Japanese Journal of Clinical Oncology

Novel Study Designs

Several alternatives to the traditional phase I and II study designs have been developed. Some of the more promising designs were briefly discussed, as were several important considerations in designing and executing multicenter phase II and III studies.

Traditional dose escalation schemes have been criticized for being overly conservative in treating too many patients at ineffective doses, for requiring too much time to complete, and for being susceptible to bias in the determination of the maximally tolerated dose. Alternatives to the traditional design have included the pharmacokinetically guided dose escalation design, the continual reassessment method and its variants, the use of single-patient cohorts and dose doubling until biologic activity is observed, and various other hybrid approaches. The National Cancer Center Hospital, National Cancer Center Hospital East and Kinki University have fulfilled the criteria for being able to conduct phase I clinical trials, and several important publications have emerged from these centers.

Two popular phase II designs in the US are the so-called `two-stage' design and the randomized phase II design. There are many variants of the two-stage design, which allows a single early look in order to decide whether to continue or terminate the study. This design is best used to estimate the response rate. The randomized phase II study, in contrast, is intended to compare different agents in similar patient populations in order to prioritize one for further development. They are, however, generally smaller and less powerful than phase III studies, and treatment comparisons from a randomized phase II study cannot be substituted for efficacy outcomes from a well-conducted, well-designed phase III study.

Investigators and regulatory authorities in both the United States and Japan are struggling with the question of how to best develop cytostatic agents. Investigations of new drugs targeting such mechanisms have become increasingly popular in both countries. Several excellent discussions focused on issues such as: the question of whether a phase I study should be designed to determine the maximally tolerated dose or the optimum biologic dose, how to evaluate the relationship between pharmacologic target inhibition and antitumor activity, and what endpoints are appropriate in these early stage (generally single arm) studies. Issues in designing phase III studies include choosing the appropriate endpoint, whether such agents are better suited to adjuvant therapy or to treatment of established and macroscopic disease, and what study sizes are both reasonable and appropriate.

Regulatory Issues and the Use of Foreign Data

The structure of the drug regulation in Japan has recently changed. Much more responsibility for review of drug applications, previously conducted by the Central Pharmaceutical Affairs Committee (CPAC), has been assumed by the OPSR, PMDEC, and the Evaluation and Licensing Branch of the MHW. The introduction of physician reviewers with clinical trials experience into the Japanese drug regulatory structure has brought about an increased emphasis on the scientific aspects of anticancer drug development. FDA procedures for granting accelerated approval, the use of outside advisory committees, and FDA perspectives on the nature of evidence required for new drug approval were discussed.

Much discussion focused on the implementation of internationally accepted (ICH) guidelines for accepting foreign data by regulatory authorities. These guidelines put forth the need for so-called `bridging studies' to address the impact of possible intrinsic and extrinsic physiologic and ethnic factors on safety, efficacy, and pharmacokinetics. `Intrinsic factors' include physiologic factors such as age, vital organ function, comorbid conditions, receptor sensitivity, pharmacokinetic factors, and genetic polymorphisms that might influence the safety and/or efficacy of a drug in Japanese patients. `Extrinsic factors' generally include ethnic factors such as cultural habits and attitudes toward illness, educational and socioeconomic factors, and medical practice that might similarly affect the safety and/or efficacy in Japanese patients relative to US and/or European patients.

The MHW currently requires that phase I studies of new agents be conducted in Japan; however, foreign clinical data can be used to reduce the number of escalation steps in Japanese studies. Subsequently, two pivotal phase II studies are generally needed for approval in Japan. However, if the results of one late phase II Japanese study are similar to those of phase II studies conducted outside Japan, then a foreign study can be used as one of the two pivotal phase II studies. Although these policies seem to be based on concern that differences between the Japanese and Western populations could result in important differences in safety and/or efficacy, this hypothesis was questioned by several participants.

