Department of Health and Human Services 
OFFICE OF 
INSPECTOR GENERAL 
Recruiting Human Subjects 
Pressures in Industry-Sponsored Clinical Research 
JUNE GIBBS BROWN 
Inspector General 
JUNE 2000 
OEI-01-97-00195  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. 
OEI's Boston regional office prepared this report under the direction of Mark R. Yessian, Ph.D., 
Regional Inspector General.  Principal OEI staff included: 
REGION  HEADQUARTERS 
Nancy L. London, Lead Analyst  Elise Stein, Program Specialist 
Laura C. McBride, Lead Analyst 
To obtain copies of this report, please call the Boston Regional Office at (617) 565-1050. 
Reports are also available on the World Wide Web at our home page address: 
http://www.dhhs.gov/progorg/oei  E X E C U T I V E   S U M M A R Y  
PURPOSE 
To evaluate the Department of Health and Human Services (HHS) oversight of sponsor 
and investigator efforts to recruit human subjects for industry-sponsored clinical trials. 
BACKGROUND 
Protecting Human Subjects 
In a June 1998 report, Institutional Review Boards: A Time for Reform, 
(OEI-01-97-00193), we identified weaknesses in the system intended to protect human 
subjects who participate in clinical trials.  Since the release of our series of reports on 
institutional review boards (IRBs), both the Office for Protection from Research Risks 
(OPRR) in the National Institutes of Health (NIH) and the Food and Drug Administration 
(FDA)  the two bodies responsible for human-subject protections within the 
Department  have taken action against many research institutions, reflecting the strong 
Federal stance we called for in the recommendations of our report.  OPRR has cited a 
number of research institutions for non-compliance with Federal regulations and 
temporarily suspended ongoing research at seven of these institutions.  More recently, 
FDA terminated all gene therapy research after finding serious deficiencies in human-
subject protections at another center.  These collective actions support and respond to the 
findings in our report concerning the safety net for protecting human subjects. 
This Inquiry 
In this report, we follow up our prior report by focusing on one aspect of the clinical 
research process, the recruitment of subjects into industry-sponsored clinical trials.  We 
have chosen to focus on industry-sponsored trials because in recent years the clinical 
research environment has become more commercialized and competitive, as industry 
sponsors have assumed a more prominent role in the search for new drugs.  In this 
changing environment, with significant increases in the number and complexity of clinical 
trials, the quest to find human subjects has intensified.  Sponsors and investigators are 
facing increasing difficulty finding enough subjects in a timely manner to bring drugs to 
market within their desired time-frame. 
1 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  In this report and our companion report, Recruiting Human Subjects: Sample Guidelines 
for Practice (OEI-01-97-00196), we focus on the recruitment practices used in industry-
sponsored clinical trials for investigational drugs.  We explain the practices, identify major 
concerns about them, and address the extent and type of oversight undertaken by IRBs 
and, within HHS, by the FDA and NIH. 
Our inquiry is based on a survey of a random sample of IRBs; a review of FDAs database 
of IRBs and investigators involved in investigational new drug research; a review of 
FDAs IRB and clinical investigator inspection process, including participation in two 
FDA inspections; six site visits to research sites; reviews of existing Federal guidelines; 
interviews with numerous parties involved in each step of the recruitment process; and an 
extensive literature review. 
FINDINGS 
In this report, we focus on human subject recruitment for two main reasons.  One is that 
recruitment is a vital first step in the consent process, one that must not in any way be 
coercive or misleading to the potential subjects.  The second is that recent investigations 
and complaints reveal disturbing recruitment practices:  a study in which patients were 
recontacted numerous times in an effort to persuade them to enroll; a nursing home 
resident who was forced to participate in a study or leave the home; and a subject, later 
found to be ineligible, who died after participating in a trial. 
Sponsors and investigators use four main strategies to recruit human subjects 
and encourage timely recruitment. 
<  Sponsors offer financial and other incentives to investigators to boost enrollment. 
<  Investigators target their own patients as potential subjects. 
<	 Investigators seek additional subjects from other sources such as physician referrals 
and disease registries. 
<  Sponsors and investigators advertise and promote their studies. 
IRB officials and others closely involved with clinical research express many 
concerns about current recruitment practices. 
Erosion of Informed Consent.  The most fundamental concern is that the consent 
process may be undermined when, under pressure to recruit quickly, for example, 
investigators misrepresent the true nature of the research or when patients are influenced 
to participate in research due to their trust in their doctor. 
2 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Compromise of Confidentiality.  Many people raised concerns about someone other 
than the patients physician searching medical records and then contacting a patient about 
participation.  They also raised concerns about investigators use of other records such as 
disease registries, school records, or mailing lists. 
Enrollment of Ineligible Subjects.  Research observers fear some investigators may be 
led to enroll subjects that are ineligible, or of questionable eligibility, in order to meet 
quotas and satisfy sponsors. 
Oversight of the recruitment of human subjects is minimal and largely 
unresponsive to emerging concerns. 
<	 IRBs are not reviewing many of the recruitment practices that they and others find 
most troubling. 
<	 IRBs limited review of recruitment practices is in part due to their perceived lack of 
authority to review certain practices. 
<	 HHS provides little guidance to IRBs on acceptable recruitment practices.  In 
contrast, some professional medical associations provide strong guidance on selected 
issues. 
<	 In their own oversight of research sites, sponsors pay minimal attention to how 
human subjects are recruited. 
<	 Nor does HHS pay much attention to recruitment practices in its inspections of IRBs 
and investigators. 
RECOMMENDATIONS 
The critical challenge is to ensure essential human-subject protections without 
unnecessarily slowing the pace of research and discovery.  With that objective, below we 
offer recommendations jointly to the FDA, NIH, and the Assistant Secretary of Health 
(ASH).  We include ASH because the Secretary of HHS recently announced that OPRR 
will soon move from NIH to the Assistant Secretarys office. 
The first two recommendations specifically relate to the oversight of human-subject 
recruitment.  The last two relate to the oversight of human-subject protections more 
generally, but are integral to the oversight of recruitment.  Although our methodology 
focused on drug research, we expect that our findings and recommendations would also 
apply to other types of human-subjects research, such as devices and biologics. 
3 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  1. Provide IRBs with direction regarding oversight of recruitment practices 
Clarify that IRBs have the authority to review recruitment practices.  FDA and 
OPRR should disseminate guidance explicitly stating this authority based on IRBs 
established authority to ensure informed consent and review anything related to human-
subject protections. 
Provide guidance to IRBs on how to exercise this authority.  FDA and OPRR should 
suggest recruitment questions that boards should address in their protocol reviews and 
should foster discussion about these issues. 
2. Facilitate the development of guidelines for all parties on appropriate 
recruiting practices 
A clearer determination of appropriate recruiting practices would be helpful for all parties 
 sponsors, investigators, and IRBs.  It is essential that this determination be made 
cooperatively with industry and the research community.  As part of their deliberations, 
these parties could explore such questions as: 
<  Is it acceptable for sponsors to offer bonuses to investigators for successfully 
recruiting subjects? 
<  Should physicians be allowed to receive fees for referring their patients as potential 
subjects for a clinical trial? 
<  Should the financial arrangements between sponsors and investigators be disclosed to 
potential subjects? 
<  Does searching medical records for potential subjects constitute a breach of 
confidentiality? 
An examination of the feasibility and effectiveness of institutional policies currently in 
place could also provide useful information for those considering an expansion of current 
Federal guidance. 
3. Ensure that IRBs and investigators are adequately educated about human-
subject protections 
<	 Require investigator education as a prerequisite for conducting research under FDA 
authority or before receiving funds under the Public Health Service Act. 
<  Require that IRBs have a training program for members. 
<	 Require more extensive representation on IRBs of nonscientific and noninstitutional 
members.  Such members can help sensitize IRBs to patient concerns about recruitment 
practices. 
4 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  4. Strengthen Federal oversight of IRBs 
<	 Require that all IRBs register with the Federal government and regularly report basic 
descriptive information. 
<  Revamp the FDA on-site inspection process. 
COMMENTS ON THE DRAFT REPORT 
We received comments on our two draft reports from HHS.  We also solicited and 
received comments from the following external organizations:  Public Citizens Health 
Research Group, Pharmaceutical Research and Manufacturers of America, Applied 
Research Ethics National Association in conjunction with Public Responsibility in 
Medicine & Research, and the Consortium of Independent Review Boards.  We did make 
a number of changes in the final reports, many technical in nature, that respond to their 
comments.  Below we summarize the major comments and offer our response to HHS 
and, collectively, to the external parties. 
HHS Comments 
HHS shared our concern about some current recruitment practices and agreed that such 
concerns could be minimized if it were to provide IRBs with guidance on appropriate 
practice.  It agreed to work with professional societies and others to develop this 
guidance.  Although HHS disagreed with our assertion that current guidance documents 
from FDA and NIH are unclear about IRBs authority to review certain recruitment 
practices, it indicated that the new office in the Office of the Secretary would revisit this 
guidance and augment it as necessary.  HHS indicated its commitment to establishing 
educational requirement for investigators, IRBs, and IRB staff and that efforts are 
underway within FDA to register IRBs. 
We are pleased that HHS has made such a significant commitment to establishing 
education requirements.  We are also pleased that HHS has agreed to work with outside 
parties in developing consensus about appropriate recruitment practices.  We encourage 
the Department to continue its current efforts to register IRBs.  Although we agree that 
NIH and FDA already have guidance documents indicating that IRBs have authority to 
review recruitment practices, we found that many IRBs are uncertain of this authority, 
suggesting that clearer guidance is needed. 
External Parties Comments 
Overall, external parties echoed the concerns we raised about some current practices for 
recruiting subjects into clinical trials and agreed that steps should be taken to identify, at 
5 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  a national level, appropriate recruitment practices.  External parties comments to our 
report raised a few common concerns.  One concern was that our recommendations would 
prompt Federal bodies to dictate appropriate recruiting practices without input from 
outside groups.  Another was that already overburdened IRBs would be asked to add to 
their duties by suggesting that they review recruitment practices.  Finally, there were 
several questions and concerns about our methodology, including the scope of the study 
and the evidence upon which our findings are based. 
We clarified some of the language we used in our draft report to elucidate our belief that 
guidelines for appropriate recruiting practices should emerge from a dialog among all of 
the key parties involved in clinical research, including IRBs, sponsors, investigators, as 
well as Federal bodies.  We believe that our recommendation that HHS clarify IRBs 
authority for reviewing recruiting practices would not add significantly to the boards 
workload.  Many IRBs already review recruitment practices; national guidelines on 
appropriate practices would reduce the time now required for IRBs to debate the future 
use of such practices.  Regarding our methodology, we sought to document current 
recruitment practices in industry-sponsored research and any concerns raised by these 
practices; we did not judge the appropriateness of any of these practices, nor did we 
differentiate these practices and concerns by funding source.  Our analysis was primarily 
qualitative, based on interviews and observations, due to the nature of the study topic. 
6 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  T A B L E  O F  C O N T E N T S  
PAGE

EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

INTRODUCTION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

The Clinical Trials Main Players  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  11

The Changing Clinical Trials Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  12

FINDINGS

Sponsors and investigators use four main recruitment strategies . . . . . . . . . . . . . . . . . .  16

Current recruiting practices raise concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Oversight is minimal and unresponsive to concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . .  26

RECOMMENDATIONS 
Provide IRBs with direction regarding oversight  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Facilitate development of guidelines on appropriate practices . . . . . . . . . . . . . . . . . . . .  33

Ensure investigators and IRBs are adequately educated  . . . . . . . . . . . . . . . . . . . . . . . . 34

Strengthen Federal oversight of IRBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

COMMENTS ON THE DRAFT REPORT  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  36

APPENDICES 
A: Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  39

B: FDA Information Sheets  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

C: Professional Medical Association Guidelines  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

D: Full Text of Comments on the Draft Report  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

