRR)  and 21 C.F.R.,  sec. 56 (FDA) 

Currently,  16 other Federal departments  and agencies abide by these regulations  through 

the Common  Rule for the protection  of human subjects in research, effective  August  19, 

1991. 

* Ibid. 
30PRR  Dear  Colleague  Letter,  10 January  1995, Continuing  Review--Institutional  and 
Institutional  Review  Board  Responsibilities.  -
41bid, FDA  Information  Sheets, 1995. 
B-l 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  APPENDIX  B 

Modifications  and Adverse  Event  Reports 
Periodically,  the IRB  may receive amendments/modifications  for active protocols.  They 
may include  a change in address of a sponsor or something  more significant  such as a   
change in the actual design of a protocol  or eligibility  requirements.  The ongoing  review 
of adverse-event  reports is another integral  and ongoing  task for IRBs.  An  adverse event 
is generally  defined  by the FDA  as a serious experience  by a subject that was not 
previously  anticipated  in nature or severity.  Serious  events include  anything  fatal, life-
threatening,  permanently  disabling,  or requiring  in-patient  hospitalization.  The 
requirements  can be found  in 21 C.F.R.,  section  312 (for drug research) and 21 C.F.R., 
section  8 12 (for device research).  They must be reviewed  by the IRB  or its 
representatives  who can then require  changes to the protocol.  The required  changes most 
often result in updating  the informed  consent document  to more accurately  explain  risks 
to subjects. 
Monitoring 
An IRB  has the authority  to directly  observe (or require  a third-party  to observe) both the 
consent process or the actual research. 5 IRBs  must also follow  written  procedures  for 
determining  which  studies require  verification  from  a source other than the investigator 
that no changes have occurred  and for ensuring  that any changes are not initiated  without 
IRB  review  and approval.6 
5 45 C.F.R.,  sec. 46 (HHWOPRR) 
21 C.F.R.,  sec. 56 (FDA) 
6 Changes may be initiated  before IRB  approval  if they are necessary to eliminate 
v-
immediate  hazards to subjects.  See Ibid. 
B-2 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  APPENDIX  C 

Federal  Oversight  of IRBs 
An estimated 3,000-5,000  IRBs  can be found across the country.  Two  agencies within 
HHS  responsible  for the oversight  of IRBs:  OPRR and FDA.  Each agency has its own set 
of regulations  which  have many similarities.  However,  their  processes for oversight  are 
markedly  different. 
The exact number of IRBs  is unknown  in part because of each agencys relationships  with 
IRBs.  The OPRR becomes aware of IRBs after an assurance is submitted  naming  the 
IRB  as its source of review.  Under  a single project  assurance (see below),  the IRB  has 
already reviewed  the protocol  and only NIH  funding  is needed.  The FDAs  contact with 
IRBs  comes only  at the time of an Investigational  New  Drug  or Investigational  Device 
Exemption  application.  By this time, the IRB  has already  reviewed  and approved the 
protocol  and the research is being  conducted.  Because the exact number is uncertain,  the 
FDA  acknowledges  that it is more difficult  to exercise their  regulatory  oversight. 
Office  for  Protection  from  Research Risks (OPRR) 
Assurances 
The OPRRs oversight  of IRBs  focuses on an upfront  assurance.  The assurance is a 
document  specifying  an institutions  commitment  to the human-subject  protections 
specified  in Federal regulations.  It outlines  the organization  and purview  of the IRB  in 
addition  to its processes for reviewing  protocols  and other procedural  issues.  Research 
funded by HHS  can only  be conducted  at a facility  holding  an assurance with  OPRR. 
There are three types of assurances: 
Multiple  Project  Assurances  (MPAs):  The MPA  allows  institutions  to conduct  any 
number  of HHS-funded  research projects  for an initial  period  of three years after which  it 
can be renewed  for 5 year intervals.  Regulations  require  the MPA  only  for HHS-funded 
efforts,  but most of the nearly  450 MPA  institutions  have extended the protections  to all 
research being conducted  at their  institutions.  Though  a minority  of IRBs hold MPAs, 
these institutions  account  for nearly  75 percent of NIH-funded  research. 
Single  Project  Assurances  (SPAS):  For those institutions  that do not have the high 
volume  of protocols  necessary to support the use of an MPA,  a single project  assurance is 
used.  For each project  an institution  wishes to conduct,  it must apply for an SPA.  This 
presents extra work  for the institution  as well  as OPRR,  who  must not only review  the 
institutional  commitments  to the IRB  and human-subject  protections,  but also must 
review  the research protocol  and informed  consent documents  for each project  assurance. 
Currently,  there are approximately  3,000 active SPAS. 
C-l 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  APPENDIX  C 

Cooperative  Project  Assurances  (CPAs):  The I-II-IS funds approximately  25 

cooperative  groups which  conduct  thousands of clinical  trials  across the country.  An 

institution  wishing  to conduct  any of the groups protocols  that does not have an MPA  can 

apply  for a cooperative  project  assurance.  The CPA  can then be used for any number of   

cooperative  projects.  Currently,  there are approximately  1,500 CPAs. 

The assurance application  process is conducted  entirely  through  document  transmittals 

and phone communication.  An  institution  wishing  to apply  for an assurance can receive a 

template  from  OPRR.  After  the institution  tailors  the template  to its specific  setting, it is 

submitted  to OPRR.  There, assurance branch  offtcers  will  review  the document.  Any 

problems  or suggestions  are worked  out through  the institutional  official(s)  and the 

assurance officer  before an approval  decision  is made. 

To ensure compliance,  OPRR  has the authority  to limit,  suspend, or withdraw  an 

institutions  assurance or require  special reporting. 

Investigations 
Compliance  investigations  are another component  of OPRRs oversight.  The OPRR 
conducts  investigations  primarily  on the basis of subject complaints,  after becoming 
aware of incidents  that appear to have resulted  from protection  breakdowns  or from 
referrals  within  the department  found  as a result of audits.8  The OPRR reports that the 
focus of the investigations  has shifted  in the past five years from micro-level  to systemic 
solutions.  There is no set investigational  protocol  as the corrective  actions are prescribed 
according  to the violation  and the needs of the IRB.  Since 1990, there have been 438 
investigations  of which  360 are considered  complete.  However,  the great majority  of 
investigations  occur through  paper and phone communication.  Only  rarely  does OPRR 
go on site.  Between  1990 and April  1996, OPRR went  on site to investigate  compliance 
only  18 times.  In fact, OPRR conducted  only  one such visit  between April  1997 and May 
1998 because of staffing  problems. 
7For an SPA, the protocol  and informed  consent document  must be reviewed  as well  as 
the assurance template.  The OPRR  reports that it spends much more time on SPAS even though 
more research projects  and more subjects are involved  under MPAs. 
Less frequently,  investigations  are conducted  as a result of suggestions  from Congress or 
the media. 
9 Technical-assistance  site visits are also conducted.  These visits are intended to be an 
educational  opportunity  for IRBs  and do not signal noncompliance.  Between  1990 and April 
1996, 13 such visits were completed. 
c-2 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  APPENDIX  C 

Food and Drug  Administration  (FDA) 
Inspections 
The FDAs  oversight  of IRBs  is one of many activities  conducted  in the process of 
evaluating  the safety and effectiveness  of the drugs, biologics,  and devices it regulates. 
The goal of the monitoring  process is to routinely  inspect an IRB  once every 5 years! 
However,  inspections  can also be conducted  as a part of the product-approval  process or 
because of possible noncompliance.  There are three centers within  FDA  that are 
responsible  for conducting  inspections:  Center for Drug  Evaluation  and Research 
(CDER),  Center for Device  and Radiologic  Health  (CDRH),  and the Center for Biologics 
Evaluation  and Research (CBER).  An  inspection  can be generated by any of the centers, 
but the inspections  are carried  out by the same group of FDA  inspectors  in regional 
offices  across the country.  The following  table illustrates  FY  1997 data for each of the 
three centers including  the number  of inspections  and the number  of official  and 
voluntary  actions indicated.   
The inspection  guidelines  focus on ensuring  compliance  through  the review  of IRB 
records and examination  of written  procedures.  Another  component  of the inspection  is 
the file review  of at least three actual research studies approved  by the IRB.  The files are 
examined to determine  such things  as a timely  continuing  review,  current  consent 
documents  were used, adverse-event  reports were submitted  and reviewed,  and whether  a 
lo This is difficult  to achieve because of workload  constraints;  IRBs  found  previously  to 
be significantly  deficient  are re-inspected  more often. 
Actions  taken are classified  according  to the strengthen  of the action  needed to correct 
the deficiencies  noted.  Official  action  indicated  (OAI)  is the most serious and warrants  FDA 
action.  Voluntary  action indicated  (VAI)  signifies  that the institution  will  correct the 
deficiencies  and often report their progress to FDA  at regular  intervals.  No  action  indicated 
(NAI)  is used for inspections  which  do not reveal any significant  deficiencies. 
c-3 
031-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  C 

quorum  was present during  the voting  procedures.  Based on the results of the inspection, 
FDA  has the authority  to issue a warning  letter signifying  serious deficiencies  or enact 
administrative  sanctions. 
Research investigators  can also be inspected  by FDA.  Generally  speaking, the inspections 
are designed to ensure data integrity  and ensure human-subject  protections  to the extent of 
whether  or not the informed  consent document  was signed and dated in a timely  manner. 
c-4  OEI-Ol-97-00193  IRBS:  A Time  For Reform  APPENDIX  D 

DETAILED  COMMENTS  ON  THE  DRAFT  REPORTS 
AND  OIG  RESPONSE  TO  THE  COMMENTS 
In this appendix  we present the full  comments  of all parties that responded to our four 
draft reports and our response to each set of comments.  In order, the comments that we 
present in this appendix  are from the following  parties: 
The National  Institutes  of Health,  U.S. Department  of Health  and Human  Services 
l 
The,Food  and Drug  Administration,  U.S. Department  of Health  and Human  Services 
l 
Assistant  Secretary for Planning  and Evaluation  and the Assistant  Secretary for Health/ 
l 
Surgeon General, U.S. Department  of Health  and Human  Services 
Public  Citizens  Health  Research Group 
l 
Applied  Research Ethics National  Association 
l 
American  Association  of Medical  Colleges 
l 
Consortium  of Independent  Review  Boards 
l 
D-l  OEI-Ol-97-00193  IRRS:  A Time  For Reform  DEPARTMENT  OF HEALTH  8r HUMAN  SERVICES  Public  Health  Service 
National Institutes  of  Health 
Bethesda,  Maryland 20892 
Ms. June Gibbs  Brown 

Inspector  General 

U.S. Department  of Health  and Human  Services 

Wilbur  J. Cohen  Building,  Room  5250 

330 Independence  Avenue,  S.W. 

Washington,  DC  20201 

Dear Ms.  Brown: 

I am writing  in response to your March  26, 1998 memorandum  that provides  four draft reports 
on Institutional  Review  Boards  (IRBs)  for review  and comment  by the National  Institutes  of 
Health  (N&I). 
The requirements  for IRB  membership,  function,  operations,  review  of research, and record 
keeping  are,described  by the core regulations  for Protection  of Human  Subjects of the 
Department  of Health  and Human  Services (DHHS)  at Subpart  A of Title  45 Code of Federal 
Regulations  Part 46.  The regulations  at Subpart A are the DHHS  manifestation  of a common 
rule, the  1991 Federal  Policy  for the Protection  of Human  Subjects.  In addition  to DHHS,  the 
1991 Federal  Policy  is shared by sixteen other agencies.  Because any proposal  to revise 
Subpart  A of 45 CFR  Part 46 would  require consideration  and concurrence  by these 16 other 
departments  and agencies, we ask that you convey  the final  versions of the four reports to your 
counterpart  at each respective  department  and agency. 
Also  to further  the broad appreciation  of your  recommendations,  NIH  will  take your final 
overview  and recommendations  to the Subcommittee  on Human  Subjects Research, Committee 
on Science,  National  Science and Technology  Council.  The Subcommittee  will  have great 
interest  in your  suggestions  for any potential  changes to the common  1991 Federal Policy  for the 
Protection  of Human  Subjects,  as it is responsible  for the uniform  implementation  of those 
common  regulations.  This committee  is chaired  and staffed by the Office  for Protection  from 
Research  Risks  (OPRR),  in the NM.  Because of OPRRs  authority  in negotiating  and approving 
assurances of regulatory  compliance  for Federal-wide  use, policy  changes by OPRR of the sort 
Institutional  Review Boards: Their Role in OverseeingApproved Research(OEI-01-97-00190); 
Institutional  Review Boards: Promising Approaches(OEI-01-97-00191); Institutional Review Boards:The 
Emergenceof Independent Boards (OEI-01-97-00192); Institutional Review Boards: A Systemin Jeopardy(OEI-
01-97-00193). 
Agency for International Development; Central Ihtelligence Agency; ConsumerProduct Safety 
Commission; Department of Agriculture; Departmentof Commerce;Departmentof Defense;Departmentof 
Education; Department of Energy; Department of Housing and Urban Development; Departmentof Justice; Social 
Security Administration;  Department of Transportation; Departmentof VeteransAffairs; Environmental 
Protection Agency;  National Aeronautics and SpaceAdministration; and National ScienceFoundation.  Page 2 - Ms. June Gibbs Brown 
contemplated  in your  reports are best not imposed  unilaterally.  Rather, such policy  changes 
need to be shaped by the departments  and agencies that will  be affected. 
Your  report  makes many valuable  suggestions  about the role of increased education  for scientists 
and IRB  members as well  as the need for institutions  to manage the process of IRB  review  with 
an eye to the growing  number  and complexity  of projects  for their review.  It would  appear that 
there could  be streamlining  in the processes from  the Federal side and from the institutional  side 
as well.  One area that may need further  elaboration  is the special challenges  posed by multi-site 
clinical  trials.  Many  of the steps that you would  recommend  the IRBs  take are already within 
their authority  to take; therefore,  we expect that your  report  will  prove useful to them as they 
seek to strengthen  their processes. 
NIH  has already  taken some steps to bring  improved  understanding  to one area - informed 
consent.  Last year we awarded  13 research grants to scientists who  are studying  informed 
consent.  In regard to the needs for education  and training,  we have issued two solicitations  for 
training  initiatives  in bioethics.  One will  provide  post-doctoral  training  for individuals  who  seek 
a concentrated  training  experience.  The other will  support  short-term  institutional  awards to 
make increased  training  in bioethics  available  to a larger number  of scientists. 
OPRR has increasingly  made information  that is useful  to IRBs  available  on its website.  OPRR 
is committed  to vigorous  consultation  with  IRBs  and institutional  officials.  This level of 
consultation,  for example,  is instrumental  in the development  of meaningful  performance 
measures for IRBs--as  called  for in your reports.  OPRR  and the Food  and Drug  Administration 
(FDA)  are scheduled  to meet with  numerous  IRB  members and staff in regional  conferences  in 
seven different  U.S. cities.  Furthermore,  NM  will  participate  in the FDAs  March  1999 
National  Forum  on Human  Subject  Protection,  at which  the recommendations  from  your reports
-__-
- as well  as other reviews  of IRB  functioning  - will  be a focus of discussion.  We look forward 
to that meeting  as an opportunity  to discuss with  the IRB  community  some best practices  in 
areas of education,  orientation,  management  and assessment of IRBs.  Your  report recommends 
additional  requirements  to be placed on IRBs,  but we hope to focus on the attainment  of the 
improvements  rather than increased Federal regulations. 
Your  suggestion  that the assurance process be reoriented  so that it rests essentially  on an 
institutional  attestation  to conform  to the IRB  requirements  set forth  in DHHS  regulations  is 
well-taken.  OPRR has been seriously  considering  a redirection  of its intensive assurance effort 
toward  performance-based  reviews  of IRBs.  Please know  that OPRR will  not abandon its 
current  preemptive  oversight  procedures  (i.e., negotiation  of institutional  assurances to comply) 
before putting  in place a next-generation,  competency-based  mechanism  for assuring 
compliance. 
Twenty-four  years after the initial  promulgation  of our Departments  rules for protection  of 
human subjects,  your  summary  of the challenges  today facing  IRBs,  and your recommendations 
for DHHS  oversight,  form  important  additions  to the evolving  body of analysis of our system of  Page 3 - Ms. June Gibbs Brown 
protecting  human subjects in research.  NIH  appreciates both the opportunity  to comment  on 
your evaluation,  and your contribution  to the ethical  conduct  of NM-sponsored  research. 
We would  be willing  to meet with  your  staff and discuss these comments. 
Sincerely,  APPENDIX  D 