One issue that has concerned the FDA in using foreign data is the extent to which medical practice patterns can be extrapolated to the US population. This is particularly important when schedule-dependent differences in drug behavior can be anticipated. For instance, showing that the comparator in an NDA package, whether it is a concurrently randomized control arm or a historical control, provides safety and efficacy outcomes similar to standard US practice may be an important issue for certain NDAs. In cases where a new treatment is being compared to a treatment that is not standard US practice for that disease indication, FDA may request that the sponsor include in the NDA package a study showing similar outcomes between the comparison arm for the new treatment and a standard US treatment.

Public Perceptions and Education

Many of the speakers and discussants cited the general lack of appreciation by the public and by patients of the importance of clinical trials. Unlike the situation in the United States, participation in clinical trials by physicians in Japan reflects negatively on the physician. This attitude has complex social and cultural roots, but the effect is to relegate the reporting to the general public of important research findings to second-rate and third-rate newspapers, according to one speaker. Other speakers pointed out that the failure of the public to properly appreciate the importance of clinical research has led to a failure of public leadership in providing necessary funding and resource allocations to institutions engaged in clinical research. Several speakers advocated the creation of a foundation to publicize and manage government-sponsored clinical trials.

Several speakers stressed the importance of educating the public about the importance of clinical trials and of publicizing ongoing clinical trials to the public. The NCI has an Internet-based patient education program, the CancerTrials website, which provides general information about clinical trials, different diseases, and specific clinical trials that are available to patients. Several speakers, particularly those from industry, stressed the critical need for educating nurses, physicians, and clinical research associates not only in the importance of clinical trials, but also in the process and procedures for assuring high-quality clinical trials. Dr Ohashi, a leading educator and statistician at the University of Tokyo, presented his plans for creating such educational programs.

Truth Telling and Informed Consent

The related issues of telling patients the truth about their diagnosis and of obtaining informed consent are important and have far-reaching implications both for routine medical practice and for enrolment in clinical trials. A recent joint NCI-FDA initiative to review the elements of the informed consent process was presented. A broad-based working group, after distilling the elements of the informed consent process to its essentials, generally recommended that the informed consent: (1) clearly and simply explain the purpose of the study; (2) relate the investigational treatment to, and distinguish it from, the standard of care; (3) avoid overstating the potential benefit of the investigational treatment; (4) keep the focus on the physical and non-physical risks associated with the investigational treatment as a whole; and (5) broadly estimate the likelihood of the risks associated with the investigational treatment. The group further recommended that the informed consent process provide supplementary and readable documents, that it maintain cultural sensitivity, and that it extend throughout the lifetime of the study. The importance of continuing to apprise patients of relevant new information using effective communication techniques in a timely manner was emphasized by requiring that this process be incorporated into all consent procedures. Specific recommendations for making informed consent documents used in the US clearer, more informative, and less bulky while implementing these recommendations were also discussed.

Support and `Infrastructure'

The US has extensive networks of centers with expertise in clinical trials, linked together into nine independent, NCI-sponsored, `cooperative clinical trials groups' which are important for conducting large-scale clinical trials in an efficient, timely, and well-executed manner. Each cooperative group has well-developed sets of operating and quality-assurance/quality-control policies and procedures and is responsible for designing, executing, and implementing group-wide studies. The central group organizations are also responsible for maintaining the necessary liaisons and communications with the appropriate regulatory and funding agencies. Although the cooperative groups receive US government funding, they also have the ability to contract with pharmaceutical companies to conduct studies on their behalf. The Japan Cooperative Oncology Group (JCOG) and the Japan Adult Leukemia Study Group (JALSG) are currently the only government-funded cooperative groups in Japan. They are not able to contract with pharmaceutical companies at present.

Critical to the operations of any major clinical trials center are the clinical research associates and data managers. Such individuals assist the principal investigators and study coordinators at the different study sites to ensure that the data are entered properly, that appropriate study monitoring procedures are followed, and that the study protocol is strictly adhered to.