E: Endnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

7 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  I N T R O D U C T I O N  
PURPOSE 
To evaluate the Department of Health and Human Services (HHS) oversight of sponsor 
and investigator efforts to recruit human subjects for industry-sponsored clinical trials. 
BACKGROUND 
Protecting Human Subjects 
In a June 1998 report, Institutional Review Boards: A Time for Reform, 
(OEI-01-97-00193), we identified weaknesses in the system intended to protect human 
subjects who participate in clinical trials.  Since the release of our report, both the Office 
for Protection from Research Risks (OPRR) in the National Institutes of Health (NIH) and 
the Food and Drug Administration (FDA) have taken action against many research 
institutions, reflecting the strong Federal stance we called for in the recommendations of 
our report.  OPRR has cited a number of research institutions for non-compliance with 
Federal regulations and temporarily suspended ongoing research at seven of these 
institutions.  More recently, FDA terminated all gene therapy research at another center 
after finding serious deficiencies in human-subject protections.  These collective actions 
support and respond to the findings in our report concerning the safety net for protecting 
human subjects. 
Recruitment as a Human-Subject Protection Issue 
In this report, we follow up our prior report by focusing on one aspect of the clinical 
research process, the recruitment of subjects into clinical trials.  Recruitment warrants 
special attention because it marks the first step in the informed consent process and, thus, 
must not be coercive or misleading.  Second, as we found in a prior report, oversight 
bodies almost never witness the actual consent process.1  The review of some recruitment 
methods, particularly advertisements, provides additional opportunity for oversight bodies 
to monitor the actual content of the consent process.  Third, little is known outside the 
research community about the ways in which subjects are recruited.  An understanding of 
these practices is important in order to target effective oversight. 
Several recent Federal investigations and complaints raise concerns associated with 
recruitment: a study in which patients were recontacted numerous times in an effort to 
persuade them to enroll; a nursing home resident who was forced to participate in a study 
or leave the home; and a subject, later found to be ineligible, who died after participating 
in a trial. 
8 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Oversight of Human-Subject Protections 
Two agencies within HHS are responsible for protecting the rights and welfare of human 
subjects participating in clinical research:  the FDA and NIH.  As part of its oversight of 
clinical trials, FDA oversees research on products it regulates.  Currently, NIH, through its 
Office for Protection from Research Risks (OPRR), oversees research funded by HHS. 
Both NIH and FDA delegate most of the direct authority for reviewing human-subjects 
research to institutional review boards.  These boards, known as IRBs, are charged with 
reviewing research protocols and ensuring that adequate human-subject protections are in 
place. 
This Inquiry 
This report focuses on industry-sponsored research.  We are focusing on this research 
because the financial incentives to create effective and competitive drugs profitably are 
more pronounced in industry-sponsored research than in research funded by the 
government.  We are aware that government-funded research is not immune to these and 
other pressures; therefore, we may follow up later by focusing on recruitment in 
government-sponsored trials. 
It is important to note that the thrust of our information gathering for this report was to 
gain a better understanding of the concerns associated with recruiting practices.  We 
recognize that there are many investigators who are conscientious in their recruiting of 
subjects and who seek to better understand how to educate potential subjects about 
clinical research and what it entails. 
Because of the potential for overlapping jurisdiction, we chose to review both FDAs and 
OPRRs oversight processes.  Our focus on industry-sponsored clinical research would 
normally lead to an examination of FDAs oversight of subject recruitment.  However, 
OPRRs oversight mechanism, the assurance document, is applied at many institutions to 
all research conducted at that institution regardless of funding source. 
We also focus on biomedical research, specifically drug-development research, rather than 
psychological, sociological, or other types of research that do not result in a marketable 
product.  Furthermore, we concentrate on drug trials rather than medical device trials, 
because drug trials represent the majority of ongoing research.  There are trials involving 
certain diseases for which sponsors have no difficulty finding a sufficient number of 
subjects; in these cases, there is a reverse struggle of trying to meet patients demands to 
be subjects in a limited number of clinical trials.  We will not be addressing this limited 
supply issue that occurs in a minority of clinical trials. 
9 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Methodology 
We surveyed a random sample of IRBs; reviewed FDA and OPRR processes; analyzed 
FDAs Center for Drug Evaluation and Research database of IRBs and investigators 
involved in Investigational New Drug research; conducted six in-depth site visits to both 
academic and independent research sites; reviewed FDAs inspection process, including 
accompanying FDA inspectors on two inspections; reviewed existing guidelines; 
interviewed numerous parties involved in each step of the clinical research process; and 
conducted a thorough literature review.  A more detailed description of our methodology 
can be found in appendix A. 
We conducted this inspection in accordance with the Quality of Standards for Inspections 
issued by the Presidents Council on Integrity and Efficiency. 
10 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  The Main Players in Clinical Trials 
Clinical trials for new drugs are complex and require the engagement of many different entities. In

recent years, the number of these entities and their agents has proliferated. Below, we attempt to

describe the roles of and interactions among these players. 

Sponsors

Pharmaceutical companies, which we refer to as sponsors in this report, are responsible for proving the

safety and efficacy of investigational drugs, through clinical trials, to the FDA.  Sponsors are also

responsible for conducting on-site oversight of their trials.  This oversight is carried out by monitors. 

Traditionally, sponsors have not only conducted basic drug research and development, but have

conducted the clinical trials needed to gain FDA approval of the drug. Recently, in an attempt to

reduce their research and development costs and to streamline processes, sponsors have started

outsourcing many aspects of clinical trials to other entities.  Sponsors often delegate a variety of

specialized functions, such as the organization and management of clinical trials, to contract research

organizations (CROs) which sometimes, in turn, outsource to other specialized entities. Patient

recruitment firms, public relation firms whose sole mission is recruiting human subjects, have emerged

in recent years in response to sponsors and CROs desire for speedy recruitment of subjects. For the

purposes of this report, the term sponsors refers to sponsors and their agents, including monitors,

CROs, and patient recruitment firms.

Investigators and Research Sites

Sponsors depend upon physicians, called clinical investigators, to actually conduct clinical trials.

Investigators often rely on their staff to handle the administrative and sometimes much of the clinical

work associated with clinical trials. Often, investigators will have a point person, or study coordinator,

a practitioner (generally a nurse) whose primary responsibility is to facilitate the conduct of clinical

trials. Coordinators may be involved in recruiting and consenting subjects, as well as maintaining the

data for the trial.  In this report, the term investigator refers to all practitioners involved in conducting

clinical trials, including study coordinators, sub-investigators and others.

Investigators conduct trials in a variety of different settings.  Traditionally, they have conducted clinical

trials primarily in university hospitals, or academic medical centers (AMCs). Increasingly, research

occurs in physicians private practices or in dedicated research sites, sites exclusively used for

research.  Some investigators and/or sites have tried to accommodate sponsors desire for efficient,

streamlined trial conduct by forming site networks, sometimes referred to as site management

organizations (SMOs).

