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Ethically Speaking: Patients deserve a stronger voice in clinical trial design

By Charles Craig
Staff Columnist

Scientific and ethical justifications for randomized clinical trials involving targeted cancer drugs are outdated and overlook the most significant players in those high stakes experiments – patients coping with an incurable illness.

The experience of Carolyn Higgins, an Atlanta mother and grandmother diagnosed nine years ago with multiple myeloma, demonstrates it is time to give patients a much stronger voice in discussions of what is acceptable in clinical research.

Higgins was told existing treatments would give her three to five years. "I did research and learned at the time there was no cure," she told BioWorld Today. "I had grandchildren born and more coming and I just didn't have the patience for an ongoing treatment that wasn't a cure."

Her physician listened and told her about a phase I trial for a new targeted treatment, a monoclonal antibody, and assured her she would receive the experimental drug. For Higgins, that was essential. She would not participate if she were randomized to receive standard of care.

She spent five and a half years in the trial, outliving her initial prognosis. When her cancer stopped responding to the drug, she left the study.

"I took a 10-month break and then my doctor said, 'I have another new drug that is showing positive results.'"

This time it was a phase II study of another monoclonal antibody. She agreed as long as she was assured of receiving the drug.

"I have been on the drug for over a year and a half and have wonderful results," she said. "This is the closest thing to a cure I've had in my whole life."

Both drugs, Empliciti (elotuzumab, Bristol-Myers Squibb Co.) and Darzalex (daratumumab, Genmab A/S/Janssen Biotech Inc.), were approved by the FDA last year. (See BioWorld Today, Dec. 1, 2015.)

Higgins is still in the phase II trial. "I won't come off until it stops working." She could continue with the drug outside the trial, tweaking the dosage, she said, "or maybe I'll look at something else."

Her advice for other patients? "At each phase there is a goal on the part [of drug sponsors, investigators and regulators]. I didn't care about their goals. My goal was to have a cure. The most important thing for patients to understand is to own their own disease, to be their own advocate."

Higgins admitted she is selfish. "I know I should be doing this for the greater good and say all the things that scientists want to hear. But I promised my two oldest grandchildren, who are 12, I will be at their high school and college graduations. I have to make it 10 more years."

What Higgins' experience describes is a narrowing of the long-held sharp ethical distinction drawn between research and medical care. Patients should know, the thinking goes, that research is designed to yield generalizable scientific knowledge for future patients. Patients should not misconstrue research as medical care aimed at directly benefiting them.

Targeted cancer drugs have changed that paradigm.


Large randomized trials, for decades, have been considered the scientific "gold standard" for confirming safety and efficacy of drugs that perform well in studies with fewer patients. They are not designed for medical care of research subjects.

Ethical justification for randomization, in which unbeknownst to test patients some of them receive the experimental drug and others receive standard of care or a placebo, is the concept of clinical equipoise.

That sleight of hand thinking, a topic of debate since its formulation in the 1980s, says that because medical investigators do not know if the experimental drug is better than what the other patients receive, none of the research subjects is harmed.

In early clinical trials, the new molecularly targeted drugs, tested in patients whose diseased cells possess the targeted cancerous properties, yield not only safety data, but also significant efficacy. They raise serious concerns about trials in which patients are randomized to receive a placebo or standard of care with response rates known to be low – much lower than those the study drug demonstrated in earlier trials. (See BioWorld Today, Aug. 27, 2010, and Jan. 20, 2011.)

Stunning phase I and II results of those new drugs have scientific experts in government, academia and industry rethinking the wisdom of expensive phase III randomized trials. (See BioWorld Insight, June 11, 2016.)

On the ethical side, enrolling patients with biomarkers for cancer cells targeted by an experimental drug clearly seems to eliminate clinical equipoise as a justification for randomization. If phase I and II data show significant benefits, uncertainty no longer exists in randomizing patients to receive poorer performing drugs or a placebo.


One way of looking at all this is simply eliminating randomization, relying on a larger study of the experimental drug to confirm findings of earlier trials. The FDA also has implemented expedited approval of some drugs it designates as breakthrough therapies without requiring randomized trials.

But reliance on randomized studies for rigorous analysis of drugs is likely to continue with debates focused on new trial designs that address both the scientific and ethical challenges.

For example, the excessively high market price of the new targeted treatments would seem to demand they prove their value for a health care system stretched to the financial breaking point. That may justify the science of randomized trials for comparative effectiveness studies, but it cannot rescue equipoise as ethical justification for patient participation.

Ethicists will have to abandon the notion of equipoise, oppose human subjects' participation in research, or find another rationale for ensuring the principles of autonomy and beneficence are respected in the scientific design of clinical research.

As they do, they should engage patients as partners and listen carefully. Carolyn Higgins has put them on notice. Randomization is unacceptable.

"I didn't think about being a guinea pig," she said. "I thought about what I wanted."

Charles Craig is a writer, editor and lecturer on bioethics and biotechnology issues with a master of arts in bioethics and master of journalism degree. He has more than 20 years of experience in the biotech industry as the former president of Georgia Bio, author and editor of Ernst & Young's annual Global Biotechnology Report (2001-05), director of publications with the Biotechnology Innovation Organization (1998-2001) and writer and editor with BioWorld Today (1994-98).

Introducing Ethically Speaking, a new column from BioWorld, exploring the intersection of patients' needs with advances in medicine

The views expressed in this column are solely those of the author and do not reflect the views of BioWorld Today or Thomson Reuters.