Balancing Act
by Elisa Ludwig
April 2007
Early access to experimental therapies can mean the difference between life and death for patients with serious conditions. But for ethical, financial and legal reasons, the process is far from simple.
For patients battling chronic, life-threatening illnesses, almost anything offering hope is a welcome development. Often, that glimmer of hope is in the form of experimental drugs for which safety and effectiveness have yet to be proven. As patient advocacy groups demand early access to these treatments, biopharmaceutical manufacturers and regulatory agencies are trying to deliver promising therapies without sacrificing safety.
From the start, Erbitux (cetuximab) looked promising. In early clinical trials, developer ImClone Systems found that the drug, a monoclonal antibody that interferes with cancer cell growth, when combined with irinotecan, shrank tumors in nearly a quarter of the patients tested. However, an initial submission of the drug failed to gain approval from the U.S. Food and Drug Administration (FDA) because the documentation was incomplete, and the drug failed to curtail cancer growth in study patients. The resulting slide of the company’s stock price led to the insider trading scandal that famously landed the company’s CEO Samuel Waksal and his friend Martha Stewart in jail.
But the bigger issue among cancer patients and the medical community was that the drug that had given them hope would take much longer to come to market than expected. For two years, cancer patients flooded ImClone’s offices with requests for pre-approval access to Erbitux. In 2003, ImClone and its partner, Bristol-Myers Squibb, responded by opening up an expanded access program (EAP) that would conditionally allow the drug to be distributed to a limited number of patients. Over the course of subsequent months, patients discovered what later trials would prove: The treatment was in many cases effective, shrinking tumors in 10.8 percent of the patients. That number almost doubled when patients took Erbitux as an adjuvant treatment to chemotherapy.
After a second submission to the FDA, Erbitux was approved in February 2004 for use on patients with advanced colorectal cancer. But for some patient advocates, the triumph was bittersweet. Some argued that had the drug been made available sooner, it could have helped many more people fight the disease.
Into the Unknown
In the existing system, there are disincentives for establishing EAPs, such as sicker patients doing poorly, or the drug gaining a reputation for ineffectiveness. Some companies have simply not offered them. “I’d say, for the most part, industry is right in being cautious—and it’s not just for liability reasons,” says Ken Fornataro, founder and director of the AIDS Treatment Data Network in New York, N.Y., USA. “The first time something goes wrong, the public and families concerned will go nuts—even if the patient was begging for access to a drug.”
In addition to the potential public relations disaster should an experimental drug cause harm, the legal and financial risks of giving patients treatments that may never go to market are high. Some industry representatives have argued that providing early access to experimental therapies may actually interfere with the drug development process because patients may be less likely to enroll in a trial if there’s a possibility they’ll get a placebo when they know they can access the same drug through an EAP.
This is not a reasonable argument against EAPs, says Dr. Rachel Behrman, deputy director of the FDA’s office of medical policy, in Rockville, Md., USA. “I can’t think of any examples of a case where a drug development program has been derailed by an expanded access program,” she says.
One well-known example of an unsuccessful experimental treatment is Iressa (gefitinib), a lung cancer drug made by AstraZeneca that was given accelerated FDA approval and was distributed to 24,000 lung cancer patients through an EAP. Subsequent comparative studies found that the drug did not prolong patients’ lives and as a result, Iressa currently is only approved for use by patients already taking it.
“In the case of Iressa, it turns out that the drug works in a very specific subset of population, which was not understood at the time,” Behrman says. “When you’re talking about access to an investigational drug, it is entirely possible that the drug’s promise is not going to be met.”
According to an FDA press release in December 2006, EAPs have offered tens of thousands of terminally and seriously ill patients cutting-edge—and in some cases life-saving—options for treatment. However, due to limited availability and the lack of a centralized repository of EAP information, many of these programs remain unknown to the patients who might benefit from them.
EAPs differ from clinical trials, in which patients enroll knowing that they may or may not have access to the drug being tested. With the permission of the FDA, EAPs offer patients guaranteed access to an unapproved drug, using clinical trial safety monitoring mechanisms, including institutional review board evaluation, adverse event reporting and informed consent. When supplies of a drug are limited, some EAPs—including ImClone’s Erbitux program—will choose participants through a randomized lottery system.
Doctors and Lawyers
Although experimental treatments have been available to patients since the 1970s, the current EAP model dates back to the 1980s, when AIDS activists, angry at the lack of treatments for the disease, pushed pharmaceutical companies to make unapproved drugs more widely available to patients who were too sick or who lived too far from an academic medical center to enroll in clinical trials. In response, the FDA introduced regulations for a Treatment IND (Investigational New Drugs) program in 1987, which allows pharmaceutical companies to offer an investigational drug in Phase II studies under a treatment protocol to a large number of patients. With a single patient IND request, individual patients also can obtain the treatments through their personal physicians.
Yet the existing system still is not working well enough for many patient advocates. In 2003, the Washington Legal Foundation and the advocacy group Abigail Alliance filed a joint lawsuit against the FDA arguing that access to experimental treatments is a constitutional right. The case was dismissed in 2004, but in May 2006 in a 2-1 opinion, the U.S. Court of Appeals for the District of Columbia reversed the lower court’s decision. At the FDA’s request, the appeal was re-heard by the court’s full panel of judges in March 2007. As of press time, the court had not reached a decision.
