Japan 2000 Pharmaceutical Change: New Good Clinical Practice (GCP) Requirements

Introduction

Japan ’s Ministry of Health and Welfare (MHW) and other government pharmaceutical regulatory organizations have implemented major changes to strengthen their review of clinical trials. Their goal is to improve the safety and quality of drugs entering the Japanese market. A Pharmaceutical and Medical Device Evaluation Center was created under the National Institute of Health Sciences in July 1997 to help with the review of New Drug Applications. Japan’s Drug Organization (KIKO) is cooperating with the Evaluation Center to ensure compliance with safety standards and review protocol, perform raw data checks and consult with companies on clinical development and trials for new pharmaceutical products.

Drug Organization (KIKO)

KIKO is a half-public, half-private organization supervised by the MHW that deals with drugs, cosmetics and diagnostics. KIKO has departments dealing with ADR Relief, R & D Promotion, Product Review, Clinical Trials Guidance, and Compliance Review as illustrated below in figure 1.

Figure 1: Organization of KIKO

 

Former Good Clinical Practice Problems (1989)

The former Good Clinical Practice regulations were plagued with problems. The Chief Investigator had a wide range of responsibilities and held a significant amount of power. Too much authority was concentrated in the hands of one person. Formalities regarding clinical trials were virtually non-existent. Oral “informed” consent from test subjects was acceptable, which meant that, in many cases, the subjects did not really know the nature of the tests or the drugs being administered to them. Oftentimes, they did not even know they were part of a clinical test. In addition, there were feeble provisions to assure the quality of clinical data. Auditors and other agencies could not directly access original data.

Because of the inconsistency and shortcomings of the old regulations, the MHW finally amended the Pharmaceutical Affairs Law and its subordinate regulations using the International Conference on Harmonization (ICH) GCP regulations as a guideline. These amendments were implemented in April 1998 and drastically changed clinical trials in Japan.

Former GCP Regulations Versus New GCP Regulations

  • Sponsors’ Responsibilities

Under the old system, the sponsor’s responsibilities included judging if a clinical trial was justified, designating a chief investigator and performing audits. After April 1998, the sponsor’s responsibilities expanded. Under the new GCP regulations, the sponsor must prepare protocols and final study reports, seek medical expert opinions (whether they be part of the internal staff or independent outside sources), select sites and investigators for clinical tests, monitor and audit the tests.

  • Chief Investigator’s Responsibilities

As mentioned above, the Chief Investigator used to have too much power. His responsibilities included such things as preparing protocols, coordinating the information submitted to subjects, ensuring proper conduct of trials, reviewing clinical study report forms (CRF) and submitting them to the sponsor and preparing final reports. Even though the new regulations officially abolished the position of the Chief Investigator, he still has similar functions and maintains his former network.

  • Site/Medical Institution’s Responsibilities

The former GCP regulations required little or nothing on the part of the medical institutions performing the clinical tests. Now, medical institutions must document the finances of the clinical tests, must accept monitoring and auditing of their tests and, for the duration of the clinical tests, are required to establish a clinical trial project office.

  • Investigator’s Responsibilities

Under the new GCP regulations, the Chief Investigator no longer directs the Investigator. The Investigator conducts the trial on site (at the medical institution, etc.) and supervises the sub-investigator’s. Other responsibilities include submitting clinical study CRFs to the sponsor and preparing written information for trial subjects. The new regulations also require the Investigator to allow monitoring and auditing of the clinical tests by the sponsor.

  • Institutional Review Board’s (IRB) Responsibilities

The IRB is an organization created by the new GCP regulations to review the entire clinical trial process. The IRB is generally organized by a government pharmaceutical regulatory organization, but may also be organized by a non-profit organization. At least one member of the board must not have an affiliation with the medical institution. The responsibilities of the IRB include reviewing CVs of the Investigator and sub-investigators as well as reviewing any documents concerning compensation for injuries related to the clinical trials and the cost of the trial itself.

  • Subject’s Informed Consent

Before the new GCP regulations, patients usually were not aware that they were in clinical studies. Previously, actual patient consent was circumvented via oral “informed” consent. Now, clinical tests cannot use subjects until submit written informed consent is submitted. This means that subjects must know the nature of the clinical test as well as the monitoring process before they sign a consent form. Compensation for subjects in case of trial related injuries is also now required. In addition, Japanese subjects also have the right to have access to their medical record — something Americans have always had and take for granted.

Problems With Clinical Trial Recruitment

Patient Mentality

Traditionally, patients did not receive much explanation from doctors in Japan. It was fairly common for doctors to conceal diagnoses (such as cancer) from the patient. It was also common for patients to be uneducated about the drug or procedure that was being prescribed or administered. Patients simply wanted to be cured and did not care about understanding the treatment. Doctors were considered omnipotent and patients generally simply accepted that fact.

Due to the nature of the doctor-patient relationship, people were often unaware that they qualified to be a clinical study test subject. Furthermore, clinical trials were considered taboo in Japanese culture and not many people understood what clinical studies were or why they were performed.

Other Recruiting Difficulties

While patient mentality is a large barrier to recruiting for clinical tests, there are many other obstacles. One of the biggest problems is motivation and incentive to participate in clinical trials. In the U.S., those who are too poor to afford treatment oftentimes rely on experimental drug trials as their only hope for treatment. There is no such incentive in Japan because Japan has a comprehensive universal health care insurance. It is also difficult to discover what is being tested in Japan because advertisements for clinical trials are not permitted.

Future Reforms by the MHW and KIKO

The MHW and KIKO plan to educate the public about pharmaceuticals and the importance of clinical trials in order to boost development of drugs. Education programs include an increase in transparency to the public (drug labeling and product inserts will be made available online) and videos have been prepared to show on national television explaining the importance of clinical research in developing drugs. There are also efforts to increase patient reimbursement for involvement in clinical trials. In addition, the MHW may even allow local newspaper advertisements to recruit test subjects.