OIG  RESPONSE  TO  NIH  COMMENTS 
We welcome  NIHs  positive  response to our reports and its readiness to use them to 
stimulate  widespread  discussion  of our findings  and recommendations.  Given that 
several Federal departments  and agencies share a common  Federal policy  on IRB 
protections,  we agree that it would  be particularly  important  and useful to involve them in 
considerations  of our reports.  We will  send our final  reports to each of the departments 
and agencies. 
At the same time, we must note that some of our recommendations  have particular 
relevance to NIH  and involve  matters that we believe warrant  near-term  action.  These 
include  our recommendations  that Data Safety Monitoring  Boards  be required  for multi-
site trials that meet specified  conditions  and that these boards regularly  provide to IRBs 
feedback on developments  concerning  these trials.  They also include  our 
recommendations  concerning  education  and training  of both investigators  and IRB board 
members.  In these areas, we believe  it is important  to move quickly  to spur developments 
that can provide  valuable  support  to IRBs  as they review  more and more research 
proposals  for NIH  funding. 
We recognize  and support  NIHs  interest  in streamlining  its review  processes and in 
reducing  any unnecessary  regulatory  burden  on IRBs  and researchers generally.  This is in 
accord with  encouragement  offered  in a House of Representatives  committee  report for 
the 1998 NIH  appropriations  bill.  It is also in accord with  our recommendations  to 
eliminate  or loosen some of the procedural  requirements  directed  to IRBs  and to revamp 
the NIH  institutional  assurance process so that it rests essentially  on an institutional 
attestation  to conform  to the IRB  requirements  set forth  in Federal regulations. 
The NIH  adds that it will  not abandon  its current  preemptive  oversight  procedures.  . . 
before putting  in place a next-generation,  competency-based  mechanism  for assuring 
compliance.  We support  this commitment  and agree that a transition  to a different 
system of oversight  must be carefully  orchestrated.  In this redirection,  a major challenge 
facing NIH  and the IRBs  themselves  is to devote more continuing  inquiry  to developing 
mechanisms  that will  help assure that the intended  human-subject  protections  sought by 
the IRB  regulations  are, in fact, being  achieved.  It was striking  to us, during  our own 
review,  how  little  inquiry  of that kind  now  occurs.  The NIH  is well-positioned  to provide 
leadership  and guidance  in this important  transition. 
Finally,  we note that the freed NIH  resources that would  result from  the streamlining 
process would  offer an important  opportunity  for OPRR to become more proactive  in 
educating  investigators  and IRB  members to become more knowledgeable  about and 
sensitized to human-subject  protections.  Such outreach could  be of great value to IRBs 
and could help in conveying  a broader  appreciation  for the importance  of ascertaining just 
how well  IRBs  are achieving  their  mission.  -
D-5 
OEI-Ol-97-00193  IRIS&  A Time  For Reform  DEPARTME~  OF HEAtTH  &  l3umAN  SEEVI- Publlo Hwlth  Service 
. 
Food ati  Drug Admkrktqtiqn 
Rockvillo  Mb  Z&fi7 
May 11,  1998 
To:  InspectorGenerai 
From:  Lead Deputy Commissioner 
Subject: 	 Comment6on the March 1998Draft Office of the InspectorGeneralReportson 
Institutional Review Boards 
We appreciatethe opportunity to commenton the March 1998draft report6on Institutional 
Review Board6(IRBs). We believethat  thesereportsrepresenta thoughtful and detallcd 
examinationof the IRB systemas well asthe rolesof the Federalandprivate sectorparties 
involved in that system. We will carefully considerthe findings, recommendationsa,nd 
supporting information containedin thesereports, which provide valuableinformation that will 
needto be consideredby FDA in collaborationwith NIH,  other federal agencies,andthe 
researchcommunity. 
While we agreewith the reports conclusionthat the IRB systemis stressed,we arc pleased 
that the reportsdescribedhow many IN38 havefound successfulandcreativemeasuresto deal 
with this stress. The reportsshould be particularly helpful to that portion of the IRB 
community still struggling with someof the problemsdescribedin the reports. 
We note that 6omeof the recommendationswhich could increasethe protection6provided to 
researchsubject6 could be very rcsourc:emtensivefor IRBs, clinical investigators,and 
alSO 
federal agenciesandcould, if implcment~  asrequirements,increasethe amountof stresson 
the IRE3system. We believethat it is, thc?fore, very Important to considerthe impact of each 
recommendationnot only in termsof its impacton the proteclion of researchsubject6but also 
in terms of burdenon the system. 
In commentingon our complianceactivities asthey relate to IRB inspections,the reports 
recommendshifting to an approachof measuringeffectiveness. We considerthe current FDA 
inspectionprogram to havegreat value, and think that establishmentof effectivenessmeasures 
would bc a major challenge, This is a very complexissue,and WCseethe ricedfor a thorough 
exploration of the possibilities in advanceof any decisions. 
WCrecognizethat thereare significant challengesfacing the IRB system. Your reports 
highlisht and add  to a number of areaswhere we believechangemay be needed(e.g., 
6UppOIt 
a registration requirementfor IREiswould, amongother things, enhanceour abilities to 
provide educationalmatorialsto all IRE3s).We look forward to receiving the final reportsand 
to working with our federalandprivate sectorcolleaguesin further improving the efftciency 
and effectivenessof the IRE3systom. We anticipateintensediscussionof a number of the 
recommendationsby the researchcommunity at IRB andclinical investigatormeetingsandwe  , 
.  . 
pnge  - 2 
intend to place someof theseissueson the agendafor our annualnational conferenceon 
humansubjectprotection to be held March 5,1999. 
I have attacheda number of specific commtn$sthat we hopeyou will considerbefore 
publishing your reports.  Again, thank you for providing us the opportunity LOcorrqncnton 
thesedraft reports. 
rnos3n~L 
Michael A. Friedman, M.D. 
Attachment:  Specific comments  I  -

Attachment 
FDAs  Specific Comments on OIG Draft Reports on 
IRBs 
mlo. nal .  Review Boards; T&i&&  in Ov~~~~roved  Research 
(pg ii)  Heightened Workload  Pressures 
Inclusion  of numbers to support statements about workload  would highlight  the 
magnitude of the problem. 
Limited  feedback on FDA Actions Against Investigators 
Last line: Insert routinely  after %om  to read precluded from routinely 
(pg iii)  FDA Oversight Focuses on Inspections... 
The FDA conducted just over ZOOsite visits in 1997. 
FoIlow  this statement with  the number of IRBs (3,000-5,000).  FDA conducts 
 inspections of lRBs, while OPRR conducts site visits, 
(pg 3)  Where Are They Located7 
An  estimated 3,000-5,000 IRRs can be found across the country. 
It should be noted that the uncertainty in the number of IRBs subject to the 
regulatory oversight by Federal agencies is part of the problem in exercising that 
oversight. 
(pg 4)  The Limits  of Informed  Consent 
They may not reaiize that the primary mission of the research is 

to advance medical knowledge rather than the welfare of the subjects. 

This could be misinterpreted to mean that the research is being conducted 

in violation  of the Declaration of Helsinki  121CFR 312.120(c)(4)].  , 

It may be clearer to state: They may not rcaliee they are being 

asked to participate in an experiment rather than being offered an 

approved medical treatment of known safety and efficacy.  This point is 

made in the section immcdiately,following,  titled The Blurring  of 

Research and Treutnient.  8 

. 
-l- (pg 9)  Limited  Feedback on FDA Actions Taken Against Investigators 
Line beginning  purged:  Change to read purged of trade secret and confidential 
commercial information,  and ... 
Next sentence: Change inspectors  to inspections 
Last line:  Insert with  IRBs and sponsors after  information 
.
Review Baards..Promisinn 
(pg 8)  Promising Approaches 
The meaning of the last sentence of the first paragraph could be improved if 
howcvcr,  as were changed to because each 
(pg 15) Federal Reference Points 
The last sentence should clearly state that FDA  information  sheets is a set of 
* 	 documcnta.  The proper citation for these sheets is FDA  Information  Sheets for 
IRBs and Clinical  Investigators 
Jostitutis&  Review 
(pg ii)  Independent IRBs Offer Advantages That Institutional  IRBs Find Hard to Match 
Third  paragraph may be strengthened by a description of what is meant by single 
souw  of review.  While it is true that the IRB would be the only review board 
for all sites it la also true that the board would  have to review the protocol  for each 
Individual  site that wants to conduct the study,  For each submission the lRB 
would  want to discuss the needs of the individual  community  (ethnic groups in the 
community,  research subjects available in each community,  cnsulc that the 
protocol can be conducted in each community,  etc.) before approving the protocol 
for that community. 
(pg iii)  Conclusion 
Last sentence in the second paragraph. Change  At the same, . . .  to At  the 
same time,  * a. 
-2- (Pg 4)  While There am Relatively Few of Them, Their Number has been Growing 
Although  the report recognizes the growth of independent IRBs, the report does 
not provide a reason for their tormation.  We suggest that the mason for more 
independent IRBs stems froms change in FDAs lcgulutions  in 1981. lqrior to 
1981, FDA required IRB review of studies involving  institutionalid  subjects or 
studies conducted in an institution  accepting responsibility  for the study (e.g., what 
would  now be considered an institution  with a multiple project assurance of 
compliance with HHS).  In 1981, FDA expanded the scope of its IRB. tegulations 
to include a requircmcnt  for IRB review of studies conducted outside of an 
institution  (e.g., by private practitioners).  In making this change, FDA  explained 
its rationale:  human subje+s, whether institutionalized  or not, aw entitled to the 
protections that these rcgu!atidns offer,  The agency rccogniztd  th$  in,somc 
instances such physicians may not be affiliated with an institution  or have direct 
accessto an IRB.  In the preamble to the regulations, the agency dc+c@bedthree 
options available to these physicians:  request review of a sludy from an existing 
IRB, request rcvicw  from an IRB crtaicd  under the auspices of a local or State 
government, institution,  society, foundation, or organization, or use an IRB 
created by the sponsor.  Inflcpcndent IRBs WCIXcreated to fill  this void and fulfill 
the 1981 r~uircment  for LRQ+vI~w  of all studies involving  FDA regulated
,  
p1@lcts. 
.  . . 
In.Ftltutlonal Review Born 
(pg 13) Recommendation  2.a 
The report should note that there is one regulation which requires the 
establishment of an indepcndcrit dath monitoring committee.  The FDA  regulation 
that provides for an cxcepiion from the informed consent requhtments  in certain 
cmergtncy  research (21 CFR 50.24) quires  that a study conducted under the 
exception have establishe! an iindependentdata safety monitoring  bovardto review 
data during the study in order to exercise oversight of the study. 
-3- APPENDIX  D 

OIG  RESPONSE  TO  FDA  COMMENTS 
We appreciate  FDAs  commitment  to carefully  consider  the findings,  recommendations, 
and supporting  information  presented in our reports  and to place some of the issues we 
raise on the agenda of the annual national  conference  on human-subject  protections  to be 
held in March  1999.  Such deliberations  can be of great importance  in fostering  the 
follow-through  that we hope will  occur as a result of our inquiry. 
As we suggested in our response to NIH,  however,  we believe it is important  to link  this 
longer term deliberation  with  some near-term  actions that can begin to address 
vulnerabilities  we point  out in our report.  With  respect to FDA,  we particularly  urge 
near-term  action in ensuring that it routinely  provide  IRBs  with  feedback on any actions it 
takes against investigators  under the jurisdiction  of IRBs.  If IRBs  are to carry out their 
protective  role adequately,  it is essential, we believe,  for them to be fully  informed  on 
such matters.  Further,  we urge FDA  to begin examining  how  it can incorporate  a more 
results-oriented  focus into its on-site  inspection  process. 
In making  this recommendation  to FDA,  we do not intend to discredit  the compliance-
oriented  inspection  process that it has established.  We recognize  the contributions  that 
process has made and that it helps to ensure that IRB  processes conform  to the letter of 
the law.  Yet, we strongly  suggest that the increasingly  results-oriented  approach that has 
come to characterize  health care quality  assurance/improvement  efforts  also has 
applicability  for both IRBs  and Federal bodies overseeing  their performance.  It is 
especially  important  that FDA  take initiative  in refocusing  Federal oversight  because, at 
least at the present time, it has more on-site  IRB  presence than any other HHS  entity. 
To focus more on how well  IRBs  are actually  protecting  human subjects, it would  be 
helpful  to develop  specific  measures of IRB  performance.  This, we recognize,  is a 
complex  undertaking  that should involve  other Federal agencies and the IRB  community. 
But progress in developing  more performance-based  reviews  should not be dependent on 
just  such measures.  There is much that FDA  can and should do in the near-term  to help it 
assess more fully  how well  IRBs  are protecting  human  subjects. 
We would  be happy to work  with  FDA  to identify  ways in which  they might  focus their 
oversight  more closely  and effectively  on results.  Among  the key questions that could 
guide this process are the following:  How  do we know  that the informed  consent process 
is carried out in a manner that minimizes  the possibility  of coercion  or undue influence? 
How  do we know  that the process of recruiting  and selecting  human subjects is being 
carried out in an equitable  manner ? How  do we know  if protocols  that should be 
subjected to review  are not being  submitted  for review?  How  do we know  if protocols 
stray from the directions  set forth  in the paperwork  reviewed  by an IRB?  The FDA  can 
begin to obtain  better answers to such questions through  selected reviews  at actual 
research sites, through  interviews  with  human subjects themselves, through  different  lines 
of inquiry  with  IRB  staff and board members, and through  other methods. 
D- 11 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  DEPARTMENT  OF HEALTH  & HUMAN  SERVICES 	 DffkOOfthOSeast#y 
W8rhiwton. 0.6.  20201 
TO: 	 Juiie Gibbs Brown 
InspectorGeneral.  . 
FROM: 	 Assistant Stcrctary for Planning and Evaluation 
Assistant Secretaryfor Health and SurgeonGeneral 
SUBJECT:  Coinmcnts on the Four Draft Reports on Institutional Review Boards 
Thank you very much for the opportunity to review andprovide comments on the four draft OIG 
reports on institutional review boards (IRBs).  We appreciatethe amount of workand  effort that 
your staff has devoted to preparing thesereports. It showsnot only in their understanding of the 
organization and functions ofinstitutional  review boardsbut also in the nature of the 
recommendationsthat have beenproposed. 
Your principal Ending that the IRB system is experiencingsignificant vulnerabilities is an issue 
that we do take seriously. Inasmuch asthis system is responsiblefor protecting human subjects 
involved in researchfunded or conductedby the F&ml  Government,we rely on it to safeguard 
the rights and interestsof all thosewho participate assubjectsof suchresearch We appreciate 
your recognition of the hundredsof diligent and conscientiousIRB members, s-and  principal 
investigators who are strongly committed to the protection of human subjectsand who labor 
towards this cndin lessthan ideal circumstances. 
Your observationsregarding the current stresseson the systemarewelltake&;  and it is certain 
that, absentstrengthening and corrective measures,suchpressureswillincrease  as a result of a 
likely  growth in the number and complexity of clinical trials, including trials to evaluateand 
validate genetic tests and trials of xenotranplantation them& 
We also recognize that institutions at which IRBs resideare our partnersin this system to protect 
human subjects. Thus we have a responsibility to shamwith them the findings that your office 
hasmade and to engagethem further in strengtheningthe IRB system. To this end, we hope you 
will  make the final reports available on the DHHS.website. 
David  Satcher,M.D., Ph.D.  APPENDIX  D 

