Development of Drug-Approval Regulations for Medical Countermeasures Against CBRN Agents in Japan

Data Sources

We selected 11 CBRN threat agents (organophosphate, cyanide, anthrax, botulism, plague, plutonium, americium, curium, radioactive cesium, thallium, iodine) for which an approved therapeutic drug existed in the US from the Bioterrorism and Drug Preparedness list on the Food and Drug Administration (FDA) website. ⁶ Japanese drug label and approval data of the corresponding drugs were obtained from the website of the Pharmaceuticals Medical Devices Agency (PMDA) in the section on package inserts and approval of new drugs.^7,8 FDA approval data and advisory committee documents were obtained from Drugs@FDA ⁹ and PharmaPendium^® (Elsevier).

Analyses and Evaluation

Documents containing information regarding the regulatory approval process and summary basis of approval were examined for administrative and review information. Approval dates, schemes, application type, target patient data, and postmarketing commitments were identified in the review report and approval package. “Review time” was defined as the time between the submission date of application for approval and the actual date of approval. We identified whether approval schemes were “priority review” or “standard review.” In the present study, postmarketing commitments in Japan included conducting postmarketing clinical trials and investigations for a certain period under conditional approval,^10,11 whereas those in the US included postmarketing requirements and commitments. ¹²

Application for Off-Label Uses

Amyl nitrite, hydroxocobalamin, and streptomycin were approved via this system. Application for off-label use allows the sponsor to avoid the need for further clinical trials to file a supplemental application if there is sufficient evidence to support the safety and efficacy of off-label use. ¹³ This situation is similar to that of the applications covered by section 505(b)(2) in the US with regard to review of published literature as an application package, but does not apply to a new active ingredient. ¹³ Submitted literature included supportive-treatment data on target patients for all 3 products. Their reviews were not prioritized, and the review time tended to be prolonged. Streptomycin was the first drug with an indication for the treatment of plague in Japan.

Expedited Review for Antiterrorism Measures

Responding to the bioterrorism-related cases of anthrax in the US in 2001, Japan introduced “expedited review for antiterrorism measures” temporarily to approve medical countermeasures against bioterrorism agents. From December 2001 to March 2002, indications for anthrax treatment were approved for 5 fluoroquinolones as well as for doxycycline and minocycline. Japanese authorities approved measures for all infections caused by anthrax and did not specify administration for inhalational anthrax, which was the cause of deaths in the 2001 anthrax attacks. ¹⁴ Simultaneously, other bioterrorism agents categorized by the Centers for Disease Control and Prevention (CDC) in the US were approved in some of these applications (eg, levofloxacin was an added treatment for plague). This approval scheme was designated “priority.” Data on safety and efficacy from the literature were reviewed in these applications. Evaluation of the effectiveness of those drugs was based on in vitro drug activity against target organisms and drug disposition in the literature. Approval for ciprofloxacin was supported by a study in rhesus monkeys in the FDA approval package. ¹⁵ Treatment data of anthrax patients for ciprofloxacin, doxycycline, and levofloxacin were provided in the application.

Expedited Review

Expedited review is one of the priority review schemes in Japan. In this approval scheme, the approach to evaluation of its efficacy and safety is identical to the standard review. Applications for pentetate calcium trisodium (Ca-DTPA)/pentetate zinc trisodium (Zn-DTPA), iron(III) hexacyanoferrate(III) (Fe₄[Fe(CN)₆]₃, Prussian blue), and potassium iodide were reviewed based on the literature, which included treatment data on target patients. For the 2 new active ingredients other than potassium iodide, FDA approval packages were evaluated in the review process, and in all cases postmarketing surveillance was required under conditional approval.

US Approval Schemes

The US has been developing countermeasures against CBRN threats,^16,17 and the US developed an innovative regulatory approach, the Animal Rule, in 2002. ¹⁸ The Animal Rule allows the FDA to approve drugs that have been shown to be effective in animal models even without standard human efficacy studies. Before the Animal Rule came into effect, there was no regulatory pathway to approve a drug in the absence of human efficacy data in the US. The federal Food, Drug, and Cosmetic Act (FDCA) gives the legal definition of the evidence necessary for the FDA to determine that a drug product has been found to be effective: “substantial evidence of effectiveness.” “Substantial evidence” was defined in section 505(d) of the FDCA. Use of the phrase “including clinical investigations” in the definition has been interpreted to mean “human.” ¹⁹ Nevertheless, several valuable countermeasure products against CBRN threats have been developed and approved without the Animal Rule.

Table 2 shows 16 approved therapeutic products, arranged by the threat agents listed. Pyridostigmine, raxibacumab, and botulism antitoxin heptavalent (BAT) were unapproved products or indications in Japan. Detailed approval information for 7 products was not obtainable because some old approval packages were not available. Approval dates were from August 2000 to March 2013, and the mean and median review times were 5.5 and 6.0 months, respectively. However, the total regulatory process for some drugs takes much longer. ¹⁶ Approval information varied depending on approved products, so these data sources are summarized in Table 2.

