Emergency Authorization of Medical Products: Regulatory Challenges from the 2009 H1N1 Influenza Pandemic in Japan

Legal Processes for Emergency Authorization

The EA legal system in Japan is compared with the EUA system in the United States in Table 1. Emergency approval is used to expeditiously grant regulatory approval of unapproved pharmaceuticals and medical devices in response to a public health emergency, as stipulated in the Pharmaceutical Affairs Law (PAL). ¹² The PAL aims to regulate commercial drug and medical device products, the conduct of relevant research, and formal procedures for drug development and approval, all under the purview of the Ministry of Health, Labour, and Welfare. The PAL was not originally intended to address emergencies, however, and the determination or declaration of an emergency, as well as the provision for its revocation, is accordingly out of its scope. Further, EA has no direct statutory relationship with emergencies stipulated by other relevant laws, except for the 2004 Act Concerning Measures for Protection of the People in Armed Attack Situations, etc (Act No. 112 of 2004). ¹³

The legal basis for declaring a public health emergency in the Japanese legal system remained unclear until enactment, on April 27, 2012, of the Act on Special Measures Concerning Countermeasures Against Novel Influenza or the Like. The Basic Act on Disaster Control Measures (Act No. 223 of 1961) empowers the prime minister to declare emergencies caused by natural disasters but does not cover the determination and declaration of health crises. Moreover, the MHLW Health Crisis Management Basic Guidelines serve as the standard procedure for addressing health crises caused by problems with drugs, food poisoning, infectious diseases, contamination of drinking water, and the like under the purview of the MHLW (Table 1), but they do not refer to the determination and declaration of a public health emergency. ¹⁴ For intentional attacks with chemical, biological, radiological, or nuclear (CBRN) agents, the Japanese EA article is applicable mutatis mutandis to declared domestic emergencies pursuant to Article 92 of Act No. 112 of 2004. ¹³ Thus, identification of emerging challenges to public health posed by naturally occurring contagious agents had not been within the scope of the Japanese legal system. In the case of the 2009 public health crisis caused by the flu pandemic, the task force for novel influenza headed by the prime minister declared the start of the pandemic on October 1, 2009 (Table 2), according to the Action Program for Countermeasures to Novel Influenza, which was developed in reference to the 2005 WHO global influenza preparedness plan.^15,16 This determination referred to the urgent importation of flu vaccines, but not to the application of EA.

In the United States, EUA was introduced as an amendment to Section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) by implementation of the Project BioShield Act, effective in July 2004.^8,17 Section 564 provides for the declaration of emergencies, including domestic, military, and public health emergencies, and the legal authority for a temporary approach to making unapproved medical interventions available during these emergencies. The scope of emergencies envisioned for EUA under Section 564 includes intentional attacks with CBRN agents as well as unintentional events. In practice, the US EUA and Japanese EA appear to apply to similar emergencies, since the latter does not stipulate a definitive range of application and is therefore sufficiently flexible to respond to any kind of health-related emergency.

In contrast, the US EUA process has clear legal processes for determining and declaring applicable emergencies. First, any cabinet secretary—including the secretaries of the US Department of Health and Human Services (HHS), the Department of Homeland Security (DHS), and the Department of Defense (DoD)—may make a determination of the existence of an emergency with public health effects. Second, the HHS secretary then makes an emergency declaration justifying the use of an unapproved product, or unapproved use of an approved product. Third, the FDA commissioner issues an EUA under authority delegated from the HHS secretary. The FDA commissioner may set forth requirements for the use of EUA products.^18,19

Target Products for Emergency Authorization

The Japanese EA is implemented “for the drugs and medical devices required for use in emergencies to prevent the spread of diseases or other health hazards that might have serious implications on the health and lives of the public and for which no appropriate countermeasures other than such drugs and medical devices exist.” ¹² However, the outstanding difference between the 2 systems is that the EA is granted only for medical agents and devices that are as yet unapproved in Japan but that have been approved in specified foreign countries (Table 1). The Cabinet Order designates the range of countries with similar regulatory system levels and standards for evaluating the quality, efficacy, and safety of medicinal products to Japan, as well as the scope of EA products. This administrative step corresponds to the emergency declaration for EUA by the HHS secretary in the United States. Consequently, the goal of EA is to enable the urgent importation of only those products whose quality, efficacy, and safety have been proven abroad. In contrast to the US EUA, new chemical entities or medical devices under investigation for which no authority has granted regulatory approval are out of its scope.

