Category | Small molecule
According to the US Food and Drug Administration (FDA), “2020 was a record-breaking year in terms of the number of orphan drug designation and rare pediatric disease designation requests submitted to the Office of Orphan Products Development.” In the US alone, there are more than 25 million patients affected by a rare disease, which is defined as a disease with fewer than 200,000 patients. It’s estimated that there are more than 7000 rare diseases, but at this time only 5% of those have a treatment approved. There is clearly a large unmet medical need for treatments to be developed from new or repurposed molecules. For sponsors of rare disease drugs, the market is estimated to be $262 billion by 2024, and with incentives such as tax credits for clinical study expenses and extended product exclusivity protection, the rare disease space can be financially viable for sponsors.
Even with government support and regulatory commitment to modernize the review of orphan drugs applications and the growth potential of the market, fast approval isn’t always assured. Given that the average cost to develop a drug starts at $300 million, sponsors of new rare disease treatments need strategies that increase the chances of approval while pursuing an accelerated development schedule.
Delays in independent portions of the program can have a greater impact on the overall program, leading to financial impacts in the start or continuation of clinical trials. Your overhead remains the same when your team sits idle—especially if you’re coordinating with other vendors.
This makes the avoidance of delays monumentally important. Typically, delays are caused by two types of roadblocks:
A typical challenge that can lead to a roadblock in the early development of orphan drugs is the design of an effective and stable formulation.
The answers to these questions will have an impact on your development strategy for both drug substance and product. A repurposed molecule likely has a formulation history that can accelerate development, but a new API needs ground-up chemical and formulation development. Initial clinical supply demand may be small and enable a simple, phase-appropriate formulation in Phase I, but as data emerges formulation complexity may increase. A drug substance and drug product will require scale-up studies and eventual process validation to build a strong technical chemistry, manufacturing, and controls (CMC) package ready for review by regulatory authorities.
Orphan drug products are usually on accelerated timelines, driven in part by the need to provide new medication for unmet medical needs, and to take advantage of streamlined review processes. While sponsors wish to go as quickly as possible, this will mean pulling forward, at risk, development activities that would normally be informed by a clinical result to guide the next CMC activity.
For example, an oral API in bottle drug product—filled semi automatically—is suitable for some Phase I trials, however, this type of process cannot be scaled up and controlled for commercial manufacturing. Conversely, a simple sterile-filled vial using a common container closure system could potentially be supported on the same clinical-scale, automated filling line from Phase I to Phase III and be supported with a process validation protocol.
Furthermore, not only does a pharmaceutical drug have to cure/treat a disease, it must be of the utmost quality as it pertains to its chemistry, manufacturing, and controls. As you start to scale up—from Phase I to commercialization—modifications of manufacturing procedures for both drug substances and drug products, are almost inevitable.
Sponsors may also change, particularly when a single investigator initiates the development that is subsequently taken up by a small or larger company. When these types of changes and transfers happen, it is important to retain and track the development history of the program.
No matter which—or both—of these roadblocks occur, they can complicate the development of a complete CMC package, which can delay approval. It’s important to remember that regulatory agencies expect a complete CMC package. From formulation to pharmaceutical needs—there can be no gaps in your drug substance and drug product program.
In order to foster a continuous and adaptive development strategy, and anticipate the two common roadblocks above, consider the below checklist. And while this checklist may seem to oversimplify the development strategy, it can be a good foundation. Consider the following:
A final consideration to address is deciding whether you should outsource parts of—or all of—your orphan drug development program. Regardless of what dosage form you choose, developing a simple pathway to clinical trial material is no easy feat. Pharma companies—both large and small—often outsource steps of their orphan drug’s journey to CDMOs who specialize in drug substance, drug product, packaging, and distribution. Traditionally, orphan drug developers take a multi-vendor approach.
And while a multi-vendor approach to outsource makes sense in theory, in practice, this approach can be a poorly coordinated and challenging strategy. Why? Because the full burden of coordinating communication between multiple CDMOs falls to the orphan drug developer. Processes from multiple CDMOs don’t naturally align—for example, a drug product vendor may not start activities until the drug substance has been received from that vendor, and any surprises or changes to shipment/receipt dates are the responsibility of the sponsor. Furthermore, various CDMOs and vendors may be in different geographic locations making different languages and timezones another burden on the orphan drug developer. Not only will geographical challenges and regional differences be presented, but there are further regulatory guidelines, importation rules, and tax implications that fall on the shoulders of the drug developer. If one vendor can manage all the above challenges, as well as align inter-site activities with responsive timelines and coordinated teams, then drug sponsors can realize a smoother program execution.
In a sea of CDMOs, it is becoming the wiser choice to find a single vendor who can strike the right balance of development, CTM manufacture, and commercialization. The right single vendor will have the capabilities and know-how to recognize that all aspects of your orphan drug’s journey are important. There isn’t a one-size-fits-all approach for these complex drugs and a CDMO who has the right expertise can better lead your orphan drug to not only clinical success, but commercial success as well. A CDMO should help: