January 1, 2017 (Vol. 37, No. 1)
How to Help the Industry Grow While Maintaining Patient Safety?
2017 not only ushers in a new year, but a new U.S. presidential administration as well. GEN interviewed top biotech/pharma CEOs to find out what they thought might be in store for the industry and what they would like to see happen in the new year. I think you will find their responses timely, thoughtful, and instructive.
This is part 4 of the GEN CEO Perspectives Roundup. It consists of five parts.
Part 1: What Would You Tell President-Elect Trump?
Part 2: Key Challenges
Part 3: Industry Growth
Part 5: Disruptive Technologies
GEN: What actions would you like the FDA and other regulatory authorities to take in 2017 to help the industry grow while maintaining patient safety?
Mr. Manzello: Clearly, the streamlined EMEA approval process, in contrast to current U.S. policies, has demonstrated itself to be less burdensome on the industry, but equally as effective in providing for patient safety through the approval and regulatory process. While wholesale change of the U.S. policies won’t be immediate, an effort to examine a streamlined approach for the U.S. regulatory process would be most welcomed in 2017.
Dr. Cohen: The FDA has made great strides over the past few years in finding a more effective balance in its risk-benefit deliberations, as well as taking into account new technologies and the patient voice. New frontiers include the most effective use of biomarkers, new clinical trial designs, and patient-centered outcomes, all of which the FDA is considering and which are advocated for in the 21st Century Cures legislation.
One of the most important issues is fairly prosaic, but no less important for that: the FDA needs resources and systems to enable it to hire the best possible medical reviewers and other personnel. This remains a gap. In addition, continuity of stone leadership is critical.
Mr. Leschly: While the FDA’s primary mandate is and should be safety, they also have to understand that there has to be a risk-benefit equation. I have been extremely pleased with the FDA's approach and willingness to engage and talk with me, both as a member of the Biotechnology Innovation Organization (BIO) board but also as bluebird’s CEO.
I'd like to see the FDA continue down the risk-benefit path. The Europeans have an interesting approach with an adaptive learning, as-you-go strategy. You can set up a system that allows you to know a certain amount of information and learn more over time, and then adjust accordingly. A clinical study, for example, no matter how big and broad, can only teach you probably a tenth of what you're ultimately going to learn. Industry certainly has to embrace this adaptive learning approach, but so do the regulators and the payors.
This notion of getting smarter over time and then making decisions is a much better way to do drug development. It also helps assure that appropriate balance between safety and efficacy, and getting drugs into the hands of providers who ultimately determine the utility of the drug.
Mr. Connor: 1) Move toward a European (CE Mark) model where safety trials and safety endpoints/hurdles are paramount, but efficacy bars are lower and the market (doctors/patients) dictate whether they see value in the drug/device. 2) Quicker regulatory cycles while still ensuring safety and leaving the market to deem whether there is a strong enough value proposition to propel commercialization. 3) More certainty and consistency in the regulatory approval process, so it is transparent to industry and capital markets. 4) Clarity on steps and process for access to and reimbursement of new technologies to those patients in need, with a clear path for industry to pursue in this regard. 5) NIH/CDC—increased research funding for undiagnosed diseases with cross-disciplinary approaches (like those being pioneered by the UNDX Consortium) and for heretofore diseases without precise diagnostics or treatments like Lyme disease, the fastest growing, least understood, and most poorly/inconsistently diagnosed and treated infectious disease in America. 6) More structured and required update training for U.S. practicing physicians, particularly front-line physicians
Mr. Equels: The FDA needs to increase the use of medical experts in disease areas in which they are unfamiliar to further the understanding of risk-benefit. The lack of understanding of serious, debilitating, chronic illness leaves patients without a choice as to the risk vs. the benefit. The FDA, in cases of unmet medical needs such as ME/CFS, needs to make a special effort to hear and understand the needs of the patient population and the views of the medical professionals with expertise in the disease.
