4
Regulations and Other Guidance Pertaining to the Development and Use of Vaccines in the Special Immunizations Program

Reviews of the national countermeasures enterprise consistently highlight challenges in advanced development and manufacturing of new vaccines and therapeutics against hazardous pathogens. Gaps identified in the current SIP also focus largely on the nature and type of vaccines included in the program, options for additional investigational or licensed products that should be considered for inclusion in an expanded SIP, and options for the future supply of SIP vaccines.

As discussed in greater detail in the following chapters the majority of vaccines currently administered within the SIP, with the exception of several licensed products, remain in Phase II clinical trials under Investigatinal New Drug (IND) status and are unlikely to continue on to licensure. The SIP program is designed to serve a small population of laboratory workers and others with potential occupational exposures to highly hazardous pathogens. Even with a potential expansion of the SIP to meet the needs of additional users from the growing community of researchers working on countermeasures against pathogens for which the civilian population may be at risk of exposure, and the incorporation into the SIP of new vaccines against additional pathogens and toxins, the SIP could only continue to serve a relatively small population of lab workers who would benefit from immunization.

The United States continues to undertake strategic planning and to expand investments in the development of countermeasures against hazardous pathogens and toxins for potential use in the civilian population or by the armed forces. Protection of the laboratory personnel working to achieve these mandates will continue to be an important component of this overall enterprise. However, the small scale of SIP vaccination, the nature of the hazardous pathogen vaccines being used in the program, and complications with conducting



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4 Regulations and Other Guidance Pertaining to the Development and Use of Vaccines in the Special Immunizations Program Reviews of the national countermeasures enterprise consistently highlight challenges in advanced development and manufacturing of new vaccines and therapeutics against hazardous pathogens. Gaps identified in the current SIP also focus largely on the nature and type of vaccines included in the program, options for additional investigational or licensed products that should be con - sidered for inclusion in an expanded SIP, and options for the future supply of SIP vaccines. As discussed in greater detail in the following chapters the majority of vaccines currently administered within the SIP, with the exception of several licensed products, remain in Phase II clinical trials under Investigatinal New Drug (IND) status and are unlikely to continue on to licensure. The SIP pro - gram is designed to serve a small population of laboratory workers and others with potential occupational exposures to highly hazardous pathogens. Even with a potential expansion of the SIP to meet the needs of additional users from the growing community of researchers working on countermeasures against pathogens for which the civilian population may be at risk of exposure, and the incorporation into the SIP of new vaccines against additional pathogens and toxins, the SIP could only continue to serve a relatively small population of lab workers who would benefit from immunization. The United States continues to undertake strategic planning and to ex- pand investments in the development of countermeasures against hazardous pathogens and toxins for potential use in the civilian population or by the armed forces. Protection of the laboratory personnel working to achieve these mandates will continue to be an important component of this overall enterprise. However, the small scale of SIP vaccination, the nature of the hazardous patho- gen vaccines being used in the program, and complications with conducting 77

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78 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH human clinical trials on vaccines against highly hazardous pathogens can lead to regulatory and manufacturing challenges. The vaccines required for the SIP have no or extremely limited commercial value and do not attract interest from the biopharmaceutical industry. As a result, there is a need to explore regulatory and manufacturing options. Furthermore, there is a need to consider whether additional vaccines already in use or in development should be considered for inclusion in an expanded SIP. The following two chapters discuss some of these challenges and options in greater detail in two primary areas: (a) current regulatory pathways applicable to vaccines and how these might apply to the use of vaccines within the SIP (Chapter 4), and (b) the state of vaccine manufacturing and options for the evolution of vaccines currently used in the SIP (Chapter 5). 4.1 OVERALL REGULATORY FRAMEWORK FOR VACCINES In the United States, all vaccines, including those in the SIP, are regulated as biologics by the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA). A single set of basic regulatory ap- proval criteria apply to all human vaccines, regardless of the technology used to produce them. CBER’s current legal authority for the regulation of vaccines derives primarily from Section 351 of the Public Health Service (PHS) Act and from certain sections of the Federal Food, Drug and Cosmetic (FD&C) Act. The PHS Act is implemented through regulations codified in Title 21 of the Code of Federal Regulations (CFR), Parts 600 through 680, which contain regulations specifically applicable to vaccines and other biologics. In addition, because a “vaccine” meets the legal definition of a “drug” under the FD&C Act, sponsors must also comply with current Good Manufacturing Practice (cGMPs) regulations in 21 CFR Parts 210 and 211, and, for all human test- ing prior to licensure, the Investigational New Drug (IND) regulations in 21 CFR Part 312. Most of the vaccines included in the SIP are directed against pathogens that are now identified as Select Agents (42 CFR Part 72; 42 CFR Part 73; 7 CFR Part 331; 9 CFR Part 121), which can cause life-threatening and/or fatal illness in exposed laboratory workers. As described previously in Chapter 3, the SIP presently consists of eight U.S. licensed vaccines, seven that are administered under active INDs held by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), and one administered under an active IND held by the Centers for Disease Control and Prevention (CDC). Given the large expansion in laboratory research for Select Agents and other existing or emerging pathogens during the past decade, the number of vaccines that might be included in the SIP is expected to grow. Given this overall regulatory framework, the current objectives of the SIP,

