Effective Strategies for Successful Global Development

Editor's Notes

• #3: Slide 33: Good afternoon ladies and gentlemen, and its honor to speak to you today on the topic of Effective Strategies for Successful Global Development.” At PAREXEL Consulting, our key objective is to partner with our clients to develop smart, efficient and targeted strategies to bring innovative products to the market on a global scale. I’ll start today’s presentation with an overview of FDA’s accelerated approval programs, and I’ll talk about PAREXEL’s findings in this area. I’ll continue with the growing impact of personalized medicine in healthcare, and I’ll finish with defining evolving regulatory paradigms in digital health.
• #4: Slide 34: Let’s get started with accelerated pathways.
• #5: Slide 35: First off, it is important to note that FDA has placed a great deal of faith and value the concept of accelerated approvals to foster its goal of bringing novel drugs to the market in the United States first in the world. On the sponsor’s side, accelerated approval designations can provide great value in attracting attention to the company and product, and having an interactive review process with FDA. These designations are also well-known to be drivers for fundraising during product development and reimbursement on the postmarket side.
• #6: Slide 36: As you can see on this slide, more than 60% of the new molecular entities approved over the last two years used at least one accelerated pathway, and we can expect that number to continue to grow.
• #7: Slide 37: FDA’s accelerated approval pathways are intended for drugs, devices, and biologics that address an unmet medical need in the treatment of a serious or life-threatening condition. So what does that mean to the FDA? FDA has stated in guidance that these are diseases that “have a substantial impact on day-to-day functioning.” However, we have found that the only true way to find out is to engage with FDA on the particulars of your program. Some indications for oncology or rare diseases are pretty obvious, but many other cases are up for debate and FDA is open to hearing creative arguments.The accelerated approval programs are designed to ensure that innovative therapies for these conditions are approved and available to patients as soon as it can be concluded that the benefits outweigh risk. This means that FDA works closely with sponsors to discuss streamlined and adaptive clinical trials to bring products to the market sooner. In some cases, FDA considers whether premarket data can be balanced with supplemental postmarket data for products with particular promise or an unmet medical need.
• #8: Slide 38: Given our limited time today, we’ll touch on four of the main accelerated pathway examples, fast track, breakthrough, accelerated approval, and priority review. It is important to note that these designations are not mutually exclusive and a specific product may be granted several throughout the development process.
• #9: Slide 39: Let’s start with the fast track program. The fast track program was implemented back in 1997 because FDA was looking for a way to identify important breakthrough products early in development, and permit a more interactive and streamlined development process. This program is intended for new drugs that are intended to treat a serious or life-threating condition and demonstrate the potential to address an unmet medical need.The bar for fast track designation is intentionally low, but this program also provides the lowest relative value to developers when compared to breakthrough and accelerated approvals. Here, FDA is looking for evidence of activity in a nonclinical model, a mechanistic rationale, or pharmacological data to demonstrate that the drug can address the unmet clinical need. The vast majority of fast track designations are granted without any clinical evidence.
• #10: Slide 40: The greatest benefit of fast track designation is that 78% of products with this designation eventually achieve priority review status, which means that FDA’s goal is to complete the review within 8 months of receipt of the complete NDA or BLA. Also, fast track provides the opportunity for rolling submissions, meaning that sections the NDA or BLA can be submitted as they are completed. However, both of these benefits could be conferred to developers without a special fast track designation. 
• #11: Slide 41: Let’s now talk about breakthrough. The breakthrough designation confers all the benefits of fast track designation, but goes several steps beyond. Unlike a fast track product, a breakthrough designation requires that you put forward clinical evidence that demonstrates that your product is a substantial improvement over existing therapies. This is definitely a high bar, but there are major benefits. In our experience, the majority of breakthrough designations are granted after Phase 2. However, we have recently seen some cases where breakthrough status was granted with very impressive Phase 1 data that demonstrated safety and preliminary effectiveness. There’s absolutely no question that breakthrough designation leads to faster approvals, with an average of a 30% faster total review time. You also get intense involvement from FDA senior management, and you’re almost guaranteed priority review status.
