Department of Health and Human Services 

OFFICE OF 

INSPECTOR GENERAL 

JUNE GIBBS BROWN 

Inspector General 

JUNE 2000 

OEI-01-97-00195 

Recruiting Human Subjects 

Pressures in Industry-Sponsored Clinical Research 
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 
EXECUTIVE SUMMARY 

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 humansubject 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. 

Recruiting Subjects in Industry-Sponsored Research 1 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 industrysponsored 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 FDA’s database 

of IRBs and investigators involved in investigational new drug research; a review of 

FDA’s 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. 

Recruiting Subjects in Industry-Sponsored Research 2 OEI-01-97-00195 
Compromise of Confidentiality. Many people raised concerns about someone other 

than the patient’s 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 Secretary’s 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. 

Recruiting Subjects in Industry-Sponsored Research 3 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 humansubject 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 humansubject 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. 

Recruiting Subjects in Industry-Sponsored Research 4 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 Citizen’s 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 IRB’s 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 

Recruiting Subjects in Industry-Sponsored Research 5 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. 

Recruiting Subjects in Industry-Sponsored Research 6 OEI-01-97-00195 
TABLE OF CONTENTS 

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

Recruiting Subjects in Industry-Sponsored Research 7 OEI-01-97-00195 
INTRODUCTION 

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. 

Recruiting Subjects in Industry-Sponsored Research 8 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 FDA’s and 

OPRR’s oversight processes. Our focus on industry-sponsored clinical research would 

normally lead to an examination of FDA’s oversight of subject recruitment. However, 

OPRR’s 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. 

Recruiting Subjects in Industry-Sponsored Research 9 OEI-01-97-00195 
Methodology 

We surveyed a random sample of IRBs; reviewed FDA and OPRR processes; analyzed 

FDA’s 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 FDA’s 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 President’s Council on Integrity and Efficiency. 

Recruiting Subjects in Industry-Sponsored Research 10 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. 

Recruiting Subjects in Industry-Sponsored Research 11 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 

Pressure for 

Quick 

Turnaround 

Times 

Higher drug development costs. The cost of developing new drugs is growing 

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 

Pharmaceutical companies claim that they need to constantly increase the percentage 

of their expenditures allocated to research and development in order to remain 

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. As 4 

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 

Search for 

Human Subjects 

More drugs in development. Pharmaceutical companies are developing more drugs 

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 

More subjects needed for each trial. In addition, clinical trials are becoming more 

complex and are requiring far more subjects per trial than before. An average of 6 

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. Sponsors are struggling to meet 7 

this increasing need for human subjects. 

Quest for More 

Efficient 

Research Sites 

Commercial research shifting to private settings. Pharmaceutical companies are 

seeking the quickest, most efficient settings to conduct their clinical trials. 

Increasingly, they are shifting out of the academic medical centers (AMCs). 

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 privatepractice based investigators increased from 3,513 in 1990 to 11,588 in 1995. This 9 

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 

Recruiting Subjects in Industry-Sponsored Research 12 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 11⁄2 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 one—rapid enrollment. Number two—rapid enrollment. Number three—rapid 

enrollment.” Virtually every investigator mentioned that a site’s 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 

Recruiting Subjects in Industry-Sponsored Research 13 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 don’t 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 

Recruiting Subjects in Industry-Sponsored Research 14 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 marketdriven research environment, where one’s ability to enroll adequate numbers quickly is 

crucial to one’s competitiveness, poor enrollment on a trial could ruin a site’s chance for 

future participation in trials. 

Recruiting Subjects in Industry-Sponsored Research 15 OEI-01-97-00195 
FINDINGS 

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 

Strategy 

Examples of 

Methods 

Brief Description 

Offering 

Incentives 

Financial 

Incentives 

< offering an additional payment per subject enrolled above 

the study budget; seen most often as an enrollment deadline 

nears and additional subjects are still needed 

Nonfinancial 

Incentives 

< items include office equipment, educational stipends, and 

authorship on journal articles presenting research results 

Competitive 

Enrollment 

< organizing trials so sites in a multi-center trial compete to 

fill available subject slots on a first-come, first-serve basis 

Targeting Own 

Patients 

Referring Own 

Patients to Trial 

< identifying eligible patients when they come in for 

appointments or through chart reviews 

Seeking 

Additional Patient 

Bases 

Referrals from 

Other Physicians 

< sending information about ongoing research to other local 

physicians, asking for referrals, and occasionally offering 

fees to induce referrals 

Dissemination of 

Information to 

Relevant Groups 

< distributing trial information to appropriate disease advocacy 

groups or student groups, perhaps by giving lectures or 

presentations to such groups 

Advertising and 

Promotion 

Media Ads < describing the trial, including study requirements, eligibility 

criteria, and a contact for more information; can be found in 

newspapers, on radio, television, or on Internet sites 

Press Releases / 

News Segments 

< compiling trial information in the form of a press release for 

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 

Recruiting Subjects in Industry-Sponsored Research 16 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, “we’ll 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. 

Recruiting Subjects in Industry-Sponsored Research 17 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 one’s 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 

to eligible patients is key. Sponsors 

seek out investigators and sites with 

large patient populations when 

looking to place trials.25 

Investigators recognize this and, in 

turn, have begun to advertise their 

large patient bases. Such 

advertisements are numerous and 

prominent, particularly on the 

Internet, as investigators reach out to 

sponsors to place a trial with them 

(see box).26 

Seeking Additional Patient Bases 

Looking for Trials! 

We are a large family practice office with 4 physicians 

and 3 Physician Assistants. We have two full time 

coordinators and a computerized patient data base of 

40,000 patients....We are looking for Phase 2-Phase 4 

trials as well as postmarketing studies. We can 

actively recruit patients for any study that can be 

conducted in the Family Practice setting. 

An Internet advertisement directed to sponsors 

by a private practice seeking research 

opportunities. 

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 

Recruiting Subjects in Industry-Sponsored Research 18 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 trial’s 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. 

Recruiting Subjects in Industry-Sponsored Research 19 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. 

Recruiting Subjects in Industry-Sponsored Research 20 OEI-01-97-00195 
 IRB officials, 

investigators, and Therapeutic Misconception? 

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 subject’s 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

ad and raise questions, many Research for Money?

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. 

Recruiting Subjects in Industry-Sponsored Research 21 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 subject’s 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 trial’s 

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 physicianinvestigators might infringe upon this voluntariness; concerns worthy of particular 

attention as we found that investigators often enroll many of their own patients into their 

Recruiting Subjects in Industry-Sponsored Research 22 OEI-01-97-00195 
trials. Patients may be reluctant to contradict their doctor’s 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 people’s “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 site’s name and number, but did not reveal that he was a site

representative.

Recruiting Subjects in Industry-Sponsored Research 23 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 patient’s 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 

these records may be used to contact 

them about participating in research. 

Many involved in clinical research 

believe that patients ought to know 

who has access to their records and to 

which records. The Secretary of 

HHS recently proposed regulations 

regarding privacy of medical records 

that may have implications for this 

recruitment practice.51 

Physician databases are not the only 

“At present, this group includes 9 cardiologists, 8 

cardiovascular surgeons, 3 electrophysiologists, 7 

nephrologists, 3 pulmonologists, as well as 7 primary 

care physicians. This gives XXX Research access to 

a patient base of over 100,000. Approximately 16,000 

of these patients are already in a computerized 

database, which allows for rapid recruitment.” 

“Access to our vast patient database enables us to send 

direct mail pieces to prospective patients.... Patients 

are listed according to ICD-9 codes for easy access.” 

From site advertisements to sponsors 

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 State’s 

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, 

Recruiting Subjects in Industry-Sponsored Research 24 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 wouldn’t guarantee what you’d 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 drug’s 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 

Recruiting Subjects in Industry-Sponsored Research 25 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 sponsorinvestigator 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, OEI01-97-00196), even though more stringent reviews may put these IRBs at a competitive 

disadvantage because the reviews take longer. 

Recruiting Subjects in Industry-Sponsored Research 26 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 

Strategy 

Method Clearly Have 

the Authority 

Are Uncertain 

of Authority 

Clearly Don’t 

Have the 

Authority 

Offering 

Incentives 

Authorship incentives 24% 42% 34% 

Financial incentives to 

investigators 

43% 32% 26% 

Targeting One’s 

Own Patients 

Review of investigators’ 

own patient databases 

60% 16% 24% 

Seeking 

Additional 

Patient Bases 

Review of other physicians’ 

databases to identify/ 

contact eligible subjects 

66% 17% 17% 

Referral fees 65% 25% 10% 

Advertising and 

Promotion 

Print ads 96% 3% 1% 

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. 