Human Subjects 
The final, and most critical, players in a clinical trial are the human subjects themselves.  Subjects may 
be recruited by an assortment of agents and/or entities: sponsors, CROs, clinical investigators, research 
coordinators, and patient recruitment firms.  In general, sponsors use healthy subjects to test the safety 
of a drug in first-in-human trials. They use subjects with the condition they are targeting to test the 
efficacy of a drug in later-stage trials. 
11 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  A Changing Clinical Trials Environment 
In a highly competitive environment, sponsors and investigators face 
growing difficulty finding subjects and finding them quickly 
The clinical research environment is evolving rapidly, with many of the changes creating 
significant competition for all players in the clinical trials arena.  There has always been, 
and will continue to be, a public interest in bringing useful, potentially life-saving drugs to 
market quickly.  However, recent changes in the research environment are causing 
sponsors to vie more aggressively to be the first to bring their product to market and are 
causing sites and investigators to compete more intensely for research contracts.  Three of 
these changes particularly impact human-subject recruitment. 
Change  Explanation 
Increased  Higher drug development costs. The cost of developing new drugs is growing 
Pressure for  rapidly. In the past 20 years, the average cost of developing a drug has grown almost 
10-fold from $50 million in the 1970s to $400-500 million in the 1990s.2 
Quick 
Pharmaceutical companies claim that they need to constantly increase the percentage 
Turnaround 
of their expenditures allocated to research and development in order to remain 
Times  competitive within the industry.3 
Increasing industry investment in research and development. Between 1998 and 
1999, sponsors increased their world-wide research and development investments by 
14 percent and have nearly tripled this investment between 1990 and 1999.4  As
developing drugs becomes more costly, sponsors are increasingly anxious to get their 
products to market quickly in order to recoup these initial outlays. Thus, they are 
trying to speed up the drug development process, of which subject recruitment is part. 
Intensified  More drugs in development. Pharmaceutical companies are developing more drugs 
Search for  now than ever before. In 1995, there were 2,585 drugs in pre-clinical testing; by 1998, 
that number had risen to 3,278.5 
Human Subjects 
More subjects needed for each trial. In addition, clinical trials are becoming more 
complex and are requiring far more subjects per trial than before.6  An average of
4,237 subjects were used in New Drug Applications from 1994 to 1995, compared 
with an average of 1,321 subjects from 1981 to 1984.7  Sponsors are struggling to meet
this increasing need for human subjects. 
Quest for More  Commercial research shifting to private settings. Pharmaceutical companies are 
Efficient  seeking the quickest, most efficient settings to conduct their clinical trials. 
Increasingly, they are shifting out of the academic medical centers (AMCs). 
Research Sites 
Approximately 50 percent of industry-sponsored trials are conducted in AMCs now, 
compared with 80 percent 5 years ago.8 
Growth of private-practice investigators. Industry-sponsored trials are increasingly 
leaving AMCs and flowing into private practice settings. The number of private-
practice based investigators increased from 3,513 in 1990 to 11,588 in 1995.9  This
growth is part of a larger influx of investigators into the clinical trials arena. The 
number of new investigators increased approximately 22% annually between 1992 and 
1996. 10 
12 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Quick Turnaround Times 
Many of the investigators, monitors, and other players in the clinical trial arena whom we 
interviewed noted a trend towards increasingly tight enrollment deadlines.  As one 
investigator stated, In the past 10 years there has been way more pressure to recruit; 
studies that used to take 112 years to enroll [are] now [supposed to] take 3 months.  A 
typical explanation we heard of these unrealistic deadlines was that, increasingly, 
business people rather than clinicians are making decisions about enrollment goals and 
deadlines.  Asked what sponsors are looking for from sites, one investigator responded, 
Number onerapid enrollment.  Number tworapid enrollment.  Number threerapid 
enrollment. Virtually every investigator mentioned that a sites ability to recruit quickly is 
one of the main qualities sponsors attempt to assess before contracting with a site, a belief 
that is supported by the literature.11 
Shorter enrollment deadlines reflect pharmaceutical companies struggle to remain 
profitable in a business that requires enormous investments of time, money, and risk before 
a product can reach the market.  The clock for a drug patent starts running when the 
patent application is filed, which is prior to the clinical testing of the drug.  Thus, sponsors 
wish to shorten the testing phase, as they are anxious to recoup research and development 
costs of their drugs before a generic or therapeutically similar drug appears on the market. 
Recruitment, a major bottleneck in the flow of drugs through the development pipeline, is 
one of the main aspects of clinical testing that sponsors are trying to shorten.12  Although 
pharmaceutical companies are setting shorter deadlines in hopes of hastening the 
recruitment process, most trials fail to meet these deadlines.13 
Sponsors and their agents constantly remind sites of the need to expedite recruitment. 
Sites report numerous phone calls from sponsors, informing them of how their enrollment 
statistics compare with those of other sites in the trial.  One investigator, who was the top 
recruiter on a trial, told us that the sponsor called every week to urge her to keep enrolling 
so that she did not lose her #1 status.  Other sites report receiving newsletters with 
charts comparing enrollment at their site to others, faxes goading them to speed 
recruitment, and other reminders comparing their enrollment with that of other sites. 
Intensified Search for Subjects 
Not only do sponsors want rapid enrollment of subjects, but they also need increasing 
numbers of subjects to fill more and larger trials.  More and more drugs are being 
developed as advances in biomedicine and genetics enable scientists to further understand 
disease mechanisms, and as pharmaceutical companies increase productivity to be 
competitive.14  These trials need to be filled by an ever-growing number of subjects. 
In addition, trials need to be filled with subjects that meet particular eligibility criteria. 
Defining appropriate eligibility criteria is an essential part of designing a trial, but these 
criteria also have broad implications for recruiting subjects.  Virtually everyone we 
13 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  interviewed cited overly restrictive eligibility criteria as one of the biggest barriers to 
enrollment.  They [sponsors] are asking us to find subjects that simply dont exist was a 
complaint we frequently heard in one form or another.15  Sponsor representatives also 
seemed well aware of this problem.  The main explanation for these tighter eligibility 
criteria, given by both sponsors and investigators, is that sponsors need to prove the 
efficacy of their drug to increasing numbers of customers, including FDA reviewers, 
foreign regulators, clinicians, and the public.  Particularly in the case of clinical trials for 
therapeutically similar drugs, even small improvements in efficacy can confer a tremendous 
marketing advantage for the experimental drug over the currently available, competing 
drug.16  Thus, sponsors design clinical trials to limit confounding factors.  One investigator 
took this explanation further, claiming that sponsors enrich trials with patients who are 
most likely to benefit. 
A particularly troublesome eligibility criterion cited by many investigators is the exclusion 
from a trial of potential subjects who are either currently on medication to treat their 
condition, or have been on medication in the past.  Subjects that have never been on 
medications are known in the industry as naive subjects.  Investigators mentioned that it 
is virtually impossible to find these naive subjects, particularly in some therapeutic areas 
for which medication is the standard of care, such as asthma or hormone replacement 
therapy.  Only those lacking access to drugs, such as the uninsured or some foreign 
populations, would not be on medication for these conditions. 
Many investigator and industry sources that we spoke to noted that sponsors are 
increasingly looking abroad for such subjects.  In the past decade, there has been 
enormous growth in the number of new foreign investigators involved in trials testing 
drugs for FDA approval.  According to our analysis of an FDA database, the number of 
new foreign investigators increased from 988 in the 1990-92 period to 5,380 in the 1996-
98 period.  Although sponsors search for naive subjects abroad has undoubtedly 
contributed to the increase in the use of foreign investigators in U.S.-based trials, other 
causes explain this proliferation of foreign investigators.  Foreign research sites are often 
less costly to operate, may provide sponsors with access to populations with a high 
prevalence of the condition being studied, and, after testing, may facilitate launching the 
drug globally.17 
Quest for Efficient Research Sites 
More, faster, and better we heard this phrase repeatedly from a variety of players in 
the clinical trials industry to describe sponsors desire for improved subject recruitment. 
Research sites are often competing with one another on the basis of their ability to recruit 
subjects. 
Sponsors seek research sites that can test drugs most efficiently and have access to the 
most subjects.  Increasingly, sponsors are finding academic medical centers, the traditional 
site of research, to be slow and cumbersome compared with private practices 
14 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  or dedicated research sites.18  The representatives of academic centers that we spoke with 
felt that it was difficult to compete with investigators in other research settings in terms of 
both numbers and speed of subject enrollment.  Private sites are able to begin enrollment 
sooner than academic centers because private sites generally use an independent IRB 
rather than the traditionally slower academic IRBs.  Finally, private-practice doctors often 
have a much larger patient base to tap for recruiting certain subject groups than 
investigators in academic centers, which are tertiary care centers.  One research nurse, 
who left research in an academic center to open her own dedicated research site, said that 
when she had conducted clinical trials in an academic center, she and her staff were always 
hustling to keep up with the private sites and, as a result, had a hard time convincing 
sponsors to contract with them. 
As industry-sponsored research has migrated out of the academic centers, the number of 
new investigators conducting clinical trials has exploded.  This proliferation of 
investigators is due, in part, to sponsors increasing acceptance of non-academic 
investigators.  The increase is also a response to a growing need for investigators, fueled 
by the growing numbers of clinical trials.  Also, many investigators have turned to clinical 
trials to compensate for managed care-driven reductions in patient-care revenue.19 
Many of the researchers we interviewed noted that the introduction of these new 
investigators into the clinical trials arena was exacerbating the competitive aspect of the 
clinical trials business, both inside and outside of the academic centers.  Sponsors seem 
to be capitalizing on the increase in the supply of investigators.  In addition to cutting 
study budgets, we found that sponsors are using their market advantage to encourage 
investigators to accelerate enrollment.20  First, before a contract is signed, sponsors will 
ask the investigator or site manager to estimate the numbers of subjects that the site can 
enroll.  Sites are aware that if they do not give a high estimate, they probably will not be 
given the contract.  Not surprisingly, sites often overestimate the number of subjects they 
expect to recruit, a frustration frequently reported by the sponsors and their agents with 
whom we spoke.  Second, sponsors will often explicitly state when contracting with a 
research site that the site will be dropped if they do not enroll adequately.  In this market-
driven research environment, where ones ability to enroll adequate numbers quickly is 
crucial to ones competitiveness, poor enrollment on a trial could ruin a sites chance for 
future participation in trials. 
15 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  F I N D I N G S  
Sponsors and investigators use four main recruitment 
strategies to recruit human subjects and encourage timely 
recruitment 
In response to the difficulties they face in recruiting subjects for clinical research, sponsors 
and investigators use myriad methods to identify, inform, and recruit subjects.21  We 
identified four broad recruiting strategies which encompass a number of specific methods. 
Below, we identify the four strategies, the corresponding methods, and a brief explanation 
of their implementation.  We further describe them and offer examples in the following 
pages. 
Recruitment  Examples of  Brief Description 
Strategy  Methods 
Offering  Financial  <  offering an additional payment per subject enrolled above 
Incentives  Incentives  the study budget; seen most often as an enrollment deadline 
nears and additional subjects are still needed 
Nonfinancial  <  items include office equipment, educational stipends, and 
Incentives  authorship on journal articles presenting research results 
Competitive  <  organizing trials so sites in a multi-center trial compete to 
Enrollment  fill available subject slots on a first-come, first-serve basis 
Targeting Own  Referring Own  <  identifying eligible patients when they come in for 
Patients  Patients to Trial  appointments or through chart reviews 
Seeking  Referrals from  <  sending information about ongoing research to other local 
Additional Patient  Other Physicians  physicians, asking for referrals, and occasionally offering 
Bases  fees to induce referrals 
Dissemination of  <  distributing trial information to appropriate disease advocacy 
Information to  groups or student groups, perhaps by giving lectures or 
Relevant Groups  presentations to such groups 
Advertising and  Media Ads  <  describing the trial, including study requirements, eligibility 
Promotion  criteria, and a contact for more information; can be found in 
newspapers, on radio, television, or on Internet sites 
Press Releases /  <  compiling trial information in the form of a press release for 
News Segments  airing on news programs or as a news article 
Special Events  <  disseminating information in speaking engagements, such as 
local community organizations, health fairs, or medical 
screenings 
16 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Offering Incentives 
The use of certain recruitment methods illustrates the transformation of clinical research 
into a traditional business model.  Sponsors provide incentives, both financial and 
nonfinancial (see box), to investigators to encourage speedy enrollment and/or reward 
those that recruit certain numbers of subjects.  Also, whereas before each site was allotted 
a certain number of subject slots, 
many trials now are conducted as 
...The order on the author list will be determined
competitive enrollment.  Because 
by the number of patients enrolled, so that the
sponsors pay sites per subject 
center which enrolls the highest number of patients 
enrolled, competitive enrollment  will obtain first authorship... 
penalizes those sites with a slow  From a sponsor-investigator contract 
start-up period and encourages 
aggressive recruiting.22 
The use of financial enrollment bonuses appears to have increased somewhat in the past 
few years, despite evidence that such incentives are often ineffective.23,24  A coordinator 
we spoke with reinforced this notion when she told us her site had gotten burned by 
enrollment bonuses in the past because it enrolled all of its subjects before the bonus was 
offered.  She told us, well think about that the next time around, and possibly wait to 
enroll all of their subjects. 
It is important to distinguish the financial incentives used to encourage timely recruitment 
from the sponsor payments to investigators for costs associated with conducting clinical 
research.  Research costs vary significantly based on the the requirements of the trial and 
can be very high when many expensive procedures are involved.  When we refer to 
financial incentives for recruitment, we are referring to payments given to investigators 
purely to encourage speedy enrollment.  Sponsors offer these incentives most often as an 
enrollment deadline nears or is passed. 
The distinction between payment and enrollment incentives, however, can get blurred in 
practice.  As sponsors continue to cut initial study budgets, many investigators that we 
spoke with reported that bonuses can help sites recoup the costs of conducting trials. 
These investigators often stated that they would rather have the initial study budgets 
accurately reflect the trials costs.  One investigator discussed a study in which he was 
initially paid $12,000 per subject enrolled.  After other investigators in the trial complained 
to the sponsor of excessively tight budgets, the sponsor added a $30,000 bonus once a site 
enrolled its first six subjects and, after these first six subjects were enrolled, the site would 
receive an additional $6,000 per subject.  The investigator, in describing this bonus 
scheme, emphasized that the sponsor had chosen to reimburse investigators by using 
bonuses to encourage recruitment rather than just revising the contract to reimburse 
investigators $18,000 per subject enrolled. 
17 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Targeting Own Patients 
For many investigators, their own patients are a vital source of subjects.  Nearly all of the 
investigators we spoke with told us that they first tried to enroll any of their patients that 
were eligible.  As an investigator at an academic center told us, he saw a direct correlation 
between his clinic time and his ability to recruit.  When he reduced his clinic time to one 
half-day per week, his recruitment declined significantly; when he increased his time, his 
recruitment resumed accordingly.  Similarly, investigators who lack certain types of 
patients often experience difficulties enrolling for those trials.  For example, an academic 
physician we spoke with told us he had a hard time recruiting for one of his clinical trials 
because the trial focused on a common ailment.  At the tertiary care center where he 
practiced, he rarely saw such common diseases which are easily treated by community 
physicians. 
Patients are an important source of subjects in both academic and independent research 
settings.  Even though many independent centers are free-standing entities, these sites 
contract with investigators who specialize in the condition under study, in large part 
because the investigators have potentially eligible subjects among their patients.  The 
investigators will then refer their patients to the research site. 
An advantage to using ones own patient base is the relative speed and ease with which 
investigators can reach these potential subjects.  In fact, when asked what sponsors are 
looking for in placing a research 
study, both sponsor representatives 
and investigators told us that access  Looking for Trials! 
to eligible patients is key.  Sponsors  We are a large family practice office with 4 physicians 
seek out investigators and sites with  and 3 Physician Assistants.  We have two full time 
large patient populations when  coordinators and a computerized patient data base of 
40,000 patients....We are looking for Phase 2-Phase 4 
looking to place trials.25 
trials  as  well  as  postmarketing  studies.  We  can 
Investigators recognize this and, in 
actively recruit patients for any study that can be 
turn, have begun to advertise their 
conducted in the Family Practice setting. 
large patient bases.  Such 
advertisements are numerous and  An Internet advertisement directed to sponsors 
prominent, particularly on the  by a private practice seeking research 
opportunities. 
Internet, as investigators reach out to 
sponsors to place a trial with them 
(see box).26 
Seeking Additional Patient Bases 
When sponsors and investigators need more subjects, they target their search efforts to 
reach large groups of potentially eligible subjects, such as other physicians patient bases 
or disease advocacy groups.  Occasionally, investigators offer fees to encourage referrals 
from other physicians or nurses.  For example, one coordinator told us that a site she had 
18 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  formerly worked at offered $75 to physicians or nurses for each subject referred.  Another 
investigator told us about a local site that offered referring physicians a reimbursement of 
10 percent more than Medicare reimburses for services that this physician provided as part 
of the trial. 
The researchers we spoke with said that they rarely hear referral fees offered.  This may be 
due, in part, to the fact that many investigators find referrals to be an unsuccessful method 
of identifying additional subjects.27  The investigators who found referrals fruitless 
believed other physicians lack the time and the interest in research to approach their 
patients about participating.  In addition, several academic physicians felt that community 
physicians were concerned that if they referred their patients to a trial, the academic 
investigators might take over all of the patients care, thus stealing their patients.28 
Advocacy groups and student populations are another source of subjects.  Advocacy 
groups often encourage researchers to develop new treatments for their disease.  Many of 
these groups are eager to disseminate research information through their member 
networks and newsletters.  Several investigators told us that they sometimes give 
presentations at advocacy meetings in which they try to mention their ongoing research 
protocols.  For trials requiring healthy subjects, many sponsors and investigators reach out 
to student populations.  Areas of high research activity are often located close to large 
universities.29 
Promotion and Advertising 
Advertisements seeking human subjects are common.  They can be found in newspapers, 
on the radio, the Internet, television, or as posters in, for example, public transportation or 
hospitals.  Ads can be very expensive, especially in certain parts of the country.  Because 
of this, many researchers are reluctant to use them unless absolutely necessary.  Several 
researchers told us that ads are cost-effective only for studies in which the eligible 
population is large and widely dispersed (i.e., depression or heart disease) as opposed to 
rarer conditions such as cystic fibrosis. 
Recently, sponsors and CROs have been helping sites recruit by initiating national 
recruitment campaigns for multi-site trials.  The national efforts have spawned a new 
industry of patient recruitment firms and research marketing companies who are creating 
professional, elaborate marketing packages.  Staff at the sites we spoke with report they 
are receiving more advertising from the sponsors at the start of the trial (including posters, 
fliers, and even prerecorded radio announcements for the local stations) than in years past. 
Many of these national advertisements include toll-free numbers.  Call centers may provide 
operators who can screen respondents according to the trials eligibility criteria and can 
schedule appointments at sites most convenient to callers.  Or, the toll-free number may 
automatically transfer to a phone at the closest site. 
19 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  The Internet is a fast-growing medium for advertising to potential subjects.  As health care 
consumers make efforts to become more informed about their options, they are turning to 
the Internet as an important resource.30  Sponsors and/or investigators may post 
information about a trial on their website or on central listings of active research.  There 
are several central listings and, in the past several months alone, there have been two 
announcements of alliances between healthcare websites and clinical trial organizations to 
post trial information on the Internet.31  Information on the Internet may prove particularly 
beneficial in recruiting for trials involving rare diseases where any one site may have only a 
small number of eligible subjects in its area. 
Investigators told us that they have recently seen more press releases or television news 
segments describing their research and any promising progress the research may hold. 
Though not explicitly advertisements, the segments can generate numerous responses.32 
IRB officials and others closely involved with clinical 
research express many concerns about current recruitment 
practices 
Two-thirds of the IRBs responding to our survey expressed concern about current 
practices used to recruit human subjects.  We not only heard concerns from IRBs, but also 
from investigators and sponsor representatives.  The IRBs had particular concern about 
those practices that occurred apart from the actual investigator-subject interaction.  Their 
concerns included the financial arrangements between sponsors and investigators (i.e., 
financial incentives), referral fees, and database searches of private medical information for 
identifying and recruiting subjects.  Both investigators and sponsors raised concerns about 
the increased pressure to recruit subjects in a timely manner.  Many of them spoke of the 
need to establish a level playing field in the recruitment of subjects in order to avoid a 
race to the bottom.  In general, the concerns permeate all four of the recruiting methods 
we described earlier.  At the core, we identified three sets of concerns. 
The most fundamental concern is that current practices may contribute to the 
erosion of informed consent, the foundation of human-subject protections. 
In 1978, the National Commission for the Protection of Human Research Subjects laid out 
the guiding ethical principles still in use today in its report, the Belmont Report.33  The 
report identified three important elements to informed consent:  information, 
comprehension, and voluntariness.  The concerns that IRBs, sponsors, and investigators 
have about recruitment practices relate, in various ways, to each of these elements. 
Information.  Potential human subjects, the Belmont Report makes clear, should have 
sufficient information that is both accurate and balanced in order to make an informed 
decision about participation.34  Misleading information may shape subjects initial 
judgment about a research study and, thus, may influence decisions about participating. 
20 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195   IRB officials, 
Therapeutic Misconception? 
investigators, and 
sponsor representatives

consistently expressed their

frustration to us over

seeing ads they

considered misleading. 

