A recent press release from the Food and Drug Administration titled “Reorganization of the Office of New Drugs with Corresponding Changes to the Office of Translational Sciences and the Office of Pharmaceutical Quality,” may have sounded like another bland and boring exercise in regulatory rhetoric. But it actually signals a revolutionary shift in regulatory velocity.
Changes in the FDA’s Office of New Drugs (OND) will create enhanced review zones that cross disease areas and divisions to maximize access to more focused and innovative areas of regulatory expertise. These changes will, among other things, increase the number of OND offices overseeing product reviews from six to eight and increase the number of specific clinical review divisions from 19 to 27. The rationale is to make the FDA more efficient and help it better understand the diseases that are the aim of treatment by the drugs being evaluated for approval.
These changes represent the FDA’s admission that it must be a leader in regulatory science — the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products — by dint of true expertise rather than for simply “being the FDA.” It recognizes that laying claim to the regulatory gold standard is a moving target.
The devil may be in the details but, as Admiral Hyman Rickover once said, “so is salvation.”
Increasing regulatory velocity
The hidden gem within the FDA’s announcement is a reorganized Office of New Drug Policy. As a former FDA associate commissioner, I see this as one of the most exciting elements of the reorganization effort.
The most potent way the FDA can enable innovation is by being a partner in advancing new approaches to both drug development and regulatory science. This begins at the conceptual policy level. Historically, there have been heterogeneous approaches to policy within the Office of New Drugs. Alas, regulatory ambiguity doesn’t instill confidence in an already high-risk developmental environment.
Under the FDA’s new plan, the new drug policy function is largely centralized in the reorganized Office of New Drug Policy. (Clinical expertise and decision rights remain firmly in the review divisions.) The policy staff — which includes clinicians, regulatory affairs experts, and lawyers — distills and aligns OND’s thinking across therapeutic areas in close coordination with clinical leadership and specialized partner offices throughout the FDA. The intent is to provide greater consistency and nimbleness regarding, for example, the appropriate use of new tools and techniques for drug development. This is as much a scientific issue as it is one of social and cultural calibration across therapeutic review divisions. Sometimes even brilliant scientists have a hard time viewing new ideas without being threatened by them.
To foster a more robust conversation about a more efficient and empowered Office of New Drugs, the FDA is holding a public meeting in November to solicit input on clinical policy priorities.
The reorganized policy function will also help identify the requisite resources for more and more-focused training of divisional review staff in new techniques for regulatory science, such as the use of real-world evidence, basket trials, N-of-1 trials, adaptive clinical trials, master protocols, synthetic trials, and the like. The object of staff training, additional staff, and other resources is to enhance the knowledge and comfort of reviewers so new initiatives can become more regularly accepted as part of the FDA review process.
These changes will result in an exciting and accelerated OND-wide review of the current and dangerous stasis of the regulatory status quo. They should help engender a similar review of the disconnect between what the upper echelons of the biopharmaceutical industry say they want from the FDA and the actual research and development programs undertaken by their companies.
One area screaming out for a more real world and coordinated policy approach is communications between sponsors and the FDA and the different views that divisions have on sponsor interactions. As sponsors become increasingly interested in discussing their development programs with the agency, more and speedier access to so-called non-binding advice is required. The FDA gives non-binding advice to companies on how best to move their development programs forward. Though such advice may be non-binding, drug developers ignore the agency’s recommendations at their own risk.
Companies can ask for three types of meeting with the FDA: Type A meetings are intended for stalled drug development programs; type B meetings can include pre-IND issues, end-of-phase discussions, or some post-marketing issues; and type C meetings are anything other than type A or B meetings about the development and review of a product.
Why should facilitating such meetings be a policy priority for the FDA? Let’s look at the numbers. In 2018, requests for meetings continued to rise across two of the three meeting types. Type A meetings jumped 27% from fiscal year 2017 to fiscal year 2018, while type B requests increased about 3%. According to the FDA, to better prioritize and expedite requests for meetings and other communications, “Additional training on meeting management goal ‘expectations’ and on assessing process improvements is intended to correct the problem.”
The need for a more nimble approach to communications between the FDA and sponsors that does not compromise review integrity or sponsor resources is crucial to advancing the uptake of 21st century regulatory science.
