By Jim Shehan, head of Lowenstein Sandler’s FDA Regulatory Practice and Donna Hanrahan, life science attorney, Lowenstein Sandler
Life sciences companies are navigating sweeping changes brought about by the 21st Century Cures Act (the “Cures Act” or the “Act”) signed in December 2016. Of most interest to those companies is how the Act is changing the pathways and processes for developing and getting approval for new drugs and devices and new uses for existing products.
The drug and device provisions of the Cures Act are designed to accelerate the discovery, development, and delivery of life-saving therapies. While the rhetoric of the new administration has been largely confined to speeding up FDA review of approval applications, knowledgeable industry veterans are well aware that current review times are historically fast and that the real opportunities to speed innovation lie in the development and testing phases that occur prior to FDA review. The Act therefore incorporates the long-standing desire of patient advocacy groups, drug and device manufacturers, and research organizations to modernize the regulation of drug and device development and minimize barriers to innovation that occur prior to submission of an application. But don’t expect most of these changes to occur soon — the Act allows the FDA several years to implement many of the most sweeping provisions and, on top of that, the FDA has a long tradition of missing deadlines set in legislation.
ADAPTIVE CLINICAL TRIAL DESIGNS
The Cures Act requires the FDA to hold a public meeting and then issue guidance on how drug companies can use complex adaptive and other novel clinical trial designs in the development of drugs. An adaptive clinical design uses prospectively planned modifications of one or more aspects of the study design based on analysis of interim data. Adaptive designs, which are already being used in the development of some products, may make studies more efficient (e.g., shorter duration), more likely to demonstrate a drug’s effect, and/or more informative (e.g., by providing more dose-response information).
"Congress directs the FDA to make it easier for drug companies to win approval for new indications of previously approved drugs."
The Act directs the FDA to issue a guidance that describes how such trials can satisfy the Federal Food, Drug, and Cosmetic Act’s requirement of a showing of “substantial evidence” of safety and effectiveness and what information about such trials that companies should provide to the FDA. The FDA must hold a public meeting and gather input from stakeholders within 18 months of enactment, and then the agency must issue guidance within 18 months of the public meeting and finalize that guidance within one year after the comment period on the guidance closes.
GREATER USE OF PATIENT EXPERIENCE DATA IN APPROVALS
Expanding upon existing legislative mandates aimed at increasing the role of patients in the drug approval process, the Cures Act requires the FDA to issue guidance on the use of patient data in the drug approval process. The agency is directed to explain how to collect patient experience data and what such data should consist of, how patient advocacy groups may propose draft guidance to the FDA, and how the FDA plans to use patient experience data when evaluating the risks and benefits of a new drug application in a structured risk-benefit assessment framework. Patient experience data includes data collected by patients, parents, caregivers, patient advocacy organizations, disease research foundations, medical researchers, and drug companies that is intended to facilitate the FDA’s risk-benefit assessments. The Act gives the FDA five years to implement a patient-focused drug development guidance.
USE OF REAL-WORLD EVIDENCE AND QUALIFIED DATA SUMMARIES FOR NEW INDICATIONS
In two separate sections of the Cures Act, Congress directs the FDA to make it easier for drug companies to win approval for new indications of previously approved drugs. The first provision allows applicants to use “real-world evidence” to support approval of new indications. The Act defines realworld evidence as “data regarding the usage, or the potential benefits and risks of, a drug derived from sources other than randomized clinical trials.” Implementation of real-world evidence has a particularly long and somewhat ambiguous deadline — the FDA is given six-and-a-half years to issue a final guidance or a “revised draft guidance.”
The second change to new indications approval allows the FDA to rely upon “qualified data summaries” when approving supplemental applications. A qualified data summary is a summary of clinical data that demonstrates the safety and effectiveness of a drug for a “qualified indication,” which is an indication that the FDA “determines to be appropriate for summary-level review.” The Act does not require the FDA to issue guidance on the use of qualified data summaries, and this section of the law appears to take effect immediately.
PRIORITY REVIEW FOR BREAKTHROUGH DEVICES AND EASING DEVICE REGULATION
The Cures Act makes some significant changes to device regulation as well, the most significant of which is the establishment of a new breakthrough device pathway. Breakthrough devices are defined as offering “significant advantages over existing approved or cleared alternatives, including the potential, compared to existing approved alternatives, to reduce or eliminate the need for hospitalization, improve patient quality of life, facilitate patients’ ability to manage their own care (such as through self-directed personal assistance), or establish long-term clinical efficiencies.” The FDA is expected to build on the existing priority review device pathway covered in a guidance issued April 13, 2015.
