Pharmacovigilance in Taiwan

WHO defines the term ‘pharmacovigilance' as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems.” During the first five years of a new drug being put on the market, pharmacovigilance is particularly important, as comparatively little about its safety profile is known until it is exposed to a much larger population. The Bureau of Pharmaceutical Affairs (BPA), Department of Health (DOH), Taiwan, has implemented numerous pharmacovigilance activities in recent years. Our ultimate goal is to enhance drug safety, hence to promote public health.


National Reporting System of Adverse Events in Taiwan

Objective
Conducting a well-organized reporting system of adverse drug reactions is the basic tool of improving drug safety. Therefore, the National Adverse Drug Reactions (ADRs) Reporting System was established by the DOH in 1998. The objectives of the National ADR Reporting System are to collect and evaluate reported cases, to analyze electronic data base, to generalize signal detection, and to carry out education program.

Background
In 1983, the DOH, Executive Yuan, Taiwan instituted the regulation of post-marketing surveillance for new drugs (new chemical entity, new indication and new formulation). The regulation was amended in 1993. Accordingly, the license holders of new drugs are required to provide the latest domestic and foreign safety reports of their products every 6 months in a 7-year drug surveillance period. In 1996, the DOH commanded the Taiwan Society of Health-System Pharmacists conducting a two-year project to discuss strategies of building up a system to monitor and collect drug safety information. It has been pointed out that establishing a nation-wide spontaneous reporting system of adverse drug reactions would be one of the most important and urgent issue.  

The DOH expanded the project to a nation wide reporting system of adverse drug reactions in July 1998. The network included a national center and four regional centers located in the northern, central, southern and eastern Taiwan. As setting up an ADR surveillance system inside medical institutions was required for hospital accreditation in 2001, ADR reporting activities are becoming more and more important. In the same year, Medical Devices Adverse Events Reporting System was added to the system. The National Taiwan ADR Reporting Center started to be operated under Taiwan Drug Relief Foundation since 2002. The web-based on-line ADR reporting system was set up the following year. In order to further harmonize data processing, the National ADR Reporting Center was centralized in 2005, and the four regional centers are to assist the national center in conducting public health education and training programs to healthcare providers. An on-line system for Medical Product Defect was also established in 2005.

Scope
According to the Article 45-1, Pharmaceutical Affairs Act , implemented in April 2004, medical care institutions, pharmacies, and license holders shall report any serious adverse reactions caused by medical products. Therefore, the guidance of the reporting of serious adverse drug reaction was announced in August 2005. This regulation covers the reporting of serious adverse reactions for marketed medical products, i.e., pharmaceutical medications and medical devices.

The current pharmacovigilance activities in Taiwan are summarized as following:

I. Post-marketing Surveillance

One of the major implementations of post-marketing surveillance for medical products is to monitor the ongoing safety of marketed medical products. To collect safety data of marketed medical products, the function of on-line reporting on the website and a computerized information database were build up. According to Article 45 and Article 45-1, Pharmaceutical Affairs Act, the main projects for post marketing surveillance include mandatory reporting of serious adverse reactions of all approved medical products, voluntary reporting of non-serious adverse reactions, and obligatory periodic safety updated report (PSUR) for medical products under monitoring stage.

I-1. All marketed Medical Products
It is required by Article 45-1, Pharmaceutical Affairs Act , medical care institutions, pharmacies, and license holders should report any serious adverse drug reaction (mandatory report) caused by all marketed medical products. On the other hand, the reporting of non-serious ADR is also encouraged (voluntary report). For further information of the annual statistics of ADR reports, please check our website.

 

1.           Definition: Serious Adverse Drug Reaction is defined as ADR that results in

  • Death
  • Life-threatening
  • Permanent disability/incapacity
  • Congenital anomaly/birth defect
  • Results in hospitalization or prolongation of an existing hospitalization
  • Needs further management for other possible permanent disabilities

 

2. Management of Reporting
According to Article 45-1, Pharmaceutical Affairs Act, the Procedure for Reporting Severe Adverse Reactions to Medicines was announced in Aug 2005. The time when serious adverse drug reaction should be reported to the reporting center is regulated as follow.

