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Section 3. Promoting Safety Measures for Pharmaceuticals

1. Reflections on AIDS Problems and Damage to Health by Pharmaceuticals

(1) Lawsuits and reconciliations regarding HIV-infections caused by blood products

1 The process toward reconciliation
As of the end of March 1999, the total number of HIV-infected persons reported in Japan was 4,493, of whom 1,434 were infected through blood products. By the same time, the number of symptomatic AIDS (acquired immunodeficiency syndrome) patients, including those who had died, reached 1,994, of whom 631 had been infected through blood products. (The number of HIV-infected people through blood products and that of the symptomatic AIDS patients are as of the end of October, 1997, from the report by the "Study Group on Prevention of Appearance of Symptoms and Treatment of HIV-Infected People".)
Lawsuits demanding compensation for damages suffered were filed successively in Osaka in May of 1989 and in Tokyo in October of the same year. Hemophiliacs sued the national government and five pharmaceutical manufacturers for HIV infections caused by blood products that were used in treating hemophilia. On October 6, 1995, both the Osaka and Tokyo Courts recommended reconciliation and presented their reasons for their recommendations.
Tadayoshi Morii, the Minister of Health and Welfare at that time, seriously considered the purport of the recommendation of reconciliation and on October 17, 1995, he declared that he would negotiate for reconciliation.
On March 7, 1996, the court presented a second proposal for reconciliation, which was accepted by the plaintiffs, the government and the pharmaceutical manufacturers. Accordingly, reconciliation was concluded on March 29, 1996.
2 Details of the reconciliation and confirmation notes
In the confirmation notes exchanged concerning the reconciliation, Naoto Kan, the Minister of Health and Welfare at that time, said that he would sincerely and seriously accept the views of the court. He further said that he realized the serious responsibility of the ministry for the spread of the HIV infection among hemophiliacs and the terrible harm that resulted, which was pointed out in the notes. He also said that he truly felt sorry about that, and he expressed his heartfelt apologies to the patients and their families.
When earlier lawsuits on adverse effect of thalidomide and quinoform were settled through reconciliation, it had unequivocally been promised that efforts would be made to prevent the reoccurrence of drug-induced problems. However, despite that promise, blood products have caused miserable damages. The Minister of Health and Welfare said that he would seriously take this fact to heart and would make further efforts to determine the cause of the recent problems. Then he definitely promised that all of the ministry's staff members would make their best, all-out efforts to prevent serious drug-induced problems, based upon deep recognition of their grave responsibility for protecting people's lives and health.
3 Promoting reconciliation
On March 29, 1996, a total of 118 patients agreed to the reconciliation at the Tokyo and Osaka District Courts. The confirmation notes that were exchanged concerning the reconciliation state that for patients who had not sued, the evidence would be examined as soon as they institute lawsuits and that such patients also would be covered by the reconciliation. In response, the Ministry of Health and Welfare has been doing its best to achieve reconciliations with patients who have not yet sued. As part of such efforts, the ministry has, since October 1996, repeatedly requested doctors treating hemophiliacs to cooperate in encouraging patients to institute legal actions to achieve reconciliations. By the end of May 1999, 1,309 patients (including nine non-hemophiliacs) had filed actions, and reconciliation had been reached with 1,291 of them.

(2) Promoting various permanent measures

Based upon the reconciliation, the Ministry of Health and Welfare has introduced following measures as permanent measures for HIV-infected persons.

