Behind schedule, FDA releases guidance describing process for obtaining access to generic drug samples

Published nearly a year after the FDA and HHS anticipated, a new draft guidance document published by the FDA aims to clarify how the process to request a Covered Product Authorization (CPA) works. The process is intended to make it easier for generic drug companies to obtain samples of certain drugs that are necessary to conduct the testing needed to obtain FDA approval. But as AgencyIQ found, FDA’s guidance is short on answers to a lengthy list of important questions.

Regulatory Background

• Historically, some generic drug companies found it difficult to develop generic versions of innovator drugs for a simple if frustrating reason: They were unable to obtain samples of the original drug. Access to the original drug to which the prospective drug is generic is essential for development efforts. Under the Federal Food, Drug and Cosmetic (FD&C) Act, companies must demonstrate that their product is bioequivalent to the Reference-Listed Drug (RLD, or the first-approved innovator drug) and also equally bioavailable.
• In simple terms: The generic drug must be the same drug (minus acceptable differences in inactive ingredients), and must have the same effect in the body and be available in equal amounts and at equal times, some small differences notwithstanding.
• But therein lies the problem: If a generic drug company is unable to obtain samples of the original drug, it would therefore be unable to demonstrate the equivalence to that drug, and therefore be unable to satisfy the basic regulatory requirements of the FDA.
• In practice, generic drug companies are quite savvy at obtaining these generic drug samples, but there were cases in which it was not possible. For example, some innovator companies were subject to Risk Evaluation and Mitigation Strategies (REMS) including Elements to Assure Safe Use (ETASU). Under these programs, the FDA places strict requirements on who may obtain a medication to ensure they were not improperly prescribed. However, those same requirements were sometimes used as an excuse by branded companies to ensure that their prospective generic competition would not have the samples necessary to develop their products. In other cases, tightly controlled supply chains between a manufacturer and the point of prescribing (such as through contracts or other tracking mechanisms) limited availability.
• The FDA began to take notice of the effect that REMS plans and other restrictions were having on generic drug competition. In May 2018, then-Commissioner of the FDA Scott Gottlieb issued a statement indicating that the agency believed that brand drug makers “sometimes use REMS as a way to restrict the sale of their drugs, keeping the drug out of the hands of generic firms.” He noted that generic drug makers “typically need up to 5,000 doses of a brand drug in order to run bioequivalence and bioavailability studies to prove the generic medicine is the same as its brand drug.” Several weeks earlier, Gottlieb had also announced the publication of a “list of companies that have potentially been blocking access to the samples of their branded products” in a bid to increase transparency around their actions. (Note: The FDA has since removed this list from its website.)
• As Gottlieb also made clear, “a path to securing samples of brand drugs for the purpose of generic drug development should always be available. Even in the case of limited distribution programs such as those required by certain REMS, there should be a path forward for generic drug development.” The statement noted that it would notify the Federal Trade Commission of any barriers to obtaining samples, and would encourage generic drug companies to do the same.

Many of these concerns were in theory alleviated upon the passage of the Further Consolidated Appropriations Act of 2020

• The law, also known as a budget omnibus bill, contained provisions of another bill called the CREATES Act. Section 610 of the law, which was passed in December 2019, created a new right of civil action “for failure to provide sufficient quantities of a covered product.” Specifically, a generic drug company could “bring a civil action against the license holder for a covered product” if it had sought to obtain samples of a drug company’s product, but “the license holder has declined to provide sufficient quantities of the covered product to the eligible product developer on commercially reasonable, market-based terms.”
• The bill effectively divided up drugs into two possible categories: Non-ETASU products, and ETASU products. To “prevail in a civil action,” the generic drug company would need to demonstrate four things. First, that it was unable to obtain sufficient quantities of the product from the license holder. Second, that it made reasonable attempts to obtain those sufficient quantities of product. Third, that it gave the company enough time to respond (31 days). And fourth, that either the drug wasn’t covered by ETASU, or, if it was, that it “obtained a Covered Product Authorization” from the FDA.
• What is a Covered Product Authorization (CPA)? Under Section 610(B), a Covered Product Authorization isn’t quite defined in practice, though its requirements are listed in the aggregate. It is a “written request” to be submitted to the FDA asking to “obtain sufficient quantities of an individual covered product subject to a REMS with ETASU.” The FDA is required to respond to the request within 120 days of the receipt of the request. FDA is required to, “by written notice, authorize the eligible product developer to obtain” sufficient quantities of the drug.
• To date, the FDA has said little about what Covered Product Authorizations should include. According to a webpage maintained by the FDA as of June 2022, developers seeking a CPA should submit the request as “controlled correspondence” through CDER”s NextGen Collaboration Portal (for generic drugs) or submit the request of the Investigational New Drug application file (for biological products or 505(b)(2) applications).
• FDA’s other advice: “Requests should specify that the product developer is seeking a CPA and the product for which a CPA is being sought. If the samples will be used for purposes of development and testing that involve human clinical trials, requests should be accompanied by study protocols, informed consent documents, and informational materials for testing demonstrating that safety protections comparable to those in the REMS for the brand product will be provided for in the study/studies for which samples are sought. If the samples will be used for purposes of development and testing that do not involve any testing in humans, the request should state that the samples will not be used for testing in humans.”
• FDA had also long maintained that it was working to develop guidance on CPAs. As of March 2020, FDA’s webpage explained that the agency “intends to issue guidance on obtaining a CPA.” HHS’s September 2021 plan to address high drug prices indicated that the guidance would be coming in the winter of 2021.
• Then, in early September 2022 the FDA announced that it had submitted its CPA draft guidance to the White House for its review. The White House cleared the guidance for release on September 15, 2022.

