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3 Ethical and Regulatory Challenges in the Development of Countermeasures The Committee on Animal Models for Assessing Countermeasures to Bioterrorism Agents heard many comments during the open-meeting sessions (see Appendix D) about the effects of the Animal Rule on the research and development of countermeasures. It is not, however, within the Committee’s purview to evaluate this law. The 2010 Public Health Emergency Medical Countermeasures Enterprise review, spearheaded by the Department of Health and Human Services, has identified a number of priorities for the Food and Drug Administration (FDA), including to “examine the current constraints posed by the Animal Efficacy Rule and identify strategies to improve its implementation” (DHHS 2010, p 11). Accordingly, this chapter presents the legal history of the Animal Rule and discusses some of the ethical challenges associated with the development of countermeasures, such as public information and disclosure of facts relating to products approved under the Animal Rule, and issues of informed consent. A short discussion of the two products approved to date under the Animal Rule is also offered, as well as a short description of the FDA’s drug development regulatory process. HISTORY OF THE ANIMAL RULE AND ETHICAL CONSIDERATIONS To respond effectively to potential biological and chemical threats, drugs and biological products are being developed and produced for which it is neither ethical nor legal to conduct efficacy studies with humans because of the unacceptably high risk of harm that testing itself would pose. The need to produce such countermeasures and the constraints imposed by their research are the underlying rationale for the FDA’s Animal Model Rule (Animal Rule; 21 CFR Parts 314 and 601; see Appendix A). With respect to the products for which it has oversight, the FDA’s statutory mission includes the provision that the agency “shall protect the public health by ensuring that human...drugs are safe and effective” (21 USC § 393(b)). In addition to its crucial public health role in preventing the distribution of unsafe and nonbeneficial substances, the FDA is also responsible for approving new drugs under the authority of the Public Health Service Act (42 USC 201 et seq.). In this role, the FDA is charged with “helping to speed innovations that make medicines more effective, safer, and more affordable; and 39
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40 ANIMAL MODELS FOR ASSESSING COUNTERMEASURES helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health” (FDA 2010). This multifaceted charge shapes the FDA’s responsibility for the use of investigational new drugs (INDs) developed pursuant to the Federal Food, Drug, and Cosmetic (FFDC) Act, as amended by the Food and Drug Administration Modernization Act of 1997, 21 USC 301 et seq. (see 21 CFR Part 312), and the approval of new indications for previously approved substances. During the 1990-1991 Persian Gulf War, the FDA granted waivers to the Department of Defense (DoD) for the off-label administration of pyridostigmine bromide (PB) tablets for prophylaxis against nerve agent and botulinum toxoid vaccine for prophylaxis against botulism to military personnel without research informed consent on the basis of 21 CFR Part 50 . In 1999, the FDA recognized that it would be contrary to the public interest and inconsistent with the public health purpose of the Public Health Service Act to conclude that a drug or biological product could not be approved because human efficacy trials could not be ethically or legally conducted (21 CFR Parts 314 and 601; FDA 1999). Therefore, the FDA recommended that when human efficacy trials could not be done ethically or legally, rather than leave its evaluators without a basis upon which to “fairly and responsibly” (FDA 1999, p 53964) conclude that a drug or biological product would be effective, animal studies could provide sufficient information to support a finding of “substantial evidence” that would warrant approval (p 53965). The agency suggested that it would approve a “new drug or biological product on the basis of adequate and well-controlled animal trials when it is scientifically reasonable to expect that the effect of the drug or biological product in animals is reasonably likely to predict clinical benefit in humans” (p 53964). The FDA proposed amending its regulations to identify the information necessary to provide sufficient evidence of the “efficacy of new drug and biological products used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances when adequate and well-controlled efficacy studies in humans cannot be ethically conducted because they would involve administering a potentially lethal or permanently disabling toxic substance or organism to healthy human volunteers without a proven treatment and field trials (assessment of use of the product after accidental or hostile exposure to the substance) are not feasible” (FDA 1999, p 53961). It advised that in such situations “certain new drug and biological products that are intended to reduce or prevent serious or life- threatening conditions could be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals, without adequate and well-controlled efficacy studies in humans” (p 53961). Safety still would be studied in human volunteers after approval and the products “would be expected to provide meaningful therapeutic benefits to patients over existing treatment” (p 53963). The agency acted under the authority of the FFDC Act in proposing amendments to 21 CFR Part 314 Subpart I (Approval of New Drugs for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted) and Part 601 Subpart G (Approval of Biological Products for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted). Three years later, in 2002, the final rule provided for “approval of certain new drug and biological products based on animal data when adequate and well-controlled efficacy studies in humans cannot be ethically conducted because the studies would involve administering a potentially lethal or permanently disabling toxic substance or organism to healthy human volunteers and field trials are not feasible prior to approval. Under this rule, in these situations, certain new drug and biological products that are intended to reduce or prevent serious or life-threatening conditions can be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals, without adequate and well-controlled efficacy studies in humans” (FDA 2002, p 37989).
