FDA Suggests Use of Biomarker Qualification Program as Possible Model for Approving Novel Excipients

To promote the development of novel excipients, FDA has suggested building upon the agency’s existing Biomarker Qualification Program (BQP) but to apply this model to new excipients.

FDA officials said that the program was established to promote the development of new drugs but could be retooled for novel excipient development as well.

Under this program, outside parties would assess the safety of new excipients while FDA would have final approval authority.

The excipient industry has long complained that the lack of a separate and independent pathway for novel excipients outside of the new drug application (NDA) review process is hindering the development of new chemicals intended to aid in drug delivery.

The excipient industry made its case on the need for such a pathway at a June 4 meeting with FDA on novel excipients.

Officials from the International Pharmaceutical Excipients Council (IPEC) and the Innovation and Quality (IQ) Consortium told FDA they would like an independent review and qualification of excipients by the agency outside of the NDA or abbreviated new drug application (ANDA) review process. These reviews would be supported by user fees.

They said that excipient suppliers do not want to take on the risk and the cost of developing new excipients only to have them rejected by FDA when submitted in NDAs.

Excipient officials told FDA that there is an unmet need for novel excipients.

IQ found that two thirds of manufacturers surveyed said they need more novel excipients to promote the development of innovative delivery systems, such as the oral absorption of peptides and proteins and the delivery of inhalation drugs, as well as to ensure peptide and protein stability and to prevent protein aggregation.

The IQ Consortium said that it can take 12 years and cost anywhere from $5 million to $10 million to develop a new polymer, while a return on investment would not be seen for 15 years. But this return on investment would only be realized for drugs that are approved.

There is a 54% chance that the drug will be approved by FDA once a pharmaceutical manufacturer decides to use the excipient in a formulation.

Excipient officials told FDA that they are not looking for an approval of the excipient but rather for a way to have the safety of the excipient evaluated and qualified for potential uses in a particular route of administration.

The excipient industry proposed that the safety information could be included in Type IV or Type V Drug Master Files (DMFs). The industry proposes that user fees under the Generic Drug User Fee Act or the Prescription Drug User Fee Act could pay for these safety assessments.

FDA would then publish a list of excipients that could be considered qualified for specific intended uses and levels in products.

This type of system, officials said, would give drug manufacturers greater confidence to include novel excipients in their products.

In response to the proposal, FDA’s Karen Davis Bruno suggested that one possible way to evaluate the safety of new excipients and qualify their use is to leverage some of the principles from FDA’s existing Biomarker Qualification Program.

Under BQP, consortiums of external scientists and clinicians develop standards for biomarkers that can be used in drug development. It is then up to FDA to qualify, or approve, their use in new drug applications. This way, when applications for new drugs are submitted, the biomarker used to evaluate them would have already been accepted by FDA. The goal is to share in the costs of drug development.

Once approved, qualified biomarkers can be referenced in NDAs and investigational new drug applications (INDs) without additional clinical studies.

Biomarkers help assess how well a patient is doing; they are also used to help select patients most likely to benefit from therapy. They are medical signs, tests or processes that can be used to measure disease activity or disease severity.

FDA officials said at the meeting that the ultimate qualification of a novel excipient, however, would depend on its context of use.

The context of use is a statement in the BQP program that describes the manner of how it is to be used. This means that once qualified, a biomarker can only be used for a specific indication.

At the meeting, FDA also suggested that IPEC/IQ develop ideas and logistics for how user fees would work given that the same novel excipient could be made by multiple suppliers.

In subsequent comments submitted to FDA on Aug. 13, IPEC’s David Schoneker said that the BQP program contained “many important concepts” and by modifying the approach for novel excipients this “could provide a foundation for how IPEC-Americas might engage with FDA on modernizing excipient development.”

In a subsequent news release IPEC said that information contained in Type II DMFs for API Completeness Assessments could be used as the basis for excipient safety reviews.

Efforts go back to 1996

Excipient industry officials have been seeking to streamline the approval path for novel excipients for almost 20 years.

IPEC member Chris Moreton, the founder of FinnBrit Consulting in Waltham, Mass., said that IPEC-Americas’ interest in this area goes back to 1996 when it published the list of studies required for new excipients. These were later adopted and incorporated into guidance for industry.

FDA’s industry guidance document, Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, which became final in 2005, provides recommendations for the safety evaluation of new pharmaceutical excipients but does not address their approval chemically.

In 2007 IPEC-Americas introduced the New Excipient Evaluation scheme using a team of independent reviewers. The goal was to provide an independent evaluation of the safety and acceptance of the new excipient before the filing.

The team reviewed the safety and toxicology packages and then gave an opinion as to whether or not it would be acceptable to FDA.

Moreton said that this initiative was not that successful because these packages were not reviewed by FDA and consequently, “industry has not accepted it.”

He said that “industry does not want to use an excipient that has not been accepted by the FDA, but under the current arrangements the only way to get an excipient accepted by the FDA is for them to review it in a drug marketing application.”

Moreton said that the pharmaceutical industry is reluctant to use excipients that are not approved and prefers to use excipients that are introduced in the Inactive Ingredient Database (IID).

An FDA official said that there are about 13,000 excipients listed in the IID. Yet some excipients are listed multiple times because they are used in a variety of dosage forms and routes of administration. The IID has a separate entry for each excipient and dosage form combination.

Few excipients

Moreton said that the current disincentives in the approval process for novel excipients means that very few have been approved by FDA.

Moreton told “The Gold Sheet” that in the last 20 years there have only been a couple of really new materials. One of these was for Afrezza, an inhaled insulin product.

The FDA approved Afrezza, a human insulin inhalation powder, in June 2014.The drug is a rapid-acting inhaled insulin that is given at the beginning of meals to treat adults with diabetes mellitus. The drug was launched by Sanofi and developed by MannKind Corp. (Also see "Looking For The New Lantus: Next-Gen Diabetes Hopefuls Defy Risks" - Scrip, 4 May, 2015.).

The formulation contains a novel excipient, fumaryl diketopiperazine (FDKP), that can form particles to carry active ingredients and deposit them deep within the lungs.

Moreton said that “the Mannkind application is an example as to why they are needed; without the fumaryl diketopiperazine the inhalation product does not work, and they were unable to find any existing excipient which was suitable.”

Other novel excipients approved in recent years include Captisol, developed by Ligand Pharmaceuticals Inc. This product was invented in 1990 by scientists at the University of Kansas. This technology has been used in over 30 formulations to improve the solubility and stability of parenteral drugs.