Information for the operation of
Safety Management system for Unapproved Drugs (SMUD)
undertaken by Ministry of Health, Labour and Welfare (MHLW)

～NPO Drug Safety and Research Unit Japan～

In this web page, the opinion of the DSRU Japan is posted.

◎ History

▼ Thalidomide tragedy

In 1961, astute scientists in Germany and Australia raised an alert that thalidomide marketed in late 1950s as a sedative/hypnotic and taken by pregnant mother caused many newborn babies with malformation. Those babies were later called as "thalidomide babies". In Japan more than 300 victims were born in late 1950s to early 1960s. Thalidomide was withdrawn from the market in late 1961 in Europe and in September 1962 in Japan.

▼ Discovery of the effect of thalidomide on erythema nodosum leprosum (ENL)(1965)

In 1965, the remarkable effect on erythema nodosum leprosum (ENL), which may develop during the clinical course of leprosy and is often accompanied by fever and pain, was detected rather accidentally in a hospital in Israel. After this report, thalidomide was widely recognized as the effective drug specifically for ENL.

▼ Discovery of the effect of thalidomide on multiple myeloma (MM)(1999)

The real "revival" of thalidomide was brought by a paper published in New England Journal of Medicine (NEJM) in 1999 which showed remarkable response to thalidomide among 84 patients with refractory myeloma. The efficacy of thalidomide was clearly shown in the randomized controlled trial of patients with newly diagnosed MM in the paper published in The Lancet in 2006.

▼ Imports of thalidomide by individual doctors in Japan

Following the publication of the paper in NEJM in 1999, individual Japanese doctors started importing thalidomide into Japan around 2000 in order to treat their patients. It is legal in Japan to import drugs from the countries outside Japan by a patient or a doctor unless the drug is demised or sold to somebody else other than the original person who imported the drug. The Ministry of Health, Labour and Welfare (MHLW) assigned thalidomide as a drug to be imported exclusively by a doctor who should obtain the permission from the administrative office regardless of the amount imported. Individual doctors imported thalidomide not only to treat their patients with MM but also to treat patients with other oncologic disorders or non-oncologic disorders including Behcet disease and Crohn’s disease.

▼ Guideline issued by the JSCH

Facing a rapid increase in imports of thalidomide in the following 2-3 years after starting the importation of thalidomide by individual doctors, the Japanese Society of Clinical Hematology (JSCH) (currently reorganized as the Japanese Society of Hematology, JSH) published "the guideline on the appropriate use of thalidomide for MM" in December 2004 to give the standards for the treatment of MM with thalidomide. One of the major aspects of the JSCH guideline was to provide the guideline for treatment of MM, but another aspect of the JSCH guideline was to show the standard to be satisfied by patients, doctors and pharmacists in order to secure the safe use of thalidomide. According to the JSCH guideline, the doctor should register gender, date of birth, initials and diagnosis (with no other personal information) of the patient treated by thalidomide to the JSCH office. The guideline also asks the doctor to explain the patient what is required to prevent the fetus from the exposure to thalidomide.

▼ A study on the system to secure the safety of unapproved drugs (2005.04 - 2006.03)

This study (Chief investigator: Kiyoshi Kubota, Department of Pharmacoepidemiology, Faculty of Medicine, University of Tokyo) was supported by the MHLW and concluded that the internet system may be developed to register the patients who use thalidomide imported by individual doctors. The projected system was named as Safety Management System for unapproved Drugs (SMUD) because the system may be expanded to cover drugs other than thalidomide imported by individual doctors in the future.

▼ A study on the safety measure of unapproved drugs imported by individual doctors in the medical institutions (2006.04 - 2008.03)

In this study (Chief investigator: the same as that in the above study) was also supported by the MHLW where a prototype of the current SMUD was developed using the resources of University hospital Medical Information Network (UMIN). Some of the important components of SMUD include:

1) SMUD was designed as a system following the JSCH guideline. For instance, only gender, date of birth, initials and diagnosis of the patient is registered with no other personal information.

