Demonstrating bioequivalence (BE) remains the key regulatory hurdle for generic drug approval. However, this is a challenging process for today’s complex drugs and alternative delivery methods. Consequently, patients lack availability of thousands of generics. This problem is especially vexing for topical drugs and trans-dermal patches.
Regulatory Support for Expediting the Development of Dermal Generics
The high cost of running clinical BE trials has diminished companies’ appetite to develop generic versions of topical drugs. As a result, many branded topical drugs remain on the market well past the originator’s patent expiration date, without the option of cost-effective generic alternatives that could benefit patients. The FDA has noted the problem and has provided new regulatory pathways and incentives such as the Complex Generics Therapy (CGT) to spur development.
Alongside financial incentives, the FDA has undertaken a major research initiative to identify and leverage in silico modeling & simulation techniques to demonstrate BE in complex generics. In many cases, options such as Q1/Q2/Q3 sameness, in vitro release (IVRT) and in vitro permeation tests (IVPT) can be used to demonstrate BE. But, in more complex formulations, including many topicals, these approaches often fall short. The agency is now turning to in silico modeling & simulation, specifically the mechanistic modeling technology called physiologically based pharmacokinetics (PBPK), rather than running an in vivo comparative clinical BE endpoint study.
Certara Simcyp’s Collaboration with the FDA: First VBE Success
The FDA has awarded Certara several grant projects under this research initiative to study complex generics, dermal, and other delivery methods and to predict the behavior of orally dosed supersaturating drugs and drug products.
These initiatives have begun to spur progress in the field of complex generic drug development. The overall number of Abbreviated New Drug Application (ANDAs) is at record highs, and the FDA has stated their willingness to meet with companies to identify novel approaches to expedite developing more complex products.
Most newsworthy, last year the agency approved an ANDA for a dermal drug using PBPK specifically using the Simcyp™ Simulator MechDermA model as an alternative for Q1/Q2/Q3 formulation in lieu of an in vivo comparative clinical endpoint study. This milestone represents the first and only application where PBPK was accepted and approved for BE without the need for a comparative clinical endpoint study. Simcyp is actively working on other breakthroughs.
Along with sharing this news, the FDA recently stated, “PBPK for locally acting products can potentially be used to support not conducting clinical endpoint studies or pharmacodynamic endpoint studies as currently recommended in product-specific guidance (PSG). This technology can be used to simulate virtual BE studies to evaluate effects of formulation and differences in systemic action at the site of drug exposure.1” Additional benefits cited by the FDA for using PBPK in complex generic drug development include:
- PSG development and risk assessment for changes in drug mechanism
- extrapolation of BE to sub-populations, including those of different ages and co-morbidities; and drug product or formulation development, acting as a virtual workspace
Simcyp’s Multi-phase Multi-layer (MPML) MechDermA™ Model
Initially developed under a FDA and the National Institutes of Health grant, Simcyp expanded its PBPK Simulator to incorporate an extensive dermal model. Called MPML MechDermA™, the multi-phase, multi-dimensional dermal absorption model is based on skin physiology (strateum corneum (SC), viable epidermis, dermis, subcutis, deep tissue, and skin appendages). The model also allows accounting for drug formulation specific components covering all major types of formulations. Further expansion of the model focuses on more mechanistic description of the skin. This allows for simulating disease specific modifications to the skin. The model is also continuously enhanced in the formulation module with additional critical quality attributes.
The mechanistic MPML-MechDermA model of the skin absorption accounts for the active pharmaceutical ingredient (API), formulation, physiology, and environmental parameters, enabling the simulation of complex diffusion through the SC for drugs with different physicochemical properties as well as different formulations, namely gels, emulsions, patches, suspensions, and pastes. The model can also simulate drug partitioning and absorption through the hair follicular pathway with blood flow to the dermis modeled as a function of cardiac output, body weight, and body surface area.
Formulation Inputs in MPML MechDermA Model
Strong Outlook for Modeling & Simulation in Complex Generic Drug Development
The FDA’s recent approval of a generic version of diclofenac sodium topical gel leveraging the Simcyp MPML MechDermA PPBK model sets the stage for increased use of M&S to speed the approval of complex generics. VBE leverages advanced modeling and simulation to demonstrate BE and provide additional insight into drug performance. These in silico studies are safer (removing the need for drug administration to often young, healthy volunteers), faster and less expensive to conduct than clinical BE studies and represent an important advance for generic and innovator drug companies alike.
In addition to dermal drug products, from trans-dermal to subcutaneous and long-acting injectables, the FDA has identified nasal, ophthalmic, orally inhaled, vaginal, and gut delivery as opportunities for PBPK.
Certara and the Simcyp Simulator are ready.
To learn more, please watch this archived webinar on this topic: