Please, come to the FDA, and help boost innovation!” It is a call that would leave the agency’s detractors rolling in the aisles. But, it is a call that Commissioner Margaret Hamburg has issued, nevertheless — as she seeks to bring new talent and perspective in to help rebuild the FDA into a clear champion rather than a suspect gatekeeper for innovation in new drugs, biologicals, and devices. And, it is a call answered notably by Dr. Vicki Seyfert-Margolis, who left her post as chief scientist at the Immune Tolerance Network and professorship at UCSF (University of California, San Francisco) to become Hamburg’s senior advisor for regulatory science and innovation.
Seyfert-Margolis completed her first main assignments late last year: a strategic plan on regulatory science that outlines the agency’s reform priorities and its “innovation agenda.” She then turned to some broad scientific issues related to implementing those plans and achieving the goals. A central tenet of the innovation agenda and related reforms is the need to prepare and equip the agency for supporting the development of personalized medicine (PM) — an ever-changing and uncertain paradigm.
Seyfert-Margolis recognizes the ongoing decline in Big Pharma R&D output and then catalogs typical FDA failings such as famously difficult procedures, inconsistent communications, and lags in scientific expertise. (See the sidebar, “How The FDA Can Unblock Innovation.”) But, she doesn’t believe the industry or the agency can reverse the decline alone.
“This is a complex ecosystem of many different stakeholders that must evolve to enhance innovation in the medical product sector — physicians, patients, academia, government, payers, small businesses and large pharmaceutical companies, as well as the FDA as a key component,” she says. “Together, we all need to put some serious thought into a national strategy for moving medical product innovation out of its current model into the next model.”
She stresses that, for the agency, a primary concern is to adopt better regulatory practices informed by advanced regulatory science. But, in the context of the innovation ecosystem she describes, the stakeholders must examine broader policy issues.
In academia, for example, Seyfert-Margolis observes that research is “still fairly focused on the individual investigator as opposed to the team.” She says it will also take broad stakeholder cooperation to make significant reforms in clinical research, such as a national network for efficient patient recruitment.
The agency’s innovation agenda focuses on small life sciences companies — doing more to help the companies navigate the regulatory process, and rebuilding the FDA’s small-business outreach services. Seyfert-Margolis makes a connection between the outreach project and the overarching goal of collaboration with key stakeholders.
One example of small-business outreach is a new FDA Small Business Liaison (SBL) program that will bring experienced life science entrepreneurs into temporary advisory positions in the agency. In tandem, a Young Entrepreneurs (YE) program will train nonbusiness students on the basics of regulatory review.
“We want to bring people in from small businesses for short-term stints within the agency, people who’ve successfully brought a product to market, and help them meet with the people in the FDA.” Currently, she says, the agency is working toward bringing in more outside experts to work on specific projects related to the agency’s Innovation Pathway. The Innovation Pathway aims to shorten the overall time it takes for the development, assessment, and review of breakthrough medical devices.
“Some key areas of focus include the development of new decision tools to help the FDA assess and characterize benefits and risks to patients and new collaborative ways for the FDA and innovators to share ideas about new device concepts. Where applicable, these new approaches, practices, and tools will be used in other pre-market programs.”
She says the goal is to give the agency staff a better understanding of the unique challenges for small businesses in product development. “We want people in the agency to have an understanding of a milestone plan, of capital, and how hard it is when you’re undercapitalized to move through product development, and of the cost of lost time.”
Seyfert-Margolis sees the SBL program as especially useful to academics who are contemplating or instigating a start-up company. The most common need among such people, based on their own frequently stated comments, is to understand what it really takes to bring a product to market, she says.
“We can enhance information and education about that process, so that when you go in, you go eyes wide open, knowing what you have to do.”
The liaison program is still at a preliminary stage of organization and communication. Ideal candidates will be former company executives who are retired or on an extended break between jobs, but ready to share their experience, lessons, and acquired wisdom in company and product development. Likewise, the YE initiative is still gearing up but has a useful prototype in the Commissioner’s two-year fellowship program for health professionals and scientists.
The FDA and NIH: Natural Allies
Small life sciences businesses have a special relationship to one of the stakeholders in the innovation ecosystem that Seyfert-Margolis describes — the NIH. She says the FDA will be working more closely with the NIH to “bring increased attention and focus to regulatory science, which really is the science between discovery and product, or the whole part of the life cycle called product development.”
The agency has identified numerous challenges in product development that it believes must be addressed scientifically — not just clinical trials, but the technology that underlies all development, such as in vitro toxicology platforms. Seyfert-Margolis cites a joint commitment by DARPA (Defense Advanced Research Projects Agency), the NIH, and the FDA to the Organ on a Chip program, tasked with developing new in vitro toxicology assays leading to better predictive platforms. “Such platform technologies not only offer new businesses opportunities for entrepreneurs, but they may also help solve a large common problem.”