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79 DEVELOPMENT AND USE OF VACCINES and the potential expansion of the program to provide immunization against additional pathogens, this chapter focuses on four major questions: • How can the SIP best ensure continuous and convenient availability of appropriate vaccines for prevention of severe disease caused by Select Agents and other high-risk pathogens to which laboratory workers may be exposed? • What regulatory pathways are available to obtain FDA approval for as many SIP vaccines as possible, both now and in the future? • How can the evaluation of investigational SIP vaccines administered under IND be improved and extended? • What are the most expeditious and cost-effective means of bringing additional vaccines into the program? 4.2 OPTIONS FOR U.S. LICENSURE 4.2.1 Traditional Approval The most convenient and expeditious mechanism in which researchers and other potential vaccine recipients can be immunized against Select Agents and other pathogens is through the use of licensed products that can be obtained either directly from commercial sources or from another readily available source (with appropriate authorization) such as the CDC Drug Service. As summarized previously, there are, at present, a total of eight licensed vaccines against six diseases included in the SIP, including vaccines against anthrax (Biothrax® [anthrax vaccine adsorbed], Emergent BioDefense Operations Lansing Inc.); smallpox (ACAM2000® [smallpox (Vaccinia) vaccine, live], sanofi pasteur); yellow fever (YF-VAX® [yellow fever vaccine], sanofi pasteur); Japanese encephalitis (IXIARO®, [Japanese encephalitis virus vaccine, inacti- vated], Intercell AG); hepatitis B (recombinant, Engerix-B®, GlaxoSmithKline; Recombivax®-HB, Merck); and rabies (inactivated virus, Imovax®, sanofi pas- teur; RabAvert®, Novartis Vaccines and Diagnostics). Six of these vaccines have commercial markets both domestically and abroad, while the remainder (BioThrax and ACAM2000) are available for use by the military or for emer- gency use in civilians via the Strategic National Stockpile approval pathway, wherein safety and efficacy (primarily immunogenicity) data were obtained in fairly large, randomized clinical trials, supplemented by post-marketing (Phase 4) safety and/or immunogenicity studies (see Section 5.1 for additional background on this process). In addition, all eight vaccines must continue to meet the requirements specified in the respective product licenses, with any adverse events (including suspected vaccine efficacy failures) to be reported to the Vaccine Adverse Events Reporting System administered jointly by FDA

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80 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH and CDC. Chronic shortages of these vaccines or withdrawal from the market by the respective manufacturer are not expected in the foreseeable future, such that each will likely remain a part of the SIP. 4.2.2 Accelerated Approval A second regulatory approval pathway that may be applicable to the SIP is accelerated approval (21 CFR Part 601, Subpart E). Such an approval may be granted for certain biological products (including vaccines) that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments. Such an approval is based on adequate and well-controlled clinical trials estab - lishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit (21 CFR § 601.41). Approval under this section will be subject to the requirement that the sponsor study the bio - logical product further to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit (21 CFR § 601.41). Post-marketing (Phase 4) studies must also be adequate and well controlled and should be conducted with due diligence (21 CFR § 601.41). The protocols for these studies should be submitted with the original Biolog - ics License Application (BLA). Under an allied provision (21 CFR § 601.42; Restricted—Approval with restrictions to assure safe use), FDA may conclude that a biological product shown to be effective can be safely used only if distribution or use is restricted. In such instances, FDA will require such post- marketing restrictions as needed to ensure safe use of the biological product. These may include (1) distribution restricted to certain facilities or physicians with special training or experience or (2) distribution conditioned on the per- formance of specified medical procedures. Limitations imposed will be com - mensurate with the specific safety concerns presented by the biological product. Recent examples of vaccines approved under this mechanism include Hiberix ® (Haemophilus influenzae Type b (Hib) conjugate vaccine, GlaxoSmithKline), Fluarix® (inactivated influenza virus vaccine, GlaxoSmithKline), Agriflu ® (inactivated influenza virus vaccine, Novartis Vaccines and Diagnostics), and Afluria® (inactivated influenza virus vaccine, CSL Limited), all of which have a surrogate endpoint (pathogen-specific antibody level) that is reasonably likely to predict clinical benefit (i.e., prevention of disease caused by the pathogen to which the vaccine is directed). It is possible that such a pathway might also be followed for one or more investigational vaccines presently utilized within the SIP program (see below), although establishment of an antibody-based endpoint as a valid surrogate of clinical efficacy is highly challenging, especially