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41 ETHICAL AND REGULATORY CHALLENGES The FDA Center for Biologics Evaluation and Research (CBER) and the FDA Center for Drug Evaluation and Research (CDER) were charged with evaluating, approving for efficacy, and regulating drugs and biological products under the Animal Rule while “the final determination that it is unethical to conduct studies in humans [would] be made by the reviewing officials in [the] FDA.” If possible, the agency would consult with an advisory committee during the approval process (FDA 2002, p 37992]).12 To date, the FDA has approved two drugs under the Animal Rule. On February 5, 2003, utilizing the Animal Rule for the first time, the FDA approved PB for combat use by U.S. military personnel to increase survival after exposure to soman “nerve gas” poisoning (FDA 2003a). On December 15, 2006, the agency approved Cyanokit (containing the drug hydroxocobalamin, a natural form of vitamin B12) for the treatment of known or suspected cyanide poisoning (FDA 2006a; for additional information, see p 44). Public Information and Disclosure Because the Animal Rule combines intervention with simultaneous collection of safety data (e.g., “…field studies, to verify and describe the drug’s [or biological product’s] clinical benefit and to assess its safety when used as indicated…such postmarketing studies would not be feasible until an exigency arises”, p 37995 and 37997) the use of products approved under it requires special disclosure. The Animal Rule emphasizes the importance of advising recipients that a product approved pursuant to the Animal Rule had not been “studied for efficacy in humans because of ethical or feasibility reasons” (FDA 2002, p 37990). It further requires product labeling “in language that is easily understood” to be available with the dispensing or administration of the product “if possible” (p 37992). Ongoing controversy about the effects of the DoD’s previous use of off-label drugs and vaccines (Connoly 2001a; Golomb 2008; Grady 2004; Miller 2002; Parmet 2010; Rettig 1999; SteelFisher et al. 2010), coupled with popular theories about the sources of new diseases and the utility of drugs and vaccines, suggests that the administration of drugs and vaccines approved under the Animal Rule could prompt a backlash against the FDA and the DoD precisely at the time that effective countermeasures would be most needed. In the past, the DoD’s targeted health education campaigns and efforts at comprehensive communication about prophylaxis against and treatment of weaponized diseases have been met with mistrust (Miller 2002; MVRD 2011; Rettig 1999). Thus, in response to a bioterroristic event or the use of bioweapons, medical uncertainty may easily give way to anxiety, fear, and panic among the public, both about the weaponized disease and about the means proposed to address it, with the concomitant refusal to be vaccinated and/or take drugs posing a threat to public health and safety. Accordingly, educational plans and disclosure strategies would be necessary to address not only these concerns but also the US public’s demand for unapproved or off-label-use drugs for when the perceived threat of disease, disability, or death is high. Research ethicists routinely observe the “therapeutic misconception”, under which study participants and investigators alike presume that clinical investigation inherently offers direct benefits to participants (Appelbaum et al. 1987). Nationally, demand for the treatment of HIV and AIDS in the 1990s and of advanced cancers to this date has shifted the ethical debate about justice away from the protection of human participants from research risks to focus on the participants’ fair access to clinical trials (London et al. 2010). A perceived medical crisis, such as a bioterroristic attack, could easily create an undue and arguably inappropriate public demand for drugs, vaccines, or other biological products under development or approved under For example, during a public health emergency such a consultative process might not be feasible. 1 An FDA advisory committee opined on the first application for approval of a novel product under the Animal 2 Rule in October 2009 (see section Newer Products under the Animal Rule).