OIG  RESPONSE  TO  ASPE/ASH  COMMENTS 
The ASPE and ASH  stress the role of 1RB.s as safeguards and agree that they face 
vulnerabilities  that must be taken seriously.  We applaud their further  comment  that 
without  strengthening  and corrective  measures  the pressures on IRE&sare likely  to 
intensify.  Our recommendations  are offered  to mitigate  those pressures and shore up 
IRBs  for the vital  roles they will  continue  to play. 
We particularly  welcome  the interest  of ASPE  and ASH  in these issues because their 
broad, department-wide  focus on the functioning  of IRBs  can be enormously  important  in 
moving  forward  with  the kind  of reforms  we urge.  As we note in this overview  report, 
the primary  HHS  agencies responsible  for oversight  of Irks,  NIH  and FDA,  have very 
different  jurisdictions,  mandates, and operating  approaches.  If they are to respond 
effectively  to the warning  we present, they will  have to collaborate.  It would  appear that 
ASPE and ASH  could play an important  role in ensuring  that such collaboration  goes 
beyond surface-level  efforts to substantive  interactions  that address the seriousness of the 
current situation. 
D- 13 
OEI-Ol-97-00193  IRBS:  A Time  For Reform  Comments  by  Sidney  M. Wolfe,  MD  and  Peter  Lurie,  MD,  MPH 
Public  Citizens  Health  Research  Group 
Concerning  the  HHS  Inspector  General  Reports  on  Institutional  Review  Boards 
(GEI-OI-97-0019-f-93) 
Since these  reports find that the System,  referring to Institutional  Review 
Boards  (IRBs),  is in  jeopardy,  it is clear to us that the health and safety  of thousands 
of human  experimental  subjects  are also in jeopardy  since the protection  of people  in 
these experiments  is the most important  function  of the IRB system.  Although  these 
reports conclude  that there  are not widespread  abuses  of human  research  subjects, 
the increasingly  large number  of violations  found  by FDA investigators  in IRB-approved 
informed  consent  documents,  the dangerous  lack of  on-site  inspections  for HHS-
funded  researcti  by NIHs Office of Protection  from Research  Risks (OPRR),  the rise of 
for-profit  IRBs-much  of whose  work  is to monitor  research  done by for-profit  clinical 
trials companies-and  many  other  problems  documented  in these  reports  belie the 
conclusion  of  no widespread  abuse.  This conclusion  seems  particularly  inappropriate 
as no systematic  search for abuses  was conducted  nor were known  abuses  examined. 
The  most  alarmina  findinas  of  the  Inspector  Generals  Reports  are: 
1. Unsafe  workload  of  IRBs:  According  to the Inspector  Generals  Report,  at the sites 

we visited,  the [IRB]  meetings  typically  lasted about 2 1Xhours and included  an average 

of 18 initial  [research  proposal]  reviews,  9 expedited  reviews, 43 protocol  amendments, 

and 21 adverse  event  reports.  The report cites other studies finding  that the average 

academic  medical  center  IRB was  reviewing  297 proposals  a year.  It is clear that 

adequate  time is not being devoted  to this difficult task. Worse, there is minimal 

attention  spent  by the IRBs on monitoring  the research  after it has begun to see if the 

studys  conduct  is consistent  with the approved  protocols. 

2. Massive  number  of  informed  consent  violations:  According  to the report, the FDA 

annually  does site visits to only about 200 of the 1,500 to 1,700 IRBs involved  in 

overseeing  research  which  includes  FDA-regulated  products.  These  investigations  are 

mainly  not done for cause  and therefore  it can be assumed  that the sites inspected  in a 

given year  are representative  of the larger universe  of IRBs.  In FY1997,  there were  a 

total of 74 informed  consent  deficiencies  found  at the 210 IRBs visited.  Since 210 is 

210/l  ,500 or only  14% of all of the  IRBs, it is reasonable  to project that in 1997 there 

were a total  of 528 informed  consent  deficiencies  (74/14%).  Of the inspection  findings 

deemed  by FDA to be most  serious,  there were 8 in FY 97 among  the 210  IRBs 

inspected  which  projects  to a total  of 56 for the whole  country  in that one year alone. 

3. 	Misleading  advertisements  to  recruit  patients  to join  experiments:  60 

newspaper  or public transportation  advertisements  were examined  to estimate  the 

extent to which  the line between  treatment  and research  was being  blurred.  People  are 

1  lured into experiments  by emphasizing  treatment  instead  of research:  the mention  of 
research  is either  placed at the end of a long list of benefits  or is embedded  in language 
so enticing  that the inevitable  risks of research  are easily  overlooked....The  danger  of 
these  advertisements  is that subjects  may come to a research  study with 
misconceptions....  They may be motivated  by the promise  of free treatment,  free 
screening  or extra money.  One ad illustrating  this stated:  Do you have asthma?  If you 
qualify  for any of our asthma  studies,  you can: learn to care for your asthma,  receive 
free medication,  receive up to $1,730! 
4. 	New  conflict  of  interest  problems  with  Independent  (For-profit)  IRBs:  Because 
a progressively  larger fraction  of research  undertaken  in order to get drugs and medical 
devices  approved  is done by for-profit  drug and device testing  companies  which  are not 
part of university  medical  centers,  there  has been a proliferation  of independent  IRBs 
to service them. Although  they are independent  of an academic  research  institution, 
as for-profit  entities  they are quite dependent  on pleasing  their customers  (the for-profit 
research  companies)  and their owners.  The Inspector  General  study found that some 
IRB officials  are concerned  that an independent,  for-profit  IRB might compromise  its 
revievu-process to advance the financial  well-being  of the firm. Such concerns  are 
heightenedtd-the  extent that corporate-equity  owners  or employees  serve on the IRB 
review boards  and are sustained  to some extent  by the fact that reviewers  are paid for 
their services.  An additional  problem  involves the fact that most of these are 
nationwide  and therefore  do not have local representation  and input from the localities 
where  the trials are being conducted. 
5. Inadequate  oversight  of  IRBs  by  FDA  or  OPRR:  As mentioned  above, only 210 
out of 1,500 to 1,700 IRBS which  review studies  involving  FDA-regulated  products  are 
inspected  by the FDA in a given year: Thus,  it may be five or more years between 
inspections,  during which  hundreds  or more studies will  have been approved  by the IRB 
with  no on-site  oversight.  OPRR does even fewer on-site  inspections  of IRB monitoring 
functions,  mainly  employing  phone  and paper  investigations.  Only  rarely does OPRR 
go on-site.  Between  1990 and April  1996, OPRR conducted  only  18 compliance 
visits...[there  were] no on-site visits between  April  1997 and February  1998 because  of 
staffing  problems.  Thus, with thousands  of NIH-funded  human  experiments  being 
monitored  by IRBs, there is dangerously  little oversight  by the OPRR which  is, in 
another  example  of conflict of interest,  part of NIH. 
6. Little  evaluation  of  real  effectiveness  of  IRBs:  According  to the Inspector 
Generals  Report,  officials  [of IRBs] reported  that during  the past year they seldom 
visited the research  site. Although  many would  like to, none oversees  the informed 
consent  process  or solicits feedback  from subjects.  One IRB member  said he reviews 
the continuing  review summaries  during  the board meeting  to see if a patient  has died. 
If no patient  has died, then he generally  will not raise questions. 
2  Inadequacies  of  lnsoector  General  lnvestiaations 
There is an enormous  amount  of important  information  and recommendations  in 
these  reports but there  are two areas of investigation  which would  have been useful to 
include: 
1. Failure  to  interview  subjects  of  human  experiments:  Since  IRBs themselves  do 
not  find out if informed  consent  was  really obtained  (see #6 above),  relying  on a review 
of the document  content  instead  of finding  out if patients  actually  understand  the nature 
of the experiment  in which they agreed  to participate,  it would  have been useful to 
interview  a representative  sample  of patients  in trials,  particularly  those who  had 
finished  trials. 
2. Failure  to  assess  differences  between  boards  based  on  review  of  a 
standardized  protocol  or  to  collect  data  on  differences  between  IRBs  in  rejection 
rates  or  rates  of  requiring  serious  modifications  in  protocols:  In the United 
Kingdom,  studies have shown that ethical  review committees,  the equivalent  of IRBs, 
differ greatly  inthe  way they approach  and criticize  a standardized  protocol.  Rather 
than collecting  such systematic-data,  the Inspector  General  reports depend  primarily  on 
site visits and qualitative  information.  Such data would  be very instructive  in better 
training  and education  of IRB members.  Data examining  the extent to which  the rate of 
rejection  or serious  modification  of studies  reviewed  by IRBs differed  from one IRB to 
the next might focus on conflicts  of interest  or other problems  with the training  and 
education  of IRB members.  It would  also set standards  by which  IRBs could  be 
objectively  compared. 
R?telocnos de  enda    e  by  the  Insp  ector  Genera  I 
1. Funding  for  more  adequate  review  by  IRBs:  This  should  be done as an automatic 
predetermined  portion  of academic  overhead  for clinical  trials.  In other words,  since 
academic  centers are getting  funded  to do the trials, a sufficient  portion  of this overhead 
should go to assuring  that a much  more  rigorous  review of the research,  initially  and 
while the trial is underway,  is done. 
2. 	Change  in  composition  of  IRBs  including  much  more  attention  to  conflicts  of 
interest,  especially  at for-profit  IRBs:  Despite  recommendations  dating  back 25 
years that scientists  from outside  the institution  and non-health  professional  lay persons 
should  be included  in IRBs,  this need,  especially  the outside  scientist  element,  is not 
being adequately  addressed.  Given the strong  institutional  bias to say yes to the 
I  Barber  B, Lally JA, Makarushka  JL, Sullivan  D. Research  on Human 
Subjects.  Russell Sage  Foundation,  New York.  1973. 
3  possible  flow of money,  it is particularly  important  to temper  the institutional  enthusiasm 
with these  more disinterested  parties. 
The  idea of a for-profit  IRB is appalling.  It is one thing for a loyal academic  to say 
yes to a research  proposal  which  will benefit  his or her institution  but another  for the 
IRB member,  possibly  an executive  or a major stockholder  in the IRB, to personally 
gain from  approving  research  proposals.  The policy for HHS-funded  research  reviews 
by for-profit  IRBs is to exclude  IRB equity  owners from  participating  in the review 
process,  but there  is no such policy for industry-sponsored  studies which  are to be 
submitted  to the FDA. If it is not possible  to abolish for-profit  IRBs, at least this extreme 
conflict  of interest for the approval  of studies  of drugs,  devices and other FDA-
regulated  products  should  be ended.  This conflict  of interest also facilitates  the 
phenomenon  of IRB-shopping,  in which  sponsors  take a protocol  rejected  at one IRB 
(perhaps  a University  IRB as in a recent  case mentioned  in congressional  testimony  2, 
and take  it instead  to a for-profit  IRB which  has every incentive to approve  the protocol 
lest it gain  a reputation  as too strict and therefore  lose business. 
3. 	Refjulatjon-by  the  FDA  of  advertising  done  by  clinical  trials  units:  As discussed 
under finding  #3 above,  patients  can easily  be lured into participating  in human 
experiments  by the misleading  advertising  discussed  in the Inspector  Generals  Report. 
The  FDA should  expand  its regulation  of IRBs to include the recruiting  materials  such 
as advertisements  and these  materials  should  also be part of the materials  received  by 
the IRBs.  Combined  with  misleading  information  in the informed  consent  forms, the 
result may  be for patients  to participate  in an experiment  without  adequate  informed 
consent. 
4. 	 Requirements  for  a central  registry  of  all  trials  and  that  the  results  of  all  trials 
be  made  public  within  one  year  of  completion.  In a recent article entitled,  Are 
Research  Ethics  Committees  Behaving  Unethically?  Some  Suggestions  for  Improving 
Performance  and  Accountabilify,  British researchers  concluded  that the committees 
were  behaving  unethically  by endorsing  new research which  is unnecessary  and by 
acquiescing  in biased  underreporting  of research which  they have approved.  3 They 
concluded  that-research  ethics  committees  should: 
2  Wilfond  B. Testimony  before the House Subcommittee  on Human 
Resources,  Committee  on  Government  Reform  and  Oversight,  U.S.  House  of 
Representatives,  May 8, 1997. 
3  Savulescu  J, Chalmers  I, Blunt J. Are research ethics  committees 
behaving  unethically?  Some  suggestions  for improving  performance  and accountability. 
British  Med  J 1996;  313: 1390-3. 
4  a/  Require  systematic  reviews of existing  research  before approving  research; 
b/  Require  that a summary  of relevant systematic  reviews  be made available  to 
potential  participants; 
c/  Require  registration  of clinical trials at inception  as a condition  of approval  [national 
registry]; 
d/  Require  a commitment  by investigators  to make the results publicly  accessible  as a 
condition  of approval;  and 
e/ Audit  the reporting  of results of research  previously  approved  by them.  (IRB 
monitoring  of publication  is critical to avoid publication  bias or .debacles such as Knoll 
Pharmaceuticals  suppression  of the levothyroxine  equivalency  study.) 
5. Analysis  of  close  votes  at  lRBs  to  see  if and  why  those  protocols  got  approved. 
6. Retrospective  analyses  of  IRB  meetings  which  approved  trials  now  considered 
unethical.
c 
I  .I 
7. Remove:  OPRR  from  NIH  because  of  conflict  of  interest:  As long as OPRR  is part 
of the institutional  block diagram  and under the control  of the NIH, over whose  research 
it is supposed  to exert independent  control,  it is highly  unlikely  that it will be able to fulfill 
its important  mission.  It should  be .moved outside  of the NIH but still within  HHS. 
8. Implementing  as  mandatory  for  lRBs  some  of  the  strategies  discussed  in 
lnstifutional  Review  Boards:  Promising  Approaches  (0E1101097-00190)  : With the 
growing  number  of research  applications,  it seems  reasonable  at the present  time to 
put a limit on the number  of applications  a given  IRB can review per year.  iRBs should 
also be required  to provide  some educational  outreach  to faculty  and students,  at a 
minimum  including  a lecture series on ethics,  including  lectures  on recent controversies 
and new directions  in ethics.  We were particularly  impressed  with the 
computer-assisted  monitoring  of research  activity  at the University  of California,  San 
Diego which  detemrined  that fully  10% of recent publications  by faculty  members  had 
not received  IRB approval;  this monitoring  function,  which  is rapid and inexpensive, 
should  also be made  mandatory.  Periodic  informed  consent  audits  by third parties,  as 
conducted  at the University  of Texas  Health Sciences  Center, should  also be required, 
as should  the presence  of a bioethicist  on the IRB. 
: 
4  Rennie  0. Thyroid  storm. JAMA  1997;  277:1238-43. 
5  APPENDIX  D 