US approval approaches were also grouped into 3 categories: Animal Rule, encouragement of applications in the Federal Register, and accelerated approval in the order shown in Table 2. Five products or indications had received FDA approval via the Animal Rule. By November 2012, only supplemental indications for pyridostigmine, hydroxocobalamin, and levofloxacin were approved under the Animal Rule. These drugs had received approval for other indications or had been approved against a CBRN agent by other countries. Raxibacumab was the first case of a completely novel product that the FDA approved through the Animal Rule and was followed by BAT. Data on supportive treatment of target patients existed for pyridostigmine, hydroxocobalamin, and BAT. Postmarketing commitments were required to verify the clinical safety and effectiveness of those drugs if used as indicated.

The FDA announced an encouragement to submit applications for 4 countermeasure products in the Federal Register on November 2, 2001, February 4, 2003, and September 15, 2003.^20-22 The FDA reviewed the literature on their safety and effectiveness, prepared draft labeling, noted the literature on which the FDA relied, and recommended labeling for application submissions. Supplemental indications of penicillin G (benzylpenicillin) and doxycycline, as well as the other 2 new active ingredients, were approved through this approach. These 2 antibiotics had been approved with indications for anthrax, ²⁰ and submission of labeling supplements to specify administration for inhalational anthrax was encouraged according to a study in rhesus monkeys. ¹⁵ Approval letters for supplemental application of doxycycline were the only available approval packages for these antibiotics. Therefore, whether those reviews were priority reviews was not clear. New drug applications for Ca-DTPA/Zn-DTPA and Prussian blue (Fe₄[Fe(CN)₆]₃) were submitted pursuant to section 505(b)(2) of the FDCA according to guidance^21-24 and approved with the postmarketing study commitments.

A new indication for inhalational anthrax on the labels of ciprofloxacin and levofloxacin was approved under accelerated approval with plasma concentrations in humans as surrogate endpoints likely to predict clinical efficacy. Regulations for accelerated approval allow earlier approval of drugs for serious or life-threatening diseases based on unmet need and a surrogate endpoint. These drugs achieved serum concentrations reaching or exceeding levels associated with improved survival of animals exposed to aerosolized Bacillus anthracis. Data on supportive treatment for subjects who had inhaled anthrax were available only for ciprofloxacin in the approval package. Postmarketing commitments were evaluated for those drugs in a large US population for inhalational anthrax if exposure should occur.

Performance of Japanese Approval Approaches

Accelerating the availability of drugs that can be used if CBRN threats occur is an important aspect of counterterrorism. The median review time (4.4 months) was sufficiently short because all applications other than 3 were designated priority reviews. Expedited review for antiterrorism measures and expedited review were originally designated priority review systems.

Conventional clinical trials involving patients with the disease for which the product was to be indicated had not been conducted for any application. Usually, drug approval is based on studies involving patients with the disease for which the product would be indicated. Although the treatment data of target patients was present in 9 applications and supported some approvals, clinical experience in victims of unexpected exposure to a CBRN agent was not necessarily important for approval. If a strictly controlled clinical trial is not feasible, unexpected exposure to a CBRN agent would provide an opportunity to collect human data on the safety and efficacy of a potential drug against a CBRN agent in the real world. The 3 products (Ca-DTPA/Zn-DTPA, Fe₄[Fe(CN)₆]₃, potassium iodide) that were approved under expedited review required postmarketing surveillance under the conditional approval.

In recent years, Japan has closed the approval gap for countermeasure products with the US by approvals of those 3 products against radiological agents. Approved products, indications, and application packages in Japan were similar to those of the US. However, there remain unapproved products and indications, as well as some concerns about Japanese regulatory approaches for drugs against CBRN agents.

The 3 products, pyridostigmine, raxibacumab, and BAT, were unapproved products or indications in Japan but approved via the Animal Rule in the US. Japan has other approval countermeasure products against organophosphate and anthrax, but no countermeasure products against botulism. Additionally, there is no medicine against anthrax other than antibacterial agents.

The results of the present study suggest that unapproved products or indications in Japan were because the Japanese regulatory scheme does not have the Animal Rule, whereby new drugs or biological products can be approved after successful testing in animals if human efficacy studies with CBRN agents are neither ethical nor feasible. In Japan, the requirement for the effectiveness of drug approval is not strictly defined in the PAL. Thus, evidence of efficacy derived from sources other than human trials and surrogate markers likely to predict clinical benefit are acceptable without legal amendments. In the review process for drugs against CBRN agents, the literature (including approval packages in other countries) was central for the evaluation of efficacy and safety, and a new study was not conducted for the applications. Although the applications for the new active ingredients Ca-DTPA/Zn-DTPA and Fe₄[Fe(CN)₆]₃ were approved based on the literature without creating a new rule, all of those approved countermeasure products had received approval for other indications in Japan or had received approval for use in other countries.