An ad may be

misleading, for

example, when it

implies that an

investigational drug is treatment rather than research (see box).  Indeed, many subjects

enter research studies with hope of receiving treatment, a phenomenon well-recognized by

the industry.35  The blurring of research and treatment, often referred to as therapeutic

misconception, can be difficult to clarify once a potential subjects initial impressions

have been formed.  One coordinator explained that it was difficult for her to field phone

inquiries following a news segment about a trial at her research site.  She felt that the news

segment portrayed the research as a potential cure; callers were eager to join the trial,

despite the fact that the research was in its earliest testing stages.  Ads also should not

overly stress any payment, monetary or otherwise, offered to subjects lest they be

considered coercive to the subject (see box below).36  Another concern we heard was

about the use of receptionists without clinical expertise who answer 1-800 phone numbers,

and serve as the first source of information for potential subjects.37

In the case of national ads,

even if IRBs do review an

Research for Money?

ad and raise questions, many 
IRBs are concerned that

sponsors do not have to

respond to their concerns. 

One IRB official explained a

recent situation in which his

IRB was asked to review the

video of a sponsor-produced

television ad.  The board had

problems with the video

because it felt the ad

strongly misrepresented the purpose and potential effect of the investigational material. 

However, despite repeated communications with the sponsor, the IRB was forced to

acquiesce its authority in this matter; the sponsor was not bound to incorporate the

changes because a different IRB had already approved the current version of the ad.38  The

use of national marketing efforts to recruit is increasing; often the products are flashy, very

general and do not reference a specific research site.  Consequently, many IRBs are unsure

of their authority in reviewing these national ads. 

21 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  IRBs also have concerns about some newer recruiting methods because the methods are 
not easily reviewed.  News briefs, interviews, or speeches at health fairs call for 
investigators to speak freely.  The focus of the presentation may not be about the research 
study per se, but the investigator may mention an ongoing study and invite interested 
people to participate.  IRBs are confused over whether these methods actually constitute a 
recruiting method and what they can or should do after-the-fact. 
Comprehension.  The way that relevant information is presented to potential subjects is 
also of vital importance.  The Belmont Report states, presenting information in a 
disorganized and rapid fashion, allowing too little time for consideration or curtailing 
opportunities for questioning, all may adversely affect a subjects ability to make an 
informed choice.39  It is important, therefore, that investigators and their staff convey the 
information in a way that facilitates potential subjects true understanding about a trials 
risks and benefits. 
Many people expressed to us their concern that the pressure-filled and competitive 
research environment may lead investigators or their staff to encourage hesitant subjects to 
participate.40  These concerns were raised particularly regarding financial incentives 
offered to investigators.  According to one survey respondent, financial incentives have 
the potential for pressure on/coercion of prospective subjects to enroll.  As one 
investigator stated, bonuses are just an incentive for bad behavior.  Although the 
informed consent document lists the potential risks and benefits of the trial, investigators 
presenting informed consent documents to subjects may, consciously or subconsciously, 
distort their descriptions of the trial.  As another respondent said, I worry about what is 
said to potential subjects.  These concerns are validated by our findings in prior work. 
We found that IRBs focus a great deal of attention on ensuring that all relevant 
information is included in the informed consent document, which can run up to 20 pages 
in length.  However, IRBs know little about the interaction between investigator and 
subject and, thus, how the study is actually presented to potential subjects.41 
The potential significance of industry incentives raises more concerns.  Both academic and 
independent investigators we spoke with expressed the importance that industry monies 
play in maintaining their position and supporting their research staff.  Nonfinancial 
incentives, such as authorship, may be important for career advancement or tenure 
decisions at academic institutions.  The concerns surrounding these incentives invariably 
lead to questions about what constitutes adequate disclosure of relevant information. 
Potential subjects may not understand that investigators are paid or receive a bonus for 
their participation in a trial. 
Voluntariness.  Even with accurate information and a balanced presentation, true 
informed consent, according to the Belmont Report, requires conditions free of coercion 
and undue influence.42  We heard significant concerns that the dual role of physician-
investigators might infringe upon this voluntariness; concerns worthy of particular 
attention as we found that investigators often enroll many of their own patients into their 
22 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  trials.  Patients may be reluctant to contradict their doctors wishes by refusing 
participation in a trial, or may agree to participate because they trust and respect their 
physician, who they believe is looking out for their best interests.  As one coordinator we 
spoke with said, patients see their doctor as God.  Another investigator recognized the 
trust patients hold in their doctors.  He told us that he was reluctant to even mention to his 
patients a trial that involved withdrawing their asthma medications.  He was afraid they 
would agree to participate because he asked them, despite the fact that their current 
medications were stabilizing their asthma.  A Presidential advisory commission went so far 
as to state that the patients of physician-investigators should be considered a vulnerable 
population.43 
Many ethicists see the doctor-patient relationship as fundamentally different than that of 
the investigator-subject.  In the former, medical care is solely for the benefit of the patient. 
The investigator-subject model differs in that the subject may or may not benefit from 
participation in research and the primary interest of the investigator is to develop scientific 
knowledge.44  Some IRBs have recognized these concerns and accordingly enacted 
policies to distance the physician-investigator from the recruiting process. 
The potential influence of physicians on their patients decision to participate in a trial is 
particularly troubling for some observers of the clinical research process when the 
physician receives a fee for referring a patient to a trial.45  The concerns focus on the fear 
that referral fees may lead physicians to further encourage their patients to enter a trial in 
order to receive a fee.  Referral fees are considered unethical by the American Medical 
Association and by some States; several IRBs and institutions also have policies forbidding 
their use.46 
We also heard concerns that peoples 
Done correctly, publicity can look like an
trust in certain health care 
endorsement by your well-respected newspaper 
professionals could influence their  reporter or TV news anchor. It can be an excellent 
perceived value of the research study  way to generate phone calls needed to fill studies. 
being promoted, whether it be on the

Internet, television, or elsewhere.  From an industry article on subject recruitment

Potential subjects views and

expectations of the research may be

altered because they trust the source of the information (see box).47  One Internet site,

associated with a widely respected former U.S. Surgeon General, received a referral fee

for each subject enrolled in a trial through its website; after coming under increasing

criticism, he dissolved this reimbursement mechanism.48  Another recruiting method we

heard about is funneling trial information through disease-support chatrooms on the

Internet.  In one instance, an investigator went into a chatroom and answered questions

about a study, providing the sites name and number, but did not reveal that he was a site

representative.

