The FDA and Regulation – Neurosurgery Partners with FDA for Patient Safety, Innovation and Regulatory Reform

Clemens M. Schirmer, MD, PhD, FAANS, FAHA (left)
Vice-Chair, AANS/CNS Communications and Public Relations Committee
Geisinger
Wilkes Barre, PA

Catherine Jeakle Hill (right)
Senior Manager for Regulatory Affairs, Washington Office
American Association of Neurological Surgeons (AANS)
Congress of Neurological Surgeons (CNS)

The entity known as the Food and Drug Administration (FDA) is familiar to most Americans. For inventors, pharmaceutical companies and medical device manufacturers it is often criticized for stifling innovation. Conversely, consumer advocates might hail the agency’s efforts to safeguard individual patient safety. Neurosurgery is a strong advocate for a regulatory system that provides an appropriate balance allowing physicians and patients access to life-saving drugs and devices while supporting the agency’s important work of ensuring the safety and efficacy of medical products.

Historical Timeline

To fully understand today’s agency, it helps to look at how it evolved.

• 1813 – The Vaccine Act was passed to encourage vaccination against smallpox. It was the first federal law concerning consumer protection and pharmaceuticals.
• 1906 – President Theodore Roosevelt signed the Pure Food and Drug Act into law and tasked the Bureau of Chemistry to inspect food and drugs, which they aggressively pursued.
• 1911 – A Supreme Court decision limited the scope of such investigations to false claims about ingredients of medicines.
• 1938 – President Franklin Delano Roosevelt signed into law the Food, Drug and Cosmetics Act.
• 1959 – FDA denied approval for thalidomide.
• 1962 – The Kefauver-Harris Amendment was passed requiring the FDA to consider not only safety but also efficacy in the product approval process.
• 1976 – The 1976 Medical Device Amendments to the existing 1968 Radiation Control for Health and Safety Act, gave the FDA the authority to require pre-approval of medical devices and created a system of three classes of devices based on risk.
• 1984 – The Drug Price Competition and Patent Term Restoration Act passed which extended the patent exclusivity terms of new drugs tying those extensions.
• 2012 – Congress provided the Humanitarian Device Exemption (HDE) authority as part of the Food and Drug Administration Safety and Innovation Act.
• 2016 – The 21st Century Cures Act was passed to streamline the drug and device approval process and bring treatments to market faster.
• 2017 – Executive Order 13777 enforcing the Regulatory Reform Agenda was issued, a directive to each federal agency ordering an evaluation of existing regulations and identification of those that may merit repeal, replacement or modification.

Modern System

The FDA is a federal agency, part of the U.S. Department of Health and Human Services (HHS), charged with enforcing the Federal Food, Drug, and Cosmetic Act. Amendments over the years have expanded the coverage to include other products as well. The FDA regulates an astonishing $1 trillion in consumer goods products — nearly 25 percent of U.S. consumer expenditures per year. Historically, the FDA’s protection of the public interest has often been reactive, taking action following a serious adverse event in the U.S. However, the agency has sometimes been presciently proactive, as in 1959 when the agency denied approval for thalidomide, touted as a remedy for morning sickness, a drug which caused thousands of babies to be born with deformed limbs (phocomelia) all across Europe. The Kefauver-Harris Amendment, passed in 1962 expanded the agency’s charge to all new drug applications to demonstrate, “substantial evidence” of the drug’s efficacy for a marketed indication, in addition to the existing requirement for pre-marketing demonstration of safety. This marked the start of the FDA approval process in its modern form, mandating evidence of both safety and effectiveness.

In the 1970s, Congress began to focus on the unique aspects of medical devices. Following pacemaker failures and reports of severe injuries attributed to the Dalkon Shield intrauterine device, Congress passed the 1976 Medical Device Amendments to the existing 1968 Radiation Control for Health and Safety Act, giving the FDA authority to require pre-approval of medical devices and created a system of three classes of devices based on the risk to the patient:

• Class I – Devices that present minimal potential for harm and do not require pre-approval.
• Class II – Devices with moderate risk. The majority of devices are Class II devices.
• Class III – Devices sustain or support life, are implanted or present potential risk of injury. About 10 percent of medical devices fall into this category.

In addition, the 1976 Amendments created two paths to FDA approval:

• Premarket Notification 510(k) — The manufacturer must demonstrate that the device is substantially equivalent to an existing device. If the device is substantially equivalent, it is placed in the same class as the equivalent device. Upon approval of a device as equivalent, the FDA will issue a letter of substantial equivalence, which authorizes the manufacturer to market the device.

• Premarket Approval (PMA) — The PMA process is more involved and requires the submission of clinical data to support claims made for the device. Generally, these devices would be in Class III.

With new regulatory requirements, the time and difficulty of bringing new drugs and devices to the market have substantially increased. This  led to the 1984 Drug Price Competition and Patent Term Restoration Act, which extended the patent exclusivity terms of new drugs tying those extensions, in part, to the length of the FDA approval process. These changes brought about the generic drug industry and also a new approval mechanism, the Abbreviated New Drug Application (ANDA), which requires only that the drug manufacturer demonstrates that their generic formulation has the same active ingredient, route of administration, dosage form, strength and pharmacokinetic properties (“bioequivalence”) as the corresponding brand-name drug. Also, to bring additional resources to FDA to shorten product approval times, Congress authorized “user fee” programs that would allow industry to pay and negotiate with the FDA for shorter approval times in exchanges for financial assistance to hire additional staff. The Medical Devices User Fee Amendments (MDUFA) were first passed in 2002.