OIG  RESPONSE  TO  PUBLIC  CITIZEN  COMMENTS 
Public  Citizen  incorrectly  states that we concluded  that there are no widespread  abuses of 
human subjects.  Our concluding  assessment on this point  was that we  do not claim 
there are widespread  abuses of such subjects.  We made that point  to place our main 
finding  about the jeopardy  that exists in context  and to try to avoid overly  alarmist 
reactions to it.  As Public  Citizen  correctly  indicates,  in this study we did not conduct  a 
systematic  search for abuses, nor did we investigate  known  abuses.  Rather, our focus was 
on the big picture.  We sought to bring  greater clarity  and understanding  to the overall 
system of protections  that exist in a varied and rapidly  changing  environment. 
Concerned  about the seriousness of our findings,  Public  Citizen  regrets that we did not go 
further  with  our review.  In particular,  it suggests that it would  have been useful to have 
interviewed  human subjects themselves and to have used a standardized  protocol  as a way 
to assess differences  among IRE&.  We agree that both of these techniques  could have 
value.  However,  we were unable to incorporate  them as part of our review.  We amended 
our report to indicate  that such techniques  should  be considered  as part of the regular 
performance-focused  evaluations  of IRE3sthat we recommend. 
Public  Citizen  also offers a number of recommendations  beyond  those that we presented 
in the report.  They are thoughtful  recommendations  that warrant  careful consideration  by 
the policy  and research communities.  In two  cases, our own  consideration  of them led us 
to make some changes in the text.  In our recommendation  calling  for more 
noninstitutional  members on IRE&., we clarified  that such members could well  include 
scientists from outside the institution.  In our findings  and recommendations  concerning 
conflict  of interest, we clarified  that while  equity  owners  are precluded  from participating 
in the review  process for studies under NIH  purview,  they are not precluded  from doing 
so for those just under FDAs  jurisdiction.  We added a recommendation  specifying  that 
such participation  should be disallowed  in all cases involving  NIH  or FDA jurisdiction. 
At the very least, the involvement  of equity  owners  of IRE& in reviewing  research 
protocols  undermines  the public  credibility  of what  should  be an independent  review. 
Public  Citizens  comments about the importance  of proper  funding  parallel  those of  FDA 
and other parties.  They are well-taken.  We reinforce  this concern in the introduction  to 
our recommendations  when we note that sufficient  financial  provisions  must be made 
to buttress IRE3and Federal efforts to protect  human  subjects. 
Finally,  we also take note of Public  Citizens  call for FDA  regulation  of advertising  done 
by clinical  trials units.  While  we are not ready at this point  to make such a 
recommendation,  we do have considerable  concern,  as we indicate  in the reports, that 
such advertising  is currently  being used in ways that give potential  subjects an unbalanced 
perspective  of the risks and benefits of  participating  in research and that both IRE3 
continuing  review  processes and Federal oversight  processes fail to give sufficient 
attention  to this matter. 
D- 19 
OEI-01-97-00193  IRBS:  A Time  For Reform  May  12, 1998 

June Gibbs  Brown,  Inspector  General 

Department  of Health & Human  Services 

Office  of the Inspector  General/Office  of Evaluations  and Inspections 

Room  5458 Kohen Bldg. 

Washington,  D.C.  20201 

Dear Dr. Brown: 

Than& you for giving  the Applied  Research  Ethics  National  Association  (ARENA)  the 

opportunity  to:comment  on the four  draft  inspection  reports  (OEI-Ol -97-00190,OO  19 1,00192, 

00 193) on the Institutional  Review  Board  (IRB)  system.  ARENA  is a subsidiary  of the Public 

Responsibility  in Medicine  and Research (PRIM&R),  which  is a nonprofit  organization 

dedicated  to promoting  the ethical  conduct  of research.  ARENA  is a professional  association 

with  over 800 members who are administrators  or members  of Institutional  Review  Boards  and 

Institutional  Animal  Care and Use Committees  throughout  the United  States.  ARENAs 

membership  is in part dedicated to the protection  of human  research subjects and compliance 

with  federal  regulations  governing  IRB  operations  and informed  consent. 

ARENA  applauds your efforts to address the complex  research culture  in which  IRBs  currently 

function.  The inspection  report entitled  Institutional  Review  Boards:  Promising  Approaches 

provides  excellent  examples of innovative  IRB  strategies  for enhancing  effectiveness  and 

efficiency  in protecting  human subjects.  This  report  illustrates  that many IRBs  have developed 

creative and effective  approaches to managing  the challenges  presented by the changing  research 

environment. 

We support  the recommendations  delineated  in the summary  report (OEI-0 l-97-001  93) but have 

general concerns about the four reports  findings.  The general concerns and our specific 

comments  on the recommendations  are discussed  below. 

GENEIWL  CONCERNS 
Use of the phrase  FRB  oversight  is not  appropriate  and is misleading  to readers  who  do 
not have  IRB  expertise.  This phrase has been confused  with  the mandated  charge of IRBs  to 
conduct  continuing  review,  review  of unanticipated  problems,  and review  of proposed  changes in 
approved  research.  IRBs are not man&ted  to conduct  data monitoring  or daily  quality  assurance 
132 BOYLSTON  STREET 
BOSTON.  MASSACHUSmS  021 f6 
61742ZJ-4112  phone:  617423-l  165  fax 
---  --  - --.  mn.,  _ .-.,,  of research procedures  carried  out under approved  protocols,  as the phrase oversight  clearly 

implies.  The responsibility  for oversight  and safety monitoring  rests with  federal  regulatory 

agencies, sponsors, and Data Safety Monitoring  Boards.  The phrase should not be used in the 

headings, subtitles,  or the narrative  of the four reports  because it does not accurately  refer to the 

IRB  mandate for continuing  review. 

The uglobal  language used in the title,  the introductory  text and the subtitles found in the 

OEI-Ol-97-00193  and OEI-01-97-00190  is very problematic.  The general public, 

congressional  leaders, and anyone who  does not read the report in detail may be left with  a 

blanket  condemnation  of the IRB  system.  Based on our assessment of the methodology  used in 

conducting  the OIG  inspection,  global  generalizations  which  appear alarmist  need to be avoided. 

The OIG  sample was small and the study used qualitative  interviews,  not quantitative  measures 

to determine  I&B  effectiveness.  Although  the reports acknowledge  the limitations  in the 

methodology  and appropriately  point  to strengths  in the system, these limitations  are lost amid 

global  statements like  rarely  does,  the  little  review  that does occur.. ., and few  IRBs  seem 

to be able.. . 

For example,  in OEI-0 l-97-00  193 the OIG  refers to a prior  study that focused on investigational 

medical  deviees in which  significant  deviations  from  IRB  approved procedures  were identified. 

The report  goes on to state in  this study,  which  was more broadly  based, we found  little  basis 

for easing those concerns;  in fact, they have been intensified.  A representative  from  one of the 

six academic health  science centers site-visited,  who  also reviewed  these draft reports,  was 

troubled  by this sweeping  statement.  That person pointed  out that during  the three day OIG site-

visit the OIG did not review  any specific  protocol.  It is therefore  difficult  to understand  why  the 

OIG would  conclude  that deviations  from  a specific  IRB  can be applied  to a more broad based 

look  at IRBs  and ascertain there is a widespread  problem. 

Another  general concern is that it is unclear in the report  on continuing  review and the 

summary  report  whether  the findings  and recommendations apply only to selected 

segments of the IRB  community  or whether  they apply to the entire community  of IRBs 

including  independent  boards.  As currently  written,  it appears that OEI-0 l-97-00  190 findings 

and recommendations  only  apply  to institutional  IRBs.  There is no mention  in the methodology 

section of the continuing  review  report  that  11 independent  IRBs were also interviewed.  There is 

no discussion  of the continuing  review  topic  included  in the report on independent  boards.  Also, 

in the methodology  section of the summary  report,  there is no mention  of interviews  with 

independent  board representatives.  However;  some of the findings  appear to include 

independent  boards;  others do not. 