23 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Concerns about voluntariness are often connected to subject payments as well.  Subject 
payment levels have been studied and most parties involved in clinical research are 
sensitive to the fact that high payments may lead subjects to enroll in research that they 
would not participate in otherwise.49  As one article mentioned, it is easier to recruit just 
before Christmas than in mid-August.50 
A second major concern is that, in the rush to recruit subjects, sponsors and 
investigators may compromise patient confidentiality. 
The ease of scanning a patient database to find potential subjects makes the use of these 
databases very attractive for investigators under pressure to recruit (see box).  Most 
people we spoke with were not concerned about investigators searching through their own 
patient database to identify eligible subjects.  Rather, they were concerned about someone 
other than the patients physician going through medical records and then contacting a 
patient about participation.  Several IRB representatives told us they did not allow their 
investigators to search any institutional databases, to the frustration of many of the 
investigators, who assumed that patients had granted access to their records by signing an 
informed consent document upon admission to the hospital. 
Patients often are unaware that their 
records are being reviewed by persons 
other than their physician and that  At present, this group includes 9 cardiologists, 8 
these records may be used to  contact  cardiovascular  surgeons,  3  electrophysiologists,  7 
nephrologists, 3 pulmonologists, as well as 7 primary 
them about participating in research. 
care physicians. This gives XXX Research access to 
Many involved in clinical research 
a patient base of over 100,000. Approximately 16,000 
believe that patients ought to know 
of  these  patients  are  already  in  a  computerized 
who has access to their records and to  database, which allows for rapid recruitment. 
which records.  The Secretary of 
HHS recently proposed regulations  Access to our vast patient database enables us to send 
direct mail pieces to prospective patients.... Patients 
regarding privacy of medical records 
are listed according to ICD-9 codes for easy access. 
that may have implications for this 
recruitment practice.51 
From site advertisements to sponsors 
Physician databases are not the only 
source of confidentiality concerns; disease registries, school medical records, mailing lists, 
court records, or other databases have been used to contact subjects.52  For example, 
reporting to some State cancer registries is mandatory.  We heard about one States 
registry that is available to any investigator working on a protocol approved by the 
registry.  Yet people listed in registries or other databases may not have consented to 
being contacted for trial participation. 
Concerns about the confidentiality of medical information extend beyond using this 
information to contact potential subjects.  We also heard concerns about confidentiality of 
personal information collected during the screening of potential subjects.  For example, 
24 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  when call centers are used to pre-screen prospective subjects, callers may be asked their 
name, contact information, and possibly sensitive information about sexual history or drug 
use.  Potential subjects have little knowledge as to what happens to that information if 
they are not accepted into the trials.  Adequate protections may not be applied to this 
sensitive information. 
IRBs have also received complaints of harassment from potential subjects.  OPRR recently 
cited a research institution when it found investigators participating in harassing 
recruitment tactics.  The potential subjects were recontacted repeatedly despite declining 
to participate. 
Another concern is that pressures on investigators to recruit may lead them to 
enroll subjects that are ineligible. 
Investigators seeking to fulfill a contract with a sponsor and/or ensure future contracts are 
under constant pressure to find subjects and recruit them quickly.  At the same time, 
investigators face tight eligibility criteria, limiting the eligible pool of potential subjects. 
Sponsors decide appropriate eligibility criteria jointly with FDA and then inform 
investigators as to how to determine whether subjects fit these criteria.  However, in a 
competitive environment, research observers fear that, while most investigators will enroll 
correctly, some investigators may enroll subjects that are ineligible or of questionable 
eligibility in order to meet quotas and satisfy eager sponsors.53 
Although it is difficult to quantify how often ineligible subjects are enrolled into trials, 
research observers tell us that it happens infrequently; most investigators enroll only 
eligible subjects.  However, what constitutes eligible is often hazy; eligibility criteria 
often involve medical judgment, adding a degree of subjectivity to enrollment decisions. 
One sponsor monitor told us that some investigators that she has overseen have stretched 
enrollment criteria, claiming that some used outrageously bad clinical judgment just to 
get subjects into a trial.  Another investigator, speaking about the use of incentives, said 
that if a bonus was set to 30 subjects and a site had 29, you could bet that the site would 
get the 30th subject.  But, I wouldnt guarantee what youd find if someone looked 
more closely at the subject.  Several investigators told us that they had questions about 
subjects true eligibility in some of their trials.  Questions arose when the investigators 
had difficulty finding subjects, and yet other sites were able to enroll great numbers. 
The participation of ineligible subjects raises concerns about human-subject safety and 
data validity.  Sponsors include certain exclusion criteria in order to prevent certain people 
from experiencing adverse reactions and/or to eliminate those at the greatest risk of harm 
from participating.  When sponsors and FDA make decisions regarding a drugs safety and 
efficacy, they base their conclusions on the assumption that the drug was tested on the 
intended population.  If these assumptions are false, conclusions of efficacy could be 
wrong.  There are many checks and balances in the clinical research system to uncover 
ineligible subjects before the trial data has been reviewed by FDA; FDA medical 
25 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  officers, field investigators, and sponsors monitors all review subjects eligibility criteria. 
Yet, there have been recent cases in which none of these groups discovered that 
investigators had been enrolling ineligible subjects until after the trials were complete.54 
Oversight of the recruitment of subjects is minimal and 
largely unresponsive to emerging concerns 
IRBs are not reviewing many of the recruitment practices that they and others 
find most troubling. 
Although financial incentives given to investigators by sponsors to boost enrollment are 
among the recruitment practices that IRBs are most concerned about, 75 percent of IRBs 
that responded to our survey do not review any financial arrangements between sponsors 
and investigators.  When IRBs do review subject recruitment practices, they primarily 
review advertisements and incentives paid to subjects, not practices involving sponsor-
investigator interactions. 
In addition, 25 percent of IRB survey respondents do not ask investigators to explain 
recruiting practices in their application for review.  The finding that a significant 
percentage of IRBs do not gather basic information about recruitment practices on their 
application for review raises the possibility that some IRBs may not be reviewing 
recruitment practices at all.  In addition, of the 23 applications provided by our surveyed 
IRBs, 13 ask only general questions about recruitment such as, How will subjects be 
recruited for the study?  Few inquire about specific recruitment practices in their 
application for review. 
On a positive note, although the IRBs that responded to our survey do not seem to be 
reviewing the recruitment practices they find most troubling, they claim to be devoting 
increasing attention to recruitment issues.  Sixty-one percent of IRB survey respondents 
reported that they had requested changes in the recruitment practices called for by a 
protocol during the past 3 years and many said that they are requesting more of these 
changes now than 3 years ago.  In addition, there has recently been a spate of messages on 
a listserv for IRB representatives regarding recruitment issues, reflecting both concerns 
and confusion about many of these issues.  Despite lack of guidance from other sources, 
some IRBs and research institutions have created their own guidelines and policies relating 
to recruitment (see Recruiting Human Subjects:  Sample Guidelines for Practice, OEI-
01-97-00196), even though more stringent reviews may put these IRBs at a competitive 
disadvantage because the reviews take longer. 
26 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  IRBs limited review of recruitment practices is in part due to their perceived lack 
of authority to review certain practices. 
IRBs may not be reviewing some recruitment practices because they do not believe that 
they have the authority to do so, or are uncertain of their authority.  Our survey indicates 
that, while IRBs are confident about their authority to review advertisements for recruiting 
subjects and subject incentives, both explicitly mentioned in FDA guidance to IRBs, they 
are much less confident about their authority to review other recruitment methods.  IRBs 
can draw their authority to review protocols from sources other than Federal regulations 
and guidelines, such as institutional policy.  Yet, any steps that an IRB were to take 
toward establishing more stringent protocol reviews would be unpopular among the 
researchers in that institution.  Given the competitive nature of the current research 
environment, such added stringency would put the IRB at competitive disadvantage. 
IRBs perceived authority to review different recruitment practices 
Recruiting  Method  Clearly Have  Are Uncertain  Clearly Dont 
Strategy  the Authority  of Authority  Have the 
Authority 
Offering  Authorship incentives  24%  42%  34% 
Incentives 
Financial incentives to  43%  32%  26% 
investigators 
Targeting Ones  Review of investigators  60%  16%  24% 
Own Patients  own patient databases 
Seeking  Review of other physicians  66%  17%  17% 
Additional  databases to identify/ 
Patient Bases  contact eligible subjects 
Referral fees  65%  25%  10% 
Advertising and  Print ads  96%  3%  1% 
Promotion 
Radio/TV scripts  92%  7%  1% 
Internet ads  83%  15%  2% 
Subject payments  92%  5%  3% 
Receptionist scripts  64%  28%  9% 
Source: OEI survey, 1999. 
27 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  HHS provides little clear guidance to IRBs on acceptable recruitment practices. 
In contrast, some professional medical associations provide strong guidance on 
selected issues. 
FDA.  The primary guidance to IRBs comes from the FDA in the form of Information 
Sheets.  Two Information Sheets relate specifically to recruitment issues, Recruiting 
Study Subjects and Payment to Research Subjects ( see appendix B for the complete 
text of these documents).  Recruiting Study Subjects gives IRBs blanket authority to 
review the methods and material that investigators propose to use to recruit subjects, 
but does little to explain how methods ought to be reviewed. 
The Information Sheets also fail to mention many recruitment methods that are currently 
in use. The Sheets focus solely on methods that come into direct contact with potential 
subjects, such as advertisements, payments to subjects, and receptionist scripts.  Notably 
absent from the Information Sheets is any guidance regarding methods that are invisible 
to subjects, such as how physician-investigators should handle their dual role when 
recruiting their own patients.  Similarly, the Sheets fail to mention anything about 
investigators or others accessing names of potential subjects (with identifiable medical 
information), through electronic databases or medical charts, to contact about trial 
participation.  Finally, the Sheets do not consider what types and degrees of financial 
incentives constitute a potential conflict of interest.  The FDA recently began requiring 
investigators to disclose to the Agency some of the investigators financial arrangements 
with sponsors, evidence that FDA believes that a certain level of financial interest is 
relevant to the Agencys own scientific review.55 
One of the most confusing issues not addressed in the Information Sheets is recruitment 
practices in multi-site trials.  Sponsors, IRBs, and sites all reported being uncertain about 
some aspect of recruitment for these trials.  IRBs were uncertain of their authority to 
change ads or telephone scripts on a multi-site trial if another IRB had already approved it. 
Private sites that used different IRBs for different trials complained about a lack of 
consistent guidelines for IRB review of ads and other recruitment materials; certain 
wording that was forbidden by one IRB might be required by another.  Sponsors faced this 
same frustration when they tried to create an ad that would be acceptable to all of the 
IRBs in a multi-site trial. 
NIH/OPRR.  OPRR has a Guidebook for IRBs that discusses a variety of recruitment 
issues not mentioned in the FDA Information Sheets.56  But, the Guidebook relies on the 
Information Sheets for specific guidance on recruiting practices.  For example, the 
Guidebook draws attention to possible conflicts when the investigator is also the subjects 
physician and to concerns of coercion when the trial offers free health care.  It also 
mentions concerns regarding searching databases for potential subjects and then 
contacting these subjects about participating in the trial.  However, the Guidebook fails to 
advise IRBs as to whether these practices should be allowed or how they ought to be 
28 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  reviewed, nor does the Guidebook link these issues explicitly with recruiting practices. 
For instance, in discussing the practice of following up a letter requesting participation 
with a phone call, the Guidebook merely states, IRBs should be sensitive to this 
concern.57 
Other Sources.  Federal oversight bodies are not the only sources of guidance available to 
IRBs.  Many investigators and IRB members are members of professional medical 
associations that provide some additional guidance on recruitment issues.  In our review of 
20 medical associations codes of ethics and position papers, we found that some 
associations have strong, explicit guidelines on certain recruitment issues (see appendix C 
and our companion report).  For example, the American Academy of Neurology 
acknowledges the trust relationship that patients have with their doctors, especially in 
cases where patients are particularly vulnerable, such as people with severe, progressive, 
or terminal illnesses.  Under such circumstances, the Academy claims that the distinction 
between medical care and experimental treatment may become blurred.58  It further 
suggests that researchers and IRBs take special precautions, perhaps by requesting that an 
uninterested party explain the research to the potential subject.  The American College 
of Emergency Physicians states that industry payments to investigators should be 
disclosed.59 
Many other associations have general guidelines about medical practice that could be 
extrapolated to the practice of research.  For instance, many professional medical 
associations prohibit the use of patients private medical information for any purposes 
other than diagnosis and treatment, unless the patient has given express permission.60 
Such a position could be interpreted to mean that these associations do not condone the 
use of private medical information for contacting subjects about trial participation. 
In their own oversight of research sites, sponsors pay minimal attention to how 
human subjects are recruited. 
Although IRBs central mission is to oversee human-subject protections, sponsors have 
responsibility for the ongoing safety of subjects in their trials.  The FDA states that the 
sponsor is responsible for assuring throughout the clinical investigation that the 
investigators obligations, as set forth in applicable regulations, are being fulfilled.61  In 
fulfilling this responsibility, sponsors may officially delegate clinical trial monitoring 
responsibilities to a CRO.62  Sponsors or CROs oversee investigators, and in turn, the 
protection of human subjects, almost exclusively through their monitors. 
We found, in speaking with monitors and investigators, that monitors focus on ensuring 
the quality of data, rather than human-subject protections.  Although monitors will often 
verify that advertisements have been approved by the sites IRB, they do not verify IRB 
approval of some of the recruitment methods that raise the most concerns.  Monitors visit 
the research site frequently and may learn of practices that raise concern.  Yet, according 
to monitors and sponsor representatives, even if a monitor were to discover that an 
29 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  investigator was doing something that raised concern, the monitor may be discouraged by 
his/her superiors from taking any action, particularly if the investigator in question were a 
prestigious one.63  Furthermore, sponsors initiate many of the practices that raise the most 
concerns, such as enrollment bonuses and authorship incentives, thus undermining their 
ability to oversee research sites recruitment practices effectively. 
Nor does HHS pay much attention to recruitment practices in their inspections of 
IRBs and investigators. 
The FDA routinely inspects investigators and IRBs under the Bioresearch Monitoring 
Program.  Its objectives for conducting investigator inspections are, ensuring the quality 
and integrity of data and information submitted to FDA as well as the protection of human 
research subjects.64  However, our review of FDAs inspection process for clinical 
investigators revealed that the FDAs main focus is on the former, ensuring the integrity of 
data submitted to the Agency. 
The FDAs stated purpose in inspecting IRBs is to determine whether an IRB is 
operating in accordance with its own written procedures as well as in compliance with 
current FDA regulations affecting IRBs.65  In our review of FDAs inspection process for 
IRBs, we found that FDA focuses on procedural compliance, not the content of IRB 
reviews. 
Neither the IRB and investigator inspection protocols, nor the inspections themselves, 
consider how investigators recruit or ensure that IRBs oversee recruitment.  The one 
exception involves ads.  Both the investigator and IRB inspection protocols instruct FDA 
inspectors to determine whether any recruitment advertisements had been approved by the 
sites IRB before subjects were allowed to participate in the trial. 
Not only are FDA inspections of investigators and IRBs limited in scope, but they are also 
limited in number, particularly at foreign research sites.  The Center for Drug Evaluation 
and Research conducted 179 IRB inspections in 1998, out of a universe of roughly 3,000-
5,000 IRBs.66  Despite the large number of foreign trials, the FDA normally does not 
inspect foreign IRBs.67  In that same year, 1998, CDER conducted 348 investigator 
inspections, of which 60 were conducted abroad. 
OPRR conducts many fewer inspections than FDA and conducts them primarily for cause. 
Unlike FDA, OPRR lacks a written inspection protocol that would enable us to determine 
exactly what they consider in its IRB inspections.  Since most of OPRRs inspections are 
for cause, its inspections are focused according to the problem at hand.  Occasionally, 
those on-site reviews will address and raise concerns about recruitment practices.  In at 
least one of OPRRs recent inspections, OPRR faulted the IRB for inadequate review of a 
protocols recruitment methods and required the IRB to establish subject enrollment 
procedures that minimize the possibility of coercion or undue influence in order to be 
allowed to continue conducting federally funded research. 
30 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  R E C O M M E N D A T I O N S  
There is a compelling national need to recruit human subjects to participate in clinical 
research  a need vital to the continued progress and discovery of new, effective drugs. 
But, there is a danger that this imperative could compromise the protection of human 
subjects.  Our inquiry reveals significant vulnerabilities concerning the recruitment of 
subjects.  It also reveals that IRBs, the Federal government, and sponsors have been doing 
little to address the recruitment practices that generate the most concern. 
It is in the best interest of all involved in the research enterprise to address concerns about 
recruitment practices.  In a highly competitive marketplace, with few rules or guidelines 
governing recruitment, there is a very real danger of a race to the bottom.  Some sponsors 
and investigators may find it difficult to refrain from recruitment practices that are 
effective in delivering a steady stream of subjects to participate in clinical trials.  But, these 
recruitment practices could compromise long-valued human-subject protections.  A 
groundswell of concern over certain recruitment strategies, or negative publicity over an 
unfortunate event, would undoubtedly lower public confidence in clinical research and, in 
turn, heighten the difficulty many sponsors and investigators experience in recruiting 
subjects. 
The critical challenge, then, is to achieve some balance  to ensure essential human-
subject protections without unnecessarily slowing the pace of research and discovery. 
This challenge is especially significant since IRBs, which serve as the main source of 
protection, are themselves in danger.  As we have shown in a previous report, they are 
increasingly overburdened, have limited helpful information, and often have inadequate 
resources. 
Below we offer four main recommendations.  The first two are specifically pertinent to the 
concerns raised about current practices used to recruit human subjects.  The third and 
fourth recommendations, which stem from our prior work on IRBs, are aimed at 
improving human-subject protections more generally, but are integral to the issues of 
subject recruitment. 
We present these recommendations jointly to FDA, NIH, and the Assistant Secretary of 
Health (ASH).  We include ASH because the Secretary recently decided that OPRR be 
moved to the Office of Public Health and Science, within the Office of the Secretary, with 
a direct reporting line to the Assistant Secretary for Health.  In those instances where we 
present a recommendation to only one of the agencies, we specify the agency directly. 
We should also note that, although our methodology focused on drug research, we expect 
that our findings and recommendations would also be relevant to other types of clinical 
research (including clinical research on medical devices or biologics). 
31 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  1.  Provide IRBs with direction regarding oversight of 
recruitment practices 
1a.  Clarify that IRBs have the authority to review recruiting practices 
The most important step that Federal bodies should take is to clarify that IRBs have the 
authority to review recruiting methods.  Our review found that IRBs are uncertain of their 
authority to review recruiting practices, some of which raise significant concerns about the 
adequacy of the informed consent process. 
Federal regulations state that informed consent may be sought only under circumstances 
that provide the prospective subject or the representative sufficient opportunity to 
consider whether or not to participate and that minimize the possibility of coercion or 
undue influence.68  IRBs have the authority to ensure informed consent of human 
subjects.  Similarly, Federal regulations require IRBs to review and approve the initiation 
and conduct of covered biomedical research activities involving human subjects.  This 
broad mandate also provides a basis for IRBs to review practices for recruiting human 
subjects. 
Federal bodies should explicitly indicate in their guidance that certain practices that may 
only indirectly impact subjects, such as investigator incentives, also fall under IRB 
purview, as they may affect the informed consent process.  FDA and NIH should 
disseminate this guidance promptly.  The focus of current Federal guidelines and IRB 
oversight is on recruiting practices that directly affect potential subjects.  IRBs most often 
review advertisements or subject payments, the subject of the two FDA Information 
Sheets. 
1b. Provide guidance to IRBs on how to exercise this authority 
FDA and OPRR should assist IRBs in their review of recruiting practices by suggesting 
questions that boards should address and by fostering discussion of the issues by IRBs at 
the local level.  A simple statement outlining IRB authority to review recruiting practices 
is inadequate.  Throughout its IRB Guidebook, OPRR does propose that IRBs pay 
attention to issues such as subject confidentiality and doctor-patient influence.  However, 
these issues should be more closely linked with the review of recruiting practices.  This 
guidance would be of immediate value to IRBs in their review of protocols, as many IRBs 
are extremely conscientious of their responsibilities as outlined in Federal regulation and 
guidance.  Such direction will allow IRBs to take steps in their oversight previously 
considered unnecessary, murky, or intrusive. 
32 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  2.  Facilitate development of guidelines for all parties on 
appropriate recruiting practices 
We recognize that the concerns raised about current recruiting practices include many 
gray areas where opinions differ on appropriate practices.  Thus, it is essential to involve 
an adequate representation of the key participants  sponsors, industry groups, 
investigators, IRB representatives, patient advocates, ethicists, and other parties (such as 
the Institute of Medicine)  in a process that addresses the concerns and seeks to develop 
consensus on appropriate practices.  Such discussions are vital to assisting Federal bodies 
in developing further recruitment guidance, thereby maintaining adequate human-subject 
protections. 
A clearer determination of appropriate recruiting practices would be helpful for all parties 
 sponsors, investigators, and IRBs.  Understanding the appropriateness of certain 
practices can be helpful for sponsors and investigators as they recruit subjects and for 
IRBs in their reviews.  Recently, there have been forums convened considering standards 
for medical Internet sites.69  Further Federal guidance on appropriate recruiting practices 
will help to ensure a level playing field in the competitive clinical research marketplace. 
As part of their deliberations, the groups should seek consensus on questions such as: 
<  Is it acceptable for sponsors to offer bonuses to investigators for successfully 
recruiting subjects? 
<  Should physicians be allowed to receive fees for referring their patients as potential 
subjects for a clinical trial? 
<  Should the financial arrangements between sponsors and investigators be disclosed to 
potential subjects? 
<  Does searching medical records for potential subjects constitute a breach of 
confidentiality? 
In addition, a greater understanding of already established guidelines and their impact 
would be helpful to the deliberating groups, including Federal bodies, as they develop 
guidance on appropriate practices.  The groups could research the existing guidelines and 
policies on issues not currently addressed in the FDA Information Sheets, many of which 
are already adhered to at local research institutions or in other countries.70  For example, 
they could assess what prompted these research institutions, foreign regulatory agencies, 
and medical professional associations to develop such guidelines or policies, any barriers 
that these entities have encountered in implementing these guidelines/policies, and how 
their members/investigators responded to them. 
33 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  3.  Ensure that IRBs and investigators are adequately 
educated about human-subject protections 
3a.  Require education for investigators before conducting human-subjects 
research 
An education requirement could be a prerequisite for signing an investigator-agreement 
form (known as a 1572) to participate in research under FDA regulation or for receiving 
Public Health Service Act funds for conducting human-subject research.  Investigator 
education is of particular importance because investigators and their staff are the ones who 
actually interact with potential subjects and often lead recruiting efforts.  Also, there are 
an increasing number of new, inexperienced investigators participating in clinical research. 
At least one research institution has created a human-subject protection training 
requirement for its investigators. 
3b. Require that IRBs have a training program for board members 
Because of their vital roles as the primary source of human-subject protections, IRB 
members must have adequate training that highlights the issues surrounding the 
recruitment of human subjects.  IRB education could inform members of current recruiting 
practices and could raise their awareness of concerns about these when conducting their 
reviews. 
3c.  Require more extensive representation on IRBs of nonscientific and 
noninstitutional members 
The requirement of at least one noninstitutional and one nonscientific member out of five 
members should be interpreted as a ratio.  IRBs often have 15 or more members and the 
requirement can be fulfilled with the appointment of just 1 person.  Nonscientific and 
noninstitutional members on IRBs can further ensure that IRBs are sensitive to human-
subject protection issues; lay members voices provide an important balance to 
institutional interests on an IRB.  Because many recruiting concerns raise issues about 
what a typical subject would wish to know in order to make an informed decision or what 
constitutes a breach of confidentiality, the perspectives of independent lay members are of 
particular importance.71 
34 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  4.  Strengthen Federal Oversight of IRBs 
4a.  Require that all IRBs register with the Federal government and regularly 
report basic descriptive information 
Federal oversight could be strengthened if IRBs were required to submit, at a minimum, 
brief descriptive information including location and contact person.  Such information 
would be extremely helpful in disseminating guidance and targeting effective oversight, 
such as inspections.  FDA has begun the process of developing such a registration system. 
We also suggest that there be one registration system for all HHS agencies involved in 
human-subject protection oversight, further facilitating communication and oversight 
efforts between the agencies. 
FDA has a database of IRBs identified on the investigator-agreement form submitted to 
review Investigation New Drug research, but the database is limited.  We used the FDA 
database to identify IRBs for our survey.  A significant percentage of the surveys were 
returned to sender or the contact person called us to say that they had never heard of the 
IRB or were never involved with its reviews.  These limitations of FDAs IRB database 
are particularly important because recruitment guidance for IRBs would be disseminated 
using the database, thus raising the possibility that a large number of IRBs would not 
receive such critical guidance. 
4b.  Revamp the FDA on-site inspection process 
In FDAs inspections, primarily the clinical-investigator inspections, the Agency could 
address many of the concerns about recruiting methods and raise questions about how 
human subjects were recruited.  Inspectors could consider assessing the range in number 
of subjects enrolled across sites.  If, for example, one site enrolled significantly more 
subjects than other sites or financial incentives were offered by sponsors, inspectors could 
probe to understand how these subjects were enrolled and why the high-enrolling site was 
able to recruit when others were unsuccessful.  Also, at these high-enrolling sites, 
inspectors could examine more closely whether enrolled subjects were truly eligible. 
35 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Comments on the Draft Reports 
We received comments on our two draft reports from the Department of Health and 
Human Services (HHS).  We also solicited and received comments from the following 
external organizations: Public Citizens Health Research Group, Pharmaceutical Research 
and Manufacturers of America (PhRMA), Applied Research Ethics National Association 
(ARENA) in conjunction with Public Responsibility in Medicine & Research (PRIM&R), 
and the Consortium of Independent Review Boards (CIRB).  We did make a number of 
changes in the final reports, many technical in nature, that respond to their comments.  We 
include the complete text of the comments in appendix D.  Below we summarize the major 
comments and offer our response to HHS and, collectively, to the external parties. 
HHS Comments 
We appreciate both HHS positive response to our reports and its commitment to address 
the issues raised in our findings and recommendations.  We are particularly encouraged by 
HHS committment to establish new requirements for human-subject protection education. 
As the primary bodies for subject protections, IRBs must be adequately educated about 
ethical issues in order to ensure protections.  Investigators interact directly with subjects 
and therefore, must be attuned to protection issues and concerns.  We note here also, that 
through the course of this study, we became increasingly aware of the fact that 
investigators staff interact with subjects much more so than investigators.  We urge HHS 
to recognize the increasing importance of investigators staff in their efforts. 
We particularly welcome, too, HHS (through FDA, NIH, and the new Office of Human 
Research Protections) willingness to work with all parties in clinical research to develop 
guidance on appropriate recruiting practices.  As we noted in our recommendations, it is 
essential that all parties be involved in this consensus-building process.  The Department, 
and particularly NIH, is a well-recognized leader in the field of clinical research and is 
well-positioned to take a leading role in this important area. 
We acknowledge in the report that both FDA and NIH have current guidance documents 
highlighting the recruitment of human subjects.  However, we found in our survey that 
many IRBs remain unsure of their authority to review recruiting practices and, therefore, 
further guidance is needed.  Clearer guidance is especially important because IRBs may 
face pressure to provide a timely review of protocols.  In reassessing the current IRB 
guidance, we urge HHS to consider our recommendation that IRBs be provided guidance 
clarifying their authority in this area.  The guidance need not be a laundry list of how to 
review each individual practice, rather a reminder that IRBs already have the authority. 
This guidance would also serve as a recognition that recruiting practices can impact 
human-subject protections. 
36 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Through its assurance process, OPRR does have identifying information on the IRBs it 
oversees.  With the move to the Office of the Secretary and the new offices central role in 
representing the Department, we urge the new office and FDA to combine its efforts to 
create one repository for information and contacts for all IRBs involved in HHS activities. 
As HHS acknowledges in its comments, this information will facilitate more effective 
education and oversight. 
External Parties Comments 
Overall, we were pleased that external parties echoed the concerns we raised about some 
current practices for recruiting subjects into clinical trials and that steps should be taken to 
identify, at a national level, appropriate recruitment practices.  The following are common 
points raised in the external parties comments to our report: 
Consensus about appropriate recruitment practices must be forged among all 
parties. 
A number of parties raised concerns that our recommendations would call for Federal 
bodies to dictate appropriate recruiting practices without input from outside groups. 
These are not easy questions and there are not easy answers.  Thus, we have 
recommended that all of the different parties involved in clinical research, including 
Federal oversight bodies, sponsors, investigators and IRBs, search for reasonable 
consensus on appropriate practices.  We hope that the concerns we raise in this report 
provide the impetus for discussions on appropriate practice. 
Other entities must share the responsibility for overseeing recruitment practices 
with IRBs. 
Many voiced concern that IRBs are already overburdened and, therefore, it would be 
unwise to add to their duties.  We share this concern, but do not believe that the 
recommendations laid out in this report would necessarily require more work on the part 
of the IRB.  First, just as we believe that decisions about appropriate recruitment practices 
should be arrived at jointly, we believe that the oversight of these practices should be a 
shared responsibility.  Presumably, as consensus develops, sponsors and investigators will 
be more aware of which recruitment practices are appropriate and will refrain from 
engaging in them, making the IRBs job easier.  In addition, many IRBs already do review 
recruitment practices, but, because of a lack of clear guidance, this review can entail much 
debate.  If clear guidance existed, such debate could be minimized.  Ultimately, if 
recruitment practices are occurring that could potentially harm human subjects, then these 
concerns must be addressed, whether by the IRB or other entities, regardless of time and 
resource constraints.  Perhaps some of the Federal IRB regulations could be revamped to 
allow IRBs greater flexibility to review issues that have direct impact on human-subject 
protections, as suggested in a prior report. 
37 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  Clarifications on our Methodology 
Several points were raised about our methodology.  In this report, we sought to document 
current practices used to recruit human subjects and identify any concerns associated with 
these practices.  We did not seek to judge the appropriateness of any given recruitment 
practice.  We also focused on industry-sponsored trials and therefore are not in a position 
to determine whether recruitment practices vary by funding source.  We should note that 
much of our information was provided by investigators who were involved in research 
from different funding sources.  It is possible that the investigators in talking with us may 
not have distinguished their research by funding source. 
Because of the variety of disease types, potential subject groups, phase of trial, and other 
factors specific to each protocol, we had to rely primarily on qualitative evidence, obtained 
through site visits and interviews with key stakeholders.  There would have been no 
feasible way to conduct this study in a strictly data-driven manner.  We drew from 
common themes that arose during the course of this study, using examples to illustrate 
these themes. 
Our IRB survey respondents included all types of IRBs: independent, hospital-based and 
academic IRBs.  We did not consider the differences among these types of IRBs.  There 
were no significant differences in responses to our survey when stratified by domestic 
versus foreign IRBs.  We believe our findings and recommendations should apply to all 
types of IRBs. 
Answers to specific comments 
Registration of IRBs.  ARENA raised concerns that our recommendation that IRBs 
register with FDA would add a burden to IRBs with little benefit.  We believe that 
registration would allow FDA to provide guidance to all IRBs in an efficient, streamlined 
fashion.  Because the Agency has limited and sometimes inaccurate information about the 
IRBs it oversees, its ability to disseminate guidance in a way that ensures that all IRBs will 
receive it is jeopardized.  The registration process need not be a significant burden to an 
already overtaxed IRB system; the process could involve IRBs providing minimal 
descriptive information to FDA (i.e., location, address, contact person and number). 
Education Requirements.  We agree with PhRMA that education of investigators, IRBs 
and sponsors should not be a one-size-fits-all model.  Our recommendation calls for an 
education requirement.  However, we do not intend to suggest that there should be a 
national standardized educational program.  The substance of the education may vary 
according to the party it is geared towards.  The important thing is that all of the parties 
are educated, as a prerequisite for taking part in FDA-regulated research. 
38 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX A 
Methodology