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81 DEVELOPMENT AND USE OF VACCINES for diseases that typically occur sporadically in humans. Such a proposal would need to be discussed with FDA prior to consideration. 4.2.3 Approval of Biological Products When Human Efficacy Studies Are Not Ethical or Feasible (21 CFR Part 601 Subpart H, as Well as 21 CFR Part 314, Subpart I, for New Drugs) (67 Fed. Reg. 3,7988 [2002]) The third licensure pathway that is applicable to vaccines utilized under the SIP is known simply as “the Animal Rule.” This rule was promulgated in 2002 and designed to permit approval of drugs and biologics (including vaccines) that are intended to reduce or prevent serious or life-threatening conditions caused by exposure to biological, chemical, radiological, or nuclear substances when human efficacy studies are not ethical and/or field trials are not feasible. While the animal rule has been viewed as critical for bioterrorism preparedness, in practice it has been extraordinarily difficult to utilize as an approval pathway, with only two drugs, pyridostigmine bromide and hydroxocobalamin, having been licensed in the United States through this pathway. Experience has shown that developing animal models that will yield efficacy results expected to be predictive for humans is highly challenging. For example, in the draft guidance document published in 2009, FDA has indicated that: • The animal studies must be adequate and well-controlled (21 CFR §§ 314.610 and 601.91), and should use the pertinent features of an adequate and well-controlled clinical study, such as a detailed protocol with randomization and adequate blinding and a statistical plan as described in 21 CFR § 314.126. • The challenge agent must be essentially identical to the agent causing human disease, unless there is very strong evidence that the use of another agent in the animal model would generate human-equivalent disease. • The pathogenesis and mechanism of toxicity should be the same as those in humans. • The sponsor must demonstrate the endpoint of interest (i.e., potential for mortality or major morbidity that might be reduced or prevented by a sufficiently effective intervention). • The route of exposure to the agent must be the same as the anticipated natural human exposure route, and that the quantification of the ex- posure dose must be equivalent to that anticipated in human disease; • The response to the etiologic agent (resulting illness or injury) mani- fested by the animal species exposed to that agent should be similar

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82 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH to the illness or injury seen in humans. In addition, when comparing the disease in animals with the disease in humans, sponsors should include time to onset of disease/condition; time course of progression of disease; and manifestations, that is, signs and symptoms (severity, progression, clinical and pathologic features, laboratory parameters, the extent of organ involvement, morbidity, and outcome of disease). • Identification of the trigger for intervention in the animal studies is critical to defining the timing of the intervention. Because animals cannot simulate the health-seeking behavior manifested by humans, the trigger for intervention should be accurately defined in the animal model. • Animal efficacy studies should reflect the expected clinical use and indication. A particular dosage form may not be suitable for the pro - posed indication, so the product’s dosage form should be considered in planning the development of the product. • Studies should be designed to mimic the clinical scenario and achieve meaningful outcomes comparable to the endpoints desired in humans. In some instances, supportive care and merciful euthanasia as ap- propriate should be administered to the animals as part of the study design. In such cases, demonstration of a product’s benefit over sup- portive care (i.e., supportive care plus investigational drug arm should be demonstrated to be superior to the supportive care plus placebo arm) will be necessary for approval or licensure (FDA 2009a). Because very few pathogens of interest to the SIP have validated animal models of human disease, and because of the high cost and long timelines required for the development of such animal models, licensure of vaccines of major interest to the SIP will not easily be accomplished by means of the Ani - mal Rule, with the possible exception of second-generation anthrax vaccines, third-generation smallpox vaccines, and plague vaccine. At the time that this report was being prepared, FDA and other government agencies are actively considering more practical and feasible ways in which the Animal Rule and its associated guidance may be implemented (FDA 2004, 2007a, 2009b, 2010b,c). 4.2.4 Potential Administration of Investigational SIP Vaccines Under Emergency Use Authorization (EUA) While not considered equivalent to a full (traditional) or accelerated approval for U.S. licensure, there is a fourth mechanism—Emergency Use Authorization (EUA)—that may enable potential recipients to receive an in - vestigational SIP vaccine outside of an IND protocol. Among other provisions, the Project BioShield Act of 2004 (Public Law 108-276) establishes a compre -