SUMMARY  REPORT  RECOMMENDATIONS 
As indicated  above, in general ARENA  supports the recommendations  in the summary  report. 
However,  we do have some specific  concerns,  which  are included  in the following  discussion.  Recommendation  1: Recast Federal IRB Requirements  so That They Grant  IRBs Greater 
Flexibility  and Hold  Them More Accountable for Results 
ARENA  agrees that IRB  effectiveness  would  be greatly  improved  if the federal policies  that 
focus upon  paper  trail  aspects of IRB  operations  or perfunctory  review  processes were 
eliminated  or recast.  For example,  in two of the reports  it is stated that ongoing  review  of 
adverse event reports  is an integral  and ongoing  task for IRBs.  An argument  can be made that 
monitoring  for adverse events is actually  a Food and Drug  Administration  (FDA)  and sponsor 
function  that has over time been delegated to the IRB  through  FDA  policy  and procedures  rather 
than regulatory  mandate.  The Department  of Health  and Human  Services (DHHS)  and FDA 
IRB regulations  do not specifically  address adverse event monitoring  responsibilities.  ARENA 
acknowledges  that IRBs  have a role in reviewing  adverse events, but the scope of that role is 
subject to debate.  In accord with  regulatory  requirements,  all adverse event reports  are sent to 
the FDA.  FDA,  with  trained  scientific  reviewers,  is in the position  to evaluate the reports  and 
determine  if risks for a test article  have changed.  The FDA  could  transmit  this information  to 
sponsors and IRBs  if the recommendation  to register IRBs  is adopted. 
In principle,  ARENA  supports the recommendations  that IRBs  undergo  performance-focused 
evaluations.  However,  based upon past experience  with  the federal regulatory  process, we are 
concerned  that developing  an evaluation  system of this type could  lead to increased bureaucratic 
workload,  which  would  further  drain limited  IRB  staff resources. 
Developing  an effective  performance-focused  evaluation  program  would  be an exceedingly 
difftcult  task, which  would  require  identification  of appropriate  performance-based  criteria  and 
considerable  infusion  of resources in both the development  and implementation  phases. 
Performance-based  criteria  should  be developed  by those heavily  experienced  in IRB  processes. 
The criteria  should  be standardized  and universal  in its applicability.  IRB  review  is a peer 
review  process.  Ethical  decision-making  does not lend itself  to traditional  procedures  for 
assessing effectiveness.  In part, that is the reason why  the current  inspection  system tends to 
focus upon the quantitative  measures (presence of a quorum,  continuing  review  conducted 
within  365 days and so forth)  rather than qualitative  ones. 
The report  also recommends  that the evaluations  be made available  to the public.  We question 
how valuable  that information  would  be to the lay public.  The performance-based  system should 
first be developed  before the decision  is made on whether  the evaluations  provide  enough 
valuable  information  to warrant  dissemination  to the general public. 
Recommendation  2: Strengthen Continuing  Protections for Human  Subjects Participating 
in Research 
ARENA  agrees that the role of Data Safety Monitoring  Boards  should  be expanded  and that 
providing  IRBs  with  feedback  on the developments  in multi-site  trials would  strengthen  human 
subjects  protections.  Also,  ARENA  concurs that IRBs  should  be provided  with  feedback  about 
FDA  actions  against investigators.  Many  IRBs  have compensated  for the lack of feedback  from  auditing  organizations  by requiring  the results of any inspection  be reported  to the IRB  as part of 
the continuing  review  application. 
In addition,  ARENA  members have expressed serious concerns about the potential  in the current 
system for sponsors to seek out IRE3s which  do not raise substantive  issues or request numerous 
modifications  in the informed  consent document.  We support  any recommendations  which 
would  discourage  IRB  shopping  for ease of approval.  We support the recommendation  that 
sponsors and investigators  notify  independent  boards of prior  reviews  of research plans. 
Implementing  this recommendation  may not be appropriate  for institutional  IRBs  which  review 
multi-site  trials that have previously  been reviewed  by numerous  other IRBs  at other sites. 
There are some safeguards currently  in the system that deter IRE3 shopping.  The FDA  form 
FD1572  requires an investigator  to report  any change of IRB.  Most  independent  Irks  ask about 
submission  to other IRBs  when  they fust  receive a protocol  for review.  Many  of the multi-site 
studies seen by independent  IRBs  are also reviewed  by one or more institutionally-based  boards. 
Also,  it is commonplace  for institutions  to require  investigators  to use their internal  IRBs.  An 
investigator  in an institution  generally  has no choice about which  IRB  to use.  He or she must use 
the ERR covered by the Office  for Protection  from  Research Risks (OPRR)  Assurance  for that 
institution.  ..i 
In principle,  we support  the recommendation  that IRBs  should have increased awareness of on-
site practices.  However,  ARENA  has two  concerns.  First, our experience  in the field  suggests 
that the most effective  IRBs  are ones that have a collegial  relationship  with  investigators. 
Violation  of the long established  ethic  of trust  would  undermine  IRB  effectiveness.  We agrzc 
with  OIG assessment that one of the most significant  challenges  facing  IRBs  is how  to achieve 
increased awareness of on-site practices  without  unde mining  the ethic  of trust.  Our other 
concern is a practical  one.  The approaches  for increasing  awareness of on-site  practices 
suggested in the report  (e.g., random  audits, observing  the consent process) would  require 
considerable  staff and IRB  resources to implement.  This concern  is addressed in more detail in 
the comments  on Recommendation  5. 
Recommendation 3: Enact Federal Requirements  That Help Ensure That Investigators  and 
IRB Members are Adequately  Educated About  and Sensitized to Human-Subject 
Protections 
philosophically,  ARENA  supports  the recommendation  for mandatory  training  of investigators 
and board members.  However,  institutions  and IRE3sdo not have adequate resources to comply 
with  mandated requirements  for training  programs.  These efforts  should  be a shared 
responsibility  and should  not fall  solely  upon the IRB  or the institution.  The responsibility  of 
conducting  ethical and sound scientific  research is a shared responsibility  of the investigators. 
Training  on the ethical  conduct  of research should become part of the medical  or graduate school 
curriculum.  Investigators  should  also be responsible  for providing  training  to their  entire 
research team. 
4 
 Responsibility  for providing  training  should  also be shared with  federal  agencies.  Both  FDA  and 
OPRR should  be provided  the resources to expand their training  initiatives.  Also,  a number  of 
national  organizations  such as ARENA  and PRIM&R  offer training  and are in the process of 
developing  new programs  which  focus on both investigators  and board members.  DHHS 
funding  programs  should be developed  to support  initiatives  of this type.  Also,  expenses for 
providing  ethical  conduct  of research training  should be an allowable  cost for all DHHS  funding 
mechanisms.  Efforts  to cap indirect  costs only  serve to further  drain  dwindling  institutional 
resources. 
ARENA  does not support the recommendation  that investigators  provide  written  attestation  of 
their familiarity  with  and commitment  to human subject protections.  This procedure  would  not 
serve as an effective  training  tool.  Our experience  suggests that investigators  submitting  grant 
proposals  have a number  of demands upon their time.  Signing  the attestation  statement will 
become just  another  bureaucratic  hoop that investigators  go through  in submitting  the grant 
application. 
Recommendation  4: Help Insulate  from  Conflicts  that can Compromise  Their 
IRBs 
Mission in Protecting  Human  Subjects 
Although  ARENA  would  agree that IRBs  should be insulated  from  conflicts,  we are 
uncomfortable  with  this recommendation  because it implies  that the IRB  mission  is currently 
compromised.  In fact, our experiences  have not supported  that conclusion.  We acknowledge 
that at institutional  IRBs  there is increased pressure from  both investigators  and the 
administration  to do  more faster.  However,  the focus has generally  been on improving 
efftciency  not upon diminishing  protections  for human subjects.  Most  institutions  are 
committed  to protecting  human  research subjects as are the IRB  members  and staff.  ARENA 
also found  this recommendation  confusing  because it did not include  any reference to 
independent  board confkts.  Not  addressing  this issue in the recommendations  implies  that 
conflicts are only  problematic  for institutional  based IRBs;  this conclusion  conflicts  with  the 
observations  regarding  potential  financial  conflict  of interest included  in the OEI-0 l-97-00  192 
report. 
Although  ARENA  agrees that nonscientific  and noninstitutional  members  serve an important 
role in reviewing  protocols,  we do not support  the recommendation  that additional  federal 
requirements  for increased representation  be enacted.  We do not agree with  the OIG  conclusion 
that the current  requirements  are inadequate.  Regulations  and federal  policy  require  that the 
membership  include  a nonscientist  and a noninstitutional  representative.  Meeting  these 
requirements  by appointing  a single  individual  is not a standard IRB  practice.  In addition,  the 
requirements  specify  that a nonscientific  member must be present to conduct  a full  review.  The 
decision  to add  additional  members  should  be left to the discretion  of the IRB.  From a 
practical  standpoint,  obtaining  a quorum  for full  review  is difficult  and increasing  the total 
number  of members will  only  serve to exacerbate this problem.  Based upon our experiences,  we 
do not agree with  the OIG  statement  that few  outside  members  are on boards.  Our experience 
suggests that this is simply  not the case.  IRBs  always  include  at least one such member  and 
many IRBs  include  additional  noninstitutional  members.  Also,  the statement Few  IRBs  seem to 
5  seek or be able, on a consistent  basis, to recruit  and maintain  lay members.. . may be true for 
some IRBs  but in our experience  is not true for the majority  of IRBs. 
Recommendation  5: Recognize the Seriousness of the Workload  Pressures that Many IR,Bs 
Face and Take Actions that Aim  to Moderate  Them 
ARENA  applauds OIGs  recommendation  to require  that IRBs  have access to adequate resources 
but does not think  that requiring  is sufficient.  One of ARENAs  overriding  concerns  about the 
recommendations  is that they have the potential  to establish a number  of Ymfunded  mandates. 
Recommendations  1,2,  and 3 will  require  considerable  additional  resources to implement.  The 
fmdings  of the assessment as outlined  in the continuing  review  and the summary  reports clearly 
indicate  that IRBs  are currently  lacking  in adequate resources; yet, the implementation  of the 
recommendations  will  only  serve to increase costs and the need for additional  staff and 
resources.  Many  institutions  are committed  to providing  adequate resources but in fact do not 
have sufficient  funds to do so.  At the federal  level, the problem  is exacerbated  by increased 
agency requirements  for cost sharing  and continual  efforts  to reduce indirect  cost rates.  DHHS 
needs to develop  support  mechanisms  to assist in funding  the new initiatives.  The OIG  should 
include  acknowledgment  that it is likely  the proposed  recommendations  will  not be effective 
unless additional  resources are available. 
Recommendation  6:  Re-engineer the Federal Oversight Process 
ARENA  agrees with  the recommendations  to revamp  the National  Institute  of Health/Office  for 
Protection  Corn Research Risks (NIWOPRR)  assurance mechanism  and refocus  the FDA  on-site 
inspection  process on performance  based criteria.  As pointed  out in our comments  on 
Recommendation  1, we support performance-based  evaluations  but are concerned  about the 
difficulties  in developing  a system of that type.  Efforts  must be made to ensure that in re-
engineering  the Federal oversight  process that the old  bureaucratic  hoops are not simply 
replaced with  new  bureaucratic  hoops with  only  marginal  relationship  to quality  and 
effectiveness  of reviews.  ARENA  feels that it is important  to periodically  evaluate the IRB 
review  system.  It is equally  important  that this system be assessed fairly  and appropriately. 
ARENA  also wants to stress the importance  of FDA  and NII-IYOPRR continuing  to coordinate 
federal policy  development.  If FDA  and OPRR  policies  are as uniform  as possible,  given the 
legislative  mandate for each agency, the bureaucratic  burden on IRBs  would  be greatly  reduced. 
Also,  we strongly  support  the recommendation  that experienced  IRB  members  and staff should 
play an on-site role in reviewing  IRB  performance  and the suggestion  that Federal  agencies 
include  a peer review  element or offer  IRBs  some type of incentive  as part of a continuous 
quality  improvement  effort.  We also support  the recommendation  that all IRBs  be registered 
with  the Federal Government,  provided  the mechanism  is streamlined.  Based upon our 
experiences  in the field,  ARENA  is concerned  that even though  the registration  process is 
proposed  to be simple  the procedures  could,  in fact, become complicated,  adding  to the 
already unmanageable  IRB  administrative  workload. 
6 
 In conclusion, ARENA  acknowledgesthe effort OIG made in reviewing IRB regulations and 
procedures. It is a difficult  task to write reports that encompassthe activities of IRBs from such 
a wide variety of facilities and institutions  involved in the conduct of human subject research. 
ARENA  also appreciatesthe inclusion of innovative proceduresselectIRBs have developed to 
copewith the ever burgeoning task of IRB review.  It provides a balancefor what will  be 
perceived as a negative report on IRB processes. Many IRBs do conduct substantivereviews 
and simply do not get the recognition deservedfor the ethical diligence. 
The recommendations made by OIG, for the most part, are onesthat could be implemented by 
many IRBs to improve the quality of their reviews. It is true that with additional resourcesmany 
IREiscould become more sophisticatedin their review processes.It is not clear Eromthe report, 
however, from where theseresourceswill  originate.  It is a long leap from requiring  such 
resourcesto actually receiving them. 
ARENA thanks you for the opportunity  to comment on the reports. If any additional information 
is required, pleasedo not hesitateto contact us. 
Sinc~ely,~,  :,! 
William  Freeman,M.D.  Ada Sue Selwitz, M.A. 

ARENA President  Chair, Public Policy Committee 

Drafting Committee: 
Gary Chadwick  Erica Heath  Gwenn Oki 

Norma Epiey  Moira Keene  JoanRachli.n 

SharonFriend  SusanKometsky  Beth Ribbeck 

Karen Hansen  Helen McGough  Pat Scannell 

7 
 APPENDIX  D 
OIG RESPONSE TO ARENA  COMMENTS 
In our review,  we gained great respect for the work  and commitment  of IRB 
administrators  and members,  often under very trying  circumstances.  We listened, 
sometimes at considerable  length,  to them articulate  concerns about the developments 
that threaten the effectiveness  of their boards.  Sometimes we were able to supplement 
these conversations  with  a review  of records and reports concerning  their operations.  In 
its response to our draft report,  ARENA,  whose members are IRB  administrators  and 
members, did not tend to reflect  the same message we heard so consistently  from the 
individual  administrators  and members during  our year-long  inquiry. 
As the ARENA  response itself  suggests, perhaps to some degree this disconnect  is 
attributable  to some of the language we used in our draft reports.  In an effort  to improve 
communication  and focus attention  on the necessary reforms,  for which  we believe there 
is considerable  support, we have changed some of the language we used.  Thus, we have 
changed the title  of this overview  report  from A  System in Jeopardy,  to A  Time for 
Reform.  We have made other such changes and elaborations  to indicate,  even to the 
casual reader, that our reports are not intended  as a blanket  condemnation  of the work 
of IRE3.s.At the same time, we must stress that we still  find that the effectiveness  of the 
system is, indeed, in jeopardy.  As an independent  overseer, it is vital that we present such 
a warning  when we find  it applicable,  and do so in a manner that is clearly 
communicated.  Thus, within  the report, the jeopardy  warning  remains as our central 
finding. 
Another  key linguistic  change we made was in the use of the term oversight.  Given 
ARENAs  concerns, we reserved that term for the monitoring  of IRBs  done by the 
Federal agencies (NIH  and FDA).  With  respect to IRE& themselves, we now  refer to their 
role in conducting  continuing  review  of approved  research rather than oversight.  This 
is consistent  with  the language used in the Federal regulations  concerning  IRE&.  We 
must note, however,  that those regulations  clearly  give IRE3sthe authority  to  observe or 
have a third  party observe the consent process and the research--something  that, in fact, 
they rarely  do.  Further,  an OPRR  Dear  Colleague  letter to IRE3scalls for continuing 
review  to be substantive  and meaningful-- a characterization  that many IRE! officials  say 
does not describe current practice.  This limited  attention  to continuing  review  is 
unfortunate,  because while  to varying  degrees other parties conduct  continuing  review  of 
approved  research, they, unlike  IRE&, do not have a central mission  of protecting  human 
subjects. 
Our focus on continuing  review  emerged because a prior  OIG  inspection  concerning 
investigational  medical  devices found,  in four case studies, considerable  evidence of 
inadequate continuing  review,  and because of the findings  of various other studies cited 
in the report.  We state in this report that our inquiry  has led us to become even more 
concerned  about the inadequacy  of continuing  review.  The ARENA  questions  the basis 
for that conclusion,  citing  the observation  of a representative  of one of the academic 
D - 27 
OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  D 

health centers we visited.  That person wondered  how  we could  reach such a conclusion 
when during  the 3 days we spent at that center we did not review  any specific protocol. 
Our response is that, as we note in the report,  we did not seek in this inquiry  to conduct 
any audits of particular  protocols  or investigations  of specific  cases.  It was our broader 
systemic analysis that led us to recognize  the limits  of the continuing  review  that Irks  do 
conduct.  It was the substantial  accumulating  evidence associated with  that awareness that 
led to the intensification  of our concerns about the adequacy of continuing  review. 
In regard to ARENAs  comments  on our recommendations,  we must stress what we 
perceive to be the importance  of IRESsbecoming  more fully  accountable  to the public.  It 
is toward  this end that we strongly  urge ARENA  to recognize  the overriding  importance 
of performance-focused  evaluation,  not just  in terms of the complex  task of developing 
performance  measures, but even more so in terms of concrete  actions that IRELscan and 
should take to assess and verify  the actual results of their  efforts  in protecting  human 
subjects.  (Our response to FDA  elaborated  on some of the questions  that could be raised 
in this regard.)  It is toward  the same end of shoring  up public  accountability  that we urge 
greater representation  of outside  interests on IRE&.  As 1-s  become more involved  in 
conducting  reviews  involving  genetics research, which  raises vital  issues involving  the 
use and confidentiality  of information,  such broader representation  will  become even 
more important.  The public  credibility  of the entire IRI3 review  process could  depend 
heavily  on such representation.  We know  that many IRB  officials  agree with  this 
assessment and that they have been frustrated  by their  lack of success in recruiting  and 
maintaining  a sufficient  core of nonaffiliated  members who  provide  an effective 
counterbalance  to institutional  interests. 
With  respect to our recommendation  calling  for investigators  to provide  a written 
attestation  of their familiarity  with  and commitment  to human-subject  protections,  we 
regret that ARENA  viewed  it as an unjustifiable  demand on investigators  time.  This 
recommendation  parallels  one carefully  considered  and presented  by the Commission  on 
Research Integrity.  We submit  that the signing  of the attestation  by investigators  would 
take minimal  time, but would  represent an important  formal  commitment  to take 
seriously  their responsibilities  in upholding  human-subject  protections  as called for in 
Federal regulations.  Many  IRB  officials  themselves suggested that they had a difficult 
time getting  investigators  to devote sufficient  attention  to those regulations. 
On the matter of insulating  IRESsfrom  conflicts,  we agree with  the comment that our draft 
report made it appear that the possibility  of conflicts  were greater for institutionally  based 
Irks  than for independent  ones.  Accordingly,  we have revised the text to more fully  and 
clearly  express our concern about how  conflicts  can compromise  the mission of all types 
of IRBs.  We also agree with  the concerns raised about the adequacy  of resources, as we 
have commented  on in response to the FDA  comments. 
Finally,  in response to ARENAs  concern  about the type of IRBs  to which  our findings 
and recommendations  apply,  we note that they are presented as applicable  to the IRIS 
D - 28 
OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  D 

community  as a whole.  Obviously,  some will  be more relevant to some types of IRBs 
than others.  Occasionally  we point  that out when we have reason to believe that to be the 
case.  Overall,  we have given more attention  to IRBs  in academic health centers, where, 
as we point  out, a significant  portion  of research continues  to be conducted.  So our 
findings  have particular  applicability  to them.  But in the course of our inquiry  we have 
interacted  with  representatives  of IRBs  in many other settings, including  hospitals  of 
various  sizes, public  agencies, and independent,  free-standing  bodies.  We would  not 
exclude them from the main thrust of our findings. 
D - 29 
OEI-01-97-00193  IRBS:  A Time  For Reform  24x)  N STFtEFL N%! WASHINGTON,  IX  20057-1127  Jordan  J. Cohen,  M.D.,  President 
PHONE  202-828-0400  FAX 202-828-1125 
May 4, 1998 

JuneGibbs Brown   

Inspector General 

Department of Health and Human Services 

Fifth Floor 

330 IndependenceAvenue, N.W. 

Washington,D.C.  20201 

Dear Ms. Brown: 

On behalf of the Association of American Medical Colleges(AAMC),  I would like to thank you 
for sharingwith us your March 1998 draft report on institutional review boards. The AAMCs 
membership- all 125 accreditedU.S. medical schools,over 400 teachinghospitals,and 89 
scientific and academicsocieties-- conductsthe majority of clinical researchin this country, and 
ensuringthe safety of those who volunteer to participate as subjectsis a significant concernof this 
Association. The keystone of the current systemof protections is the institutional review board 
(IRB), and thus the sound functioning of thesebodies is of the utmost importance. 
The study your office conductedwas reported in four volumes,but they include many recurrent 
themesand observations. Thus, for the sakeof simplicity and brevity, this letter will focus on the 
most salient issuesand recommendations,rather than comment on eachreport separately. First, a 
few very general observationsare in order. 
Taken together, the reports do not adequatelyacknowledgethe proper role of IRBs in assuring 
the protection of human subjectsin research. IRBs were establishedas a consequenceof the 
report of the National Commission for the Protectionof  Human Subjectsof Biomedical and 
Behavioral Research(Belmont Report), which identified the basicprinciples of beneficence, 
justice, and respectfor personsthat havebecomethe cornerstonesof ethical clinical research. 
Guided by theseprinciples, the role of the IRB is to weigh the risks posedby the researchagainst 
the benefits that the researchmay offer to the patient and society. IRBs arethus constituted in a 
way that enablesexamination of theseethical considerations. They were establishedto work 
collaboratively with investigators,the vast majority of whom arealtruistically motivated and 
intend to do the right thing.  IRBs aid investigators in their work by ensuringthat subjectsare 
fully informed, and that any risks are reasonablein relation to anticipatedbenefits. 
In contrast to theseobjectives,the report seemsto presumeinsteada policing or auditing role 
that, in fact, is inconsistentwith the mission articulated for IRBs in the Belmont Report. For  June Gibbs Brown 

May 4, 1998 

Page 2  . 

example, the summary report observes,the IRB processis rooted in trust, and assertsthat this 

characteristic is in conflict with the oversight role of theseboards. This observationseemsto 

serve as a premise for much of the report and reflects a fundamental tisunderstandiig  about how 

IRBs were intended to function.  It is the trust that existsbetween the IRB and investigator that 

permits this systemto work effectively becauseit encouragesopenness,responsivenessa,nd 

collaboration. 

