Department  of Health  and Human  Services 
OFFICE  OF 
INSPECTOR  GENERAL 
Institutional  Review  Boards: 
Their  Role  in  Reviewing  Approved  Research 
JUNE  GIBBS  BROWN 
Inspector  General 
JUNE  1998 
OE.r-nl-97-nnl9n  OFFICE  OF INSPECTOR  GENERAL 
The mission  of the Office  of Inspector  General (OIG),  as mandated by Public  Law  95-452,  is to 
protect the integrity  of the Department  of Health  and Human  Services programs  as well  as the 
health and welfare  of beneficiaries  served by them.  This statutory  mission  is carried out through 
a nationwide  program  of audits, investigations,  inspections,  sanctions, and fraud alerts.  The 
Inspector  General informs  the Secretary of program  and management problems  and recommends 
legislative,  regulatory,  and operational  approaches to correct them. 
Office  of Evaluation  and Inspections 
The Office  of Evaluation  and Inspections  (OEI)  is one of several components  of the Office  of 
Inspector  General.  It conducts  short-term  management  and program  evaluations  (called 
inspections)  that focus on issues of concern to the Department,  the Congress, and the public.  The 
inspection  reports provide  findings  and recommendations  on the efficiency,  vulnerability,  and 
effectiveness of departmental  programs. 
OEIs Boston regional  office  prepared this report under the direction  of Mark  R. Yessian, Ph.D., 
Regional  Inspector  General.  Principal  OEI staff included: 
REGION  HEADOUARTERS 
Laura C. McBride  Lisa Foley 
Elizabeth  A. Robboy 
Nathan P. Rouillard 
Dana M. Miller 
To obtain copies of this report, please call the Boston Regional Office at (6 17)565-1050. 
Reports are also available  on the World  Wide Web at our home page address: 
http://www.dhhs.gov/progorg/oei  EXECUTIVE  SUMMARY 
PURPOSE 
To review  the performance  of institutional  review  boards in reviewing  ongoing  research 
involving  human subjects. 
BACKGROUND 
Role  of Institutional  Review  Boards 
Institutional  review  boards (Irks)  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. 
Continuing  Review:  The Focus of This  Report 
Continuing  review  can serve as a key safety net for human subjects.  This protective  role 

has become especially  significant  as many individuals  have signed up to participate  in 

research trials with  little  understanding  of the risks involved  or of the distinction  between 

research and established therapy.  Its importance  has also been heightened  as the research 

environment  has become increasingly  affected by marketplace  pressures and as some 

protection  lapses have occurred,  causing harm to human research subjects. 

In this report, which  is one of four we are issuing  on IRBs,  we address the IRBs 

continuing  review  function.  Given our focus on the overall  system of protections 

provided  to human subjects, 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 IRBs  at 

6 academic health centers where extensive clinical  research is taking  place; attended IRE3 

meetings;  and accompanied  FDA  inspectors  on IRE3 site visits. 

FINDINGS 
The  Continuing  Review  Conducted  by IRBs  Is of Limited  Scope and  Significance. 
Minimal  Substantive  Review  of Reports.  Once IRBs  complete their reviews  of initial 
research proposals, they often have little  time left for continuing  reviews.  Thus, their 
i  OEI-01-97-00190 IRBs: Continuing  Review  reviews  of the annual reports, adverse-event reports, and protocol  amendments  submitted 
by research sponsors are often hurried  and superficial. 
Minimal  Field  Presence.  The continuing  review  that IRBs  carry out is limited  almost 
entirely  to paperwork  reviews.  They rarely visit the research site to determine  how the 
consent process is actually  working  or to review  the records of active protocols.  To 
varying  degrees other parties do conduct on-site monitoring,  but unlike  the IRBs, they do 
not have a central mission  of protecting  human subjects. 
A Number  of Factors  Limit  IRBs  Capacity  to Conduct  Continuing  Review. 
Heightened  Workload  Pressures.  IRBs  are inundated  with  research proposals. 

Working  in competitive  environments  with  major institutional  cost pressures, many of 

them have been unable to add the staff and other resources to keep up with  the workload 

increases.  At the same time, volunteer  IRB  members, pressed to concentrate  their time on 

revenue-enhancing  clinical  activities,  find it more difficult  to devote time to the boards. 

Limited  Useful  Feedback  on Multi-Site  Trials.  A significant  portion  of the research 

being reviewed  by IRBs  is now part of multi-site  trials.  These trials  often include  an 

active monitoring  component  carried out by Data Safety Monitoring  Boards (DSMBs) 

and/or by clinical  audit teams.  Such monitoring  involves  expert peer review  of IRB-

approved research.  But, the DSMBs  and audit teams rarely  report their findings  to IRBs. 

Limited  Feedback  on FDA  Actions  Against  Investigators.  Correspondence  regarding 

FDA  actions against research investigators  is not routinely  disclosed  to IRBs.  A number 

of IRB  officials  reported  to us instances in which  they heard about an FDA  action 

indirectly,  from other (often  media) sources.  Officials  at FDA  indicated  that they are 

precluded  from routinely  disclosing  such information  by legal concerns under the Privacy 

Act. 

Limited  IRB  Expertise.  IRBs  find that they often have insufficient  scientific  expertise 

to assessthe results of active protocols.  This can present particular  vulnerabilities  in the 

case of protocols  that are not subject to peer review  by other bodies. 

Limited  Nonscientific  and  Noninstitutional  Input.  IRBs  typically  have minimal 

outside  representation.  This limitation  deprives them of a valuable  counterbalance 

during  the continuing  review  process when important  questions  can be raised concerning 

the interests of human subjects. 

The  Trust  Factor.  The IRB  process is rooted in trust, assuming the best of intentions  of 

investigators  and sponsors.  This tradition  makes substantive  continuing  review  suspect. 

It holds that the IRBs job  is to ensure protections  upfront,  not to serve as watchdogs  or 

police. 

ii  OEI-01-97-00190 IRBs: Continuing  Review  Federal  Oversight  of IRBs  Provides  Little  Basis for  Determining  the Effectiveness  of IRBs 
Continuing  Review  of Approved  Research. 
Two  agencies within  the Department  of Health  and Human  Services are responsible  for 
the oversight  of IRBs:  the National  Institutes  of Health  (NIH),  through  its Office  for 
Protection  from Research Risks (OPRR),  and the Food and Drug  Administration  (FDA). 
The  OPRR  Oversight  Focuses on Upfront  Assurances.  Only  Rarely  Does Its 
Oversight  Involve  On-site  Assessments  of IRB  Performance.  The assurance is an 
upfront  document  of an institutions  commitment  to human-subject  protections.  It does 
not involve  an assessment of performance.  The OPRR is in a better position  to make 
such assessments when it conducts for-cause site visits, but because of resource 
constraints  it conducted  only  one such visit between April  1997 and May  1998. 
The  FDA  Oversight  Focuses on Inspections.  Its Reviews,  However,  Stress 
Procedural  Compliance,  with  Only  Minimal  Attention  Given  to IRB  Effectiveness. 
The FDA  conducted just under 200 inspections  in 1997.  These inspections  aim to ensure 
IRB  adherence to Federal requirements  and frequently  result in deficiency  notices to the 
IRBs.  But here, too, there is little  attention  to assessing results.  For instance, while  FDA 
calls for IRBs to ensure that subjects understand the implications  of their participation  in 
research, FDAs  own inspection  process does not enable it to determine  how well  IRBs 
are able to do that. 
CONCLUSION 
The IRBs  limited  efforts in conducting  continuing  review  of active research is a serious 
national  issue because it compromises  their protection  of human subjects.  It inhibits  their 
capacity to identify  and address situations  where unacceptable  risks emerge, or research 
results prove to be too favorable to continue,  or protocols  stray beyond  approved limits. 
It also inhibits  their capacity to ensure that the subjects have sufficient  understanding  of 
the risks they may incur in the research process. 
With  this conclusion,  we do not claim that widespread  abuses exist.  We recognize  the 
important  contributions  that IRBs have made and continue  to make.  The system of 
protections  they provide  is supported by many conscientious  investigators  committed  to 
protecting  human subjects and by many dedicated IRB  members and staff doing their best 
under trying  circumstances.  But, our inquiry  offers an important  warning  signal--one  that 
could  get stronger in view  of current developments.  These include  Federal plans to 
increase significantly  the numbers of subjects in clinical  trials  and various proposals that 
would  give IRBs  increased responsibility  in the areas of genetics and confidentiality. 
This warning  signal warrants  a Federal response.  We address the elements of such a 
response in our parallel  inspection  report entitled,  Institutional  Review Boards:  A Time 
For  Reform. 
. . .
111  031-01-97-00190 IRBs: Continuing  Review  COMMENTS  ON THE  DRAFT  REPORTS 
Within  the Department  of Health  and Human  Services, we received comments  on our 

four draft reports from the National  Institutes  of Health,  the Food and Drug 

Administration  and, jointly,  from the Assistant  Secretary for Planning  and Evaluation  and 

the Assistant  Secretary for Health.  We also solicited  and received comments  from the 

following  external parties:  the Applied  Research Ethics National  Association,  the 

