Use of Unapproved Products, Off-Label Use, and Black-Box Warning ... A Variation of Newton’s Third Law or the Practical Application of the Rule of Unin- tended Consequences … Considerations in Military Operational Medicine Jerome F. Pierson, RPh, PhD Executive Editors Note: As multiple medical research and development efforts (both in SOF and in conventional research units) offer new drugs and medical equipment to the battlefield, we need to understand the rules of engagement for use, which, are dif- ferent for individual providers versus military heath care systems. ABSTRACT This article discusses the regulatory requirements for the use of unapproved drugs and off-label use of drugs and provides specific examples for military medicine. Additionally, it explains issues associated with standardization by the Service as a designated set, kit, or outfit as opposed to a general guidance. The former situation can be interpreted as a de facto policy whereas the latter is an adaptation of practice of medicine. Recent news stories brought to light the challenges assaulted from many sides to include consumer groups who facing military medicine in an environment where dramatic at times advocate for greater safety and at other times de- life-saving measures have become the expected rather then mand quicker access to therapeutic breakthroughs as well the exception.1,2 However, many of these same life-saving as the pharmaceutical industry which faces demands from measures have the potential to place a practitioner in situa- stockholders for return on investment. Reliance upon re- tions of “damned if you do, damned if you don’t” with re- sults from controlled clinical trials is problematic in that it gard to adherence to various regulatory and legal hurdles. is difficult to derive a robust safety profile of a product due This paper is intended to help explain the regula- to the tight inclusion/exclusion criteria involved with an ef- tory issues associated with unapproved (investigational new ficacy study. The FDA is well aware that when a product drug – IND) products, off-label use of approved products, is introduced into the market place, the patient population and the practical implications of black-box warnings on will be anything but homogenous and the manner in which drug labels. Furthermore, specific examples will be de- prescribers use the product will not necessarily reflect the scribed with regard to the application of the respective reg- labeled indications. In recent years, the FDA has addressed ulations. Finally, practical considerations will be discussed the potential blind spot associated with limited safety data to guide practitioners as they wade through the medical- through the requirement for additional post-marketing stud- legal environment. ies, also known as Phase IV studies, and reliance upon 4 The Food and Drug Administration (FDA) regula- MedWatch reports submitted from practitioners. Regard- tory processes for approval of new pharmaceuticals, bio- less of these initiatives, the introduction of a pharmaceuti- logics, and medical devices focus on the evaluation of these cal, biological, or medical device into a human host can be products from well-controlled clinical trials. The approval viewed as an application of Newton’s Third Law: For every process for a new product or a labeling change to an ap- action, there is an equal and opposite reaction. The prob- proved product requires several years and several hundred lem with the introduction of that pharmaceutical, biologic, million dollars.3 Furthermore, regardless of the exhaustive or medical device is that it is difficult to know how that op- nature of the approval process, it is not perfect and has been posite reaction will manifest itself. Therefore, managing Journal of Special Operations Medicine Volume 7, Edition 4 / Fall 07 50 medication related adverse events is often an exercise in the key consideration for the FDA is the balancing of the seri- application of the law of unintended consequences. Con- ousness of the emergency against the body of knowledge of sequently, various laws and regulations have been imple- the risks and benefits of the proposed product. For exam- mented over the years to address some of the potential ple, EUA approval for a product with a known safety pro- problems that can arise when the best intentions of pre- file that is in Phase III clinical trials for use in a fatal disease scribing by policy can result in unintended consequences. pandemic represents one end of a spectrum for FDA evalu- ation as compared to a novel product that has yet to be in- APPLICABLE LAWS,REGULATIONS AND POLICIES troduced in humans. Of note with the EUA is that the FDA Department of Defense policy regarding unap- also evaluates the information to be provided to healthcare proved medical products (investigational new drugs – providers on how to use the product and the information to INDs) and off-label use of medical products in military op- be provided to recipients of the product. Furthermore, in erations emanate from 10 United States Code (USC) 1107,5 the absence