IRB Survey 
We surveyed a total of 200 IRBs.  We selected the random sample of IRBs identified 
through the FDA Investigational New Drug database.  In an attempt to ensure that our 
respondents had adequate and recent experience to draw on and to improve the response 
percentage, the sample included only those IRBs involved in four or more IND trials in 
1997 and 1998 and those that identified a contact person.  Of the 624 remaining unique 
IRBs in this group, we randomly selected 150 U.S.-based IRBs and 50 foreign IRBs. 
The surveys focused on any experiences or concerns they may have about any recruitment 
techniques and the extent and nature of their oversight.  We received responses from 108, 
or 54 percent, of the IRBs we sampled. 
Review of FDA and OPRR Oversight Processes 
We reviewed each offices oversight processes to determine whether and to what extent 
they address subject recruitment issues.  For FDA, we reviewed the Bioresearch 
Monitoring inspection protocols for both IRBs and investigators.  In addition, we 
accompanied FDA inspectors on the routine inspection of both a clinical investigator and 
an IRB.  We observed the inspection process and reviewed files for IND clinical trials 
seeking information on subject recruitment.  For OPRR, we examined the assurance 
process, reports from previous inspections, and its IRB Guidebook. 
In-depth Site Visits 
We visited five research sites, both academic and independent, to learn about individual 
investigators and research staffs experiences recruiting subjects.  We chose the sites 
based on their research activity, location, and our ease of access to the research 
community.  In each of the institutions, we interviewed, among others, research 
investigators; research coordinators and nurses; IRB administrators and members; and 
institution administrators. 
Review of Existing Guidelines 
We collected relevant ethics codes or guidelines from 20 professional medical 
associations, numerous IRBs, and Canada.  We then reviewed these guidelines to 
determine their applicability to the recruitment of subjects. 
39 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX A 
Analysis of Data in IND Database 
We analyzed the FDA Center for Drug Evaluation and Researchs Investigational New 
Drug database, current as of July 29, 1999, by importing the database into SAS to identify 
trends in, for example, the selection of sites and the activity of research investigators. 
Interviews with Key Parties 
We interviewed representatives of groups with national perspectives on recruitment issues, 
including: sponsors, CROs, SMOs, patient recruitment firms, IRBs, and ethicists. 
Literature and Document Review 
We reviewed relevant literature, including Federal documents, scientific and trade 
literature, the lay press, and relevant websites, for information on the issues surrounding 
recruitment. 
40 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX B 
FDA Information Sheets

