FDA’s Center for Drug Evaluation and Research’s (CDER) Office of New Drugs (OND) recently launched a pilot program on Novel Excipient Review. The pilot program offers a new pathway for drug manufacturers to obtain FDA review of certain novel excipients (inactive ingredients) before the excipients are used in drug formulations.
On December 5, 2019, a Request for Information (RFI) was posted in the Federal Register to gather input from industry to evaluate interest in developing a pilot program and to identify potential challenges. FDA considered this public feedback in developing this pilot.
In this CDER Conversation, Karen Davis Bruno, PhD, OND Associate Director of Pharmacology/Toxicology, speaks about the Novel Excipient Review Pilot Program.
Karen, can you begin by explaining what a novel excipient is?
Certainly. Excipients are inactive ingredients that FDA reviews as a component of a finished drug in a new drug application or a generic drug application.
An excipient is any ingredient or substance intentionally added to a drug that is not part of the active substance. These inactive ingredients can work to stabilize medications and help the body absorb the active ingredients. Excipients can play a central role in the drug development process, in the formulation of safe, balanced, and reliable dosage forms, drug performance, and how the drugs are taken or given.
Ideally, an excipient is pharmacologically inactive, non-toxic, and does not interact with the active ingredients or other excipients. Many excipients have more than one use, which can be good because this reduces the number of excipients needed and minimizes the risk of interactions among them.
Examples of excipients are diluents to increase the weight or volume of tablets, flavoring agents in chewable or disintegrating tablets, a coating solution for bad-smelling tablets, sustained-release excipients, and coloring agents. Excipients can also be used to improve drug safety, help maintain drug integrity during storage, and move the drug to the part of the body where it is needed. Other benefits of excipients include facilitating opioid abuse-deterrent formulations or promoting the development of new therapies for serious life-threatening diseases
And for the purposes of this pilot program, a novel excipient is any excipient that is not fully supported by existing safety data. For this pilot program, we will consider novel excipients that have not been previously used in FDA-approved drugs and that do not have established use in food.
What exactly is the Novel Excipient Review Pilot Program and what does it do?
Although excipients can play an important role in helping patients tolerate medications or transporting the drug within the body, excipients can also carry risks. For example, some excipients can include materials that trigger allergies. For that reason, FDA evaluates excipients for safety and stability. In some cases, FDA may find issues with the excipients used in a drug development application, which can affect and even delay the application.
The pilot aims to address this problem head-on. With this pilot program, FDA will offer a pathway to evaluate excipients that could provide important public health benefits, such as increased drug bioavailability or absorption, more comfortable drug administration, new abuse-deterrent opioid formulations, new routes of drug delivery, and the facilitation of new technologies.
The intention of the pilot is to evaluate novel excipients for specific contexts of use that address drug development needs. We’re hopeful the pilot will encourage innovation through incentivizing use of novel excipients in drug development by demonstrating use and safety for potential developers.
Submission is voluntary and intended to allow excipient manufacturers to obtain FDA review of certain novel excipients prior to their use in drug formulations.
Those interested can find more information on the Novel Excipient Review Pilot Program web page. FDA will accept submissions through December 7, 2021.
What prompted FDA to introduce this pilot program now?
Feedback from stakeholders encouraged us to establish a program for the submission and review of toxicological and quality data supporting the use of novel excipients in drugs. And for novel excipients we mean drugs outside of an Investigational New Drug (IND) application, a New Drug Application, or a Biologics License Application.
The Novel Excipient Review pilot program was under development prior to FDA’s Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program and is now a part of the ISTAND pilot. ISTAND is designed to encourage the development of DDTs that are out of scope for existing DDT qualification programs but may still be beneficial for drug development.
For reference, DDTs are methods, materials, or measures that have the potential to facilitate drug development. As described in the 21st Century Cures legislation, DDTs include biomarkers, clinical outcome assessments, and other methods, materials, or measures that aid drug development and regulatory review. To support DDT development efforts, FDA has established qualification programs for biomarkers, clinical outcome assessments, and for animal models for use under the Animal Rule.
Can you describe the current challenges of using excipients in drug development, and how the pilot aims to address those challenges?
FDA has heard about and recognizes that drug developers may fear that introducing novel excipients could cause problems or delays with their drug applications. For this reason, these manufacturers may avoid using novel excipients in drug development -- even when the excipients have potential public health benefits. This pilot program is designed to encourage the use of novel excipients in drug development.
When FDA evaluates a novel excipient, drug developers will be reassured that the novel excipient can be used in a drug development program. This also minimizes the risk that FDA would raise safety concerns during application review.
What are your expectations for the Novel Excipient Review Pilot Program? What does FDA hope to gain?
Again, FDA is aware of the developmental challenges that excipient manufacturers and drug developers face regarding the use of certain excipients.
The goal of the pilot is to assess the value of an excipient program in promoting drug innovation through the use of novel excipients. We will evaluate novel excipients for specific proposed uses that address specified drug development needs and encourage innovation through use of novel excipients in product development. Areas identified being impacted by novel excipients are bioavailability, solubility, drug delivery, pediatric formulas and continuous manufacturing
What is FDA looking for from participants?
We expect to receive strong interest from stakeholders within medicine, science, and engineering, including: drug developers and manufacturers, pharmaceutical sponsors and associations, and academia.
During this pilot phase, FDA anticipates accepting four proposals over two years -- two proposals per year.
FDA will give selection preference to proposals that demonstrate:
a potential public health benefit of the novel excipient – for example: excipients that may facilitate opioid abuse-deterrent formulations or excipients that may promote development of new therapies for serious and life-threatening diseases
potential of the novel excipient to meaningfully improve characteristics that may lead to new drug development such as time course of drug absorption, distribution, metabolism, and excretion
likelihood of the novel excipient manufacturer’s ability to submit a complete package within the timeframe established in the Federal Register Notice announcing the pilot’s establishment
And lastly, how will the FDA measure the pilot program’s success?
A few successful examples for the pilot program would be:
Data to show the impact of a Novel Excipient Program. This could include the number of proposals submitted, number of novel excipients that FDA deems is safe to use in drug development, the interest drug companies have in using the novel excipients, and potential to improve product development.
FDA recognition of a novel excipient. This would mean FDA has determined it is appropriate to use the novel excipient in an IND within the defined use without additional justification
The pilot program will work to promote development and use of new excipients that may be beneficial in scenarios in which excipient manufacturers and drug developers have cited difficulty in using existing excipients. The success of the pilot program will be measured with the review and identification of novel excipients that address a drug development need such that a new product is introduced to the market for an unmet medical need.