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42 ANIMAL MODELS FOR ASSESSING COUNTERMEASURES the Animal Rule, even for products developed solely for combat use. For example, the 2001 mailings of B. anthracis prompted panic buying and hoarding of Ciprofloxacin and an increased civilian interest in the DoD’s approved anthrax vaccine, even as controversy grew about the vaccine’s mandatory military use and whether the vaccine was effective against inhalation anthrax (Annas 2005; Connolly 2001b; Miller 2002). More recently, during the H1N1 pandemic of 2009-2010, critics protested shortages, allegedly unfair priorities and geographic distribution of vaccines and antiviral medication at the same time when others expressed suspicion of the speed with which a vaccine was developed, tested, and produced and states debated mandatory vaccination plans (Parmet 2010). The FDA public information program and specific disclosures for drugs and vaccines approved under the Animal Rule will play a key role in the DoD’s plans for responding to the threat of bioweapons and bioterrorism. The DoD’s plans will need to be consistent with approved indications for the administration of the drugs and vaccines. Indeed, advising not only the individuals targeted for the receipt of new drugs and vaccines but also the general population, civilian as well as military, is critical for the acceptance and, therefore, success of any product approved under the Animal Rule. Public education about the real and projected threat of bioterroristic agents and the development of countermeasures is a crucial step in preparing at-risk groups to receive more specific information if intervention becomes necessary. The Unresolved Issue of Informed Consent As Richard Rettig pointed out in 1999, the use of investigational drugs and vaccines in response to chemical and biological weapons is not easily classified as either clinical treatment or research. The use of off-label or newly developed drugs or biologics is traditionally permissible only under a formal research protocol, but their use as countermeasures would have a primarily therapeutic rather than a research purpose. This distinction is further blurred when the goal is prophylaxis against an anticipated threat rather than an emergency response to an actual exposure or infection. Furthermore, unlike the off-label use of past countermeasures, drugs and vaccines developed for use in response to bioweapons and biothreat agents and approved under the Animal Rule probably will not have established prior uses in other contexts. This fact will almost certainly generate public concern about any attendant risks. The DoD’s waiver of informed-consent requirements for combat use of PB and botulinum toxoid vaccine became a lightning rod for controversy in the 1990s (Rettig 1999, 2000), even though their use fell within the battlefield exceptions to informed consent requirements for INDs (e.g., 21 CFR 50.23). The DoD’s 1998 mandatory administration of anthrax vaccine to 2.4 million service members sparked further debate that persists today (Annas 2002, 2010; Connolly 2001a,b; Miller 2002; MVRD 2011). In standard usage, “informed consent to treatment” refers to the process in which a physician proposes an intervention (drug, device, or procedure) to a patient of record that, in the physician’s professional judgment, would serve the patient’s specific medical interests. The physician explains (1) the nature of the proposed intervention; (2) its likely consequences, including anticipated benefits and risks of harm; and (3) the reasonable alternatives, including forgoing treatment, and their benefits and risks. The patient is then free to accept or refuse the proposed intervention. Although legal requirements call for variable levels of detail in required disclosures, depending on the nature of the intervention and its attendant risks and anticipated benefits, the ethical grounds for informing the patient and seeking his or her consent extend to all treatment (Beauchamp and Childress 2001; Faden and Beauchamp 1986). By contrast, the standard usage of “informed consent to research” refers to the process in which an investigator (often but not always a physician) recruits an individual to undergo a new or modified intervention “as part of a systematic investigation designed to develop or contribute to generalizable
