FDA Today | A New Pilot Program for Drug Excipients

We are back from our Labor Day respite and already preparing for a busy, busy month for regulatory developments. At the top of our list right now is next RAPS’ Regulatory Convergence conference next week where most of the FDA’s top regulators are due to speak. Nearly our whole team will be in attendance, and several of our researchers will also be giving presentations. If you’re interested in seeing which sessions we’ll be speaking at (or want to speak to us at the conference), you can learn more here .

In today’s newsletter, though, we want to talk about something exciting happening in a field that is normally quite boring: Excipients. Those are the binders, solvents, preservatives and flavors that basically make up the majority of a drug’s physical form. The FDA has a new plan to help spur the development of novel excipients, and it’s finally out after years of development. AgencyIQ’s Lily Rosenfield has the details for us below.

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After years in development, FDA launches pilot to review novel excipients

The top line: Almost two years after it was first proposed, the FDA has finally announced its plans to launch the Novel Excipient Review Pilot Program in a bid to help accelerate the development and use of novel excipients outside of the typical drug development process.

First, let’s talk about how excipients are defined and regulated.

• The FDA defines an excipient, or inactive ingredient, by what it’s not. Excipients are substances that are not an active ingredient under 21 CFR 210.3(8), defined as a substance “intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.”
• The agency recognizes many different types of excipients, which include fillers, extenders, diluents, wetting agents, solvents, emulsifiers, preservatives, flavors, absorption enhancers, sustained-release matrices and coloring agents.
• Once an excipient has been used in an approved product, the FDA adds it to the inactive ingredients database . Inclusion in the database indicates to other developers that it has been previously found acceptable to use, and therefore may be acceptable to use in other cases as well. However, outside of being deemed acceptable through a full approval package (NDA or BLA) or an Investigational New Drug application (IND), the FDA does not have a review pathway dedicated to excipients.

This creates problems for manufacturers looking to use novel excipients.

• Conducting testing on novel excipients takes time, money and effort. When developing a new drug, a manufacturer may be reluctant to experiment with the development of a new excipient for fear of causing delays that could add to overall development costs or introduce regulatory concerns about the safety of a drug product. These complexities limit innovation and research in excipients that could potentially enhance therapeutic effects or have other benefits.
• The FDA has been working on a pilot program for novel excipient review for the past two years. In December 2019, the agency published a notice outlining a new Novel Excipient Review Program, which would de-couple the review of novel excipients from product reviews. The agency wrote that the pilot would “reassure drug developers that the novel excipient can be used in a drug development program while minimizing the risk that safety concerns would be raised by FDA during application review.” [Read our analysis of that notice here .]
• Industry raised questions about the program’s scope and the proposed definitions. In its original proposal, FDA stated that within the program a novel excipient would be defined as an excipient “that has not been previously used in FDA-approved drug products and that does not have established use in food.” In response, Bayer wrote that the FDA’s current focus should be expanded to excipients without a well-established history in drugs or a particular route of administration. The International Pharmaceutical Excipients Council (IPEC) Europe , an association focused on excipients, said it also disagreed “strongly” with the FDA’s scope. [Read AgencyIQ’s analysis of the comments FDA received on the proposal here]
• Commenters highlighted key questions related to the definition of “novel excipients.” BASF wrote that “co-processed excipients also [need] to be specifically addressed.” Similarly, DFE Pharma and Meggle Pharma asked if a novel route of administration for an existing excipient would be classified as a “novel use” under the pilot program.”

Almost two years later, the FDA has now announced the launch of the Novel Excipient Review Pilot Program.

