Letters to the Editor

June 1, 2002

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-06-01-2002,

Readers respond to articles and editorials.

Why consent?


In the sidebar to Jill Wechslers column in the May 2002 issue of

Applied Clinical Trials,

the question was posed: Should subjects decide instead of consenting? A quotation from Dr. Koski (director, OHRP) highlighted the suggestion that the term informed consent in clinical research might better be replaced with the term informed decision making. Informed consent could seem to presume foregone agreement without a fair weighing of the information, while informed decision making may seem to insist on the subjects own decision based on full understanding.

Of course, this is not a question of pure semantics. We are concerned with what the terms intend, both with regard to deeds and consequences. Above all is a shared concern for the dignity of (potential) research participants, that they decide their own fate regarding the manner of medical care and ultimately of health. A care for dignity requires an insistence that the decision to participate in research lies with the subject, and that this decision be fully informed.

But does not consent imply decision, decision based on understandingand then something more? My evaluation is that by replacing informed consent with informed decision making, we would lose the something more, something vital to the needs and expectations of (potential) research participants. Full information is essential to good decision making; however, information alone is neither the impetus nor the final arbiter for the (potential) research participant.

The impetus for the weighing of the information is an invitation on the part of an investigator (for the patient, a physician) to participate in a research project. This invitation has already been considered and weighed, based on objective criteria (inclusion criteria) as well as a direct evaluation by the investigator that this research project is suited to the health interests and needs of the potential participant. It is in this context that the potential participant is first offered a role in the research.

Once the invitation has been extended, and the required (full) information imparted, the decision itself still remains to be taken. Certainly a large part of that decision will be based on the context of the initial offer as well as a weighing of the information. However, there is more. The decision is never simply a yes or a no to the methodology of a study, but it is also the acquiescence to a course of treatment and care. The something more of informed consent is trust.

No patient-physician relationship should be based simply on sharing information, and similarly no decision to participate in research should be based exclusively on the measuring of potential benefits and risks. Without the patients trust in her physician as well as in medicine and science, the invitation would not have been possible. Informed consent reaffirms that trust by reconfirming it in the context of transparency and understanding.

Perhaps we will never feel entirely comfortable basing our justification for human experimentation on informed consent, but we would be found even more wanting to suggest that understanding alone could support such a decision. Without the trust of society, science could not be a viable enterprise. Without the trust in a physician-investigator, the patient-subject could not be presumed to accept the invitation to participate in that science.

Francis P. CrawleySecretary General
European Forum for Good Clinical Practice

Informed consent
Those who are not new to the industry are well aware that the environment of human subject protections is continually evolving. The human subjects protection industry (research and bioethics, drug development, regulatory, and so on) is currently more reactive than it has been at any time since the current basic regulatory framework appeared in 1981.

The topic of informed decision-making continues to be discussed in the context of exploring the ethics of obtaining (truly informed) consent versus the practice (or the actual process of obtaining informed consent). In reality, informed consent has always been thought to be accomplished only by the serious consideration of informed decision during the process of obtaining consent for research.

The process of obtaining informed consent for research is being discussed in multiple clinical practice and research venues with more serious attention and structured study than previously. We predict that this will indeed filter into the routine practice of medicine.

Many researchers of long-standing (particularly study coordinators, but also including some investigators) have long advocated that qualified subjects are most likely to be successfully retained (as distinguished from those recruited), through the completion of the study, when the prospective subject makes the decision to participate based on informed decision making. They would argue that indeed obtaining appropriate and adequate informed consent is one and the same as informed decision making. The upshot of the increased visibility of what had been previously categorized as academic or ethical concerns is that the resultant expansion of the minimum required consent interview process in practice now includes most of what was the theoretical ideal.

Simply as an aside, some readers may recall the JAMA article (March, 2000) about what makes clinical research ethical. The authors contended that informed consent, rooted in many experiences but most notably in the Nuremberg Code, is one of seven conditions that must be satisfied for clinical research to be considered ethical. (Recently, the authors have since added one more to those seven conditionscommunity perspective.)