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83 DEVELOPMENT AND USE OF VACCINES hensive program that enables the emergency use of medical products against biological, chemical, radiological, and nuclear attacks or potential attacks for both civilian and military personnel, thereby permitting the FDA Commis - sioner to approve the emergency use of drugs, vaccines, medical devices, and diagnostics that were not previously licensed for a particular purpose (FDA 2007b). A related act, the Public Readiness and Emergency Preparedness Act of 2005 (Public Law 109-148), provides immunity from liability claims arising from administration and use of covered countermeasures under EUA. In July 2007, FDA developed a guidance document explaining FDA’s poli- cies for authorizing the emergency use of medical products under section 564 of the Federal FD&C Act (FDA 2007b). The guidance is intended to inform industry, government agencies, and FDA staff of the agency’s general recom - mendation and procedures for issuance of EUAs, and includes sections on (1) eligibility determination, (2) the process of requesting consideration for an EUA, (3) FDA processing of an EUA, and (4) conditions for authorization. Once the secretary of HHS declares an emergency (in consultation with DHS and DOD), the FDA commissioner may issue an EUA only if, after consultation with the director of NIH and the director of CDC (to the extent feasible and appropriate given the circumstances of the emergency), the FDA commissioner concludes that: 1. The agent specified in the declaration of emergency can cause a serious or life-threatening disease or condition. 2. Based on the totality of scientific evidence available, including data from adequate and well-controlled clinical trials, if available, it is reasonable to believe that the product may be effective in diagnos - ing, treating, or preventing (a) the serious or life-threatening disease or condition; or (b) a serious or life-threatening disease or condi- tion caused by a product authorized under section 564, or approved, cleared, or licensed under the FD&C Act or PHS Act, for diagnosing, treating, or preventing the disease or condition and caused by the agent specified in the declaration of emergency. 3. Known and potential benefits outweigh the known and potential risks of the product when used to diagnose, prevent, or treat the seri- ous or life-threatening disease or condition that is the subject of the declaration. 4. There is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such serious or life-threatening disease or condition. Experience has already been gained with EUAs, beginning with the emer- gency use of anthrax vaccine adsorbed (AVA) for prevention of inhalation

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84 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH anthrax in military personnel in 2004 (terminated in 2006), an EUA for doxy - cycline hyclate tablet emergency kits for inhalational anthrax (2008), and more recently, a series of EUAs for diagnostic test kits and antiviral agents for the detection and treatment, respectively, of the novel influenza A/H1N1 pandemic strain of 2009 (all terminated as of June 23, 2010).1 At the present time, the importance and relevance of the EUA provisions to the SIP lie chiefly in the ongoing collection of safety and immunogenicity data under the various active INDs (see below), which may someday provide sufficient evidence of risk/ benefit to enable an EUA for a specific vaccine to be used by military personnel and/or civilians should a public health emergency be declared. 4.3 ADMINISTRATION OF SIP VACCINES UNDER AN INVESTIGATIONAL NEW DRUG APPLICATION FDA regulations 21 CFR Part 312 (drugs) and Part 601 (biologics) contain procedures and requirements governing the use of investigational new drugs and biologics. All clinical research projects involving drugs or biologics (includ- ing vaccines) that are not FDA-approved for marketing must be reviewed by FDA. This is accomplished by filing an IND for each of the following instances: (1) any use of a drug or biological (including a vaccine) not approved for mar- keting by FDA, even if no formal study is being conducted; (2) studies involving an approved (i.e., commercially available) drug or biological that is being tested to support a new indication or significant change in labeling of the drug or bio - logic; and (3) studies involving an approved (i.e., commercially available) drug or biologic that is being used or tested in a new route of administration, new dosage level, or new patient population that may increase the risk of the drug or biologic. All studies conducted under IND must also be in compliance with the requirements for Institutional Review Board (IRB) review and informed consent (21 CFR Part 50 and 21 CFR Part 56, respectively). There are, at present, four types of IND Applications, all of which apply to the SIP: • Conventional (a.k.a. “commercial”) IND (21 CFR § 312.20)—submitted by a sponsor, typically a commercial entity, usually with the intent to market the product at some future date upon FDA approval. • Investigator-initiated IND (21 CFR § 312.22[d])—submitted by a phy- sician who both initiates and conducts an investigation. • Individual patients, including for emergency use (21 CFR § 312.310; formerly 21 CFR 312.36)—issued by FDA to allow the use of an experimental drug or biologic for the treatment of one (so-called “named”) patient when (1) the administering physician has determined 1 For further information, see FDA 2010a.

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85 DEVELOPMENT AND USE OF VACCINES that the probable risk of the drug (or vaccine) is not greater than the probable risk of disease; and (2) FDA determines that the patient can - not obtain the drug under another IND or protocol. Research may not be conducted under an emergency use IND.2 An emergency use IND exemption may be used one time only for a particular drug or biologic in a particular institution. Subsequent uses require prior IRB review and approval. • Treatment IND or treatment protocol (21 CFR § 312.320; formerly 21 CFR §§ 312.34–35)—submitted for experimental drugs (including vaccines) already showing promise in clinical testing for serious or life-threatening conditions, either in an ongoing clinical trial under an existing IND or in instances where all clinical trials have been com - pleted and the sponsor is actively pursuing marketing approval. 4.3.1 Conventional IND As described previously in Chapter 3, a total of eight vaccines are presently being utilized in the SIP under INDs held by USAMRIID or CDC. These vac- cines, many of which are in short supply, include botulinum toxoid, eastern equine encephalitis (EEE) virus, RVF virus, VEE virus (strains TC83 and C84), WEE virus, Q fever, and tularemia. A number of other vaccines relevant to laboratory workers are also being studied under IND, but are not currently in - cluded in the SIP. A complete listing of such vaccines is not available, although a partial listing based on documents available in the public domain is provided in Chapter 5. 4.3.2 Investigator-Initiated IND Investigator initiated INDs are typically submitted by a single investiga - tor or academic institution, often with the full knowledge and cooperation of the primary (conventional) IND holder. Such INDs are usually submitted to study an investigational vaccine for a different indication (e.g., post-exposure prophylaxis), patient population, schedule, or route of administration. The pri - mary IND sponsor typically provides information (usually via cross-reference to the primary IND) that is not available to the investigator, such as chemistry, manufacturing, and controls (CMC) data; the Investigator’s Brochure; or other data relevant to the clinical study proposed by the investigator. 2 “Research Use”: Most use of unapproved devices, drugs, or biologics is part of a systematic clini- cal trial or other clinical investigation designed to test the safety and/or efficacy of the test article. All such clinical investigations, including pilot studies, require prior IRB review and approval. In addition, almost all clinical studies are conducted under an Investigational Device Exemption (IDE) or an IND exemption obtained from FDA, which require that research protocols be filed with FDA prior to study commencement.

