Magazine Article | August 1, 2019

Strategies For Success: Developing Drugs For Orphan Diseases

Source: Life Science Leader

By Sanjeev Luther

Drug development, in general, is a challenging feat. When it comes to orphan drugs, however, those challenges are compounded. It takes more than two years — 18 percent longer — to develop orphan drugs as compared to non-orphan drugs. In the 1970s, there were fewer than 10 drugs available to treat rare diseases. Pharmaceutical companies did not invest in developing drugs for rare diseases because the population of patients needing the drugs would be so small that it was unlikely the companies would recover the costs, let alone make a profit. That all changed with the enactment of the Orphan Drug Act in 1983, and since then, more than 600 orphan drugs have been approved.

The act introduced game-changing incentives. For example, orphan drug companies receive tax credits for specific R&D costs (e.g., a tax credit worth 50 percent of qualified clinical-testing expenses) as well as the waiving or reduction of certain procedural fees. Additionally, any unpatented drugs for the treatment of rare diseases have seven years of market exclusivity. The FDA’s review and approval process is fast-tracked for orphan designations. An additional impactful incentive is the introduction of federal and state grants for orphan drug development; for example, companies can apply for a research grant from the National Institutes of Health.


While the incentives have drastically advanced the industry, there are still significant challenges in orphan drug development at nearly every step of the process

With rare diseases come a lack of predictability and historical data on symptoms, severity, reactions, and all other aspects of a disease, as well as few — if any — previous clinical trials. The heterogeneity of orphan diseases makes the situation even more complex. With such limited information and few trials on the indications being researched, scientists do not have much data to build on. This lack of data makes it difficult to evaluate patients’ responses to treatments and impacts clinical trial design. For example, with common diseases that are well studied and understood, researchers have established endpoints from previous clinical trials to measure the impact of a treatment. In the case of orphan diseases, researchers have limited resources to tap into when building and executing the trials.

Identifying suitable sites and investigators can be significantly more challenging when it comes to orphan diseases. Study sponsors need to ensure that the sites are in countries where the disease in question is prevalent enough to drive a sufficient number of patients who qualify for the study. Furthermore, the sites need to be of high caliber and have the medical and logistical capabilities to execute the trial. Because patient populations of orphan diseases are so small, they are also geographically dispersed, with no heavy concentration of patients in any specific region. As such, in order to enroll enough patients, companies need to have more clinical trial sites than they would for non-orphan drugs. With more sites in more countries, more resources need to be allocated than in traditional clinical trials.

Finally, and one of the biggest challenges in orphan drug development, is recruiting enough patients for a trial. With each rare disease already having small patient populations, specific patient segments and qualifications necessary for the clinical trials reduce the pool even further. Approximately 80 percent of all clinical trials fail to meet their enrollment timelines, and 30 percent of all Phase 3 clinical trial terminations are due to lack of enrollment. As difficult as it is to enroll patients into non-orphan drug clinical trials, it is even more difficult with the smaller patient populations with rare diseases.


As more orphan drugs are developed and come onto the market, pharmaceutical companies can adopt some of the successful strategies that have worked previously.

With the lack of available data, the FDA suggests companies conduct natural history studies. This can inform on the progression of a disease, its symptoms, how and when it is diagnosed, and how quickly and severely it advances. With such insights, drug developers are more likely to design more successful and efficient programs.

When designing a clinical trial for an orphan drug, among the greatest resources are the patients themselves. Tapping into the knowledge and experiences of the patients and their caregivers may not only enhance the clinical trial process for the participants, but it may actually improve study outcomes. Firsthand knowledge of patients’ experience during site visits and treatments, as they also deal with the unique challenges associated with their disease, may better inform drug developers on strategies they can implement to make patients more willing to participate and remain enrolled in the trial.

"With orphan disease clinical trials, drug developers must get creative when it comes to participant recruitment."

Collaboration throughout the entire drug development process is critical, too. Due to the small number of study participants for orphan drug trials, data collected from each patient is critical and impactful on the program development and trial results. Ensuring engagement and collaboration with all parties involved — sites, investigators, patients, and caregivers — significantly contributes to enrollment, retention, and long-term outcomes.

With orphan disease clinical trials, drug developers must get creative when it comes to participant recruitment. Tapping into patient advocacy groups can be incredibly useful in alerting and educating patients about a trial. While orphan disease advocacy groups may be very small or even nonexistent for some diseases, when possible, a partnership should be created early on. General registries and organizations can be useful as well. Some of these include the Rare Disease Registry Program, Orphanet, National Organization for Rare Disorders, and European Organisation for Rare Diseases. Tapping into these resources may not only be invaluable in clinical trial recruitment, but also in site selection earlier on in the process to determine where your target patients are located.

Another critical set of tools in recruiting patients is digital and social media. Sixty-six percent of internet users search online for a specific disease or medical problem. Digital and social media also enables drug developers to target very specific and niche groups. Connecting with patients through social media gives drug developers another way to listen and learn from their patient experiences and create more patient-centric trials.

Due to the difficult nature of orphan diseases, patients often drop out of a clinical trial. Thus, whenever possible, drug developers should reduce the burden on the patient and caregiver — whether that means the frequency of travel for the visits or the intensity and complexity of the treatment itself. Drug developers should strongly consider covering travel and logistical costs to make the experience a bit easier on the patient.

Finally, working closely with scientific and regulatory advisors with extensive experience in dealing with authorities and orphan drug development can help ensure a more efficient, thought-out, and successful process. They can offer guidance based on other orphan indications, mitigating risk, and providing rationale for innovative trial strategies and designs.

As much effort as we have put into orphan drug development over the last several decades, 95 percent of rare diseases still lack an approved treatment. So, our work is cut out for us, and the road ahead is a long and bumpy one. But this is a critical mission on which we can never give up. As we say at Rafael, “To save a life is to save a universe.” Our effort is worthwhile for every patient we can save.

SANJEEV LUTHER is president and CEO of Rafael Pharmaceuticals. He has more than 25 years of experience in healthcare, specialty pharma, and the biopharma industry.