Similarly, the Center for Drug Evaluation and Research (CDER) has started a partnership program for qualification of new drug-development tools (DDTs). A company may apply to qualify a tool or a marker for clinical use, and if qualified, the tool will be put into the public domain. It can still be patented but must be shared.
What does the company gain? The same as the industry in general: the ability to use the tool — say, a specific biomarker or other patient-rating instrument — in developing its products. An FDA guidance, “Qualification Process for Drug Development Tools,” furnishes the details of application, evaluation, and terms of the program.
“All the new tools and strategies for applied science offer opportunities for the NIH and the FDA to work together in a different way,” Seyfert-Margolis says. “The NIH SBIR [Small Business Innovation Research] program, for example, might be one way you can spur a generation of new technologies to help fill in gaps that still hold major challenges in the regulatory science arena.”
The Gamble Of Personalized Medicine
In product development, much depends on wise, informed company management and careful FDA guidance. But, products — therapies, diagnostics, and platforms — ultimately rise or fall on their demonstrated risks and benefits, on their safety, efficacy, and cost for performance in clinical practice.
Perhaps the largest gamble in innovation is one that industry and regulators are making together: personalized medicine (PM), which has yet to prove itself as a scientific, medical, or business model. Only isolated and highly limited cases offer clear proof of the concept. What are the consequences for the agency and for industry if PM stalls short of its promise?
The badly needed turnaround in biopharma R&D productivity could be delayed for many more years. And, the innovation ecosystem will have sustained great damage and wasted many resources.
“The basic issue of personalized medicine usually comes down to what level of understanding we have of the underlying biology of disease and how to treat it, reverse it, or prevent it, and that’s always been the first order of challenge,” Seyfert-Margolis says.
She points to the recent FDA approval of the cystic fibrosis (CS) drug, Kalydeco (ivacaftor), approved January 2012, as an example of “how science can really work, and how, when you have an understanding of the genetics underlying a disease, you can go about developing a targeted therapy and bring that to market. It can be highly innovative and highly effective.”
An admirable breakthrough, Kalydeco nevertheless treats only about 4% of CS patients in the United States, those with the G551D mutation. And, by some estimates, it is among the world’s top ten costliest drugs at a reported $294,000 per year.
But, Seyfert-Margolis signals some balance to the PM approach in FDA thinking. “Clearly, not every personalized drug is going to fall into the breakthrough category, so our new Deputy Commissioner for Medical Products, Steven Spielberg, will be looking more deeply into the considerations and challenges associated with the personalized medicine paradigm.”
She observes that a common definition of PM can be self-limiting. “It’s not truly personalized in many cases; it’s really subpopulation by definition. The size of the subpopulations may vary greatly from disease to disease. Gaining an understanding of what influences the different subpopulations is a huge challenge.”
In type 1 diabetes and multiple sclerosis, where knowledge has long existed about the genetics and the increased risk for certain HLAs (human leukocyte antigens), identical twin studies suggest a larger story, she says. “We have to go well beyond genes and gene variance, even though I believe that’s an incredibly important contribution to our understanding of disease.”
Seyfert-Margolis believes PM may actually lead to greater understanding of common mechanisms among different diseases. “The immune system is central to many chronic diseases, not only in their initiation, but in their maintenance. We still don’t truly understand the inflammatory component of many diseases, but we know it can be influenced by environmental impacts. We have such a long way to go toward a clearer understanding of the elements that affect immunity and immune responses, which is a very dynamic system, but it will be critical for moving so many areas forward.”
She also envisions the possibility that such greater understanding of disease mechanisms may one day lead to a great leap forward in safety and efficacy for most drugs, even ones treating large patient populations.
“To the detriment of trying to get better products to patients, we have not been investing enough in some of the broader, practical research programs, like the Serious Adverse Events Consortium, that really help us use science to overcome development obstacles, achieve a higher level of innovation, and improve overall product quality. We need to use some of the intellectual capital of academia and industry — large companies to small companies — to work together in partnership to address some of the most common problems and solve them. The primary need is not just for basic research that tells us the next interesting pathway or gene, but also applying what we know in biology to practical innovations in product development.”
HOW THE FDA CAN UNBLOCK INNOVATION
Starting in mid-2011, FDA Special Advisor Vicki Seyfert-Margolis and Commissioner Margaret Hamburg conducted meetings around the United States with leaders of small life sciences companies, who voiced near consensus on what the agency should do to encourage their innovative efforts.
• Do more to inform, engage, and help small life sciences businesses navigate the FDA regulatory process.
• Adapt current FDA policies and procedures to address the scientific realities and opportunities presented by personalized medicine.
• Take advantage of cutting-edge information technology and scientific computing to enhance benefits to patients and the American public.
• Address regulatory uncertainty within the FDA.
• Streamline FDA policies and procedures whenever possible.
• Develop more efficient regulatory pathways to support devices and diagnostics, including highly innovative devices.
• Build regulatory science capacity both within the FDA and the broader medical development community.