NEWS
Patient Group Seeks Overhaul of FDA Clinical Trial System in Court
Karyn Hede
Forces are allied for what could become an epic battle over the U.S. Food and Drug Administration's (FDA) authority to regulate the safety and efficacy of new drugs. In a two-pronged test of the FDA's current new drug standards, would-be reformers are challenging the constitutionality of the FDA's drug approval standards and seeking legislative action that would overhaul the current system of clinical trials.
The movement has both researchers and patient advocates worried about hurting vulnerable, desperate patients with drugs that haven't proven effective and may, in fact, cause harm. Its debate hinges on the point at which terminally ill patients should have access to experimental drugs.
In 2003, the Abigail Alliance for Better Access to Developmental Drugs and the Washington Legal Foundation sued the FDA on the grounds that patients have a constitutional right to assume the risk of taking an unproven experimental drug. On May 2, the U.S. Circuit Court of Appeals for the District of Columbia reversed a lower court dismissal of the suit, reviving the group's argument.
"There's no stopping [the lawsuit] now, I mean as far as the legal path, all the way to the Supreme Court if necessary," said Frank Burroughs, president of the Abigail Alliance, an organization dedicated to getting drugs to patients much sooner than current standards allow.
In a parallel tactic, the group worked with Sen. Sam Brownback (R-Kan.) to introduce legislation that would create a new three-tiered approval system for drugs. The bill, S.1956, questions the necessity of placebo-controlled clinical studies and gives greater weight to "clinical judgment" than statistical analysis in evaluation of the safety and efficacy of drugs, biological products, and devices. The bill also states that seriously ill patients should have access to investigational drugs approved under "Tier I," in which drugs would be available based "primarily upon clinical evaluation, not statistical analysis." The bill has been referred to a Senate committee for review.
The lawsuit and bill are part of a larger push for expedited review of drugs that would reduce the reliance upon large, blinded, placebo-controlled clinical trials, long the mainstay of the FDA's regulatory system.
Under the current clinical trial structure, phase I testing is designed to determine only how much of a drug can be given safely, not whether it effectively treats a disease. Because of the inherent risk to patients of such trials, particularly for cancer drugs, patients enrolled in phase I trials typically are terminal and have already exhausted other treatment options. Only in phases II and III are drugs tested for efficacy. Reformers want the FDA to make drugs available to seriously ill patients after phase I testing.
Many physicians and medical researchers have serious reservations about the proposed shift toward deregulation, which removes much of the science from drug development. Calls to the FDA seeking comment on the challenge to its regulatory authority went unanswered, but some patient advocacy groups have taken strong stances against the measures, saying that radical change of the FDA's regulatory authority would put patients at risk.
"We're talking about a system that is put in place for the protection of the public," said Fran Visco, executive director of the National Breast Cancer Coalition. "Once you start reducing those protections you are going to be harming many more people than you are helping. And I can't even say helping because, let's face it, most of these [experimental] drugs don't work."
Indeed, among cancer drugs that look promising after phase I testing, only about one in 10 are ultimately approved, according to the Parexel Pharmaceutical R&D Statistical Sourcebook.
The proposed Senate bill has particularly raised the ire of the Society for Clinical Trials (SCT), a nonprofit organization dedicated to reliable clinical trial study design. The group published a paper opposing the bill in the July 2006 issue of the journal Clinical Trials (
http://www.sctweb.org/positionpapers...al-trials.pdf).
"We are concerned at a fundamental level about the repudiation of the scientific method that is embedded in the bill," the group states.
"The legislation and the court case are predicated on the idea that you can really tell which [drugs] are going to work well before they get very far through the clinical trials process," said Susan Ellenberg, Ph.D., professor of biostatistics and associate dean for clinical research at the University of Pennsylvania School of Medicine in Philadelphia, and a coauthor of the SCT position paper. "It's not even the case that 90% of the drugs that seem very promising get approved. Nothing that gets into phase III trials isn't perceived to be very promising. Companies aren't going to put the money into phase III trials that they are not enthusiastic about. And yet half of the products that going into phase III never get approved. The trials fail."