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86 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH While there are no vaccines presently included in the SIP that are being evaluated under an investigator-initiated IND, this mechanism could be utilized in collaboration with a willing manufacturer and/or primary IND holder. Such a mechanism could be especially relevant to manufacturers who have obtained regulatory approval outside the United States and who may desire potential ex - pansion to the U.S. market (see previous discussion above). These manufactur- ers could either allow a U.S.-based investigator to cross-reference their IND (if one exists) or they could prepare and submit a Master File that the investigator may cross-reference for relevant CMC, preclinical, and/or clinical information. 4.3.3 Emergency Use IND The need for an investigational vaccine could arise in an emergency situa - tion that does not allow time for submission of a conventional or investigator- initiated IND. For such instances, FDA issued a final rule on August 13, 2009, to facilitate the availability of drugs (including vaccines) to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy in a program known as “expanded access to investigational drugs for treatment use.” Among other provisions, the final rule authorizes shipment of the vaccine for a specified use (21 CFR § 312.36). Such authorization is usually conditioned upon the sponsor filing an “Expanded Access Submission” within 15 working days of the original request to FDA. It is important to appreciate and understand the provisions listed in 21 CFR § 312.300 (general provisions), § 312.305 (requirements for all expanded access uses), and § 312.310 (individual patients, including for emergency use). Under typical circumstances, the following six criteria must be met to comply with federal regulations and IRB policy: • The patient has a condition that is serious or immediately life-threatening. • No standard treatment is available. • The potential patient benefit justifies the potential risk of the drug (or, in this case, a vaccine), and those potential risks are not unreasonable in the context of the disease to be treated. • The vaccine cannot be obtained or utilized under another IND or protocol. • If requested by telephone, the physician or sponsor must explain how the expanded access will meet CFR requirements and must agree to submit a formal Expanded Access Submission within 15 working days of FDA’s authorization for use. Given these circumstances and regulatory requirements, the administration of an investigational vaccine in the SIP under an emergency use IND would be done infrequently, if at all, given the prerequisites of a preexisting IND or

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87 DEVELOPMENT AND USE OF VACCINES a preexisting study protocol at the requesting institution. The most probable scenario in which this might occur would be a request from the prospective emergency IND holder (e.g., USAMRIID) to an existing IND holder (e.g., domestic or foreign manufacturer) to submit a conventional clinical research protocol to the manufacturer’s existing IND. If emergency use of the vaccine is required for a patient who otherwise does not meet entry criteria for the standing protocol, then an emergency IND could be filed by another institu - tion (e.g., USAMRIID), in order to administer the vaccine to that patient. Emergency use of such a vaccine in the SIP setting might also occur as part of a post-exposure prophylaxis scenario in which the vaccine is administered in combination with an antimicrobial treatment and/or passive immune therapy in order to allow sufficient time for a protective immune response to develop. A form of emergency use of an investigational vaccine was employed in Germany in 2009, when a laboratory worker sustained a needlestick while handling Ebola virus. An investigational vaccine developed in Canada and based on vesicular stomatitis virus expressing an Ebola virus envelope glycoprotein was adminis - tered to the worker, who did not develop symptoms of disease (Enserink 2009). 4.3.4 Treatment IND A Treatment IND or treatment protocol (21 CFR § 312.320; formerly 21 CFR §§ 312.34–.35) is a mechanism for providing eligible subjects with inves - tigational drugs (including vaccines) for more widespread prevention or treat - ment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments. In addition to meeting the general criteria for expanded access (21 CFR § 312.305(a)), the following additional criteria must be met: • The drug (vaccine, in this instance) is either being investigated in a controlled clinical trial under an IND designed to support a market- ing application, or all clinical trials of the vaccine have already been completed. • The sponsor is actively pursuing marketing approval with due diligence. • For serious diseases, there is sufficient evidence of safety and effective - ness (generally Phase III data). • For immediately life-threatening disease, there is sufficient evidence that the vaccine would not pose an unreasonable or significant risk of illness or injury. Treatment IND studies require prospective IRB review and informed con - sent. A sponsor may apply for a waiver of local IRB review under a treatment IND if it can be shown to be in the best interest of the subjects, and if a sat - isfactory alternate mechanism for ensuring the protection of human subjects is available, e.g., review by a central IRB. Such a waiver does not apply to the

