As FDA weighs the creation of an Expanded Access Navigator program, an independent panel's leaders say written assurance that adverse events will not damage a drug's prospects for continued development or approval would have far more impact in enabling pre-approval access for desperate patients.

FDA should "publish a statement assuring companies that the agency understands serious adverse events can and will happen in compassionate use setting and that such events will not constitute a 'kiss of death' in the eyes of the regulator," Alison Bateman-House, a postdoctoral fellow at New York University Langone Medical Center's Division of Medical Ethics, said.

Bateman-House is deputy chairman of the Compassionate Use Advisory Committee (CompAC), which was created a year ago to vet requests for pre-approval access to Janssen Pharmaceutical Cos.' multiple myeloma drug Darzalex (daratumumab) ([A#00160509005]).

Her remarks came in written comments submitted for a May 16 meeting on a Reagan-Udall Foundation proposal for a navigator program. The goal of the Expanded Access Navigator would be to make it easier for physicians and patients to seek access to unapproved drugs (often referred to as expanded access or compassionate use) by providing a central repository of information about FDA requirements, biopharma manufacturers' policies and points of contact ([A#14160516003]).

Although FDA has stated multiple times that it does not routinely halt drug trials when patient deaths occur during expanded access, "what is needed is for the FDA to put this statement in writing," Bateman-House said.

'Fearful' Of Patient Deaths

Arthur Caplan, professor and founding head of the Division of Bioethics at NYU's Langone Medical Center and the chairman of CompAC, made similar comments at the Orphan Drug World Congress meeting in Washington, DC in April.

When asked whether the risk of legal liability is a disincentive for biopharma companies to make drugs available for expanded access, Caplan said manufacturers are more concerned about a patient death in such circumstances.

"FDA tells us again and again they are not stupid, they understand that [for] dying people who take drugs many of them are going to die anyway and that shouldn't be held against the drug," Caplan said. "Our position with FDA, we keep asking them … write it down. I think that it would be good to have a written statement saying what I just said."

"That's probably where the legal issues loom largest," Caplan said. "Companies are still fearful. So are investors. So are angel investors, so is Wall Street. So that's where the legal liability tension is."

Mostly 'Anecdotal' Information

The regulatory impact of adverse events occurring during expanded access – including their potential to derail a drug's development – has been a longstanding concern for companies Also see "Making Expanded Access Programs Work For - Not Against - Your Trial Drug" - Pink Sheet, 7 June, 2010..

Industry representatives also have asked FDA to issue a formal written position on the subject.

"It is our view that by formally specifying how adverse events in expanded access cases will be treated, FDA would be providing much needed clarity for companies considering expanded access requests," a spokesman for the Biotechnology Innovation Organization said.

At the Reagan-Udall Foundation meeting, Center for Drug Evaluation and Research Deputy Director for Science Operations Richard Moscicki acknowledged industry's worry. "They have voiced concern that if they offer expanded access, this might adversely affect their clinical development and regulatory progress for that particular situation or that program," he said.

However, FDA has not indicated it is prepared to make a formal policy statement on the subject.

Serious adverse events during expanded access resulted in clinical holds in only 0.2% of cases over a 10-year period, FDA said.

When asked about Caplan's remarks and FDA's position on the impact of serious adverse events during expanded access, a CDER spokesman told the Pink Sheet that agency officials "consider the disease state of the patient, which may be further advanced than those of clinical trial participants, when evaluating adverse events from use through expanded access to investigational drugs and biologics."

"Patients receiving access to investigational products through expanded access are often receiving other therapies for their disease or condition, and may be receiving therapies for comorbidities that disallowed them from entering the clinical trial for the investigational product, which can also confound the results of IND treatments," CDER said. "For the most part, the information is considered anecdotal, outside the context of the trial data."

At the Reagan-Udall meeting, Richard Klein, director of FDA's Patient Liaison Program, suggested concerns that the agency will slap a clinical hold on a development program due to a serious adverse event during expanded access are not supported by the data.

FDA has reviewed the number of clinical holds placed on product development studies resulting from sudden and severe adverse events reported during expanded access. From 2005-2015, FDA placed a clinical hold on only two commercial INDs out of approximately 1,000 that involved expanded access INDs or protocols as a result of adverse events. Development of the two products continued after the clinical holds were lifted, CDER said.

Agency staff who review expanded access adverse event reports "are very aware that you're talking about patients who have exhausted other treatment," Klein said. Such patients are "dealing with multiple disease issues and concomitant drugs and problems and … death or adverse events is not necessarily unexpected."

When asked by the Pink Sheet whether FDA planned to issue formal guidance on the impact of adverse events during expanded access, the agency said it was not on the 2016 guidance agenda.

However, agency officials said they expect to soon finalize three guidances related to expanded access, including documents on general issues and charging for investigational drugs. The third guidance relates to a new, simpler form for physicians seeking an expanded access IND ([A#14150204009])

In her comments on the Expanded Access Navigator program, Bateman-House urged the agency to conduct an audit, either retrospectively or prospectively, of the percentage of new drugs approved despite deaths or other serious adverse events during non-trial use.

"If companies understand that the FDA will not automatically penalize them for SAEs [serious adverse events] in the compassionate use setting but will rather use discretion in deciding which SAEs to investigate, will all companies open their doors to those seeking access to their investigational drugs? No," Bateman-House's comments state.

"But this one factor is more likely to expand patient access than building a navigator or any other proposal currently on the table."

Expanded Access Programs Need FDA Policy Changes To Really Expand

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