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43 ETHICAL AND REGULATORY CHALLENGES knowledge” (45 CFR 46.102(d)).3 The intervention may or may not serve the specific interests or needs of the individual, but meeting those needs and interests is secondary to gathering data through a standardized protocol designed to answer the research question. The investigator must explain to the participant (1) the nature of the proposed intervention; (2) its likely consequences, including anticipated benefits and risks of harm; (3) reasonable alternatives, including not participating in the investigation, and their risks and potential benefits; and (4) the voluntary nature of participation and the individual’s right to leave the study at any time. The individual is free to accept or refuse participation. The standards of informed consent in research contexts, including required documentation, are more stringent than those in treatment contexts because (1) the risks and unknowns of research are greater than those of established treatments, and the anticipated benefits are less well known; and (2) the specific interests of the individual undergoing the intervention are secondary to the goals of the study. Nonetheless, in both contexts, informed consent is predicated upon the individual’s understanding and voluntariness. In public health crises, such as disease outbreaks or bioterrorism events, it may not be possible to obtain individual consent for treatment. The absence of a clearly articulated legal and ethical framework opens the door for renewed confusion and conflict over the DoD’s (or other government agencies’) authority to administer new drugs and biologics that have not been previously tested on humans for their efficacy and were developed through the use of animal models to prevent or treat life-threatening diseases resulting from bioweapons or biothreat agents. Furthermore, in light of the complex historical debate about the ethical and legal grounds for waiving consent requirements in treatment and research settings, the use of the Animal Rule creates a pressing need to clearly define when and why new drugs and vaccines are investigational and the criteria by which consent requirements for their use may be waived. As discussed in the previous section, public information and disclosure about informed-consent procedures for dispensing or administration of these products will be crucial to the public understanding and acceptance of the Animal Rule and the drugs and biologics approved under it. Draft Guidance and the Animal Rule On January 21, 2009, in accord with the agency’s Administrative Practices and Procedures/Good Guidance Practices regulation (21 CFR 10.115 ), the FDA issued for comment the “Draft Guidance for Industry: Animal Models—Essential Elements to Address Efficacy Under the Animal Rule” (FDA 2009a). The draft was prepared by the Animal Model Characterization Working Group in CDER in cooperation with CBER. The draft announced that “when human efficacy studies are neither ethical nor feasible, animal efficacy studies may be relied on under the Animal Rule to support approval or licensure of a drug or biological product. This guidance identifies and discusses the critical characteristics of an animal model” (FDA 2009a, p 3610). Comments were requested for consideration before the agency began work on the final guidance. To date the guidance remains in use as interpretive only. As noted in the announcement for comment “this draft guidance, when finalized, will represent the [agency’s] current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public” (p 3610). 3 On July 26, 2011 the Department of Health and Human Services issued an advanced notice of proposed rulemaking for revisions to the current human subjects research regulations. These would impact the “Common Rule”, i.e., 45 CFR Part 46 Subpart A, and potentially the FDA’s regulations governing human subjects research, i.e., 21 CFR Parts 50, 56, 312, and 812. See http://www.federalregister.gov/articles/2011/07/26/2011- 18792/human-subjects-research-protections-enhancing-protections-for-research-subjects-and-reducing-burden#p- 20.