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88 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH informed-consent requirement. An IRB may still opt to review a study even if FDA has granted a waiver. Based on these considerations, the most likely scenario in which an inves- tigational vaccine would be administered in the SIP under a treatment IND would be during the late stages of a pivotal (Phase III) study (for which the SIP recipient would be ineligible), during the review period of a pending BLA for the vaccine in question, or when very compelling Phase II data were available in the instance of the potential for life-threatening disease. In any of these in - stances, the SIP would have to obtain permission from the primary IND holder to cross-reference applicable sections. 4.3.5 Optimization of IND Program Administration As discussed previously, an overarching goal of the SIP is to provide more convenient access to existing vaccines included in the program. Ready access has been achieved for the eight licensed vaccines, but remains some - what cumbersome for laboratory workers outside of DOD to be immunized because of centralized administration of the program at USAMRIID. Although a centralized approach to manage these INDs has a number of important ad- vantages—including detailed knowledge of each IND dossier, complete and careful documentation of adverse event and immunogenicity data, and timely revisions of regulatory documents such as appropriately updated Investigator’s Brochures—the requirement that vaccinees must, in nearly all instances, travel to USAMRIID to be vaccinated has appeared to impede participation in the program severely. Therefore, the committee believes that the utilization of other IND mechanisms such as investigator-initiated INDs or treatment INDs held by investigators at other government or academic institutions should be strongly considered, contingent on a continuing strong commitment for complete and standardized data and fulfillment of responsibilities under the IND collection. 4.4 OTHER REGULATIONS AND GUIDANCE OFFERING POTENTIAL INCENTIVES TO THE DEVELOPERS OF SIP VACCINES Because the SIP is directed exclusively at prevention of serious and life threatening disease typically caused by Select Agents or other highly virulent pathogens, FDA regulations have several other provisions designed to speed review and approval of BLAs and/or provide significant financial incentives to developers. These include (1) priority review (which mandates a 6-month FDA review period, rather than the standard 10-month period); (2) fast track (allows for a “rolling” BLA submission); (3) orphan drug designation (which allows for marketing exclusivity for 7 years following BLA approval); and (4)

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89 DEVELOPMENT AND USE OF VACCINES accelerated approval (which allows for the establishment of efficacy based on surrogate endpoints likely to predict clinical benefit). All four provisions will often apply to most of the pathogens targeted by the SIP, both currently and in the future, and can potentially accelerate and incentivize the approval process in many instances. In addition to these regulations, FDA published a guidance document in 2008 (FDA 2008) that is intended to provide pharmaceutical manufacturers with further financial incentives to develop drugs (including vaccines) for the prevention and treatment of certain tropical diseases. More specifically, the guidance provides information on the implementation of section 1102 of the FDA Amendments Act of 2007, which adds new section 524 to the Federal FD&C Act (21 U.S.C. § 360n). Section 524 authorizes FDA to award priority review vouchers to sponsors of certain tropical disease product applications that meet the criteria specified by the Act. A priority review voucher may be used by the sponsor who obtains it or another sponsor to obtain a priority review for a different application (typically a product with a very large and/or lucrative marketing potential). Although most of the specific diseases listed in the guidance do not yet apply to the SIP, a few do (e.g., dengue), and impor- tantly, the more general category of “any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations, designated by regulation by the Secretary (section 524(a)(3)).” 4.5 REGULATORY CONSIDERATIONS: LOOKING TOWARD THE FUTURE As described elsewhere, the SIP has, to date, provided substantial benefits for current and future laboratory workers and others exposed to hazardous pathogens. The SIP has maintained, provided, and administered a comprehen - sive program to support the availability of vaccines that are a key component of a comprehensive strategy to promote the highest standards in biosafety and disease prevention safeguards for protecting these individuals from potentially lethal disease. Moreover, continuing efforts to collect both safety and efficacy data have the potential to contribute further to the advancement of science, in - cluding use of existing data to further describe the safety, immunogenicity, and efficacy profiles of the existing SIP vaccines; to consider further development of at least some of them to enable U.S. licensure; to provide an existing platform to benchmark performance for purposes of comparison in the development of the next generation of vaccines; and to better prepare for the possibility of other licensure pathways in the future. With these objectives in mind, the following approaches should be considered to improve the effectiveness of the program with respect to regulatory considerations in the coming decade.