This EA mechanism presupposes that Japan continues to lag behind other countries in drug approval and that foreign clinical data, which are generated at the expense of clinical trial participants and sponsors in other countries, can be used for regulatory review for emergency approval. The Japanese EA approach thus avoids exposing patients to unauthorized products with yet-to-be proven risks; rather, it narrows the range of applications to eliminate unapproved but potentially promising drugs, such as those in later stages of development.

In the case of the Japanese EA for the 2009 H1N1 influenza vaccine, the Cabinet Order designated the UK, Canada, Germany, and France as countries with similar regulatory levels and standards in which regulatory approval or emergency authorization for these vaccines had been granted (Table 2). ²⁰ With this Cabinet Order, 2 vaccines for novel influenza H1N1 were specified as EA products, and EA was subsequently granted for both on January 20, 2010—namely, GlaxoSmithKline's Arepanrix H1N1 intramuscular injection, a monovalent split virus influenza vaccine containing H1N1 antigen and adjuvant that had gained regulatory approval in Canada on October 21, 2009, ²¹ and the Novartis cell-cultured H1N1 antigen–containing influenza vaccine “Novartis” intramuscular injection suspension (hereinafter Novartis H1N1 vaccine), a pandemic H1N1 monovalent influenza vaccine (surface antigen, inactivated, prepared in cell cultures, adjuvanted) that had been approved under an emergency use procedure with rolling submission and review in Germany on November 4, 2009, as CELTURA suspension. ²²

In the United States, following declaration by the HHS secretary in April 2009 of a public health emergency due to the H1N1 pandemic, unapproved peramivir was first made available outside of development clinical trials through the emergency investigational new drug (eIND) mechanism to ensure access to a parenterally administered neuraminidase inhibitor for severely ill hospitalized H1N1 flu patients (Table 3).^23,24 This eIND scheme enabled emergency use of an investigational drug for a single patient on the basis of a request made by a physician outside of the investigational new drug application in accordance with the expanded access rule. ²⁵ The FDA asked the sponsor of clinical trials for peramivir, BioCryst Pharmaceuticals, Inc., to permit the eIND program for peramivir IV and then activated the EUA process for peramivir as the number of eIND requests for peramivir increased. Twenty adults and 11 children with respiratory failure received peramivir under the eIND application before the FDA commissioner issued the EUA for unapproved peramivir on October 23, 2009.

Submission for Emergency Authorization

The US EUA appears to require a more comprehensive submission data package than does the Japanese EA (Table 1). ¹⁸ This is understandable given that the target products of EUA include absolutely new chemical entities that have not been approved by any authority. On the other hand, the sole mandatory section for the EA application dossier is the clinical section, according to Article 41 of the Enforcement Regulations of the PAL. Submission of other sections, such as administrative information and prescribing information, including the origin of the medical product and its authorization status in foreign countries, chemistry, manufacturing and control, and nonclinical information, are not necessarily required at the time of the initial EA application, and their submission may be deferred for a certain time. For both H1N1 vaccines, Arepanrix and Novartis H1N1, the submitted dossiers for EA included the administrative information and prescribing information section and the main section, including abbreviated quality and nonclinical sections, and clinical overviews and summaries of domestic and overseas clinical trials in Japanese and Caucasians.^22,26 English summary reports for quality, nonclinical, and overseas clinical studies as originally submitted to the regulatory agencies in Canada and Germany were also attached. Despite the minimal requirements for EA submission stipulated by the PAL, the actual volume of dossiers submitted for these products appeared close to that of the full package required for regular submission of a new drug application in Japan. We speculate that the Japanese regulatory agency might have requested the sponsors to submit near-complete package dossiers because no such adjuvanted flu vaccine had been previously subject to regulatory review for authorization, or because these were the first cases of an EA application in Japan.

For EUA issuance, the submission package does not need to take the formal format of a new drug application in accordance with international standards for the application dossier of a marketing registration, and the FDA may accept greater flexibility in format, in consideration of the circumstances and extent of the emergency in question.^18,27 Indeed, contents recommended for inclusion in the EUA application are relatively abbreviated compared with those for the usual submission dossier (Table 1).