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44 ANIMAL MODELS FOR ASSESSING COUNTERMEASURES The absence of a final guidance makes the evaluation and enforcement of the use of the Animal Rule problematic. Under these circumstances, any consistent engagement with research that could expedite the development of drugs and biological products is discouraged; for instance, the sharing of data to avoid known fruitless studies and repetition of completed work; to yield better models; to lower costs; and to reduce the number of animals (including the numbers of nonhuman primates) with the concomitant reduction in animal pain, distress, and deaths. THE LOW APPROVAL RATE TO DATE UNDER THE ANIMAL RULE The Animal Rule Has Been Used Rarely and for No Novel Products To date, the Animal Rule has been used only twice to approve new products. The countermeasures were not novel in either case; one approval was for a new clinical indication of an already approved drug, and the other approval was for a product that was in use in France. As noted above, the first countermeasure approved under the Animal Rule was pyridostigmine bromide (PB) in 2003. PB was indicated for pretreatment of exposure to the nerve agent soman. Since a different dose of the drug had previously received the FDA’s approval for treating myasthenia gravis in 1955, the Animal Rule was not used for a novel compound but to extend the indicated use of an already existent drug as a countermeasure (Gronvall et al. 2007). The second approval, in late 2006, was for Cyanokit (FDA 2006a). This drug is indicated for the treatment of known or suspected cyanide poisoning as a result of terrorism or smoke inhalation. Hydroxocobalamin (i.e., vitamin B12), the ingredient in Cyanokit, was approved in France in 1996 and was available in the United States at a much lower dose (Gronvall et al. 2007). There was already human data available to indicate that the drug would be effective. PB Enhances the Effect of Nerve Agent Antidotes PB is an acetylcholinesterase inhibitor with a short half-life. It reversibly binds to peripheral acetylcholinesterase for several hours and temporarily blocks the irreversible inactivation of the enzyme by nerve agents. PB by itself does not counteract the effect of nerve agents, but it enhances the effects of antidotes and “is intended to be used in conjunction with protective garments, including a gas mask, and atropine and pralidoxime therapy at the first sign of nerve agent poisoning” (FDA 2003b, p 4). The animal studies used to support the approval of PB demonstrated the differences among animal species. PB was effective as a pretreatment to soman exposure in rhesus monkeys. However, PB was not effective in rats, mice, or rabbits because they are naturally resistant to the nerve agent. These animals have high levels of carboxylesterase, which binds soman in the blood. Rats pretreated with a carboxylesterase inhibitor had a clear mortality support following PB plus atropine administration compared with untreated controls (FDA 2003b). Cyanokit Dog and Human Data Indicates Effectiveness The Cyanokit package insert indicates “that hydroxocobalamin is likely to produce clinical benefit in humans” (FDA 2009b, p 5). This conclusion was reached in studies done on dogs and in four French studies done on humans. Although clear conclusions could not be drawn from these four human studies, as they were not controlled and three were retrospective, in two of the studies there were
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45 ETHICAL AND REGULATORY CHALLENGES survivors after treatment, even though blood cyanide levels before therapy were generally considered to be in the lethal range (FDA 2006b). The mechanism of action of the drug is the same in humans and dogs. Hydroxocobalamin binds with cyanide to form cyanocobalamin, which is a stable, nontoxic compound excreted in urine. Cyanide-poisoned adult dogs were assigned to hydroxocobalamin at 75 or 150 mg/kg or vehicle (0.9% saline). The primary endpoint was survival at 14 days (FDA 2006c, Table 1, page 11, and Table 4, page 29). Anesthetized dogs received IV administration of a lethal dose of potassium cyanide. Dogs then received hydroxocobalamin at 75 or 150 mg/kg or vehicle intravenously (IV) over 7.5 minutes4. The doses at 75 and 150 mg/kg “are approximately equivalent to 5 and 10 g of hydroxocobalamin (respectively) in humans based on both body weight and the Cmax of hydroxocobalamin (total cobalamins-(III)).