Several important issues facing JCOG and JALSG that must be addressed in order for these organizations to develop and contribute significantly to clinical trials in Japan were identified by key speakers. These include the need to rigorously assure the credentials of institutions and investigators to participate in clinical trials conducted by these groups, the critical lack of human resources (specifically clinical research associates, data managers, biostatisticians, and medical oncologists), and a need for increased direct governmental support of cooperative group organizations. JCOG and JALSG have both identified areas that they themselves are working to improve. These include developing auditing mechanisms and contingency provisions for encouraging institutions to increase accrual to ongoing clinical trials, shifting the emphasis from early phase trials to the larger phase III studies in which the power of the cooperative group's resources can be used more effectively, instituting site visits to audit records and ensure protocol compliance and data quality, and proactively approaching the pharmaceutical industry to seek out industry-sponsored trials. The NCI quality assurance auditing procedures were reviewed and discussed extensively. These procedures require regular on-site visits by teams of investigators, quality-assurance experts, and clinical research associates to audit all aspects of trial conduct at the site. These include the IRB reviews, records of informed consent, and records of drug administration and disposition, eligibility, treatment data, adverse events data, and efficacy assessment data.

On a different level, the lack of support afforded to clinical research by the academic structure in Japan was a frequently cited problem impeding the development of an effective clinical trials infrastructure. Many speakers emphasized that creating and maintaining an efficient and reputable clinical trials organization requires a core team of dedicated professionals that can perform the necessary medical, nursing, pharmacy, administrative, and data management tasks. Other speakers pointed out that, in Japan, the lack of significant pharmacy and nursing support personnel, and a heavy emphasis on basic research in the universities leads to a drain on investigator time, energy, and a lack of the financial and human resources needed to conduct high-quality clinical research in all but a very few exceptional institutions.

The Role of the Surgical Oncologist

Since a large amount of cancer patient care is provided by surgeons, it is important to understand how medical and surgical oncologists can collaborate in clinical trials. In fact, the interests of both specialties overlap in many areas of research: for instance, certain surgical questions (such as the best operative approach to treat or stage a certain disease, whether or not surgery should be performed, or whether certain intraoperative interventions are useful), whether adjuvant or neo-adjuvant therapy is useful for certain disease settings, and certain perioperative questions (such as immediate postoperative chemotherapy in treatment of colon cancer or the value of prophylactic mastectomy for prevention of breast cancer in patients with BRCA 1 and 2 mutations). This commonality of interest is manifested in the use of similar endpoints in surgical and medical oncology trials, such as overall survival, disease recurrence, and quality of life. There are, however, unique aspects to surgical trials, such as the fact that there is no equivalent to the phase I dose escalation trial of a new drug. Rather, feasibility, adverse effects, and efficacy are evaluated in phase I/II and comparisons with accepted standards are undertaken in phase III. Unlike trials of a new drug, the skill of the individual surgeon is an important potential variable affecting the outcome of study, blinding of the arms in a randomized trial is impossible, and placebo controls are also impossible. In surgical trials, there is a well-established appreciation of the need for quality of life evaluations in assessing the effects of surgical sequelae. This is an area which is evolving rapidly in medical oncology trials, and may be one in which medical and surgical oncologists can collaborate in refining the current methodologies.

Summary and Conclusions

The ultimate goal of this workshop is to make effective anticancer therapies available to Japanese patients. Dr Nagahiro Saijo, of the National Cancer Center Hospital, summarized the meeting and identified important steps to the future.

After reviewing the US accelerated approval mechanism and the changes in Japanese regulatory agencies, he concluded that making more effective drug therapy available more quickly requires that investigators create well-documented protocols, that these protocols be quickly reviewed by the OPSR, and that study sites quickly accrue patients. Following completion of the required studies, industry sponsors must put together and submit non-defective NDAs, and the PMDEC must quickly and thoroughly evaluate the application and take appropriate action. He urged that the US model of including an open public forum for discussion and evaluation by advisory committees and of disseminating publicly available criteria for anticancer drug approval be adopted by MHW.

