Regulatory perspectives on herbal medicinal / botanical drug product development: Joint FDA / EMA workshop

https://www.ema.europa.eu/en/events/regulatory-perspectives-herbal-medicinal-botanical-drug-product-development-joint-fda-ema-workshop?utm_medium=email&utm_source=govdelivery Thank you, Dr. Sokolowska and Dr. Thirstrup for speaking today on the joint FDA and EMA workshop “Regulatory Perspectives on Herbal Medicinal / Botanical Drug DevelopmentExternal Link Disclaimer.” Let’s get started by sharing your roles in the FDA and EMA respectively, and what interested you about the workshop. Thirstrup: I'm the Chief Medical Officer at the EMA. I'm a medical doctor by background and spent the first 10 years of my career in different hospital positions. I'm also a clinical pharmacologist, so I have a lot of interest in pharmacology and how some drugs used today, at least some of the old ones, they come from herbal products. We know on both sides of the Atlantic there is a huge amount of out-of-pocket money being spent on food supplements or unregulated products, some products with very questionable health claims. I was glad to participate in the FDA & EMA joint workshop so I could put on my public health hat and speak about what the EMA does and does not do for these products. Sokolowska: I am currently serving as a Senior Policy Advisor to the FDA’s Office of Policy, Legislation, and International Affairs. My permanent role is the Deputy Center Director for Substance Use and Behavioral Health in the FDA’s Center for Drug Evaluation and Research. Many people around the world use botanical products to self-treat different conditions, and they want to use these products safely. There is a great need to provide information to these individuals, but sometimes information on the potential benefits and harms of these products isn’t available. Just because it's natural doesn't always mean that it's safe. That's why I think this workshop with the EMA was so important. It's clear that across the jurisdictions, we all need to do more to address the public's needs, and it’s important to note how our systems are similar and how they are different. This workshop was one way to address that need for information, and I hope anyone interested watches the workshop recordingExternal Link Disclaimer. Let’s discuss the current regulatory frameworks for herbal and botanicals in the United States and European Union. Dr. Sokolowska, can you start with the FDA’s regulatory approach? Marta Sokolowska Sokolowska: Absolutely. When you look at the regulatory framework for botanical products within the FDA, you have multiple pathways through which a botanical product can be marketed, depending, among other things, on the product’s intended use. If you are focusing on regulating botanical products as medicines, these products can become an over-the-counter monograph product or go through the application or licensure process. In addition, botanicals can be regulated as foods or dietary supplements, though we specifically did not discuss them during this workshop. Steffen Thirstrup Thirstrup: Europe is a little bit more complicated because you can bring an herbal product, as we call them here, to the EMA or one of the national competent authorities in Europe, under the same framework as prescription medicine. We have a framework equivalent to the new drug application (NDA) or biologics license application (BLA) in the U.S. where you submit a full application or a mixed application with documented quality and safety with a product being approved as a medicinal product. But what is different from the U.S. is that we also have two additional pathways. One is for well-established use, where it’s up to the applicant to document that substance has been used in a medicinal use for at least 10 years in the European Union. The other is traditional use where the requirement is even greater because you must document 30 years of medicinal use, of which at least 15 years must be within the EU. We have been developing monographs through both the traditional use and well-established use pathways for many years. You can find those monographs on our websiteExternal Link Disclaimer, and there are currently more than 170. The EU monographs describe the product similarly to the label in U.S. and the prescriber information or the summary of products that we have in Europe. The monographs are not for a specific product, but for a product that complies with the monograph, as the monograph also describes manufacturing. This means national authorities can then license products if they refer to the monograph. What was the workshop’s value to public stakeholders and what did you consider the main takeaways to be? Thirstrup: The workshop was the first time the EMA and FDA had this kind of interaction specifically on herbal medicinals / botanical drugs. As I said at the workshop, we decided to be very courageous and jump out into the deep end of the swimming pool together without knowing whether we could swim together. I think we figured out we could swim, or at least float, together, but we couldn't do synchronized swimming yet. Put in other words, we know we have different legal frameworks. We have a lot of the same