Approvals and Labeling Information

PAL article 14-3 stipulates that the EA confers a legal status comparable to that under the formal approval granted according to the routine legal process. Emergency approval is therefore regarded as a kind of expedited authorization mechanism to make a nonapproved product available during an emergency through the use of clinical trial data that were derived for regulatory review in other advanced countries (Table 1). In this sense, the regulatory stance on EA appears similar to that for a different formal regulatory scheme under which foreign clinical trial data are used for regular Japanese marketing authorization through the “bridging strategy” described in the ICH E5 “Ethnic Factors in the Acceptability of Foreign Clinical Data” guideline. ²⁸ By conducting “bridging studies” to show the clinical equivalence of trial results between Japanese and non-Asians, pharmaceutical companies can omit a number of domestic clinical trials in Japanese subjects during development in Japan and can proceed to the speedy submission of new drug applications for importing medicinal products.

In contrast, EUA is “a temporary measure for making a product available during an emergency” ³ and is not intended to confer any kind of formal marketing authorization. It therefore represents a quite different regulatory scheme with lower evidentiary standards than are required for formal marketing authorization in the United States. ³ The legal status of EUA products remains “investigational” during the declared emergency, in contrast to the EA products described above.

The EA labeling formats of the H1N1 vaccines appeared similar to the package inserts for products under normal marketing authorization, apart from being marked with “Emergency Approval Product,”^29,30 as was the Fact Sheet for Healthcare Providers for the peramivir EUA. ³¹ Of note, for both the EA of adjuvanted H1N1 vaccines in Japan and the EUA of peramivir in the United States, clinical experience in pediatric populations was insufficient or lacking at the time of authorization. Authorization for pediatric use was nevertheless granted in both cases in recognition of the clinical significance of administration to pediatric subjects during the pandemic.^3,21,32 In the case of the EUA for peramivir, given the complete lack of available pediatric data (Table 4), the establishment of recommended doses with a model-based approach and the provision of pediatric dosing information were quite challenging. ³³ In contrast, the EA for H1N1 vaccines in Japan included pediatric usage without posing any specific conditions.^29,30 Domestic clinical trials for EA vaccines were still ongoing in a relatively small pediatric population, and only the interim results were available for regulatory review at the time the emergency authorizations were granted.^21,32 Interestingly, the MHLW invited public comment on the EA of the H1N1 vaccines until 4 days prior to the granting of the emergency approval. This late comment period was due to public concern over the safety of the first-ever approved adjuvanted vaccines in Japan and indicated the heightened concern of the Japanese government about public criticism of the first-ever emergency approval. ³⁴

Distribution and Postauthorization Requirements

Although EA vaccines could have been subject to special postauthorization requirements, vaccination with these vaccines was handled no differently than with other domestic H1N1 vaccines without adjuvant throughout the entire mass vaccination program for 2009 H1N1 influenza in Japan, which were approved according to the routine process. ³⁵ The MHLW, the organization responsible for the procurement and distribution of vaccines for this national program, contracted with the vaccine suppliers to allow the central purchasing of a sufficient quantity of domestic H1N1 and imported EA vaccines. The MHLW provided an implementation plan and procedures for the distribution and prioritized administration of the H1N1 vaccines, including the EA products, to vaccine suppliers, wholesalers, and end-user medical institutions. H1N1 vaccination itself was not mandatory, and, consistent with standard vaccination practice in Japan, subjects were required to provide written informed consent for vaccination and pay a fee (Table 4). A pamphlet for the public published by the MHLW explaining vaccination with novel influenza vaccines stated that these adjuvanted vaccines were “imported” vaccines, but it did not emphasize the fact that they were approved under the EA mechanism, presumably due to major concerns on the part of the regulatory agency regarding the possibility of excessive reaction and worry among the public arising from their knowledge of the differences in the regulatory mechanism for approval. ³⁶ Further, the national reporting scheme for adverse reactions to the H1N1 vaccines in the vaccination program covered both the domestic H1N1 vaccine products and EA vaccines under identical procedures.