Other significant changes to device regulation include:
- the permitted use of centralized IRBs (institutional review boards) for device clinical trials
- a mandate that FDA consider the least burdensome appropriate means for demonstrating safety and effectiveness when reviewing premarket approval applications
- the designation of five categories of medical software that will not be regulated as medical devices
- a raised cap for humanitarian devices eligibility from 4,000 to 8,000 patients.
DRUG COMPANIES MUST PUBLICIZE THEIR EXPANDED ACCESS POLICIES
The Act makes a significant change to the regulation regarding the compassionate use of unapproved drugs outside of clinical trials. Companies that develop drugs for “serious diseases” must, within 60 days of enactment, post on a website their policies for expanded access, thereby making investigational drugs available to patients who are not in their clinical trials. These expanded-access policies must include procedures for making requests, the company’s criteria for evaluating and responding to requests, and the length of time required to typically respond to a request. While less extensive than some proposals advocated by the right-to- try movement, this provision will require significant and immediate action by most drug companies.
STREAMLINING HUMAN SUBJECT RESEARCH REGULATIONS
The Cures Act simplifies human-subject and informed-consent research regulations. It requires harmonization of the HHS and FDA regulations within three years of enactment, directs the FDA to allow the use by researchers of joint or shared IRB review, and allows use of an independent IRB (institutional review board) or an IRB of an entity other than the sponsor of the research. Further, the Act provides additional opportunities for obtaining waivers of informed consent and allows medical device and drug trials posing “no more than minimal risk” to bypass the informed consent process if other safeguards are in place to protect the rights, safety, and welfare of patients.
The Cures Act contains a number of other provisions of significance to research-based life sciences companies. For example, it extends the pediatric priority review voucher program for drugs until Sept. 30, 2020. Another provision adds to the FDA’s 2012 Drug Development Tools Qualification Program by establishing a review pathway at the FDA for biomarkers and other drug development tools that can be used to shorten drug development time and reduce the failure rate in drug development.
The Cures Act aims to speed the approval of drug-device combination products by clarifying how the “primary mode of action” of a product is to be determined and by requiring the FDA to meet with sponsors and agree early in development how best to study the combination product to meet approval standards. The Act also establishes procedures governing disagreements between sponsors and the FDA on how to treat a combination product.
In addition, the Act clarifies the FDA’s authority over genetically targeted drugs by allowing sponsors to rely on data for the same or similar technology from previously approved applications by the same sponsor.
The 21st Century Cures Act is rightfully regarded as landmark legislation. Although implementation will be slow, and it is not clear how the Act will be interpreted by the FDA and new FDA Commissioner Scott Gottlieb, it is clear we are in a new era of drug and device development. There will be challenges in navigating this brave new world that will require collaboration with legal counsel in order to take full advantage of opportunities and avoid pitfalls.
A large number of provisions in the 21st Century Cures Act are aimed at swift approval of new drugs and devices. About $430 billion is allocated over 10 years to allow the FDA to:
- Rely on data summaries and “real-world evidence” instead of the results of randomized clinical trials when weighing the approval of existing drugs for new uses.
- Use a “limited population” approval pathway for new antibiotics that would rely on a risk-benefit analysis weighing the needs of patients facing severe and untreatable infections against the possible harms to them.
- Expand its programs for expedited approval of breakthrough medical technologies for patients with life threatening diseases that have limited treatment options.
- Modernize clinical trials and the means by which safety and efficacy data is accumulated and analyzed.
- Put patients at the heart of the regulatory review process.
- Support broader, more collaborative development, qualification, and utilization of biomarkers, which help assess how a therapy is working, and on whom, earlier in the process.
- Streamline regulations and provide more clarity and consistency for innovators developing health software and mobile medical apps, combination products, vaccines, and regenerative medicine therapies.
- Incentivize the development of drugs for pediatric diseases and medical countermeasures, and empower the agency to use flexible approaches in reviewing medical devices that represent breakthrough technologies.
- Use more funds to recruit and retain the best and brightest scientists, doctors, and engineers.