challenges independent of these different frameworks. So, this workshop was an opportunity for us to exchange our challenges and focus on how we potentially could work on moving forward. We also wanted to inform the public that there are currently frameworks in place to reassure that some products you buy in European pharmacies, would have well-established efficacy and safety and there will be some quality control. The risk of adulterated products under these frameworks is lower compared to other products that are non-controlled as food supplements. As Dr. Sokolowska mentioned, it was about conveying a common message: just because a product is natural does not necessarily mean it is safe. What I also found valuable was hearing directly from pharmacists, patients, and developers about the role these products can play in our health systems. Pharmacists see properly regulated herbal medicines as useful options for helping people manage some mild conditions, but they also reminded us how important professional advice is, particularly when patients are taking other medicines. Patients told us that reliable information is not always easy to find or understand, especially information about possible drug-drug interactions. And from developers, we heard that a clear and predictable regulatory framework can support the development and availability of quality-assured products. We heard that the use and sales of natural products are increasing, reflecting a growing interest from citizens in natural health and self-care; therefore, the value of herbal/botanical products depends on patients knowing what they are taking, having access to quality products, trustworthy information, and being able to make an informed choice. Dr. Sokolowska, can you provide an overview of the scope of products discussed at the workshop? Sokolowska: This workshop focused on development of herbal medicinal and botanical drugs. From a regulatory framework perspective, we wanted to emphasize that we were not covering food or dietary supplement frameworks. The second aspect we wanted to make clear is we were not discussing herbals or botanicals that have or could have abuse potential, such as cannabis or kratom. Dr. Thirstrup, anything I missed? Thirstrup: The reason we decided not to talk about herbals with abuse potential was simply to avoid getting sidetracked. You could easily end up discussing cannabis and psychedelic mushrooms for years. We agree they are all interesting, but if you look at the broader perspective about botanical and herbals that have a health claim and therefore regulated as a medicinal product, it goes way, way beyond herbals with abuse potential. Sokolowska: Yes, herbals or botanicals with abuse potential are a small subset of botanicals, and we recognize that the world of botanicals that people are using is so much broader. Thirstrup: We also didn’t include food supplements, as, while they are regulated by the FDA, the EMA doesn’t have any role to play in food, which is regulated in the EU by the European Food Safety Agency. From a broad perspective of herbal and botanical drug products, what makes developing and regulating these products challenging? Sokolowska: Botanical drugs are complex mixtures and are different than single molecule drugs. You have a whole range of molecules as part of an herbal product. The growing conditions of raw materials, complex structures of the different constituents, or manufacturing of multi-herb products can contribute to batch-to-batch variabilities. It is important that there is comprehensive characterization and proper manufacturing of these products under controlled circumstances to ensure consistency of these products. At the end of the day, we want to know exactly what patients and consumers are getting. In addition to product characterization, sponsors of NDAs or 351(a) applications generally need to evaluate the safety and efficacy of their product. Finally, we heard that the incentive for drug development might not be adequate to offset the unique challenges of botanical development programs. Thirstrup: To Dr. Sokolowska’s point, prescription medicines are typically one, maybe two active ingredients. They're well controlled, we know how they are synthesized and manufactured, and then there are some excipients and other ingredients that we know and are very well controlled. Botanical products are actually harvested. You may be able to grow them under controlled circumstances, but many of those “controlled circumstances” will be very much dependent on the soil, the watering, the sun, and other factors. It is a big challenge for the producers of these molecules to meet regulatory standards in terms of characterizing these molecules. We want to make sure that the product that patients and the public buy today is the same as the one tomorrow and next year. We also want the product they buy to be equivalent to a product where clinical efficacy and safety have been established, similar to any other medicine, and that gives an extra challenge to these products that are naturally derived. Are there specific programs, or resources, herbal and botanical drug developers should utilize at the FDA or EMA? Thirstrup: In Europe, developers