While informed decision-making has been attributed to Dr. Greg Koski of OHRP, as a result of the National Human Research Protections Advisory Committee (NHRPAC) discussions that have transpired, many others such as Ezekiel Emmanuel, Charles MacKay, Charles McCarthy, Jonathan Moreno (member of NHRPAC), Evan DeRenzo, and Ernest Prentice have discussed this topic in various public and private settings for quite awhile.

If we follow Dr. Koskis statement and the logic as noted, a question we might ask is: What is the potential subject deciding if we talk about informed decision making?Many scholars and practitioners have long argued that no subjectirrespective of how educated they arewill ever make a decision to participate whose ...decision is based on full understanding of the risks involved. This is true not because they may not have the capacity to fully understand the risks, but because of the pure nature of the clinical research environment being one that puts an individual in a vulnerable (or compromised) position in the first place.

The most we can truly hope to achieve is to have the subject (or appropriate surrogate) give informed consent to the ability that s/he can, under the given circumstances, with the available knowledge (time, explanation, and so on) at that point in time. This further, then, begs the notion of obtaining ongoing or continuous informed consent throughout the subjects participation in the study, a principle held to be of high importance and regard in the clinical research process.

One more thought: Whose informed decision-making are we really talking aboutespecially when we look at specific vulnerable populations such as the decisionally impaired and either educationally or socio-economically disadvantaged groups? And this question need also embrace the complexity associated with cultural differences in information sharing and giving consent.

Felix Khin-Maung-Gyi, PharmD, MBA, CIPCEOPaul W. Goebel, Jr., CIPVice PresidentMatthew D. Whalen, PhDPresident
Chesapeake Research Review, Inc.
Columbia, MD

I would like to voice my opinion regarding informed consent. I prefer that the word consent remain in common language for research subjects. I cannot imagine that anyone would not understand this language.

Informedbased on factual knowledge. Consentvoluntary allowance of what is planned.

The language informed decision making does not really convey the aspect of a subject giving consent. A subject should make an informed decision about whether or not they wish to give consent to participate in a trial.

Brenda Smith, CCRC Neurological Associates of Tulsa, Inc.

Time on clinical trials
Id like to comment on the Time magazine cover story for the issue dated 22 April, 2002. The article, At Your Own Risk, which has a cover noting How Medical Testing Has Turned Millions of Us into Human Guinea Pigs, is about clinical trials, and can be found on the Web at http://www.time.com/time/covers/1101020422/story.html. As a clinical research professional with years of experience and high standards and scruples, I find it appalling when I come across stories such as this in popular media that show clinical research in a poor light. Not that I have not come across questionable investigators and research personnel, or deny or challenge the events as reported in this article, but I am deeply disturbed by them because articles like this give the impression that noncompliance is the norm rather than the exception.

The only way we, those who are part of the clinical research industry, can address these issues and curb malpractice related to research is by increasing the awareness on the part of all research personnel and the public (that is, potential subjects) of what is to be expected in properly conducted clinical research, thereby giving them an opportunity and knowledge to identify and report on anything that is contrary. I firmly believe that this can be achieved by stepping up the education and training regarding clinical research. All too often though, education and training get placed on the back burner. No one can deny that the training budget, if present, is unfortunately one of the first to be cut whenever a biopharmaceutical company or CRO has to undertake austerity measures in these times of necessary belt-tightening. Until this attitude changes, and education and training are given their rightful place at the top, there is little scope for avoiding the 100 Oklahomas, 100 Hopkinses, that are prophesied in the Time article.

Kay Ranganathan, MD, MPAPresident and CEO
ClinfoSource, Inc.