Change is uncomfortable. A universal truth from human behavioral science is that those doing the work are uncomfortable when the ground rules change. According to Rosabeth Moss Kanter, professor of business administration at Harvard Business School, “The best tool for leaders of change is to understand the predictable, universal sources of resistance in each situation and then strategize around them.”
Such resistance can range from fairly subtle avoidance or passive aggressive behavior all the way to outright defiance, hostility, and sabotage. The best way to avoid resistance to change is to try to uncover it before implementing change. The FDA’s reorganized Office of New Drug Policy can act as a regulatory MapQuest for advancing regulatory science.
What will success look like?
Many health policy experts, developers of medical products, and investors view the FDA as a sea anchor to innovation. They see the agency as slow, risk averse, and unpredictable. But the FDA can — and must — become an innovation accelerator.
The 21st Century Cures Act empowered the agency to use new science to speed product development and review as well as advance and evolve how the products under its jurisdiction are measured for both safety and effectiveness once they are approved and on the market. But the uptake of new pathways and tools has been slow and uneven.
What senior management in the FDA says publicly about the value and urgency of regulatory innovation has yet to permeate through its product review divisions. These actions — and inactions — are leading to a loss of faith within the broader health care ecosystem that the FDA can be a potent ally in lowering costs and advancing patient access to new and important medical technologies.
As management guru W. Edwards Deming once said, “What we need to do is learn to work in the system. Every team, every platform, every division, every component is there for contribution to the system as a whole on a win-win basis.” In short, the FDA must strive to be not only an innovation accelerator but also an enabler of competitiveness.
For the FDA’s revamped and empowered Office of New Drug Policy, success will take the form of robust scientific discussions among divisional review teams about the pros and cons of new and different approaches to drug development programs and review criteria. Success means overcoming the “that’s not the way we do it” mentality, while at the same time being clear-eyed about the risks and uncertainties of innovation. That’s a mighty task, and a mighty difficult one. It will require designing a “learning health system” that enables research to influence practice and practice to influence research.
A more centralized, standardized, and predictable FDA-wide approach to best practices for new drug-development policy will encourage developers to use more cutting edge, efficient, and swifter approaches to bringing lifesaving therapies to market, making the drug development and review process less of an ambiguous twilight zone and more of a regular and robust regulatory partnership.
Peter J. Pitts is the president of the Center for Medicine in the Public Interest, a visiting professor at the Paris Descartes University Medical School, and a former FDA associate commissioner.
Why not focus on preclinical development as well? The FDA should emulate the EPA. According to the September issue of the “Good Medicine” Newsletter (published by the reputable Physicians Committee for Responsible Medicine) in the article “EPA’s New Plan o End Animal Testing” The EPA Administrator Andrew Wheeler recently committed the agency to gradually move away from tests on mammals. Their target is 30% reduction by 2025 and complete replacement by 2035.
Rather than mired in regulatory rhetoric tricks for political purposes, the FDA should tackle animal studies requirements as well. It is a well known fact that about 95% of promising drugs candidates fail in human clinical trials due to toxic effects not adequately predicted by animal models.
Why can’t there be collaboration among the FDA, academia, and drug companies to devise new animal models such as tissue-on-chip, blood-brain barrier on a chip, or heart-on-a-chip. These innovative and revolutionary technologies can ten prove that The FDA can turly strive to be not only an innovation accelerator but also an enabler of competitiveness, rather than lip service and organizational overhaul.
I am flabbergasted by “In short, the FDA must strive to be not only an innovation accelerator but also an enabler of competitiveness.”. Totally disagree with this statement. Regulators do not INNOVATE. They can facilitate but have to practice what they preach at home. FDA has been suggesting QbD when its own ANDA filing and approval process is arcane and infested with “QbA”, I call quality by analysis (aggravation).
There are not many at FDA who have ever work a process design or manufacturing hat. Thus it is very difficult to understand what innovation is. Simply it is day in and day out quality drugs at the lowest cost. I am sorry to say FDA does not know what cost is was it has never earned a dime.
It can smash the current arcane methods. If it can do that, it would be a SMASHING success.
Thanks for the Insightful article, Peter. Looking forward to your talk about pain innovation at the Alliance for Balanced Pain Management Summit on 12/4 in DC.
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