Nonetheless,asthe report amply notes, IRBs indeed face tremendousstressesat this time.  They 

unquestionably bear enormous workloads and could undeniably benefit from additional resources. 

The AAMC  is sympatheticto many of the observationscited in the report along theselines, but 

finds that the title of the report and some of the introductory text are disproportionately alarming. 

The systemis neither in crisis, nor on the verge of collapse,as somemight infer.  As your cover 

letter-appropriately states,the system is supported by many conscientiousresearchinvestigators 

committed to protecting human subjectsand by many dedicatedIRB membersand staffdoing 

their best... This fact is beautifully illustrated by the volume of your report on Promising 

Approaches, which provides in a very constructive and positive way useful examplesof how 

particular JRBs havebeen especially innovative in overcoming obstaclesand in enhancingtheir 

effectiveness.As a consequenceof this dedication and resourcefulness,the systemhasworked 

remarkably well in the face of many challenges. 

The report is also prone to generalizations and very sweepingconclusions,eventhough it is based 

on a literature review, interviews with alimited  sampling of IRB representatives,andvisits to only 

six  institutions.  While certain observations are certainly true anecdotally, an impressionis given 

that they apply to all, or even a majority, of IRBs, which may not be the case. Statementsin the 

report concerning continuing review are a particularly salient exampleof this type of writing. 

On the topic of resources,the report notes the extent to which IRBs needto have adequate 

material SUppOtt  to  enable  them to carry out their responsibiities. The AAMC  concurswith this 

statement,but notes that the greatest challengeis finding the necessaryfunds to develop and to 

make available such resourcesas office space,computers, and administrative support. Institutions 

face both increasing cost sharing on federally supportedresearch(through the cap on  . 

reimbursementof administrative costs, for example) coupled with an accretion of compliance and 

other regulatory requirements, and thus funds for thesesorts of resourcesare increasingly scarce. 

One solution may be to develop a specially-designatedsource of federal support for IPB 

activities, either through a mechanismthat would be funded in proportion to NlIMmded  human 

subjectsresearch,or through a more general&d  flexible fimdiig  mechanism,such asthe 

ResearchInnovation Oppot-&mit$. program, which the AAMC  hasproposed as a substitute for 

the now defunct BRSG program. 
 June Gibbs Brown 
May 4, 1998 
Page 3 
While many of the recommendationsin the report are reasonable,some are problematic or in need 

of refinement. Detailed commentsare provided below: 

Recommendation  1: Recast Federal  IRR  Requirements  so that  They  Grant  JR.&  Greater 

Flexibility  and  Hold  Them  More  Accountable  for  Results  - The Association agreesthat IRBs 

spendtoo much of their attention on perfunctory review responsibilities, and that lesseningsome 

of theserequirementswould be a usefbl step, particularly review of protocols that ultimately 

neverget funded. Performance-focusedevaluationscan be desirablefor certain activities, but may 

be problematic for IRBs.  The key will be to discernthe appropriate performance-basedcriteria to 

usefor evaluation of IRB performance, which is very qualitative in nature. The report 

recommendsmaking IRB evaluationsavailableto the public, but it is not clear what types of 

information,would be provided and how lay people could assessit meaningfully. Until this is 

better defined, the AAMC would discourageroutine public disseminationof suchreports. 

Recommendation  2: Strengthen  Continuing  Protections  for  Human  Subjects  Participating 

in Research  - Multi-site trials do indeed pose specialchallengesfor oversight, and it would be 

reasonableto require that Data Safety Monitoring Boards play a significant role in assessing, 

summarizing,and determiningwhen and how to follow up on adverse-eventreports. The AAMC 

also agreesthat IRBs shouldbe informed about the progressof multi-site trials as a whole, even 

though an individual boards review may be limited to the,work being conducted at a particular 

institution.  Indeed, IRBs needto be aware of adverseeventsoccurring elsewhere,suchthat the 

risks of the protocol canbe reassessedfor the local study population.  More systematic 

communication from the FDA to IRBs about actionstaken againstinvestigatorsis also a laudable 

objective, asunderscoredin the report. 

Finally, while appreciatingthe intent of recommendation2e -- increasedIRB awarenessof on-site 

researchpractices- it should not be conducted in a mannerthat threatensthe collaborative 

relationship betweenthe IRB and investigator.  As statedearlier, IRBs are not watchdogs, and 

neither havethe resourcesnor mission to be expectedto conduct surprise visits on investigators. 

Recommendation  3: Enact  Federal  Requirements  that  Help  Ensure  that  Investigators  and 

DU3 Members  are Adequately  Educated  About  and  Sensitized  to Human-Subject 

Protections  - This is perhapsone of the most important recommendationsin this report. 

Problems,when they occur, are most often attributable to inadequatetraining and sensitizationon 

the part of investigators. Individual institutions, aswell as national organizations, suchasPublic 

Responsibility in Medicine and Research(PRIM&R),  are developing educational programs, some 

targeted at investigatorsand others focused on IRB members. NE&supported mechanisms 
 JuneGibbs Brown 
May 4, 1998 
Page4 
should be developedto support thesekinds of outreachand clinical researchtraining activities 
that require significant resourcesto function effectively. 
Recommendation  4: Help  Insulate  IRBs  from  Conflicts  that  Can  Compromise  Their 
Mission  in Protecting  Human  Subjects  - This recommendationis improperly tied  and 
problematic in practice. The observationsmadeat the outset of this recommendation imply that 
IEU3sregularly havethe institutional interest in heart at the expenseof those of researchsubjects. 
This setsup a false logic whereby the subjects interestsare presumedto be in conflict with those 
of the institution, and that the IRB somehow must choosebetweenthe two.  The fact of the. 
matter is that nothing could be more in the institutional interestthan protecting the subjectsof 
research. Apart from the firm commitment that all medical schoolshaveto the ethical principles 
underlying the Belmont Report, violations of those principles put institutions at extremerisk. 
Thus, the predominant pressurethat IRBs feel fi-om their parent institutions is to be rigorous in 
their review.  -
At the very least, any amplification of the current requirementfor representationof non-scientific 
and non-institutional membersshould be at the discretionof the IRB.  First, participation on an 
IRB is done voluntarily and demandssign&ant  amount of time. Finding membersof the public 
who are willing  to give of themselvesto this degreecanbe exceedinglydifiicult.  Second,once 
appointed, theseindividuals often do not becomesignificant contributors to IRB deliberations 
until they have servedfor a long enough period of time to developa relevant ethical and scientific 
knowledge base. At that point, they generally bring the sameconcernsand perspectivesto the 
table astheir other colleagueson the board. Adding additional non-scientific and non-institutional 
membersis thus likely to put a strain on IRBs while theseindividuals are recruited andbrought 
up to  that will not be outweighed by the ongoing contributions of suchparticipants. In the 
speed 
end, what benefits the IRB processand patientsthe most is the quality of outside membersand 
the contributions they make, not simply the numberof them on the committee. 
Recommendation  5: Recognize  the  Seribusness  ofthe  Workload  Pressures  that  Many  IRBs 
Face and  Take  Actions  that  Aim  to Moderate  Them  - The needthat JRBs havefor ample 
resourcescannot be overstated,yet merely to require adequateresourcesis insufficient. As stated 
earlier, bureaucratic accretion coupled with institutional cost sharingis making the provision of 
resourcesincreasingly d*ZEiculatt a time when IRBs faceunprecedentedburdens. Institutions do 
their best to provide IRBs with the materials they need,but a specialNJH support mechanismas 
previously describedshould be developed. In addition, the provision of adequateresources 
should be a priority, but is not implementable asaformaZ requirement. It would be diicult  if not 
impossible to develop workable criteria for determiningthe types and levels of resourcesthat 
would be adequatefor the very diverse set of IRBs that are now in existence. Their workloads 
and local circumstancesarevery different, as are consequentlytheir resourceneeds.  JuneGibbs Brown 
May 4, 1998 
Page5 
Recommendation  6: Reengineer  the Federal  Oversight  Process - The report repeatedlycites 
the inadequaciesof IRB oversight of ongoing protocols. It is important to note that the needfor 
oversight varieswidely, dependingon the complexity and risks posedby eachprotocol.  Thus, 
any performance-basedassessmentsshould take this into account. With this in mind, the AAMC 
particularly supportsthe proposalsto emphasizeinstitutional assurancesof confommncewith 
federal IRB requirements,and education to help investigatorsandIRB membersbecomeas 
attuned as possibleto human subjectsconcerns. Similarly, the shift in emphasisproposedfor 
FDA review - from narrow compliance checksto more performance-basedcriteria - may be 
workable, but should take into account the caveatexpressedearlier about-theneedto develop 
soundperformancebasedcriteria first.  We particularly applaudthe proposed involvement of 
experiencedIRB membersin reviewing  II&  performanceasa form of peer review.  The 
registration of all IRBs with the government seemsreasonable,aswell. 
Special  Issues: Advertising  to Recruit  Human  Subjects  - All advertising for the purposesof 
patient recruitment is consideredpart of the researchprotocol, andthus must be reviewed and 
approvedby an IRB.  IRE3sthus examinethe text of theseadvertisementswith an eyeon ensuring 
that they are not overly coercive with regard to financial inducements,nor misleadingwith regard 
to the statedbenefits of participation in research. Nonetheless,patient recruitment canbe a 
challenge,sincevolunteers must give of their time and often must be inconveniencedto 
participate in a protocol.  Thus somemodest level of compensationis generally reasonable. 
The specific advertisementsprovided in the report are highly anecdotaland do not enhancethe 
readersunderstandingof the predominant way in which suchadvertisingoccurs. Nor doesthis 
approachrecognizethe extent to which subjectsbecomeinformed of clinical researchthrough 
their physicians,voluntary health societies,or patient advocacygroups, which havehistorically 
actedquite responsiblyand often with the benefit of IRB input, either directly or indirectly. 
In conclusion, it is important to emphasizethat, overall, this is a systemthat hasworked 
remarkably well, and one that is not on the verge of collapse. Thus the alarmist tone in some 
sectionsof the report, particularly the overview, shouldbe lessenedto make the level of concern 
expressedmore proportional to the magnitude of the problemsidentified in the report. We also 
strongly suggestthat the title of the report be changedto be lesssensationaland more 
constructive in tone. In addition, the traditional and proper role of IRBs in ensuringthe 
application of the Belmont Report principles to humansubjectsresearchmust be emphasized,and 
text implying an auditing or policing role should be eliminated. 
On the other hand, the AAMC  findsthe OIGs report to raisemanyvalid and important 
observations. The most salient include those that relateto the extent to which IRBs face  JuneGibbs Brown 
May4,  1998 
Page6 
tremendousworkloads and could benefit Corn additional resources. The report also provides 
much useful and constructive information on how specific institutions havebeeninnovative in 
enhancingIRB effectiveness. This material, found largely in the volume on Promising 
Approaches, should be amplified andbecomea central focus of the report. 
The AAMC  thanks you once again for this opportunity to comment and invites you to cantact the 
Association again if we can be of service.  APPENDIX  D 

OIG  RESPONSE  TO  AAMC  COMMENTS 
We concur with  AAMC  that the IRBs  are the keystones  of the current  system of 
protections  and that the  sound functioning  of these bodies  is of the utmost significance. 
That is why  we have given so much attention  to just  how  they are functioning  and how 
they might  be improved.  Obviously,  we disagree with  AAMC  on a number of the 
particulars. 
One of the most important  of these particulars  has to do with  how  we interpret  the role of 
IRBs  in carrying  out their protective  responsibilities.  The AAMC  stresses that from the 
beginning  the essence of that role has been one based on trust, whereby  IRBs  work 
collaboratively  with  investigators  to help them ensure that the necessary human-subject 
protections  are in place.  It points  to the Belmont  Report,  produced  in 1979 by the 
National  Commission  for the Protection  of Human  Subjects of Biomedical  and 
Behavioral  Research, as establishing  the basis for this collegial  role.  It suggests that we 
misunderstand  this backdrop  and assume a policing  or auditing  role  for IRBs. 
As we note in our reports, we recognize  the fundamental  importance  of trust between 
IRBs  and the research community.  At the same time, we underscore  that trust in itself is 
insufficient.  This is particularly  true today as IRBs  face many possible  conflicts  in an 
increasingly  commercialized  research environment.  But even in the 1970s  the National 
Commission  noted above had more than trust and collegiality  in mind when delineating 
the role of IRBs.  The Belmont  Report  cited by AAMC  is an important  report setting forth 
ethical principles  of research.  But prior  to it,  the National  Commission  produced  many 
other reports.  One, as we elaborate on in Footnote  28 of our report  on continuing  review, 
focused specifically  on IRBs.  In that report, the Commission  elaborated  on the 
verification  efforts that IRBs  might  undertake.  These included  interviews  with  human 
subjects, requirements  that investigators  give subjects a form  through  which  they may 
report their research experiences to IRBs,  and even, in certain  cases, requirements  that a 
neutral party be present to help a potential  subject to consider  the pros and cons of 
participating  in a research effort. 
We emphasize this matter here at the outset of our response because it is fundamental  to 
the kind  of reforms  we (and many others) regard as necessary.  If our calls for greater 
accountability  through  more results-focused  assessments, broader  representation  on IRBs, 
and other measures,  are routinely  dismissed as violating  the essential principles  of IREs, 
then little  progress is likely.  Thus, further  discussion  of this important  matter in the 
research and policy  communities  would  be highly  desirable.  Our intent is to maintain  the 
foundation  of trust, but to complement  it with  various  types of verification  that are 
essential for a review  body  having  a vital role in protecting  human beings. 
The changes we have made in some of the language we use, as we noted in our response 
to ARENA,  may help address some of the concerns AAMC  expresses about our 
generalizations  and conclusions.  We do not conclude  that the IRB  system is necessarily 
D - 36  OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  D 

on  the verge of collapse,  but we certainly  do have reason to conclude  that its 

effectiveness  is in jeopardy.  We have tried  in these final  reports to use language even 

more carefully  to express our serious concern without  conveying  a greater degree of 

imminent  danger than we have basis to suggest. 

