A Difficult Balancing Act

Two recent incidents illustrate the opposing challenges of the current clinical trial and drug approval system. In the first, a 36 year old woman was enrolled as a subject in a Phase I clinical trial of gene therapy for rheumatoid arthritis, with an adeno-associated virus(AAV) as the delivery vector:

In the trial, the AAV vector delivered a transgene encoding the receptor for tumor necrosis factor (TNF)-alpha, a cytokine that causes joint swelling in arthritis patients. The receptor, secreted by the target cells, binds to TNF-alpha, to reduce inflammation and protect the joint.

However, she tragically died after receiving her second injection of the AAV, even though she was otherwise healthy:

Robb Mohr sat by his wife's hospital bed two weeks ago, trying to take it all in. His wife, Jolee Mohr, was breathing with the help of a ventilator in a Chicago intensive care unit -- her body bloated from internal bleeding, her liver failing -- and no one could figure out what was wrong with her.

Robb Mohr had his suspicions. Jolee, 36, had been feeling fine just a few weeks earlier, save for occasional stiffness from her arthritis. Her decline had begun the day after her right knee was injected with an experimental drug made of genetically engineered viruses. Doctors at the hospital shared his concern.

Jolee Mohr died from massive bleeding and organ failure July 24, leaving behind a 5-year-old daughter and a host of questions about why she was recruited into a gene therapy experiment whose chief goal was to test the safety of a novel arthritis treatment that had virtually no chance of helping her.

No one knows yet whether the treatment was to blame. ...

And as noted by the blog Health Care Renewal:

The Washington Post reported that a US National Institutes of Health (NIH) panel that reviewed the initial project protocol had some serious doubts.

How serious were these doubts?

Suspended Gene Therapy Test Had Drawn Early Questions

A gene therapy experiment that has triggered a federal investigation after the death of a patient on Tuesday raised a variety of concerns when it was first proposed to federal reviewers in 2003.

Unlike the vast majority of such proposals, all of which aim to treat diseases by giving patients new genes, the plan to inject trillions of genetically engineered viruses into the joints of patients with arthritis was flagged for a special public review by the federal Recombinant DNA Advisory Committee, part of the National Institutes of Health.

At that Sept. 17, 2003, meeting, representatives of the sponsoring company, Targeted Genetics Corp. of Seattle, listened as a panel of experts wondered aloud why such a novel and possibly risky approach was to be offered to patients who were not especially ill, including some who had not even tried standard treatments.

Reviewers questioned the justification for the study, given that animal studies had found only a "limited correlation" between the treatment and any improvements in subjects' condition. And they asked for more assurance that the engineered viruses were not going to spread around the body or cause untoward immune system reactions in patients.

Some also expressed concern that the informed consent document the researchers planned to use to describe the risks and benefits to participating patients was not upfront enough about the fact that the study was unlikely to help them and was designed merely to test the new approach's safety.

The second incident deals with the opposite end of the spectrum. An appeals court ruled that dying patients do not have a constitutional right to receive unapproved drugs that may prolong their lives:

Court Rejects the Right to Use Drugs Being Tested

A federal appeals court ruled yesterday that patients with terminal illnesses do not have a constitutional right to use medicines that have not yet won regulatory approval.

The 8-to-2 decision by the Court of Appeals for the District of Columbia Circuit came in a closely watched and emotional case that pitted desperate patients willing to try unproven, even risky, therapies against those arguing that drugs should be proved safe and effective before they are made available.

The decision preserves the current regulatory system. If it had gone the other way "it would have undermined the entire drug approval process," said William B. Schultz, a former deputy commissioner of the Food and Drug Administration, who wrote an amicus brief arguing against the early access to drugs.

The case was filed against the Food and Drug Administration in 2003 by the Abigail Alliance for Better Access to Developmental Drugs, a group founded by a man whose daughter Abigail died from cancer after a long battle to receive treatment with experimental drugs that were eventually approved.

The group, joined by the Washington Legal Foundation, argued that forcing patients to wait years for a drug to go through the process of clinical trials deprived dying patients of their right to self-defense and violated the Fifth Amendment clause stating that people cannot be deprived of life, liberty or property without due process of law.

It's a difficult task to determine the most ethical stance in each of these instances. Who decides? People's lives hang in the balance.