Medical care institutions, pharmacies, and license holders of medicaments (drug and medical devices) shall report serious adverse reactions of medicaments. Medical institutions and pharmacies should inform the license holders of the suspected serious adverse reactions of the medicaments.

A.      For Fatal or Life-threatening Serious Adverse Reactions

I.            Medical care institutions and pharmacies should report fatal or life-threatening cases no later than 7 calendar days. A complete follow-up report should be submitted within 8 additional calendar days. The follow-up report must include an assessment of the findings and/or relevant previous experience of the same or similar medicaments.

II.           License holders of medicaments should report fatal or life-threatening cases within 15 calendar days.

  1. For All Other Serious Adverse Reactions
    license holders of medicaments should report fatal or life-threatening cases within 15 calendar days
  1.  For Non-Serious Adverse Reactions
    The DOH encourages all suspected adverse drug reactions to be reported voluntarily at anytime.

 

3. How to Report
Please fill the Post-marketing ADR Reporting Form to expedite the ADR reporting. All ADR reports can be sent to the National ADR Reporting Center by facsimile (Fax: 886-2-2358-4100), postal mail (Mail address: National ADR Reporting Center 2F, No.32, Roosevelt Rd., Taipei , 100, Taiwan ), and email (adr@doh.gov.tw) or simply submit on-line through ADR website. ( http://adr.doh.gov.tw/default.asp )

 

I-2. Newly Marketed Medical Products
Since safety data from clinical trials for newly marketed drugs is limited, in order to get more safety information, newly marketed drugs are required to have a five-year surveillance period. In addition to the requirement for serious ADR reporting, the license holders have to submit the periodic safety update reports (PSUR) during the surveillance period. The DOH declared the Drug Safety Monitoring Procedure in September 2004, along with Procedure for Reporting Severe Adverse Reactions to Medicines to enhance the surveillance of new drug safety. According to the regulation and the governmental announcement No. 0930333410, the license holders of drugs should submit PSUR every 6 months in the first two years and every year in the next three years during the 5-year drug surveillance period.

 

1. Definition
The term "new drugs" as defined in Pharmaceutical Affairs Act, Article 7, refers to the drugs with preparations of new chemical entities, compounding medications of new therapeutic activities, or new route of administration of old chemical entities. Furthermore, the medical preparation which is new dosage form, new dose, new dose per unit or new route of administration for chemical entity that is still under the safety monitoring period, is required to be under monitoring with a monitoring end date the same as the first preparation of the same component.  

2. Schedule of Reporting PSUR
Based on the Regulation of Medical Products under Monitoring declared on September 2004, license holders of new drugs are required to report PSUR every 6 months for two years, and annually for the following three years in the 5-year surveillance period. However, if the drug license was issued before September 2004, the license holders can choose to follow either the old rule or the new one. The two rules are compared in the following table.

　

New drug, drug with a license issued before September 2004
(Old rule)

New drug license issued after September 2004 (New rule)

Surveillance period

7 years

5 years

Reporting PSUR

Every 6 months

Every 6 months for two years and annually thereafter

 

3. Content in the Periodic Safety Update Report (PSUR)
The content of PSUR should include the following information:

  1. Drug information
    1. Generic name
    2. Brand name
    3. Dosage form and dosage
    4. Manufacturer name and address
    5. MAH in Taiwan
    6.  Sales of the drug in Taiwan market as well as in international market (recommended)
  2. Period covered by this report (dates)
  3. Collection of the adverse drug reactions
    1. Domestic and foreign serious adverse drug reaction reports
    2. Domestic and foreign non-serious adverse drug reaction reports (cases presented as line listing)
    3. All adverse reaction related cases report in medical literatures
  4. Summary Tables
  5. Tabulation of all Adverse Drug Reactions by SOC (System Organ Class) in Taiwan
  6. Tabulation of all Adverse Drug Reactions by SOC (System Organ Class) in Others Countries

4. Final Summary Bridging Report

Final summary bridging report should be submitted along with the last PSUR. The safety data should cover the whole surveillance period.

