Title: Prerandomization in Trial Designs and Research Ethics

Author: Aaliyah Eaves-Leanos

Description: A plastic surgeon uses an alternative study design to get high enrollment in his study.

Keyword(s): alternative study designs, plastic surgery research, informed consent

Based On: (Murphy, 2004, pp. 38-39)
Additional Source Information: (Saunders, Baum, & Haughton, 1994, pp. 457-469)

Case: Dr. A is a plastic and reconstructive surgeon with a private practice in a small southern city. His practice had grown rapidly over the last two years as word of mouth spread that he was L.A. trained and had cutting edge techniques. Dr. A also had a reputation for spending lots of time with each of his patients and for making every patient feel as though she/he was the only patient in the world. In short, Dr. A had a very powerful and comforting bedside manner.

Before Dr. A went into private practice he headed the plastic surgery department at the local University. Dr. A found his work at the University personally and morally fulfilling because the vast majority of his patients were indigent reconstructive patients that needed a life changing plastic surgery to restore them to normalcy. Dr. A left the University for private practice, however, because he felt the work at the University was professionally unfulfilling and undervalued. He often found he spent every hour of every day working and he was destroying the quality of his life. Dr. A did not make his decision to leave the University lightly because he valued the public good the University did for the community. As a compromise Dr. A personally committed to performing reconstructive surgery on mastectomy patients in his private practice.

As Dr. A’s private practice boomed he struggled to schedule in the time consuming reconstructive mastectomy patients between the lucrative cosmetic patients. Unfortunately, insurance companies set reimbursement levels on reconstructive mastectomies so low that Dr. A was basically performing a charitable act to the detriment of his practice by accepting reconstructive patients. Dr. A found that his reconstructive patients required more time and had far more complications than his cosmetic patients. Dr. A’s practice was now creating the poor quality of life scenario that drove him from the University in the first place. Dr. A was contemplating taking on a new partner or no longer accepting reconstructive patients. Dr. A discussed his dilemma with Dr. M, a colleague he knew and trusted from his plastics residency, at the annual American Society of Plastic Surgeons (ASPS) meeting.

Dr. M told Dr. A that when she decided to start a family she choose to cut back her clinical hours and was able to make up the lost revenue by conducting clinical trials for large medical device companies that needed physicians for breast implant trials. Based on her conversations with some of the medical device representatives she felt there was a growing interest in testing a new type of silicone breast implant in mastectomy patients. Dr. M was not interested in reconstructive work but thought that Dr. A would be a perfect investor on the silicone breast implant trials. Dr. M set up a meeting between Dr. A and  the sponsor reps that were at the ASPS meeting.

Dr. A decided to contract with a major medical device company to conduct a phase 2 clinical trial on a new silicone breast implant. Dr. A saw the business opportunity as a means to continue his reconstructive work and receive what he considered fair compensation for his time and effort. The clinical trail protocol compared the ‘best’ standard of treatment with the new silicone implant. Dr. A’s patients were randomized into one of the groups before being informed. The patients in the group receiving the best standard therapy (S1) did not need to give informed consent. The patients in the group receiving the new treatment (E1) received detailed information regarding the treatment and were asked if they were willing to enter the trial. If a patient refused she was transferred to S1.

The sponsor was pleased with the initial results of Dr. A’s investigation, so much so that Dr. A was asked to join a multi-phase 3 trial that the sponsor set up with the local University’s plastic surgery department. Dr. A did not really want to take on another clinical trial, but this new trial presented the opportunity for Dr. A to mend his broken relations with the University and also presented potential for long term benefit for his practice.

In the phase 3 study there was no clear cut ‘best’ treatment. Eligible patients were placed into study groups S1 or E1 via ‘uniformed’ randomization, and both groups of patients were informed about the trial and asked to participate. Approximately 90 percent of Dr. A’s patients consented to participate in the trial, whereas only 35 percent of the University’s patients agreed to participate.

In the phase 3 trial, where both groups of patients were fully informed after randomization, a University surgeon, Dr. U voiced his concern to an IRB member that Dr. A may be achieving such a high rate of consent because his patients may feel somewhat coerced into agreeing to continue with the trial because the patient was entered and then asked. When pressed to explain why he held that opinion Dr. U pointed to the fact that Dr. A’s patients typically demonstrate an unusual dependence and trust in Dr. A’s opinion since he often goes beyond what one normally expects in terms of time and concern for each individual patient he treats, and has been known to even make house calls for his patients, whereas the University doctors have virtually no continual contact with their patient population.

When Dr. U learned that the IRB member had no intention to take action he contacted the trial’s monitor with his concern that the trial may be audited for validity because Dr. A was reportedly overly enthusiastic when explaining the trial to his patients, rather than giving a more balanced view. The monitor brought the issue to Dr. A, who defended his enthusiastic endorsement as part of his therapeutic strategy that he used with all his reconstructive patients, thus engendering a positive attitude that appeared to be an important aspect of treatment for some patients. Dr. A also told the monitor that he and Dr. U had a history of discord when Dr. A worked at the University and that was probably the real source of Dr. U’s concern.

  1. Why might prerandomization be a desirable way to enroll patients into trials? What concerns does prerandomization raise?
  2. Dr. A’s phase 2-S1 study patients who received the standard (best available) therapy functioned as the control group. Is sthe fact that the patients are being randomized into a trial without their consent an ethical problem?
  3. Is it important to advise all patients that there might be another intervention to treat their condition even though it is still unknown value? Would your answer change if you knew that one of Dr. A’s phase 2-S1 patients had strong feelings about which type of implants she received, and she would in fact have preferred the experimental silicone implants.
  4. Is there merit to the view that advising patients after randomization that they have been enrolled in a study may lead them to believe they must participate?
  5. Was the sponsor’s monitor justified in accepting Dr. A’s explanation without further follow up? Did the IRB member have a duty to follow up on Dr. U’s concerns? If you said either the monitor or the IRB member should  have done more, give examples of what they should have done.

 

Source: Murphey, T. (2004). Case Studies in Biomedical Research Ethics. Cambridge, MA: The MIT Press.
Saunders, C., Baum, M., & Haughton, J. (1994). Consent, Research, and the Doctor-Patient Relationship. In R. Gillon (Ed.), Principles of Healthcare Ethics. Chichester: John Wiley & sons.