• #12: Slide 42: You can see on this slide that oncology products are still king in achieving breakthrough designation. However, we have had recent experience with a breakthrough designation for an osteoarthritis drug where the primary benefit was significantly reducing the risk of surgery. Our message here is that substantial improvement may be based on eliminating a major risk factor associated with current standard of care.
• #13: Slide 43: With that, I’d like to spend a quick minute on accelerated approval. They key feature of accelerated approval is that you are able to achieve conditional approval for your product with only one adequate and well-controlled clinical study instead of two. The catch is that a surrogate endpoint is typically required for the conditional approval (for example, systolic blood pressure for the occurrence of stroke or LDL level for the risk of heart attack). Also, you will almost always be required to submit a postmarket trial to confirm and validate the chosen surrogate endpoint.
• #14: Slide 44: Because I’m an engineer and I’m biased, I want highlight that the Center for Devices at FDA has just recently started a breakthrough designation program for devices. Only 13 designations have been granted to date, and the advantages are very similar to CDER’s breakthrough program. PAREXEL has facilitated 4 of the 13 existing designations, and I’m happy to discuss this process with any of you that are interested. PAREXEL is very experienced in the understanding current FDA thinking behind accelerated pathways, and we’ve helped our clients with at least 30 designations in the last two years alone. Our strength in this area is helping you lay out your clinical development plans and assisting with robust risk-based justifications. Accelerated approval requests are becoming increasingly common, and more than 65% are denied by FDA’s latest count. As with many things, strategy and timing are key.
• #15: Slide 45: With that, I’d like to shift into a discussion around personalized medicine, which I think is one of the most exciting frontiers in healthcare today.
• #16: Slide 46: So what do we mean by the term “personalized medicine”? Generally, most treatments are designed for the “average” patient as a one-size-fits-all approach, which may be successful for some patients but not for others as seen on the left here. Personalized medicine is an innovative approach to tailoring disease prevention and treatment that takes into account differences in peoples’ genes, environments, and lifestyles. The goal of personalized medicine is to target the right treatments to the right patients to derive maximum benefit and minimize adverse effects. This field integrates the latest research advances into individual treatment. It includes medications themselves, including targeted therapies against mutations found in certain cancers, gene therapy and immunotherapy. Precision medicine seeks to know as much about a patient as possible, from understanding the genome to considering metabolomics, proteomics, the microbiome, and even pharmacogenomics. It’s important to note that personalized medicine is generally comprised of two elements. One is the drug or the biologic, and the second is the diagnostic test. Precision care will only be as good as the tests that guide diagnosis and treatment. From a regulatory perspective, the companion diagnostic for a precision medicine should be developed and validated in parallel with the therapy so that it can be targeted to the right patients. PAREXEL has dedicated expertise in validating companion diagnostics and can help you design a clinical program that accounts for both the diagnostic and the therapy.
• #17: Slide 47: Drug development pipelines are full of targeted treatments that offer new hope for patients. Take a look at the numbers on this slide. More than a quarter of new drugs approved between 2014-2016 were precision medicines. Currently, the FDA lists almost 200 approved medications with pharmacogenomics biomarker information in their labeling and 132 are considered precision medicine. Over the next five years, the proportion of personalized medicines in clinical development is expected to increase to nearly 70%. Biopharmaceutical companies nearly doubled their R&D investment in personalized medicines in the last five years, and that number is expected to double again in a decade.
• #18: Slide 48: For many years we’ve been using the phrase—the right drug to the right patient at the right dose and time--- to indicate the promise of personalized medicine and we are now recognizing that promise. Technological advances have resulted in quantum advances in our understanding of the human genome and the development of tools and methods to study it. As technology has advanced, costs associated with study of the genome have reduced, making it more attainable. Demand from stakeholders, drug developers, regulators, and patients have increased. Data has shown that drugs are twice as likely to attain regulatory approval when there is genetic evidence linking the drug target or mechanism of action to the disease indication. Scientists are seeking information to help select the best targets, and understand mechanism of action in which the target interacts. All of this information will ultimately to inform trial design, including patient selection and stratification. 