On the legislative front, U.S. Sen. Sam Brownback introduced a bill in 2005 that would widen access for drugs in as early as Phase I testing to seriously ill patients.
In late March 2006, the National Coalition for Cancer Survivorship (NCCS) and the American Society of Clinical Oncology (ASCO) petitioned the FDA for clarification regarding the standards for expanded access programs. “We were looking for a regulatory solution to a problem confronting many cancer patients,” says Ellen Stovall, president and CEO of the NCCS, in Silver Spring, Md., USA. The petition, a culmination of five years’ worth of discussion with patients, advocates and physicians, is what Stovall calls a “reasonable approach to expanding access to unapproved therapies.”
Under mounting public pressure, the FDA published a new draft regulation in December 2006. The new guidelines clarify existing regulations and reflect the range of options for access. The FDA also announced that it is developing a program to distribute cancer treatments in Phase II and Phase III trials to thousands of patients through a network of community oncologists.
“What we’ve heard is that, because various subtypes of access are not embodied nor codified in the regulations, there could be a lack of clarity or a lack of accessibility to those that are less familiar with the FDA,” Behrman says. “We know that the more transparent the agency is, the easier it will be for companies that want to develop these programs effectively and efficiently.”
The draft regulation also addresses cost recovery coverage for EAPs. Although in most EAPs the manufacturer will cover the cost of the product, the new regulation addresses a broader range of circumstances and outlines the procedures in greater detail. It also encourages smaller manufacturers to establish EAPs by allowing them to charge for the cost of the drugs, which in the case of experimental treatments, means companies could charge for development costs and the administrative costs of making drugs available before approval.
The draft regulation articulates the FDA’s primary and sometimes conflicting concerns: offering treatment to individuals and safeguarding the drug development process. “We want these products to get to market,” Behrman says. “One can run an access program and have it not impede any efficient and effective drug development efforts. If any access program interferes with development then that access program would have to be halted,” she says.
Stovall is less concerned with whether the regulation or proposed distribution program will discourage pharmaceutical companies from starting EAPs, she says. She is more interested in continuing a dialogue with companies who have existing programs and continuing to build patient awareness of treatment options, she says. “Right now, expanded access programs vary widely in their design and administration, and NCCS and ASCO hope the FDA will provide guidance to those who do want to sponsor programs and make sure there is some equity in the system.”
High Risk
Although patient advocacy groups agree upon expanded access, they may disagree about the level of access patients should have and the best means for assessing risks and benefits of access to unapproved therapies.
Some advocates such as the Abigail Alliance have pushed for a tiered system of approval that would allow patients access to drugs as early as Phase I, but others have taken a far more cautious approach. “You can do a lot of harm by enabling access to medication that’s experimental,” Fornataro says. “Everyone wants to speed things up, but if you’re uncertain about the safety profile of a drug or if you haven’t done extensive drug-drug interaction testing and good pharmacokinetic studies in a heterogeneous population, there are certain things you need to know before making a drug available.”
As long as drug development continues to be a long, expensive process, patients running out of hope will want access to emerging treatments before they’ve been approved. Although EAPs can offer researchers a way of gleaning information outside of tightly controlled trials, they never will be a substitute for the traditional clinical trial system, Stovall says. “It sounds almost too simple to be profound, but the best way to expand access is to get the drug approved.”
Web Extra: Early Access Legal Developments
In March 2007, the U.S. Court of Appeals for the District of Columbia reheard the arguments of a 2003 case filed by the Abigail Alliance for Better Access to Developmental Drugs against the FDA. The case holds that access to experimental treatments is a constitutional right. No decision has been made yet.
“I don’t think they’re going to win, because the case basically says that people who are terminally ill should have access to any drug that’s been through Phase I trials,” says Arthur Caplan, Ph.D., director of the Center for Bioethics at the University of Pennsylvania, in Philadelphia, Pa., USA. “There are Phase I drugs that look promising, and Phase I drugs that are too new to know what to make of them. You have to have some judgment before you can start throwing stage one drugs willy-nilly to the terminally ill.”
According to Caplan, there are several problems with opening up access to drugs that have only been through Phase I trials:
- “The definition of ‘terminal illness’ is hard to pin down,” he says. “There’s not consensus [on its meaning].” Although some cases clearly can be labeled “terminal,” others are not so clear-cut.
- Phase I studies do not establish safety. “They start toward that, but they don’t get there,” he says.
- “Drug companies are under no obligation to provide anything,” he says. “They’re private parties. The insurance companies won’t pay [for experimental treatments] and the drug companies don’t have to give them out.”
As an alternative to allowing complete access, Caplan recommends a broader compassionate user program. Such a program would entail an 800-number and a faster process for requesting access to a trial. “The FDA would need to have a special appeals board,” he says.
For now, the pharmaceutical industry is waiting and watching. “The pharmaceutical industry is not willing to cross swords with the patient groups,” he says. “The prudent course here is to just watch. But I think if there’s more compassionate use allowed, drug companies will be expected to give out more drugs for free or at a lower cost. We’ll have to see if they’re willing.”
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