The AAMC,  as other commenters,  addressed the matter of resources and how they might 

best be tapped to support the IRBs  important  role.  It suggested that some specially 

designated  source of Federal support might  be developed.  As we have noted in other 

responses in this appendix  and in the introduction  to our recommendations,  we recognize 

that this is an important  issue warranting  further  examination,  especially  as IRB 

responsibilities  expand. 

The AAMC  supports our recommendation  that IRBs  be granted greater flexibility  in 

carrying  out their responsibilities,  but is wary  of performance-focused  evaluations, 

especially  if made available  to the public.  As we have noted in response to FDA  and 

ARENA,  there are many practical  ways of incorporating  a greater focus on results, both in 

the IRBs  own  continuing  review  efforts and in outside assessments of IRBs.  And  we 

would  add that these could be carried out and presented in ways that lay people would 

find quite possible  to understand.  Further,  we  stress that a greater accountability  for 

results must be integrally  associated with  efforts to grant IRBs  greater flexibility. 

In regard to our recommendation  urging  that NIH  and FDA  help insulate IIU3s from 

conflicts  that can compromise  their protective  mission,  AAMC  indicates that nothing 

could be more in the institutional  interest than protecting  the subjects of research.  We 

agree with  the principle  expressed in that comment.  But  in settings where clinical 

research represents as much as a quarter or more of the operating  income of IRBs  parent 

institutions,  where IRBs  are urged to expedite their review  processes and make other 

adaptations  to accommodate  sponsors, where IRBs  serve under the auspices of 

organizational  units primarily  responsible  for bringing  in research dollars,  we submit that 

it is reasonable to be concerned  about the kind  of conflicts  we point  out.  Many  IRB 

officials  themselves have emphasized this point  to us, quite  strongly. 

Finally,  on the matter of advertising  to recruit  human subjects, AAMC  indicates that our 

warning  is highly  anecdotal  and that we exaggerate the danger associated with  these 

advertisements.  Our response is that with  little  difficulty  we accumulated  60 

advertisements  that were highly  imbalanced  in presenting  risks (rarely  mentioned)  and 

benefits and that we could  easily have collected  many times that number. 

Notwithstanding  the fact that many subjects are recruited  through  quite responsible  means 

and that all must sign an informed  consent form, we suggest that the advertisements  do 

represent a danger that warrants  careful  attention.  Just a mere glance at the inducements 

offered  in many of these advertisements  makes that quite obvious. 

D - 37 
OEI-01-97-00193  IRBS:  A Time  For Reform  INDEPENDENTREVIEWBOARDS 
CONSORKWMOF 
May.4, 1998 
June Gibbs Brown 

.. 

Inspector General 
Oflke  of Inspector General 

Department of Health  and h&n  Se&c 

330 Independence Avenue, S.W. 

Washington, DC.  2020 1 

Rt:  Draft  Reports  Conttrnlng  Institutional  Rtvitw  Boards 
Dear Ms. Brown: 
On behalf of the Consortium of Independent Review Boards (CIRB),  we congratulate 
the Department of Health and Iiuman Services (I-NY)  Office of Inspector General (OIG)  on 
its four comprehensive reports on a difficult  issue. In addition, CIRB thanks you for the 
opportunity  to meet with you and comment on the 010 reports concerning the effectiveness of 
current Institutional  Review Board (IIZB)  regulations, policies, and practices.  Provided below 
are our comments concerning the following  documents: (1) Inrtifutional  Revtew Boar&  A 
System in Jeopardy  (Drafl);  and (2) Institutional  Review Boards:  The Emergence  of Independent 
Boards  (Drafi).  The CIIU3 membership hopes that these comments will  be helpful to 010  as it 
finalizes the draft documents. 
1. 	 INSTITUTIONAL  REVIEW  BOARDS:  A SYSTEM  IN  JEOPARDY 
(DRAFT)  .. . 
As the document fnsritlitfonal  Review Boar&  A System in Jeopardy  (Drafi)  clearly 
reflects, the environment within  which IRBs currently operate is very different from that which 
existed when the Federal IRB regulations were first implemented. Thus, CIRB agrees with the 
OIGs recommendation to recast these regulations so that the focus wiil  be on IRE performance 
rather than merely IRB compliance.  OIGs suggestions to mod@ or eliminate certain 
perfunctory  Federal requirements that may not be necessaryto proteot human subjects, and to 
establish new Federal regulations or guidances that require, and set standards for, IRB 
Performance-Focused Evaluations wilI  greatIy assistin implementing this recommendation.  The 
time
OIG report correctly observes that many IRBs operate under significant  and resource 
constraints.  While a large proportion of the Federal regulations certainly support human subject 
protection, when IRBs must spend precious time complying with redundant or unnecessary 
Consortium of Independent Review Boards  Phone:  (513) 7614100 
10 Knollcrest Drive, Suite 200  Fax:  (513) 761-1460 
Cincinnati, OH 45237  MS. June Gibbs Brow 

May 4,  1998 

Page 2 

Federal regulations, inadequate time and resources are I&  for ongoing activities.  Elimination  of 

such regulations would  allow IRBs to focus their limited resourceson strategies that would  allow 

more effective initial review of rescarch activities by providing time to carefully consider the 

research and the protocol. 

In addition, CIFU3strongly endorses rho recommendation that NIH/OPRR  and FDA 
convene symposia with IRBs to discuss performance measuresand self-evaluation measures that 
will  encourage IRE3accountability  to its stated purpose: the protection of human subjects.  We 
believe that such symposia would~result in fruitful  dialogue between the agencies, the Irks,  and 
other interested parties or users of IRBs, such as investigators and sponsors, and would allow the 
agencies to develop effective oversight policies. 
We also strongiy support the 010s recommendations concerning information  sharing. 
While the majority of sponsors and investigators have demonstratedintegrity during the IRE3 
review process, we believe it is important that these parties be obligated to inform a reviewing 
IRE3about any prior reviews.  Further, so that an 1RB can function effectively, it should be 
provided copies of a11FDA and OPRR regulatory inspectional reports and correspondence with 
investigators concerning clinical  studies which the IRB has approved and for which it continues 
to provide oversight.  Finally, becauseclinical investigations are already subject to government, 
contract research organization, and sponsor auditing and tnonitoring, we believe that extending 
the required information-sharing  between the parties could bc extremely helpful in providing 
oversight  without  adding the burdens of additional site visits to an already overworked clinical 
investigator. 
We do have one concern, and that is the definition of the following  terms:  continuing 
review,  monitoring,  oversight,  visits, and inspections.  Chrly,  these terms can have 
different meanings to different people and it is not completely clear how these terms are being 
defined in this report. 
2. 	 INSTITUTIONAL  REVIEW  BOARDS:  THE  EMERGENCE  OF 
INDEPENDENT  BOARDS  (DRAFT) 
While we agree with much of what is reported in the document entitled Institutional 
Review Boar&:  The Emergence of Independent  Boa&  (Drafi),  we are concerned about the 
reports emphasis on the independent IRBs ability to consider local concerns and attitudes as it 
reviews research protocols.  We note at the outset that the ready availability of information 
sharing tools, such as the Internet, has made it more feasible for independent IRBs to become 
knowledgeable about local attitudes and interests. Moreover, as the OIGs draft report, 
Institutional  Review Boards:  A e.rfem  in Jeopardy,  aptly reflects, the environment in which 
IRBs operate has,changed significantly  over the past twenty years in that, among other things, 
there has been a steady rise in national and multi-site studies. An advantage of an independent 
board reviewing a multi-center or national trial is that it can develop a benor understanding of the 
safety profile of the product because it receives a broad spectrum of serious adverse event reports  Ms. June Gibbs Brown 

May 4, 1998 

Page 3 

from multiple sites. Such information may not be made available to single site boards. Thus, 

while it is important to maintain a review system that addresseslocal attitudes and concerns, in a 

national or multi-center study environment, the local community is best protected where IRBs 

have the ability to work with a number of sites. 

Moreover, as the report notes, in the last twenty yeara there has been an incredible 
increase in the number of protocols requiring IRB review, while at the same time, the research 
community  and pharmaceutical industry are demanding that protocols be reviewed more quickly 
and efficiently.  As a result, the need to address local attitude must be assessedin light of the 
national nends that have developed since the early 1970s. We believe that this is a multi-faceted 
issue which is ripe for discussion in a symposium setting.
. .. 
Again, we txtend,qur  congratulations on the report and thank you for the opportunity  to 
comment on these draft documents. We hope that the OIG will  feel tie  to contact  CIRB if we 
can be of any assistance. 
Sincerely, 
John Isidor, J.D. 
Chairman 
AMBfamb 
cc: 	 ChesapeakeResearchReview, Inc. 
Essex IRB  _. 
Ethical Review Committee 
Independent Review Consulting 
Quintilw,  Inc. 
New England IREl 
Research Consultants Review Committee 
Schuhnan Associates IRB, Inc. 
WestemIRB  1.  APPENDIX  D 

OIG  RESPONSE  TO  CIRB  COMMENTS 
We appreciate CIRBs  generally  positive  comments  about the reports.  With  respect to its 
concerns about the definition  of certain terms, we have, as noted in prior  comments, 
sought to be more precise in our use of the terms continuing  review  and oversight. 
We use the term monitoring  infrequently  and mainly  in context  of the work  of bodies 
other than IRE&s. We use the term inspections  mainly  in context  of FDAs  regular  on-
site inspections  of IRE3and the term visits  to refer to visits to the IRE3 site, whatever  the 
basis for the visit. 
The CIRE3 also expresses concern  about our emphasis  on independent  IRIS  ability  to 
consider  local concerns and attitudes  as it reviews  research protocols.  It elaborates on 
how  these IRE& are able to take into account  local issues and how  in the case of multi-site 
trials the independent  IRE& are able to tap into a broad spectrum of information  from 
multiple  sites. 
We recognize  the latter as one of the perceived  advantages of independent  IRE3sand 
indicated  that in our report  on independent  IRBs.  At the same time, we felt compelled  to 
note the lack of a local presence as one of the perceived disadvantages  of independent 
IRE3.s. We did not emphasize the point.  We simply  cited it as one of the factors that 
many in the IRB  community  express concern about when assessing the role and 
contributions  of independent  IRE3s. We reiterate here that our report  on the independent 
1-s  is not an evaluation  of their performance  but rather a description  of their growing 
role and of the major  advantages and disadvantages attributed  to them. 
D-41 
OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  E 

Endnotes 

1. Presidents  Commission  for the Study of Ethical  Problems  in Medicine  and Biomedical  and 

Behavioral  Research, Implementing  Human  Research Regulations:  Second Biennial  Report  in 

the Adequacy  and Untformity  of Federal  Rules and Policies,  and of their Implementation,  for  the 

Protection  of Human  Subjects, (Washington,  DC: U.S. Government  Printing  Office,  1983). 

2.  For a fuller  explanations  of these concerns see Nancy  E. Kass and Jeremy Sugarman, Are 

Research Subjects Adequately  Protected?  A Review  and Discussion  of Studies Conducted  by the 

Advisory  Committee  on Human  Radiation  Experiments,  Kennedy  Institute  of Ethics Journal, 

Vol.  6, (1996),  No. 3, pp. 27 l-82,  and the Advisory  Committee  on Human  Radiation 

Experiments,  Final  Report,  (Washington  DC: U.S. Government  Printing  Office,  1995). 

3.  U.S. General Accounting  Office,  Scienttfic  Research:  Continued  Vigilance  Critical  to 

Protecting  Human  Subjects, GAOHEHS-96-72,  March  1996. 

4.  Department  of Health  and Human  Services, Office  of Inspector  General, Investigational 

Devices: Four  Case Studies (OEI-05-94-OOl OO), April  1995. 

5.  According  to the Presidents  Budget  for Fiscal Year  1999, the NIH,  which  is the flagship  of 

the Presidents  Research Fund for America,  would  be increased by nearly half over five years. 

For more discussion,  see Robert  Pear, Medical  Research To Get More  Money  From 

Government,  New  York Times, Saturday,  3 January  1998, pp. Al  and A8. 

