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Posted 24 June 2021 | By Joanne S. Eglovitch 

FDA’s OGD hears ways to accelerate complex generic development

2703 Pharmaceutical industry officials speaking at a Wednesday workshop on complex generics suggested that the US Food and Drug Administration (FDA) create alternative pathways for assessing bioequivalence for some of these products and provide more guidance on assessing the bioequivalence of metered-dose inhalers.
A series of industry officials spoke at a 23 June public workshop on ways the agency could accelerate the development of complex generics. The agency is required to ask the industry for this input under the Generic Drug User Fee Amendments of 2017 (GDUFA II). The agency uses this input in developing its annual list of science and research initiatives specific to generic drugs. The advice solicited at the workshop will inform FDA’s FY 2022 GDUFA regulatory sciences initiatives.
Robert Lionberger, director of FDA’s Office of Research and Standards in the Office of Generic Drugs (OGD), announced that the input gleaned from the workshop “helps the development of more generic competition in areas where bioequivalence evaluation is scientifically challenging.”
Last year, FDA officials said that a key area of focus for OGD will be the growing arena of complex generic drug products because they are “harder to ‘genercize’ and often have less market competition.” (RELATED:  FDA kicks off GDUFA III reauthorization process, Regulatory Focus, 21 July 2020).
In a recent notice, FDA announced interest in receiving input in the following research areas:  determining how formulation differences in generic injectables products affects their substitutability; developing more generic versions of oligonucleotide products; exploring artificial intelligence; supporting model integrated evidence for developing generic products; and supporting best bioequivalence practices and convergence on global bioequivalence standards.

Different approach needed to assess bioequivalence

Partha Roy, director of the Office of Bioequivalence in OGD, said that the agency is open to new approaches for assessing bioequivalence of generic drugs. He observed that FDA requires both fasting and fed studies for immediate-release products, to assess a generic’s bioequivalence to a reference-listed drug whereas other regulators only require fasting studies for these products.
As a result, there are “lagging generic drug approvals for long acting injectables and oncology products” due to the cost and challenge of conducting the additional clinical studies. He asked the workshop whether “novel study designs” can be used to “reduce the regulatory burden.”
Use non-US based RLD
Raja Velagapudi of Sandoz recommended that to ease the BE testing burden for certain generics, including long-term injectables, inhalation products, and drugs products with a “high clinical burden” such as oncology and anti-psychotic drugs, the agency should waive its bioequivalence testing requirements if the drugs have been approved outside the US. In other words, FDA should approve the ANDA based on its bioequivalence to a non-US reference listed drug (RLD).
However, he proposed that the drug would have to be assessed according to similar pharmacokinetic and bioequivalence studies as the US RLD.
Velagapudi also suggested that the FDA work with the International Council of Harmonization to harmonize and develop a “common understanding” for mutual utilization of bioequivalence data “as much as possible for products that require high clinical burden to register.”
More guidance needed from FDA on MDIs
In other areas, Beatriz North, the senior director of global clinical affairs for Perrigo Pharmaceuticals, said that FDA needs to provide additional guidance on bioequivalnce testing for generic metered-dose inhalers.

She said that the approaches outlined in current guidance are “unclear” for these products. “For metered dose inhalers we are working with multiple products and with multiple strengths and there is potential for dose variability in the subjects or variability in the data if the analytical methods are not robust. FDA has provided ample evidence on drug device combination, there is still advice needed for generic MDI products.”
Alternative research areas suggested
One industry representative suggested that the agency should add another item to its list of research priorities: studying acceptable nitrosamine levels in drug products, and which levels present actual safety risks. 
Martin Ehlert of Apotex said FDA’s guidance on nitrosamines sets an overly conservative threshold for acceptable levels of nitrosamines in products.  FDA’s guidance on assessing nitrosamine risk, issued last year, outlines the steps to be taken to detect and prevent the introduction of potentially carcinogenic nitrosamine impurities into finished drug products and active pharmaceutical ingredients, and specifies that acceptable intake limits for all nitrosamine impurities do not exceed 96 ng/day. (RELATED: N-Nitrosamine impurities: FDA issues detection, prevention guidance, Regulatory Focus, 1 September 2020)
Ehlert said that nitrites are prevalent in common excipients and amines are prevalent in active pharmaceutical ingredients, adding that FDA’s expectations for testing and detecting the presence of nitrosamines at such low levels are unrealistic.
Complexity defined
According to FDA’s 2016 GDUFA commitment letter, a complex generic drug product is found complex because it either has a complex active ingredient, such as a peptide or polymeric compound; is a complex formulation; has a complex route of delivery; or has a complex dosage form.
These complexities often result in lagging approvals for these products. In January 2020, a bipartisan group of House Energy & Commerce leaders sent a letter to former FDA commissioner Stephen Hahn seeking information on the agency’s efforts to approve complex generics more quickly, and said they are trying to understand if FDA needs additional authority  to improve the approval process for complex generic drugs, (RELATED: House committee quizzes FDA on complex generic drugs, Regulatory Focus, 20 January 2020)
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Tags: Complex, FDA, generics

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