41 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX B 
42 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX B 
43 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX C 
Professional  Medical  Association  Guidelines

The following chart indicates which medical associations have such guidelines or codes of ethics. 
Guidelines that specifically pertain to clinical trials are denoted by a U.  Associations that have 
general medical practice guidelines or codes of ethics that could have implications for clinical 
research are denoted by a k. 
Professional Association  Associations Guidelines or Codes of Ethics 
Dua 
Confidential  Other 
Incentives  l 
Records  Guidance 
Role 
D
Referral fees  financial arrangements Disclosure to subjects of  for conducting clinical trial Compensation to investigator ual investigator-physician ro potential subjects for identifying /contacting Use of medical records  payment to subjects Advertisement/  News briefs  sources of guidance Also defers to other 
s  le
 
American Academy of Allergy, 
Asthma and Immunology 
American Academy of Family  k  k 
Physicians 
American Academy of  U 
Neurology 
American Academy of  k  k 
Ophthalmology 
American Academy of  k  U  AMA Code 
Orthopaedic Surgeons  of Ethics 
American Academy of  U  U 
Pediatrics 
American Academy of  k  Nuremberg 
Physical Medicine and  laws 
Rehabilitation 
American Association of  k 
Neurological Surgeons 
44 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX C 
Professional Association  Associations Guidelines or Codes of Ethics 
Dua 
Confidential  Other 
Incentives  l 
Records  Guidance 
Role 
D
Referral fees  financial arrangements Disclosure to subjects of  for conducting clinical trial Compensation to investigator ual investigator-physician ro potential subjects for identifying /contacting Use of medical records  payment to subjects Advertisement/  News briefs  sources of guidance Also defers to other 
s  le
 
American College of  k  U  Declaration 
Emergency Physicians  of Helsinki 
American College of  k 
Obstetricians and 
Gynecologists 
American College of  U  k  U  k  U 
Physicians 
American College of  k 
Radiology 
American College of Surgeons  k  k 
American Geriatrics Society 
American Medical Association  U  k  U 
American Womens Medical 
Association 
American Pharmaceutical 
Association 
American Psychiatric  k  U  k  AMA Code 
Association  of Ethics 
American Society of  k  AMA Code 
Anesthesiologists  of Ethics 
American Society of Plastic  k  k 
and Reconstructive Surgeons 
National Medical Association 
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Comments on the Draft Reports and OIG Response 
In this appendix, we present the full comments of all parties that responded to our two 
draft reports.  In order, the comments that we present in this appendix are from the 
following parties: 
<  The U.S. Department of Health and Human Serivces 
<  Public Citizens Health Research Group 
<  Pharmaceutical Research and Manufacturers of America 
<	 Applied Research Ethics National Association (in conjunction with Public 
Responsibility in Medicine & Research) 
<  Consortium of Independent Review Boards 
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Endnotes

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

Boards: A Time For Reform, OEI-01-97-00193, June 1998.

2.  Niblack, J.F. Why are Drug Development Programs Growing in Size and Cost?  A View from

Industry, Food and Drug Law Journal 1997; 52: 151-154.

3.  Association of Clinical Research Professionals, ACRPs White Paper on Future Trends, Spring

1999, p.3.

4.  In 1990, total (domestic and foreign) drug research and development expenditures was $8.4

billion.  This number rose to an estimated $24 billion in 1999. 

Pharmaceutical Research and Manufacturers of America, PhRMA Industry Profile 1999, Chapter

2, p. 15. 

5.  Miller, K.L. and Pryce, S.L. Better, Faster, Worldwide Too Update on Pharmaceutical

Contract Support Organizations, a Hambrecht & Quist, L.L.C., Industry Report, Jan. 4, 1999.

6.  For example, in 1995, the average number of clinical and outcome procedures per protocol

was 189, up from an average of 100 in 1991.  From DataEdge, 1995 as cited in PAREXELs

Pharmaceutical R&D Statistical Sourcebook, 1998: p.51. 

Trials are becoming more complex as they attempt to provide information to more customers. 

According to Niblack, these customers include, but are not limited to, the sponsors business

management and shareholders, both national and international government regulators, opinion

leaders in academic medicine, practicing physicians, formulary managers, and patients and their

families.  Each of these customers are seeking different types of information that can only be

ascertained by adding more procedures or more subjects to a trial. 

Niblack, JF. Why are Drug Development Programs Growing in Size and Cost?  A View from

Industry, Food and Drug Law Journal 1997; 52: 151-154.

7.  Pharmaceutical Research and Manufacturers of America, PhRMA Industry Profile 1998, 
Chapter 3, p. 27. 
8.  Association of Clinical Research Professionals, ACRPs White Paper on Future Trends: 
Faster Time to Market, 1998, p.10. 
9.  Hovde, M. and Seskin, R. Selecting U.S. Clinical Investigators, Applied Clinical Trials 
1997: p. 35. 
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10.  Association of Clinical Research Professionals, Sponsor Strategies To Reduce Development

Costs and Cycle Times, ACRP White Paper Part 2, 1997, p. 5. 

Another indication of the inexperience of investigators is that, according to our analysis of the

FDA investigational new drug database, 58 percent of investigators listed in it have only

conducted one trial between 1980-98.

11.  Association of Clinical Research Professionals, Sponsor Strategies To Reduce Development

Costs and Cycle Times, ACRP White Paper Part 2, 1997, p. 8.

12.  Poor enrollment has been blamed for 25 percent of delays in drug development. 

Harper, B and Moench, L. Emerging Patient Recruitment Performance and Cost Metrics in 

PAREXELs Pharmaceutical R&D Statistical Sourcebook, 1998: p. 57.

13.  Nearly 78 percent of clinical trials miss enrollment deadlines established by the sponsors. 

Ibid.

14.  The drug industry estimates that in order to sustain corporate earnings and Wall Street

expectations, [pharmaceutical industry] output must be doubled in order to meet this minimum

hurdle. Moving beyond this requires a tripling of output. 

Association of Clinical Research Professionals, ACRPs White Paper on Future Trends: Faster

Time to Market, 1998, p.5.

15.  DataEdge gives an example of a real case study in which a database with 1.8 million patients

was queried to find the numbers that meet a particular protocols eligibility criteria.  The query

revealed that 9,700 patients had the condition called for in the protocol, yet only 581 met all of

the 18 eligibility criteria (or .03 percent).  See DataEdge, Patient Treatment Data: the Hidden

Key to Faster Studies, pg. 3. [http://www.dataedge.com/La1297.html, accessed Sept. 1999] 

In cancer trials, the largest single reason for the very low proportion of patients who are enrolled

in clinical trials ...is eligibility rather than patient...refusal to enroll. 

Freedman, B. Multicenter Trials and Subject Eligibility: Should Local IRBs Play a Role? IRB

1994;16(1):2. 

16.  Langreth, R. Drug Marketing Drives Many Clinical Trials, The Wall Street Journal, 16

November 1998, A10.

17. Kaitlin, K. Global Drug Development and International Harmonization: the Emergence of

China as a World Pharmaceutical Player, Drug Information Journal 1998; 32: 1187S.

18.  The termination in June 1999 of the Clinical Research and Investigator Services (CRIS)

portion of the University Health System Consortium, a consortium of 35 major academic research

centers, is evidence of academic health centers struggle to compete with non-academic sites. 

CRIS was created to help academic centers compete with other research sites for industry-

sponsored research.  However, according to a recent Centerwatch article, it was determined that

73 
Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX E 
the clinical trials market was too competitive and changing too quickly for UHC to keep pace. 
UHC Closes Its Doors to Clinical Research, Centerwatch 1999;6(8):8. 
19.  A. Miller, Trial Run, American Medical News, 27 September 1999; 42(36):17.  Also,

Harris, S.M. Issues to Consider in Clinical Trial Agreements, American Medical News, 27

March 2000; 43(12):17.

20.  A 1996 survey of 55 investigative sites found that the average research contract dropped

from $50,000 in 1994 to $43,000 in 1996. 

Association of Clinial Research Professionals, Sponsor Strategies To Reduce Development

Costs and Cycle Times, ACRP White Paper Part 2 1997; p. 5. 

Also see AMC Models for Reform, Centerwatch 1997; 4(7):1 and Bonuses to the Rescue,

Centerwatch 1998; (5)11:1.

21.  For each trial, sponsors and investigators may use any combination of the available methods

and the methods are chosen based on the type of trial, the target population, and available

resources. 

22.  According to one recruitment specialist, this method encourages sites to compete with one

another rather than working collaboratively to establish effective recruitment strategies. 

23.  In a survey of 35 sites, the percentage of their contracts that included subject recruitment

bonuses increased from 14 percent in 1996 to 21 percent in 1998.  Bonuses to the Rescue,

Centerwatch 1998; 5(11):1. 

