Ethics case study

When are industry-sponsored trials a good match for community doctors?

From the March 2001 ACP-ASIM Observer, copyright © 2001 by the American College of
Physicians-American Society of Internal Medicine.
This is the 26th in a series of case studies with commentaries by ACP-ASIM's Ethics and Human
Rights Committee and Center for Ethics and Professionalism. The series uses hypothetical
examples to elaborate on controversial or subtle aspects of issues not addressed in detail in the
College's "Ethics Manual" or other position statements.
Case history
Drs. Smith and Jones, senior partners of Internal Medicine Associates, have never before done
office-based industry-sponsored drug research. Recently, Dr. Brown from DrugCo invited them to
serve as co-investigators in a randomized double-blind clinical trial of a new medication to treat
type two diabetes. It is the last trial DrugCo needs to complete before applying for FDA review
and approval of the drug.
Rather than going to University Hospital's Institutional Review Board, DrugCo has arranged for a
contract research organization (CRO) to manage the whole trial, including institutional review
board (IRB) review, study design, data analysis, article preparation and FDA applications.
Subjects who enroll will be randomly selected to receive either one or two doses of the new drug
or a placebo for six months. The prospect that some of his patients will get the placebo—not
treatment—for that length of time concerns Dr. Smith. Subjects cannot take any other oral drugs
for diabetes.
DrugCo will pay the doctors $3,000 per enrolled subject and will pay for all study-related care. In
addition, if Drs. Smith and Jones enroll 10 subjects in three months, they will receive an additional
$5,000. (Dr. Jones is a bit surprised by the level of these fees and worries about the practice
becoming dependent on this kind of income.) Finally, a number of papers will be published from
the study and Drs. Smith and Jones are welcome to participate as co-authors.
After taking courses in evidence-based medicine and putting their practice database online, Drs.
Smith and Jones are definitely interested in office-based clinical research. They serve an urban
population that includes many chronically ill, elderly and low-income patients. They believe that
better data is needed to substantiate best practices for this population.
Moreover, the trial is attractive because it promises free medication, and so many of their patients
have been hard hit by drug costs. But they want to think through the ramifications before going
forward.

