BETHESDA, MD 31 August 2009—FDA in August released a final rule that outlines the agency`s policies for ensuring patients` access to investigational drugs outside of a clinical trial setting.
The rule, titled "Expanded Access to Investigational Drugs for Treatment Use," mostly codifies and clarifies existing agency policies governing access to these drugs, Janet Woodcock, director of FDA`s Center for Drug Evaluation and Research, told reporters August 12.
Access to experimental drugs. FDA in 1987 issued the first regulations explicitly allowing the use of investigational new drugs for the treatment of seriously ill patients not participating in a clinical trial.
The following year, the agency allowed trimetrexate to be distributed in accordance with the new regulations to AIDS patients with Pneumocystis carinii pneumonia who could not tolerate standard forms of treatment.
Woodcock said "tens of thousands" of patients have received investigational drugs outside of clinical trials over the years for what FDA calls treatment use of the drugs. She said she does not expect the new rule to "radically expand access" to investigational drugs but rather to make more patients and physicians aware that they may be able to obtain these medications outside of clinical trials.
"Clearly, this opens up more scenarios for patients and provides clarity, and we would expect that many more people will take advantage of this," Woodcock said.
The rule states that under FDA`s current system, as many as 53,159 patients each year try an investigational drug under treatment-use protocols, also known as compassionate-use protocols. The agency estimates that, once the new rule becomes effective on October 13, that number may increase by up to 3,095 patients.
The new rule requires that before applying to use an investigational medication, the patient`s physician must conclude that the probable risk to the patient of taking the drug is not greater than the risk from the illness itself. The decision to use a drug whose risks and benefits are not clearly understood will depend on a patient`s individual circumstances.
"The more dire the patient`s situation, the more justifiable taking that risk is," Woodcock explained.
FDA presumes that the physician is well informed about the patient`s clinical situation and able to make good use of what may be limited information about the risks of an investigational drug.
The rule also states that FDA has proprietary information about the risks of investigational drugs that, combined with the treating physician`s input, will produce the best decision for the specific patient.
Under the new rule, the physician must determine that the patient cannot gain access to the investigational drug by participating in a clinical trial or any other established protocol for treatment use of the drug.
This provision is intended to ensure that patients who are eligible and able to participate in a clinical trial do so, allowing the drug maker to obtain the data necessary for FDA to evaluate whether it can approve the drug for marketing.
Woodcock said FDA can allow patients to receive an investigational drug very early in the development process—as early as the end of Phase I safety testing.
"We want some controlled safety testing of drugs to make sure...there are not going to be horrendous human toxicities," Woodcock said.
She said FDA in the past has allowed patients to receive investigational drugs for treatment use after initial Phase I dose-tolerance data became available.
Phase I testing is often done in normal human volunteers and is not intended to produce data on the drug`s effects on a disease. But Robert Temple, director of FDA`s Office of Medical Policy, explained that Phase I testing of cancer drugs is often done in oncology patients and could yield preliminary efficacy data.
"You sometimes get a hint of something promising at the end" of such a Phase I study, he said.
An important prerequisite for treatment use of an investigational drug is that the manufacturer has enough of the medication available and is willing to provide it to patients who are not enrolled in a clinical trial. FDA requires the patient`s physician to make arrangements with the manufacturer to ensure the availability of a supply of the experimental drug before the agency will authorize the patient`s use of the drug.
A federal appeals court ruled in 2007 that seriously ill patients do not have a constitutional right to experimental therapy [see October 1, 2007, AJHP News]. The case involved a young woman with squamous cell carcinoma who sought but was denied access to investigational drugs and later died of the disease. The U.S. Supreme Court in 2008 declined to hear an appeal of the case, rendering the earlier decision final.
A price to pay. A second final rule dealing with investigational drugs clarifies situations under which manufacturers can charge patients for the drugs. This rule, like the one on patient access, mostly explains policies that have been in place since 1987.
Only costs that are directly related to the production of a drug can be considered for recovery from patients. Manufacturers cannot add a profit or ask patients to pay for research and development costs.
"By permitting charging for expanded access, we hope to stimulate more companies to provide investigational drugs, companies that might not otherwise have been able to offer expanded access for that particular drug," Woodcock said.
The rule differentiates between clinical trial participants and individual patients seeking treatment use of a drug. According to the rule, treatment use of an investigational drug is not part of the normal cost of drug development, and charging for such use is "more appropriate" than charging participants for drugs in clinical studies.
"Charging for a drug during a clinical trial...is expected to be very unusual, reflecting the view that the party developing the drug should generally bear the financial burden of development, not the patient," Woodcock said. "Charging would be permitted only if the drug has the potential to provide a significant advantage over available therapy, if the data developed in the trial would be essential to establishing that the drug is safe and effective, and if the drug could not be developed absent charging."
The rule requires that drug-production costs to the manufacturer must be "extraordinary" in comparison with the organization`s resources for FDA to allow clinical trial participants to be charged for the experimental therapy.
According to the rule, FDA receives about 23 requests each year from manufacturers to charge patients for investigational drugs used in clinical trials or for treatment. The agency expects to receive about a dozen additional charging requests each year in response to the final rule.