a. Efforts have been made since 1993 to establish model hospitals for AIDS treatment. The model hospitals selected under this system function as bases for AIDS treatment and provide medical information to other institutions in various regions. By January 1, 1999, a total of 364 medical institutions in 47 prefectures had been designated as model hospitals. In addition, the AIDS-treatment/R&D center was founded at the International Medical Center of Japan in fiscal 1997 and eight core model hospitals were constructed, each of which takes charge of one of the eight districts of Japan. Thus, efforts are being made to improve treatment standards in respective regions and to rectify the disparity in treatment standards among regions.
b. In May 1996, a new system was introduced for calculating additional remuneration, when an HIV carrier was hospitalized in a private room. This is one of the efforts being made to eliminate the inappropriate collection of extra charges. In addition, on and after July 1996, expenses for the treatment of AIDS do not have to be paid by HIV-infected people, including symptomatic patients and certain carriers, who have been infected through blood-coagulation-factor preparations, or secondarily or tertiarily infected by such carriers, as is for hemophiliacs.
c. In order that AIDS drugs and drugs for opportunistic infections (hereinafter called "AIDS drugs, etc.") that have been authorized in the United States can be used by patients and carriers in Japan at the earliest possible time, the advance evaluation system was introduced in November 1998. Under the system, clinical trial results and data attached to authorization applications in the United States are referred to in examination of the drug in Japan. The Japanese government has also adopted a principle to greatly shorten the approval-examination period for such drugs.

In addition, with regard to AIDS drugs, etc. for which the demand in Japan is small, efforts are being made to secure and provide such drugs through the AIDS Treatment and Study Group.

Further efforts will be made in the future to collect international data on these topics and to expand related research in Japan, with the aim of promoting the development of AIDS drugs so as to prevent the proliferation of AIDS viruses and to strengthen immunological function.

d. Since April 1, 1998, HIV infection has been acknowledged as a "disorder in immunity caused by human immunodeficiency viruses" under the Law for the Welfare of People with Physical Disabilities. Accordingly, welfare measures to support the living of HIV-infected people have been realized, including services provided by visit-care staff (home-helpers). In the meantime, disability pensions have traditionally been paid to HIV-infected people, as well. Discussions were made at "the Council on the Recognition of Disability" to clarify the procedure for recognizing HIV-infected people as being disabled, in order that such procedure will be completed appropriately and smoothly. As a result, it has been agreed that appropriate disability recognition procedure shall be taken in accordance with the disease conditions of the HIV-infected people.
e. With regard to criteria regarding AIDS symptoms, "AIDS-Diagnosis Standards for Surveillance" was revised at the "Subcommittee on Reconsideration of AIDS-Diagnosis Standards" under the AIDS Trend Committee, aiming to make the description easier to understand.
f. As part of measures to help foster peace of mind among those bereaved through AIDS, a Consultation Services for Survivors System was introduced in fiscal 1997. Under the system, consultation meetings and so forth are held where such bereaved can talk with each other about their problems and to receive advice from experts. As for the proposed construction of a monument in relation to problems of HIV infection through blood products, discussions are under way for the realization of the plan.

While promoting such permanent measures, staff members at the ministry are doing their best to secure the safety of pharmaceuticals, in order that people would never experience the miseries of HIV infection again.

2. Securing the Effectiveness and Safety of Pharmaceuticals

(1) Smooth implementation of "Good Clinical Practice"

The "Ministerial Ordinance on Standards for Conducting Clinical Trials on Pharmaceuticals", which was established as legislation in April 1997, was fully enforced in April 1998. For smooth implementation of the new GCP, explanation meetings on GCP have been held while trial activities for appropriate operation of GCP have been conducted. At the same time, measures aiming to improve the system of such trials are being promoted, including the inauguration of clinical trial management divisions in national hospitals and sanatoriums, university hospitals, etc. In addition, clinical trial promotion conferences were founded in six districts in Japan in March 1999, which consist of chiefs of medical institutions conducting clinical trials. This is to promote closer cooperation and information exchanges among medical institutions. A "Discussion Meeting for Smoothly Promoting Clinical Trials" has also been held since February 1998 to consider concrete measures. In future, efforts will be made in light of the discussion results at the meeting, in order that appropriate clinical trials will be promoted even more smoothly.

