Drug Development for Asthma and COPD: A Regulatory Perspective Marianne Mann MD and Robert J Meyer MD Introduction General Regulatory Overview Asthma Drug Development Overview Asthma Drug Development by Class COPD Drug Development Overview COPD Drug Development by Class Generic Inhaled Drug Development for COPD and Asthma Summary This review addresses drug development intended to support United States clearance for asthma and COPD by explaining basic regulatory terms and broadly discussing the regulatory pathways to clearance. Some of the key clinical regulatory challenges that are faced by drugs for asthma and COPD are explained and clarified, both overall and by class of drug, citing relevant examples that emphasize key lessons. Generic drug development of inhaled drugs is also addressed. The purpose of this review is to provide the reader with a greater understanding and appreciation of asthma and COPD drug development from the regulatory perspective. Key words: COPD; asthma; drug devel- opment; regulatory. [Respir Care 2018;63(6):797–817. © 2018 Daedalus Enterprises] Introduction ommend the use of products for asthma or COPD on the basis of evolving clinical data and experience, the U.S. The development of drugs for asthma and COPD in the Food and Drug Administration (FDA) clearance of drugs United States involves regulatory oversight and clearance, is based on regulatory and legal standards, including the the specifics of which are not familiar to many prescribers. need for sponsors to provide substantial evidence for ef- While clinical guidelines and individual prescribers rec- fectiveness. The FDA follows the rules and regulations set forth in the Code of Federal Regulations (CFR), which implements the Food, Drug, and Cosmetics Act. Substan- tial evidence for efficacy is determined in 21 CFR 314.126 Dr Mann is an independent clinical/regulatory drug development consul- tant in Highland, Maryland. Dr Meyer is affiliated with Greenleaf Health, based on reports of adequate and well-controlled investi- Washington, DC and the University of Virginia, Charlottesville, Virginia. gations. Generally, this is interpreted as at least 2 pivotal trials that show clear evidence of efficacy based on clinically Drs Mann and Meyer both serve as regulatory consultants to industry to relevant end points of efficacy. Even with this standard met, provide clinical and regulatory input to facilitate drug development. Confi- dentiality agreements preclude naming these companies. Dr Meyer discloses the FDA must weigh all of the clinical, non-clinical, and a relationship with Cardiome Pharma. Dr Mann discloses a relationship with quality data (ie, chemistry and manufacturing information) Juniper Pharmaceuticals. Previously, both Drs Mann and Meyer worked at the Food and Drug Administration in the Division of Pulmonary and Allergy Drug Products, but they do not represent that agency in this article and all opinions in this paper are their own. Dr Meyer’s opinions do not necessarily represent those of the University of Virginia or the Commonwealth of Virginia. Correspondence: Marianne Mann MD, 7105 Biter Lane Highland, MD 20777. E-mail: [email protected] or Robert J Meyer MD, Dr Mann presented a version of this paper at the 56th RESPIRATORY CARE 1055 Thomas Jefferson Street, NW, Suite 450 Washington, DC 20007. Journal Conference, Respiratory Medications for COPD and Adult Asth- E-mail: [email protected]. ma: Pharmacologic Actions to Clinical Applications, held June 22–23, 2017 in St Petersburg, Florida. DOI: 10.4187/respcare.06009 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 797 DRUG DEVELOPMENT FOR ASTHMA AND COPD for a product to determine its overall benefit/risk. The clear- Guidance entitled Providing Evidence of Effectiveness for ance of a drug and the resulting labeling reflects the key Human Drug and Biological Products3 further clarifies what evidence provided to and reviewed by the FDA. types of studies should be done to support an FDA clear- The purpose of this review is to describe the develop- ance and addresses special situations in which a single ment of drugs for asthma and COPD intended for market- pivotal trial may provide sufficient evidence for efficacy. ing in the United States, and to help clarify the types of The FDA’s regulations on adequate and well-controlled well-controlled clinical investigations that are necessary studies (21 CFR 314.126) describe the types of controlled for regulatory clearance. This review will also address trials that best provide evidence of effectiveness. Placebo- briefly the development of generic inhaled drugs. This controlled trials are done most often because superiority review will give practitioners a fuller understanding of trials are in many ways the most robust in design. Impor- drug development for COPD and asthma. tantly, these trials are often performed upon a background standard of care, and subjects randomized to placebo re- General Regulatory Overview ceive placebo plus effective standard of care therapy, while subjects randomized to active therapy have this added to Development for any therapeutic