Orphan drug experts discuss new book on developing rare disease treatments

Regulatory NewsRegulatory NewsRAPSRAPS' Latest | 27 January 2022 |  By 

Developing therapies for rare diseases involves complex incentives, unique requirements, and often extensive patient engagement. The authors of RAPS’ Orphan Drug Development for Rare Diseases, Sundar Ramanan, PhD, MBA, and Sunny Kamlesh Dave, MPharm, recently took time to discuss with RAPS Senior Editor Gloria Hall the importance of orphan drugs, the peculiarities and challenges of obtaining an orphan drug designation (ODD), and what is covered in the book. During a “meet the authors” webcast, the experts answered questions from Hall and from webcast participants. Following is an edited transcript of that conversation.

Gloria Hall: Why this topic? Why was it important to develop this book?

Sundar Ramanan: It's a great question. Over the past two decades, we've seen significant improvement in access to new technologies in addition to rapid advances in science and technology with the application of cell and gene therapy in a more precise manner. More importantly, we have more than 7,000 rare diseases, a vast majority of them with no treatment or cure, affecting about 30 million patients, roughly 10% of the patient population. So even though the conditions may be rare, collectively, there's a huge unmet medical need as well as a need for information.

As we found no single source that captures all the components that are important for stakeholders involved in drug development for patients with rare disease, this book is our attempt to address this important need.

GH: What was your thought process when developing the structure and scope of this book?

Sunny Kamlesh Dave: Based on our drug development experience in the rare diseases space and extensive research on this topic, we designed the book in such a way that it covers and connects all the elements involved in the drug development process for rare diseases.

We felt it was important to cover the history of how the orphan regulations originated in a particular country, developments in rare diseases areas, initiatives, the crucial role of patient/patient advocates, benefits, ODD/MAA, market access, and case studies to illustrate what’s been done.

GH: What was the rationale for including countries or regions where there is no true orphan drug regulatory oversight and how did you handle that?

SR: The book starts with regions where the framework for drug development—specifically for rare diseases—is mature. The first country to implement an Orphan Drug Act was the US, followed by the EU. The rest of the countries have roughly followed the US framework. Right now, many other countries don't even have orphan drug policies. So, we wanted to include a framework that other countries could utilize.

GH: Can you give us a brief overview of the story this book tells?

SKD: The book can be used as an encyclopedia or guide to all the elements involved during orphan drug development. We have included the history, incentives and benefits, country requirements, patient engagement, and orphan drug designation. Then we cover the orphan drug development required during marketing authorization and market access. And for each element and wherever possible, we have tried to give real-world examples and case studies.

GH: Does the book cover the impact of the registrational clinical study design by an ODD pathway?

SKD: We have covered clinical trial design throughout drug development. ODD does not require a clinical design assessment. A clinical study is not mandatory for the ODD designation.

GH: What will the readers gain from reading this book?

SR: We intended this book to be an easy-to-use reference guide for anyone involved in the regulatory space. Readers will get a complete understanding of what it takes to develop a drug for a rare disease, as well as the available tools and resources, specifically incentives. We also have included a framework to follow, which tools the US Food and Drug Administration provides, and which incentives are available. We intended for readers to get the entire picture of drug development for a disease from start to finish—from discovery to reimbursement.

GH: What is the importance of the countries and regions covered?

SKD: Most available resources focus on regulatory bodies that belong to the International Council on Harmonisation (ICH). This book is unique because we have included information on regulatory bodies in the Asia-Pacific region, the Middle East, Latin America, as well as Ukraine and Russia.

GH: In the Indian market, how do you see orphan drug development in next five years considering local data generation is a mandate for getting NDA approval?

SKD: In India, orphan drug development policies are becoming mature compared to ICH countries, and  there are also state policies for orphan drug and rare disease drug development. In five years, model local data generation will be much more compared to what we see now. In India, we don't have a rare disease registry like we have in the US, so that is the first step, to develop one.

SR: I can add a couple of points here. Even though the current climate is requiring—the word mandate was used—more data from the local population, the policies are emerging, and there's a strong case that has been made by multiple trade associations and patient organizations to do away with local data to enable faster access to data from the ICH regions. So, I do expect in the interest of patients and with a continued push, that the mandate may be diluted to a certain extent, and hopefully it gets done away with because it's not in the interest of patients for faster access to these medicines.

GH: What are the benefits of orphan drug designation?

SKD: In general, we can say that a few of the benefits are tax credits, protocol assistance, and exclusivity. There are similarities and differences between the exclusivity based on the country. For example, in the US, it is seven years of exclusivity for ODD, and in the EU, it is 10 years.

GH: Does the book cover early-access programs (EAP) for ODD to reach patients faster? For example, the new French regulation for EAP?

SKD: The book does not include EAP information specific to countries; however, in the EU, the development for orphan drugs follows a centralized procedure. So, the ODD and marketing authorization will be through this centralized procedure. I believe in France, there is an orphan reimbursement, and they have an EAP, but we have not elaborated on that topic.