For the peramivir EUA, the target population was expected to be rather small and its authorization status was acknowledged as being based on lower evidentiary standards, in contrast to the Japanese EA vaccines. Therefore, the US Centers for Disease Control and Prevention (CDC) was asked under the EUA to implement a strong management system for its distribution and administration and, to this end, constructed a web-based infrastructure to manage the distribution of the product from CDC to medical institutions at substantial taxpayer expense.^3,37 HHS purchased 10,000 courses of peramivir from BioCryst, and CDC had BioCryst air-courier each course of treatment to the requesting hospital. ³⁸ In total, more than 1,200 patients were treated with peramivir under the EUA before its termination in July 2010.^39,40 The peramivir EUA required healthcare professionals to inform patients of treatment alternatives to peramivir and that they were to receive an unapproved product under EUA and to report medication errors and specific adverse reactions. ³¹ Of note, the EUA authority itself does not stipulate informed consent for administration.

Termination of Emergency Authorization

Termination of a declared state of public health emergency was not provided for in either the PAL or any other legislation (Table 1). Consequently, revocation of an EA was not stipulated anywhere in Japanese law but rather was determined at the discretion of the government. The EAs for these H1N1 vaccines were voluntarily withdrawn by the supply companies in consequence of an administrative notification of the MHLW novel influenza task force that, as of March 31, 2011, swine A/H1N1 influenza was no longer legally specified as a “new” pandemic influenza (Table 2). ⁴¹ This meant that the novel A/H1N1 influenza could be subsequently handled as a usual seasonal influenza and that the associated public health emergency no longer existed. Clinical use of the imported EA vaccines consequently ceased from the date of notification, and these vaccines are currently no longer available in the Japanese market, despite ample clinical experience of good safety accumulated from more than 5,000 doses of Arepanrix H1N1 and 2,500 of Novartis H1N1 vaccine. ⁴²

In the United States, Section 564 of the FD&C Act stipulates that the emergency declaration for EUA terminates 1 year after its issuance or earlier. The associated EUA is in effect during the declared emergency. The FDA commissioner made notification that the peramivir EUA terminated on June 23, 2010, and healthcare professionals were no longer able to access peramivir from CDC after this date. ⁴³ Nevertheless, the development of peramivir is ongoing as of July 2012 and is at the Phase III study stage in patients hospitalized with acute influenza (Table 4). ⁴⁴

Regulatory Challenges and Lessons Learned

After the flu pandemic was over, the Japanese cabinet secretariat postulated the necessity of new legislation for countermeasures to an emergency with public health effects due to natural contagious agents, in consideration of the non–legally binding processes and rather haphazard countermeasures taken in response to the pandemic. It was pointed out that new legislation should include preparedness; a framework for partnership with localities, the private sector, and foreign countries in response to a pandemic; and emergency measures aimed at maintaining a national social and economic framework and at stopping or mitigating an outbreak. ⁴⁵ The new Act on Special Measures Concerning Countermeasures Against Novel Influenza or the Like was enacted by the Japanese Diet and promulgated on May 11, 2012. After coming into effect within a year of promulgation, this act will provide the first-ever legal authority for the government to declare a public health emergency due to an emerging infectious disease, and to implement enforceable countermeasures in response to such an emergency in Japan.

The Japanese EA law may have compromised Japan's opportunity to use promising products developed by domestic technologies during the pandemic. In fact, the sponsor of peramivir in Japan, Shionogi & Co., Ltd., announced in July 2009 its positive efficacy and safety data from a pivotal phase III study in patients with uncomplicated flu in several Asian countries, which was completed in April 2009, and from a phase III study in 42 Japanese flu patients at high risk due to complicated uncontrolled diabetes, respiratory failure, or treatment with immunosuppressive agents.^46,47 The new drug application for peramivir IV products in Japan was filed on October 30, 2009, and designated for fast-track review, and the world-first marketing approval was swiftly granted on January 27, 2010. ⁴⁸ Nonetheless, Japan would have benefited more if it had allowed emergency use of the as-yet unapproved peramivir during the most active period of the pandemic, between October and December 2009, because ample and concrete clinical evidence was available for hypothetical emergency use authorization before the pandemic period. The impact of serious health hazards due to the pandemic in Japan appeared minor compared with other countries; only 199 Japanese patients died of 2009 H1N1 influenza infection, and a lower mortality rate in Japanese patients compared with those from the United States and other countries was reported.^49,50 Even though the expected decrease in deaths during the pandemic due to hypothetical peramivir emergency use was small because of its low mortality, the reported high proportion of critically ill patients and resulting burden in these patients might be sufficient to justify its emergency use. ⁵¹ Through these adjuvanted vaccine EA cases, the Japanese authority appeared to be proven rather conservative in ensuring as much safety and efficacy as possible before permitting the EA, as it required “not-necessarily-mandatory” domestic clinical trials. This conservative attitude may be ascribed to the nature of the products in the EA case—namely, to adjuvanted vaccines—but will likely jeopardize the speed of EA processing in response to the next public health emergency.