With respect to approval schemes in the present study, expedited review for antiterrorism measures enables immediate drug approval, but it is a temporary scheme and implemented on the verge of a crisis. Expedited review seems to be a broad utility scheme, but the criteria for its implementation and approval are vague and unpredictable. Although application for off-label uses provides approval criteria,^13,25 it has a disadvantage in that a new active ingredient cannot be applied. Unfortunately, those schemes do not seem to lead to the research and development of novel countermeasure products against CBRN agents.

Additionally, the Japanese regulatory approaches for drug development and approval are devoid of an emergency response in a crisis. ¹ For example, they do not permit compassionate use ²⁶ —that is, administration of an investigational drug outside a clinical trial for the treatment of a patient with a serious disorder who has no other satisfactory alternative treatment options. There is still room for improvement in Japanese regulatory approaches for drugs against CBRN agents.

Improving Japanese Regulatory Strategies

We selected the US regulatory approach as an informative system for improvement of Japanese regulation because the US has various regulatory mechanisms that can permit the approval of potentially useful countermeasure products. We can learn a lot from various US regulatory approaches for medical countermeasure products. Above all, the Animal Rule allows the FDA to approve a novel drug without standard human efficacy studies.

Introduction of the Animal Rule to Japan could make positive contributions to the development and approval of CBRN countermeasure products. It focuses on animal studies designed to provide definitive efficacy information. ²⁷ It can also encourage development of a novel product if collecting human data for establishing the efficacy is possible only in an emergency caused by a CBRN agent.

One can speculate on the reasons that the Animal Rule is not easily applied in Japan. One of main reasons is that efficacy evaluation of drugs under the Animal Rule is difficult for applicants and reviewers. For example, none of the antisepsis drugs that were effective in a reliable preclinical model had proven efficacy in clinical trials. ²⁸ An “ideal” animal model for predicting the response in humans has not been demonstrated. ²⁹ The regulatory agency cannot rely on findings to make regulatory decisions unless the evidence obtained from the animal efficacy study is rigorous, reproducible, and robust. When the Animal Rule was implemented in the US, it seemed to play an auxiliary part in accelerated approval by November 2012.^16,29 That is, review of the new indication of pyridostigmine was attempted under accelerated approval regulations.^29,30 The FDA has obtained knowledge and information through evaluation of countermeasures and published new draft guidance intended to assist industry with developing products under the Animal Rule. ³¹ Nevertheless, the Animal Rule is not without its challenges. Developing acceptable animal models is a very difficult task. Because of technical challenges and the lack of a lucrative commercial market for some novel products, many pharmaceutical companies are not sufficiently motivated to develop these needed medical products. ³² Most of the countermeasure products have never been used, so people have very little opportunity to appreciate them. To incentivize development of many new medical countermeasures under the Animal Rule, more research is needed to establish acceptable criteria for approved drugs without human studies.

The progress of efficacy evaluation in animals and winning public support for medical countermeasure products are essential if the Animal Rule is to be introduced in Japan. Three main approaches can be considered. The first is to encourage basic research for animal models of efficacy and assimilate the “fruits” of these basic studies into evaluation guidelines. The second is to establish a national/regional stockpile system that ensures stable supplies in the face of catastrophically large events and contributes to scheduled production in the pharmaceutical industry. The third approach is to establish a postapproval monitoring program—that is, a system of collecting future experiences made with countermeasure products that support safe use and provide data for benefit-risk assessment in human cases. Japan can undertake the regulatory actions mentioned above for introduction of the Animal Rule because a national stockpile system ³³ and all-patient investigation system ³⁴ have been established.

In addition to the approval pathways investigated in the present study, the US has programs to coordinate medical countermeasure preparedness (eg, Emergency Use Authorization, or EUA, ³⁵ and Expanded Access Program, or EAP^26,36). The EUA was introduced as an amendment to Section 564 of FDCA by implementation of the Project BioShield Act of 2004. Although the EUA is only a temporary means for making a product available during an emergency and is not intended to confer any type of formal marketing authorization, the EUA ensures the availability of several products, including anthrax vaccine adsorbed for prevention of inhalation anthrax. ³⁷ The Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 amends the EUA authority in several ways to better facilitate preparedness and response activities. ³⁸ The Japanese EA has characteristics comparable to the US EUA. ³⁹ The Japanese EA is applicable only to products that have been approved in other advanced countries, whereas the US EUA may include products under a more experimental status (ie, investigational products). As pointed out above, Japanese regulation does not authorize compassionate use, which is called EAP in the US.^26,36 Authorities continue efforts to institutionalize compassionate use in Japan. ⁴⁰ Compassionate use enables administration of an investigational drug outside a clinical trial for patients with a serious disorder and not only because of unexpected exposure to CBRN agents during an emergency.

Some advantages of the US strategy are attributable to the government's policy other than just drug-approval strategies. The US government has taken steps beyond drug approvals to develop medical countermeasure products^4,5,17 and has continued to provide financial assistance to support health security–related programs. ⁴¹ US efforts provide us with useful information. The present study could be used to help ascertain effective regulatory approaches for the development of drugs against CBRN agents in Japan.