drug intended for mar- the standard of care, as long as it is not contraindicated keting in the United States begins with an Investigational with the study drug. Criticism of the ethics of placebo- New Drug application that is filed with the FDA to allow controlled trials has been raised, but sometimes it is not studies in humans to proceed. Drug development proceeds understood or appreciated that with a thoughtful design, in several phases, although these do not need to be distinct placebo does not equate to no therapy. A new long-acting or serial. Phase 1 studies are intended to explore the phar- muscarinic antagonist (LAMA), for instance, can be eval- macokinetics (PK) and tolerability profile of the drug in a uated versus placebo in subjects with COPD who are tak- relatively small number of healthy volunteer subjects (or, ing long-acting ␤ agonists (LABA), inhaled corticoste- less commonly, patients). Later PK studies may involve roids (ICS), and rescue albuterol, as needed. special populations (eg, renal impairment) or explore drug– Another way to study a drug and show efficacy is to drug interactions. Phase 2 studies enroll well-defined sub- perform dose-response trials in which a higher dose of the jects with the intent to explore efficacy, establish the dose drug is demonstrated to be superior to a lower dose. A range/or regimen, and further delineate safety and tolera- superiority trial that shows improved efficacy of the new bility. Phase 3 studies are large, randomized, controlled test drug over an existing therapy is also a rational and clinical trials that establish the safety and efficacy of the accepted additional study design that can be considered, drug for the desired indication and are often referred to as and is sometimes considered when placebo-controlled tri- pivotal studies. Phase 4 studies are post-clearance studies als are unethical. In certain situations, the FDA will con- that are done to further clarify the safety profile and/or the sider a trial in which subjects are exposed to the new drug efficacy of the drug, often in new subject groups or for and results are compared to historical data. These trials are related indications. Once the range of phase 1–3 studies considered in conditions, for instance, in which there is a are complete, applicants submit a New Drug Application high mortality rate and the drug therapy proposes to dra- (NDA) for a small molecule drug or a Biologic License matically change that known mortality rate, or for condi- Application for a product produced in a biologic system, tions in which the desired effect (anesthesia for instance) such as a monoclonal antibody. These applications include is well known and understood. Non-inferiority trials com- not only the clinical data from the phase 1, 2, and 3 stud- paring a new drug to a cleared reference drug can be ies, but also include data on product quality, manufactur- considered, yet these are generally done only when supe- ing, and animal toxicology/pharmacology. While timing riority designs are not feasible or ethical. Many question may vary, it generally takes 10–13 y for a new medicine why the FDA cannot rely more on non-inferiority trials to to go from initial discovery to the marketplace, with clin- substantiate efficacy, as such studies would be easier to ical trials alone taking 6–7 y.1 enroll, and would not pose as many ethical concerns. The CFR outlines the many rules by which the FDA A 2016 FDA guidance entitled Non-Inferiority Clinical guides drug development, but the interpretation of those Trials to Establish Effectiveness4 describes non-inferiority rules is what is most important to guiding drug develop- studies and why they are generally less desirable than ment. Many helpful guidances related to drug develop- superiority trial designs. While evidence of superiority in ment are available on the FDA Website.2 The federal Food, a clinical trial is “entirely interpretable without further Drug, and Cosmetic Act Drug Efficacy Amendment of assumptions (other than lack of bias)...thenon-inferior- 1962 requires that the effectiveness of products be dem- ity study is dependent on knowing something that is not onstrated through adequate and well-controlled clinical tri- measured in the study, namely, that the active control had als. In general, at least 2 adequate and well-controlled its expected effect.” Non-inferiority trials rely heavily on phase 3 trials are required for clearance. A 1998 FDA trusting that the active comparator worked and that it would 798 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 DRUG DEVELOPMENT FOR ASTHMA AND COPD have beaten placebo by a predictable margin, had a pla- FDA’s published action summaries and its public advisory cebo arm been in the study. For many cleared asthma and committees. As the underlying pathology of asthma be- COPD drugs, it is appreciated that their effect sizes versus came better elucidated in the latter part of the last century placebo can vary from trial to trial, and may, at times, even and drove therapeutic guidelines (eg, the National Asthma fail to distinguish from placebo.