Accelerated dose escalation study designs should be more widely adopted and encouraged, especially for development of cytostatic agents, and the development of resources to support these early phase studies should be expanded. For later phase studies, the cooperative group mechanism is a powerful tool for designing studies and accruing patients. However, the quality assurance monitoring and support, both financial and human, of these groups is poor and must be improved. Increased funding for clinical trials, increases in the numbers of medical oncologists, biostatisticians, data managers, and clinical research associates, and the development of strong quality assurance and quality control guidelines, are essential. Expanding the pool of clinical investigators in Japan is an urgent issue.

The popularity of cytostatic drugs as a new therapeutic approach will require innovative thinking to design appropriately powered studies that can both be completed using a reasonable amount of resources and provide useful answers to both mechanistic and clinical questions.

However, the overarching and most critical needs are in education. The public must be educated about the importance of clinical research through print and broadcast media, Internet and computer-based information, and by making information on ongoing clinical trials available by telephone. Patients must be educated about the importance of clinical research through more specialized efforts using these same avenues. Moreover, the informed consent concept must be fully embraced and a comprehensive process for informing patients must be developed. Finally, the medical and scientific community must be educated about the importance of clinical research. The imbalance in perceived importance between basic and clinical research must be corrected. Physicians and scientists must be taught as part of their basic education that important clinical evidence can only be obtained through well-controlled, well-conducted clinical trials, and physicians must be encouraged to participate in such trials as principal investigators or study coordinators. Clinical research must be recognized as an important scientific inquiry and deserving clinical investigators must be rewarded with promotion and increased support. The practice of diverting funds for clinical research into basic and translational research must be halted, and all funds provided for clinical trials must be used to support the clinical research program.

Dr Saijo pointed out that Japan has a long and proud history of overcoming obstacles and meeting new challenges. For some time, Japan has suffered from a limited interest in high-quality clinical research. The Japanese drug regulatory authorities and several leading members of the oncology community have now recognized the need for change and are beginning the process of implementing meaningful reforms. However, such efforts will succeed only if the general medical community also steps forward to meet this challenge and supports these initiatives.

Japan

Kaoru Abe, National Cancer Center

Yutaka Ariyoshi, Aichi Prefectural Hospital

Yasuhiro Fujiwara, Pharmaceuticals and Medical Devices Evaluation Center

Haruhiko Fukuda, National Cancer Center Research Institute

Masahiro Fukuoka, Kinki University

Yoshinobu Hirayama, Organization for Pharmaceutical Safety and Research

Tatsuhiko Ichiki, Rhone-Poulenc Rorer Japan, Inc.