The SCT points out that the result of the legislation would mean seriously ill patients suddenly have access to dozens of unproven agents, many of which will at best do nothing and at worst hasten a patient's death.
"The advocates have written the bill around patients who have exhausted all their options, but it's clear from the writing of the bill that they have a much broader agenda here," said Colin Begg, Ph.D., senior author of the SCT position paper and chair of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center in New York. "What will happen is the floodgates will be opened and the market will be flooded with agents, the vast majority of which will be ineffective, and the patient won't have a clue which one to choose because there will be no evidence out there to distinguish the wheat from the chaff."
A linchpin of the legislation is the concept that the FDA's current standards are overly conservative and rely on a statistical standard that is too stringent.
Burroughs says that the Abigail Alliance position is "whenever efficacy starts to show up, drugs should be available for patients."
Frank Rockhold, Ph.D., vice president of biomedical and data sciences at GlaxoSmithKline Pharmaceuticals in King of Prussia, Penn., and former president of SCT, said changing the amount of risk we are willing to accept in new drugs is a societal decision, but he disagrees with the idea that somehow statistics are getting in the way of making reasonable decisions about which drugs reach patients.
"Everything is on a continuum," he said. "If you're looking at a scale of zero to 100 in the intensity of the science, and you think we are at a 95 and you want to dial it down to an 87 and you are willing to accept the risks of doing that, that's OK. I think [S.1956] puts us at about a 9.5."
Learning From History
Opponents of the movement toward deregulation point to the history of drug development and wonder why anyone would want to return to the days when unproven treatments were the norm.
The SCT points to several instances where seemingly promising treatments appeared to offer a benefit only to be shown ineffective or even harmful when they underwent rigorous testing in randomized clinical trials. Epidemiological studies once suggested that -carotene supplements could help prevent lung cancer in smokers, until two large cancer prevention trials showed that the opposite was true. And more recently, estrogen and progestin hormonal therapy was found to increase the risk of cardiovascular disease in postmenopausal women, not reduce it as previously thought.
"You know, we forget about the extent to which we are all benefiting, we are all here in this current state of health because we had access to the results of clinical trials," said Ellenberg.
Cancer patient advocates are divided in their support for earlier access. Some groups, particularly those that represent patients with rare cancers, support the Abigail Alliance approach. But others are wary of turning back the regulatory clock and worry that the public will be misled by a few heart-wrenching stories rather than thinking about what's best for the entire patient population.
"There's a general lack of understanding, even among very well-educated people, about the scientific method and clinical trials," said Musa Mayer, a patient advocate and breast cancer survivor. "It's just simply not a part of our public education. I certainly never understood before I became involved in patient advocacy anything about levels of evidence."
Mayer has served as a patient consultant to the FDA Cancer Drug Development Program and as a patient representative on the Oncologic Drugs Advisory Committee. She is currently developing a Web-based tutorial for cancer advocates on evidence-based health care and the clinical trials system.
"What people need to understand is that we already have in place a mechanism for accelerated approval of drugs that has shown that it works," said Mayer.
Mayer has worked with the National Coalition for Cancer Survivorship (NCCS) to hold a series of public roundtable discussions that resulted in a citizen petition to the FDA on March 27 requesting that the FDA clarify when patients who have run out of treatment options may be eligible for expanded access.
"We are looking for ways to expand access appropriately and at the same time enhance opportunities for patients to participate in research," said Ellen Stovall, president and CEO of NCCS. "If you want evidence-based medicine, which is the approach that we've always taken, then the best way to get there is to get people involved in randomized clinical trials. But that's not practical for everyone in today's marketplace. So we've been looking for ways that we could expand access and not compromise clinical research."
Their approach would also include an expanded discussion of the role of hospice and palliative care for cancer patients who have exhausted all other options, rather than holding out hope for a miracle from an untested experimental agent.
"There is a place for reasonableness in this, and what I have found lacking in the polar points of view is a determination of ‘who is in the place of reasonableness?’ and ‘how are we going to have a real discussion?’" Stovall said. "This is a very important decision that I am concerned is being determined by Congress and the courts, I think to the detriment of clinical research and of patients."
Copyright © 2006 Oxford University Press (unless otherwise stated)
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