Now the FDA has finally released its guidance on Covered Product Authorizations. Here’s what you need to know

• The guidance, How to Obtain a Covered Product Authorization, is relatively brief at just 11 pages and begins with an overview of the CREATES Act provisions of the Further Consolidated Appropriations Act of 2020 and the purpose of CPAs. Much of the guidance is relatively basic; for example, it provides an overview of generic drug, biosimilar and 505(b)(2) application types – things most regulatory professionals are already deeply familiar with. An entire section is devoted to reasons why non-innovator companies might need samples of products and why it has historically been difficult to obtain those samples (see AgencyIQ’s overview above for our take on the same information).
• As FDA’s guidance notes, a “covered product” isn’t just a code word for a generic drug. In fact, three different types of products are eligible for a CPA: Generic drugs (under a 505(j) application), biosimilars (under a 351(k) application), and 505(b)(2) applications, which are used to support approval of a drug that is mostly generic but may differ in a key respect, such as a route of administration or form factor.
• The guidance also helpfully recaps a few key terms from the legislation. For example, an eligible product developer is any person seeking to develop a product. That’s a rather wide definition that might make it difficult for innovator companies not to make their drugs available to interested parties under a CPA request. A license holder is the company with the approved application to which a generic/biosimilars/505(b)(2) product developer is seeking access. Interestingly, this section indicates that a license holder may also be another generic drug company or biosimilar manufacturer with a 505(j) or 351(k) application. That’s important since sometimes those companies’ drugs become the de-facto RLD after the innovator pulls its drug from the market.
• Another key term defined is “sufficient quantities,” which is defined as basically the amount necessary to allow the eligible product developer to conduct testing to support an application for approval or to “fulfill any regulatory requirements relating to approval of such application.”
• A note about shortages: The guidance explains, citing the CREATES Act provisions, that a covered product includes “any device that is marketed or intended for use” with a drug or biological product. It also includes products that have been in shortage for longer than 6 months, although it doesn’t define “shortage” in any particular way. The FDA maintains some regulatory requirements related to shortages, and defines it at 21 CFR 314.81 as “a period of time when the demand or projected demand for the drug within the United States exceeds the supply of the drug.” As far as definitions go, that’s not exactly precise.
• It’s also worth noting that the release of this guidance also marks the withdrawal of another guidance maintained by the agency, the 2014 guidance document How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD. That guidance had described a voluntary process by which generic drug companies could seek the blessing of the FDA (known as a “Safety Determination Letter”) regarding the controls of their study protocols; Such a blessing would, in theory, satisfy any concerns the RLD holder might have about making a product available under an ETASU. In practice, it was often unhelpful. The CPA now replaces this process.