American  Association  of Medical  Colleges,  the Consortium  of Independent  Review 

Boards, and Public  Citizens  Health  Research Group.  We include  the detailed  text of all 

of these comments and our responses to them in appendix  D of our overview  report, 

Institutional  Review Boards;  A Time for  Reform (OEI-01-97-00193).  In the executive 

summary of that report, we summarize  the thrust of these comments  and our responses. 

iv  OEI-01-97-00190 IRBs: Continuing  Review  PAGE 

EXECUTIVE  SUMMARY 

INTRODUCTION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..l 

IRBs:  THE  BASICS  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 

IMPORTANCE  OF CONTINUING  REVIEW  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 

FINDINGS 

The Continuing  Review  Conducted  by IRBs  Is of Limited  Scope and Significance.  . . . .7 
Numerous  Factors Inhibit  Their  Capacity  to Conduct  Continuing  Review  ............  9 
OPRR and FDA  Pay Little  Attention  to IRB  Effectiveness.  ......................  12 
CONCLUSION  ............................................................  ..15 
APPENDICES 
A: Federal Requirements  on IRB  Continuing  Review  .........................  A-l 
B: Federal Oversight  of IRBs  .............................................  B-l 
C: Advertising  to Recruit  Human  Subjects  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-l 
D:Endnotes  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  D-l 
031-01-97-00190 IRBs: Continuing  Review  INTRODUCTION 
PURPOSE 
To review  the performance  of institutional  review  boards in reviewing  ongoing  research 
involving  human subjects. 
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 (HHS).  Appendix  A offers further 
background  on the Federal requirements  that apply to these boards, particularly  with 
respect to their continuing  review  function. 
Prior  Inquiries 
For about a quarter of a century,  IRBs have been playing  an important  part 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 
IRE&, about how well  some of the members of these boards understood  their roles, and 
about the commitment  of some of the institutions  to their Irks.  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 
We, too, found particular  reason to be concerned about IRB  oversight  in a recent inquiry 
of our own.  In examining  clinical  trials involving  four investigational  medical  devices, 
we discovered  inadequacies related to IRB  continuing  review  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  changes that the IRB  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 
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.5 This report is one of four that has resulted from our overall  inquiry.  A 
1  OEI-01-97-00190 IRBs: Continuing  Review  second report, Institutional  Review Boards.. Promising  Approaches,  presents innovative 
approaches that IRBs  have undertaken  in six key areas of responsibility.  A third, 
Institutional  Review Boards:  The Emergence of Independent  Boards,  indicates  how those 
IRBs that are separate from research institutions  are a growing  force;  it addresses the 
advantages and disadvantages associated with  independent  boards.  A fourth  report, 
Institutional  Review Boards:  A Time For Reform, serves as the big picture  report, viewing 
the overall  functioning  of IRBs  and presenting  recommendations  emerging  from our 
inquiry. 
In this report, we focus on the continuing  review  function  of the IRBs--that  is, on the 
review  activities  they undertake  subsequent to their initial  approval  of research protocols. 
We examined these review  activities  because of the concerns we noted in the previous 
section and because, as our inquiry  progressed, we became increasingly  aware of 
continuing  reviews  importance  as a human-subject  protection.  We elaborate on that 
importance  in the following  section before we present our findings  on the extent of 
continuing  review  that takes place, the factors inhibiting  that review,  and the nature of the 
Federal oversight  of this process. 
Our inquiry  draws on a rich variety  of sources.  These include  interviews  and group 
discussions with  representatives  of about 75 IRBs of varying  sizes and auspices;6 
government  documents  and national  commission  reports produced  over the past 25 years; 
articles and books addressing human-subject  protections;  Federal records on IRBs;  issues 
raised on an electronic  e-mail  forum  by those associated with  IRBs;  attendance at IRB 
meetings;  site visits with  FDA  inspectors;  and site visits to 6 IRBs  based in academic 
health centers.7 At these centers, which  are among the most heavily  funded biomedical 
research centers in the country,  we interviewed  not only  IRB  administrators  and 
members, but also many others in the parent institutions  whose functions  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. 
We conducted this inspection  in accordance with  the Quality  Standards for  Inspections 
issued by the Presidents Council  on Integrity  and Efficiency. 
2  031-01-97-00190 IRBs: Continuing  Review  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 research plan before the research is carried out.  This review 
encompasses the research protocol,  the informed  consent document to be signed by subjects, any 
advertisements to be used in recruiting  subjects, and other relevant documents.  In carrying  out this review, 
the boards seek to ensure that any risks subjects may incur  are warranted in relation  to the anticipated 
benefits, that informed  consent documents clearly  convey the risks and the true nature of research, that 
advertisements are not misleading,  and that the selection of subjects is equitable and justified.  IRBs focus 
much attention  on the informed  consent document because it is the vehicle  for providing  information  to 
potential  research subjects. 
Continuing  Review:  The continuing  review  process is multifaceted  and includes required reviews at an 
interval  appropriate to the degree of risk but not less than once per year.  In addition  to this continuing 
review,  study amendments and reports of unexpected adverse experiences by subjects are received 
periodically  and reviewed to ensure that the risk-benefit  ratio of the research has not changed and remains 
acceptable. 
Why  Were They  Established? 
As public  awareness and concern about the treatment of human subjects in research increased, the need for 
additional  review  mechanisms was evident.  These concerns grew from stories of the abuse of subjects during 
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 patients at a 
hospital  in New York,  and others.  A 1966 article by Henry Beecher brought prominent  attention to human 
research abuses in medical schools and hospitals citing  22 cases involving  highly  questionable  ethics.  The 
formal requirements  for the establishment of IRBs were outlined  in regulations  stemming from the National 
Research Act of 1974 and in FDA regulations  issued in 198 1. 
Where  Are They  Located? 
An estimated 3,000-5,000 IRBs can be found across the country.  They are most commonly  associated with 
hospitals and academic centers. Boards also exist in managed care organizations,  government  agencies (such 
as the National  Institutes  of Health, the Centers for Disease Control,  and State governments),  or as for-profit 
entities that are independent of the institutions  in which  the research takes place. 
How  Are  They  Organized? 
Federal regulations  require that boards have at least five members with  varying  backgrounds.  At least one 
member must have primarily  scientific  interests, one must have primarily  nonscientific  interests, and one must 
be otherwise unaffiliated  with  the institution  in which  the IRB resides.  A quorum, with  at least one member 
whose interests are primarily  nonscientific  present, is needed for voting. 
How  Does the Department  of Health  and Human  Services (HHS)  Oversee Them? 
Two agencies within  HHS share responsibility  for IRB oversight:  the Office  for Protection  from Research 
Risks (OPRR) in NIH  and the FDA.  The OPRRs main tool for oversight  is the assurance document.  Any 
institution  that intends to conduct HHS-funded  research must have an assurance on file with  OPRR.  The 
assurance is a written  statement of an institutions  requirements  for its IRB and human-subject  protections. 
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,  use a single project assurance (SPA) for each such project it conducts.  The OPRR also conducts a 
small number of site visits.  The FDAs  main mechanism for IRB oversight  is the inspection  process.  The 
FDA also inspects research sponsors and scientists (known  as research investigators).  A more detailed 
explanation  of the agencies oversight processes can be found in appendix B. 
3  OEI-01-97-00190 IRBs: Continuing  Review  IMPORTANCE  OF 
CONTINUING  REVIEW 
The IRBs  ongoing  review  of research involving  human subjects can serve as an 
important  safety net for human  subjects.  It provides  a means of addressing 
vulnerabilities  that may not have been adequately  identified  and/or corrected  during  the 
initial  review  process.  It also offers a way of addressing vulnerabilities  that may have 
emerged during  the course of the approved  research. 
In recognition  of the importance  of continuing  review,  Federal regulations  call for IRBs 
to conduct  reviews  at intervals  appropriate  to the degree of risk, but not less than once 
per year,  and specify that IRBs  have the authority  to  observe or have a third  party 
observe the consent process and the research.  On January  10, 1995, the Office  for 
Protection  from Research Risks (OPRR)  in the National  Institutes  of Health  reaffirmed 
this IRB  responsibility  through  the issuance of a Dear  Colleague  letter to IRBs.  That 
letter noted that continuing  review  must be substantive  and meaningful,  and elaborated 
on associated operational  matters, most especially  that the annual reviews  must be 
completed  within  1 year of a previous  IRB  review.  Similarly,  on October  1, 1995, the 
FDA  issued an Information  Sheet to IRBs  and clinical  investigators  that reinforced  the 
importance  of continuing  review  and sought to clarify  the minimum  requirements  that 
IRBs  have in that regard.12 
In recent years, the safety net role that continuing  review  represents may have become 
more important  than ever.  Four factors lead us to this conclusion.  We wish  to emphasize 
the importance  of continuing  review  before presenting  our findings.  These factors are as 
follows: 
The  Limits  of Informed  Consent 
Individuals  who consent in writing  to participate  as a research subject do not necessarily 
understand the implications  of their  decision.13 They may not realize that the primary 
mission  of research is to advance medical  knowledge  rather than to provide  subjects with 
medical  treatments.  Further,  they may develop unrealistic  expectations  about both the 
potential  benefits and risks associated with  their participation.4  The 1995 presidential 
advisory  commission  concluded  that there was, indeed,  reason to worry  that such 
misunderstandings  may be common.15 
On the front  lines, the informed  consent process is much more about forms--determining 
their content and making  sure they are signed--than  it is about ensuring  understanding  by 
the potential  subjects.  This limitation  is widely  corroborated  in the literature,16 in 
convenings  of IRB  officials,  and in our own discussions  and site visits.  Many  IRBs 
strive to see that consent forms are as informative  and clear as possible.  But these efforts 
often run against the grain as the forms become longer  and more complex,  serving more 
4 
OEI-01-97-00190  IRBs:  Continuing  Review  as documents  to protect  the institutions  and the sponsors rather than the human subjects. 
Some IRBs  also strive to encourage researchers to interact  with  potential  subjects in ways 
that facilitate  understanding.  But, they generally  have little  basis for knowing  how  well 
they succeed in that regard.* 
The  Blurring  of Research  and  Treatment 
It is also the case, as the 1995 Advisory  Commission  underscored,  that individuals  who 

