Generic products can be safe, effective, and lower cost alternatives to brand name drugs. Therefore, they’re important to reduce healthcare costs and increase the access to medicines. Since the clinical trial data supporting the safety and efficacy of the active pharmaceutical ingredient (API) is already available and approved for the innovator product, generic drug manufacturers don’t need to spend extra time and money in these drug discovery and clinical studies.

Instead, the FDA asks applicants to demonstrate that the generic candidate is bioequivalent to the reference listed drug.

In the next sections we’ll give you an overview of some strategies to streamline your generic drug approval process.

So, what is bioequivalence about

According to the FDA, two products are bioequivalents when “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 other words, two products are bioequivalents when they display comparable bioavailability. To assess this, the applicants must perform bioequivalence studies.

The importance of bioequivalence studies

To obtain approval from the FDA, the generic drug must be therapeutically equivalent to the reference listed drug. This means it must be both pharmaceutically equivalent, i.e., same active ingredient, dosage form, amount and route of administration, and bioequivalent to this innovator product. Thus, bioequivalence studies are essential for a successful application and approval of generic drugs.

When it comes to bioequivalence studies, there are different types of tests that you can perform. As outlined in 21 CFR 320.24(a), you should select the most accurate, sensitive, and reproducible approach available. Thus, there is not one universal method to assess bioequivalence. According to the analytical methods available, and the drug’s nature, certain methods would be more suitable than others.

Which brings us to the different kinds of bioequivalence studies. 21 CFR 320.24(b) admits the following main approaches to determine the bioavailability or bioequivalence of a drug product:

  • Pharmacokinetic (PK) study – in vivo test in humans measuring active ingredient in appropriate biological fluid as a function of time
  • Pharmacodynamic study – in vivo test in humans in which the pharmacological effect is measured
  • Clinical endpoint study
  • In vitro study (e.g., dissolution rate test)

These are listed in a descending order of accuracy, sensitivity, and reproducibility, making the PK study typically the preferred method.

 In general, the PK study is appropriate for most solid oral drugs since their site of action is normally the systemic circulation. This means that the concentration of the active ingredient can easily be determined in a biological fluid, and it’s directly correlated to the drug effect.

However, this is not the case for a vast number of other drug products and FDA has been developing guidelines to support the generic pharmaceutical industry.

Strategies to streamline your generic drug approval

Follow FDA’s Product-Specific Guidelines

As mentioned before, the method to assess bioequivalence depends on the nature of the drug. This naturally brings a certain degree of complexity in the moment of choosing and designing the study. To assist generic drug manufacturers in selecting the most suitable method, FDA has published Product-Specific Guidelines (PSG) with study recommendations for specific products. As of June 2021, nearly 1,900 PSGs have been published. Following the recommendations outlined in these guidelines can help you streamline your generic drug product development and approval, allowing a faster time-to-market.

Request a waiver of the in vivo bioequivalence study requirement

Besides recommending different kinds of bioequivalence studies, some of these PSGs guidelines might also suggest a waiver of the in vivo bioavailability or bioequivalence study requirement. In many cases these studies are not necessary because the in vivo bioavailability or bioequivalence of your drug product is self-evident.

21 CFR 320.22 lists different criteria and products for which you may request FDA to waive the requirement for the submission of evidence of in vivo bioavailability or bioequivalence. For example, if your product is a parenteral solution, an ophthalmic or otic solution, and contains the same active and inactive ingredients in the same concentration as another drug product that is the subject of an approved full or abbreviated new drug application, a waiver might be a possibility. This waiver approach, if possible, is another effective way to speed your generic drug application and approval process.

Challenges in bioequivalence studies

Despite these efforts from the FDA to support generic drug production and market approval, you might still face some challenges while performing these bioequivalence studies. The study design itself is a critical step and if there is any mistake in the design, protocol, sample collection, manipulation and storage, the subsequent tests and analysis might not be correct.

Furthermore, there are numerous complex drugs in which demonstrating bioequivalence is not as easy and simple. For example, products with local sites of action, such as orally inhaled and nasal drug products and topical products. In these kinds of products determining the rate of absorption might be extremely difficult.

We can support you with your Bioequivalence Studies

To better overcome the challenges listed above, it’s essential to have knowledge and experience in performing bioequivalence studies and you might consider getting external support for this. 4TE’s bioequivalence studies allow you to guarantee the equivalence of the quality and safety between your generic candidate and your reference product. This will help you getting your generic drug to market faster!

Additionally, our 4TE experts will start with a thorough Benefit-Risk Assessment, making sure the path ahead is smooth, and will support you in your Study Design.

Learn more about our services here. And if you think we may be able to help you out, don’t hesitate to book a call!

Related topics

If you’re also interested in the approval process of biosimilars, we’re sure you’ll enjoy reading our blog post: Biosimilars Regulatory Approval: the key role of Analytical Similarity Assessment.