Orphan Drug Product Development: Incentives and Outsourcing Considerations
Would it surprise you to know that more than 40% of novel drugs approved in the past 35 years are for some of the smallest patient populations1?
Though the word “orphan” might imply something lost or lacking attention, orphan diseases have been anything but in recent years. An orphan disease is defined as one of the following:
- A condition that affects fewer than 200,000 people nationwide
- A condition that affects more than 200,000 people nationwide, but for whom “there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from the sale in the United States of such drug2.”
The average number of patients per orphan treatment is only 5,730 individuals3,4. However, despite these relatively minute populations, 55% of FDA-approved new molecular entities (NMEs) in 2014 were for the treatment of rare diseases (Figure 1)1.
But this wasn’t always the case.
Less than four decades ago there were a mere 34 treatments available for rare diseases in the United States, even though there are more than 7,000 of these disorders in existence3,5. This was largely due to the fact that, with such small patient populations per indication, the potential profit margin for a drug was slim. Pharmaceutical companies simply could not financially justify pursuing orphan disease therapies. This resulted in very few treatment options being available and little optimism for the 25 million people affected by a rare disease in the United States, over half of which were children4.
Enter the Food and Drug Administration.
The FDA AccommODAtion
In 1983 the FDA recognized this area of unmet need and took steps that altered the industry forever. The Orphan Drug Act (ODA) was passed and suddenly created highly attractive incentives for pharmaceutical companies to pursue otherwise unprofitable disease areas. As a result, there are now treatment options available for more than 700 orphan diseases, improving the lives of millions of previously underserved patients4.
There is still room for substantial growth in this market, however, as approximately 90% of rare diseases still lack an available treatment option4. Pharmaceutical developers not already in this space should take the many potential benefits offered by ODA into consideration when deciding whether to pursue rare disease treatments.
What Are the Incentives of the Orphan Drug Act?
The benefits of ODA are clear but can be essentially boiled down into four main topics:
- Longer exclusivity timeframes
- Shorter approvals times & improved odds of success
- Expedited clinical development programs
- Higher profit margins
Longer Exclusivity and Stronger Market Positioning
The exclusivity timeframe for a standard drug product is five years in the United States. This relatively brief period doesn’t allow pharmaceutical companies much time before competition can enter the same market. The potential for rivalry is often a major consideration when companies contemplate pursuing a project, as generic competition will inevitably lower sales over time. In recognition of this challenge, the FDA granted therapies with orphan disease designation a seven-year exclusivity period to motivate the industry and benefit underserved patients down the line4.
In addition, the duration of protected status is often even longer than seven years, as patent protection frequently applies beyond the date of expiration for orphan market exclusivity6. Furthermore, even when a patent does expire, there is a substantial lack of generic competition in the orphan drug market as compared to other industry segments. It is estimated that only around 50% of orphan drug therapies that have lost exclusive rights face generic competition6. This advantage should be strongly considered when looking into developing an orphan drug, as should choosing an outsourcing partner that knows the in-and-outs of these niche products. Selecting an organization with extensive experience handling unique formulations with small batch sizes can expedite your product to market and allow you to take full advantage of the benefits offered by ODA.
“The FDA granted therapies with orphan disease designation a seven-year exclusivity period to motivate the industry and benefit underserved patients.”
Smaller Clinical Trials and Higher Rates of Approval
It is no secret to anyone in the industry that the time and effort expensed in bringing a new drug to market is significant. A standard drug product takes an average of 12 years to develop and market, with a large portion of that time spent in clinical trials. Clinical trials typically require hundreds to sometimes thousands of subjects, making them expensive and absorptive of the development team’s time and talents. Through it all, drugs with well-designed clinical programs still face the risk of failure.
Hence, the attractiveness of the Orphan Drug Act.
Under the FDA’s legislation, an orphan drug product can achieve approval with as few as 20 patients in a clinical trial3. For example, Luxturna, a first-of-its-kind therapy that has restored the vision of those suffering from a rare genetic disease, had only 31 patients in its Phase 3 clinical trial3. When ODA was first conceived, the FDA recognized that since rare diseases have such a small patient population to begin with, finding a standard sample size for clinical trials is often not realistic. The decision was therefore made to ease study restrictions for orphan indications.
And the effort has not gone unappreciated, or underutilized: A 2012 study found that clinical trials for orphan drugs were typically shorter and had a 5% higher chance of regulatory success than standard clinical trials3. This translates into reduced development headaches and greater potential rewards for the sponsoring company. And it’s exactly why you should be knowledgeable about the Orphan Drug Act.
Orphan Drugs: Prime Candidates for Expedited Clinical Development Programs
The FDA has established several expedited programs “to target serious diseases with unmet clinical needs when a new treatment could provide meaningful clinical benefit.” While each expedited program is designed with a different product type in mind, nearly every orphan drug falls into one or more of these categories. The programs include:
- Fast Track: A process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
- Breakthrough Therapy: A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
- Accelerated Approval: Regulations that allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint.
- Priority Review: A designation indicating the FDA’s goal is to act on an application within 6 months.
An FDA report analyzing drug approvals from 2008-2016 showed that 87% of NMEs for rare diseases qualified for one or more expedited clinical development programs (see Table 1)7. Utilizing an expedited program can have a significant impact on time to market—another internal FDA study found that drugs receiving a Breakthrough Therapy designation had 3 years less clinical development time and review cycles that were 1-2 months shorter than standard designation drugs7.