Recruiting Subjects in Industry-Sponsored Research 27 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 Agency’s 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 subject’s 

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 

Recruiting Subjects in Industry-Sponsored Research 28 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 site’s 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 

Recruiting Subjects in Industry-Sponsored Research 29 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 FDA’s inspection process for clinical 

investigators revealed that the FDA’s main focus is on the former, ensuring the integrity of 

data submitted to the Agency. 

The FDA’s 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 FDA’s 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 

site’s 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 OPRR’s 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 OPRR’s recent inspections, OPRR faulted the IRB for inadequate review of a 

protocol’s 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. 

Recruiting Subjects in Industry-Sponsored Research 30 OEI-01-97-00195 
RECOMMENDATIONS 

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 humansubject 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). 

Recruiting Subjects in Industry-Sponsored Research 31 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. 

Recruiting Subjects in Industry-Sponsored Research 32 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. 

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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 humansubject 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 

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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 FDA’s 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 FDA’s 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. 

Recruiting Subjects in Industry-Sponsored Research 35 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 Citizen’s 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. 

Recruiting Subjects in Industry-Sponsored Research 36 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 office’s 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 IRB’s 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. 

Recruiting Subjects in Industry-Sponsored Research 37 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. 

Recruiting Subjects in Industry-Sponsored Research 38 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 office’s 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 staff’s 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. 

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APPENDIX A 

Analysis of Data in IND Database 

We analyzed the FDA Center for Drug Evaluation and Research’s 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. 

Recruiting Subjects in Industry-Sponsored Research 40 OEI-01-97-00195 
APPENDIX B 

FDA Information Sheets

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APPENDIX B 

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APPENDIX B 

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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 

Incentives l 

Dua 

Role 

Confidential 

Records 

Other 

Guidance 

Referral fees 

financial arrangements Disclosure to subjects of 

Compensation to investigators 

for conducting clinical trial 

Dual investigator-physician role 

potential subjects for identifying /contacting Use of medical records 

payment to subjects Advertisement/ 

News briefs 

sources of guidance Also defers to other 

American Academy of Allergy, 

Asthma and Immunology 

American Academy of Family 

Physicians 

k k

American Academy of 

Neurology 

U

American Academy of 

Ophthalmology 

k k

American Academy of 

Orthopaedic Surgeons 

k U AMA Code 

of Ethics 

American Academy of 

Pediatrics 

U U

American Academy of 

Physical Medicine and 

Rehabilitation 

k Nuremberg 

laws 

American Association of 

Neurological Surgeons 

k

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APPENDIX C 

Professional Association Associations’ Guidelines or Codes of Ethics 

Incentives l 

Dua 

Role 

Confidential 

Records 

Other 

Guidance 

Referral fees 

financial arrangements Disclosure to subjects of 

Compensation to investigators 

for conducting clinical trial 

Dual investigator-physician role 

potential subjects for identifying /contacting Use of medical records 

payment to subjects Advertisement/ 

News briefs 

sources of guidance Also defers to other 

American College of 

Emergency Physicians 

k U Declaration 

of Helsinki 

American College of 

Obstetricians and 

Gynecologists 

k

American College of 

Physicians 

U k U k U

American College of 

Radiology 

k

American College of Surgeons k k

American Geriatrics Society 

American Medical Association U k U

American Women’s Medical 

Association 

American Pharmaceutical 

Association 

American Psychiatric 

Association 

k U k AMA Code 

of Ethics 

American Society of 

Anesthesiologists 

k AMA Code 

of Ethics 

American Society of Plastic 

and Reconstructive Surgeons 

k k

National Medical Association 

Recruiting Subjects in Industry-Sponsored Research 45 OEI-01-97-00195 
APPENDIX D 

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 Citizen’s 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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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX D 

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APPENDIX E 

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, ACRP’s 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 PAREXEL’s

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 sponsor’s 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, ACRP’s 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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APPENDIX E 

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 

PAREXEL’s 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, ACRP’s 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 protocol’s 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 industrysponsored research. However, according to a recent Centerwatch article, “it was determined that

Recruiting Subjects in Industry-Sponsored Research 73 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 Don’t 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 competitor’s 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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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. “Surf’s 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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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. “Finder’s 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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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. “What’s 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 regulation’s 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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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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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 OPRR’s 

recommendations to one institution following an investigation in which OPRR cited the institution 

for inadequate review of recruiting practices. 

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