The part of the guidance that’s likely to be most helpful to companies is its explanation of how the Covered Product Authorization process actually works

• As previously noted, the license holder has just 31 days after the receipt to ensure that the product is delivered to the eligible product developer.
• The CPA itself “is a document obtained by the eligible product developer from FDA” that is requested by the developer. The FDA is required to respond to a request for a CPA within 120 days. They are only applicable to products that are subject to REMS with ETASU; all other products do not require a CPA request.
• There is a key difference between the Safety Determination Letter process established in 2014 and the CPA. Notable, the FDA does not send the CPA to the RLD sponsor. Rather, the eligible product developer is responsible for this communication.
• To obtain a CPA from the FDA, sponsors are asked to undergo the same process as was previously listed on the FDA’s website. Sponsors of prospective generic drugs should submit controlled correspondence to the CDER NextGen Collaboration Portal. Sponsors of biological products and 505(b)(2) products should submit the request to either an IND file or a pre-IND file or, if one does not exist, a request for a file number copied to [email protected].
• The exact contents of the CPA request are also included in the guidance. The request should be prominently identified as a “REQUEST FOR COVERED PRODUCT AUTHORIZATION.” It should also specify the product for which the CPA is sought. For any covered products that will be used in testing, the FDA wants to see study protocols, informed consent documents and “information materials for testing demonstrating that safety protections comparable to those in the REMS for the band product will be provided for in the study or studies for which samples are sought.” This should likely have the effect of ensuring that requests for covered product are legitimate. Alternatively, if covered samples won’t be used for any testing in humans, the FDA should be told that.
• In addition, if a CPA is related to a product in shortage, the FDA asks that the request “specify … that the product is on the drug shortage list.”
• Finally, the FDA offers some notes about what it’s review process for CPA requests will look like. It notes that it may ask for additional information through a “information request” (IR), common to any drug review process. If the drug is in shortage, the FDA will determine if either of two criteria exist: If the shortage has been ongoing for more than 6 months, or if its inclusion as a covered product might help alleviate the shortage, then the CPA will be granted. If not, the rejected company is asked to re-apply after the six-month waiting period.
• Finally, and perhaps most important of all, the substance of FDA’s CPA review will be focused on whether the safety protections are “comparable to those provided by the applicable REMS with ETASU.” If FDA’s questions are substantial and cannot be answered by IRs, then the CPA request will be rejected, and a resubmission must await until after the 120-day clock terminates for the original submission of the CPA.

Analysis

• We read a lot of guidance documents here at AgencyIQ, and so we’re well aware that guidance documents aren’t supposed to create new requirements, but rather explain and interpret existing ones. But we can’t help think that this guidance is quite basic. Recall that the FDA has been working on this guidance as a high priority for several years. It was a top priority for Gottlieb when he led the agency, and HHS’s plan to address high drug prices mentioned this guidance by name and indicated it would be out soon. So what did industry get for all the wait? Basically a re-telling of the exact requirements of the legislation, with a few other sparse details about the submission process. In our view, there’s nothing in this guidance document that would have required more than two years to assess, or would have required a delay of almost a year beyond the projected date of publication.
• The lack of detail is a shame, because there are a significant number of questions that companies are likely to have about this process in practical terms. Of particular interest to AgencyIQ is the lack of clarity around the term “sufficient quantities” that are required to be made available. Perhaps it’s the job of Congress, rather than the agency, to answer these questions, but we’ll still ask them: How is this quantity defined – by the license holder and eligible product developer, or by the FDA? What happens if the amount turns out to be insufficient – may a product developer demand additional product? May a license holder place contractual restraints on the use of its covered product that is not used for testing (i.e., a requirement to return the product), or would that violate the requirement that “no additional conditions [be] imposed on the sale of the covered product?” May a license holder prevent the transfer of its product to a secondary entity to avoid having multiple companies work together to obtain a large quantity of covered product? What happens if a drug requires the use of a specific device, but that device is sold by another company not within the control of the license holder and does not make the device available for use – is this a violation? If a drug is in shortage (say, for a small population) for more than 6 months, and the company is struggling to maintain supply of its product for that population, is there a situation in which the FDA might not require that “sufficient quantities” of that drug be made available so as not to exacerbate the shortage? What happens if a company says it expects its product to be in shortage, but it later turns out that the shortage notification was inaccurate? How does the FDA define “31 days of receiving the request” of a product – does it define “delivery” as in-hand product, or in-transit product (to account for potential logistics-related delays)?
• And in terms of the covered product, we have lots more questions, too: What about the covered product – what are the qualities of the drug product that must be made available to the eligible product developer? How should drug product made available under a CPA be labeled, and must they comply with the Drug Supply Chain Security Act? Are Covered Products exempt from most federal regulations, or will certain regulations (such as adverse event reporting) still be applicable?

To contact the author of this analysis, please email Alec Gaffney ([email protected])
To contact the editor of this analysis, please email Kari Oakes ([email protected])

Key Documents and Dates

• How To Obtain a Covered Product Authorization
• Comment due date: November 21, 2022
• Federal Register Notice