(2) Revision of approval-examination system

1 Upgrading examination system
The structure of pharmaceutical administration was drastically revised in July 1997. The "Pharmaceuticals and Medical Devices Evaluation Center" was organized and "team examinations" conducted by examination officers specializing in a variety of fields such as medicine, pharmaceutical science, veterinary science and biostatistics were introduced. To add to this is a three-year plan to double the number of examination officers by fiscal 1999. Through such efforts, the professional level in approval-examinations for pharmaceuticals is being raised in order that the effectiveness and safety of pharmaceuticals can be more definitely promised. It has also been agreed that efforts will be made for more promptly completing approval-examinations, shortening the approval-examination period from 18 to 12 months as for new drugs whose applications are filed in and after April 2000.
2 Information disclosure in approval-examinations
As for the disclosure of information on the process of approval-examinations, all of the minutes of the Central Pharmaceutical Affairs Council are to be made open to the public in principle, with the exception of those relating to personal private information, corporate intellectual-property rights, and so on. With regard to the disclosure of information relating to approval-examinations, it has been agreed that review reports, the deliberation process, and a list of attached documents regarding deliberations on new drugs are to be made available to the public after the relevant drugs are approved. Accordingly, such data relating to new drugs approved in and after October 1996 and those relating to new medical devices approved in and after April 1998 have been publicly disclosed.
As for some of the new drugs, a summary basis of approval for each drug has been prepared and disclosed. The summary presents summarized data on non-clinical and clinical studies that provide a basis for the approval, proving the indication and justifying the use and dosage of each drug. It has been agreed that such a summary will be prepared and disclosed for all new drugs in future.

(3) Upgrading post-marketing measures

1 Improving the system to collect and transmit information on side-effects of pharmaceuticals
According to a newly established law aiming to secure increased safety of pharmaceuticals and medical devices, pharmaceutical manufacturers have been obliged by law to report side effects and so forth to the Ministry of Health and Welfare since April 1997. In addition, a "Reporting System on Drug Safety Information" to collect information on side effects, etc. directly from all medical institutions and pharmacies was inaugurated in July of the same year. It has also been agreed that a "Drug Information Offering System" will be put into operation in fiscal 1999, which provides medical professionals with the latest information upon pharmaceuticals through the Internet.
2 Securing quality of generic drugs
Some experts have pointed out that the quality of some of the ethical drugs, particularly generic drugs, may not have reached an acceptable level. In response to this, it has been agreed that reevaluation will be conducted upon the quality of pharmaceuticals, in addition to their effectiveness and safety that have traditionally been subject to reevaluation, to secure the quality of drugs more strictly. The first results of such reevaluation were announced in March 1999. Also, a collection of data on the quality of pharmaceuticals is to be prepared and published in and after fiscal 1999, which gives a list of sales names of drugs whose appropriateness has been confirmed by such reevaluation.

(4) Promoting the separation of dispensing practice

The aging of the society and changes in disease patterns have caused an increase in combined use of drugs and in the long-term taking of drugs, and the use of appropriate medications has emerged as an important requirement. Separation of Dispensing Practices aims to prevent duplicate dispensing of drugs and the undesirable interactions of incompatible drugs by having a patient's local pharmacy keep a record of the drugs taken by each patient (a patient-medication profile) and check the safety of the combination of drugs prescribed by plural hospitals as well as the allergic record of the patient. Such a system is essential to promote the appropriate use of drugs. The implementation of this system has progressed rapidly in recent years, with the rate of complete separation (the number of prescriptions to pharmacies/the number of prescriptions for outpatients (total)) reaching 26.0% in fiscal 1997.

In April 1997, pharmacists were placed under obligation to provide information necessary for appropriate use of prescribed drugs (Paragraph 2, Article 25, Pharmacists Law). Thus, pharmacists are required to play an increasingly important role in regional medical care services.

