Generic drug development increasingly involves the development of complex formulations of products for which it can be difficult to demonstrate that an ingredient is the “same as” another active ingredient. Now a new guidance document from the FDA offers some pointers for companies hoping to bring generic drugs to market, as well as an in-depth definition of what it considers to be an “active ingredient.”
- Unlike new drug product approvals, generic drugs do not require extensive new clinical evidence about their safety or efficacy. Rather, under the terms of the 1984 Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman Act), sponsors of generic drug products may instead rely on evidence that the drug to which it is generic (i.e., the “brand name” drug) is safe and effective to support market access.
- This means the generic drug must show it is effectively the same as the original drug, known as the Reference-Listed Drug (RLD). Under federal law, companies are required to show that “the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions,” in an Abbreviated New Drug Application (ANDA) for their generic.
- When it comes to the “sameness” of products, the FDA considers several approaches, including qualitative sameness (also known as Q1), quantitative sameness (Q2) and – for certain drugs – “look and feel” sameness (Q3). Under 21 CFR 314.92(a)(1), the term “sameness” is defined as a drug that is “identical in active ingredient(s), dosage form, strength, route of administration, and conditions of use, except that conditions of use for which approval cannot be granted because of exclusivity or an existing patent may be omitted.”
- But while many factors affect whether a drug is the “same” as another drug – including its form factor and inactive ingredients – the active ingredient is especially important. An active ingredient is defined by the FDA as “any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.” Critically, the active ingredient must be the same in the finished drug, meaning companies must pay close attention to the effects of the manufacturing and finishing process on the ingredient.
- The stakes for prospective generic drug developers are therefore high. According to the FDA, it will “refuse to approve an ANDA if the [application] contains insufficient information to show that, among other things, the active ingredient of the proposed generic drug product is the same as that of the RLD.” For companies developing fixed-dose combination products, this requirement extends to “each active ingredient.”
Today the FDA published a new guidance document exploring how the FDA makes “sameness” evaluations for active ingredients in generic drugs.
- The FDA makes clear: A finding of “sameness” is its call to make. As it explains in the guidance, it has “broad discretion to determine whether an ANDA applicant has submitted information sufficient” for it to determine if an ingredient is the “same.” That’s because the Hatch-Waxman Act of 1984 didn’t “describe the type or amount of information that an ANDA applicant must submit to demonstrate sameness.” FDA has also adopted what it considers to be a “flexible approach” to making these determinations, including conformance with the U.S. Pharmacopoeia’s (USP) standards of identity for specific drug products.
- If no USP standards exist for a drug product, then the FDA will expect more from an ANDA sponsor. Specifically, “If there is no USP identity standard for an active ingredient in an official monograph, FDA recommends an applicant establish the identity of the active ingredient by using appropriate analytical methods (e.g., high performance liquid chromatography, titration, etc.). In other cases, ‘FDA may prescribe additional standards that are material to the ingredient’s sameness.’”
- What is an active ingredient? While federal regulations contain a precise definition of an active ingredient, FDA’s guidance serves to expand this definition, stating that FDA considers an active ingredient to “generally” include “the entire molecule, including those portions of the molecule that cause the drug to be an ester or salt.” For the purposes of determining sameness, FDA “may also” consider “noncovalent derivatives of the molecule,” such as a complex, chelate or clathrate.
- This is primarily a problem of chemical complexity: As FDA’s guidance notes, some chemicals are more challenging than others to regulate. Some active ingredients have various physical forms – such as polymorphs or co-crystals – which can differ in structure. However, “differences in physical form will not prevent a prospective ANDA applicant from demonstrating active ingredient sameness between the active ingredient in the ANDA drug product and the RLD,” according to the guidance.
- Peptides: In February 2020, the FDA issued a final rule establishing a new definition of the term “biological product” which included peptides with more than 40 amino acids. As a result, any peptide with fewer than 40 amino acids is considered to be a drug, rather than a protein, and is therefore eligible for generic competition. As FDA’s guidance notes, for such products, sameness can generally be established “through physicochemical characterizsation and biological evaluation,” and it is “recommended that applicants also perform comparative testing of the proposed generic synthetic peptide to the RLD.”
- Complex Mixtures: As the guidance notes, FDA has previously identified “Several different categories of complex mixtures,” including naturally derived mixtures with multiple components, synthetic polymers and synthetic or semi-synthetic mixtures. However, it tends to treat these mixtures not as a combination product but instead as a “single active ingredient because it is not possible to distinguish each and every specific constituent component in the complex mixture that is intended to furnish pharmacological activity or other direct effect […].” If, however, it is possible to distinguish the ingredients and their effects, then the FDA will “treat each constituent component as a separate active ingredient,” although it will not consider them to be fixed-combination drug products. To support a determination of “sameness,” FDA recommends that ANDA applicants characterize components of the complex mixtures “in multiple batches of both the proposed generic drug product and reference product under similar conditions.” It is generally appropriate for sponsors to proposed “ranges for each molecule in common based on the comparative testing,” along with a justification for the ranges.
- What matters is the final active ingredient: FDA’s guidance notes that often, the chemical form of the active ingredient is the “same as the chemical form introduced at the start of drug product manufacture.” However, in cases where it is different – perhaps it undergoes a chemical change during manufacture – then FDA will generally consider the converted chemical form for the purposes of comparison.
- FDA’s guidance contains a fairly extensive section (Pages 7-9) elaborating on the agency’s definition of the term “active ingredient” and what would be considered to be a “part of the active ingredient.” However, sponsors will see a lot of language that is far from definitive – the terms “In general” and “In some cases” make frequent appearances, thereby reducing the potential benefit of the guidance. We expect that industry comments on this guidance are likely to focus both on this section and exceptions to the general approaches it proposes (especially since such approaches are often the focus of Citizen Petitions seeking to delay or deny the approval of a prospective generic).
- A final note on development approaches: As noted previously, FDA’s guidance is meant to be a sort of philosophical, general guidance describing likely approaches rather than a catalogue of every conceivable edge case imaginable. As a result, FDA’s guidance implores sponsors to review product-specific guidances where they exist, since they may “include recommendations on how to demonstrate active ingredient sameness.” Or to paraphrase the FDA — RTG: Read the Guidance.
- Science advances, so stay current: A few years ago, when FDA first began to confront reports about the presence of nitrosamine impurities in numerous drug substances, we heard an interesting argument from the then-head of FDA’s Center for Drug Evaluation and Research (CDER), Janet Woodcock. The argument: “Improved technology enables us to detect even trace amounts of impurities in drug products and may be the reason why more products have been found to have low levels of NDMA,” said Woodcock. Put another way: As science gets better, regulators and industry may need to reconsider existing approaches or demand higher degrees of excellence. FDA’s new guidance makes a rather similar argument: “As scientific understanding and technology evolve, FDA will continue to assist in and support the adequate characterization of an active ingredient so that prospective ANDA applicants may adequately demonstrate sameness.” The implication here for sponsors, such as sponsors of complex mixtures, is that scientific advances may ultimately require them to characterize and quantify that which they previously could not.
To contact the author of this analysis, please email Alec Gaffney ( [email protected])