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Drug Product , Integrated Programs , Dr. Asma Patel , Rare Diseases , Orphan Drugs

Accelerated pathways and CMC challenges in rare disease drug development

Summary: Dr. Asma Patel, Vice President of Integrated Development Services at Quotient Sciences, explores how accelerated regulatory pathways support rare disease drug development. While these fast-track routes help bring treatments to patients faster, they also introduce complex CMC challenges. Dr. Patel outlines strategies to manage risks, including early planning, flexible development, and integrated approaches. 

The development of therapies for rare diseases has been significantly aided by fast-tracked regulatory approval processes. 

Accelerated pathways, established by global authorities, aim to bring much-needed treatments to market more quickly. While fast tracking processes offer numerous benefits, they also introduce specific CMC risks that must be carefully managed. 

In our latest webinar, we outline the challenges CMC face when developing these often life-saving treatments and discuss strategies to mitigate CMC risks

Rare diseases globally: By the numbers

Approximately 7,000 rare diseases affect between 25 and 30 million Americans according to data from the National Institutes of Health (NIH) In the EU, the European Commission estimates that up to 36 million people live with a rare disease.

Of the 7,000 known rare diseases globally, about 95 percent have no treatment. Many of these conditions are under-researched, resulting in few or no effective treatments available.

How can drug developers address unmet needs for patients? 

The smaller patient populations and associated market size for rare diseases mean that the potential financial return on investment is lower compared to treatments for more common conditions. This economic reality often makes pharmaceutical companies hesitant to invest heavily in developing new treatments for rare diseases. 

Recognizing this, global authorities have introduced additional regulations to encourage R&D investment in this area of high unmet clinical need. 

What are incentives for rare disease drug development in the US and EU?

Key regulatory incentives have been established to promote the development of orphan drugs, such as the Orphan Drug Act of 1983 in the US and the Orphan Regulation of 1999 in the EU. 

In the US, one of the primary incentives is market exclusivity, which grants companies exclusive marketing rights for their orphan drug for a period of 7 to 10 years. Additionally, expedited review timelines, tax credits for clinical research expenses, and waived prescription drug user fees help reduce costs and protect investments, making it more feasible for pharmaceutical companies to develop treatments for rare diseases. 

Accelerated pathways are also available in the US, offered by the US Food and Drug Administration to speed up the availability of these medicines to patients. Similar programs exist in the EU as well as in the UK.

What is a traditional drug development timeline vs. an accelerated pathway?

For patients suffering from serious diseases and unmet clinical needs, the typical drug development timelines of up to 15 years can seem excruciatingly long. As a result, global health authorities have developed multiple pathways to expedite drug development and review times. The expedited approval is granted based on an agency finding that the drug is safe and effective for its intended use – exactly the same approval standard as that used for the traditional drug development pathway. 

Accelerated approval simply allows the FDA to evaluate drugs based on surrogate endpoints or intermediate clinical outcomes that predict clinical benefit. Because these endpoints are expected to predict clinical benefit, the agency can calculate the risk/benefit that an accelerated approval pathway’s benefits outweigh its risks, which are then rigorously confirmed in post-marketing confirmatory studies conducted after accelerated approval.

In the US, several pathways are available to expedite the development and approval of these treatments. For instance, the Accelerated Approval pathway targets new medications that address unmet clinical needs. The Breakthrough Therapy designation is granted to drugs that demonstrate significant improvement over existing therapies. Additionally, Priority Review can be sought to reduce the review timeline to six months for therapies where no adequate treatments currently exist. 

What challenges does CMC face, and how can CMC best manage these risks?

Expedited pathways can significantly reduce development timelines from the typical 10-15 years to as few as 3-5 years, but the accelerated pace ultimately introduces several pressures on CMC teams. 

Traditional manufacturing and supply chain models already do not align with the small-scale, specialized needs of rare disease therapies, but other considerations that add to the challenge are: 

  • Reduced commercial potential and limited research and development budgets because of smaller patient populations
  • Difficulty developing stable and effective formulations for rare diseases due to their unique and specialized nature
  • Challenges recruiting participants for clinical trials due to small and dispersed rare disease patient populations

The accelerated submission pathways for orphan drugs offer a vital opportunity to bring much-needed therapies to patients with rare diseases more quickly. However, the associated risks require careful management through robust CMC strategies.

How to choose a rare disease CDMO

Quotient Sciences specialize in addressing unmet needs in rare disease treatment. In the last five years alone, we have supported more than 50 development programs for rare diseases with a range of CRDMO services.

One area that makes Quotient Sciences an ideal CDMO partner for rare disease programs is our willingness to be adaptive, with capabilities for clinical up to commercial drug product manufacturing. We have capabilities to manufacture smaller scale commercial batches that are ideal for rare disease and pediatric therapies. 

Watch our recent webinar to learn how we help identify creative development strategies for accelerated submission pathways for rare disease programs from early clinical studies through commercial launch.

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