The ethics of “seeding trials”
A recent story from The Calgary Herald has raised concerns over the payments to physicians who enroll their patients in a CIHR and pharma-funded trial being conducted in Quebec on first-time statin users.
For their $100, doctors must write the prescription, ensure their patients have never taken the drug before, and have them fill out a consent form, which the physicians fax back. The research team contacts the patients and has them respond to questionnaires over the three years of the study.
Researchers usually ask physicians for permission to enrol existing patients in their trials, not start them anew on a drug, said Dr. Colin Rose, a Montreal cardiologist and longtime statin skeptic.
There is justification for the OBSTAT study from a clinical perspective. Statins are well documented for secondary prevention in those with diagnosed cardiovascular disease but their efffectiveness as a primary preventative measure in persons with high cholesterol levels who don’t yet have a diagnosis of heart disease (i.e. first-time users) is less clear. Add to that a reported high incidence of these first-time users who stop taking their statins before a therapeutic effect can be noted.
But the way that this study is being carried out and the method by which physicians are being reimbursed is problematic, suggesting that the motives for the trial are related to marketing instead of advancing therapy. In fact, it looks an awful lot like a “seeding trial” in which marketing is basically disguised as research. Seeding trials are frequently used in industry in order to introduce new consumer products like Post-it notes and household cleaners (through interventions described as “testing”) but in a medical context, the use of seeding trials raises particularly serious ethical concerns.
There are three things that are worrisome about the $100 compensation to physicians. First, and most obviously, physicians are being paid to simply write a prescription for a first-time statin user, get the patient to sign the consent and then fax it to the research group. The physicians aren’t responsible, necessarily, for any follow-up from a research perspective (certainly they need to be responsible from a clinician perspective as statins can have serious side effects). Second, the payments to physicians are all covered by the Astra Zeneca and Pfizer funding portion of the trial, not the CIHR funding. CIHR will not provide funding for physician compensation, although it appears that they will certainly permit it in a CIHR-funded trial as long as the compensation funds come from somewhere else. Finally, the payments to physicians were originally 50$ but due to “lack of interest”, the payments were raised. This increase in compensation with an explicit goal of raising interest is highly problematic.
In a seeding trial, a drug company conducts marketing usually aimed at physicians, but presents the project as research. The goal is usually to introduce a drug or medical intervention to physicians for a particular use, instead of actually “testing” a hypothesis. Kessler et al., in a 1994 New England Journal of Medicine article discuss the kinds of things that might alert someone that a particular “clinical trial” is, in fact, a “seeding trial”.
Here is a link to their article: Therapeutic-Class Wars — Drug Promotion in a Competitive Marketplace
Features that distinguish such trials from scientifically rigorous studies include the use of a design that does not support the stated research goals, the recruitment of investigators not because they are experts or leading researchers but because they are frequent prescribers of competing products in the same therapeutic class, disproportionately high payments given to “investigators” for their work (although the only work may be to write prescriptions for the drug), sponsorship of the studies by the company’s sales and marketing division rather than its research department, minimal requirements for data, and the collection of data that are of little or no value to the company.
In the story above, the OBSTAT trial clearly demonstrates more than one of these characteristics of a seeding trial. The drug isn’t being tested in first time users against a placebo or against no intervention. Physicians are being used to recruit participants mostly because they can prescribe statins. Finally, the amount of compensation is disproportionately high compared to the work required.
Seeding trials are unethical. It’s one thing to send out Post-it notes to senior managers for their suggestions on use in a veiled attempt to market them. It’s another thing to try to have an effect upon the prescription habits of physicians through marketing disguised as research.