of herbal products use the same entry as any other developers, so they can come for scientific advice or approach our innovation task force. Typically, they will be assisted by our Herbal Committee. Many developers may seek out national competent authorities across Europe to gauge their interest in particular products because there are a limited number of experts in phytopharmacology across Europe, and they are in a few countries. Sokolowska: In the U.S., drug sponsors developing a botanical product for prescription use would apply through the NDA, BLA, or abbreviated new drug application (ANDA) pathways, as appropriate, in the same way they would for a non-botanical product. The FDA would then connect the sponsors with a specific review division within the FDA. We do have botanical experts who are available to the review divisions for consultation, but there's no specific pathway or program. More information on marketing of botanical drugs under an application or license (e.g., NDAs or BLAs) is available in our “Botanical Drug Development: Guidance for Industry.” The most up-to-date information on the OTC monograph process is available on our Over-the-Counter (OTC) Drug Review webpage. The patient voice and experience have been mentioned as an essential component for both the FDA and EMA. Is there anything patients, or other stakeholders, should know about herbal and botanical products and the respective regulatory frameworks? Thirstrup: I think the message for patients and the community pharmacies is, again, that just because things are natural, they are not necessarily safe. I could twist it around as a pharmacologist and say if something has a pharmacological action and can do something with your body, it will most likely also have some safety concerns. Conveying that message is important not only for herbal and botanical products but for all the unregulated food supplements and so forth. People spend millions of dollars buying those products, hoping they will live longer and don't get different diseases. At best, certain products may be a waste of money and worse, it may be a health risk. So, it’s important to let the public know that some of these natural substances have been scrutinized by regulatory authorities. Having a better knowledge of efficacy, safety, and control of the product that you end up buying is essential. Sokolowska: I agree and want to highlight that people are starving for information. We want to convey both the information we know and the many knowledge gaps that exist in the botanical drug development space. To address those gaps, we have started engagement with the botanical community by holding a roundtableExternal Link Disclaimer with the Reagan-Udall Foundation for the FDA to start the dialogue with key stakeholders to better understand the barriers they see. We are trying to accelerate progress in bringing more FDA-approved botanical products to the market, while maintaining our high standards for safety, efficacy, and quality. The second critical piece for the public is to know we have opened a request for information regarding the challenges of developing botanical products. We recognize the value of feedback from patients, developers, and researchers and greatly appreciate interested individuals submitting comments to the docket. Our findings will also be shared with our regulatory colleagues to identify any similar themes they encounter and further our efforts to be consistent as regulators. Thirstrup: You're perfectly right. Another important message is that we want access to reliable, trustworthy information. I think sometimes we regulators believe we have them but they are difficult for patients and citizens to find, and being even more transparent is always something we can strive for when it comes to herbals and botanicals. What is next for the EMA and FDA collaboration on herbal and botanical products? Thirstrup: As I said earlier, we jumped out in the deep end of the swimming pool and realized we could swim together. But we can do more to do synchronize our work together. We had a very long list of potential topics to collaborate on, and we spent some time after the public part of the workshop to discuss what could be potential topics for further collaboration. We identified two topics, one being batch-to-batch quality variation and how to set the right standards. The other topic is related to drug and herbal interactions, knowing that many patients may be taking medications and supplementing with herbal or botanical products. There is the potential for these to create interactions with prescription medicines, and sometimes life-threatening ones. Sokolowska: To close our conversation, I want to recognize that despite our different regulatory frameworks, we share the same goal: supporting botanical drug development while acknowledging existing data gaps. Harmonized research efforts can help close these gaps. Ultimately, we rely on similar data, so when data are lacking, neither of us can adequately address patients' and clinicians' questions about the safe use of these products. Coordinating our expectations around the type of research that would advance both regulatory frameworks is, therefore, a shared priority.