Two final guidance documents published by the FDA help establish the study requirements needed to support the approval of new generic versions of drugs intended to help treat patients with COVID-19. But as an AgencyIQ analysis shows, the impacts of the guidance documents could be limited.
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Executive IQ Analysis
- How Things Work Now: The FDA often publishes Product-Specific Guidance documents (PSGs) to help companies demonstrate that their generic drug product is “bioequivalent” to an original product. These PSGs include information about the design of the studies, as well as any waiver criteria that could allow a company to skip testing.
- What’s New: The FDA has now published two new PSGs intended to help guide the development of generics for two drugs intended to treat patients with COVID-19: Chloroquine and hydroxychloroquine. In general, the PSG for hydroxychloroquine calls for two in vivo studies, while the PSG for chloroquine states that most testing can be waived.
- What’s Next: The impact of the new guidance is likely to be minimal, since there are major barriers to new generics coming to market quickly. Those barriers include the difficulty of a company developing and testing a product, the FDA’s inability to inspect many manufacturing sites, countries limiting the export of certain essential medicines and the time it takes for the FDA to review applications for approval.
Regulatory Background and Context
If a company wishes to obtain approval for a generic drug, they must submit an Abbreviated New Drug Application (ANDA) to the FDA containing evidence that their proposed generic product is “bioequivalent” to the original substance, known as a Reference-Listed Drug (RLD).
Bioequivalence refers to a drug being free of any significant differences between two substances, which is defined as “the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”
That last part of the definition—“in an appropriately designed study”—is critical. A generic drug company must design the appropriate in vivo or in vitro studies to assess the bioequivalence of its generic substance to the RLD.
Though companies may design their own studies to demonstrate bioequivalence, the FDA may also facilitate those studies by providing recommendations on how companies can demonstrate bioequivalence through recommended studies. The FDA has published more than 1,800 of these recommendations, known as Product-Specific Guidances (PSGs), which help companies to improve the odds of their ANDA submission getting approved.
Recommendations might include the type of study (e.g., fasting or fed), the exact dose to be tested, the subjects who should be enrolled, and the design of the trial itself.
The FDA has primarily emphasized the use of PSGs as a means of accelerating the development of generic drugs to address drug pricing. Because many companies will begin developing a generic drug years before the patent or market exclusivity protections for the RLD end, the FDA has begun to publish PSGs soon after a product’s initial approval.
As the FDA works to reconfigure its regulations and policies to confront COVID-19, it is now turning to its PSGs to help potentially increase the availability of generic drugs, particularly chloroquine and hydroxychloroquine.
On April 13, the FDA said it had finalized separate PSGs for the two substances to help expedite development of generics.
The PSG for hydroxychloroquine sulfate had already been developed and published in draft for in April 2011. The FDA said it had finalized that guidance without any changes. The FDA had not previously published a PSG for chloroquine phosphate, but was issuing an immediately-in-effect guidance since it determined that “prior participation … is not feasible or appropriate in light of COVID-19.”
For hydroxychloroquine sulfate, the FDA said it would recommend in vivo bioequivalence testing involving two single-dose, two-treatment, randomized, parallel studies using a 200 mg dose of the drug. One of the studies would be in patients who had fasted prior to (and during) the study, while the other would look at patients who had been fed (typically a high-fat food). These studies are helpful to determine if the rate and extent of absorption of the drug is affected by food intake.
The PSG also noted that companies may request a waiver of testing if they can document that their product is highly soluble and dissolves rapidly.
For chloroquine, the new immediately-in-effect PSG is complicated by the approval history of the drug. Some products were in use prior to the FDA’s modern authority, established in 1962 under the Kefhauver-Harris Amendments to the Federal Food, Drug and Cosmetic Act, required drugs to be approved based on studies indicating both safety and efficacy of a drug substance. The FDA has since reviewed many of these products under its Drug Efficacy Study Implementation (DESI) process, and issued determinations about which products may remain on the market. Chloroquine phosphate is one of these DESI drugs permitted to remain on the market.
The FDA’s PSG for the product notes that “there are no known or suspected bioequivalence problems” with the drug, which may occur for some “narrow therapeutic index” products which may be ineffective outside of a narrow window. Instead, the guidance recommends that companies may skip in vivo testing and instead conduct in vitro dissolution testing.
While PSGs are normally helpful in accelerating new generic entrants to the market, both chloroquine and hydroxychloroquine are already off-patent and available in generic form. The FDA’s PSGs are therefore unlikely to be aimed at the creation of novel generic competition, but rather additional generic competition.
There are several challenges to this approach. First, it could be difficult for the FDA to qualify a new facility to make a generic drug. Typically, the FDA conducts a Pre-Approval Inspection (PAI) before it will approve an ANDA to ensure that facility is capable of manufacturing a product and that data was not falsified. As AgencyIQ explained last week, the FDA may not be able to conduct these inspections, which may make new approvals difficult.
Second, facilities that are located outside of the US may find it difficult to export products to the US. For example, many generic drug manufacturing facilities are located in India. In March, the Indian government ordered drug manufacturers to stop exporting more than two dozen drugs used to treat COVID-19, though chloroquine and hydroxychloroquine were not among them. Finland, where pharmaceutical company Amneal Pharmaceuticals is based, has restricted the export of hydroxychloroquine. Companies might also find it difficult to procure sufficient amount of the Active Pharmaceutical Ingredient (API) used to make the drugs, which could further challenge production—or even the testing needed to satisfy the FDA’s guidance documents.
Finally, the development, testing and production of a generic often takes years to complete. The FDA would still need to approve the company’s ANDA as well. It seems unlikely that the guidance documents would help any company to rapidly develop new hydroxychloroquine or chloroquine products.
Ultimately, these challenges may limit any effects caused by the FDA’s new PSGs.