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February 19, 2009

Abigail Alliance case discussed: Balancing study drugs, safety

A 21st-century case at the fulcrum between law and ethics will continue to be discussed and have implications for the medical community as well as for the Food and Drug Administration (FDA), said a medical ethics expert speaking here.

“Abigail Alliance v. von Eschenbach is one of the most fascinating cases in many years, with many implications,” said Peter D. Jacobson, professor of health law and policy at the University of Michigan. “It is a paradigmatic example of the pressures pulling in each direction: How do you balance the need for more drugs with patient safety? It also asks the question: How should the law and the regulatory system respond?”

The case initially involved Abigail Burroughs, a 19-year-old woman suffering from terminal head and neck cancer, who was ineligible to participate in clinical trials of the drug Erbitux. At the time, Erbitux was available only to participants in clinical trials for colon cancer drugs.

At the recommendation of her physician, Burroughs asked for access to the drug under the FDA’s “compassionate use exception doctrine,” which in certain circumstances permits an unapproved drug to be used. Those circumstances are: when there is no comparable treatment alternative; clinical trials of the drug are underway, and formal FDA approval for the drug is being sought.

In the Erbitux case, all these conditions were met. However, the FDA is allowed to deny a compassionate-use request if the scientific evidence does not provide a reasonable basis to conclude that the drug may be effective for its intended use or if it would add an unreasonable and significant risk of illness.

When the FDA denied Burroughs’s request, her father, Frank Burroughs, formed the Abigail Alliance for Better Access to Developmental Drugs shortly before his daughter’s death in 2001. In July 2003, the Abigail Alliance sued the FDA. The suit alleged that the failure of the FDA to permit the sale of investigational drugs to terminally ill patients violated the patients’ rights to privacy and due process under the 14th Amendment.

In August 2004, the U.S. District Court for the District of Columbia ruled in favor of the FDA, holding that its policies did not violate the constitutional rights of patients.

Abigail Alliance’s appeal, however, was upheld in a 2-1 decision by a three-judge appellate panel in the U.S. District Court for the District of Columbia in May 2006.

The FDA then appealed in July 2006 for a re-hearing before all the judges of that court (in legal parlance, an en banc hearing) on the grounds that the May 2006 decision presented a serious threat to the FDA’s ability to ensure the safety and effectiveness of prescription drugs sold in the United States.

The re-hearing was granted in November 2006 and an 8-2 en banc decision in August 2007 held for the FDA.

Abigail Alliance filed another appeal with the U.S. Supreme Court, which in January 2008 declined to hear the appeal, in effect leaving the FDA regulations intact.

According to Jacobson, who also is director of Michigan’s Center for Law and Ethics and Health and a 1970 graduate of Pitt’s law school, the question at the heart of the case is whether terminally ill patients who lack alternative treatment options have a constitutional right to purchase drugs that have not been authorized for treatment uses by the FDA.

“This is really a case of individual rights versus population safety,” he said. “The key is whether the right to life is a fundamental constitutional right; otherwise Abigail Alliance has no real case,” Jacobson said. “The FDA is delegated to make those [drug approval] decisions by the federal government. This would undermine the FDA’s mission and could put it out of business.”

In the 2006 three-judge panel decision, the majority argued that Abigail Burroughs had a fundamental right to purchase the drug and, further, that an individual is free to assume the risks of taking an unapproved medication.

Absent a fundamental right, the FDA need only show a rational relationship between its regulation and a legitimate goal of the state, in this case the health of the population, Jacobson said.

“If it is a fundamental right, the strict scrutiny standard would apply and [the FDA] must show that its regulation is narrowly tailored to serve a compelling state interest, a much higher standard,” he said.

“The panel also held that completion of a phase I trial means a drug is probably a medical benefit with sufficiently minimal risk. That is just plain wrong. A phase I trial means a drug is tested on a small group of healthy patients. Only an estimated 5-8 percent of all cancer drugs that are approved in phase I are ultimately approved for marketing,” Jacobson said.

“At any rate, there was a lot of very creative lawyering in these various opinions,” he said.

For example, to decide whether the right claimed is fundamental, the panel majority relied heavily on the Supreme Court’s analysis in Washington v. Glucksberg, which held that there is no fundamental right to physician-assisted suicide. In that case, the Supreme Court articulated a relatively restrictive test requiring courts to consider the right claimed as narrowly as possible and look to the nation’s history and legal traditions for evidence of whether that right has been treated as fundamental, Jacobson said.

The panel ruled that on a physician’s recommendation, mentally competent terminally ill patients with no alternatives have a constitutional right to obtain potentially lifesaving drugs that are eligible for post–phase 1 testing. Believing that the nation’s history and traditions support recognizing such a right, the panel majority reasoned that federal regulation of pharmaceuticals is only 100 years old and that not until 1962 did the government require pre-market review of a drug’s safety and effectiveness, Jacobson pointed out.

The panel majority further relied on the Supreme Court’s decision in Cruzan v. Director, Missouri Department of Health that competent individuals have a constitutionally protected right to reject life-sustaining medical treatment. The corollary of that right, the panel majority stated, implies “that an individual must also be free to decide for herself whether to assume any known or unknown risks of taking a medication that might prolong her life.”

Had the panel decision been upheld by a higher court, there would be a continuous stream of cases pushing for greater access to more drugs, Jacobson maintained. “But keep in mind the consequences on human safety. What if the patient taking an unapproved therapy dies sooner with more suffering? In other words, the drug may not help and in fact it may do harm. That has liability implications for physicians who [profess] to do no harm and raises a range of legal and ethical issues, including: Why should the government tell doctors they can’t prescribe it?”

The situation also would undermine participation in phase II and III clinical trials, he added. If the Abigail Alliance had prevailed in court, the effect would have altered clinical cancer research by providing nearly unfettered legal access to unapproved drugs by terminally ill patients, who as a result would have little or no incentive to participate in phase II or III clinical trials, Jacobson noted.

“What are the limits? The fundamental rights analysis, rooted in patient autonomy, could easily apply to medications expected to prevent pain or disability. Why not unapproved drugs for non-terminal patients?” he said. “What is especially dangerous about the panel’s decision is that it would simultaneously permit drug companies to stimulate demand via advertising while removing the regulatory safety net designed to protect patients from untested therapies.”

While the en banc decision vacated the panel’s decision, the Abigail Alliance has continued the fight for greater access to unapproved drugs on the legislative front, Jacobson noted. “But neither the court’s adoption of the panel’s opinion nor legislation codifying that approach would provide a sound solution. The idea that the way to save lives is through unapproved drugs offers the illusion of choice and the reality of false hope — not an acceptable basis for public policy,” he said.

“I believe the FDA is correct on both law and ethics, that the government has a compelling interest to protect the population and that the courts, ultimately, got it right.”

—Peter Hart

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