2) SMUD is linked with the administrative processes for the permission of the importation of thalidomide so that the registration is actually mandatory. Owing to this component, SMUD may be regarded as a sort of "performance-linked access system" in the risk minimization action plan. In brief, importing of thalidomide is not permitted by the administrative office unless the total of imports of individual patients shown on the output list downloaded from the SMUD is the same as that in the purchase order. In order to make the patient appear in the output list, the doctor should register the patient to SMUD in advance.

3) SMUD is designed to allow health professionals to exchange the safety information on serious adverse events and occurrence of pregnancy. This aspect is unique to SMUD which deals with the unapproved drugs for which no drug company exists that may collect and distribute the information. The MHLW is also allowed to get the information on the safety directly from SMUD.

▼ Approval of thalidomide in 2008

In October 2008, the MHLW approved thalidomide for the indication of MM on condition that the manufacturer (Fujimoto Pharmaceutical Corporation) implements a risk management program named as Thalidomide Education and Risk Management System (TERMS). In TERMS, prior to the hospital visit, a patient must complete a 　questionnaire, which is faxed to the TERMS center located in the manufacturer. In TERMS, thalidomide should be dispensed within the hospital where thalidomide was prescribed. For each visit of the patient, the doctor and pharmacist must send a completed questionnaire to the TERMS center by fax and receive a document sent from the center by fax to authorize prescribing and dispensing of thalidomide. In TERMS, the off-label use of thalidomide is allowed only as a clinical trial recognized by the institution.

▼ Implementation of SMUD in 2009

In Japanese health insurance plan, the drug fee is in general not reimbursed for off-label use. Even after approval, imports of thalidomide are likely to remain for patients with disorders other than MM. The MHLW decided to implement SMUD as a registration system for thalidomide imported by individual doctors. Non-Profitable Organization (NPO) Drug Safety Research Unit Japan (DSRU Japan) is selected as a body which operates SMUD under the service contract with the MHLW in May 2009.

◎ Significance of SMUD

▼ A registration system with some aspect of the performance-linked access system.

As given above, SMUD is linked with the permission of thalidomide importation given by the administrative office so that the registration is mandatory. SMUD will allow the estimation of the number of patients using thalidomide subdivided by date of birth and sex. SMUD will also provide the information on the distribution of disorders of patients and the dose of thalidomide used by the patient with each indication. For the use of thalidomide imported by individual doctors, SMUD will work as a tool for exchanging the safety information between health professionals.

▼ A prototype for the official system specifically made for drugs imported by individual doctors.

In the current era of the Internet, the patient can easily access the information for the treatment available in the foreign countries before it becomes available in his/her own country. It is not extraordinary that the patient wishes to try one of such treatments proven effective elsewhere in the world. Nevertheless, such use of unapproved drugs (or treatments) can raise several problems. For example, as no drug company is responsible for the drug, the number of patients who use the drug can not be known unless a specific system like SMUD independent from the drug company is created. In addition, no drug company will be responsible for collecting and distributing the information on serious adverse events which the patient may have during the course of treatment. Such information will be valuable for health professionals who care the patient using the unapproved treatment. In addition, such information may be also potentially valuable in the processes of marketing authorization application of the drug and its approval when the submission for the drug is made later by the relevant drug company. SMUD may be regarded as a prototype of the system independent from the drug companies for registration of the patients who use the unapproved drugs as well as a system for collecting and exchanging the safety information between health-care professionals.

◎ Double Standard of risk management of thalidomide in Japan.

SMUD is different from TERMS in nature. TERMS is a system composed of specifically designed risk minimization tools for approved thalidomide. On the other hand, SMUD is a system of the patient registration for thalidomide imported by individual doctors. However, SMUD has some mandatory components which urge the patient registration. It should be noted that SMUD and TERMS actually impose different standards that doctors and patients should satisfy in order to use the same teratogen of thalidomide. The redundancy or inconsistency provided by this double-standard may create a trouble in the medical practice. We therefore advocate to search for the way to mitigate the problems emerging from the double standard of the risk management of thalidomide in Japan.

◎ Limitation of SMUD

As SMUD is primarily a system of the patient registration, it has many limitations when viewed as the system for the risk minimization of thalidomide. The 3 major limitations are discussed below.

▼ Lack of education tools in SMUD.

