key: cord-0693625-o6y32awk
authors: Beninger, Paul
title: Covid-19: The Regulatory Landscape of Medicinal and Medical Device Products for Human Use
date: 2020-06-28
journal: Clin Ther
DOI: 10.1016/j.clinthera.2020.06.014
sha: 8545d93c06eb4fac359ce4d6679d7aad92d0ef99
doc_id: 693625
cord_uid: o6y32awk

Abstract Against the backdrop of the Covid pandemic, the scientific and medical communities are working with all deliberate speed with state-of-the-art technologies to develop diagnostic and therapeutic products that can identify, treat and prevent SARS-CoV-2. This can only happen with the necessary statutes and regulations in place to facilitate the timely development, manufacturing, evaluation, and distribution of products that meet quality standards. The present regulatory landscape for medicinal and medical products for human use has been shaped by nearly twelve decades of statutory history that followed in reaction to disasters and tragedies. Five distinct, closely woven threads of developments have led to the regulatory infrastructure we have in place: (1) Regularized processes for routine development of medicinal and medical products for human use; (2) Expedited development processes to shorten time frames and expand patient populations; (3) Expanded Access mechanisms to make medicinal products available to patients prior to FDA approval; (4) Emergency Use Authorization during public health emergencies; and (5) the development of the generic drug and biosimilar biologics pathways to market. These mechanisms are being brought to bear to facilitate the defeat SARS-CoV-2.

On May 1, 2020, FDA issued an Emergency Use Authorization for remdesivir, intended only to treat adults and children with suspected or laboratory confirmed COVID-19 and severe disease defined as SpO2 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 1 Given the medical community's general lack of familiarity with this particular regulatory mechanism, a useful description of the statute and its use would be helpful. This is best considered in the context of nearly twelve decades of statutory history promulgated in response to major disasters and tragedies that have led to the development of our present regulatory landscape. There are 5 distinct, closely woven threads of developments that have come to form our present regulatory framework for making medicinal and medical products available to patients under varying clinical and societal conditions and pressures: (1) Regularized processes for routine development of medicinal and medical products for human use; (2) Expedited development processes to shorten time frames and expand patient populations; (3) Expanded Access to medicinal products prior to FDA approval; (4) Emergency Use Authorization during public health emergencies; and (5) the development of the generic drug and biosimilar biologics pathways to market. Though of fiscal importance to federal and state programs and of financial importance to company and family budgets, this fifth series of developments will not be discussed further. 2, 3 Introduction: Relevant historical events that led to the eventual regulation of medicinal products, including drugs, biologics and vaccines, include the following: the Biologics Control Act of 1902 that established the concepts of safety, purity, and potency standards for biologics, 4 the Pure Food and Drug Act of 1906 that established the concepts of adulteration and misbranding of drugs, 4 the Food, Drug and Cosmetic Act of 1938 that created a safety standard for drugs that must be met prior to entering the market, and that developed the concepts of Investigational New Drug Exemption (IND) and New Drug Application (NDA), 1 and the Kefauver-Harris Drug Amendments of 1962 that established an efficacy standard for drugs that must be met prior to entering the market. 1 Other important populations of patients that have been specifically addressed through statutes and enabling regulations include patients with orphan diseases 5 and children. 6 There is a parallel series of statutes that directed the regulation of medical device products, including scalpels, personal protective equipment, orthopedic and cardiovascular implants, heart-lung pumps, and in vitro diagnostic tests. These include the Medical Device Amendments of 1976 that created a risk-based classification system and accompanying controls to assure safe use, the Safe Medical Devices Act of 1990 that established adverse event reporting requirements, 4 and the Unique Device Identification system that established a system for tracking implantable devices. 7 Important events that have occurred in the current era of regulation include the quinquennially renewed User Fee Acts that began in 1992. 8 This was a sea change in how funding for pre-market and post-market regulatory science would be sourced, shifting from wholly Congressional-budgeted funding to partially Congressional-budgeted funding that is augmented by user fees obtained from the regulated industries seeking market access. In Fiscal