Mr. MacMillan: At Hologic, we have enjoyed a productive relationship with the FDA. I mentioned our Zika virus assays—the FDA moved very quickly to expedite review of those products in the face of the potential epidemic. The FDA is actively working to speed up and streamline its approvals process. The Medical Device User Fee Amendments, the fourth reauthorization of which has recently been negotiated, will further reduce review times for new devices and diagnostic tests. The FDA is also contributing to the passage of the 21st Century Cures Act, which passed the House in November. This bill will modernize clinical trial design, boost scientific expertise within the FDA, and establish priority review for breakthrough technologies. All of these would contribute to a more efficient submission and review process, which would be a tremendous benefit to the industry.
Dr. Brandon: The FDA’s center for devices and radiological health is one area of the agency that does not allow electronic submissions. That needs to change. I imagine that the FDA is eventually going to get around to having electronic regulatory submissions across its whole organization.
There is also room for better funding for the FDA as a whole, and for more specific funding for certain divisions based on areas identified as healthcare priorities for this country. Reduction of unnecessary regulation—without compromising patient safety—is urgently required.
When you add IT to healthcare (as is currently taking place in this market), and we know that IT innovation occurs at lightning speed, the applicable regulatory requirements for diagnostics which integrate algorithms and software stifle speed-to-market. As healthcare relies more on IT, regulation around this intersection is going to be a challenge for regulatory authorities to facilitate and not hinder time-to-market for innovative technologies.
Dr. Lichtenberg: Streamlined and updated regulatory approval processes will help drive innovation for the industry. While all stakeholders agree that drug safety is a core principle of any regulatory process, more efficient guidelines will help reduce time-to-market while extending the effective intellectual property protection on new drugs. From my personal perspective, practical guidelines on the use of in-vitro models to assess potential drug liabilities at early stages would be extremely helpful to enable more efficient IND filings.
Dr. Liu: Resolution of the LDT issue, hopefully through incentives for data sharing, and the establishment of community standards would relieve a logjam of uncertainty.
Dr. Wilson: The discovery and development of innovative drugs to treat serious and often life-threatening diseases is the most fundamental driver of the biotech and Pharma sector. The FDA has taken criticism recently for bowing to pressure from patients, physicians and the public. It is imperative that the FDA remain committed to its mandate to protect patients and require companies to commit to conducting rigorous clinical trials with data so convincing that the FDA must approve new therapeutics and insurance companies must reimburse them.
Dr. Schwieterman: As an ex-FDA-er, this is a question that's true to my heart because I believe the FDA has done a generally good job since the 1962 Kefauver-Harris Amendments in designing guidelines and statutory regulations that promote clinical trial design.
The whole history of the FDA is one of adapting and modernizing itself as medicine advances. I'm talking about things like the 1984 Hatch-Waxman Act for orphan drugs and the critical path initiatives that Janet Woodcock put together in the late 1990s. I'm also talking about priority review and accelerated markers and approvals, all in the ‘90s and early 2000s.
What I think the FDA needs to fully face right now, however, is the realization that these old kinds of large, clinical trial designs for large populations just aren't going to work as the science moves forward and as we get into disease areas where there are smaller patient populations. It gets harder and harder to perform good clinical trials in these areas.
I would hope that the FDA fully recognizes this—and I think they do. I have seen enough guidance from them that I think they understand that the industry is now having to cope with the complexity that can be associated with these small patient populations.
So, for example, adopting Bayesian approaches to clinical trials, which is what is being used in Europe in many respects, needs more credence in the U.S. Using statistical priors—which is just a fancy way of saying earlier observations—and Bayesian analyses to test for therapeutic effects have a larger role in that.
I also think the FDA has to provide greater guidance on certain validated surrogate markers that can be used in sub-populations—it’s all about demonstrating clinical benefit. I get that; but as the science advances and as we get more sophisticated about using biomarkers, the FDA is going to have to be much more open to using some of these surrogate markers for approval.
