The Food and Drug Administration (FDA) began requiring drug efficacy, in addition to safety, for approval in 1962 based on the Kefauver-Harris Amendment. Despite this requirement, many drugs that have been approved by FDA have limited efficacy (eg, drugs that treat cancer or Alzheimer’s disease). In many cases, some portion of the limited efficacy is due to dosing limitations, route of administration, or formulation issues.

One possible solution to address the dosing, route of administration and formulation issues that contribute to the limited efficacy has been the development of prodrugs for some of the minimally effective drugs. Prodrugs are pharmacological substances administered in an inactive or less active form and are then converted into active drugs by metabolism or physico-chemical transformation in the body after administration. Some prodrugs exist naturally, including L-dopa, psilocybin, and aspirin; others, such as codeine, were discovered serendipitously during drug development. The specific advantage of some prodrugs is often related to issues of limited bioavailability (low systemic exposure) or high first pass extraction (elimination by the liver through metabolism before the drug gets to the blood stream), instability of the active drug, dosing limitations, or tolerability.

NCE Status for Prodrugs

An important consideration from a commercial protection standpoint when developing a prodrug of a previously approved active compound is whether the prodrug will be designated as a new chemical entity (NCE) by FDA. An NCE is defined in the Code of Federal Regulations (CFR) a drug that “contains no active moiety that has been approved by FDA in any other application”. Further, an active moiety is defined as “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance”. (21 CFR §314.108)

The determination that the new drug is an NCE is critical because NCE status allows for 5 years of market exclusivity (also referred to as Hatch-Waxman exclusivity) after approval regardless of the patent situation. NCE exclusivity is granted for products “containing chemical entities never previously approved by FDA either alone or in combination”. This type of exclusivity protects against submission of applications (ANDA and 505(b)(2)) by a different manufacturer using the same In the July 28^th, Federal Register, (Under “Meetings”) FDA announced the availability of the draft guidance “Request for Quality Metrics-Guidance for Industry.” Although there are “requests” for quality metrics in the guidance, the bulk of the document tells industry what quality metrics they will be reporting, at least initially.

FDA primarily cites Sections 706 and 707 of the Food and Drug Administration Safety and Innovation Act (FDASIA) as authority for its plan to require most Finished Dosage Form (FDF) and API manufacturers to supply specified quality metrics. Section 706 states that FDA “…may require the submission of any records or other information that FDA may inspect under Section 704 of the FD&C Act, in advance or in lieu of an inspection by requesting the records …” The stick is provided, per FDA, by Section 707 of FDASIA which makes a drug “adulterated” if the owner, operator or agent of the establishment manufacturing the drug “…delays, denies or limits an inspection…”, i.e., the request from FDA for quality metrics constitutes a component of their statutory authority to inspect manufacturing facilities, so a failure to comply with the planned request for quality metrics would constitute impeding or denying an inspection, and potentially effect inspection frequency of the establishment. (Yes, this is in a guidance and the guidance does have the usual, “doesn’t bind me, doesn’t bind you” language at the beginning)

The guidance repeatedly cites the proposed quality metrics as a potentially useful tool in avoiding drug shortages. FDA also asserts a number of other reasons for the creation of the quality metric program in how it intends to use the quality metrics:

“FDA intends to use quality metrics data to further develop FDA’s risk-based inspection scheduling, to identify situations in which there may be a risk for drug supply disruption, to improve the efficiency and effectiveness of establishment inspections, and to improve FDA’s evaluation of drug manufacturing and control operations. FDA expects that the initial use of the metrics will be to consider a decreased surveillance inspection frequency for certain establishments.”