consent to participate  as human research subjects do not necessarily  distinguish  research 

from  standard therapy  or treatment.  In a survey of 1,882 randomly  selected patients in the 

waiting  rooms of 16 hospitals,  the Commission  found  that 37 1 had been research 

subjects.  Yet, almost 20 percent of these research subjects incorrectly  stated that they 

were not and never had been research subjects.  Worse yet, about 40 percent of the studies 

reviewed  involving  these individuals  were experiments  that posed greater than minimal 

risk.  I9 

In recent years, potential  human subjects themselves have often been the ones blurring  the 

distinctions  between  research and treatment.  Patients, especially  those with  life-

threatening  diseases, have often placed more emphasis on gaining  access to experimental 

efforts than on being protected  from the harm they can cause.2o Yet some researchers 

have also been contributing  to this blurring  through  their own tendency to emphasize the 

personal benefits rather than the risks of research (see appendix  C) and/or through  use of 

their own patients as human subjects.  One researcher, who  is also a member of an IRB, 

told us that over the years his own patients accounted  for nearly  all the subjects in his 

many studies and that this did not prove to be a problem  because they trusted him.  In 

contrast, another researcher, who was a participant  in one of the commissions  addressing 

human-subject  protections,  told us that physicians  own patients represented one of the 

most vulnerable  categories of subjects. 

The  Changing  Research  Environment 
The research culture  in which  IRBs  function  has been significantly  transformed  over the 
past 20 years.  As the proportion  of industry  sponsored research has increased, this culture 
has been increasingly  shaped by the realities  of the marketplace.  Sponsors, with 
significant  amounts of money at risk, emphasize the rapid development  of products  and 
seek to work  with  IRBs  that will  conduct  their reviews  quickly.  At the same time, the 
parent institutions  of many IRBs  are eager to gain the revenue associated with  large 
industry  sponsored projects.21 While  they tend to be careful  not to jeopardize  the role of 
the IRBs, they also expect them to respect the sponsors need for quick turnaround. 
These pressures to accelerate initial  IRB  reviews  heighten  the importance  of continuing 
review  as a safety net.  So, too, does the emergence of newer kinds of research that have 
major implications  for human subjects.  This is especially  true for genetics research 
which  can produce  sensitive and troubling  information  pertinent  not only to a subject 
directly,  but to a subjects relatives, potential  offspring,  insurers, employers,  and others. 
5 
OEI-01-97-00190  IRBs:  Continuing  Review  How  access to such information  is controlled  and how well  subjects are informed  and 
counseled about it are vital matters that are certain to warrant  continuing  attention  during 
the course of a research effort. 
The Protection  Breakdowns  Involving  IRB-Approved  Protocols 
The system of protections  now  in place is certainly  much better than that which  existed 
when the Federal requirements  were first established in the 1970s.  But even with  these 
protections,  lapses do occur and they serve to reinforce  the need for continuing  review.  A 
few of these lapses have been highly  publicized  ones that resulted in significant  harm, 
even death, to human subjects or have exposed them to unnecessary risks.22 Other lapses 
may remain unnoticed.  In fact, in our previous  study on investigational  devices, we found 
reason for concern in 11 of the 20 sites we visited.  These involved  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 IRB  had suspended it.23 
A number of the IRB  officials  we spoke with  mentioned  a continuing  concern they have 
with  protocol  creep, wherein  the number  of human subjects, the drug doses, or some 
other aspect of the research ventures beyond  that approved by the IRB.  Some also 
expressed concern about whether,  in research involving  placebos, the IRB  is getting 
sufficient  up-to-date  information  about investigational  treatments to ensure that the use of 
placebos remains justified. 
6  OEI-01-97-00190 IRBs: Continuing  Review  The Continuing  Review  Conducted  by IRBs  Is of Limited  Scope 
and Significance. 
Minimal  Substantive  Review  of Reports 
In accord with  Federal regulations,  IRBs  receive and must review  significant  amounts of 
paperwork  on active research projects.  They must review  annual reports, adverse-event 
reports, and amendments to research protocols.  In each case, however,  little  substantive 
review  tends to take place. 
Annual  Reviews.  The OPRRs  1995 Dear Colleague  letter on continuing  review  has had 
the intended effect of getting  IRBs  to pay more attention  to annual reviews,  but the 
attention  has focused much more on complying  with  procedural  requirements  than on 
conducting  substantive continuing  review.  Many  IRBs  find that with  significant  increases 
in the quantity  of new research protocols  to review,  they have little  time left for annual 
reviews.  Not at all uncommon  is the situation  we found at one IRB  meeting  where the 
board relied on prior  reviews  of a primary  reviewer  and administrative  staff and quickly 
approved several annual reviews  in the last 15 minutes of 2% hour meeting.24 
Many  board members regard the annual review  requirement  as unproductive  unless it has 
become apparent that there are significant  problems  concerning  a protocol.  Otherwise, 
they say it is unnecessarily  duplicative  of the initial  review  and even undermines  the 
voluntary  commitments  that busy board members make to the IRBJ5  Along  this line, 
some board members we spoke with  regarded annual reviews  as essentially  a staff 
responsibility  and gave little  if any time to reviewing  the annual reports prior  to the board 
meetings. 
Adverse-Event  Reports.  The FDA  requires that sponsors and investigators  report to the 
FDA  and participating  IRBs  any adverse events involving  both serious and unanticipated 
effects on human subjects.  As with  the continuing  review  requirement,  the Federal intent 
was to foster substantive review.  But here, too, the reality  has been quite different.  The 
IRBs have, indeed, been receiving  adverse-event reports (AERs).  In fact, those IRBs that 
oversee projects that are part of large, multi-site  trials are being inundated  with  them, as 
sponsors, eager to minimize  liability  exposure, choose to err on the side of reporting 
rather than not reporting.  One IRB  we visited  had received several boxes of AERs  within 
the past few weeks.  Another  indicated  that it was receiving  an average of 200 AERs  a 
month. 
The IRB  officials  equate the review  of AERs  to that of looking  for a needle in a 
haystack.26 They say that the reports seldom inform  them of how many patients are 
enrolled  in a multi-site  trial  and tend to include  little  if any analysis of the significance  of 
7  OEI-01-97-00190 IRBs: Continuing  Review  the adverse event reported.  Thus, the IRBs  find themselves hard-pressed to use AERs  as 