• #19: Slide 49: As with all great journeys there are challenges along the way. The field of study, technology and associated regulations are evolving. There are challenges with managing the data and computational resources, ensuring the accuracy of results, and ultimately being able to translate those results for drug development scientists who are not genomics experts. Here I’d like to bring up a quick case example that draws from our experience in this area. Back in the early part of this decade, Merck and Bristol Meyer Squibb were competing to bring two very innovative oncology drugs to the market first. Bristol took a relatively traditional approach for its drug Optivo, and was eventually granted approvals for specific subpopulations of melanoma and lymphoma before Merck’s Keytruda. Merck took a different approach, and tied approval of Keytruda to a specific biomarker. Keytruda was the first cancer treatment approved based on a common biomarker rather than the location in the body where the tumor originated. While both drugs are very commercially successful, the scope of Keytruda’s approval is arguably wider. Keytruda ran a smaller, targeted study using the biomarker and yet their approval has the potential to cover more patients. A targeted approach in this case proved to be beneficial even though the competitor hit the market first.As I close on this topic, I would like to reiterate that we have moved beyond just hypothesizing and anticipating the benefits of genomics in drug development. Genomics is impacting how we discover and develop precision medicines and how we, together with our clients, can get the right medicines to the right patients. 
• #20: Slide 50: I’d like to close today with a discussion about digital health, which in many ways is intricately connected to the idea of personalized medicine. In my field of medical devices, the idea of personalized medicine extends to custom 3-D printed implants and wearable monitoring technologies.
• #21: Slide 51: The exponential growth in computing power is leading to a seismic shift in the data that available to us and our healthcare providers. I recently saw an estimate from the Mayo Clinic that it is currently possible to extract over 4 terabytes of data from a single patient, including the genome, medical images, and lab reports. 
• #22: Slide 52: The concept of digital health is to leverage computing power, sensors, connectivity and software to provide information about how patients are using and reacting to treatment outside of the healthcare facility. This applies to commercial products and products used in clinical trials. Just a few months ago, FDA approved a drug with an ingestible Bluetoooth sensor embedded in the pill that records when a medication is taken. Even more recently, FDA approved wearable technology that can detect early signs of a stroke. More and more, digital health can provide valuable input on preventative measures and precision therapies.
• #23: Slide 53: FDA recognizes that digital health products cannot be regulated in the same way as medical devices. By their nature, software products shift and iterate much more frequently than traditional medical devices. At the same time, digital health technologies often present unique challenges with cybersecurity and patient customization. While FDA is managing the process currently, they have already started a pilot pre-certification program for medical device software and I expect that there will be an entirely new regulatory paradigm for the review of digital health technologies by 2020. I know this because I was actively working on this when I left FDA and I know that the current commissioner supports it.
• #24: Slide 54: In determining a new regulatory paradigm, these are some of the core ideas that FDA is thinking about. Whether we are talking about mobile medical applications or software that provides clinical decision support, the regulatory approach will be risk-based and will be designed to encourage continual improvement and patient engagement.
• #25: Slide 55: With that, I’d like to like to close with some key messages to summarize. Regulatory paradigms are continuously evolving and it is critical to stay up to date. We’ve found that it is always a good idea to engage with regulators early in the development process and to leverage programs that can help you optimize and accelerate development.Broadly, I believe that personalized medicine is the future of healthcare, and we’ve barely seen the tip of the iceberg. We encourage our clients to take a patient-centric approach to product development and to think carefully about how they can target medications to the patients with the greatest chance of deriving a clear benefit. Finally, we encourage you to think about the big picture throughout all phases of development. Consider market access and reimbursement at early stages, and tailor your development accordingly. Always think about the future evolution of your product and plan ahead to the extent possible.Thank you.