• According to the announcement , “the pilot program seeks to foster development of excipients that may be useful in scenarios in which excipient manufacturers and drug developers have cited difficulty in using existing excipients.”
• The FDA updated the definition of excipient – but doubled down on the program’s intended scope. In response to comments from industry, the FDA stated that for this program a novel excipient “is any excipient that is not fully supported by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration.” However, despite comments regarding the pilot’s scope, the FDA maintains that the program will be open only to novel excipients that “have not been previously used in FDA-approved drug products” and “not have an established use in food,” at least initially.
• Submissions under the pilot will be in two phases: First, developers interested in the pilot will be asked to submit an initial proposal that includes a “high-level overview of their novel excipient” to the FDA. The agency will accept four of these proposals to participate in the pilot for full review. The four submissions accepted into the pilot will be expected to provide toxicology and quality data as outlined in FDA guidance on excipients.
• The FDA outlined its top priorities for the first four excipients. The agency noted that it will consider the proposals it receives based on the excipient’s potential public health benefit, the likelihood of the submitter to be able to product a complete package in the allotted timeframe and the excipients potential to “meaningfully improve pharmacokinetic characteristics that may lead to novel drug development.”
• FDA will also determine if the four selected novel excipients are appropriate for use in clinical trials. If the FDA finds that a novel excipient is appropriate for this use under the pilot program, sponsors be able to utilize the novel excipient in an IND “within the defined use without additional justification.” However, the FDA adds that “the drug sponsor would still need to demonstrate that the excipient is safe in the proposed formulation.”
• This means excipients reviewed under the pilot program would not be able to be used in a generic drug application – at least not yet. FDA explains that Abbreviated New Drug Applications typically include information that would be inadequate to support using a novel excipient. Instead, the agency suggests that after approval of an NDA or BLA with the novel excipient it would be added to the Inactive Ingredient Database , at which time the excipient could be used by generic manufacturers.
• What’s next? The FDA is looking for initial proposals for the voluntary program and will be accepting submissions until December 6th (90 days from the notice publication).

What we're watching and reading

• …this report by our POLITICO colleague Lauren Gardner that “pressure is mounting on the Food and Drug Administration to authorize Covid-19 vaccines for children under 12 — even though the data needed to support the move is still being collected.”
• …this new study which sought to assess the implementation of the 21st Century Cures Act’s requirement that companies publicly disclose their expanded access policies (i.e., if someone could obtain compassionate access to a drug outside of a clinical trial, how would they obtain it?). The study authors found that “about one-third of applicable biopharmaceutical companies (32%, 140/423) implemented the Cures Act requirement to have a public expanded access policy. Less than 1/3 of public policies contained all described information (31%, 44 /140).”
• …this warning from the Coalition for Epidemic Preparedness Innovations (CEPI) that the world risks impeding the development of future Covid-19 vaccines – including boosters – due to a shortage available to support clinical trials. “So far, COVID-19 vaccines have received approval on the basis of data from unvaccinated participants in placebo-controlled efficacy trials. These trials become increasingly difficult to carry out as the number of people who are immunized rises. Comparator vaccines, essentially replacing placebos, are therefore needed for trials that assess whether new candidate vaccines provide comparable levels of protection, including against emerging variants.” ( More from STAT here ).
• …this research looking at the number and types of challenges to critical patents for FDA-approved novel drugs and biologics.
• …this report looking at two new analyses which found “wide variation in Patient-Reported Outcomes measures in cancer trials.”
• …this FDA hiring notice for an Associate Director for Counter-Terrorism and Emergency Preparedness.
• …this report looking at how actions by the U.S. Copyright Office could “have profoundly favorable implications for the use by servicers of electronic medical device equipment manuals.”
• …this upcoming FDA meeting to discuss the enhanced drug distribution security provisions of the Drug Supply Chain Security Act (DSCSA).
• …this report that TransMedics has received FDA approval for its OCS Heart system. FDA had convened an Advisory Committee to review the device, which supported its approval with some significant caveats. The device acts as a sort of organ-life extender after the death of a patient, allowing the organ to be preserved for a longer period of time between transplants.
• …this meeting notice that the Alpine Group’s Michael Hogan is set to meet with the White House’s Office of Information and Regulatory Affairs about the FDA’s OTC Hearing Aids proposed rule. Hogan is representing AARP, the Bose Corporation and the Hearing Loss Association of America.
• …this interesting notice by French regulator ANSM (in French) that starting this month, manufacturers of pharmaceutical drugs deemed to be of “major therapeutic interest” will need to maintain a two-month supply of the product for safety reasons. The change is an effort to limit the effects of any potential shortages during public health emergencies.

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