Shining Light on (So-called) Informed Consent to Clinical Trials

Research Ethics in Clinical Pharmacology

Tens of thousands of clinical trials involving drugs are taking place each year. When the researchers are clinicians, they often recruit amongst their patients.

Given the asymmetry existing between the caregiver and the patient, ethical practice requires full transparency when a new situation arises in the doctor-patient relationship, which then becomes a researcher-participant relationship. When the university specialist, already well paid, becomes an investigator paid by a drug manufacturer, it is clear in the mind of any ethicist that this investigator must declare any Conflict of Interest (COI), whatever his or her personal opinion in this regard, and whatever the speech to be made to recruit patients.

The dual role of clinician AND researcher can intensify these COIs and make it difficult for the patient to choose whether or not to participate in a project, having no real knowledge of what is at stake and assuming, among other things, that participation will surely lead to him or her getting a better treatment. This would be called a “therapeutic misunderstanding.” The situation is even more delicate for the guardian of a child or a relative with advanced dementia.

When recruiting, the clinical investigator is in danger of showing too much enthusiasm about the potential benefits or relevance of the study to the patient, or too much discretion about the details regarding risks of harm. During the clinical trial, when confronted with an obvious lack of efficacy or unacceptable adverse drug reactions, the clinician-scientist must choose between the interest of the promoter (to continue participation) and the interest of the patient (to abandon the study).

Experience in meetings of Clinical Research Ethics Boards (CREB) teaches us that when criticizing too strongly the ethical and methodological weaknesses of a manufacturer-sponsored protocol, one causes discomfort among board members and risks being eventually thanked for one’s services. In addition, clinicians who are well aware of a protocol’s weaknesses could seek and obtain a CREB complacent approval for a lucrative research project, thanks to the political weight such clinicians may have within their academic hospital environment. And this may happen even when some CREB members oppose the project for good reasons, and would not encourage relations or relatives to participate in it.

The motivation of patients who agree to participate varies: wish of being followed closely during the project, blind trust in a famous doctor, desire to please one’s doctor and fear of being dropped by him or her when refusing to participate, appeasement of one’s distress when the prognosis is dark (for example, patients suffering from advanced cancer who are “ready for anything” or relatives working as caregivers for a person suffering from Alzheimer).

Physicians who agree to evaluate new pharmaceutical products may be paid directly or indirectly for the recruitment, inclusion and retention of subjects until the end of the study; there are anecdotes regarding clinicians who make as much, if not more money from clinical trials than from their practice.

The academic hospital establishment—used to protecting its members—should rather encourage CREBs to first require complete transparency during the consent process and, second, to require that prior to deciding, a prospective patient consults someone competent and without COIs who can explain the protocol and consent form. One would hope that CREBs could also monitor the clinical trial progress by consulting the participants’ dossiers from time to time, although pharmaceutical companies are fiercely opposed to it and, were CREBs to be authorized, they would lack the financial and human resources to do it.

To Participate or Not?

Is it advisable to participate in a sponsored clinical trial whose objectives are mostly market driven? The answer is uncertain and could be rather related to the above-mentioned motivations. However, were a project to be methodologically rigorous, designed in the interest of a population in need of better drugs, and meant to answer a question emerging from the prescribers’ practice, participation would be a good idea if the individual risk and the protocol-related constraints were acceptable and the consent, truly informed. This presupposes that consent would happen after a detailed and frank disclosure of the risks of adverse reactions (as much as they are known), compared to the expected health benefits…

The argument of some recruiters (“You will contribute to the quality of future care,” “You could respond favorably to the treatment,” “An opportunity not to be missed”) may be biased when the trial is marketing or sales driven.

That being said, the consequences of participating in clinical trials are rarely as serious as hospitalizations or disabilities although quality of life may decrease. Indeed, participants must adhere to the protocol (e.g. transportation to appointments, samples taken after fasting, measurements taken at home) and receive the studied product free of charge only until the end of the trial. They may experience unexpected and serious adverse events, but obtaining legal redress would be difficult since they consented to the uncertainties associated with the research.

A sponsored trial favorable to a new drug could contribute to the doctor’s academic career and promote his or her role as a Key Opinion Leader, to be pampered by promoters to peddle the “good news” (i.e. international congresses, training seminars, press conferences, clinical guidelines panels, expertise requested by drug regulatory authorities). Such promotion by proxy illustrates the COIs that compromise the integrity of prescription profiles, inflate budgets for novelties, greatly favor over-prescription, and seriously underestimate adverse events, constraints and costs.

Full transparency is therefore necessary both upstream, in the development of the protocol and the investigator’s brochure (i.e., the “CV” of the new product) as submitted to the CREC, and downstream, that is, in the consent process and the freedom to withdraw, especially in oncotherapy. After all, it is the patient who is taking risks. The situation is complex, but ethics should prevail without compromise; this would require a change of attitude from higher administration in both medicine and academia.

When the Doctor Recruits

Here is what can happen when a manufacturer sponsors a clinical trial for a new product and the doctor gets to recruit:

— “Hello Madam. I would like to suggest that you participate in the international study of a promising new drug. This could advance medical knowledge and, you never know, improve your own treatment. The Clinical Research Ethics Board has approved the project and the consent form. You will be randomly assigned to either the group that takes the product or the one that takes the placebo. We will follow you closely, you will not wait for appointments, and everything will be free.”

— “Doctor, I trust you, do what is best for me. I am happy to contribute to medical science and perhaps to benefit personally. I am ready to sign.”

Now, here is what should happen in an ideal world where transparency would prevail:

— “Hello Madam. I would like to offer you a new drug, because the manufacturer has just offered me an enticing contract of several thousand dollars per participating patient and a bonus for those who remain in the trial until the end. This money will be used to pay my staff and the scheduled exams.

“If the results are favorable, this could contribute to the marketing, reimbursement and sales of the new product, even if it is more expensive than the old ones. I will spread the good news at conferences in distant countries, since the sponsor will pay all my expenses, in addition to speaker fees. I may even co-author publications written by the firm. The grant will increase the prestige of our institution. The CREB, which has accepted the project by a majority vote, is bound to the confidentiality of this approval.

“My research nurse will summarize the protocol to follow religiously, explain the potential risks and benefits, and answer your questions. Nevertheless, take the time to read the highly technical consent form and then show it to a competent person you trust. If you refuse, I will continue to follow you diligently, in collaboration with your family doctor. You can, without pressure from me, assert your right to leave the study at any time. If chance affects you to the new drug, you take the risk that it will not give you the desired benefits and even that it may have adverse effects that we have not foreseen.

“If the results of the study do not appear to be beneficial, the sponsor may discontinue the trial and your participation will have been useless. The manufacturer will own the intellectual property rights to your research dossier and I will not have the right to view the raw data from the multi-center trial, nor to post an unfavorable report without its approval.”

— “Thank you for your frankness, doctor… I’ll think about it… Give me time to speak with my family doctor.”

About the Contributor

Pierre Biron is a Honorary Professor of Medical Pharmacology at the Université de Montréal.

Translated by Geneviève Rail

This text is a revised and translated version of an article that appeared in February 2018 on the Paris based website Pharmacritique (see the original article). A shorter version was also published in the Montreal daily digital newspaper La Presse Plus (see this shorter version).