It is necessary to promote a "horizontal-separation" system that each patient receives drugs from one particular pharmacy even if the patient goes to several medical institutions, because such separation will promote the appropriate use of drugs and will improve the quality of medical services. The Ministry of Health and Welfare intends to promote to a greater degree the appropriate Separation of Dispensing Practice, i.e., a horizontal-separation system. To that end, the ministry will upgrade the Support Center to Promote the Separation of Dispensing Practice that stores drugs, etc. and will formulate a program of Separation of Dispensing Practice.

(5) Revising ideal features of blood business

Blood products are produced from blood that is taken out of human bodies. Because of this, there is always the risks of viral infection or side effect resulting from immunoreactions, which cannot be eliminated even by the state-of-the art scientific technology of today. It is an emergent task to secure the safety of blood products in consideration of their characteristics.

The self-sufficiency rates of albumin and globulin products have tended to rise for the last few years, but a considerable portion of them are still being imported from abroad. Furthermore, further aging of the society will lead to an increase in people who need blood products, while the population in an age category who can donate blood is likely to become smaller. This has made it necessary to redouble efforts for attaining domestic self-sufficiency.

In light of this, discussions concerning ideal features of blood programs started in October 1996 at the "Meeting for Discussion of Ideal Features of Blood Administration" that consists of experts from a variety of fields. They prepared a report in December 1997, which, in consideration of the characteristics of blood products, presented 1 encouraging domestic supply of blood products, 2 securing safety, 3 appropriate use, 4 effective utilization, and 5 securing transparency as the five principles. The report also clarified the roles and responsibilities of the related parties, i.e. the national and local governments, Japanese Red Cross Society, pharmaceutical manufacturers, and so forth, while proposing concrete measures for promoting self-supply and securing safety. In response, the Central Pharmaceutical Affairs Council started deliberating ideal features of blood programs in March 1998. Necessary measures including the adjustment of the legal system will be introduced based upon the results of such deliberations.

In the meantime, it is necessary to secure more certainly the safety of plasma-fraction products through upgrading interview checks and a variety of tests and the inactivation and elimination of viruses during the manufacturing process, in order to secure the safety of blood products. In light of this, the NAT (Nucleic Acid Amplification Test) is to be introduced in fiscal 1999 for blood products for transfusion, which will realize higher accuracy in detecting hepatitis viruses (HBV, HCV) and HIV. Also in fiscal 1999, the Blood Center of Red Cross will start notifying the results of antibody tests against human T-lymphotropic virus type I to the people who donate blood and hope to know the results of such tests. At the same time, the center will launch counseling activities, in cooperation with medical institutions, health centers, and so forth, in order that such results can be reflected in the health management of the people donating blood.

3. Measures for Preventing Drug Abuse

Drug abuse in Japan has tended to increase since 1995. Continued attention must be paid to these problems, including an increase in the volume of seized stimulants, although the number of people in custody decreased in 1998.

The government formulated a "Five-Year Drug Abuse Prevention Strategy" in May 1998. According to this strategy, the Ministry of Health and Welfare is enhancing and strengthening measures for preventive enlightenment, control, direction/supervision, and prevention of reoccurrence, in close cooperation with Headquarters for the Promotion of Measures to Prevent Drug Abuse and related ministries and agencies.

In particular, drug abuse prevention caravan cars were increased to four in fiscal 1998, for activating preventive enlightenment activities for the youth. Enlightenment activities utilizing the caravan cars are conducted throughout the nation. In addition, guidebooks for enlightenment of the parents of junior high and high school students as well as enlightenment materials for a variety of events (panels with televideos, etc.) were newly prepared and distributed.

In the meantime, the ministry gave notifications concerning appropriate storage, management and sales of psychotropics to prefectural governments in January 1999 in light of the frequent occurrence of cases involving psychotropics since the end of 1998, in order that the appropriate methods in such matters will be adopted for sure. Thus, directions and supervision upon related traders, etc. are being strengthened.

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