Bioequivalence Studies & Complex Generics – BioPharma Services

Global medicine spending is projected to be significantly increased close to 2 trillion by 2027 with the annual increase rate from 3 to 6%. And that figure excludes the impact of COVID-19 therapeutics and vaccines. The therapeutics areas with the highest projected spending include oncology, immunology, and diabetes. These high costs may translate into even more unaffordable out-of-pocket costs for patients, strained budgets for healthcare systems, and decreased funding for other areas needing public investments. 

Generic drugs, including complex generics, have emerged as one of the most important avenues to address these challenges. Both traditional bioequivalence studies and novel, advanced bioequivalence approaches have contributed to the development of generics.

Significance of Generic Drugs for Pharmaceutical Cost Reduction

Generic drugs are one of the most important avenues to relieve the financial burden of pharmaceutical products, as the costs of generics, including complex generics,  are reportedly 80% to 85% lower than those of their reference brand name drugs. Importantly, generic drugs should be bioequivalent to their brand-name drugs and have the same active ingredients, dosage form, strength, and route of administration.

Moreover, the quality standards for the manufacturing, testing, and packaging sites are identical for generics and their respective brand-name products. A slight level of variability between a generic and a brand name product is inevitable as a result of the manufacturing process, just like between two batches of the brand name drug itself. Still, this difference should not be medically significant.

In the United States, the uptake of generics in clinical practice is very high, with almost eight of 10 prescriptions filled with generic drugs. Moreover, the United States Food and Drug Administration (FDA) has defined improving access to safe and effective complex generic products as one of its missions, further promoting the development of generics.

Drug Development Process and Bioequivalent Studies for Generic Products

The process of developing and approving generic drug candidates is strictly regulated. It includes comparing the bioavailability, bioequivalence, and general quality of complex generic products to those of the corresponding brand-name drugs. To compare two pharmaceutical products, they should be administered in an appropriately designed study, in the same molar dose, and under similar conditions.

Two pharmaceutical products are considered bioequivalent if there is no significant difference in the extent and rate with which their active ingredients or moieties reach their site of action. The findings of bioequivalence studies can then be used as a surrogate to predict therapeutic equivalence. Typically, bioequivalence studies are conducted in healthy adults who are ³18 years old and above.

Increasing Complexity of Pharmaceuticals Challenges Generic Drug Development

Initially, the FDA put forward a pathway for generic drug regulation with the Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman Amendments) in 1984. To request regulatory approval for a new generic drug, an abbreviated new drug application (ANDA), which includes data from the assessment of the bioavailability and bioequivalence of the generic drug candidate, should be submitted. However, an ANDA does not require data from a prolonged clinical evaluation like an NDA.

Notably, the Hatch-Waxman Amendments originally considered the development of generics primarily for brand drugs that were small molecules and whose manufacturing was reproducible and straightforward. Generics for these types of drugs could be well characterized by traditional bioequivalence studies. However, since then, the complexity of reference drugs and, correspondingly, the complexity of developing generics for them have increased.

Complex Generics

Complex generics have been defined as medical products with complexity or uncertainty regarding the approval pathway or the possible use of alternative approaches, which would benefit from early scientific engagement. They include:

• Products with a complex active ingredient, such as peptides, naturally sourced ingredients, or polymers
• Complex formulations, including liposomes and colloids
• Products with a complex route of delivery, including locally acting drugs, such as dermatological, complex ophthalmological, and otic dosage products formulated as gels, emulsions, or suspensions
• Complex dosage forms, such as extended-release injectables, metered dose inhalers, and transdermal products
• Complex drug-device combination products, including metered dose inhalers and auto injectors

Generics with complex active ingredients or formulations, which are called complex generics, are often more challenging to develop. In addition, drugs acting locally on a target tissue rather than via their blood concentration may exhibit therapeutic effects that do not directly correlate with their blood levels.

Therefore, the standard techniques and metrics employed to develop and evaluate generic drugs may not always be adequate for complex generics. As a result of the challenges associated with the development of complex generics, there are fewer generics available for complex generic drug products than for simple drug products.