GH: Where can readers find information about rare diseases, for example a list of orphan drugs approved, etc.?

SKD: Readers can get information on rare diseases through the orphan drug database website of the US FDA, the National Organization for Rare Disorders (NORD), the EU Commission website, and Orphanet.

GH: Does the book capture the different strategies for getting fast-track approvals in regulated and non-regulated markets, for example, the reliance pathway? Also, is any scope of RWE included in getting ODD?

SKD: Yes, we have included the orphan drug designation pathway and the reliance pathway as means for fast-track approval. We also have covered the importance of real-world evidence and electronic health record (EHR) data, as tools to evaluate the data.

SR: This is also an emerging space. Recently, FDA issued a guidance document on the use of real-world evidence in regulatory decision making, but it's fairly recent. This is extremely important in emerging markets, especially for rare diseases, where the patients engage in in the drug development process. We also have the emergence of technology using distributed clinical trials, where the quality of the data that is self-reported by the patients, as well as from the EHR, is much better than before, thereby enabling it to be considered towards the label.

GH: Can you provide insight on patient engagement?

SKD: We wrote the book with patients in mind since patients are always at the center of drug development.

GH: Can we use the personalized healthcare concept for ODD?

SR: The orphan drug designation has specific criteria to seek it, and so in personalization, if the data fits within the framework outlined by either the FDA or the EMA, then yes, but the framework for ODD is very well defined to seek and obtain.

GH: What is your key takeaway from the book ?

SR: We developed this book as a patient focused book—so we focus on the tools, incentives, resources, and practices for developing drugs for rare diseases, and how best to use them. It should serve as a catalyst, enabling faster access to information. It can be used by any number of people, starting with academic institutions, non-profit organizations, small or large pharmaceutical companies, and subject matter experts and regulatory professionals at all levels. Our focus was to provide a one-stop shop for easy access to all the available resources, tools, and incentives for people engaging in this space, so that we can bring drugs to patients faster.

GH: How can a company reduce its financial burden in the orphan drug development process?

SKD: The financial burden can be reduced by collaborating with different stakeholders, like patients, regulatory agencies, and academic institutes. We also suggest that orphan drug developers apply for grants. We have described the similarities and eligibility criteria for these grants in our book.

GH: What roles do patients and advocacy groups play in  orphan drug development?

SR: They are central, actually. The 21st Century Cures Act places emphasis on the role of the patient. So, we have embodied that, and each chapter emphasizes the critical and multidimensional role of patients and patient advocacy groups during various stages of drug development. Rare disease organizations are actively involved at various stages, including, say for example, characterization of the disease, defining the eligibility criteria, during the FDA review and approval process, and in FDA Advisory Committee meetings. With the advent of digital tools, patient groups can help accelerate the drug development process, making the treatment options available much faster than would have been possible even a decade earlier.

GH: Can you describe some of the strategies used to overcome developer challenges?

SKD: One of the challenges developers of orphan drugs face is patient recruitment and retention due to the small number of patients. This challenge can be mitigated by involving patients globally and including patient-reported outcomes, real-world evidence, and EHR data. And because trials for orphan drugs mostly will be multinational, multi-site, it is advisable to use tools like e-consent forms and mobile applications for monitoring the parameters.

GH: You discussed natural history studies in depth, especially in the US chapter. If a company already has an investigational new drug (IND), can they submit a natural history study to that IND or would it be best to meet with the agency first to make that determination?

SR: A little bit more context will be needed for that. This is a very specific question, and it depends on which stage the IND is in, but it's always advisable to set up a meeting with the agency, discuss and present the evidence so that they can reach agreements before they go into the IND tracking.

GH: How long did it take you to complete your research for this book and what were some of the obstacles or challenges you encountered along the way?

SKD: We started the book in October 2020, and we completed the book in November 2021. But prior to  that, we had a lot of background from working on orphan drugs. Sundar has more than 15-20 years of experience in industry and drug development. We were aware of things like where to find information.

SR: And some of the obstacles… We would have liked to include information from more countries. But for most countries, we could not find information, or they don't have it. Access to medication in these countries is also difficult. So, we have covered where information is available and where it’s just not available. But we will continue to evolve this book for the next edition.

GH: I'd like to add that the proposal that Sunny and Sundar submitted to RAPS Editorial Advisory Committee (EAC) was well researched in and of itself. They provided a lot of information, which helped the EAC evaluate to see if it would meet the needs of and be beneficial to the regulatory community. So even before that proposal was submitted, there obviously was a lot of research done.

GH: Sunny, any closing thoughts?

SKD: I would say that I hope the book is useful and is informative to the readers, and please provide feedback on the book so it will help us in future revisions.

GH: Sundar, any closing remarks?

SR: I hope readers find it as useful and enjoyable as we found writing it. This was very enriching for us, and a meaningful endeavor facilitating the drug development process. And as Sunny mentioned, we look forward to your comments and feedback, and making this better in the next version.

Orphan Drug Development for Rare Diseases is available as an e-book for $130 for RAPS members, and $180 for nonmembers.


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