a tool of substantive oversight.  Rarely  does an AER  lead to any IRB  intervention 

concerning  an active protocol.  On the few occasions when it does, it is likely  to involve 

some change in the way risks are explained  on an informed  consent form.  In reviewing 

the last two  meetings of the IRB,  one IRB  official  calculated  that the members had 

reviewed  32 AERs  in one meeting  and 21 in the other, none of them leading to any 

changes.  This experience was not at all unusual  at that IRB  or at the others we contacted. 

Protocol  Amendments.  Federal regulations  also call for sponsors and investigators  to 

obtain IRB  approval  for any changes that they wish  to make in research protocols.  This 

results in a steady stream of amendments  submitted  to and reviewed  by IRBs. 

Occasionally  these changes will  trigger  a substantive  review  of a project  but, they 

typically  involve  minor  matters that are routinely  processed.  It is important  to recognize 

that the IRB  is highly  dependent on investigators  and sponsors to be attuned to changes in 

the course of a research project  and to call for amendments when necessary. 

Minimal  Field  Presence 
The continuing  review  that IRBs  do carry out is limited  almost entirely  to paperwork 
reviews  by IRB  members and staff.  Although  the IRBs  have the authority  to visit the 
research site as part of their continuing  review,  our inquiries  and other studies indicate 
that they rarely visit the research site to determine  how the informed  consent process is 
actually  working  or to review  the data and records of active protocols.27  This may be 
particularly  worrisome  with  regard to independent  IRBs,  which  are often located far from 
the research site.  Five of the eleven independent  boards we interviewed  reported that 
they have no routine  policy  for visiting  the research sites under their purview. 
On those few occasions when IRBs  do become more directly  involved  in reviewing  a 
research practice,  the action tends to be triggered  more by particular  concerns that have 
come to their attention  than by random reviews.28 As a result, IRBs typically  have little 
basis to know  for themselves how research teams approach the informed  consent process, 
how well  human subjects understand  the implications  of their participation  in research, 
and how  fully  research teams remain true to the research design set forth  in their 
approved protocols.29 
In this context,  it is important  to recognize  that to varying  degrees other parties do 
conduct reviews  at the research site.  These include  commercial  sponsors and/or the 
contract research organizations  representing  them, clinical  research centers and/or other 
parts of the institution  to which  an IRB  belongs,  and, as we note in a subsequent section 
of this report, the monitoring  bodies associated with  multi-site  clinical  trials and federally 
funded cooperative-group  trials.  Unlike  the IRBs,  however,  none of these parties has the 
protection  of human subjects as its central mission. 
8  OEI-01-97-00190 IRBs: Continuing  Review  A Number  of Important  Factors  Inhibit  IRBs  Capacity  to Conduct 

