Orphan Drug Designations and Orphan Subsets



In this episode of Advancing Revolutionary Therapies, Mara Holinger, Senior Vice President of Regulatory Affairs at Veristat, speaks to Alexis Northcutt, Regulatory Strategist, and Ellen Truitt, Associate Regulatory Affairs Strategist, of the Veristat regulatory team, about Orphan Drug Designations and Orphan Subsets. FDA’s Orphan Drug Designation provides incentives to encourage the development of treatments for rare diseases.  

Check out the full episode and learn more about ODD classification and the strategic use of subsets in study design – or read the summary below. 


FDA’s Orphan Drug Designation Program 


Mara: Can you explain what the Orphan Drug Designation Program is? 


Alexis Northcutt: FDA’s Orphan Drug Designation (ODD) program is meant to provide incentives and support to encourage the development of treatments for rare diseases. Although there have been incredible medical and scientific advances throughout the 20th and into the 21st centuries, it became apparent that we were neglecting smaller populations of patients whose diseases were uncommon. The Orphan Drug Designation program gives FDA the authority to grant orphan drug status to a drug or a biologic that prevents, diagnoses, or treats an “orphaned” or rare disease. 


Some of the incentives that ODD designation provides includes exemption from user fees, a potential for 7 years of market exclusivity, and tax credits for some clinical trials. 


Ellen Truitt: One of the common questions we get from sponsors seeking orphan drug designation is whether their population is appropriate and whether a chosen disease subgroup could be a suitable for a successful ODD request. To be eligible for an Orphan Drug designation, the disease must afflict less than 200,000 people in the U.S. 


Mara: What makes a subgroup of a disease “inappropriate”? 


Ellen Truitt: If the population the sponsor has chosen is a disease subgroup that is not scientifically justified, it doesn’t qualify per the regulation. For example, you cannot request ODD for the pediatric population of a disease when your drug has the potential to treat patients of all ages safely and effectively. 


Mara: Can you elaborate on a ‘scientifically justified’ subgroup? 


Ellen Truitt: Some diseases have subgroups which may exhibit different biological mechanisms, manifestations, or disease severity. For example, subgroups in oncology commonly include patients with a specific genetic aberration which may not be present in the total disease population. What makes these groups scientifically justified in the eyes of FDA is whether the subgroup is based on disease mechanisms which have a relationship to the drug or therapy which it is intended to treat. Essentially, the point is to prove that your drug will only work in these smaller groups and will likely not be effective for the broad indication. 


Alexis Northcutt: In situations where a sponsor has identified a subgroup of a specific indication, they need to consider whether it is truly a scientifically justified subgroup or if they are guilty of what we refer to as ‘salami slicing.’ Salami slicing refers to a scenario when we take a disease and divide it into an artificial subgroup, with the idea that each subgroup would be considered a rare disease but there’s not scientific justification for that. 

RAPS ODD webinar recording Cover Oct2022


Webinar: Orphan Drug Designation – The Considerations, The Rewards, and How They Differ Between the U.S. and Europe 


Determining 'Scientifically Justified' Orphan Subsets

Let’s discuss some scenario examples to understand how a sponsor would justify a subgroup.  

Scenario #1

The sponsor has a product intended to treat burn scars, which as a broad indication does not fall under the 200,000-prevalence requirement. However, the prevalence for restrictive burn scars, scars that inhibit the range of motion around a joint, is less than 200,000. The sponsor would like to pursue an ODD application for this target population now, and then pursue a broader indication later on. 

Ellen Truitt: That might be an example of salami slicing. Can you provide an explanation for why the mechanism of your product is specific to restrictive burn scars as a subgroup, rather than other types of burn scars, or potentially all types of burn scars? 
Mara: No, there is no reason that the product would not have the potential to treat other types of burn scars. The sponsor is hoping to request orphan designation in this group since it is a rare population and they have included these patients in their studies.  

Alexis Northcutt: A common example of a scientifically justified subgroup would be developing an oncology product to target a specific genetic variant. In this scenario, the subgroup of NSCLC patients with an ALK mutation would meet prevalence requirements for orphan drug designation. If the product’s mechanism of action (MOA) is based on the presence of the ALK mutation and wouldn’t be effective in the larger NSCLC indication, then this is a good scientific justification for the ALK+ NSCLC subgroup. 
Mara: What type of data is needed to demonstrate that the drug is specific to ALK+? Does that need to be clinical data? 
Alexis Northcutt: It could be clinical data, or the data generated earlier in product development, such as in vitro or in vivo non-clinical studies – as long as it demonstrates that the product’s MOA depends on the presence of the ALK+ mutation. 

Mara: How did this treatment qualify for ODD if the applicability of the subgroup was not as straightforward as the previous NSCLC example? 
Ellen Truitt: Although melanoma overall does not qualify for orphan drug designation, the sponsor was able to justify exclusion of the early stage and pre-resection patients from the target population. By distinguishing the mechanism of action and demonstrating the lack of efficacy for other melanoma patients, this smaller subgroup was justified for ODD. 



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