Aha, there’s the carrot in that last one. In brief, firms that measure up well during inspections and turn out to have favorable metrics may be tagged for less frequent inspections. FDA also point out that the metrics may allow them to focus on firms which pose significant risks to consumers, including drug shortages However, how exactly that’s going to play out is still undetermined. FDA hasn’t even determined how they’re going to look at the data:

“FDA intends to evaluate whether data reported by manufacturers is consistent with the Agency’s understanding of the specific quality data requested (e.g., definitions). In addition, we intend to evaluate how best to interpret and use the metrics. For example, is it more meaningful to compare metrics for different products within the same establishment, or for the same product manufactured at different establishments, or as an establishment-specific trend over time? Is it more appropriate to use certain metrics to compare all types of establishments (or a subset making the same dosage form or same drug) against each other? What is the best way to compare metrics for products that vary in manufacturing complexity (e.g., biotechnology and biological products are often considered more complex to manufacture)?”

In the guidance FDA also gives itself the option of making any changes it sees fit to the metrics once things get underway.

So who will have to report quality metrics? The guidance lists the following:

“FDA intends to request quality metrics data from owners and operators of each establishment that is (1) required to register under with FDA under section 510, and (2) engaged in the manufacture, preparation, propagation, compounding, or processing of the FDF of a covered drug product, or an API used in the manufacture of a covered drug product. For purposes of these requests, a covered drug product would mean a drug product that is:

• subject to an approved application under section 505 of the FD&C Act or under section 351 of the PHS Act.
• marketed pursuant to an OTC monograph.
• a marketed unapproved drug product.”

This includes (but is not limited to) contract laboratories, contract sterilizers, contract packages, and other establishments engaged in the preparation, propagation, compounding, or processing of the FDF or API for a covered drug. Notably, foreign establishments that are not required to register are not included, but covered establishments are encouraged to provide the metrics whenever they can access the information

Something that will require some sorting out is who reports in the case where a number of firms are involved in the manufacture of the FDF, a fairly common situation these days.

“FDA intends to ask industry to submit one report for each FDF and one report for each API of a covered drug product, which includes quality metrics data from each covered establishment that has the requested data. FDA believes that, as part of its responsibility for oversight and controls over the manufacture of drugs to ensure quality, one establishment will already possess or have access to all of the quality metrics data needed to submit such reports — for example, through contract or because all of the covered establishments with quality metrics data related to a FDF of a covered drug product or API used in the manufacture of a covered drug product will be under common ownership or control. This establishment should combine the data so that a single report is submitted for each FDF and each API. In this guidance, we refer to the establishments that submit reports to FDA as “reporting establishments.”

So what exactly will firms have to report for each FDF? FDA specifies 10 items:

• The number of lots attempted of the product.
• The number of specification-related rejected lots of the product, rejected during or after manufacturing.
• The number of attempted lots pending disposition for more than 30 days.
• The number of OOS results for the product, including stability testing.
• The number of lot release and stability tests conducted for the product.
• The number of OOS results for lot release and stability tests for the product which are invalidated due to lab error.
• The number of product quality complaints received for the product.
• The number of lots attempted which are released for distribution or for the next stage of manufacturing the product.
• If the associated APRs or PQRs were completed within 30 days of annual due date for the product.
• The number of APRs or PQRs required for the product.

Using the reported data described above, FDA intends to calculate the following quality metrics for each product and establishment, where applicable:

• Lot Acceptance Rate = 1 – x (x = the number of specification-related rejected lots in a timeframe divided by the number of lots attempted by the same establishment in the same timeframe).

• Product Quality Complaint Rate = the number of product quality complaints received for the product divided by the total number of lots of the product released in the same timeframe.

• Invalidated Out-of-Specification (OOS) Rate = the number of OOS test results for the finished product invalidated by the establishment divided by the total number of OOS test results divided by the total number of tests performed by the establishment in the same timeframe.

• Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate = the number of APRs or PQRs completed within 30 days of annual due date at the establishment divided by the number of products produced at the establishment.

FDA also proposes some optional metrics, dealing with Quality Culture, including Senior Management Engagement and CAPA Effectiveness, and Process Capability /Performance. Further, FDA solicits input from all concerned for revisions to the proposed metrics or any additional metrics which would be useful. (Hence the “Request” in the title of the Guidance)

FDA plans to implement the program once the guidance is finalized and the initiation is announced in the Federal Register. FDA plans to send requests for the metrics to the effected registered establishments, while reporting the metrics will be done via the ESG. The guidance includes a proposed sample worksheet for assembling the requested data.