SMUD does not have the specific education tools. Such education tools for patients, pharmacists and doctors may be developed in the future and their use should be encouraged.

▼ Lack of monitoring the pregnancy test in the hospital for female patients of child-bearing potential.

As the system for the known teratogen of thalidomide, SMUD should have at least a tool to monitor the results of pregnancy test conducted in the hospital for female patients of child-bearing potential. As the number of female patients of child-bearing who use thalidomide may be not a lot, the component may be designed as an ad hoc tool such as collecting the information through the telephone.

▼ Lack of the capacity to record actual use of thalidomide by individual patients.

A means of monitoring the number of tablets (capsules) of thalidomide used by each patient may be developed. For instance, a periodic report on the amount of thalidomide dispensed to and actually used by each individual patient may be submitted from the pharmacist. If this information is available, any discrepancy between the total amount of thalidomide imported for a particular patient and the amount actually used by that patient may be easily identified.

◎ Ways to resolve double standard

▼ Implementation of a single system.

A single centralized system should manage all the patients treated with a drug requiring special risk management. There could be some obstacles however which impede the implementation of a single centralized system. For example, patients with disorders other than MM will not be readily covered by TERMS. The official label has the close association with the reimbursement in the healthcare plan in Japan and the drug is normally not reimbursed for off-label use. In addition, at least formally, the health service covered by the health insurance is prohibited to be simultaneously used with the service not covered by the insurance. Unless some new rules for these issues are stipulated, off-label use will remain exceptional and the importation of thalidomide by individual doctors may remain for the time being.

▼ Improvement of SMUD to overcome the limitation.

As the second best option (the best option is the implementation of a single risk management system), SMUD may be augmented in the future. The 3 issues described under the title "Limitation of SMUD" may be improved:

1) to develop education tool.

2) to create some new component for monitoring the results of pregnancy test in the hospital for female patients of child-bearing potential.

3) to improve SMUD so that the amount of thaliodmide dispensed and used by each patients can be recorded.

◎	History
	▼	Thalidomide tragedy
		In 1961, astute scientists in Germany and Australia raised an alert that thalidomide marketed in late 1950s as a sedative/hypnotic and taken by pregnant mother caused many newborn babies with malformation. Those babies were later called as "thalidomide babies". In Japan more than 300 victims were born in late 1950s to early 1960s. Thalidomide was withdrawn from the market in late 1961 in Europe and in September 1962 in Japan.

	▼	Discovery of the effect of thalidomide on erythema nodosum leprosum (ENL)(1965)
		In 1965, the remarkable effect on erythema nodosum leprosum (ENL), which may develop during the clinical course of leprosy and is often accompanied by fever and pain, was detected rather accidentally in a hospital in Israel. After this report, thalidomide was widely recognized as the effective drug specifically for ENL.

	▼	Discovery of the effect of thalidomide on multiple myeloma (MM)(1999)
		The real "revival" of thalidomide was brought by a paper published in New England Journal of Medicine (NEJM) in 1999 which showed remarkable response to thalidomide among 84 patients with refractory myeloma. The efficacy of thalidomide was clearly shown in the randomized controlled trial of patients with newly diagnosed MM in the paper published in The Lancet in 2006.

	▼	Imports of thalidomide by individual doctors in Japan
		Following the publication of the paper in NEJM in 1999, individual Japanese doctors started importing thalidomide into Japan around 2000 in order to treat their patients. It is legal in Japan to import drugs from the countries outside Japan by a patient or a doctor unless the drug is demised or sold to somebody else other than the original person who imported the drug. The Ministry of Health, Labour and Welfare (MHLW) assigned thalidomide as a drug to be imported exclusively by a doctor who should obtain the permission from the administrative office regardless of the amount imported. Individual doctors imported thalidomide not only to treat their patients with MM but also to treat patients with other oncologic disorders or non-oncologic disorders including Behcet disease and Crohn’s disease.