Commentary
Drs. Smith and Jones are carefully considering participating in a study in order to advance sound,
clinic-based effectiveness research. A decision to participate could affect them, their patients,
their patient-physician relationships and their practice.
Physicians who do research involving their patients have a dual role and must be aware of
potential conflicts between what is best for the patient-subject and what is optimal for the conduct
of the research. However, the lines between clinician and researcher can become fuzzy, as can
the lines between patient and subject (1, 2).
Nevertheless, physician-investigators must consider their role as physicians first, and as
investigators second, and they should ensure that research they participate in is ethically
conducted (3). Therefore, as they consider this opportunity, Drs. Smith and Jones should
evaluate the validity and value of the research, the ethical and scientific review that it has
undergone, and compensation and authorship issues. We discuss each of these below.
• Validity. Drs. Smith and Jones’ first consideration should be the study’s validity. A study
is scientifically valid if it answers the questions that it asks (4).
 The study in question would be considered valid if it has a large enough universe of
subjects to provide statistically significant results, and if the intervention and
measurement techniques are sufficient to settle a research hypothesis. For instance, the
goal of the study could be to prove that the new medication is more effective than another
similar product.
Validity is a threshold requirement for all research, because it is unethical to expose
human subjects to risks in studies that peer reviewers agree cannot adequately answer a
research question (5). Because of this peer-review element, assessing the study’s validity
might be beyond the scope of what Drs. Smith and Jones can answer independently.
If the study were funded by the NIH or another institution that requires careful peer
review, Drs. Smith and Jones could rely on this process as an assessment of validity. But
the study they are considering is privately funded, with no such process of external
review. However, they might look at the reputations of the study’s investigators and
advisory panel. If they are still unsure of the study’s scientific quality, they could seek
permission to send the protocol for informal, independent review.
To find a reviewer, they can contact medical schools, which may be able to recommend a
faculty member with relevant experience. If serious questions arise about the study’s
validity, further considerations are irrelevant. Drs. Smith and Jones should not participate.
• Value.If they believe the study meets initial validity criteria, they should next carefully
consider the study’s value. A study’s scientific value is based on the relevance or
importance of its results (4). Good research is designed to produce knowledge that
ultimately proves “important”(6), “fruitful”(7) or “valuable”(8). Unlike assessments of
validity, judging value does not yield a yes or no answer, but a ranking on a continuum.
A useful test for Drs. Smith and Jones might be to ask whether a study’s results have the
potential to change their practice immediately or in the future. If the study seeks
determine whether a new medication is superior to an existing one, for example, it may
offer considerable value. On the other hand, if DrugCo is seeking to simply obtain
approval for a “me-too” medication that offers no advantages over currently available
therapies, its value is suspect.
A study’s value also depends upon who will benefit from the results. Drs. Smith and
Jones believe their patients lack the resources to pay for medications. Therefore, it
seems likely that they will also be unable to afford the study medication if and when it is
approved. The study’s value may not apply to them.
A lack of value, unlike a lack of validity, should not necessarily cause Drs. Smith and
Jones to reject the study. However, they should view it with muted enthusiasm.
• Ethical review. Drs. Smith and Jones should next consider carefully the processes of
ethical review that the study has undergone. At a minimum, most research carried out in
the United States must go through review by an interdisciplinary IRB or meet stringent
criteria for exemption from review (6). IRBs evaluate several aspects of a proposed
study, including its risks, benefits, consent process, confidentiality issues, recruitment
practices and the importance of the knowledge to be gained (6).
If an institution has an IRB, as University Hospital likely does, that IRB should review the
protocol. Indeed, if University Hospital accepts federal money for research, it is required
to adhere to regulations governing the conduct of research, including IRB review (6).
Local review is important because a committee whose members are drawn from the
institution and the community are best prepared to assess a study’s risks and benefit in
light of the unique needs and concerns of that institution’s patient population.
For all of these reasons, Drs. Smith and Jones should make sure that the protocol is
reviewed by their hospital’s IRB. “All proposed clinical research, regardless of the source
of support, should be approved by the local IRB to assure that the research plans are
reasonable and that the research participants are adequately protected”(3).
 If clinicians are not affiliated with an institution that has an IRB, they must rely on the IRB
affiliated with the CRO to provide ethical oversight. To expedite trials, industry has
increasingly used CROs and site-management organizations, rather than academic
medical centers. In fact, industry funding for trials in academic centers fell from 80% in
1991 to 40% in 1998 (9).
Although this CRO-based review process should be objective, it lacks understanding of
the local patient population required for adequate review. An outside IRB may not
scrutinize studies as carefully as a local IRB, which needs to maintain community
relations and patient trust. Therefore, clinicians who participate in research should be
aware that they will have to take on the role of the local IRB to some degree, particularly
by ensuring that the consent information is appropriate for their patients. Clinicians
without access to an IRB may wish to contract with a nearby academic medical center
IRB that may be willing to review protocols for a fee which could then be billed to the
CRO.
• Compensation. Drs. Smith and Jones should also seek advice from local or distant IRBs
regarding their other concerns, particularly the compensation they have been offered. A
reasonable rule of thumb is that payments should be commensurate with the time and
effort spent and the expenses incurred in recruitment. Compensation above this level is
pure profit, and constitutes—or could be perceived to constitute—a conflict of interest.
Providing finder’s fees to individual physicians for referring patient to a study “generates
an unethical conflict of interest” (3). Drs. Smith and Jones should refuse the offer of a
bonus for active recruitment.
This recommendation reflects commonly accepted standards for referrals in clinical care.
For instance, if a laboratory approached Drs. Smith and Jones and offered them
payments for each patient they referred, they would no doubt refuse, citing guidelines
about improper business relationships and fee-splitting (3, 10, 11, 12). The same is true
for this study.
• Drs. Smith and Jones should seek advice from the IRB about the added expenses of trial
recruitment and follow up (which may be substantial) and for advice about proper
compensation. Not all IRBs consider recruitment practices and incentives to be within the
scope of their review (13). Some do; some specify what is permissible and what is not;
and some require investigators to disclose any potential conflicts of interest (1).
• Placebo controls. Another big concern Drs. Smith and Jones might have about the
study is the use of placebo controls. The World Medical Association Declaration of
Helsinki on Ethical Principles for Medical Research Involving Human Subjects exhorts
researchers to test against the “best current prophylactic, diagnostic and therapeutic
methods” and to use placebo or no treatment only in studies where no proven method
exists (14). Human subject research advocates see this principle as a way to protect
subjects’ welfare, especially for research done in developing countries.
Those who support the wider use of placebo-controlled trials cite the scientific necessity
of such studies in certain circumstances. They contend that, as long as alternatives are
fully disclosed, the ethical appropriateness of placebos should be determined based on
whether the subject will be harmed by deferring therapy (15, 16).
• Authorship. This study raises other concerns beyond the purview of most IRBs, such as
the CRO’s offer of authorship opportunities. Although it is not, strictly speaking, an issue
of research ethics, this offer involves broader issues of professionalism and scientific
propriety.
In general, subject recruitment alone does not warrant authorship. Instead, authorship
requires involvement in developing a study’s conception and design, analyzing and
interpreting results, drafting or revising the article’s intellectual content, and approving the
final version (17).
 Drs. Smith and Jones have not been involved in conception and design. Unless they are
invited and agree to participate in interpreting and reporting the study results, their level
of participation is unlikely to warrant authorship in many medical journals.

Making a decision
The ethical conduct of research, like the scientific conduct of research, requires careful
consideration, planning and attention to detail. Clinicians who are interested in contributing to
research should spend some time learning about the responsible conduct of research, perhaps
through courses now required by the NIH at most academic medical centers. Clinicians should
also identify resources like IRBs, ethics centers and experienced investigators that can advise
them.
Acknowledgements: The Ethics and Human Rights Committee would like to thank David
Cassarett, MD, Lois Snyder, JD, and Jason Karlawish, ACP-ASIM Member, authors of the case
history and commentary.

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