Tomowo Kobayashi, Sankyo Co., Ltd

Tatsuo Kurokawa, Organization for Pharmaceutical Safety and Research

Hironobu Minami, National Cancer Center Hospital East

Yutaka Natsumeda, Banyu Pharmaceutical Co., Ltd

Susumu Nishimura, Banyu Pharmaceutical Co., Ltd

Makoto Ogawa, Aichi Cancer Center

Yasuo Ohashi, The University of Tokyo

Ryuzo Ohno, Hamamatsu University

Nagahiro Saijo, National Center Center Hospital

Yasutsuna Sasaki, National Cancer Center Hospital East

Mitsuo Sasako, National Cancer Center Hospital

Kiyoshi Terada, Yakult Honsha Co., Ltd

Takashi Tsuruo, The University of Tokyo

Toru Watanabe, National Cancer Center Hospital

Shigeaki Yoshida, National Cancer Center Hospital East

US

Michaele C. Christian, Cancer Therapy Evaluation Program

Gary M. Clark, Cancer Therapy and Research Center

Charles A. Coltman, Jr, Cancer Therapy and Research Center

John J. Crowley, Fred Hutchinson Cancer Research Center

Ken Kobayashi, Food and Drug Administration

Kim Lyerly, Duke University

Steven Piantadosi, Johns Hopkins Oncology Center

Eric Rowinsky, Cancer Therapy and Evaluation Center

Margaret Tempero, Eppley Cancer Center

Appendix 2. Organizing Committee

Co-Chairpersons:	Charles A. Coltman, Jr Kaoru Abe
Secretary General:	Shigeaki Yoshida Daniel D. Von Hoff Margaret Foti Masaaki Terada Nagahiro Saijo Daizo Saito Haruhiko Fukuda Atsushi Ohtsu Yasutsuna Sasaki Jiro Akagawa Taro Tsukahara Masashi Tamauchi Yasuhiro Fujiwara Susumu Nishimura Tatsuo Kurokawa

Appendix 3. Program

February 8, 1999

Japanese meeting - Current Problems in Clinical Trials in Japan

Keynote address

Problems in clinical trial in Japan - Why our move is so slow?

   Shigeaki Yoshida (National Cancer Center Hospital East)

1. Facilitation of infrastructure in clinical trials

1. Local and central data management

   Haruhiko Fukuda (National Cancer Center Research Institute)

2. The roles of research nurse/clinical research coordinator, and how to train them

   Yasushi Mochizuki (Ministry of Health and Welfare, Japan)

3. Suggestions from companies to improve clinical trials

   Thoru Uwoi (Nippon Seiyaku Kogyo Kyokai)

4. What is missing? - From the viewpoint of a clinician

   Astushi Ohtsu (National Cancer Center Hospital East)

5. Regulations to conduct clinical trials at national hospitals

   Toshiro Nakagaki (Ministry of Health and Welfare, Japan)

2. Governmental regulations to develop new drugs

1. Changes in the process for evaluation of new anticancer drugs

   Yasuhiro Fujiwara (Pharmaceuticals and Medical Devices Evaluation Center, MHW)

2. Assessment of preclinical data in new anticancer drugs

   Takashi Tsuruo (The University of Tokyo)

3. How to use foreign data for the approval of new anticancer drugs
   Yoshinobu Hirayama (Organization for Pharmaceutical Safety and Research)

4. How to use academic data from non-industrial trials to obtain the approval

   Masanori Shimoyama (Nagoya National Hospital)

5. What bridging studies can do?

   Hirofumi Hagimoto (Taiho Pharmaceutical Co., Ltd)

3. The problems awaited solution

1. Patient merit in phase I study

   Hironobu Minami (National Cancer Center Hospital East)

2. Study designs for evaluating non-cytotoxic drugs

   Kazuhiko Nakagawa (Kinki University)

3. Clinical trials of post-marketing drugs

   (a) Evaluation of drug efficacy and safety

   Kappei Tanaka (Ministry of Health and Welfare of Japan)

   (b) Who is a sponsor? A comment from NSAS trial

   Toru Watanabe (National Cancer Center Hospital)

4. Commercial merit and pitfalls to carry out clinical trials outside of Japan

   Tomowo Kobayashi (Sankyo Co., Ltd)

4. Conference Summary

   Nagahiro Saijo (National Cancer Center Hospital)

February 9, 1999

US-Japan Joint Meeting

1. Introduction

From yesterday's conference summary of the Japanese meeting

1. Clinical trials in Japan 1; New drug development

   Yasutsuna Sasaki (National Cancer Center Hospital East, Japan)

2. Clinical trials in Japan 2; Need to improve infrastructures

   Shigeaki Yoshida (National Cancer Center Hospital East, Japan)

2. New oncology drug approval

1. Anticancer drug development: an FDA perspective

   Ken Kobayashi (Food and Drug Administration, USA)

2. Improvement of evaluation process for new anticancer drugs in MHW and PMDEC in Japan

   Yasuhiro Fujiwara (Pharmaceuticals and Medical Devices Evaluation Center, MHW, Japan)

3. How to use foreign data for the approval of new anticancer drugs

   Charles A. Coltman, Jr (Cancer Therapy and Research Center, San Antonio, USA)

   Yoshinobu Hirayama (Organization for Pharmaceutical Safety and Research, Japan)

   Panel Discussion

   Panelist: Speakers and T. Ichiki (Rohne-Poulenc Rorer Japan, Inc.)