The Task Force on Genetic Testing  calls for placing  greater emphasis on the role of the IRB  in 
evaluating  genetic research protocols.  (Eds. Neil  A. Holtzrnan,  and Michael  S. Watson, 
Promoting  Safe and Effective  Genetic  Testing in the United States: Final  Report  of the Task 
Force  on Genetic  Testing, NIH-DOE  Working  Group  on Ethical,  Legal,  and Social Implications 
of the Human  Genome Research, September  1997.)  In addition,  a recent Senate bill  would  rely 
on the IRB  to determine  measures of confidentiality,  such as whether  subject identifiers  should 
be retained  (S. 192 1, 105h Congress,  sponsored by Senators Jeffords  and Dodd). 
6.  The body is the National  Bioethics  Advisory  Commission.  It was established  by Presidential 
executive order on October  3, 1995.  Its charter, issued in July  1996 by the Assistant  to the 
President for Science and Technology,  calls for it to focus its attention  on: A.  Protection  of the 
rights and welfare  of human research subjects; and B. Issues in the management  and use of 
genetics information  including  but not limited  to human gene patenting.  For some background 
on the Commission  and its emergence, see Alexander  Morgan  Capron,  An  Egg takes Flight: 
The Once and Future Life  of the National  Bioethics  Advisory  Commission,  Kennedy Institute  of 
Ethics Journal,  Vol.  7, (March  1997) No.  1, pp. 63-80. 
7. We use the term academic  health centers  in accord with  the following  definition  offered by 
Blumenthal,  et al: One  of 125 institutions  in the United  States that consist of at least a medical 
school and an owned  or closely  affiliated  clinical  facility  in which  faculty  instruct  physicians-in-
E-l 
OEI-Ol-97-00193  IRRS:  A Time  For Reform  APPENDIX  E 

training.  These centers classically  conduct  teaching,  patient  care and, in many cases, research. 
(David  Blumenthal,  Eric G. Campbell,  Joel S. Weissman, The  Social Missions  of Academic 
Health  Centers,  New England  Journal  of Medicine,  Vol.  337,20  November  1997, No.  2 1, pp. 
1550-53.) 
8.  These IRBs  are overseeing research at institutions  receiving  over 1.4 billion  dollars  of Public 
Health  Service (PHS)  awards.  As of March  1998, these institutions  received over 27 percent of 
the PHS dollars  awarded extramurally  for human-subject  research. 
9.  These six institutions  alone account for over half a billion  dollars  of Public  Health  Service 
(PHS)  awards.  As of March  1998, these institutions  received over 11 percent of the total PHS 
dollars  awarded  extramurally  for human-subject  research. 
10.  Charles Mar-wick,  Institutional  Review  Boards Under  Stress: Will  they Explode  or 
Change?  Journal  of the American  Medical  Association,  Vol.  276, (27 November,  1996), No. 20, 
pp. 1623-1626. 
11.  Charles MacKay,  NIH  Office  of Policy  for Extramural  Research Administration,  Letter  to 
Reports  Clearance Officer,  PHS, Request for Office  of Management  and Budget  (OMB)  Review 
and Approval  for the study Evaluation  of NIH  Implementation  of Section 491 of the Public 
Health  Service Act,  Mandating  a Program of Protection  for Research Subjects,  Concept 
Clearance 9025-0404,  March  10, 1995.  See also Harold  Edgar and David  J. Rothman,  The  IRB 
and Beyond:  Future  Challenges  to the Ethics of Human  Experimentation,  The Milbank 
Quarterly,  Vol.  73 (1995) No.4,  pp. 489-506. 
12.  This according  to the comments of Dr. Jim Childress,  meeting  transcript  of the National 
Bioethics  Advisory  Commission,  9 January  1997, (Eberlin  Reporting  Service: Silver  Spring, 
MD),  p. 20. 
While  this phenomenon  was true for drug studies, the situation  wasreversed  for medical  device 
studies.  The intraocular  lenses studies involved  thousands of subjects.  Most  of the studies were 
conducted  at small community  hospitals. 
13.  Comments  of Dr. Jim Childress,  meeting transcript  of the National  Bioethics  Advisory 
Commission,  9 January  1997, (Eberlin  Reporting  Service: Silver  Spring,  MD),  p. 21. 
14.  Between  1974 and 1975, IRBs reviewed  an average of 43 proposals  per annum.  (Institutional 
Review Boards:  Report  and Recommendation  of the National  Commission for  the Protection  of 
Human  Subjects of Biomedical  and Behavioral  Research, 43 Federal Register,  10 November 
1978, p. 56186.) 
15.  Barbara Mishkin,  Ethics,  Law  and Public  Policy,  Professional  Ethics Report  (a publication 
of the American  Association  for the Advancement  of Science), Vol.  7, (Spring  1994), No.  2, 
pp. 4-6. 
E-2  OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  E 

16. U.S. General Accounting  Office,  Scientljic  Research:  Continued  Vigilance  Critical  to 
Protecting  Human  Subjects, GAOIHEHS-96-72,  March  1996, p. 17. 
17.  The FDA  reports, however,  that it is in the process of revising  its policies  on disclosure  of 
such information. 
18.  We do not claim that this practice  is widespread,  but IRB  representatives  we spoke with  did 
identify  situations  where such information  was not conveyed.  These representatives  emphasized 
a certain vulnerability  they felt about not being sufficiently  informed  about any prior  IRB 
reviews.  Some of the independent  IRB  officials  we spoke with  were particularly  concerned 
about this practice. 
The FDA  cites 2 1 C.F.R.,  sec. 8 12.150(b)  when this situation  occurs:  A  sponsor shall upon 
request by a reviewing  IRB  or FDA,  provide  accurate complete,  and current  information  about 
any aspect of the investigation.  We believe, however,  that the rules regarding  notification 
should be made more explicit. 
19.  The FDA  and OPRR also offer  frequent  interpretations  in more informal  ways:  over the 

telephone,  by electronic  mail,  fax, or in person.  Many  IRB  officials  we spoke with  stressed that 

these clarifications  were helpful  to them. 

20. 	 Charles Marwick,  Institutional  Review  Boards Under  Stress: Will  They  Explode  or 

Change? Journal  of the American  Medical  Association,  Vol.  276, (27 November  1996), No. 20, 

pp. 1623-1626. 

2 1. Contract  Research Organizations  manage clinical  trials  for drug and device manufacturers. 

22.  For more information  about the independent,  for-profit  IRBs,  see our companion  report 

Department  of Health  and Human  Services, Office  of Inspector  General, Institutional  Review 

Boards:  The Emergence  of Independent  Boards  (OEI-0 l-97-00  192) June 1998. 

23.  Gregory  J. Hayes, Steven C. Hayes, and Thane Dykstra,  A  Survey of University 

Institutional  Review  Boards:  Characteristics,  Policies,  and Procedures,  IRB, Vol.  17, (May-June 

1995), No. 3, pp. 1-6. 

24.  The National  Service Research Award  Act of 1974 established  the assurance as the primary 

mechanism  by which  the Department  was to oversee research involving  human subjects. 

(National  Service Research Award  Act  of 1974, Public  L. No.  93-348,  sec. 474, 88 Stat. 342.) 

25.  We use NIH  and FDA  as the two  focal points because they are parallel  constituent  agencies 

of HHS.  We add OPRR to the NIH  side because in the IRB  community,  OPRR,  a component  of 

NIH,  is typically  viewed  as the focal point  for IRB  oversight. 

26.  Department  of Health  and Human  Services, Office  of Inspector  General, Institutional  Review 

Boards:  Promising  Approaches  (OEI-01-97-0019  1) June 1998. 

E-3  OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  E 

27.  HCFA  Press Office,  New  Results-Oriented  Medicare  Rules Proposed For Hospitals, 
December  19, 1997.  Available  on the world  wide  web at www.dhhs.gov. 
28.  The suggested revisions  to the IRB  expedited  review  list move in the direction  we call for 
here. (Federal Register,  Vol.  62, No. 217,  10 November  10 1997, p. 60604.) 
29.  Advisory  Committee  on Human  Radiation  Experiments,  Final  Report,  (Washington  DC: 
U.S. Government  Printing  Office,  1995), Chapter  18, Recommendation  13( 1). 
30.  Ruth Ellen  Bulger,  Elizabeth  Meyer  Bobby,  and Harvey  V. Fineberg,  Editors,  Societys 
Choices:  Social  and Ethical  Decision  Making  in Biomedicine,  (National  Academy  Press: 
Washington,  DC,  1995) p. 182. 
3 1. In reviewing  our reports, the group Public  Citizen  suggested that the following  types of 
evaluations  would  provide  useful information  about IRBs.  While  these suggestions were not 
directed per se to NIWOPRR  or FDA,  we felt that they might  help to stimulate  discussion.  The 
suggestions include:  (1) assessing the differences  between  IRBs  based on a review  of a 
standardized  protocol;  (2) collecting  data on differences  between  IRBs  in rejection  rates or rates 
of requiring  serious modifications  in protocols;  (3) analyses of close votes at IRBs  to see if and 
why  those protocols  got approved;  and (4) retrospective  analyses of IRB  meetings which 
approved trials now  considered  unethical. 
32.  These concerned  serious matters such as the implantation  of a device in three times the 
number of human  subjects specified  in the IRB-approved  research protocol,  the initiation  of a 
research effort  without  changes that the IRB  called for in the informed  consent document,  and the 
continuation  of a research project  for six weeks beyond  when the IRE3had suspended it 
Department  of Health  and Human  Services, Office  of Inspector  General, Investigational  Devices: 
Four  Case Studies (OEI-05-94-00  loo),  April  1995. 
33.  Comments  of Dr. Jim Childress,  meeting  transcript  of the National  Bioethics  Advisory 
Commission,  January  9, 1997, (Eberlin  Reporting  Service:  Silver  Spring,  MD),  p. 20. 
34.  At some large research institutions,  multi-site  trials now  account for about one-half  of all 
active research protocols. 
35.  There is one regulation  which  requires the establishment  of an independent  data monitoring 
committee.  The FDA  regulation  that provides  for an exception  from the informed  consent 
requirements  in certain  emergency research (21 C.F.R.,  sec. 50.24) requires that a study 
conducted  under the exception  have established  an independent  data safety monitoring  board to 
review  data during  the study in order to exercise oversight  of the study. 
36.  One large academic health center we visited  reported  that it has requested and regularly 
receives feedback  from  DSMBs.  But this is contrary  to the experience  of other IRBs  we had 
contact with. 
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OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  E 

37.  A cooperative  group  is a formal,  free-standing  government-sponsored  entity  responsible  for 
conducting  multi-site  trials.  There are, for example,  11 such groups associated with  the National 
Cancer Institute  (NCI).  According  to Federal requirements,  NC1 cooperative  groups are required 
to monitor  their research sites once every 36 months. 
38.  Periodically,  when the cooperative  group  believes that its monitoring  has identified 
information  that may be pertinent  to the IRB,  it will  inform  OPRR, which,  in turn, will  inform 
the IRB.  In addition,  the IRBs  sometimes  will  obtain  information  from the on-site principal 
investigators. 
39.  The FDA  cites 21 C.F.R.,  sec. 812.50(b)  when  this situation  occurs: A  sponsor shall upon 
request by a reviewing  IRB  or FDA,  provide  accurate complete,  and current  information  about 
any aspect of the investigation.  We believe,  however,  that the rules regarding  notification 
should be made more explicit. 
40. 	 The National  commission  that developed  the current  system of human protections  in the 
197Os, envisioned  a more proactive  role for IRBs.  In its report, it noted that IRBs  may interview 
human subjects about their  research experience  or require  that investigators  provide  subjects with 
a form through  which  they may report  to the IRB  their research experiences.  It cautioned  about 
observing  the consent process, but noted that certain  research will  warrant  observation  to assure 
the protection  of subjects and in such cases IRBs  have an obligation  to take suitable measures. 
It further  noted that the documentation  of informed  consent should not be confused with  the 
substance of informed  consent and that in certain  cases the IRB  may well  require  that a neutral 
party be present to assist a potential  human  subject  considering  participation  in a research effort. 
(Institutional  Review  Boards:  Report  and Recommendations  of the National  Commission for  the 
Protection  of Human  Subjects of Biomedical  and Behavioral  Research, 43 Federal Register,  10 
November  1978, p. 56174.) 
The IRB  regulations,  which  were adopted  in 198 1, provide  IRBs with  the authority  to observe  or 
have a third  party observe the consent process and the research.  (45 C.F.R.,  sec. 46.109(e)  and 
21 C.F.R.,  sec. 56.109(e)) 
41. 	 Some cancer centers and clinical  research centers are particularly  active in auditing 
investigators  and assuring that protocols  are being  conducted  as approved.  Many  IRBs  do 
attempt from time to time to visit research sites to obtain  first-hand  knowledge  about research 
practices.  But, certainly,  the workload  pressures and other barriers we noted in our report  on 
continuing  review  significantly  limit  the frequency  and effectiveness of such efforts. 
42.  Remarks by the President  in Apology  for the Study Done in Tuskegee, White  House Press 
Release, May  16, 1997. 
43. 	 See Alicia  K. Dustira,  The  Federal Role  in Influencing  Research Ethics Education  and 
Standards in Science,  Professional  Ethics,  Vo1.5, Nos.  1 & 2, pp. 143-4; and Office  of Research 
Integrity,  NIH  Strengthens  Responsible  Conduct  of Research Requirement  in Training  Grant 
Applications,  Office of Research Integrity  Newsletter,  Vol.1,  No.2,  April  1993, pp.1 and 8. 
E-5  OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  E 

44.  The Commission  on Research Integrity.  Integrity  and Misconduct  in Research,  (Washington, 
DC: U.S. Government  Printing  Office,  November  1995.) 
45.  In the Statement  of Investigator  (FDA  Form  1572), the investigator  is asked to make a 
number  of attestations  (or as the form  states, commitments).  These include  the following: 
1. I  agree to inform  any patients or any persons used as controls,  that the drugs are being 
used for investigational  purposes and I will  ensure that the requirements  relating  to obtaining 
informed  consent in 21 C.F.R.,  sec. 50 and institutional  review  board (IRB)  review  and approval 
in 21 C.F.R.,  sec. 56 are met. 
2.  I will  ensure that an IRB  that complies  with  the requirements  of 21 C.F.R.,  sec. 56 
will  be responsible  for the initial  and continuing  review  and approval  of the clinical 
investigation.  I also agree to promptly  report to the IRB  all changes in the research activity  and 
all unanticipated  problems  involving  risks to human subjects or others.  Additionally,  I will  not 
make any changes in the research without  IRB  approval,  except where necessary to eliminate 
apparent immediate  hazards to human subjects. 
46.  For example, the NIH  has developed  a computer-based  tutorial  about human-subject 

protections.  It is available  to the public  and can be downloaded  from the NIH  web site. 

47. 	 Harold  Edgar and David  J. Rothman,  The  Institutional  Review  Board  and Beyond:  Future 

Challenges  to the Ethics  of Human  Experimentation,  The Milbank  Quarterly,  Vol.  73, 1995, 

No. 4, pp. 489-506. 

48.  In that statement, the President  said: We  commit  to increase our community  involvement  so 

that we may begin restoring  lost trust.  The study at Tuskegee  served to sow distrust  of our 

medial institutions,  especially  where research is involved.  (Remarks  by the President in 

Apology  for the Study Done  in Tuskegee, White  House Press Release, May  16, 1997.) 

49. Institutional  Review Boards:  Report  and Recommendation  of the National  Commission for 

the Protection  of Human  Subjects of Biomedical  and Behavioral  Research, 43 Fed. Reg., 10 

November  1978, p. 56178. 

50.  At present the HHS  regulations  for IRBs  address this issue by calling  for research 

institutions  engaged in federally  funded research to assure that provisions  are made for meeting 

space and sufficient  staff to support  the IRBs  review  and record keeping  duties. 

(45 C.F.R., sec. 46.103(2)) 

5 1. In such cases, OPRR has been quite explicit  in informing  an IRB  of its lack of adequate staff 

support and in calling  for an increased commitment  of staff and other resources.  It has also 

called for the parent institutions  to give greater recognition  to IRB  members for the critical 

services they provide. 

52.  Such a reorientation  would  be in accord with  the directive  set forth  in the House 

Appropriations  Committee  report  on the 1998 Balanced  Budget  Act to lessen the regulatory 

burden associated with  extramural  scientific  research. 

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OEI-01-97-00193  IRBS:  A Time  For Reform  APPENDIX  E 

53.  This parallels  a recommendation  called for by a Presidential  advisory  commission  15 years 
ago: A  broad educational  and monitoring  program  covering  the protection  of human  subjects 
and designed to reach investigators,  IRB  members, research administrators  should be conducted. 
Among  the various  activities  included  in the program  should be site visits of research institutions 
.using experienced  IRB  members and staff as site visitors.  (Presidents  Commission  for the 
Study of Ethical  Problems  in Medicine  and Biomedical  and Behavioral  Research, Implementing 
Human  Research Regulations:  Second Biennial  Report  in the Adequacy  and Uniformity  of 
Federal  Rules and Policies,  and of their  Implementation,  for  the Protection  of Human  Subjects, 
Washington,  DC:  U.S. Government  Printing  Office,  1983, pp.  135-137.) 
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OEI-01-97-00193  IRBS:  A Time  For Reform