The 1980s brought the AIDS epidemic which highlighted humanitarian crisis concerns over the lengthy and costly approval process. The FDA was accused of unnecessarily delaying the approval of medications to fight HIV and opportunistic infections. As a result, the FDA issued new rules to expedite the approval of drugs for life-threatening diseases and expanded pre-approval access to drugs for patients with limited treatment options. Similarly, for devices for small populations with rare conditions, called Humanitarian Use Devices (HUDs), Congress provided the Humanitarian Device Exemption (HDE) authority as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on July 9, 2012. The 21st Century Cures Act was passed and signed into law in December 2016 to streamline the drug and device approval process and bring treatments to market faster. The FDA and other agencies are currently in the process of promulgating the regulations and have issued a working plan to put the law into action. Neurosurgery strongly supported this important bipartisan initiative.

Neurosurgery and the FDA

To better address the aforementioned challenges, the AANS/CNS Washington Committee created the AANS/CNS Committee on Drugs and Devices to actively engage with the FDA and other scientific, governmental, clinical and industry representatives to provide neurosurgical expertise on drugs, devices and biologics used to treat patients and to foster innovation and patient safety. These activities include recommending neurosurgeon experts to serve on the FDA Advisory panels, providing input on FDA Guidance Documents and testifying at panel meetings. Additionally, organized neurosurgery is an official partner with the FDA’s Network of Experts program to provide rapid clinical assistance to FDA reviewers.

Highlights of Neurosurgery’s Drugs and Device Activities

Off-label Device Regulation — The AANS and CNS have been active on the issue of preserving physician-directed, referred to as “off-label,” use of FDA approved products. On Nov. 19 and 20, 2016, the AANS and CNS presented their views at an FDA held a public hearing on off-label promotion issues, held as part of a comprehensive review of FDA regulations and policies governing firms’ communications about unapproved uses of approved/cleared medical products. In March 2017, the AANS and CNS joined the Alliance of Specialty Medicine in updating its Statement on Physician Directed Use. Included in the updated document is the recommendation that the FDA add language to drug and device labels to highlight the fact that, after marketing approval, additional scientifically valid data may become available to justify new uses, dosages, or contraindications and physicians will consider this information when prescribing the product. The goal of adding the language is to destigmatize the concept of off-label use and foster communication with patients. The updated Alliance statement was included in the FDA’s docket of materials on the issue.

Opioid Regulation — Organized neurosurgery has been active on the issue of opioid safety and appropriate prescribing of opioid medication for many years. FDA too has ramped up its attention to this important issue and took the very rare step of removing an opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market. Recently, the AANS and CNS provided expertise to the agency for its public hearing on the issue. In addition, the AANS and CNS are active members of the AMA Opioid Task Force. That initiative includes a number of educational products for physicians.  For example, the AANS and CNS recently developed a co-branded fact sheet on naloxone, which encourages physicians to consider co-prescribing naloxone when clinically appropriate.

Device Innovation — Neurosurgery has participated in numerous activities with the FDA to foster innovation and safety for a wide variety of leading-edge spinal and cranial products to help save lives and improve patient outcomes and functionality. For example, the AANS and CNS are on the forefront of new treatments for endovascular disease to help prevent the devastating mortality and morbidity of cerebrovascular disease. As such, the AANS and CNS have joined with the FDA in many multi-stakeholder activities and will continue to do so at an upcoming FDA workshop on aneurysm treatments on March 1, 2018.

Registry Data — The Neurosurgery led NeuroPoint Alliance (NPA) has worked closely with the FDA and other societies on a number important initiatives to explore “real world” data sources and alternatives to costly and time-consuming randomized controlled trials. The Society of Neurointerventional Surgery (SNIS) and the AANS/CNS Section on Cerebrovascular Section have agreed to use a single registry for neurovascular surgical procedures, run by the NPA, and are working with the FDA to use the data to evaluate acute thrombectomy devices. In February 2017, leaders from neurosurgery participated in an FDA workshop on the use of registry data for stroke intervention devices. Also, NPA has formed the Spine Quality Outcomes Database (SQOD) developed with the American Academy of Physical Medicine and Rehabilitation (AAPM&R) and is working with the FDA to use the database for device evaluation and post-market surveillance.

Conclusion

It is without question that the FDA processes have particular significance to neurosurgery, a subspecialty of innovation requiring sophisticated drugs, devices and tools. Regulatory relief is necessary, and revisions to FDA processes should be carefully examined and reassessed to ensure they meet the dual challenge of fostering innovation while also protecting patient safety. To this end, the AANS/CNS Drugs and Devices Committee is developing a response to the FDA notice regarding recommendations for regulatory reform for device approval. Neurosurgeons will continue to advocate policies that will decrease the regulatory burden for medical-device innovation and ensure patient access to new and improved medical technology.

Editor’s Note: We encourage everyone to join the conversation online by using the hashtag #RegRelief.