Optimizing Regulatory Considerations for Orphan-Drug Development on a Global Scale

Rare disease and orphan drug research has a long history of serious challenges, thanks to both intrinsic factors—fewer patients means less available data; less available data means a less complete picture—and market forces—it’s more difficult to find investors when a smaller pool of patients may mean a more uncertain potential return on investment.

Luckily, recent changes in the international regulatory landscape have started to provide a favorable environment for the development of orphan drugs.

“Rare” Diseases: More Common Than You’d Think

Key players are now recognizing the serious need for rare-disease drug development. Taken as a whole, “rare” diseases are common. After all, it’s a designation that covers some 7,000 different types of rare diseases and affects an estimated 350 million people worldwide. Many of these conditions have no effective treatments or established standard of care. Unlike drug development for more prevalent conditions, research is consequently less focused on perfecting methods of treatment and more about giving patients options at all.

Rare-disease research is also an economically important sector for sponsors to consider. It’s a booming field with nearly 2,900 Orphan Drug Designations given since 1983 and a market growth projected to hit $127 billion by 2018.

The Key to Success: Effective Regulatory Engagement

In rare-disease research, there is an especially strong need for early regulatory engagement when developing and operationalizing plans for drug development. Rather than adversaries standing in the way of getting a product to market, today’s regulators are more deeply involved in rare-disease research and should be considered as partners by other stakeholders. Through changes to policy and a commitment to providing clinical researchers with useful advice, many regulatory agencies around the world have made clear their intentions for supporting orphan-drug development.

Key areas of focus when considering the regulatory environment for orphan-drug development include early engagement, development incentives, FDA focus, global regulatory awareness, regulatory strategy, and lifecycle management. The right choice for each product is highly individualized, a philosophy that applies more to rare-disease drug development than any other treatment area. When deciding on a regulatory engagement strategy, remember there is no one-size-fits-all approach.

Despite sporting evocative names, such as “Fast Track” and “Accelerated Approval,” on average, there is no significant time savings between orphan-drug and non-orphan drug designations—the FDA approval time of orphan drugs is 9 months compared with 10 months for non-orphan drugs. However, the advantage of the designation comes in the resources required. A Phase III trial for an orphan drug enrolls an average of just 528 patients, whereas the average non-orphan Phase III trial takes on 2,234. As a result, the industry’s expected Phase III costs for an orphan drug is just $5.5 billion compared with $21.8 billion for non-orphan drugs. A difference of over $16 billion in R&D costs is a clear incentive to pursue the orphan-drug designation where appropriate.

The Shifting Regulatory Landscape of Rare-Disease Research

In the past, the global regulatory landscape for rare-disease research made pursuing orphan-drug development unappealing for sponsors, investors, and researchers. These problems stunted orphan drug development:

  • No real regulatory strategy
  • No collaboration between different agencies and stakeholders
  • Little patient advocacy
  • No development incentives
  • No financial advantage
  • No fundamental knowledge of rare disease development
  • A lack of payers willing to reimburse treatment costs

Luckily, regulatory agencies have since then moved away from these ineffective strategies and have helped evolve the present regulatory landscape into one where there is:

  • Mutual recognition between the FDA and EMA
  • Widespread collaboration between multiple agencies, including the FDA, EMA, PMDA, and TGA
  • Fewer silos between key stakeholders
  • A high degree of incentives, exclusivity, and optimization of development pathways
  • A lifecycle approach to orphan-drug development
  • Open discussions on pricing and reimbursement
  • Innovative approaches accepted by regulators
  • Important resources, such as the FDA patient network

Your Dashboard of Development Options

To give a better idea of the global orphan-drug regulatory environment, let’s take a look at the specific policies of three key markets: the U.S., the EU, and Japan. Regulators in the U.S. offer 7-year market exclusivity for orphan drugs, which the EU and Japan extend to 10 years. The designation is applicable to pharmaceuticals, devices, and dietary products in the U.S., whereas it only applies to pharmaceuticals in the EU and Japan. In the U.S., orphan-drug grants are available for research in the form of programs from the NIH and other organizations designed to support research and development. In the EU, support comes in the form of “Framework Programs” and individual national measures. Japan likewise provides governmental funds to support rare-disease research. The regulatory authorities of all three markets offer scientific advice, fee reduction options, and special regulatory tools. In the U.S., special regulatory pathways include Fast Track, Priority Review, Accelerated Approval, and Breakthrough Designation. The EU offers Centralized Procedure, Accelerated Approval, and Exceptional Circumstances, whereas Japan gives the option of Priority Review.

What’s the bottom line, though? Soliciting early feedback from multiple regulatory agencies (e.g., both the FDA and EMA) is often a worthwhile investment. The advice received is frequently universally applicable and one may be able to fill gaps another misses.

Regulatory Optimizations at Each Step

Each stage of clinical research requires regulatory optimization to ensure success. Likewise, success at each step also becomes an opportunity to attract investor involvement.

Pre-/Investigational New-Drug Application

At this stage, sponsors can benefit from going to regulators for scientific advice, finding out more about development incentives, soliciting protocol assistance, looking at the literature, conducting or reviewing natural history studies, pursuing orphan-drug designation, and performing regulatory gap analyses.

Clinical Development (Phase II and III Trials) and New-Drug/Biologic License Applications

Here, sponsors should pay special attention to obtaining global regulatory guidance, selecting an appropriate accelerated approval pathway, discussing pricing and reimbursement, partnering with advocacy groups, and negotiating market exclusivity.


The work isn’t over once a new drug has been granted market approval. In the rare-disease world, the most effective way to extend a product’s lifecycle is to eschew the traditional, sequential approach to product lifecycle and instead focus on a modern, parallel strategy—researchers should be on the lookout for possible future indications throughout the entire development cycle. Always take note of additional indications to be explored later on—and keep in mind some may be unexpected.

In some cases, a product may end up suited for multiple orphan-drug indications, or in other situations, a drug originally approved for a more common condition may be useful in the management of one or more rare diseases. However, the greatest monetary gains come from the transition of an orphan drug into non-orphan indications. Translating an orphan drug into a wider patient population takes a relatively small financial investment that produces a large payoff, both in terms of financial profitability and in the number of patients who can be helped.

An important modern example of this situation is Avastin (bevacizumab). In Japan, Avastin was originally approved for the treatment of pleural mesothelioma, a rare cancer. Since then, the drug has been approved for multiple treatment indications, including more common conditions, such as cervical and colorectal cancers.