Advancing Revolutionary Therapies
Advancing Revolutionary Therapies
Orphan Drug Designations and Orphan Subsets
FDA’s Orphan Drug Designation provides incentives to encourage the development of treatments for rare diseases. Listen as Mara Holinger, SVP of Regulatory Affairs at Veristat and members of the regulatory team shed light on ODD classification and the strategic use of subsets in study design.
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Speaker 2:Hi everyone, and welcome to Art Podcasts, Advancing Revolutionary Therapies, a podcast series presented by the Centers of Excellence at Vata. My name is Mara Hollinger. I'm the Senior Vice President of regulatory affairs here at Vata, and I'm delighted to kick off season three, a dedicated series of regulatory podcasts on topics that cover everything from smart regulatory strategies to maintaining continued regulatory compliance to the influence of health authorities on clinical trials and more. Today I'm joined by Alexis Northcutt, regulatory strategist and Ellen Truitt, associate regulatory strategist, both also with Baratt to discuss today's topics on orphan drug designation and specifically orphan subsets. So welcome Alexis and Allen. Thank you for joining today.
Speaker 3:Thank you, Mara. Happy to be here today.
Speaker 4:Yeah, thanks Mara. Me as well.
Speaker 2:Okay, I'm going to hand it right over to you, Alexis, to just explain in general what the Orphan Drug Designation Program is.
Speaker 3:Sure. So FDA's Orphan Drug Designation Program, which you will hear us referring to as O D D, is meant to provide incentives and support to encourage the development of treatment for rare diseases. So I don't think there's any argument that there have been incredible medical and scientific advances throughout the 20th and into the 21st centuries, but at some point in the seventies and eighties we began to realize that we were neglecting this smaller population of patients whose diseases just weren't that common. So this program gives FDA the authority to grant orphan drug status to a drug or a biologic that prevents diagnosis or treats an orphan or a rare disease. So some of these incentives that are included with this orphan drug designation are exemption of from user fees, potential for seven years of marketing exclusivity and tax credits for some clinical trials.
Speaker 4:And this is Ellen. I also wanted to add, you know, in order to be eligible for this designation, the disease must afflict less than 200,000 people in the us. One of the most common questions we get from sponsors seeking O D D is whether their population is appropriate, and in some cases, whether a chosen disease subgroup could be suitable for a successful O D D request.
Speaker 2:Ellen, could you expand on what would make a subgroup of a disease suitable or unsuitable for the request?
Speaker 4:Sometimes the population the sponsor is chosen is a disease subgroup that is not scientifically justified, so it doesn't qualify per the regulation. A broad example of this would be trying to request O D D for the pediatric population of a disease when your drug has the potential to safely and effectively treat patients of all ages.
Speaker 2:Okay. Can you elaborate a little more on what scientifically justified subgroups would be?
Speaker 4:Sure. Some diseases have subgroups which may exhibit different biological mechanisms, manifestations, disease severity, et cetera. For example, in oncology, these subgroups 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 the FDA is whether the subgroup is based on disease mechanisms which have a relationship to the drug or therapy which is intended to treat it. 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.
Speaker 3:Right. So in situations where a sponsor has identified a subgroup of a specific indication, they need to carefully consider whether they have a scientifically justified subgroup or if they might really be guilty of what we refer to as salami slicing. Salami slicing is when we have a disease and we divide it into these artificial subgroups with the hope that each subgroup might be considered a rare disease, but really there's not scientific justification for that subgroup.
Speaker 2:Okay, thank you both for those explanations. I think it would be really helpful if we could get into some examples in order for folks to understand how a sponsor would scientifically justify an orphan subset. So I'll start, Let's assume that I'm the sponsor of a product intended to treat burn scars, which as a broad indication does not fall under the 200,000 prevalence requirement, but it looks like the prevalence for restrictive burn scars or scars that inhibit the range of motion around a joint is less than 200,000. So it seems like that could be a good target population for an O D D application and then we could later pursue the broader indication. Would that work?
Speaker 4:So Mara, that sounds like it might be an example of salami slicing unless you can 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.
Speaker 2:Okay. So I would need to demonstrate as the sponsor that the mechanism of action of my drug is somehow specific to the restrictive or joint mobility scars as opposed to all scars.
Speaker 4:Yeah, Correct.
Speaker 2:Got it. Thank you. Can either of you share an example of a scientifically justified subgroup that would be appropriate for O D D?
Speaker 3:Sure. An example that Ellen actually alluded to earlier, and one that's becoming more common would be developing an oncology product to target a specific genetic variant. So let's take non-small cell lung cancer on its own. This type of cancer doesn't meet prevalence requirements for orphan drug designation. It actually accounts for like 80% of lung cancer diagnoses. However, there is a small percentage of non-small cell lung cancer patients who have an ALK mutation. So an ALK mutation causes cells in the lungs to grow up normally and behave like cancer cells. So this subgroup would meet prevalence requirements for orphan drug designation, but importantly in this example, my product's mechanism of action must be based on the presence of that ALK mutation. In that case, then my product wouldn't be effective in the larger non-small cell lung cancer indication. So this would be a good scientific justification for that ALK positive non-small cell lung cancer subgroup.
Speaker 2:Okay, thank you for that example. Can you expand a little on the type of data that would be needed to demonstrate that the drug is specific to that ALK mutation? Would that data need to be clinical?
Speaker 3:Yeah, that's a really good question. It could be clinical. It also could be data that a sponsor might generate earlier in product development, such as in vitro or in vivo non-clinical studies. As long as that data demonstrates that your product's mechanism of action is dependent on the presence of, for this example, that ALK mutation, then that uh, data would be supportive for your application.
Speaker 2:All right. Thanks a lot. Alexis. Have either of you seen examples of a product that received orphan designation where the applicability of the subgroup was not quite as straightforward as the non-small cell lung cancer example?
Speaker 4:Sure. One example I've seen, Mara, is a treatment to prevent recurrence of melanoma after resection, which was able to qualify for orphan drug. The treatment was designed to activate immune cells against the resurgence of cancerous melanoma cells. Therefore, it only really demonstrated efficacy against disease recurrence after surgical cure. Although melanoma overall does not qualify for orphan and it is actually one of the most commonly diagnosed cancers in the United States. A sponsor could justify exclusion of the early stage and pre resection patients from the target population using that understanding of the mechanism of the drug and likely lack of efficacy for other melanoma patients. The smaller subgroup was then justifies and then they had a successful O D D application.
Speaker 2:Okay, great. I really appreciate both of you attending today and giving us these examples. One, the Bern scar, one of a clearly artificial subgroup that wouldn't work for O D D and then to scientifically justified subgroup examples. I think that's really helpful for folks to understand. So thank you for providing that information.
Speaker 3:Sure. It was our pleasure to be here today.
Speaker 4:Yeah, definitely. Thank you, Mara.
Speaker 2:So we'll
Speaker 3:Leave our listeners with the recommendation that you leave the salami slicing for your charcuterie boards and make sure that you've carefully considered a scientifically supported rationale for your disease subgrouping for your orphaned drug designation request.
Speaker 2:Great. Thanks so much Alexis and Ellen for the discussion. I really appreciate you being here today to get your take on these topics. So just to wrap, Verta has a wealth of experience in all facets of clinical regulations and can help you develop a detailed strategic plan tailored to your product that will reduce your regulatory risk. I encourage you to listen to future episodes of our regulatory podcast series and to reach out through the links available on the various stat website. You can also subscribe to Art podcasts on your favorite podcast player. So thank you for listening, and until next time,
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