Comments on the Department of Health and Human Services' Inspector General's Study on Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research (HRG Publication #1523)
HHS Inspector General's Study Recruiting Human Subjects:
Comments by Sidney M. Wolfe, M.D. and Peter Lurie, M.D., M.P.H.
Somewhat buried in the middle of this highly disturbing report, the authors mention "the transformation of clinical research into a traditional business model." As a result of the shift to this business mindset, the often highly unethical and possibly illegal recruitment practices documented in the Report appear to be increasing rapidly. The rise of separate (from the drug companies themselves) for-profit Human Experimentation Corporations (HECs), a more accurate name for the more benign-sounding name currently in use--Contract Research Organizations (CROs)--has introduced new techniques for rapidly recruiting patients. When combined with the appallingly inadequate Federal regulation of human experimentation in general, and recruitment practices in particular, and the failure (as usual) of the medical profession to police itself, the risk of abuse of patients increases dramatically.
This Report is the first attempt to thoroughly address the issues involved in the recruitment of patients to clinical trials. Most previous writing has been terribly non-specific; this Report is the best available on current practices in this area. However, as good as the Report is in description, it remains weak in prescription. We advocate a much stronger set of recommendations than is provided by the Inspector General's Report; in particular, we advocate promulgating strong new regulations based, in part, on models that are being successfully employed in various settings and which are described in the Report. (See last paragraph of our comments)
More drugs are in clinical trials now than even a few years ago. In addition, many therapeutic categories of drugs, such as those for hypertension, are becoming saturated with drugs, leading to increased competition. More human subjects are therefore needed and the competition to get them approved quickly and beat the competitor drug to the market has intensified. For some drugs, one month earlier to market can mean tens of millions of dollars in additional revenue before the drug is challenged by a generic. Speed and efficiency, from the drug industry's perspective, favor the privatization of human experimentation, moving research away from the academic medical centers where it has traditionally resided. Whereas in 1993, only 20% of pharmaceutical company research was done in the private, for-profit research setting, the fraction has gone up 2 ½ times and by 1998, 50% was being done outside of academic medical centers. The number of private practice-based investigators has grown from 3,153 in 1990 to 11,588 in 1995, an increase of almost four-fold.
According to Richard Friedman of Cornell University in the British journal, the Lancet, "In the USA, monetary incentives have spawned a whole industry of private physicians who don't necessarily have any experience in research or with protocols in the specialty areas in which they're testing." These private entities "push patients through trial after trial", with little concern for what happens to them afterwards. The result is "stop-gap" medicine for vulnerable patients who can't afford treatment any other way, he says. A recent article in the New York Times documents how, with 43 million Americans uninsured, many are forced to turn to a series of research studies to remain treated. This invites exploitation.
The Growth of International Research
Drug companies can increase the likelihood of a drug's success by using exclusion criteria to, as one investigator told the Inspector General's office, "enrich trials with patients who are most likely to benefit." One way to accomplish this is to exclude patients who are currently on medication to treat their condition or even those who have been on medication in the past. Such patients are known in the industry by the double entendre "naive" subjects. These prized subjects are hard to locate but, according to the Report, can often be found among the uninsured or in foreign countries. Many researchers told the Inspector General's staff that drug companies are increasingly looking abroad for such subjects. One advertisement, in this case directed toward possible drug industry customers by the world's largest HEC, North Carolina-based Quintiles--with offices all over the world--promised that they can "even help you tap the vast drug-naive patient populations of China, Korea and other emerging markets."
The Report points out that the number of new foreign investigators in the FDA's database grew from 988 in the 1990-1992 period to 5,380 in the 1996-1998 period. Aside from easier access to drug-naive patients, the costs for foreign studies are often less than in the United States. Despite this, the FDA only conducted 60 drug investigator inspections abroad in 1998 and, according to the Report, the FDA does not normally inspect foreign Institutional Review Boards (IRBs).
While the Report makes clear that there is increasing internationalization of research, it fails to state that there are ongoing efforts by the research industry to water down the existing international ethics documents to facilitate some of the practices the Report finds troubling. The current version of the Declaration of Helsinki states that, if the patient has a dependent relationship with the investigator, "the informed consent should be obtained by a physician who is not engaged in the investigation and who is completely independent of this official relationship." (It is noteworthy, as the Report documents, how widely this international ethics document is ignored.) Some have proposed that this language be replaced by the following: "In some cases of this type, it may be preferable if the informed consent were to be obtained by a qualified person who is not engaged in the investigation, independent of the dependent relationship, or both." This is precisely the wrong direction for changes in ethical practice at a time when pressures to recruit are increasing.
Recruitment Method Concerns
The four main categories of findings in the Report which we believe demand action are:
Because human experimentation has been transformed to a "business model", this newly emerging "business" of experimenting on people has every imaginable incentive for fast recruitment and fast results. A bonus of $30,000 after recruiting the first six patients and a bonus of $6000 per additional patient captures the "competitive enrollment" which, according to the Report, "encourages aggressive recruiting."