Year 2020, FDA's budget is $5.94 billion, of which $2.67 billion (45%) is expected to come from user fees. 9 This has been successful in having the intended effect of facilitating product development activities and of reducing standard NDA review times to the goal of 10 months, and priority NDA review times to the goal of 6 months. It has also had the further effect of offering regularly scheduled opportunities to legislate innovation and other prospectively considered concerns, issues and activities that might otherwise be limited to statutory remedies in response to disasters and tragedies. Similar benefits have followed adoption of user fees for medical devices. Drugs that provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications may be granted a Priority Review designation that shortens the anticipated review time from 10 months to 6 months. 12 Drugs in development that have recently been given a Priority designation include capmatinib for patients with certain non-small cell lung cancers and belantamab mafadotin for patients with relapsed or refractory multiple myeloma. 13 There has been a total of 41 Priority designations by FDA's Center for Drug Evaluation and Research (CDER) in 2018, the last available year of cumulative information. 14 An Accelerated Development designation relies on the use of laboratory surrogate markers as primary endpoints that may significantly shorten the study duration, rather than on clinical endpoints, for drugs intended for serious or life-threatening illnesses that lack satisfactory treatments. 15 Drugs recently approved that were granted an Accelerated Development designation include golodirsen for patients with Duchenne Muscular Dystrophy and voxelotor for patients with sickle cell disease. There has been a cumulative total of 208 Accelerated Approvals by CDER through December, 2019. 16 A Fast Track designation addresses a broad range of serious diseases with unmet medical needs, which creates whole new populations of treatable patients. 17 Drugs recently approved that were granted Fast Track designation include triclabendazole for patients with fascioliasis and esketamine for patients with treatment-resistant major depression. There is a total of 29 Fast Track approvals in the calendar year 2019. 18 A Breakthrough designation directs the expedited development and review of drugs that can provide substantial improvement over available therapy which expands the benefits that patients experience over prior treatments. 19 Drugs recently approved in 2020 that were • There is a serious or life-threatening illness/condition caused by the identified agents • There is a reasonable belief the product "may be effective" in preventing, diagnosing, or treating serious or life-threatening diseases or conditions caused by the agents • The known or potential benefits outweigh known or potential risks • There is no adequate, approved, and available alternative to the product Covid-19: With this description of the regulatory framework that is in place for medicinal and medical device products for human use, we can begin to understand how regulations support and contextualize responses to the Covid-19 pandemic.

To diagnose SARS-CoV-2 in the population of interest, there must be an in vitro diagnostic kit that has received either an FDA 510(k) clearance or a Pre-Market Approval. However, in a public health emergency, the HHS Secretary can make a determination of need and declare that a public health emergency exists, and the FDA Commissioner can issue Emergency Use Authorizations for specific in vitro diagnostic test kits. The same process may serve for the issuance of EUAs for serological test kits to measure convalescent antibody titers. Thus far, there are 81 individual EUAs for molecular diagnostic tests, an umbrella EUA for molecular diagnostic tests for labs that are CLIA-certified to perform 37 high complexity nucleic acid tests, an individual EUA for antigen diagnostic tests, 20 individual EUAs for serologic tests, an umbrella EUAs for an independently validated serologic test, and an individual EUA for a test for management of Covid-19 infected patients. 29, 30 Forty-one EUAs have also been issued for Personal Protective Equipment 31 and 66 EUAs for ventilators. 32 EUAs will be withdrawn after there is adequate supply of 510(k)-cleared or approved products on the market and the emergency has abated.

To treat patients with acute SARS-CoV-2-induced disease, physicians are generally limited to prescribing off-label, FDA-approved antiviral drugs indicated for other viral diseases.

Development of new anti-viral drugs specifically targeted against SARS-CoV-2 will have to undergo pre-market evaluation under an IND to generate data to support an NDA for submission to FDA, which will likely take years. The manufacturer of new, SARS-CoV-2-targeted drugs will receive a priority review, and will likely receive Fast Track designation that is accompanied by close collaboration with FDA to speed development, review and approval.

To prevent new infections and to end the pandemic quickly, vaccine candidates are being evaluated through the IND mechanism. Expedited development and FDA review mechanisms will likely be applied, including possibly a Regenerative Medicine Advanced Therapies designation.

To employ expanded access mechanisms, both acute antiviral treatments and prophylactic vaccines can be expected to be widely distributed under a treatment IND as soon as manufactured product is available and evaluated by FDA.

To assure continued collection of clinical data, it is likely that each manufacturer of a drug, biologic, or vaccine product will have near-term and long-term post-marketing commitments to continue collecting efficacy data post-marketing, as well as to consider special populations and issues (for example, pediatrics, elderly, patients with hepatic or renal insufficiency, and risk of drug-drug interactions) in the further evaluation of the product.

To maintain the safety profile of marketed products, all products will be subject to passive collection of adverse event reports.

Finally, EUAs may be issued for antiviral drug products as well as anti-inflammatory drug/biologic medicinal products as they are identified and directed toward specific patient populations, possibly as early as Phase 2 for new products and possibly any time after a repurposed product is found that "may be effective." EUAs may also play a role in making vaccines available. We have also seen the EUA withdrawn for chloroquine and hydroxychloroquine after FDA determined that they "… are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA." 33 Summary. The EUA that was issued for remdesivir is part of a well-developed landscape of regulatory infrastructure intended to meet the needs of patients faced with a broad range of societal and environmental demands created during routine development, expedited development, expanded access and public health emergencies or threats. To that end, the long historical experience of disasters and tragedies has not been in vain.

In 2019 and 2020, the author received compensation as a consultant from a pharmaceutical company, as a subject matter expert for a non-profit company, and as a topics editor for an Elsevier journal. The author was employed by FDA 1987-1995.

Legend: Figure 1 

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