Continuing  Review. 
Heightened  Workload  Pressures 
IRBs  of all sizes are facing major 
No Time  for  Chit-Chat 
workload  demands.  These are 
generated in part by the significant 
The agendas of the IRJ3 review  meetings at academic 
numbers of adverse-event reports and  centers are packed, leaving  busy reviewers  little  time 
protocol  amendments submitted  to  to reflect on and debate issues raised by research 
them for review.  But, the key force is  protocols.  As an illustration,  at the sites we visited, 
the meetings typically  lasted about 2% hours and 
a dramatic  increase in the number  of 
included  an average of 18 initial  reviews, 9 expedited 
research protocols  being submitted  for 
reviews,  43 protocol  amendments, and 2 1 adverse-
initial  review.  Our study sites  event reports. 
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.30  This finding  is in accord with  that of a recent survey of academic health 
centers which  found that their IRBs  were reviewing  an average of 297 proposals a year. 
Ten percent of them were reviewing  1,000 to 2,500 proposals  annually. 
Most IRBs appear to be struggling  to keep up with  these demands.  In increasingly 
competitive  environments  where market developments  are triggering  greater cost 
pressures on health care institutions,  many IRBs  report that they have not been able to add 
the staff needed to respond to the demands.  At the same time, IRB  members, particularly 
in the large medical  centers, find themselves increasingly  pressured to concentrate their 
time on revenue-generating  clinical  activities,  with  the result that voluntary  commitments 
to IRB  work  have become more difficult  to meet.32 The IRBs  cope with  these 
developments,  sometimes in innovative  ways,33 but with  a steady increasing  flow  of 
protocols  to review,  the time demands on members continue  to mount.34  Summing  up 
this situation,  one experienced,  well-informed  IRB  official  commented:  Many  IRBs, 
especially  in large institutions,  are on the verge of imploding. 
These workload  pressures jeopardize  the protections  afforded  by IRBs.  The General 
Accounting  Office provided  an alert in this regard when it noted in its 1996 report that 
IRBs may spend only  one to two minutes  of review  per study, relying  mainly  on reviews 
conducted by primary  reviewers  prior  to a board meeting.  Our own  inquiry  reinforces 
this concern and makes it especially  clear that little  time is left for conducting  substantive 
continuing  review  or for educational  outreach that can help the research community 
become more knowledgeable  about the obligations  and importance  of human-subject 
protections.  Such outreach, IRB  officials  note, can help ensure that investigators 
themselves serve as a continuing  source of protection  for human subjects and that 
applications  submitted  to the IRBs  are properly  completed.  Many  IRBs  report that they 
spend a considerable  amount of time on research protocols  and informed  consent forms 
that are flawed  in various ways and must be sent back to the investigators  for corrections. 
9  OEI-01-97-00190 IRBs: Continuing  Review  Limited  Useful  Feedback  on Multi-Site  Trials 
More  and more of the research being reviewed  by IRBs  is part of national  or even 
international  multi-center  trials funded by the Federal government  or commercial 
sponsors.36 Many  are vast, far-reaching  operations.  For example, the Pediatric  Oncology 
Group funded by the National  Cancer Institute  conducts  trials through  more than 1,000 
researchers from over 100 sites in the U.S., Canada, and a few as far away as Europe. 
Each of our study sites reported  significant  increases in the number  of multi-center  trials. 
At two  sites, these trials  constitute  about one-half  of the research overseen by the IRB.38 
These trials typically  include  an active monitoring  component.  For instance, since 1992, 
some of the cooperative-group  projects  funded by the National  Cancer Institute  (NCI) 
have required  a Data Safety Monitoring  Board  (DSMB).39  These are independent  bodies 
that include  scientists expert in the area being investigated,  statisticians,  ethicists, and 
sometimes subject advocates.  Their  role is to analyze study data on a regular basis and to 
ensure patient  safety through  the analysis of adverse-event reports among other things. 
Many  commercially  sponsored trials also include  DSMBs,  especially  if they involve  large 
numbers of subjects.  In these cases, however,  there is no Federal requirement  for a 
DSMB. 
The monitoring  of multi-site  trials also tends to involve  on-site reviews.  Sites 
participating  in cooperative-group  projects  funded by the National  Cancer Institute  must 
be audited once every 36 months.40 These are highly  substantive audits typically 
involving  scientists, statisticians,  and others.  Other federally  funded cooperative  groups 
have similar  requirements.  Commercial  sponsors also have an on-site review  component 
(according  to FDA  requirements).4 
These monitoring  efforts by DSMBs  and audit teams represent substantive ongoing 
oversight  of IRB-approved  research.  But, strikingly,  little  of what is learned is shared 
with  IRBs.  Neither  the DSMBs  nor the audit teams report their findings  to the IRBs.~~ 
Their  orientation  and feedback is to the research sponsors and investigators.  Only rarely 
do any of the results of this valuable peer review  get to the IRBs to support their own 
continuing  review  responsibilities.43 
Limited  Feedback  on FDA  Actions  Taken  Against  Investigators 
The FDA  conducts routine  and directed inspections  of research investigators.  Directed 
inspections  may be initiated  as a result of complaints  from  subjects or others about 
human-subject  violations,  concerns about an investigator,  or questions that arise from a 
review  of the study data.  Inspections  can result in a variety  of actions, such as the 
rejection  of study data, letters to an investigator,  or, at the extreme, a disqualification 
from participating  in pre-market  research.  The FDA  does not, on a routine  basis, 
affirmatively  disclose all correspondence  to sponsors and IRBs.  A number of IRB 
officials  pointed  this out to us and reported  instances in which  they heard about an FDA 
action indirectly,  from other (often media) sources, about an action taken against a 
10  OEI-01-97-00190 IRBs: Continuing  Review  research investigator  involved  in one of their  approved research plans.  Officials  at FDA 
indicated  that legal restrictions  under the Privacy  Act preclude  FDA  from routinely 
disclosing  all investigator-related  correspondence  to sponsors and IRBs  on a routine 
basis.  However,  certain information,  such as warning  letters purged of trade secrets and 
confidential  commercial  information  and the names of disqualified  or restricted 
investigators,  are available to the public  on the FDA  web site.  In addition,  certain 
information  about the inspections,  including  classifications  of FDAs  inspections,  is 
available  to the public  through  the Freedom  of Information  Act (FOIA).  But overworked 
IICE& generally  do not have the available  time to regularly  scan the web site to see if any 
of their investigators,  often numbering  in the hundreds, have been disciplined.  Likewise, 
they might  not know  when to make a FOIA  request to 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  IRE& and sponsors 
will  be made easier. 
Limited  IRB  Expertise 
The IRBs  find that they often do not have sufficient  scientific  expertise on their boards to 
deal with  the increasingly  complex  areas of research.  They also often lack staff to 
adequately  assessthe results of an active protocol.  In contrast, the expertise represented 
on a DSMB  or audit team tends to be geared specifically,  at least in part, to the protocol 
under review.  From time to time, IRBs  will  seek consultant  assistance to fill  the gap, but 
this can be costly and slow down  a review  process that is already overburdened.  This 
deficiency  is a significant  source of concern to a number of IRB  officials  we met with. 
For the cooperative  and commercial  projects  subject to peer review,  these officials  at least 
know  that substantive continuing  review  is occurring  in other places.  But for the 
significant  amount of IRB-approved  research for which  no such peer review  takes place, 
this safety net does not exist. 
Limited  Nonscientific,  Noninstitutional  Input 
The HHS and FDA  regulations  require  that all IRBs have a minimum  of five members. 
The regulations  further  stipulate  that there be at least one member whose primary 
concerns are nonscientific  and one who  is not affiliated  with  the parent institution. 
Boards can satisfy both requirements  with  the appointment  of a single individual  who is 
not affiliated  with  the institution  and who  is not a scientist.  The IRBs we spoke with 
typically  had more than five members but seldom maintained  a 1 to 5 ratio of outside 
members.44 More  importantly,  few seem to seek or be able, on a consistent  basis, to 
recruit  and maintain  lay and/or nonaffiliated  members who play an active, effective  role 
in helping  the IRB  stay closely  attuned to the perspectives and experiences of human 
subjects.  Such members, once sufficiently  experienced  and trained,  can provide  an 
important  counterbalance  to scientific  and institutional  interests.  This may be especially 
important  during  the continuing  review  process when important  questions  (including  how 
the informed  consent process is approached,  whether  human subjects understand 
11  OEI-01-97-00190 IRBs: Continuing  Review  sufficiently  the risks associated with  the research, and the adequacy of outreach efforts to 
diverse populations)  can be raised concerning  the interests of human subjects. 
The Trust  Factor 
The IRB  process is rooted  in trust.  The IRB  reviews  traditionally  have been approached 
in a collegial  manner assuming the best of intentions  on the part of researchers and 
sponsors.  This tradition  makes substantive IRB  continuing  review  suspect at best and 
counterproductive  at worst.  As one IRB  member said: Our job  is to ensure human-
subject protections  upfront;  we are not watchdogs.  Many  IRB  officials  and much of the 
literature  on IRBs warn that any movement  toward  policing  could undermine  the 
credibility  that IRBs  have developed over the yearsP5 These considerations  are extremely 
important.  The trust that exists is a strength of the system.  Any  erosion in it could, 
indeed, threaten human-subject  protections. 
Yet, in subtle, but significant  ways, this tradition  of trust inhibits  effective  continuing 
review.  It inhibits  IRBs  from identifying  deviations  in approved  research plans, as we 
found in our previous  study on investigational  medical  devicesc6 or from learning  that 
many human subjects have little  understanding  of the informed  consent forms they sign, 
as the Advisory  Commission  found in its 1995 review;47 or from finding  maverick 
researchers who have not even submitted  their research for IRB  review,  as one IRB  found 
through  the use of computer-assisted  literature  monitoring.48  How  to achieve substantive 
continuing  review  along the lines represented by these examples while  maintaining  a core 
of trust with  the research community  may well  be the most significant  challenge facing 
IRBS. 
Federal  Oversight  of IRBs  Provides  Little  Basis for  Determining  the 
Effectiveness  of IRBs  Continuing  Review  of Approved  Research. 
As noted in our IRB  primer  on page 3, two  agencies in the Department  of Health  and 
Human  Services are responsible  for the oversight  of IRBs:  the National  Institutes  of 
Health  (NIH)  through  the Office  for Protection  from Research Risks (OPRR)  and the 
Food and Drug  Administration  (FDA).  These two  agencies enforce what is essentially  a 
common  set of regulations.  Appendix  B provides  an overview  of their oversight 
mechanisms. 
The OPRR  Oversight  Focuses on Upfront  Assurances.  Only  Rarely  Does Its Oversight 
Involve  On-site  Assessments  of IRB  Performance. 
In the early years of Federal oversight,  the assurance documents  were relatively  brief and 
the process of negotiating  them was highly  educational  in nature!9  Over the years as the 
number of assurances (especially  single project  assurances) has grown  and as IRB 
workloads  have increased, the assurance documents have become much more extensive 
and the process more routinized.  At present, the overall  value of this process remains 
12  OEI-01-97-00190 IRBs: Continuing  Review  questionable.  In institutions  with  multiple  project  assurances (MPAs),  where about 75 
percent of NIH-funded  research takes place, many of the IRB  officials  we spoke with 
reported  that the assurance process does little  to foster institutional  commitments  to IRB 
operations.  At the same time, OPRR officials  recognize  that if they were to use this 
process to press for further  institutional  commitments  to IRBs,  the institutions  might  be 
much less likely  to include  all non-HHS  funded research under their assurance. 
This assurance process, as it now functions,  does not yield  much information  about the 
actual effectiveness  of IRBs in providing  continuing  protections  to subjects enrolled  in 
approved protocols.  The OPRR is in much better position  to obtain  such information 
when it conducts on-site reviews,  either as part of a technical-assistance  visit or 
noncompliance  investigation.  Indeed, the most substantive  assessments of performance 
and the most forceful  recommendations  for improving  performance  that we have 
identified  during  our inquiry  have occurred  as part of investigations  of IRBs that have 
been responsible  for and/or involved  in a significant  and highly  publicized  lapse in 
human-subjects  protections.  Yet, OPRR informs  us that because of resource limitations  it 
conducted  only  one such visit between April  1997 and May  1998.  Its investigations,  of 
which  about 75 are open at the current time, are almost always  conducted  from a distance. 
The FDA  Oversight  Focuses on Inspections.  Its Reviews,  However,  Stress Procedural 
Compliance,  with  Only  Minimal  Attention  Given  to IRB  Effectiveness. 
The FDA  estimates that there are about  1,500 to 1,700 IRBs  involved  in reviewing 
research of FDA-regulated  products,  mostly  pharmaceuticals.50  For this universe of IRBs, 
which  includes  most of the IRBs having  assurances with  OPRR, FDA  conducts periodic 
inspection  visits.  In 1997, the FDA  conducted just under 200 site visits (see appendix  B). 
They are carried out by FDA  inspectors who  also have responsibilities  for inspections 
focusing  on food products, research sponsors, and even investigators. 
The on-site  inspections  focus almost entirely  on determining  IRB  compliance  with  FDA 
regulations.  They involve  some interviewing  of IRB  leadership,  but mainly  a review  of 
IRB  records, including  those of three IRB-approved  studies.  They examine the IRBs 
conformance  to discrete Federal mandates concerning  matters such as attendance at board 
meetings,  completeness of board-meeting  minutes,  annual protocol  reviews,  and informed 
consent forms.  These and many other compliance  issues examined  can be important 
indicators  of IRB  performance,  but they provide  FDA  with  little  direct feedback on the 
actual effectiveness of the IRB  in protecting  human subjects.  For instance, FDA  has 
issued an information  letter to IRBs  calling  for them to make sure that individuals 
understand  what they are consenting  to when they agree to participate  in a research effort. 
Yet, the FDAs  inspection  process affords  it little  basis for determining  if such 
understanding  takes place; nor does it even review  the adequacy of the IRBs  own 
mechanisms  for making  such a determination. 
The IRB  inspections  often do result in deficiency  notices to the IRB.  The most frequent 
of these concern inadequate compliance  with  various  written  procedures  and with 
13  OEI-01-97-00190 IRBs: Continuing  Review  continuing  review  procedures.  Most  of these are not regarded by FDA  as being of major 
significance  and thus result in a request to the IRE3to take corrective  action.  In those 
instances where FDA  identifies  what it regards as a significant  deficiency,  it issues a 
warning  letter to the IRB.  The warning  letter calls for an immediate  IRE3response to 
FDA,  spelling  out how the identified  problem  will  be corrected. 
14  OEI-01-97-00190 IRBs: Continuing  Review  The IRBs  limited  efforts  in conducting  continuing  review  of active research is a serious 
national  issue because it compromises  their protection  of human subjects.  It inhibits  their 
capacity to identify  and address situations  where unacceptable  risks emerge, or research 
results prove to be too favorable  to continue,  or protocols  stray beyond  approved 
parameters.  The IRBs  may not be vigilant  enough to notice and to intervene  on behalf of 
the subjects.  It also inhibits  their capacity  to ensure that the subjects have adequate 
understanding  of informed  consent forms they have signed and that they recognize  the 
distinctions  between research and established therapy. 
In offering  this conclusion,  we do not claim that widespread  abuses exist.  We recognize 
the important  contributions  that IRBs  have made and continue  to make.  The system of 
protections  they provide  revolves around the participation  of many conscientious 
investigators  committed  to protecting  human subjects and many dedicated IRB  members 
and staff doing their best under trying  circumstances.  But, our inquiry  provides  an 
important  warning  signal, especially  given the scope of the changes occurring  in the IRB 
environment.  These include  current Federal plans to raise the level of NIH  funding, 
which  would  significantly  increase the number  of human subjects participating  in clinical 
trials,  and proposals to give IRBs  increased responsibility  in the areas of genetic testing 
and confidentiality.51  The signal we present warrants  careful attention  and a Federal 
response.  In our summative report, Institutional  Review Boards.. A Time For  Reform, we 
present recommendations  on how the National  Institutes  of Health  and the Food and Drug 
Administration  could respond to the findings  presented in this report and that emerge 
from our overall  inquiry. 
15  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  A 