	▼	Guideline issued by the JSCH
		Facing a rapid increase in imports of thalidomide in the following 2-3 years after starting the importation of thalidomide by individual doctors, the Japanese Society of Clinical Hematology (JSCH) (currently reorganized as the Japanese Society of Hematology, JSH) published "the guideline on the appropriate use of thalidomide for MM" in December 2004 to give the standards for the treatment of MM with thalidomide. One of the major aspects of the JSCH guideline was to provide the guideline for treatment of MM, but another aspect of the JSCH guideline was to show the standard to be satisfied by patients, doctors and pharmacists in order to secure the safe use of thalidomide. According to the JSCH guideline, the doctor should register gender, date of birth, initials and diagnosis (with no other personal information) of the patient treated by thalidomide to the JSCH office. The guideline also asks the doctor to explain the patient what is required to prevent the fetus from the exposure to thalidomide.

	▼	A study on the system to secure the safety of unapproved drugs (2005.04 - 2006.03)
		This study (Chief investigator: Kiyoshi Kubota, Department of Pharmacoepidemiology, Faculty of Medicine, University of Tokyo) was supported by the MHLW and concluded that the internet system may be developed to register the patients who use thalidomide imported by individual doctors. The projected system was named as Safety Management System for unapproved Drugs (SMUD) because the system may be expanded to cover drugs other than thalidomide imported by individual doctors in the future.

	▼	A study on the safety measure of unapproved drugs imported by individual doctors in the medical institutions (2006.04 - 2008.03)
		In this study (Chief investigator: the same as that in the above study) was also supported by the MHLW where a prototype of the current SMUD was developed using the resources of University hospital Medical Information Network (UMIN). Some of the important components of SMUD include:
		1)	SMUD was designed as a system following the JSCH guideline. For instance, only gender, date of birth, initials and diagnosis of the patient is registered with no other personal information.

		2)	SMUD is linked with the administrative processes for the permission of the importation of thalidomide so that the registration is actually mandatory. Owing to this component, SMUD may be regarded as a sort of "performance-linked access system" in the risk minimization action plan. In brief, importing of thalidomide is not permitted by the administrative office unless the total of imports of individual patients shown on the output list downloaded from the SMUD is the same as that in the purchase order. In order to make the patient appear in the output list, the doctor should register the patient to SMUD in advance.

		3)	SMUD is designed to allow health professionals to exchange the safety information on serious adverse events and occurrence of pregnancy. This aspect is unique to SMUD which deals with the unapproved drugs for which no drug company exists that may collect and distribute the information. The MHLW is also allowed to get the information on the safety directly from SMUD.

	▼	Approval of thalidomide in 2008
		In October 2008, the MHLW approved thalidomide for the indication of MM on condition that the manufacturer (Fujimoto Pharmaceutical Corporation) implements a risk management program named as Thalidomide Education and Risk Management System (TERMS). In TERMS, prior to the hospital visit, a patient must complete a 　questionnaire, which is faxed to the TERMS center located in the manufacturer. In TERMS, thalidomide should be dispensed within the hospital where thalidomide was prescribed. For each visit of the patient, the doctor and pharmacist must send a completed questionnaire to the TERMS center by fax and receive a document sent from the center by fax to authorize prescribing and dispensing of thalidomide. In TERMS, the off-label use of thalidomide is allowed only as a clinical trial recognized by the institution.

	▼	Implementation of SMUD in 2009
		In Japanese health insurance plan, the drug fee is in general not reimbursed for off-label use. Even after approval, imports of thalidomide are likely to remain for patients with disorders other than MM. The MHLW decided to implement SMUD as a registration system for thalidomide imported by individual doctors. Non-Profitable Organization (NPO) Drug Safety Research Unit Japan (DSRU Japan) is selected as a body which operates SMUD under the service contract with the MHLW in May 2009.

◎	Significance of SMUD
	▼	A registration system with some aspect of the performance-linked access system.
		As given above, SMUD is linked with the permission of thalidomide importation given by the administrative office so that the registration is mandatory. SMUD will allow the estimation of the number of patients using thalidomide subdivided by date of birth and sex. SMUD will also provide the information on the distribution of disorders of patients and the dose of thalidomide used by the patient with each indication. For the use of thalidomide imported by individual doctors, SMUD will work as a tool for exchanging the safety information between health professionals.

