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MD Reviewers' Role in the New Anticancer Drug Approval Process in the Newly Established Japanese Regulatory Agency, PMDEC (Pharmaceuticals and Medical Devices Evaluation Center)
Reform of Japanese NDA Review System
NDA Approval Process in Japan
Roles of MD Reviewer
Perspective on Anticancer Drug Approval Process
1. Approval requirements
2. Off-label Usage
3. Oral Anticancer Drugs
4. Non-cytotoxic Anticancer Drugs
Proposal to Clinicians
References
MD Reviewers' Role in the New Anticancer Drug Approval Process in the Newly Established Japanese Regulatory Agency, PMDEC (Pharmaceuticals and Medical Devices Evaluation Center)
Reform of Japanese NDA Review System
The Japanese Ministry of Health and Welfare (MHW) has amended the Pharmaceutical Affairs Law and related laws and is reforming its New Drug Application (NDA) review system on the basis of the report by the Committee for Drug Safety Ensuring Measures (1). One of the most important changes in the review system was the establishment of Pharmaceuticals and Medical Devices Evaluation Center [PMDEC (pee-em-dec), so-called `Review Center' or `Shinsa Center'] on July 1, 1997, under the National Institute of Health Sciences (NIHS), as a research institute under MHW.
Until recently, there has been no MD reviewer [corresponding to medical officer in the US Food and Drug Administration (FDA) (2)] in the Japanese regulatory authorities for new drug approval, hence its approval process has relied heavily on pharmacists or those with PharmD or PhD degrees. However, as of October 1, 1997, two physicians were recruited based as part of the ongoing reform of the Japanese NDA review system (1). As of September 1, 1998, there are now three MD reviewers with adequate clinical experience and three other MD officers with ample administrative experience within MHW, among the approximately 60 member staff at PMDEC.
NDA Approval Process in Japan
The Evaluation and Licensing Division at MHW, along with PMDEC and the Organization for Pharmaceutical Safety and Research (so-called `Drug Organization' or `Kiko') are now jointly responsible for drug approval (Fig. 1) and re-examination and re-evaluation applications. Before the reform, NDA reviews of anticancer drug were conducted largely by the Central Pharmaceutical Affairs Council (CPAC), especially by the Subcommittee on Anticancer Drugs. (Although comparable in purpose to the US Oncology Drug Advisory Committee (2), consisting mainly of physicians, this subcommittee includes several preclinical pharmacologists, toxicologists and a biostatistician but no consumer-nominated representative or patient representative. The reorganization of CPAC is in progress and every subcommittee is scheduled to be repealed by April 2000). After the reform, the Evaluation and Licensing Division of MHW took charge of administrative matters, such as making final decisions on approvals, developing guidelines for preclinical testing or clinical trials, coordinating international affairs, formulating regulatory instructions; the Drug Organization became responsible for conducting a compliance review of all documents, submitted by a sponsor (company) including NDA, and for carrying out a GCP (Good Clinical Practice) inspection during the early part of the review process; PMDEC assumed the pivotal and practical role for reviewing NDAs and this process is becoming independent of CPAC. An important development has been that several experts in clinical pharmacology and in biostatistics have joined PMDEC. Each NDA review is performed by a review team, consitsting of three to four pharmacists (some of them have a PharmD or PhD degree), one toxicologist, one biostatistician and one MD reviewer. The PMDEC evaluation report has now become as important as the CPAC evaluation report in making the final decisions in new drug approvals. For new drugs approved after October 1996, the CPAC evaluation reports on the drug, the lists of instructions and questions from relevant CPAC meetings (subcommittee, committee and executive committee) and the list of documents submitted with the NDA have been made public. Furthermore, both PMDEC evaluation reports and GCP inspection reports written by the Drug Organization will be made public in the near future.
Figure 1. Overview of the Japanese New Drug Application Review System. PMDEC, along with the Evaluation and Licensing Division at MHW and the Drug Organization, are jointly responsible for drug approval. The CPAC consists of 18 committees (including one executive committee) and 59 subcommittees as of November 4, 1997. The Committee on Drugs and the Subcommittee on Anticancer Drugs are practically responsible for the new anticancer drug approval process. The Drug Organization is legally authorized by the Minister of Health and Welfare, whose character and functions are stipulated in the Law Concerning the Organization for Drug ADR Relief, R&D Promotion and Products Review. Most of the personnel within the Drug Organization are derived from government offices, primarily MHW (1). The position of MD reviewer is a multi-faceted role. (i) They are responsible for reviewing application documents including `Gai-yo' (3) [the Gai-yo is similar to the US NDA's application summary, ISE (integrated summary of efficacy) and part of ISS (integrated summary of safety), and should include detailed technical sections on the composition, manufacture and specification of the drug substance and the drug product; toxicology; non-clinical pharmacology; human pharmacokinetics and bioavailability; and clinical sections including statistical descriptions (3)], with special attention to the section on clinical trials. A common misunderstanding exists that the reviewer only checks the sentences, tables and figures of published articles, whose names are later made public. In fact, MD reviewers thoroughly check the written clinical trial reports prepared specifically for NDA reviews by sponsors. Furthermore, MD reviewers evaluate each patient's case report form, X-ray/computed tomography films, ECG or other materials, if necessary. (ii) Reviewers evaluate severe ADR (adverse drug reaction) reports regarding ongoing clinical trials of all INDs (Investigational New Drugs) and reviewers check about 150-200 ADR reports each week. (iii) Reviewers conduct GCP inspections at domestic sites, especially when serious fraud is suspected, or foreign countries. (iv) Reviewers sometimes comment on clinical trial protocols as follows. All clinical trial notifications with protocols attached are submitted to PMDEC before the trial starts. MD reviewers comment on the safety profiles of some protocols. When an IND is to be proposed for administration to humans for the first time in Japan, a sponsor must submit