of a Presidential waiver, recipients are to pro- 21 Code of Federal Regulations (CFR) 50.23,6 and Depart- vide consent approved by the FDA to receive the product. ment of Defense Directive 6200.2.7 For most practitioners, However, the consent does not necessarily need to be ap- the laws and regulations are somewhat nebulous numbers proved by an institutional review board as the FDA research that do not pertain to their practice environments. How- rules do not typically apply for EUAs. ever, while the specific numbers associated with these laws The EUA is different from an emergency use of an and regulations may represent relatively low priority infor- investigational product for the treatment of an individual mation in the context of required knowledge in order to treat patient or for the conduct of emergency research. The FDA patients, an orientation to the precepts of these documents has specific provisions to allow for an investigational prod- will help the practitioner understand the basis for why the uct to be used in an emergency situation when that product laws/regulations exist. represents the only potential life-saving intervention.9,10 10 USC 1107 describes the basic legal require- These are distinctly different situations where in one case, ments for the use of unapproved, investigational products in an unapproved drug or device may represent an interven- military operations. These requirements center around the tion of last resort. The other situation involves a deliberate need to inform recipients of the investigational or unap- effort to conduct a well controlled trial with an investiga- proved nature of the product provided, the reasons for pre- tional product where the study involves enrolling research scribing, and the respective risks and benefits associated participants who cannot provide their own consent due to with the product. Furthermore, regarding any exception the nature of their illness or injury.11 Both of these situa- from informed consent requirements, the President is the tions will be briefly discussed later in this paper. approval authority. 10 USC 1107 reflects a Congressional Another consideration for healthcare providers is recognition that when an IND product is the only means the language in Department of Defense Directive (DoDD) available to protect against a lethal chemical or biological 6200.2. DoDD 6200.2 states that “DoD Components shall weapon, the lives of individual members, the safety of their make preferential use of products approved by the FDA for comrades who rely on them, and the success of the military general commercial marketing, when available, to provide operation may require uniform use of the medical protec- the needed medical countermeasure.” DoDD 6200.2 goes tion. 21 CFR 50.23 (an FDA regulation) describes the pro- on to describe the requirements for using unapproved prod- cedures for review of the use of force health protection ucts and off-label products for force health protection. Key investigational products by the FDA and requirements for in this description is the definition of force health protec- an Institutional Review Board (the Army Human Subjects tion, “an organized program of healthcare preventive or Research Review Board – HSRRB). These reviews are re- therapeutic treatment, or preparations for such treatment, quired prior to implementation of any usage and prior to designed to meet the actual, anticipated, or potential needs any requests through the Secretary of Defense to the Pres- of a group of military personnel in relation to military mis- ident if a waiver of consent is requested. sions.” The practical take home point from DoDD 6200.2 In the BioShield legislation of 2004, Congress pro- is the differentiation between practice of medicine and force vided some relief to the many stringent requirements asso- health protection when it comes to off-label prescribing. ciated with investigational products and created a category Practice of medicine is the interaction between a provider known as the Emergency Use Authorization (EUA).8 The and his/her patient based on a personal knowledge of the EUA allows the FDA to authorize the use of products that medical history and needs of a specific patient. Off-label have not been fully approved in the event of a real or po- use of prescription products in the practice of medicine is tential public health or military emergency if there is suffi- not regulated by the Food and Drug Administration. The cient evidence to demonstrate safety and effectiveness. A FDA regulation on investigational products specifically Use of Unapproved Products, Off-Label Use, and Black-Box Warning ... 51 states that the document “does not apply to the use in the FDA pulled the approval status. The DoD went through practice of medicine for an unlabeled indication of a new the process of identifying the potential emergency situa- drug approved under part 314 or of a licensed biological tion that existed for the use of anthrax as a biological product.”12 However, misadventures associated with off- weapon and submitted an EUA request to the FDA.