Court order raises ethical questions about research

Treatment INDs should be balanced decision

When a judge recently ordered a pharmaceutical company to provide an investigational drug to a teenage boy who had not met the enrollment criteria for a phase II trial, the IRB world took note.

The case raised ethical questions about the court's involvement in research, as well as about how the sponsor, investigators, and IRB handled subject recruitment.

Judge William J. Martini of the United States District Court in Newark ruled on Aug. 20, 2008, that 16-year-old Jacob Gunvalson of Gonvick, MN, should be allowed to receive an experimental drug called PTC124 even though the teenager does not meet the criteria for clinical trial eligibility, according to published reports.1

PTC124 is being studied by PTC Therapeutics of South Plainfield, NJ, a small pharmaceutical company that has been enrolling subjects in phase IIa trials to study the drug's potential as a therapeutic agent for patients with Duchenne muscular dystrophy.

PTC Therapeutics will appeal the court's decision, says Stuart Peltz, president and chief executive officer, in a statement issued Aug. 20, 2008.

"The issue here is that a judge can't order a pharmaceutical company to supply a drug to an individual without the FDA's approval, and because the drug is available only under an IND [investigational new drug], IRB approval is also required," says Mark S. Schreiner, MD, an associate professor of anesthesia in pediatrics at the University of Pennsylvania. Schreiner is the chair of the committee for the protection of human subjects at The Children's Hospital of Philadelphia.

The court's order remains subject to FDA approval, just as all individual treatment INDs need to be approved by the FDA before the test article can be used outside of the clinical trial, says LaDale K. George, JD, a health care attorney with Foley & Lardner in Chicago, IL.

The FDA allows sponsors to apply for an individual treatment IND, which some people call "compassionate use" drugs.

"But these applications typically are made after a drug has some proven efficacy, [via] phase II or phase III trials," Schreiner says.

Whether an individual treatment IND is requested by a physician or a sponsor, it has to be approved by the FDA, George explains.

This case has moved the decision-making process from the sponsor and thrust it right on the FDA's doorstep, he notes.

One ethical problem with the court decision is that neither the patient nor the judge are equipped to assess the risks and benefits of an investigational drug, and yet these should be assessed before an individual is allowed to take the IND, experts say.

"I have a problem with a judge mandating clinical care," says Merit E. Cudkowicz, MD, an associate professor of neurology at Harvard Medical School and Massachusetts General Hospital in Charlestown, MA.

"This is a drug with no known efficacy, and it's early in development," Cudkowicz adds. "There is no knowledge of what dose to give, and it's not right for a non-medical person to mandate the treatment."

When a drug still is in phase II testing, as is PTC124, it is difficult to make a risk-benefit assessment, which is the whole point of conducting clinical trials, Schreiner says.

"There could be an individual treatment IND with a phase II drug, but it depends on the strength of evidence and rarity of condition and alternatives available," he adds.

"A lot of these treatment INDs happen in drugs in phase III trials and they're for life threatening conditions where the patients wouldn't qualify for the trial," Schreiner explains. "I believe we should not release agents until there is some more substantive evidence of efficacy from clinical trials."

IRBs face ethical quagmire

For IRBs, this situation is fraught with ethical conflicts.

For example, is it ethical to permit a sponsor to release an investigational drug to non-trial patients when it's still a major risk that the drug could cause the patient more harm than benefit?

"Ultimately, we could end up doing more harm to the individual and more harm to other patients if we were to permit uncontrolled access to unproven, potentially toxic medications," George says.

And if a judge does order a sponsor to make the drug available to patients who do not meet the study's criteria, how will these patient's experiences impact the overall study's recruitment and adverse event reporting?

"Randomization is the hallmark of clinical trials, and if you remove the randomization element from a clinical trial then you have no control group, and therefore no evidence is being produced," George says.

In addition, investigational drugs cannot be sold because they haven't received marketing approval from the FDA, so on what basis would these free drugs be denied to the many sick people who think they need them, he asks.

"So a pharmaceutical company would have to produce a product that's unproven and for which they have to give it away without compensation," George says. "That's the wrong outcome for everyone, and in the long term it's detrimental."

This court case has been a hot topic because it puts drug companies in an awkward position, says Stephanie J. Zafonte, MSN, RN, CCRP, CQA, RAC, director of operations at George Washington University, biostatistic center, in Rockville, MD.

"If you allow compassionate uses of an IND, you don't know what the implications will be," Zafonte says. "What if something happens to this boy after he takes the drug?"

The judge's decision could put the boy in risk and even result in the company stopping drug development because of an adverse event that occurs to a patient who should not have been included in the study, Zafonte adds.

"This could impede drug development that could, in fact, help hundreds or thousands of others," she adds. "So how do you choose this single person vs. society?"


  1. Grynbaum MM. Judge orders drug maker to provide experimental treatment to terminally ill teenager. NY Times. Aug. 21, 2008.