24.  Glass, H.E. Higher Payments to Investigators Dont Speed Study Completion, Applied

Clinical Trials 1995; 4:40-48. Also in Harper, B.S. The Effectiveness of Sponsor/CRO-Site 
Performance Incentives, The Monitor 1997; [http://www.acrpnet.org/monitor/fall97/html/article1.html, 
accessed Nov. 1998]. 
25.  We also heard that sponsors are beginning to analyze prescribing patterns in order to identify 
physicians for a study.  Prescribing patterns can help to identify physicians with a large number of 
patients with a certain ailment and, in turn, areas of market potential (i.e., physicians that are 
prescribing a competitors drug). 
26.  The combined power of a group of independent physicians, and hence patient databases, have 
made site management organizations (SMOs) a new force in the clinical trials arena. 
27.  The reluctance of physicians to refer patients into research trials is problematic not only 
because it can lead to a dearth of subjects, but also because it can be a source of selection bias. 
See Dicker, B. and Kent, D. Physician Consent and Researchers Access to Patients, 
Epidemiology 1990; 1(2): 160-3. 
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Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX E 
28.  The researchers who found referrals a valuable source of subjects were those whose research 
focused on terminal or life-threatening conditions, such as cancer or AIDS, where participation in 
research represented a last chance for treatment.  Physicians were eager to find research 
opportunities for their patients. 
29.  The attractiveness of student volunteers is also due, in large part, to their perceived eagerness 
to participate for financial reimbursement. 
30.  For further discussion, see Getz, K. and Kennon, A.  Surfs Up: An Update on Recruiting 
Subjects via the Internet, Applied Clinical Trials 1998 May; 58-61. 
31.  The National Institutes of Health launched a website [www.clinicaltrials.gov, accessed Apr. 2000] 
containing an online database of clinical trials, sponsored both by the government and private 
industry, in February, 2000.  In addition, Centerwatch.com has recently announced its joint 
venture with americasdoctor.com to post trials.  Drkoop.com formed an alliance with Quintiles, 
one of the leading CROs, to post its trials through the drkoop.com website. 
32.  For example, see: R. Saltus, Sign-up Starts for Trials of Cancer Drug, Boston Globe, 28 
September 1999, p.A1.  and L. Miller, Cancer Victims Flood Phone Lines for Shot at New 
Drug, AP Newswire, 28 September 1999. 
33.  The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research.  (Washington, D.C.: U.S. Government Printing Office, 1978.) DHEW 
Publication No. (OS) 78-0012.  Reprinted in Federal Register 44 (April 18, 1979): 23192. 
34.  Ibid. 
35.  In one report on effective strategies for recruiting subjects, the author outlined this point and 
stated, panelists are eager to participate if they think they may receive a new treatment or 
possibly even a new cure. Shiffer, M. Strategies for Recruiting Research Subjects, Applied 
Clinical Trials 1994;3(5):54-61. 
36.  A marketing group, in an advertisement to sponsors and investigators, offered its services for 
consulting in the advertising development process to help insure that ads are persuasive and 
compelling yet will pass IRB scrutiny. 
37.  One coordinator we spoke with mentioned calling a number she found in a newspaper ad and 
finding that the receptionist mispronounced the inclusion/exclusion criteria. 
38.  The IRB official also told us that his IRB could have taken the position that either the ad 
would be changed or they would not allow the research to be conducted at their site.  However, 
the IRB agreed that it did not want the ad to be the deciding factor over whether or not the 
research took place. 
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Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX E 
39.  The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research.  Washington, D.C.: U.S. Government Printing Office, 1978. DHEW 
Publication No. (OS) 78-0012.  Reprinted in Federal Register 44 (April 18, 1979): 23192. 
40.  For a discussion of these concerns, see:  Isidor, J.M., Kaltman, S.P., Fast Track to Disaster: 
Considerations Raised By Current Techniques for Recruiting Clinical Research Subjects, Food, 
Drug, Cosmetic and Medical Device Law Digest 1998; 15(1): 21-22. 
41.  Department of Health and Human Services, Office of Inspector General, Institutional Review 
Boards: A Time for Reform (OEI-01-97-00193), June 1998. 
42.  The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research.  Washington, D.C.: U.S. Government Printing Office, 1978. DHEW 
Publication No. (OS) 78-0012.  Reprinted in Federal Register 44 (April 18, 1979): 23192. 
43.  Advisory Committee on Human Radiation Experiments, Final Report, (Washington, D.C.: 
U.S. Government Printing Office, 1995). 
44.  This dual role may also be confusing for the physician-investigators; many physicians believe 
they are doing the best for their patients by enrolling them in research.  See Miller, F. et al. 
Professional Integrity in Clinical Research, The Journal of the American Medical Association, 
28 October 1998; 280(16):1449-1454. 
45.  For further discussion of these concerns, see Lind, S. Finders Fees for Research Subjects, 
The New England Journal of Medicine, 19 July 1990; 323(3):192-195. 
46.  There is Federal legislation that highlights concerns in this area, though not specifically 
directed to the clinical research process.  The anti-kickback statute forbids physicians or other 
health care providers from receiving inducements to provide services reimbursable under the 
Federal health programs (i.e., Medicare and Medicaid).  However, though the statute is not 
explicitly directed to clinical research, the statute may become more of an issue if, in the future, 
the Health Care Financing Administration reimburses for clinical research under Medicare as is 
currently under debate. [42 U.S.C. 1320a-7b] 
The Stark I and II laws (Omnibus Budget Reconciliation Act of 1989 (P.L. 101-508) and the 
Omnibus Budget Reconciliation Act of 1993 (P.L. 103-66), respectively), which limit self-referral 
to certain entities, also highlight concerns about the potential impact of financial incentives on 
physicians referring practices.  The statutes are applicable only to certain types of providers (i.e., 
clinical laboratory or imaging services), but are based on observations that physicians with a 
financial stake in a providing entity more often refer their patients for these services than those 
that lack such ownership. 
47.  Box citation:  Westrick, J. Effective Subject Recruitment, Applied Clinical Trials 1997; 
July:41-44. 
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Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX E 
48.  Noble, H. Hailed as a Surgeon General, Koop Criticized on Web Ethics, The New York 
Times, 4 September 1999. 
49.  For further discussion on this topic, see: Dickert, N and Grady, C. Whats the Price of a 
Research Subject? Appropriate Payments for Research Participants, The New England Journal 
of Medicine, 15 July 1999; 341(3):198-203.  and Ackerman, T. An Ethical Framework for the 
Practice of Paying Research Subjects,: IRB 1989; 11(4):1-4. 
50.  Shiffer, M. Strategies for Recruiting Research Subjects, Applied Clinical Trials 1994; 
3(5):54-61. 
51.  Patient-identifiable medical records that are electronically maintained or transmitted would 
fall under the proposed regulations definition of protected health information.  Therefore, the 
proposed rule would establish conditions for researchers access to such medical records to 
identify potential subjects.  Thus, the release of this information to researchers would require 
either prior authorization by the respective patients or documentation of approval by an IRB or 
privacy board, as specified in the proposed regulation. [Standards for Privacy of Individually 
Identifiable Health Information announced in: 64 Fed. Reg. (No. 212), 3 November 1999.] 
The General Accounting Office also identified limitations in the IRB oversight of medical records 
privacy and the Common Rule in its recent report. [U.S. General Accounting Office, Medical 
Record Privacy: Access Needed for Health Research, but Oversight of Privacy Protections Is 
Limited, GAO-HEHS-99-55, February 1999.] 
52.  Concerns about confidentiality are not limited to patients.  A recent highly publicized case 
involved researchers contacting the younger brothers of males convicted through the juvenile 
court system.  Researchers obtained the records, and identities of the offenders, through a review 
of court records and the boys probation officers. 
Institutional Review Boards A System in Jeopardy: Hearing Before the Subcommittee on 
Human Resources of the House Committee on Government Reform and Oversight, 105th Cong., 
June 7, 1998 (statement of B. Timothy Walsh, M.D., Co-Chair, New York Psychiatric Institute 
Institutional Review Board). 
53.  This concern is amplified by the influx of new, and inexperienced, investigators into clinical 
research.  Without experience or training, investigators may not understand the importance of 
eligibility criteria and/or who meets these criteria, not to mention what constitutes a reportable 
adverse event.  These departures from good clinical practice have potential implications for 
human-subject protections as well as data validity and study results. 
54.  Most notable among these are the cases of two Georgia researchers, known as high enrollers 
in the research industry, convicted of fraud in 1998 and a California physician convicted in early 
1999. 
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Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX E 
55.  FDA recently issued regulations requiring clinical investigators to disclose certain financial

conflicts of interests to the FDA.  However, draft guidance for industry states that [recruiting

incentives such as enrollment bonuses] do not meet the definition of compensation that may be

affected by study outcome (which as used in the rule refers to study results) and therefore are not

reportable under the rule. 

See FDA Draft Guidance for Industry [http://www.fda.gov/oc/guidance/financialdis.html, accessed Dec.

1999] announced in: 64 Fed. Reg. (No. 206), 26 October 1999.

56.  National Institutes of Health, Office for Protection from Research Risks, Protecting Human

Research Subjects Institutional Review Board Guidebook, 1993.

57.  Ibid.  The OPRR Guidebook for IRBs includes a discussion of:  concerns relating to dual

patient-subject and physician-investigator roles (p.3-24), finding potential subjects through

databases (pp. 3-35 and 3-36), contacting them through letter and telephone (p.4-20), and

offering free health care to research participants (p. 3-45).

58. Ethics Subcommittee of the American Academy of Neurology, Position Statement: Ethical

Issues in Clinical Research in Neurology, Neurology 1998 March; 50:594.

59.  American College of Emergency Physicians, Policy Statement: Code of Ethics for

Emergency Physicians (June 1997)  and  Policy Statement: Gifts to Emergency Physicians from

the Biomedical Industry (reaffirmed March 1997).

60.  American Academy of Family Physicians, Compendium of AAFP Positions on Selected

Health Issues, Fees, Confidentiality, and Proprietary Practices. [http://www.aafp.org/policy,

accessed Dec. 1999],

American Association of Neurological Surgeons, Code of Ethics, American College of Physicians,

Annals of Internal Medicine Position Paper-- Ethics Manual, 4th edition, April 1999.

[http://www.acponline.org/journals/annals/01apr98/ethicman.html, accessed Dec. 1999], 

American Medical Association, Current Opinions of the Council on Ethical and Judicial Affairs,

A-99 Edition, American Psychiatric Association, The Principles of Medical Ethics with

Annotations Especially Applicable to Psychiatry (and Addendums), 1998 Edition, American

Society of Anesthesiologists, Guidelines for the Ethical Practice of Anesthesiology, amended

October 1997. [http://www.asahq.org/standards/10.html, accessed Dec. 1999].

61.  FDA Office of Regulatory Affairs, Guidance for Industry: Guideline for the Monitoring of

Clinical Investigations, Jan. 1988, p. 3.  See [http://www.fda.gov/ora/compliance_ref/bimo/clinguid.html,

accessed Dec. 1999].

62.  21 CFR  312.52. 

63.  This phenomenon has also been cited in the literature.  A legal compliance officer for a

pharmaceutical company stated, ...While few people wish to acknowledge it, [monitors] and

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Recruiting Subjects in Industry-Sponsored Research  OEI-01-97-00195  APPENDIX E 
auditors sometimes are placed in the awkward position of reporting on non-compliance by 
important and influential investigators, which can put a company in the uncomfortable position of 
having to confront the alleged offender, who may be a very important customer.  Thus, there can 
be a tendency either to rationalize why these issues are not signs of non-compliance or to 
encourage the [monitors] or auditors to downplay the significance of their original findings. 
Whitelaw, S.B. Evaluating IRBs and their Roles, Food, Drug, Cosmetic and Medical Device 
Law Digest, 1999;16:20. 
64.  Food and Drug Administration, FDA Inspections of Clinical Investigators,  FDA 
Information Sheets, September 1998. 
65.  Food and Drug Administration, FDA Institutional Review Board Inspections, FDA 
Information Sheets, September 1998. 
66. This number is an estimate.  Because IRBs are currently not required to register with FDA, no 
one, including FDA, knows the exact number of IRBs in this country. 
67.  According to FDA officials, FDA lacks the authority to inspect foreign IRBs.  Even if FDA 
had the authority to inspect these foreign entities, their enforcement ability is limited. 
68.  Similar language is used in both FDA and overall HHS regulation (see, 21 CFR  50.20 and 
45 CFR  46.116, respectively). 
69.  A recently convened forum of medical and health Internet sites met to discuss appropriate 
ethical guidelines for their sites around such issues as privacy, content, and sponsorship. 
Chin, T. Health Sites to Develop Ethics Guidelines, American Medical News, 8 November 
1999; 42(42):1. 
70. The Information Sheets are currently being revised.  Additional recruitment guidelines may 
appear in them. 
71.  A call for increased representation of independent members corresponds with OPRRs 
recommendations to one institution following an investigation in which OPRR cited the institution 
for inadequate review of recruiting practices. 
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