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90 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH 4.5.1 Comprehensive Review of Individual SIP Vaccines Tested Under IND As discussed previously, U.S. licensure has simplified access to and avail- ability of eight vaccines included in the SIP, and, importantly, provides eligible laboratory workers the confidence that these vaccines meet stringent require - ments for safety and efficacy. Because of these clear advantages, detailed review of the investigational vaccines included in the SIP should be undertaken to determine whether there would be any possibility of obtaining U.S. licensure. These reviews could consist of, at a minimum: • Examination of CMC information to determine (1) the extent to which the existing stocks of each vaccine may have met cGMP requirements, and if not, whether remedial compliance actions might be instituted; (2) if the manufacturing process could be replicated in whole or in part to generate new lots for purposes of physical and biochemical characterization and clinical bridging studies; and (3) if the manu - facturing process or product cannot meet cGMP standards, whether critical starting materials (e.g., vaccine seed strains) are still available and could be utilized to make additional cGMP-compliant lots. • Examination of all available clinical data (safety and immunogenicity) available for each SIP vaccine studied under IND, with an assessment of the apparent risk-benefit ratio. For those vaccines with an unfavor- able risk-benefit ratio, consider the development of a next-generation replacement vaccine as soon as possible. Also consider the potential withdrawal of current vaccine(s) from the SIP based on the detailed risk-benefit assessments. • Explore the most likely means of U.S. licensure, which, for the major- ity (if not all) of the current investigational SIP vaccines, would likely consist of either accelerated approval (if a suitable antibody correlate is available) or full approval under the Animal Rule. In reference to the Animal Rule, a review of existing or potential animal models that might be used to generate efficacy data should be pursued. 4.5.2 Exploring the Potential to Expand the SIP Portfolio with Vaccines Developed Outside the United States Three vaccines against pathogens either already included in the SIP or that could be added in the near-term are currently approved outside the United States: Q-Vax® (whole-cell Coxiella burnetii vaccine, CSL Limited, Australia); Encepur® (whole-virus, formaldehyde-inactivated tick-borne encephalitis virus vaccine, Novartis Vaccines and Diagnostics, Germany); and FSME-IMMUN ® (whole-virus, formaldehyde-inactivated tick-borne encephalitis vaccine, Baxter BioScience Vaccines, Austria). Because the U.S. market for these vaccines is

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91 DEVELOPMENT AND USE OF VACCINES highly limited (because of absence of, or extremely low, disease incidence), none of the manufacturers appear to be interested in seeking U.S. licensure, even though it is reasonable to assume that each product would likely meet FDA requirements in terms of manufacturing process, testing and controls, and clinical safety and immunogenicity. It is unknown whether these companies would consider submitting a BLA if sufficient financial and/or other incentives might be made available by the U.S. government. In addition to the three vaccines made by the three well-established, multi- national companies, there are a number of other vaccines potentially applicable to the SIP that are approved in other, more limited regulatory jurisdictions. These include vaccines against hemorrhagic fever with renal syndrome (ap - proved in South Korea and China), Argentine hemorrhagic fever (approved in Argentina), Kyasanur Forest disease (approved in India), Crimean-Congo hem- orrhagic fever (approved in Bulgaria), SARS (approved in China), and plague (approved in the former Soviet Union). It is presently unknown whether any of these vaccines could potentially meet FDA requirements for licensure, but if they did, the respective companies may also require an incentive to submit a BLA in the same manner as the multinational companies listed above. Discussions with the relevant manufacturers as to the potential for BLA submission (for U.S. licensure) and/or biologics Master File submission (to enable incorporation of the vaccines under a U.S. IND held by the U.S. Army Medical Department Office of the Surgeon General or other U.S.-based entity) should be pursued. Similarly, discussions with manufacturers in other regula - tory jurisdictions (e.g., China, India, Eastern Europe, and Latin America) might also be considered, especially for those vaccines that have promising safety and immunogenicity profiles. Joint development programs between these and U.S.- based entities might also be a means to accelerate development of additional vaccines of interest to the SIP. Teams of vaccine development experts might also be assembled to carry out on-site reviews, patterned after successful “due diligence” approaches carried out by large pharmaceutical companies and ven - ture capital groups for merger and acquisition and/or in-licensing opportunities for SIP portfolio expansion. 4.5.3 New Regulatory Approaches Because of the unique medical and epidemiologic circumstances surround- ing the SIP—that is, (1) the typically very high risk of severe morbidity or death following percutaneous, respiratory, or other exposure to a Select Agent or other highly virulent pathogen; (2) the typically very low risk for exposure to such pathogens among the general population, except for potential instances of biological terrorism; (3) the very low numbers of persons who would be qualified to receive a SIP vaccine (e.g., persons who may be exposed as a con - sequence of laboratory-based exposure)—typical regulatory pathways gener-