… Hydroxocobalamin reduced whole blood cyanide concentrations by approximately 50% by the end of the infusion compared with vehicle” (FDA 2006d, 2009b, p 5). Two weeks after exposure and assigned intervention, 18% of the dogs in the placebo control group, 79% of dogs in the 75-mg/kg group and 100% of dogs in the 150-mg/kg hydroxocobalamin groups survived, respectively. “Histopathology revealed brain lesions that were consistent with cyanide-induced hypoxia. The incidence of brain lesions was markedly lower in hydroxocobalamin- treated animals compared to vehicle-treated groups” (FDA 2009b, p 5). Furthermore, this dog study directly contributed to determining an appropriate dose of Cyanokit in humans. These dose levels were found to correspond to a 5-g and 10-g dose, respectively, in a 70-kg human (FDA 2006b). The FDA reviewed the proposed animal efficacy study in the dog model via a special protocol assessment before initiation of the study. In a clinical study that evaluated the effects of hydroxocobalamin administration to healthy subjects (no cyanide exposure), Cyanokit was shown to be well tolerated at the 5-g dose (FDA 2006c). The package insert indicates that “a second dose of 5 g may be administered by IV infusion”, depending on the severity of the poisoning and the clinical response (FDA 2006e). The FDA found that one well-controlled pivotal efficacy study in beagles was adequate for approval under the Animal Rule. Both groups that received Cyanokit had highly statistically significant improvement in survival compared with the control group at day 15; the mechanism of action appears to be the same in humans and dogs, and the animal study found a reduction in cyanide and an increase in cyanocobalamin in the Cyanokit-treated groups (FDA 2006f). Newer Products under the Animal Rule To date, no product developed using only animal efficacy studies has been licensed by the FDA. A prime example is the development of a therapeutic for inhalation anthrax. Human Genome Sciences (HGS) was awarded a contract from the Department of Health and Human Services (HHS) Biomedical Advanced Research and Development Authority (BARDA) of the Office of the Assistant Secretary for Preparedness and Response for developing and testing its human monoclonal antibody, raxibacumab, for inclusion in the U.S. Strategic National Stockpile. As a result of animal efficacy studies, in April 2009, HGS delivered 20,000 doses of raxibacumab to the stockpile to treat inhalational anthrax in an emergency. Three months later, “HGS received a second order for 45,000 doses to be delivered over a period of three years, beginning near the end of 2009. Both purchase awards were made under the Project BioShield Act of 2004 [P.L. 108-276], which is intended to hasten the development, purchase, and availability of medical countermeasures for the stockpile” (HGS 2011). The FDA pharmacology and toxicology review discusses the rationale for the route of challenge. 4
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46 ANIMAL MODELS FOR ASSESSING COUNTERMEASURES In 2009, HGS applied for the licensure of raxibacumab as treatment against inhalational anthrax pursuant to the Animal Rule (BLA 125349; FDA 2009c). Two doses of raxibacumab (20 and 40 mg/kg intravenously) were tested in randomized, placebo-controlled studies with rabbits and nonhuman primates and the higher dose was subjected to safety testing in human volunteers. The study concluded that a single dose of intravenous raxibacumab (40 mg/kg) improved the survival rate of monkeys (64%) and rabbits (44%) diagnosed with inhalational anthrax (Migone et al. 2009). However, an FDA advisory committee on October 27, 2009, suggested additional animal experiments and human safety studies,5 which the company is currently undertaking (FDA 2009e; S. Bolmer, presentation to the Committee, see Appendix D). REGULATION OF DRUG DEVELOPMENT The FDA Center for Biologics Evaluation and Research (CBER) and the FDA Center for Drug Evaluation and Research (CDER) are responsible for regulating any products in the United States that would be approved under the Animal Rule. Current authority for the regulation of drugs resides in the Federal Food, Drug, and Cosmetic Act as amended by the Food and Drug Administration Modernization Act of 1997 (FFDC Act; 21 USC § 301 et seq.). Current authority for the regulation of biological products other than drugs (e.g., vaccines and monoclonal antibodies) is primarily Section 351 of the Public Health Service Act, 42 USC 201 et seq., and specific sections of the FFDC.6 Drugs and biological products have the same general development pathway. Both drugs and biological products are subject to the IND application regulations (21 CFR Parts 312, 314 and 316). “A sponsor who wishes to begin human clinical trials…must submit an IND” (FDA 2009d) to the appropriate FDA division. “The IND describes the [product,] manufacturing, and quality control tests for product release. The IND also includes information about the product’s safety testing” (FDA 2009d) and pharmacokinetic testing in animals. In the case of vaccines, the immunogenicity testing in animals would be provided. In addition, the IND would include the proposed clinical protocol for a study in humans. In the human studies, premarketing clinical trials for new products are usually done in three phases. In phase 1, safety and pharmacokinetic (or, in the case of vaccines, immunogenicity) studies are “performed in a small number of closely monitored subjects. Phase 2 studies are dose-ranging studies Additional animal studies were suggested in response to (1) whether the evidence from the animals treated with 5 the 40 mg/kg dose predicted the response in humans with inhalational anthrax (i.e., accurate depiction of the course of disease in humans; timing of treatment after exposure; benefit of raxibacumab in relation to timing post exposure; additional studies with special populations, including children); (2) whether the evidence supports the conclusion that raxibacumab will not diminish the anticipated efficacy of antimicrobials against inhalational anthrax (i.e., timing of administration; proper dosing of antimicrobials; use of different antimicrobials); (3) whether evidence should be requested that raxibacumab make a contribution to the efficacy over the antimicrobial alone in rabbit and nonhuman primate models (i.e., standard or suboptimal doses of antibiotics in humans to see a contributing effect of raxibacumab; use of timing to mimic the course of infection in humans; use of rabbits instead of primates; when to start treatment; the state of the animal prior to the treatment with raxibacumab); (4) whether to further evaluate central nervous system (CNS) effects of raxibacumab (i.e., in rabbits to determine if the antigen-antibody complex is the reason for increased pathology due to complement activation). Additional studies to evaluate safety in humans were suggested including studies in pediatric and elderly populations as well as studies to distinguish the effects of the infection, toxins, and the immune response. These studies should address the issue of timing (FDA 2009e). 6For definitions of biologics, see “What Are ‘Biologics’ Questions and Answers” at http://www.fda.gov/AboutFDA/CentersOffices/CBER/ucm133077.htm.
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47 ETHICAL AND REGULATORY CHALLENGES and may enroll hundreds of subjects. Finally, phase 3 trials typically enroll thousands of subjects and provide the critical evaluation” (FDA 2009d) of efficacy as well as important additional safety data required to make a risk-benefit assessment of the product. In certain novel cases, the FDA may seek input from the appropriate FDA advisory committee, especially for issues relating to trial design and endpoints, before the initiation of phase 3 studies. The FDA advisory committee members are external experts, typically physicians, scientists, statisticians, and a consumer representative. Following the completion of all three phases of clinical development, the sponsor can make a determination on whether the data support the submission of a marketing application to the FDA. The marketing application would be either a new drug application (NDA) or a biologics license application (BLA), depending on the type of product.7 The NDA or BLA must “provide the multidisciplinary FDA reviewer team with adequate efficacy and safety information” to make both a risk-benefit determination and a recommendation to approve or not approve the product. During this stage, the manufacturing facility undergoes a preapproval inspection for new products (FDA 2009d). The FDA may convene an advisory committee meeting before taking a final action on a BLA or NDA. In general, products (or new indications) that are novel or present new issues would be evaluated by the appropriate FDA advisory committee. The committee provides advice to the FDA regarding the safety and efficacy of the product for the proposed indication as well as what postmarketing clinical trials should be considered, if applicable. As part of the approval process, the FDA works with the applicant on the product package insert and other labeling. Following approval, the FDA continues to oversee the manufacture of products and their safety. Specifically, the FDA performs periodic facility inspections on an ongoing basis and it also engages in post market surveillance, i.e., the process intended to identify safety issues or new problems prior to approval, and any problems that occur because a product may not be used as described in the product package insert. Medwatch is the FDA Safety Information and Adverse Event Reporting Program, “…a computerized database designed to support the FDA Postmarketing Safety Surveillance Program for approved drug and therapeutic biologic products” (FDA 2009d). For vaccines, postmarketing surveillance is accomplished separately with the Vaccine Adverse Event Reporting System (VAERS), cosponsored by the FDA and the Centers for Disease Control and Prevention (CDC). Specific studies are often conducted after a product has been approved to obtain further information about a product's safety and efficacy. “Postmarketing requirements (PMRs) include studies and clinical trials that sponsors are required to conduct by statute or regulation. In contrast, postmarketing commitments (PMCs) are studies or clinical trials that a sponsor has agreed to conduct” (FDA 2009d); however, the studies or clinical trials are not required by statute or regulation. PMRs and PMCs are listed in the FDA approval letters. Results of these postmarketing studies are often used to modify product labeling. 7 If the application is for a new indication for an already approved product, the submission would be an NDA or BLA efficacy supplement.
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