The Challenge
When the market landscape for a pharmaceutical drug changes, there is a need to respond swiftly and decisively. This was the case when a second-generation isotretinoin formulation entered the market.
Isotretinoin is a treatment for severe acne, and while Douglas had already developed and launched a first-generation isotretinoin product, it had to be ingested with food. The launch of a second-generation isotretinoin product from a competing innovator saw the market landscape for isotretinoin change. The second-generation drug allowed patients to take the drug in a fasted state (on an empty stomach), expanding consumer choice.
When presented with an opportunity to partner with a mid-sized US based pharmaceutical company to develop a generic isotretinoin drug, Douglas rose to the challenge. With its market-leading position and proven track record with the existing softgel isotretinoin product, Douglas had the technology and expertise to modify its existing first-generation isotretinoin formulation into a generic drug that could be taken in a fasted state.
To expedite the approval and launch of a generic product ahead of the expiry of the patents listed with the US Food and Drug Administration (FDA) on the second-generation isotretinoin, Douglas and its pharmaceutical partner filed a paragraph IV abbreviated new drug application (ANDA). Chris Cuthbertson, Programme Manager of New Product Development at Douglas , was a central driving force behind this project. He explains: “with the paragraph IV ANDA submission approach, we developed a formulation that did not infringe the formulation patent that existed. You formulate around the patent, but your product must still demonstrate bioequivalence to the reference listed drug, have a stable shelf-life, and validated processes must be demonstrated”.
These factors can make for a technically challenging development process, especially with the added time pressure of launching prior to patent expiry. Chris explains the benefits of partnering with Douglas in this case:
“At Douglas, we have deep experience with softgel capsules, and we know how to develop and manufacture a quality product from decades of experience. If you are a company using this technology for the first time, there are learning curves that can add extra challenges. Following the successful manufacture and launch of our existing isotretinoin products, we confidently took on this project.”
The Approach
The innovator product required the development of four distinct dosage strengths: 10, 20, 30, and 40 mg. The initial hurdle for the Douglas team was that each strength demonstrated non-linear pharmacokinetic properties. Consequently, formulations had to be individually developed for each dosage strength capsule as their release mechanisms varied.
Chris explains that bioequivalence (BE) studies demonstrating that the generic product exhibits identical biochemical and pharmacokinetic characteristics to the second-generation isotretinoin product are integral to an ANDA submission. Part way through the development process, the FDA updated its guidelines regarding its criteria for BE studies. Previously, only two BE studies were required for the maximum dose – in this case, studies in a fed and fasted state for the 40 mg dose. However, the FDA’s updated requirements mandated fed and fasted BE studies for each dose were to be included in the application. “So instead of the two BE studies we were already working on, suddenly we had to plan for considerably more pivotal BE studies,” Chris recalls. He credits the close working relationship with the partnering company for retaining momentum during the testing phases.
“Developing the formulation and demonstrating bioequivalence was a complex task, that we successfully achieved, at speed. Keeping our partner informed, addressing their technical questions, and introducing new technology to help us deliver the project, all without delaying the project timeline, was imperative. Through regular meetings, transparent reporting and solution-based problem solving, we developed a strong working relationship between our two companies.”
As this was a paragraph IV ANDA submission, the goal was to launch as swiftly as possible before patent expiry, to secure market value. To achieve this, Douglas’ partner made two ANDA submissions for this project, as the 10, 20, and 30 mg products were ready earlier than the 40 mg product. Chris acknowledged that the submission process took a “huge amount of time and perseverance from both teams to ensure the product launched in time.”
Integral to the project’s success was the project management. For example, Chris and his team implemented a risk register containing anticipated questions from the FDA in response to the ANDA submissions. In consultation with the partnering company, the team were able to start work on areas considered of critical or high importance, so that FDA questions could be addressed proactively.
The Result
Douglas and its partner company successfully launched the generic isotretinoin drug in 2021, experiencing rapid sales growth. With the involvement of a third partnering company for sales and marketing efforts, the drug achieved a much larger market share than anticipated, leading to a doubling of the initial sales forecast. Dedicated resource planning meetings for the commercial and technical teams at Douglas ensured production could be scaled up quickly to meet market demand.
The strong relationship developed between Douglas and the partnering company, built on trust, collaboration and mutual success, as well as the commercial success of the project, resulted in further collaborations. “We’ve launched four additional projects into the market with this company, which is an extraordinary achievement,” Chris says. He concludes that a client centric approach, based on being transparent, and solution-driven enabled Douglas to swiftly address any challenges that arose during the development process, contributing to the overall success of this partnership.