Further, institutionalization of US-like emergency use of unapproved products appears impermissible under such a culture. Granting emergency use authorization for investigational products must be accompanied by arduous discussion on the potential benefit-risk balance and uncertainty. In the case of peramivir, however, sufficient time and data were available between the completion of peramivir registration trials and the start of the pandemic in Japan to allow the regulatory authority to make the decision to undertake the process and to allow the sponsor to prepare for emergency use. Although public willingness to accept unapproved medications might also be of concern, ⁵² a degree of uncertainty in emergency use of yet-to-be approved drugs may be acceptable in the face of serious or life-threatening harms posed by a disease. The current EA, which waives authority for the emergency use of investigational products, therefore appears to warrant amendment to ensure its effective application. ⁵³

With regard to the EUA for peramivir in the United States, substantial concern was expressed concerning ensuring timely access to the drug for eligible patients, monitoring of treated patients, and collection of reliable data on clinical use under EUA.^40,54 Because peramivir was handled as an “unapproved” product and distributed by CDC on single request by a physician for a single patient, it did not support the stocking of inventory at hospital pharmacies, which inherently delayed administration to patients who required it urgently. This was in contrast to the Japanese EA system to grant formal approval and allow distribution via the normal distribution network.

Next, because of insufficient clinical experience, the provision of presumed dose information for adult and pediatric patients with impaired renal function using modeling and simulation was resource-consuming for both the regulatory authority and manufacturer.^33,37 Further, despite clinical experience with a large number of critically ill patients and pediatric patients, which could have been accumulated outside of the framework of IND registration trials, the data from these patients under the EUA were not collected and the opportunity to use them in further drug development was lost; even the number of patients treated under the EUA is not accurately known. ⁵⁴

Potential means of addressing these significant issues might include controlled formal authorization of unapproved products for a strictly limited disease population and limited period, similar to the scheme for adaptive licensing.^55,56 A complete surveillance program covering all users, with a registration system for patients and healthcare professionals following a controlled launch, is a type of post-marketing requirement and risk minimization method frequently used in the Japanese regulatory system and may work well in ensuring adequate patient eligibility screening and the prospective collection of complete data. Permitting distribution via a registered distribution network under temporary formal authorization would enable stocking of the drug at registered medical institutions for immediate use, which in turn might release concerned regulatory authorities from the burden of distribution and allow them to focus on monitoring drug use under temporary formal authorization. Given the extreme limitations placed on resources during disaster situations, however, the practicality of this proposal requires further scrutiny.

A major limitation in this article warrants mention. Because this comparison of emergency authorizations between the 2 countries was based on the available cases, some of the differences in the authorizations would be ascribable to differences in the products themselves—namely, between vaccine and drug—and in their administration route. In particular, vaccines are administered to healthy people, and acceptable standards of risk are therefore substantially lower than those for therapeutic agents for patients in life-threatening conditions. This difference might have inclined the Japanese government to take a more conservative approach in the EA for adjuvanted vaccines.

Conclusions

Although the US and Japanese emergency authorization schemes for unapproved medical products share the same objective, the regulatory stances of the 2 governments fundamentally differ with regard to authorization status and the target products they cover. The Japanese EA is stipulated as a type of legal authorization status, with special consideration for the submission data package and postlaunch requirements and is only applicable to products that have been approved in other advanced counties. This contrasts with the US EUA stance, which may include products under a more experimental status, such as investigational products. Assuming a public health emergency that cannot be overcome by emergency use of medical agents and devices approved in other countries, it seems prudent to provide the Japanese regulatory system with the option to use strictly “investigational” products, as is permitted under the US EUA.

However, securing timely access to investigational products under EUA and complete data collection on their use is challenging, as was seen with the US peramivir case. Further, as labeling information is subject to change during clinical development, a second regulatory challenge to the emergency authorization of absolutely unapproved products is the provision of posology information without sufficient experience in clinical trials. Introduction of an adaptive licensing approach to help address these difficult regulatory challenges may be worthwhile and warrants further discussion.