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Tackling the Complexity of Complex Generic Drug Development

Sabina Paglialunga, PhD Director, Scientific Affairs

Generic drugs account for nearly 90% of all prescription medication filled in the US. Generic drugs are substitutes of a brand-name innovator medication, having the same (bioequivalent) active ingredients, dosage form, route of administration, safety profile and performance compared to a reference list drug (RLD). The FDA approves generic drugs through an abbreviated new drug application (ANDA) process, and has prioritized generic drug development to promote marketplace competition and make drugs more affordable. 

As more “complex” drugs are marketed, the need to develop complex generic drugs has arisen. Over the past year, the FDA issued several key generic product guidance documents (see links below) as well as hosted workshops and webinars specifically addressing complex generic drug development. 

Complex Generic Drugs

Complex generic products can contain a mixture of active ingredients, peptides or polymeric compounds. They can also comprise liposome, suspension or emulsion formulations; dermatological or inhalation drugs which may be part of a drug-device combination; or possess complex dosage forms such as long-acting injectable or implantable drugs. 

Recently approved complex generic drugs include: Glucagon injection to treat hypoglycemia (December 28, 2020); Ferumoxytol injection RLD: Feraheme for iron deficiency anemia (January 15, 2021); and Linaclotide capsules RLD: Linzess to treat IBS and chronic idiopathic constipation (February 9, 2021). 

Recommendations for some complex generic products can be found in Product-Specific Guidance (PSG). PSGs represent the FDA’s current thinking on bioequivalence (BE) approaches for generic drug development. A PSG will cover the recommended number of studies, study design, study population, fasting conditions, analyte(s) to measure and biological matrix as well as special considerations.  Presented in early May during a PSG-focused webinar (May 5, 2021), the FDA reported that nearly 40% of recent PSGs published pertain to complex products.  Moreover, a list of planned new PSGs for complex generic products is also available.

FDA Feedback on Complex Generic Drug Development

The “nuts and bolts” of an ANDA submission were reviewed in April during the FDA Generic Forum (April 28-29, 2021).  Special attention was paid to the types of communication pathways available to generic drug sponsors, such as Pre-ANDA Meeting and Controlled Correspondences. Overall, a Pre-ANDA Meeting are highly encouraged for complex products, especially when no PSG exists. This is an opportunity to obtain FDA feedback on new approaches to BE studies prior to submitting an application to the agency.  Meanwhile, Controlled Correspondence are for questions related to existing PSGs or alternative proposals to PSG recommendations. 

Bioequivalence Studies

BE studies may have pharmacokinetic (PK) or comparative clinical endpoints. Generally, a two-period, two-sequence, two-treatment, single-dose crossover study is sufficient for typical small molecule BE studies with PK endpoints. However, parallel or fully/semi-replicate study designs may apply for compounds with a long half-life or high variability. The PSG for a clinical endpoint BE study may recommend a placebo-arm as well as specific enrollment criteria for the patient population, prohibited medications and clinical endpoints. Additional studies for complex products may also be required; for instance, adhesion, skin irritation and sensitization studies are recommended for generic adhesive patch products.

Bioequivalence and Biosimilar Experts 

Over the past decade, Celerion has successfully conducted over 170 BE studies with approximately one-quarter classified as complex products, including inhaled, adhesive and sublingual products. Our expert team can support complex drug development through optimized protocol design, efficient clinical conduct at our 3 clinical pharmacology units as well as regulatory support. In addition, we offer an extensive list of validated bioanalytical assays that are readily available to evaluate test and reference PK endpoints.  Furthermore, Celerion also supports biosimilar drug development and provides turnkey and bioanalytical solutions for these drug programs. Biosimilar products are generic versions of approved biological therapies such as peptides, enzymes and antibodies. 

Lowering the Cost of Prescription Medication

There are less costs involved in an ANDA by avoiding duplication of non-clinical and clinical studies, and these savings can be passed along to patients. The price reductions are considerable with generic prices being approximately 80-85% lower than those of the brand-name medications, which translates into billions of dollars in savings per year to the US healthcare system.  As newer drugs on the market rely on more sophisticated devices for administration, advanced formulations as well as molecular-based therapies, the field of complex generic products and biosimilars is anticipated to grow.  Working with a CRO with a strong track record in complex generic products and biosimilar drug development with world-class bioanalytical facilities is just another efficient cost-saving step in this process.   

Links to Recent FDA Guidance Documents for Generic Drug Development 

Upcoming PSGs for Complex Generic Drug Product Development