As I said, the agency has generally done a good job. It's important to recognize that you can't approve drugs on attributes that you haven't proven to have shown benefit. There is an onus on not only the FDA, but on industry to find these markers that are going to provide compelling evidence of benefit.
There is already some sort of partnership between the FDA and industry that needs to go forward. A lot of it is still in its earliest stages, and just think it needs to be promoted.
Ms. Cournoyer: There is an important regulatory balance between safety and efficacy, I understand that. Innovation needs to be encouraged, to find breakthrough solutions, while simultaneously balancing patient safety and ensuring there is no undue harm.
I would encourage the President-elect to think about having the U.S. find a common ground with Europe and other places around the globe, so that U.S. companies can perform clinical trials and sell their drugs and devices in the U.S. and, at the same time, in other countries where approvals are sometimes much easier.
I would like to see us reduce the clearance approval time of drugs and devices, but without sacrificing patient safety. There are many small, innovative companies that cannot manage the overhead of a fully compliant FDA quality system. Yet, they are doing the right things—R&D-wise and from a regulatory perspective. We should streamline what's required in the approval process, particularly as it relates to the documentation.
The FDA's recent decision to step back and slow down the regulatory process with respect to laboratory-developed tests is a wise one. They're relying on a clear process which is robust and maintains high standards for labs that are developing diagnostic tests. I think this is the right way to go.
With respect to the FDA's stance on drug approvals, I would commend them for their actions over the last year or so, in trying to speed new classes of drugs. I would also say that increased after-market monitoring of drugs and continued trials after a drug has been approved will help to ensure patient safety and get that drug onto the market sooner.
Finally, I recognize that the FDA needs more resources in order to manage its staff in a complex industry, and I would encourage us to look at adding additional resources to the FDA.
Dr. Clarke: I can speak from our own experience as developers of pulmonary drugs. We constantly hear from buy-side investors and others that the pulmonary field is notoriously difficult. I’m not saying that but it's just that we've heard this over and over.
I think that there's a disconnect among the different branches of the FDA in terms of how they get certain reputations over the medical area for which they are responsible. In the case of the pulmonary group, they are highly concerned with safety and rightly so. You're inhaling things into the lungs and the FDA wants to know if these are going to be safe for patients, particularly because pulmonary drugs are often used chronically.
Again, the burden is on us, the drug developers, to show safety but as we do so, it would be advantageous to know that our path is not going to be more difficult than someone else's path. So getting more of an alignment along the different branches of the FDA would be something I would very much like to see in 2017.
Mr. Farrell: We would like the FDA to keep engaging with various industry stakeholders to develop appropriate and balanced regulatory requirements for digital health applications, and continue meeting MDUFA expectations in both timing and consistency of review of all medical device applications, with a particular focus on efficiency and transparency in the 510k process. We have made good progress and have a good pathway ahead; we must continue on it to ensure that patients get the care that they need.
Dr. Gruber: I strongly encourage federal adoption of early access legislation such as Right to Try legislation, which allows terminally ill patients to access investigational treatments that have passed Phase I testing, but are not FDA approved. These types of laws have already been passed in 31 states. For this patient population, time is of the essence, and compassionate use requests could take months to possibly be approved. The experimental treatment should be reimbursed, which would enable the company to complete the trial and potentially advance an effective, new treatment while receiving financial support.
The recent Ebola crisis demonstrated how this legislation works. After two U.S. missionaries fell ill, they were able to receive an experimental drug called ZMapp. Today they have recovered from the illness, which could certainly be attributed to the medical care they received. This is an example of a critical situation where Right to Try was appropriately applied.
Other modifications to reimbursement laws related to clinical trials would make a big impact on trial enrollment. For example, allowing physicians to be reimbursed for their time, to run trials or for referring patients to trials, would provide important incentives to accelerate enrollment and potentially help patients fight their disease, while generating useful scientific information. As noted above, speeding trial enrollment speeds development of new treatments and thereby decreases drug development costs.