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February 19, 2008 • Volume 5 / Number 4 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Special ReportA Closer Look

Navigating Access to Investigational Drugs

NCI's mission includes extensive funding and performance of clinical research, better known as clinical trials. The modern clinical trials system takes promising new cancer drugs through three main phases, culminating in approval by the Food and Drug Administration (FDA) for successful agents. Most patients who receive investigational drugs do so through clinical trials.

For more information
Information about eligibility for particular cancer clinical trials can be found at
. Information about NCI's Treatment Referral Center is available at
. FDA's Cancer Liaison Program provides information at

But not all patients seeking access to investigational drugs are eligible for a clinical trial, due to factors as varied as co-existing illness, time since prior treatment, and extent of disease. Both the FDA and NCI currently manage programs to respond to demands for investigational drugs outside of the clinical trials system.

Expanded Access
Individual patients and their physicians seeking permission to use an investigational drug outside a clinical trial must go through FDA's special exception use process. "In order to pursue access to unapproved drugs outside of a clinical trial, the patient must have been through everything that is currently approved for that disease - not just approved by FDA, but used in practice to treat that disease," explains Patricia Delaney, director of FDA's Cancer Liaison Program.

In addition, to get FDA approval for special exception use, a drug must also be considered safe. "If a patient has a life-threatening disease and has exhausted all of their treatment options, FDA almost always says yes, unless there is a safety issue that the public doesn't know about," says Ms. Delaney. However, a patient cannot simply go directly to FDA and request access, because FDA itself does not control these drugs - they belong to the company developing and testing them. "The first stop [for permission] is the company," she explains. "And that's usually a pretty big threshold, because most companies are not sanguine about providing their unapproved drugs to patients outside of a clinical trial."

Evolving Questions
Risks to patients, drug developers, and the clinical trials system itself underlie the ethical dilemmas surrounding expanded access to investigational drugs. Recently, the Abigail Alliance for Better Access to Developmental Drugs brought a lawsuit all the way to the Supreme Court of the United States, advocating that terminally ill patients had a constitutional right to purchase investigational drugs directly from companies after preliminary - phase I clinical trial - evidence of safety and efficacy.

Although the Court declined to hear the appeal, many questions it raised remain actively debated in the medical community. Would such unfettered access pose undue risk to patients? Does such increased risk matter for patients facing a terminal disease? Would excluding the FDA encourage unethical direct marketing to patients? How would the clinical trials system - which provides the eventual proof that these drugs do or do not work - be affected?

For Dr. Nancy Kass, professor of Bioethics and Public Health at the Berman Institute of Bioethics at Johns Hopkins University, the shifting risk/benefit ratio that patients face when choosing to take drugs with largely unknown side effects and unproven therapeutic efficacy is not the only pressing question. "I think…people who are pretty vocally asking for the drugs are saying that they appreciate there is less known about the risks of the drugs, and they're saying they don't mind."

What interests her is that "we need to navigate a balance between duties to respond to patients in front of us, and duties to learn about what does and doesn't work in cancer treatment, so that the next group of people diagnosed with cancer also has something to help them. If we have something that we know works, the balance gets flipped - we'd give it to you, end of story. But if we have something where we don't know if it works, I would argue…that's exactly the time when that drug should be given in the context of a highly structured, well-organized clinical trial, so we can not only determine if it's helpful for you, but learn about it, to see if it makes any difference for future cancer patients."

Access at NCI
In one of its many roles, NCI functions as a drug developer, creating and testing new anticancer compounds. NCI coordinates its own special exception program with the FDA, as would a pharmaceutical company, through the Treatment Referral Center, located in the Cancer Therapy Evaluation Program (CTEP). "We work directly with the company, local oncologist, and FDA to obtain permission to distribute investigational agents to individual patients not eligible for clinical trials," explains Matthew Boron, a CTEP senior clinical research pharmacist.

As with any pharmaceutical company request, the agent must have a safe dose and schedule determined from phase I trials. In addition, "we need to see that there's some evidence of activity in a particular tumor type," says Mr. Boron. If an experimental drug seems promising for an individual patient, CTEP will first try to identify a clinical trial that could enroll the patient. That failing, "we would look to alternate mechanisms," he continues.

One alternative is developing collaboratively with CTEP a Special Exception/Single Patient Protocol. To obtain an investigational agent under this mechanism, the patient must be ineligible for a research protocol and also have exhausted all standard therapies. In addition, the requested agent must have demonstrated activity in their disease with no unacceptable risk to the patient.

NCI has also used two unique programs to provide experimental drugs in the later stages of development to larger groups of patients. These two programs - called Group C/Treatment IND and Treatment Referral Center (TRC) protocols - have provided access to promising new drugs to almost 20,000 patients since their inception. Unlike most protocols sponsored by CTEP, the Group C and TRC protocols are generated from within CTEP in an effort to provide access to promising therapies that would otherwise not be accessible.

The Group C and TRC protocols "are typically instituted to bridge the gap between positive phase II or positive FDA registration data, and drug availability. They're usually designed to get up and running quickly and to close quickly," explains Mr. Boron.

The Group C classification, which is no longer used, went to agents near the end of the approval process that were expected to rapidly change the standard of care. Clinical trials had already shown their reproducible efficacy in one or more tumor types, but wider distribution and marketing awaited FDA approval. Any NCI registered physician could register with NCI to receive Group C agents. Drugs first distributed widely through Group C protocols include paclitaxel for ovarian cancer and levamisole for colorectal cancer. The Group C classification has been replaced by the Treatment Protocol or Treatment IND.

Unlike Group C protocols, TRC protocols are restricted to distribution through NCI-designated Cancer Centers and designated secondary centers. In fact, explains Dr. James Zwiebel, chief of CTEP's Investigational Drug Branch, one of the focuses of the program is to make sure distribution of a new drug "is done in an equitable way, in a way that's sensitive to geographical distribution." They also function more like multicenter single-arm clinical trials with relatively open eligibility criteria and simple objectives. They usually only require limited data collection focusing on safety and efficacy. To be eligible for a TRC, a drug must show highly promising activity or target a tumor type considered to be a high priority by CTEP.

For example, nelarabine (Arranon), now an approved treatment for T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma - both rare cancers - was available for almost 10 years through a TRC while waiting for review, approval, and marketing. "It's a small population of patients…but an effective therapy that they otherwise would not have had access to," says Mr. Boron.

—Sharon Reynolds