FDA Encourages Expanded Access for Trial Subjects
The FDA is encouraging sponsors to offer expanded access (EA) to investigational products to subjects after clinical trials are completed.
“We urge sponsors to consider EA in appropriate settings; and especially after patients who are showing promise on an experimental drug complete therapy in a clinical trial setting,” a March 29 joint statement from FDA Commissioner Scott Gottlieb, Center for Drug Evaluation and Research director Janet Woodcock, and Center for Biologics Evaluation and Research director Peter Marks said.
“Although we often focus on EA as providing access to patients who cannot enter clinical trials, EA can also be considered as a mechanism for those who have participated in a trial in order to allow them to continue receiving a drug that may have provided benefit,” the statement said.
“At the end of a trial, sponsors may continue to provide treatment to participating patients through an extension study to gather additional rigorous information that’s needed to support the subsequent marketing application. Alternatively, if the purpose is primarily to provide the drug to patients who continue to need it, an EA program may be used for either moderately sized populations (intermediate EA) or large size populations (treatment EA), often when most studies in support of approval have been completed. As another option, a sponsor could authorize a patient’s own physician to obtain a single patient EA investigational new drug (IND) application,” the statement said.
The FDA noted that once a trial is completed, EA is generally available when clinical trial results show that the drug is effective in the studied population. However, sometimes drugs that have not shown benefit across the overall study population may still be providing benefit for individual patients.
“In such situations, EA may have a role in allowing patients to have continued access to the drug. We would generally support such efforts,” the statement said. “Providing EA to patients who undertook the risks that are inherent to participating in any clinical trial is an acknowledgement of the contribution these patients have made to the overall drug development program. Of course, in situations where an experimental treatment is potentially associated with substantial risk – and where the therapy has not been demonstrated to be effective in a trial – continued access must be carefully considered by the physician and the patient, and weighed by the sponsor, especially if further development of the drug is being reconsidered.”
The FDA noted that a decision regarding starting an EA program must be weighed against the potential effect on the product’s development program. “The primary goal of any drug development program must be to expeditiously bring the drug to the market, thereby providing broad access to patients who need the drug. Many novel therapies are being developed by small companies that may have only a single product. The supply of investigational product may only be sufficient to support the clinical research trials, and not be adequate to support EA. In addition, certain biologics, such as cell and gene therapies, are particularly complex and expensive to manufacture, so the cost to the company of providing such access may be prohibitive,” the statement said.
FDA: EA ‘Rarely’ Affects Development
The FDA added “there are persistent misperceptions among pharmaceutical companies about the risks of providing a drug under EA, despite evidence to the contrary. We want to reassure sponsors that providing a drug under EA very rarely impacts development timelines.”
The statement cited an agency analysis of more than 10,000 EA applications from 2005 to 2014 that found the incidence of a clinical hold due to an adverse event on an EA IND was 0.2 percent compared to 7.9 percent for clinical holds for all commercial investigational drug development programs.
“The two cases of clinical hold resulting from an adverse event in an EA IND occurred in response to the deaths of two cancer patients, who were receiving treatment under different EA INDs, shortly after infusion of the investigational drug,” the statement said. “In both cases, the clinical holds were resolved.”
In addition, a review of more than 300 regulatory decisions between 2010 and 2016 showed expanded access “did not result in a negative decision on any application. In only one case did a final label include a drug interaction based on EA experience alone,” the statement said, adding FDA reviewers “understand that assessment of any serious adverse event that occurs during EA must consider the context in which the investigational drug is provided, as described in our guidance.”
“It’s very rare that EA impacts a clinical development program in a negative way,” the statement said. “While perhaps not commonplace, EA may add to the evidence for approval.” The statement cited the approval of uridine triacetate, which was based solely on experience within EA programs – 60 single-patient INDs and one treatment protocol and Lutathera (lutetium Lu 177 dotatate, which was approved for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) based in part on data from more than 1,200 patients who received Lutathera at a single site initially through an EA program.
“These are not the only examples where information from EA programs was combined with information from clinical trials and supported approval decisions,” the statement said. “EA has been an important program, providing access to innovative therapies that can provide meaningful benefits to patients with serious diseases who lack therapeutic alternatives and cannot participate in clinical trials.”
“We support efforts by sponsors to offer promising medicines to patients through EA. This includes continued access after the completion of a clinical trial, sometimes through an extension study,” the FDA concluded.