Christopher-Paul Milne on Orphan Drug Development

Earlier this month, Rare Disease Report covered results from a study, “Orphan Drug Development Takes 2.3 Years Longer Compared to Other Drugs is 2.3 Years Longer Vs. Other Drugs, according to the Tufts Center for the Study of Drug Development” that was published by Tufts CSDD Impact Report and conducted by the Tufts Center for the Study of Drug Development.

The findings revealed that, on average, orphan drugs take 15.1 years to move from first patent filing to product launch, which is 18% longer than the average time required for all new drugs. For ultra-orphan diseases, the drug development time was found to be even longer at 17.2 years.

In effort to learn more about the significance and reasoning behind the study’s statistics, RDR asked Christopher-Paul Milne, research associate professor, director of research at Tufts CSDD at Tufts University School of Medicine and the analysis conductor of the study, for further explanations.

Rare Disease Report^® (RDR^®): What do you think are the greatest hurdles facing orphan drug development?

Milne: It may be axiomatic, but the greatest challenge is that these are rare diseases, so the top challenges identified in our study are the result of that circumstance. First, researchers are often starting with a blank slate, ie., [which means there is] very little in the way of a pre-existing body if knowledge to build on, and so you learn as you go, which makes early development take longer, especially when you take into account the second major factor. Second, patient populations that are few and far between who are hard to diagnose and perhaps present with variable symptom clusters make for logistically challenging trials that hard to organize and execute.

RDR^®: Do you have any inclinations why central nervous system (CNS) and cardiovascular (CVD) indications face the most developmental challenges?

Milne: The reasons are complex and probably different for CNS versus CVD. In CNS, for example, the lack of animal models and the challenging nature of the biology of the brain and nervous system are extremely problematic, which then exacerbates the overall challenge of development for orphan diseases. For CVD, diagnosis and onset of identifiable discreet symptom patterns may contribute to accrual of enough patients for a study. Also, both CNS and CVD are less likely to be monogenic diseases, so that single enzyme deficiency or pathway can’t be tracked down as easily as it might be, for example, in a metabolic DS therapeutic area.

RDR^®: How does the lack of animal models and biomarkers contribute to the slow progress of orphan drug development?

Milne: This speaks to the knowledge base in mainstream biopharma development about 50% of animal models have some utility for studying the disease in humans…not so in orphan diseases due to the rarity of the disease. As far as biomarkers, our study found that close to half of orphan diseases were proceeding through development without biomarkers to guide them as opposed to mainstream development where also all research projects that reach the clinical stage have done so with the help of biomarkers.

RDR^®: How do you think some of the challenges and hurdles can be overcome regarding orphan drug development?

Milne: [It’s] hard to say. There are so many diseases, 7,000 in the US and 30 new ones [are] identified each year and thousands more worldwide. Only 5%-10% of the orphans in the US have been addressed with specific treatments. The [National Institute of Health] NIH has a rare disease program to help develop the basic science necessary to begin accumulating a knowledge base, and the FDA has started a grant program for studying the natural history of orphan diseases, which will also help with building a knowledge base to start from. Big data mining and advances in genomics will help with making diagnoses of new disease clusters more efficient and [the National Organization of Rare Disease] NORD and its international counterparts are providing the networking communication and education vehicles to pool resources and information.

RDR^®: Do you see the orphan drug development time improving or worsening over time?

Milne: I don’t see it worsening unless the field as a whole becomes too difficult for major companies to stay in the game or for smaller companies to attract the investment they need to get through the “valley of death” where many R&D projects die because outside funding dries up. The increasing number of diseases is not likely to negatively impact the development time of a particular disease because it’s not as if anyone has a mandate to address all orphan diseases at the same time, so resources will just be applied differentially, which highlights another factor that may begin to have an impact over time.

Patient advocacy groups for specific orphan diseases are developing their own research capacity either just as a source of grants or as a de facto virtual R&D research organization, e.g. Cystic Fibrosis Foundation. Also, regulatory authorities are continually creating or enhancing programs to assist orphan disease programs once they reach the clinical stage of development and submit applications for approval.

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