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92 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH ally do not apply. The most analogous regulatory circumstance pertains to an orphan drug (per the Orphan Drug Act [ODA] of 1983, §§ 525 [360aa] and 526 [360bb]). This legislation, which is intended to provide incentives to the pharmaceutical industry to develop drugs with very small commercial potential, provides benefit from a 50% deduction tax credit for clinical trial expenses and a market exclusivity of 7 years. In addition, protocol assistance in the form of written recommendations from the secretary of HHS for the nonclinical and clinical investigations needed for marketing approval can be obtained to accel - erate the approval process. In this respect, a more flexible approach has often been adopted for the development of orphan drugs, such as potential waivers for preclinical toxicologic data, including teratogenicity and/or carcinogenicity studies, so long as the safety to human subjects is not significantly compro - mised. The legislation also states that the clinical dossier of an orphan drug (including vaccines) should be built on a realistic assessment of the qualitative and quantitative nature of the studies that can realistically be performed. Such an assessment is highly relevant because of the orphan nature of the disease and its low prevalence in the general population—or, in the case of the SIP, low prevalence among laboratory workers and other at-risk populations—may make it difficult to recruit a large enough number of qualified participants for a clinical trial. An important drawback of this approach is that the approval of such a vaccine, if granted, would have a relatively limited amount of safety data when compared with the typical safety database for a vaccine (which often includes a minimum of 4,000–5,000 subjects). Therefore, if an Orphan Drug Designation is pursued as an ancillary regulatory mechanism, attention must be given to the potential concern among SIP vaccine recipients that assurances regarding the safety of the product may be less robust than those for vaccines given to the general population. An additional approval pathway available in Europe, but not in the United States, is the granting of a marketing authorization “under exceptional circum- stances,” pursuant to Article 14(8) of the European Commission (EC) Regula - tion No. 726/2004 (EMA 2005). More specifically, the European Medicines Agency (EMA) has determined that if the applicant (the equivalent of an IND sponsor in the U.S.) can show that he is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because: 1. the indications for which the product in question is intended are encoun - tered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence; or 2. in the present state of scientific knowledge, comprehensive information cannot be provided; or 3. it would be contrary to generally accepted principles of medical ethics to collect such information

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93 DEVELOPMENT AND USE OF VACCINES a marketing authorization [equivalent of U.S. licensure] may be granted sub - ject to certain specific obligations. These obligations, in turn, may include the following: • “The applicant shall complete an identified program of studies within a time period specified by the competent [regulatory] authority, the results of which shall form the basis of a reassessment of the benefit/risk profile”; • “The medicinal product in question may be supplied on medical prescrip- tion only and may in certain cases be administered only under strict medical supervision, possibly in a hospital”; and • “The package leaflet [package insert] and any medical information shall draw the attention of the medical practitioner to the fact that the par- ticulars available concerning the medicinal product in question are as yet inadequate in certain specified respects.” This approval pathway is most analogous to the EUA regulatory provi - sion in the United States (see previous discussion), but has the important advantage of being implemented in the absence of a public health emergency. Such a potential pathway seems especially relevant to vaccines included in the SIP, both now and in the future. Thus, exploration of the possibility of poten - tial new regulatory pathways such as “restricted” or “conditional” licensure (FDA 2010d: 128), which would be relevant to use of a SIP vaccine, should be considered. In addition to these possibilities, continuing advancements in manufactur- ing and analytical technologies and biomarkers may eventually mature to the point where the licensure of manufacturing “platforms” might be considered under special circumstances, rather than licensing of individual drug products per se. As discussed in more detail in Chapter 5, platform technologies are applicable to the development of multiple products for different indications based on a single technical approach. The best example in vaccinology is the use of a single vector virus, bacteria, or yeast to deliver foreign genes against the pathogen to which immunity is desired. The same vector backbone, with or without some modifications, could then be reused to deliver other genes. If expression of those genes consistently resulted in, for example, the generation of recombinant viral capsid protein antigens critical to a protective immune response, then the clinical profile of one vaccine might be easily bridged to another, without the need for extensive clinical testing of each recombinant vaccine individually. Experience gained with such a platform could also be leveraged for other pathogens that might be of greater commercial interest, and thus provide a continuous “warm base” for the manufacture of large batches to be used commercially as well as smaller batches to be used as “orphan vac - cines” for the SIP or other biodefense purposes. In addition to predictable manufacturing platforms, ex vivo testing in the form of appropriate biomarker

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94 PROTECTING THE FRONTLINE IN BIODEFENSE RESEARCH generation may also be predictive of a robust antibody response in the absence of any concerning safety signals. If so, rapid approval of new vaccines against Select Agents and other highly virulent pathogens might be further enabled in the coming decades. The recent Public Health Emergency Medical Countermeasures Enterprise Review (HHS 2010b) includes recommendations to explore and develop new “regulatory innovation, science, and capacity” applicable to the development of medical countermeasures such as vaccines. Efforts undertaken by FDA and others should continue to advance this area in the future, and the committee endorsed these goals. 4.6 FINDINGS AND CONCLUSIONS ON REGULATORY PATHWAYS APPLICABLE TO THE SIP • Finding 8: There are provisions within existing FDA regulations that could apply to the SIP and, in particular, that could be used to enable the administration of additional SIP immunizations and/or to enable the use within the SIP of additional IND vaccines (both domestic and foreign). • Finding 9: New regulatory approaches and further development of science to support regulatory approval mechanisms might offer addi - tional options for use of SIP IND vaccines and/or licensure pathways for existing or new vaccines relevant to the SIP.