3. Infrastructure

1. SWOG: Southwest Oncology Group

   John J. Crowley (Fred Hutchinson Cancer Research Center, USA)

2. JCOG: Japan Clinical Oncology Group

   Haruhiko Fukuda (National Cancer Center Research Institute, Japan)

3. A quality assurance monitoring system: the National Cancer Institute Clinical Cooperative Oncology Group experience

   Michaele C. Christian (Cancer Therapy Evaluation Program, NCI, USA)

   Panel Discussion

   Panelist: Speakers and M. Fukuoka (Kinki University)

4. Practice and problems in early clinical trials

1. Methodology for early clinical trials

   Gary M. Clark (Cancer Therapy and Research Center, San Antonio, USA)

2. The logistics of conducting phase I and clinical evaluations of `antiproliferative' or `cytostatic agents'

   Eric Rowinsky (Cancer Therapy and Research Center, San Antonio, USA)

3. Recent progress in phase I studies in Japan

   Hironobu Minami (National Cancer Center Hospital East, Japan)

   Panel Discussion

   Panelist: Speakers, M. Tempero (Epply Cancer Center), and T. Kurokawa (Organization for Pharmaceutical Safety and Research)

February 10, 1999

US-Japan Joint Meeting

5. Study designs and biostatistics

1. Study designs in developmental clinical trials

2. Study designs in multicenter trials

   John J. Crowley (Fred Hutchinson Cancer Research Center, USA)

3. How to evaluate noncytotoxic drugs

   Margaret Tempero (Epply Cancer Center, USA)

   Panel Discussion

   Panelist: Speakers and H. Fukuda (NCCRI)

6. Industry-sponsored Trials

1. What should we do after ICH-GCP? - Experiences on CPT-11

   Kiyoshi Terada (Yakult Co., Ltd, Japan)

2. Japanese experience of drug development in US

   Tatsuhiko Ichiki (Rohne-Poulenc Rorer Japan, Inc., Japan)

3. Commercial risk and benefit for developing anticancer drugs outside of Japan

   Tomowo Kobayashi (Sankyo Co., Ltd, Japan)

   Panel Discussion

   Panelist: Speakers and Y. Natsumeda (Banyu Pharmaceutical Co., Ltd)

7. Practice and problems in cooperative multicenter trials

1. How to expand resources for US cooperative clinical trials

   Charles A. Coltman, Jr (Cancer Therapy and Research Center, San Antonio, USA)

2. Surgical aspects of cancer clinical trials

   Kim Lyerly (Duke University, USA)

3. Practice and problems of the Japan Adult Leukemia Study Group

   Ryuzo Ohno (Hamamatsu University, Japan)

   Panel Discussion

   Panelist: Speakers, H. Ariyoshi (Aichi Prefectural Hospital) and M. Sasako (National Cancer Center Hospital)

8. Education of clinical trials

1. How to educate investigators and research nurses

   Yasuo Ohashi (The University of Tokyo, Japan)

2. Educating the public regarding clinical trials

   Michaele Christian (Cancer Therapy Evaluation Program, NCI, USA)

3. Educational activities of AACR (Cancelled)

   Margaret Foti (American Association of Cancer Research, USA)

   Panel Discussion

   Panelist: Speakers and J. J. Crowley (Fred Hutchenson Cancer Research Center, USA)

9. Conference Summary

Conference summary and steps for the future

   Nagahiro Saijo (National Cancer Center Hospital, Japan)