The guidance is worth a thorough reading. Although the metrics that will be initially required don’t deviate that much from the contents of a typical Annual Product Review, the program will at minimum require a somewhat significant application of resources. After that, it depends what FDA decides to do with the information.

A sponsor can gain exclusivity for a prodrug (NCE) for a 5-year period, except for those containing a certification of patent invalidity or noninfringement, which allows for submission after 4 years. Exclusivity for 3-years (called “other” exclusivity) may be granted for a drug product that contains an active moiety that has been previously approved if new clinical investigations (other than bioavailability studies) have been conducted by the sponsor in support of approval.

There is a controversial history with FDA’s decision to grant NCE status for prodrugs. In certain cases, FDA has reevaluated its decisions months or years after drug approval due to a variety of factors. One such example is that of Emend [fosaprepitant dimeglumine] injection (NDA 022023), wherein FDA reversed their exclusivity decision from 3-years exclusivity to 5-years as an NCE. The active ingredient in Emend injection (fosaprepitant dimeglumine) is a prodrug phosphoramide derivative of aprepitant, the active ingredient in Emend capsules (NDA 021549). In their reversal, FDA concluded that Fosaprepitant dimeglumine is neither an ester, salt, nor other noncovalent derivative of the molecule aprepitant and thus, by 21 CFR §314.108, FDA concluded that the prodrug was an NCE and awarded 5-years exclusivity. Although not a reversal, Vyvanse (lisdexamfetamine dimesylate), which has been discussed in a previous blog post, is another example of a prodrug that received 5-years exclusivity. FDA determined that the API was a new molecular entity (NME) as a non-ester covalently bonded molecule.

ALKS 8700 Prodrug for Treatment of Multiple Sclerosis

As FDA’s decisions on NCE status for prodrugs have been inconsistent (although they have reversed previous decisions to account for this), it will be interesting to follow the outcome for new prodrugs like ALKS 8700, Alkermes novel prodrug of monomethyl fumarate (MMF) for the treatment of multiple sclerosis (MS). Although MMF is not approved for MS, the closely related dimethyl fumarate (MMF) ester of fumaric acid was approved in 2013 (Tecfidera). Information on the actual chemical in ALKS 8700 that is the prodrug is not available in the patent or in the public domain at this time. However, it would be reasonable to assume that ALKS would receive 5-years exclusivity, if the compound is not a previously approved moiety.

Currently, approximately 400,000 individuals in the US and 2.5 million people worldwide have MS, an autoimmune disorder of the central nervous system. The most common form of this disease is relapsing-remitting MS, which is characterized by defined episodes of worsening of neurologic functioning followed by partial or complete recovery periods free of disease progression. Alkermes recently announced initiation of a randomized, double-blind, Phase 1 study investigating the safety, tolerability, and pharmacokinetics of several formulations of ALKS 8700 in 125 healthy volunteers.

If approved, ALKS 8700 would compete commercially with Tecfidera (dimethyl fumarate) delayed-release capsules, Biogen Idec’s multibillion dollar blockbuster therapy for MS approved last year. Tecfidera is administered as a twice-daily oral therapy that functions by suppressing the immune system. ALKS 8700 is targeted for once daily dosing with reportedly and potentially fewer side effects than Tecfidera. Administration of dimethyl fumarate (DMF), the active pharmaceutical ingredient in Tecfidera, leads to side effects such as gastrointestinal upset (nausea, vomiting, and diarrhea) and transient flushing of the skin (see prescribing information). The pharmacodynamics profile of the prodrug of MMF under development by Alkermes could demonstrate a reduction in flushing, which could improve patient adherence. Alkermes hopes to use the results of their Phase 1 study to determine the therapeutic utility and differentiating features of ALKS 8700 compared to current therapy.