 

5. How to report
The report of serious adverse reactions for new drug under surveillance period should follow the Regulations Governing Reporting of Severe Adverse Reactions to Medicines. Non-serious adverse drug reactions can be included in the content of PSUR and submitted to National Center. All PSURs should be mailed to the National ADR Reporting Center with paper or electronic file attached if necessary.

Mailing address: National ADR Reporting Center
2F, No.32, Sec. 1, Roosevelt Rd., Taipei 100, Taiwan

　

I-3. Medical Devices

 

With the increasing life expectancy and attention to health, the use of medical devices increased rapidly. Medical devices related adverse events were also becoming an important issue. Therefore, the National Medical Device Adverse Event Reporting System was set up in 2002.

The reporting of adverse events of medical devices is regulated by article 45 and article 45-1, Pharmaceutical Affairs Act, as well as the Regulation of Reporting Serious Adverse Reactions and Regulation of Medical Products under Monitoring as drugs. However, the surveillance period of medical device is usually 3 years after the license was issued unless announced individually.

Serious adverse event (SAE) Report for Investigational medical devices under Pre-marketing clinical trials is according to Medical Device Good Clinical Practice which is amended on the 17th May 2007.

We also have a computerized database to integrate related reports. For further information, please check our website: http://adr.doh.gov.tw/adr-med/

　

II. Unexpected Serious Adverse Drug Reaction (SUSAR) Report for Investigational Drugs under Pre-marketing clinical trials

Each unexpected serious adverse drug reaction (SUSAR) during clinical trails should be reported to the DOH for the judgment on the approval of drugs. The purpose of submitting these reports is to make regulators, investigators, and other appropriate people aware of new important information on serious reaction. Therefore, according to the Application Guideline for Clinical Trails , the sponsor has to expedite each unexpected serious adverse drug reaction of the DOH approving clinical trial regardless of happening in Taiwan or not.

 

1. Definition
Serious Adverse Drug Reaction is defined as ADR that results in：

  • Death,
  • Life-threatening,
  • Permanent disability/incapacity,
  • Congenital anomaly/birth defect,
  • Results in hospitalization or prolongation of an existing hospitalization,
  • Needs further management for other possible permanent disabilities

Unexpected is defined as：

     An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational medicinal product). ( ICH E2A ):

2. Reporting Time Frames
According to Article 106, Guidance of Good Clinical Practice, published by the DOH, the reporting time frames of SUSAR are listed below:

  1. Fatal or life-threatening
    DOH or the National ADR Reporting Center should be notified by sponsor as soon as possible, but no later than 7 calendar days, after first acknowledged by the investigator, and a complete report should be followed 8 additional calendar days. This report must include an assessment of the importance and implication of the findings and/or previous experience on the same or similar medical products.
  2. All Other SUSARs
    DOH or the National ADR Reporting Center should be notified by sponsor in a complete report as soon as possible but no later than 15 calendar days after first knowledge by the investigator that a case qualifies.
  3. How to Report
    Please fill the Clinical Trial Reporting Form to expedite SUSAR reporting. All SUSAR reports should be sent to the National ADR reporting center by facsimile, postal mail ( adr@tdrf.org.tw) , or submitted on-line through the website with a password required. To assure the report has been received, please attach the reply form with your report. We will reply you by facsimile transmission within a few working days after receiving the report. If you submit the report on-line, an automated return email will be generated.

III. Reporting of Defect Medical Products 

Reporting of defect medical products is to ensure the quality of medicines By setting up the reporting system, we could prevent people from harm due to defect medical products. 

When the defect medical products are detected, health care providers, manufacturers, and the public are encouraged to report the cases to National ADR Reporting Center through mail, fax, email, or the on-line reporting system.
Please also check our website for related information: http://recall.doh.gov.tw/

　

For Further Information
If further assistance is needed, please contact us:
By Mail: National ADR Reporting Center
2FI., No.32, Roosevelt Rd., Sec.1, Taipei 100 Taiwan
By Telephone: 886-2-2396-0100
By FAX: 886-2-2358-4100
By E-mail: adr@doh.gov.tw

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