Table 1: Use of Expedited Review Programs for Rare Disease NMEs (2008-2016)
|Expedited Programs||NMEs for Rare Diseases (Orphan Drugs)|
|Priority Review||87 (77%)|
|Fast Track||62 (55%)|
|Accelerated Approval||31 (27%)|
|Breakthrough Therapy||22 (19%)|
|Used Any Expedited Program||98 (87%)|
The main takeaway here is that expedited clinical development programs are both effective and highly applicable to orphan drug products. Nearly 9 out of 10 orphan drugs from 2008 – 2016 qualified for some level of expedited review, meaning the benefits of shortened development and clinical studies are likely to apply to future orphan drugs as well.
The regulatory and approval incentives of ODA contribute strongly to the third benefit of developing orphan drugs: increased profitability. The average cost of bringing a new drug product to market is estimated to be $300 million to several billion, depending on the therapeutic area and patient population. Pharmaceutical companies take on considerable risk when it comes to investing in product development, so being motivated by a higher potential profit margin, in addition to helping patients, is more than reasonable.
To add to the numerous advantages already outlined within orphan drug development, one study concluded that organizations with approval to market an orphan drug product are more profitable than those without. Between 2000 and 2012, companies with a marketed rare disease treatment experienced an approximately 10% higher return on investment than standard pharmaceutical companies3. This profitability, once again, is partially due to the provisions of ODA. In addition to longer product exclusivity and shorter clinical trials playing a role, the act offers reduced regulatory fees and subsidies for clinical trials to projects that fall under its purview3.
Rare disease therapies are also sold at higher prices than other drug products. For example, gene therapies are some of the most expensive treatments on the market, and 80% of orphan diseases are monogenic—meaning they are linked to a single gene3. The first gene therapy approved in the U.S. for an inherited ophthalmic disorder holds a price tag of $450,000 per eye, and the first gene therapy ever approved in Europe sold for $1 million for a one-time treatment3. The elevated pricing of orphan drug products offsets the large investment in drug product development and often results in greater profit margins for their developers.
“Between 2000 and 2012, companies with a marketed rare disease treatment experienced an approximately 10% higher return on investment than standard pharmaceutical companies.”
Finding the Right Outsourcing Partner for Orphan Drug Development
So, your company is developing an orphan drug and you are determining your development and manufacturing pathway. A growing number of pharmaceutical companies are relying on outsourcing to get products through the development pipeline. A 2017 report found that 30% of pharmaceutical development and manufacturing is performed by CDMOs, and this number is expected to increase to 40% by 20208. The use of outsourcing is likely higher for orphan drugs, which pose unique challenges to both small and large pharmaceutical companies, including:
- Limited sources of API
- Long formulation development cycles
- A need for reliable small-batch manufacturing
These are not trivial issues, and they should play a major role in the CDMO selection process.
Orphan APIs are expensive to manufacture and often only available in limited quantities. As a result, efficiency is a priority when developing orphan drug products. Early-stage development must be process-oriented and data-driven to make the most of limited resources. At Lubrizol Life Science Health (LLS Health), we employ a Quality-by-Design (QbD) approach coupled with thoughtful experimental design throughout the formulation development process. This helps us identify and solve issues such as poor solubility/bioavailability and inadequate stability long before scale-up, GMP validation, and manufacturing.
Long formulation development cycles
A 2018 report from the Tufts Center for the Study of Drug Development found that orphan drug products took, on average, 18 percent longer to go from patent filing to product launch than drugs for more common indications9. For start-up companies with limited funding and larger companies operating under tight timelines, this can be a major hurdle in getting to market. While speed is always desired during development, a truly experienced outsourcing partner understands the importance of optimizing a formulation for scale-up and manufacturing, even if that requires additional development and testing. At LLS Health, we strive to create formulations and analytical methods that are robust, reliable, and ready for scale-up. When you partner with us, you can rest assured that we will design a thorough development plan that simplifies the transition to clinical and commercial manufacturing.
The relatively low patient populations for orphan drug products often require small-batch clinical and commercial manufacturing. In addition, orphan APIs are typically complex molecules, such as biologics, that require specialized equipment or facilities to manufacture. Production of orphan drugs requires flexibility—both in terms of batch size and process design. To this end, LLS Health has designed a purpose-built commercial manufacturing facility that is ideally sized for small-batch orphan drug products. Our facility features 6,000 ft2 of cleanroom space, including areas for aseptic manufacturing and sterile fill-finish operations. The commercial manufacturing facility is separate but adjacent to our existing development and clinical trial manufacturing site, offering customers a seamless flow from development through manufacturing. Whether you are looking for a post-discovery development partner or you are seeking a technology transfer/scale-up site, LLS Health can help. Reach out today to learn more.
Orphan Drugs: A Growing Opportunity
From longer patent exclusivity to reduced regulatory fees, the Orphan Drug Act has undoubtedly transformed the rare disease industry and contributed to the uptick in approved therapies. Thanks to ODA, pharmaceutical companies have and should continue to explore the many available opportunities in this industry, which is still characterized by high patient need.
When it comes to intricate, high-value products such as orphan drugs, however, effective legislation alone isn’t enough to bring a formulation to market. Trusting the right people to aid you in taking your drug product from concept to commercial production efficiently and effectively is essential to reaping the benefits of ODA.
LLS Health is a full-service CDMO with over 20 years of experience working with complex, niche products such as those for rare diseases. We have a specialized understanding of the many challenges orphan drug development can present, whether it be in selecting the optimal delivery technology for a gene therapy or formulating a water-insoluble orphan drug for parenteral administration. We also feature a purpose-built commercial manufacturing facility that is ideally sized for orphan drugs and other small-batch products. LLS Health is equipped to handle every step of the orphan drug development process, from early-stage formulation through clinical and commercial production. Contact us today to see how we can take your orphan drug product from concept to commercial.