Federal  Requirements  on IRB  Continuinp  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.2  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.4  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 (HHSOPRR)  and 2 1 C.F.R., sec. 56 (FDA) 
Currently,  16 Federal departments  and agencies abide by these regulations  through  the 
Common  Rule for the protection  of human  subjects in research, effective  August  19, 
1991. 
2Ibid. 
OPRR  Dear  Colleague  Letter,  10 January  1995, Continuing  Review--Institutional  and 
Institutional  Review  Board Responsibilities. 
41bid, FDA  Information  Sheets, 1995. 
A-l  031-01-97-00190 IRBs: Continuing  Review  APPENDIX  A 

Modifications  and Adverse  Event  Reports 
Periodically,  the IRB  may receive amendments/modifications  to 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 continuous  task for IRBs.  An adverse 
event is 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.  See 21 C.F.R.,  sect. 3 12 
(for drug research) and 21 C.F.R.,  sec. 812 (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 
 45 C.F.R.,  sec. 46 (HHS/OPRR) 
21 C.F.R.,  sec. 56 (FDA) 
6 Changes may be initiated  before IRB  approval  if they are necessary to eliminate 
immediate  hazards to subjects.  See Ibid. 
A-2  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  B 

Federal  Oversipht  of IRBs 
There are an estimated 3,000-5,000  IRBs  across the country.  Two  agencies within  HHS 
are responsible  for the oversight  of IRBs:  OPRR and FDA.  Each agency has its own  set 
of IRB  regulations.  Although  there are many similarities  between the two  sets of 
regulations,  the agencies 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 an IRB  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  and approved the protocol  and the researchers are awaiting  NIH 
funding.  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  of IRBs  is uncertain,  the FDA  acknowledges  that it is 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.  An institution  must apply for an SPA for each project  it wishes to conduct.  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. 
B-l  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  B 

Cooperative  Project  Assurances  (CPAs):  The HHS  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 officers  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 audits2  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 43 8 
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.3 
For 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. 
2Less frequently,  investigations  are conducted  as a result of suggestions  from  Congress or 
the media. 
 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. 
B-2  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  B 

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.5 
FY  1997 Inmection  Data 
11Center  1 ft  Tnrn~rtinnr  1 ff  f3AT  1 
IICBERI  9  13141  n/a  I  n/a  II 
lb=  1  I  II 
149  5  1  124  1  68  1  31 
CDRH  36  0  1191  6  i  11  II 
I  8 
Totals  194  1  147  1  74  1  42  11 
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 tile 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,  the use of the most 
current consent documents, the submission  and review  of adverse-event reports, and for 
4 This is difficult  to achieve because of workload  constraints;  IRBs  found previously  to be 
significantly  deficient  are inspected more frequently. 
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. 
B-3  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  B 
the presence of a quorum  during  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 informed  consent was signed and dated in a timely  manner. 
B-4  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  C 

Advertisinp  to Recruit  Human  Subiects 
When Federal human-subject  protections  were established  in the 1970s  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 
risks of research are easily overlooked.  The advertisements  cite an overwhelming  array 
  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. 
C-l  031-01-97-00190 IRBs: Continuing  Review  APPENDIX  C 

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 and not personal  gain.  Much 
more commonly,  the 
advertisements  supported 
Examples  of Marketing  Efforts  Aimed  at Recruiting 
the view that participation  in 
Human  Subjects 
research was an opportunity 
for the subject. 
DO YOU  HAVE  ASTHMA? 
The danger of these 
advertisements  is that  If you qualify  for any of our asthma studies, you can: 
subjects may come to a  - Learn to care for your asthma! 
research study with  - Receive free medications! 
misconceptions.  For  - Receive up to $1,730! 
example, a person may enter 
into research believing  it 
Women: Receive $271 O! 
will  treat his or her 
depression, panic disorder, 
Healthy,  non-smoking/drug-free  women (20-40)  needed 
diabetes, etc.  The allure of 
for USDA  research study.  Live-in  24 hrs/day for 78 days 
freedom from such an 
ailment  is likely  to be highly 
motivating.  Persons may 
Speed or Cocaine? 
also become attracted to 
research participation  by the  Need help getting clean? 

promise  of alleviation  from  Free Treatment & Medication. 

financial  as well  as physical  Repeat Callers Welcome! !! Get Paid $$$ 

distress.  They may be 
motivated  by the promise  of 
Women With  PMS 
free treatment,  free 
screening, or extra money. 
If you are between the ages of 18 and 40 and suffer from 

It is essential, therefore,  that 
PMS (Premenstrual  Syndrome), you may qualify  to 

both the informed  consent 
participate  in a research study using an investigational 

document  and the individual 
drug for the treatment of PMS. 

involved  in the recruitment 
of subjects are vigilant  in  If you qualify  to participate  you will  receive: 

making  sure the risks  Free Medical  Exams  Free Pap Smears 

involved  in research are  Free Labwork  Study Medications 

clear.  But as we have noted  Up to $455 for Time and Travel 
in this report, IRBs  devote 
little  attention  to how the 
consent process works,  focusing  all too often solely on the documents  language. 
c-2  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  C 

The following  two photos were taken on a Philadelphia  subway  car in January  1998. 
Photos courtesy of the OIG Office  of Evaluation  and Inspections,  Philadelphia  Regional Office 
c-3  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  D 

ENDNOTES 

1. Presidents  Commission  for the Study of Ethical  Problems  in Medicine  and Biomedical  and 
Behavioral  Research, Implementing  Human  Research Regulations:  Second Biennial  Report  on 
the Adequacy  and Uniformity  of Federal  Rules and Policies,  and of their Implementation,  for  the 
Protection  of Human  Subjects, Washington,  D.C.:  U.S. Government  Printing  Office,  March 
1983. 
2. 	 For more detailed  explanations  of these concerns see (a) 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. 271-82.  (b) The Advisory  Committee  on Human 
Radiation  Experiments,  Final  Report,  Washington  D.C.:  U.S. Government  Printing  Office,  1995. 
3.  U.S. General Accounting  Office,  Scienttjk  Research:  Continued  Vigilance  Critical  to 
Protecting  Human  Subjects, GAO/HEHS-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.  The National  Bioethics  Advisory  Commission  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 managements  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. 
6.  These IRBs  are reviewing  research at institutions  receiving  over 1.4 billion  dollars of active 
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. 
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-
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. 21, pp. 
1550-53.) 
8.  These six institutions  alone account for over half a billion  dollars of active 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. 
D-l  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  D 

9. 	 It is important  to note that while  the IRB  has a key responsibility  for protecting  human 
subjects, sponsors also have responsibility  for the monitoring  and oversight.  According  to 
2 1 C.F.R., sec. 3 12, sponsors are required  to ensure proper monitoring  of investigations  and they 
are also required  to select a monitor  to oversee investigations  through  site visits.  In addition,  the 
sponsor may require reports from investigators.  There is, however,  little  information  sharing 
between  sponsors and the IRB. 
10.  See 45 C.F.R., sec. 46.109(e)  and 21 C.F.R.,  sec. 56.109(e). 
11.  Dear Colleague  letter from Office  of Protection  from Research Risks, Continuing  Review-
Institutional  and Institutional  Review  Board  Responsibilities,  10 January  1995. 
12.  FDA  Information  Sheets, Continuing  Review  After  Study Approval,  1 October  1995. 
13.  Several factors may contribute  to the lack of understanding.  In our previous  study, where we 
conducted  four case studies of medical  devices, we found that the reading  level of the informed 
consent documents related to each of the four medical  devices ranged from college  level to 
graduate level ability  (Department  of Health  and Human  Services, Office  of Inspector  General, 
Investigational  Devices; Four  Case Studies (OEI-05-94-OOl OO), April  1995).  Compounding  the 
difficult  reading level may be deficiencies  in the informed  consent documents themselves.  The 
Center for Drug  Evaluation  Research, located with  the FDA,  has found an increasing  number of 
deficiencies  in informed  consent documents  at the IRBs  it inspected.  In  1995, it found 24 
percent of IRBs inspected had informed  consent documents deficiencies;  in 1996, it found 28 
percent had deficiencies;  and in 1997, it found  4 1 percent had deficiencies. 
14.  A full  and clear understanding  of risks is especially  important  in Phase 1 clinical  trials when 
relatively  little  is known  about an interventions  effect in humans and the aim of the research 
may well  be to determine how much of a medication  can be tolerated  by humans. 
15.  Advisory  Committee  on Human  Radiation  Experiments,  Final  Report,  Washington,  D.C.: 
U.S. Government  Printing  Office,  1995. 
16.  For example, see (a) 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;  (b) U.S. General Accounting  Office,  Scientzjic 
Research:  Continued  Vigilance  Critical  to Protecting  Human  Subjects, GAOIHEHS-96-72, 
March  1996; and (c) Philip  J. Hilts,  Psychiatric  Research Under  Fire,  New  York Times, 19 May 
1998. 
17.  To a significant  degree, we found that research investigators  were quite removed  from the 
informed  consent process.  In some of the larger departments,  staff are primarily  responsible  for 
preparing  the consent forms. 
18.  IRB  and Federal officials  typically  recognize  the importance  of the interactive  process, but 
find the consent form itself as a more practical  tool for review  purposes.  Indicative  is the 
following  comment of a Food and Drug  Administration  official  in her testimony  before 
D-2  031-01-97-00190 IRBs: Continuing  Review  APPENDIX  D 

Congress: It  is the interactive  information  exchange that is most important  to the informed 
consent process.  FDA  focuses on the consent form  during  our inspections  because it is the best 
evidence that we have of the basic information  that was exchange during  that process. 
(Oversight  of HHS:  Bioethics  and the Adequacy  of Informed  Consent, Hearing  before the 
Subcommittee  on Human  Resources and Intergovernmental  Relations  of the Committee  on 
Government  Reform  and Oversight,  U.S. House of Representatives,  8 May  1997, Testimony  of 
Mary  Pendergast.) 
19.  Advisory  Committee  on Human  Radiation  Experiments,  Final  Report,  Washington,  D.C. : 

U.S. Government  Printing  Office,  1995: Chapter  16, Section 3. 

20. 	 See (a) Paul McNeil,  The Ethics and Politics  of Human  Experimentation,  New  York: 

Cambridge  University  Press, 1993.  (b) Dont  Let It Happen Again,  The Economist,  17 May 

1997, pp. 27-28.  (c) Michie  Hunt,  The FDA:  Promoting  Access to New Drugs,  Biologics,  and 

Medical  Devices, National  Health  Policy  Forum,  The George Washington  University,  July  1997. 

21.  These projects tend to be part of national  or even international  multi-site  projects  involving 

research in out-patient  settings.  They are subject to oversight  mechanisms  carried out by the 

sponsors themselves.  But, they do not tend to have the level of safeguards and monitoring 

typically  provided  to patients in inpatient  settings. 

22.  See (a) Keith  Epstein and Bill  Sloat, Drug  Trials:  Do People Know  the Truth  About 

Experiments?  The Plain  Dealer,  15-18 December  1996, Special Sunday Insert, pp. 2-16; and 

(b) Oversight  of HHS:  Bioethics,  and the Adequacy  of Informed  Consent, Hearing  before the 

Subcommittee  on Human  Resources and Intergovernmental  Relations  of the Committee  on 

Government  Reform  and Oversight,  U.S. House of Representatives,  8 May  1997; and 

(c) Steve Stecklow  and Laura Johannes, Drug  Makers  Relied  on Clinical  Researchers Who Now 

Await  Trial  The Wall Street Journal,  15 August  1997, pp. Al  and A6. 

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

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

24.  The GAO report also noted the limited  attention  to continuing  reviews.  It indicated  that in 

their reviews,  IRBs relied heavily  on investigators  self-assessments. (U.S. General Accounting 

Office, Scienttfic  Research:  Continued  Vigilance  Critical  to Protecting  Human  Subjects, 

GAO/HEHS-96-72,  March  1996.) 

25.  The situation  differs  somewhat  for the independent  IRBs.  Board members of these IRBs  are 

paid for their time.  Whether  or not they are any more or less favorable  toward  annual reviews, 

we do not know. 

26.  Each report must be compiled,  documented,  and reviewed  by the IRB.  Also,  the IRB  must 

notify  the investigator  of any changes. 

27.  In its 1996 report, the GAO  stated that IRB  reviews  generally  do not involve  direct 

observation  of the research study or of the process in which  a subjects  consent is obtained. 

D-3  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  D 

(U.S. General Accounting  Office,  ScientiJic Research.. Continued  Vigilance  Critical  to 

Protecting  Human Subjects, GAO/HEHS-96-72,  March  1996.) 

Edgar and Rothman  stated that it  is rare for an IRB  to leave the confines  of its committee  room 

and examine what actually  occurs in the consent process.  (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.) 

These sentiments are echoed by McNeil  in his book.  (Paul McNeil,  The Ethics and Politics  of 

Human  Experimentation,  New  York:  Cambridge  University  Press, 1993, p. 244.) 

28. 	 The National  Commission  that developed the current  system of human protections  in the 
1970s  envisioned  a much 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)). 
29.  Of particular  note here is the Federal informed  consent requirement  which  calls for 
investigators  to seek informed  consent only  under circumstances  that provide  the prospective 
subject or representative  sufficient  opportunity  to consider  whether  or not to participate  and that 
minimize  the possibility  of coercion  or undue influence.  (See 21 C.F.R., sec. 50.20 and 
45 C.F.R.,  sec. 46.116)  Without  any direct observation  or feedback by independent  parties, it is 
extremely  difficult  for IRBs to ascertain that such circumstances  exist at the time that human 
subjects provide  their written  consent. 
30.  Three sites with  10 year data reported  increases of over 80 percent.  One reason for the 
escalating numbers may be that investigators,  claiming  that it is increasingly  difficult  to receive 
grants, are submitting  more research protocols.  The NIH  requires IRB  approval  prior  to funding 
decisions  so IRBs may review  a significant  number  of protocols  that will  not go on to be funded. 
3 1. Hayes et al., A  Survey of University  Institutional  Review  Boards:  Characteristics,  Policies, 
and Procedures,  IRB, Vol.  17 (May-June  1996), No.  3, pp. l-6. 
This highlights  the importance  of academic medical  centers to human-subjects  research when 
compared to another survey of all hospitals  with  at least 400 beds which  reported  an average of 
D-4  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  D 

84 proposals per year. (Jones et al., Structure  and Practice of Institutional  Review  Boards in the 
United  States, Academic  Emergency  Medicine,  Vol.  3, August  1996, No.  8, pp. 804-809.) 
32.  One former  IRB  member indicated  that these pressures are particularly  intense on physicians 
whose fields involve  a significant  amount of patient contact.  As a result, IRBs are finding  it 
especially  difficult  to recruit  and retain physician  members who  regularly  interact with  patients 
and may be more attuned to their concerns. 
33.  For a more detailed explanation,  see our companion  report:  Department  of Health  and 
Human  Services, Office  of Inspector  General, Institutional  Review Boards:  Promising 
Approaches,  OEI-0 l-97-00  191. 
34.  These demands apply both to the time spent outside of meetings  in reviewing  proposals and 
to the time spent during  meetings discussing them. 
35.  U.S. General Accounting  Office,  Scientific  Research:  Continued  Vigilance  Critical  to 
Protecting  Human Subjects, GAO/HEHS-96-72,  March  1996. 
36.  Since the 1950s trial  of poliomyelitis  vaccine involving  over a million  school-age children, 
large randomized  clinical  trials conducted  simultaneously  at a network  of sites across the country 
have become a standard in determining  treatment effectiveness.  These multi-center  trials are 
becoming  even more important  as scientists  and physicians  knowledge  of disease improves. 
Specific  subpopulations  of patient  groups are being identified  and are required  to test more 
targeted treatments and drugs.  Any  one institution  may only  have a few patients in each group, 
rarely enough to statistically  determine  effectiveness.  Therefore,  data from small patient groups 
at sites around the country,  or even the world,  must be combined. 
37.  Brad H. Pollock,  Quality  Assurance for Interventions  in Clinical  Trials:  Multicenter  Data 
Monitoring,  Data Management,  and Analysis,  Cancer Supplement,  Vol.  74, (1 November  1994) 
No. 9, pp. 2647-265 1. 
Furthermore,  NIH  funding  alone for such cooperative  group projects  has increased almost ten-

fold in the past decade, from $49.2 million  in 1985 to $419.2 million  in 1994. (NIH  Extramural 

Trends--FY  198.51994). 

Data available on the NIH  website  at http://www.nih.gov/grants/award/trends94/chapter  1.htm 

38.  Multi-center  trials may represent even larger percentages of active research at smaller 
institutions  that do not have the patient base to support  single-investigator  studies. 
39.  There are 11 cooperative  research groups associated with  NC1 alone.  Each is a formal,  free-
standing entity  which  has its own board of directors,  but is responsible  for following  federal 
guidelines.  Each cooperative  group oversees multiple  protocols,  ranging  in number from 20 to 
well  over 100.  Other institutes  at the NIH  also have cooperative  research groups with  which  they 
are associated. 
D-5  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  D 

40. 	 Approximately  700 to 800 audits of project  sites are conducted  annually.  As another 
example, the Division  of AIDS  at the National  Institute  of Allergy  and Infectious  Disease at NIH 
contracts with  a CR0  to monitor,  four times a year, each clinical  site it sponsors. 
41. 	 Beyond  these, some academic health centers, particularly  in their cancer programs,  are 
carrying  out their  own audit component.  See the section entitled  Management  of the Workload 
in our companion  report:  Department  of Health  and Human  Services, Office  of Inspector 
General, Institutional  Review Boards:  Promising  Approaches,  OEI-0 l-97-00  191. 
42.  The IRB  at one large academic health center we visited  reported that it has regularly  been 
requesting  DSMB  data from the research sponsors and to this point  has not been refused access 
to the data.  We have not heard of others making  such requests and having  similar  success. 
43.  From time to time, the DSMBs  and audit teams associated with  cooperative-group  projects 
will  provide  some information  to OPRR if they have information  they find to be particularly 
relevant to the IRB.  The OPRR will  then share the information  with  the IRB.  Similarly,  from 
time to time, some investigators  or sponsors will  share with  the IRBs  information  or instructions 
they received from the DSMBs  or audit teams. 
44. 	 The IRB  regulations  require that each IRB  shall include  at least one member who  is not 
otherwise  affiliated  with  the institution  and who  is not part of the immediate  family  of a person 
who  is affiliated  with  the institution.  Since 1994, the FDAs  Division  of Scientific 
Investigations  in CDER  began to put forth  in some post-inspection  letters and a few conference 
presentations  the benefits of interpreting  this regulation  as a ratio. 
The independent  IRBs tend to have more outside  review  members on their boards.  While 
these members are paid for their review  services, the great majority  are not otherwise  affiliated 
with  the IRB  or its parent institution  and many are nonscientific  members. 
45.  The  presumption  that informs  the current  so-called  monitoring  activities  of most IRBs  is 
that members of the institution  are to be trusted until  some contrary  evidence is brought  forward. 
If the IRB  is obliged  to function  as a police  force, it can only  indicate to the community  of 
investigators  that it is operating  from presumptions  of distrust.  Presumptions  of distrust  cost a 
lot of time and energy of IRB  members, most of whom  have no training  in police  work  in the 
first place.  (Robert  J. Levine,  Ethics and Regulation  of Clinical  Research, Baltimore:  Urban  & 
Shwarzenberg,  1986, p. 348-349.) 
46.  Department  of Health  and Human  Services, Office  of Inspector  General, Investigational 
Devices:  Four  Case Studies (OEI-05-94-OOlOO),  April  1995. 
47.  See Advisory  Committee  on Human  Radiation  Experiments,  Final  Report,  Washington, 
D.C.:  U.S. Government  Printing  Office,  1995: Chapter  16, Section 3. 
48. 	 For more information  see Department  of Health  and Human  Services, Office  of Inspector 
General, Institutional  Review Boards:  Promising  Approaches,  (OEI-01-97-00  191). 
D-6  OEI-01-97-00190 IRBs: Continuing  Review  APPENDIX  D 

49.  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, P.L. No. 93-348,  sec. 474, 88 Stat. 342.) 
50.  IRBs  subject to FDA  oversight  only  become known  to the agency after an IND  or IDE  has 
been filed.  Thus, the IRB  has been operating  for some time before the FDA  becomes aware of its 
presence.  The FDA  has told us that the uncertainty  in the number of IRBs  subject to regulatory 
oversight  is part of the problem  in exercising  that oversight. 
5 1.  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  for the development  of genetic protocols.  (Eds. Neil  A. 

Holtzman,  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,  S. 1921, would  rely on the IRB  to determine  measures of confidentiality,  such 

as whether  subject identifiers  should be retained.  (S. 1921, 105h Congress, sponsored by 

Senators Jeffords and Dodd) 

D-7  OEI-01-97-00190 IRBs: Continuing  Review