DTC clinical trial advertising
A special advertising section in Newsweek (6 May 2002), Cancer Clinical Trials: Your First Decision Counts, looks like an attempt to advertise clinical trials directly to cancer patients. No doubt there will be more of these ads in more magazine and more television commercials exhorting patients to sign up for a clinical trial as soon as theyve been diagnosed with cancer.

The ad is written in ways that would offend most IRBs. The word subject is never used; participant is used 7 times, but patient is used 39 times. Everyone in their clinical trials is a patient. A careful reading of the ad suggests that clinical trials are just another form of cancer treatment. Cancer patients participate in cancer research/clinical research/clinical studies, but nobodys in an experiment or takes an experimental drug. Every testimonial seems to be from a person who received the investigational drug, and no one had any adverse reactions.

Three outcomes can happen in a clinical trial: Subjects can get better; they can stay the same; or they can get worse. The ad suggests that everyone gets better.

The ad was produced by the Colaizzi group on behalf of the Coalition of National Cancer Cooperative Groupsa dozen of the largest drug companies.

Since reprints of the section are available, I suspect that this ad will be handed out by physicians and researchers to prospective research subjects. Any responsible IRB would reject this as a recruiting technique; its just not balanced enough. The ad doesnt tell you

  • the percentage of experimental cancer drugs that actually make it to market. Overall, the FDA reports only about 20% of drugs tested in humans make it to market.
  • the percentage of trial participants who get the investigational drugs. Maybe only 50% if half get the experimental drug and half get conventional treatment.
  • the risks of being in a cancer clinical trial. The ad cites only benefits, not a single adverse event.

Most subjects do not benefit in most clinical trials. About 45,000 adults are enrolled in cancer clinical trials. If 50% get standard treatment, and 50% get the experimental drug, then there are about 23,000 in each group. Only 20% of drugs tested make it to market, so Im guessing that about 4,600 people benefit from getting the experimental drug (23,000 3 20%).

The ad simply furthers the problem of therapeutic misconception that Paul Appelbaum and his colleagues identified almost 20 years ago. The advertising section cites a survey of public attitudes toward cancer trials without mentioning that the company conducting the survey is in the subject recruitment business. After another survey, the same company concluded,
The challenge for clinical research is to persuade more people that they will not suffer as a result of participating and that they will be treated as patients and not as guinea pigs. They should understand that they are not likely to suffer more pain or side effects from the experimental treatments than they would from standard treatments.

How about treating them as subjects/research participants? No more side effects from the experimental treatments than from standard treatments? Then we can disband all the IRBs. No risks at all? Yet a recent Time magazine cover story was titled How Medical Testing Has Turned Millions of Us into Human Guinea Pigs.

Clinical trials get curiouser and curiouser.

Mark HochhauserReadability Consultant
Golden Valley, MN

Important omission
I read ACT on a regular basis and believe it to be one of the best resources I have come across for the industry. My comment regards a recent article, Drug Accountability at the Investigative Site (Applied Clinical Trials, March 2002). I found the article to be very well written but lacking an extremely important aspect of all drug accountability records. It failed to mention expiration dating for investigational study drugs. Without information sufficient to assure the products stability during the planned clinical studies (21 CFR 312.23b), all other drug accountability is quite useless. Otherwise, I applaud the article.

Kathy UrbinQuality Assurance Associate
Clinical Trial Management
Services, Inc.
Bristol, TN

Thank you
Congratulations on ACTs 10th anniversary and many thanks for the two copies of the May issue containing my article, Designing Clinical Research for Better Patient Care. I appreciate the efforts you and your editors put into the article. It shows the gains in style, clarity, presentation and accessibility that people will now expect of me!The point I had in mind for this article was not to fight the academic games of publishing and pursuing obscure details but to present to those who do clinical trials and patient care how they could be better coordinated. I am very happy I found ACT since I do not think I could achieve my aim any better than I have in working with you. Please thank your editors.

Robert Becker, MDResearch Fellow, Center for the History and Philosophy of Science, Boston University

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