Targeting Own Patients
In concordance with a New York Times investigation documenting doctors getting paid as much as several thousand dollars per patient to recruit patients from their own practices, the policy of recruitment by physicians of patients from their own practices is further documented in the Report. The vulnerability of a doctor's own patients to be persuaded to become an experimental research subject because of their trust in their doctor, combined with signing bonuses which the doctor pockets for the referral sets up a toxic situation where some doctors are literally selling their own patients into human experiments. In a gross commercialization of this practice, one large family practice group advertised its "computerized patient data base of 40,000 patients" to HECs and others running clinical trials as one from which "We can actively recruit patients for any study..."
Seeking Additional Patient Bases
In addition to plumbing their own files for potential experimental subjects, some researchers pay "finder's fees" to other doctors who do not even conduct the research: "Occasionally, investigators offer fees to encourage referrals from other physicians or nurses," such as an offer of $75 to physicians or nurses for each subject referred, according to the Report. The use of patients reached through patient advocacy groups, also described in the Report, similarly has the taint of using a relationship of trust to recruit patients who might otherwise not be interested in participation in such experiments.
Advertising and Promotion
The "new industry of patient recruitment firms and research marketing companies" has produced, according to the Report, more advertising for human subjects than in the past. Until public criticism changed this practice, the website DrKOOP.com was using the formerly good name of this medical huckster to recruit patients, for a finder's fee, to the multinational HEC Quintiles.
Erosion of Informed Consent
The Report expresses serious concern about the way the business model of research, as manifested through the practices described above, might erode the essential elements of informed consent.
Information: The Report describes misleading advertisements which blurred the distinction between treatment and research, an excessive focus on monetary or other compensation which can become coercive and the lack of response by drug sponsors to concerns raised by IRBs in the less-than-frequent instances in which the IRBs actually review the advertisements.
Comprehension: The failure to conduct research on or to audit the extent that the patient actually understands the recruitment materials and the informed consent forms is of concern. According to the report, the performance of the physician/investigator in fully informing patients may be compromised by bonuses for more patients recruited and by promises of top authorship on papers emanating from the research tied to recruiting success.
Voluntariness: One medical journal article concerning effective human subject recruitment strategies noted that "Done correctly, [media] publicity can look like an endorsement by your well-respected newspaper reporter or TV news anchor. It can be an excellent way to generate phone calls needed to fill studies." This part of the Report reiterates the concerns about doctors recruiting patients from their own practices and states that "patients see their doctor as God" because of the trust they place in them.
While the Inspector General's Report makes clear that there is little in the way of guidelines or regulations to prevent the kinds of abuses the Report documents, it does contain a number of examples of innovative approaches that the Report should endorse, rather than merely mention. These fall into the categories of recruitment incentives, the dual physician-investigator role and confidentiality of medical records. Unfortunately, the Report merely identifies four questions that need to be addressed (page 31 of the current draft), rather than recommending the answers that the Report's evidence would seem to require and which these models prove is feasible.
Several groups (University of Rochester IRB, Partners HealthCare System) have banned the use of bonus payments designed to encourage patient recruitment, while Partners HealthCare System and the American Medical Association also ban fees for referring patients to other investigators, HECs or drug companies. We strongly endorse these initiatives. We believe that physicians have a right to reasonable reimbursement for any costs incurred or time spent beyond what they would ordinarily expend in the care of the patient, but no more. We agree in general with efforts to increase disclosure of potentially conflicting interests to patients. But we are opposed to using disclosure of such interests as a substitute for banning the more egregious of these incentives.
Disclosure has also been the preferred approach (when any approach is put forth) by universities (University of California at Los Angeles) to the problem of the dual physician-investigator role. However, some groups have stated that, at least in some circumstances, the preferred approach is to have a more neutral intermediary, without the conflict of interest of the investigator approaching the patient. We believe that this approach should be more the norm than the exception. As is almost always the case, the preferred method for resolving potential conflicts of interest is to involve neutral third parties.
Finally, the Report makes clear how little work has been done, particularly by medical associations, in addressing the problem of researchers using databases that include patients cared for by another health care provider to recruit study participants. This is an improper invasion of privacy and is precluded by some IRBs (Medical College of Ohio, University of California Los Angeles, Partners HealthCare System). All IRBs should follow this model.
In sum, the Report has clearly identified a wide range of relatively new threats to patients in clinical research studies. Furthermore, this burgeoning field is largely unregulated. Even when the IRBs have particular authority, they appear unwilling or unable to exercise their authority. And some of the Report's solutions are to give more authority to IRBs, which the Inspector General's previous reports have already documented are hopelessly overworked. The following are appropriate subjects for regulation: banning finder's fees; banning reimbursement to physicians beyond research-related expenses and time expended; mandatory disclosure to the potential participant of the source and amount of all recruitment fees; and restrictions on the ability of health care providers other than the patient's physician from gaining access to a patient's medical records for the purpose of recruitment. In the absence of regulation, therefore, sponsors will be able to choose the route least protective of patients' rights in their quest to maximize recruitment--the ethical "race to the bottom" of which the Report warns and which has characterized much of globalization to date.
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