FDA simplifies patient access to investigational drugs

ABSTRACT: Rules balance access to promising new therapies against the need to protect patient safety.

The FDA published two rules designed to help cancer patients gain access to investigational drugs and biologics. The rules clarify the options available to those patients who are not eligible for clinical trials or who have no satisfactory treatment options.

"The final rules balance access to promising new therapies against the need to protect patient safety, and seek to ensure that expanded access does not discourage participation in clinical trials or otherwise interfere with the drug development process," said Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research.

"Despite our best efforts to increase access, we understand that there are still inequities," added Ann Farrell, MD, deputy director in the FDA's division of drug oncology products. "By improving regulations and making the public more aware, there will be greater use of these programs. We also wanted to clarify submission requirements, to reduce the economic burden of administering these agents, and to enhance safeguards."

The FDA expects that the rules will continue to protect the safety of subjects, preserve the integrity of drug development, and facilitate access for individuals, Dr. Farrell said.

Understandably, access to investigational agents is extremely important to some cancer patients. The simplest means is through an expanded access protocol for drugs in late-stage development. Examples of these programs and the numbers of patients served include gefitinib (Iressa) for non-small-cell lung cancer (24,000), oxaliplatin (Eloxatin) for colorectal cancer (8,500), gemcitabine (Gemzar) for pancreatic cancer (2,500), and imatinib (Gleevec) for chronic myelogenous leukemia (7,000).

Beyond this type of open access, physicians can apply for a drug on behalf of their patients through the single-patient investigational new drug (IND) request or, less often, a special protocol exception program, which is for cases in which ambiguity is greater than eligibility. These requests are addressed by the pharmaceutical company on a case-by-case basis and are not very common, according to Andrew P. Krivoshik, MD, PhD, medical director of the oncology group at Abbott Laboratories. For one compound in development at Abbott, for example, only 40 requests submitted through the special protocol exception program have been granted over four years.

That's because the data supporting the request must be very sound and the compound must be available, Dr. Krivoshik said. "For a drug early in development, there's no guarantee of access. There can be a limited supply, validation issues, and other obstacles. Even patients who may qualify for the investigational drug on a compassionate use basis may not be able to get it."

“While patients participate in trials through altruism and to help us improve care for future patients, we know from common sense...that many patients seek clinical trials for their own needs.” - Jeffrey peppercorn, MD, MPH

To enhance the possibility of obtaining a drug, Dr. Krivoshik urged oncologists to "begin the dialogue with the patient early on." For many requests, the process takes just one month, but these are critical times in the lives of seriously ill patients, he said.

Ideally, an oncologist will be able to direct a patient to the appropriate clinical trial. But if the patient is ineligible for a trial, the process to obtain compassionate or emergency use of the drug or biologic can be initiated.

The manufacturer will want detailed information about the patient and the treatment plan, backed by a strong rationale for use of the drug. If the request is accepted, the manufacturer and physician will collaborate on a single-patient IND proposal to the FDA.

If the FDA grants access, the physician seeks prompt approval from his or her institutional review board. The process from patient request to FDA approval can often be completed in less than a month.

But some argue that treatment with an unproven agent outside of a clinical trial cannot be justified on either clinical or ethical grounds, said Jeffrey Peppercorn, MD, MPH, an assistant professor of medicine at Duke University in Durham, N.C. In spite of the FDA's reassurance, for example, there remains a concern that increased access to off-protocol treatment will further slow accrual to clinical trials.

"While patients participate in trials through altruism and to help us improve care for future patients, we know from many studies and common sense that many patients seek clinical trials for their own needs," he said.

Other concerns are the possibility of imbalance of access according to socioeconomic background, unexpected toxicities, and the diversion of focus and resources.

Apparently, attitudes and practices vary among clinicians, though most generally support novel interventions, according to a survey of oncologists conducted by Dr. Peppercorn and colleagues. Of the 146 of 471 survey recipients who responded, 93% reported ever discussing off-protocol therapy with their patients and 81% prescribed it; 66% prescribed investigational treatments at least once a year and 12% did so at least once a month. While 61% believed that patients should be discouraged from off-protocol treatments, only 31% felt they should not be available (J Clin Oncol 26:5994-6000, 2008).