Accelerating the development of complex generics has been identified as one of the priorities of the FDA. In addition, complex generics are an important component of the FDA Drug Competition Action Plan, which aims to encourage market competition for generic drugs and to promote the transparency and efficiency of the generic drug review process while maintaining the scientific rigor of its generic drug program.

Implementation of Advanced Methods for Complex Generic Development

The successful development of complex generics requires strategic thinking regarding the study protocol and design, engagement with regulatory agencies, and trial parameters and locations. Moreover, evaluating drug candidates for generic drug products may necessitate using advanced analytical techniques, quantitative methods, modeling, and data analytics. Advances in the analysis of complex generics include implementing quantitative methods and modeling (QMM) and model-integrated evidence (MIE), combining information from empirical studies and computational models.

Importantly, the FDA prioritizes the development and optimization of methods that aim to establish bioequivalence between complex generics and their reference drug products.

Examples of Recent FDA Approvals for Complex Generics

The prioritization of the development of complex generics by the FDA has led to successful approvals that will help facilitate patients’ access to more affordable therapeutics.

Several examples highlighted by the FDA include:

 A complex generic of glucagon that can be used for treating severe hypoglycemia in patients with diabetes was approved by the FDA in 2020. Previous research by the FDA on peptide analytical methods and immunogenicity testing rendered this approval possible. 

• A complex generic of an ophthalmic suspension of loteprednol etabonate was approved in 2021 for treating eye inflammation. The approval was made possible by implementing a novel in vitro bioequivalence approach, facilitating and streamlining the generic drug evaluation and approval process.
• A first complex generic of a parenteral iron product that can be used for treating iron deficiency anemia was approved in 2021. The evaluation and approval of this generic drug was based on the development of advanced bioequivalence study designs.
• The first complex generic of the inhalation aerosol Symbicort (composed of budesonide and formoterol fumarate dihydrate) that can be used to treat asthma and chronic obstructive pulmonary disease (COPD) was approved in 2022.

Areas of Future Development for Complex Generics

To assess which types of complex products and analytical methods should be prioritized in developing complex generics, the Center for Research on Complex Generics (CRCG) conducted an online survey among generic industry stakeholders. The types of products stakeholders most frequently mentioned were complex injectables, nanomaterials, and formulations; drug-device combination products; and nasal and inhalation products.

The most frequently mentioned methods for analysis included locally acting physiologically based pharmacokinetic modeling, oral absorption models and bioequivalence, and data analytics and machine learning. These findings highlight important focus areas for future complex generic research and development.

Partner With the Right CRO for Your Bioequivalence Studies and Complex Generics

BioPharma Services is a full-service, award-winning contract research organization (CRO). We can efficiently and competently advance all aspects of our client drug development programs, including studies on complex generics. The multifaceted set of advantages we offer our clients include:

• A multidisciplinary team includes over 250 experts and at least eight Ph.D. graduates.
• A modern in-house bioanalytical laboratory equipped with a liquid chromatography with tandem mass spectrometry (LC/MS/MS) platform operates with a wide range of validated and custom LC-MS/MS-based assays.
• Expertise in assessing various formulations, such as solid oral formulations, orally disintegrating tablets, soluble liquid formulations, long-acting depot injections, inhalation products, transdermal patches, creams, ointments, and suppositories.
• Experience with different routes of administration, including oral, intravenous, intramuscular, subcutaneous, topical skin, and intraperitoneal administration.
• Flagship state-of-the-art Phase I clinical centers in Toronto, Canada which is fully equipped to efficiently and safely perform bioequivalence studies for generic and hybrid drug filings and 505(b)(2) NDAs.
• An extensive database of study volunteers, including over 18,000 potential study participants, enables us to streamline recruitment.
• Expert statistical support and data management throughout all stages of bioequivalence studies.

Experienced regulatory scientists ensure that our client generic programs comply with all relevant regulatory requirements and can even participate in regulatory meetings.