a `First Clinical Trial Notification' 30 days in advance of the trial start date. In this case, the Drug Organization primarily reviews the notification's contents (1). (v) Reviewers cooperate with the Drug Organization's `Clinical Trial Advice', which is a system established on April 1, 1997, that resembles the FDA system. Four kinds of advice are now provided: Pre-First Clinical Trial Notification advice, End-of-Phase II advice, Pre-Approval Application advice and Individual advice; the first three kinds of advice correspond to Pre-IND meeting, End-of-Phase II meeting and Pre-NDA meeting, respectively, at the FDA. Almost 1 year has passed since MD reviewers first joined the Japanese NDA review process. In this time, I have recognized several problems in the approval and clinical trials process for anticancer drugs. As a medical oncologist, some of my concerns are as follows. In contrast to the FDA (4), there is no open-to-public detailed criteria for anticancer drug approval in Japan. However, there exists a guideline describing how to conduct clinical trials for an anticancer drug NDA (5), but it is out-of-date. We are now trying to develop the new Japanese approval criteria. For that process, I think it necessary to consider the recent change in FDA approval criteria for anticancer drugs, which is similar to, but not identical with, our traditional stance (6,7). FDA adopted `accelerated approval' by which the anticancer drug is approved if it demonstrates objective tumor shrinkage, including partial response, and it is intended to be used for patients with refractory malignant disease or for those who have no adequate alternative. Irinotecan (for refractory colorectal cancer; US approval date June 14, 1996) and Docetaxel (for locally advanced or metastatic breast cancer which has progressed during anthracycline-based therapy; US approval date May 14, 1996) are two of the examples of drugs approved by this new criterion. In the case of accelerated approval, studies confirming a clinical benefit (increased patient survival, decreased recurrence rate, increased disease-free interval and/or improved quality of life) should be completed soon after approval. Although similar criteria have been adopted for Japanese NDA approval for a long period of time, it should be noted that post-approval restriction has not been as rigid; the quality of post-approval studies has been poor and it has been difficult to collect `scientifically sound' clinical data. The recent legal obligation of GPMSP (Good Post-Marketing Surveillance Practice) will improve the quality of post-approval studies conducted by sponsors (8). In any case, we have to learn more about the merits and demerits of the FDA's accelerated approval and I am now seeking a possible `two-stage approval process' for anticancer drugs. For many years, this has been a serious problems not only in Japan, but also in the USA (9,10). However, the FDA shows a more flexible stand in contrast to MHW for off-label use. One example of their flexibility is their recently proposed regulation describing `scientifically sound' criteria for off-label promotions by the company (11). Although the newly implemented Notification of ICH-E5 (International Conference on Harmonization-Efficacy 5; Ethnic Factors in Acceptability of Foreign Clinical Data) describes how to use foreign clinical data for NDA in Japan (12), several good anticancer drugs still are not approved and several marketed anticancer drugs do not have adequate indications on their labelings (10,13). We are, therefore, seeking possible approval of supplemental indications by using foreign data from the NDA submitted to the regulatory agencies in the USA or the European Union or by using published articles in internationally recognized peer-reviewed academic journals. Furthermore, we are trying to establish detailed in-house criteria to use/evaluate foreign clinical data in both bridging study protocol designs and NDA for anticancer drugs. Although oral anticancer drugs are receiving more attention than ever in foreign countries (14), the situation in Japan is different. Here many oral anticancer drugs are marketed and are easily prescribed in an adjuvant setting without clear and reliable evidence of clinical benefit. Some of these reasons are that there has been no tradition of using evidence-based medicine. We are not accustomed to the decision-making process for determining what the standard regimen is for first choice, for second choice, and to prescribing drugs with marked benefit but several side-effects, but we are accustomed to prescribing drugs with little benefit and almost no side-effects. We are cautious about NDAs for those drugs and are seeking possible re-evaluation of older oral anticancer drugs. Increasingly MD reviewers will be required to advise on how to conduct clinical trials and how to prepare an NDA for novel anticancer drugs such as angiogenesis inhibitors (15), metastasis inhibitors (16) and so forth. Guidelines for these matters are needed. In solving the aforementioned problems, the regulatory agency needs more help and advice from general practitioners, academic physicians, members of CPAC and professional medical and scientific societies. Collaboration between the regulatory agency and academic medicine/national centers is a routine phenomenon in the USA (17). Therefore, we, MD reviewers, encourage Japanese clinicians to take more interest in the how and the why of the IND that they are testing and that will be approved for use in clinics and wards, rather than paying so much attention to the price of new drugs or to their own profits. Since April 1997, when the legal obligation of GCP (so-called `new GCP') was imposed (18), medical professionals began paying attention only to the economic part or restrictive nature of GCP. However, now is the appropriate time for clinicians to recognize and to advocate the importance of patient-oriented research and clinical trials. Clinical trials for NDA (so-called `Chi-ken') is only one small part of a broad spectrum of clinical trials and `Chi-ken' no longer is the sole means for obtaining funds for basic or translational research using human-derived samples, nor are reports published in non-peer-reviewed academic journals acceptable. Concurrent with NDA review system reform, Japanese clinicians' perceptions of clinical trials and research needs to change. However, we are not alone in this struggle: the USA is also contending with the same problems regarding clinical research. (19).
Roles of MD Reviewer
Perspective on Anticancer Drug Approval Process
1. Approval requirements
2. Off-label Usage
3. Oral Anticancer Drugs
4. Non-cytotoxic Anticancer Drugs
Proposal to Clinicians
References
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