	▼	A prototype for the official system specifically made for drugs imported by individual doctors.
		In the current era of the Internet, the patient can easily access the information for the treatment available in the foreign countries before it becomes available in his/her own country. It is not extraordinary that the patient wishes to try one of such treatments proven effective elsewhere in the world. Nevertheless, such use of unapproved drugs (or treatments) can raise several problems. For example, as no drug company is responsible for the drug, the number of patients who use the drug can not be known unless a specific system like SMUD independent from the drug company is created. In addition, no drug company will be responsible for collecting and distributing the information on serious adverse events which the patient may have during the course of treatment. Such information will be valuable for health professionals who care the patient using the unapproved treatment. In addition, such information may be also potentially valuable in the processes of marketing authorization application of the drug and its approval when the submission for the drug is made later by the relevant drug company. SMUD may be regarded as a prototype of the system independent from the drug companies for registration of the patients who use the unapproved drugs as well as a system for collecting and exchanging the safety information between health-care professionals.

◎	Double Standard of risk management of thalidomide in Japan.
	SMUD is different from TERMS in nature. TERMS is a system composed of specifically designed risk minimization tools for approved thalidomide. On the other hand, SMUD is a system of the patient registration for thalidomide imported by individual doctors. However, SMUD has some mandatory components which urge the patient registration. It should be noted that SMUD and TERMS actually impose different standards that doctors and patients should satisfy in order to use the same teratogen of thalidomide. The redundancy or inconsistency provided by this double-standard may create a trouble in the medical practice. We therefore advocate to search for the way to mitigate the problems emerging from the double standard of the risk management of thalidomide in Japan.

◎	Limitation of SMUD
	As SMUD is primarily a system of the patient registration, it has many limitations when viewed as the system for the risk minimization of thalidomide. The 3 major limitations are discussed below.
	▼	Lack of education tools in SMUD.
		SMUD does not have the specific education tools. Such education tools for patients, pharmacists and doctors may be developed in the future and their use should be encouraged.

	▼	Lack of monitoring the pregnancy test in the hospital for female patients of child-bearing potential.
		As the system for the known teratogen of thalidomide, SMUD should have at least a tool to monitor the results of pregnancy test conducted in the hospital for female patients of child-bearing potential. As the number of female patients of child-bearing who use thalidomide may be not a lot, the component may be designed as an ad hoc tool such as collecting the information through the telephone.

	▼	Lack of the capacity to record actual use of thalidomide by individual patients.
		A means of monitoring the number of tablets (capsules) of thalidomide used by each patient may be developed. For instance, a periodic report on the amount of thalidomide dispensed to and actually used by each individual patient may be submitted from the pharmacist. If this information is available, any discrepancy between the total amount of thalidomide imported for a particular patient and the amount actually used by that patient may be easily identified.

◎	Ways to resolve double standard
	▼	Implementation of a single system.
		A single centralized system should manage all the patients treated with a drug requiring special risk management. There could be some obstacles however which impede the implementation of a single centralized system. For example, patients with disorders other than MM will not be readily covered by TERMS. The official label has the close association with the reimbursement in the healthcare plan in Japan and the drug is normally not reimbursed for off-label use. In addition, at least formally, the health service covered by the health insurance is prohibited to be simultaneously used with the service not covered by the insurance. Unless some new rules for these issues are stipulated, off-label use will remain exceptional and the importation of thalidomide by individual doctors may remain for the time being.

	▼	Improvement of SMUD to overcome the limitation.
		As the second best option (the best option is the implementation of a single risk management system), SMUD may be augmented in the future. The 3 issues described under the title "Limitation of SMUD" may be improved:
		1)	to develop education tool.

		2)	to create some new component for monitoring the results of pregnancy test in the hospital for female patients of child-bearing potential.

		3)	to improve SMUD so that the amount of thaliodmide dispensed and used by each patients can be recorded.

Information for the operation of Safety Management system for Unapproved Drugs (SMUD) undertaken by Ministry of Health, Labour and Welfare (MHLW)

～NPO Drug Safety and Research Unit Japan～

Information for the operation of
Safety Management system for Unapproved Drugs (SMUD)
undertaken by Ministry of Health, Labour and Welfare (MHLW)