Guidance For Industry Safty Reporting

GUIDANCE FOR INDUSTRY SAFETY REPORTING REQUIREMENTS FOR REGISTERED MEDICINAL PRODUCTS

CENTRE FOR DRUG ADMINISTRATION HEALTH SCIENCES AUTHORITY SINGAPORE FEBRUARY 2005

Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

TABLE OF CONTENTS 1

Introduction ………………………………………………………………………………….

2

1.1

Purpose & scope ……………………………………………………………………...

2

1.2

Background ……………………………………………………………………………

2

2

Responsibilities of licence holders ……………………………………………………..

2

3

Reporting requirements …………………………………………………………………...

3

3.1

Spontaneous suspected ADR reports ………………………………………………

3

3.1.1

Content of suspected ADR reports .……………………………………..

4

3.1.2

Follow-up reports ………………………………………………………….

4

3.1.3

ADR reporting forms………….……………………………………………

4

3.1.4

Local non-serious ADR reports & overseas ADR reports …………….

4

3.1.5

Reports from consumers …………………………………………………

5

Scientific literature & other post-marketing safety information..………………….

5

Reporting requirements in special situations .………………………………………..

5

3.2 4

4.1

5

6

The period between submission for registration & the granting of a product licence ………………………………………………………………………………….

5

4.2

Unregistered drugs ..…………………………..……………………………………...

6

4.3

Lack of efficacy ………………………………………………………….…………….

6

4.4

Reporting of outcomes of use during pregnancy ………………………….………

6

4.5

Drug overdoses ……………………………………………………………………….

6

Periodic safety update report (PSUR) ………………………………………….……….

6

5.1

Reporting requirements .……………………………………………………………...

6

5.2

Content of PSUR ..…………………………………………………………………….

7

Update of regulatory authority or company actions taken for safety reasons ….

7

Annex I

Summary of safety reporting requirements ……….…………….………..

9

Annex II (a)

ADR reporting form …………………………………………………………

10

Annex II (b)

General instructions for filling up the ADR reporting form .……………..

12

Annex III

Periodic safety update report submission form ………………….………

13

Annex IV

Glossary ……………………………………………………………………...

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

1

INTRODUCTION

1.1

PURPOSE & SCOPE

February 2005

The purpose of this document is to guide licence holders on the submission of relevant safety information to the Centre for Drug Administration (CDA) of the Health Sciences Authority (HSA). This guidance applies to licence holders who are responsible for introducing registered western medicinal products into Singapore. It addresses the types of documents to be submitted, the timelines and the requirements for reporting drug safety information. The topics covered include the following: Spontaneous suspected adverse drug reaction (ADR) reports ADR reporting in special situations Periodic safety update reports (PSURs) Update of regulatory authority or company actions taken for safety reasons 1.2

BACKGROUND When a new medicinal product is submitted for registration, the demonstration of its efficacy and the evaluation of its safety are generally based on a small number of patients. The limited number of patients included in clinical trials, the exclusion of certain patient groups atrisk, the lack of significant long-term treatment experience, and limitation of concomitant therapies do not allow a thorough evaluation of the safety profile. Under such circumstances, the detection or confirmation of rare ADRs is particularly difficult during the pre-registration development of the product. In order to develop a comprehensive picture of clinical safety, marketed medicinal products have to be closely monitored for their safety when used in actual practice. Surveillance of registered medicinal products is a shared responsibility between the regulatory authority and the licence holder.

2

RESPONSIBILITIES OF LICENCE HOLDERS The licence holder must have a system in-place that will assure the responsibility and liability for its products on the market and to be able to take appropriate action, when necessary. Written procedures for the receipt, evaluation and reporting of ADRs should be established. The licence holder should also appoint a person responsible for matters relating to drug safety. It is the responsibility of the licence holder to contact the Pharmacovigilance (PV) Unit,

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

CDA, proactively whenever there are any changes in the contact details, such as the name of person responsible, designation, telephone number, fax number, email address and mailing address. The contact details should be maintained up-to-date at all times. The responsibilities of the designated person are: To report all safety information as described in this guidance to the CDA. To respond promptly to any request for provision of information necessary for the evaluation of the benefits and risks of a medicinal product. This includes the sales figures and the list of purchasers.

3

REPORTING REQUIREMENTS The licence holder is responsible for reporting suspected ADRs to the CDA and should keep a record of, or have access to, all reports of suspected ADRs that are received from all sources including healthcare professionals, published / unpublished studies and reports.

3.1

SPONTANEOUS SUSPECTED ADR REPORTS A spontaneous report is a clinical observation that originates outside of a formal study. An ADR is suspected if either the reporting person or the licence holder believes there is a possible causal relationship between the adverse reactions and medicinal products in question. Spontaneous reports of suspected ADRs should be reported to the PV Unit, CDA, even if the licence holder does not agree with the reporter’s assessment of a possible causal association, or if the reporter has not provided a causal assessment. Adverse events which are not suspected of being product-related by the healthcare professional attending to the patient should not be reported unless the licence holder has reasons to suspect a causal association. All serious spontaneous ADRs occurring in Singapore should be reported immediately and in no case later than 15 calendar days. The clock for reporting starts as soon as any personnel of the licence holder, including sales representatives, is made aware of the ADRs. There should also be no delay in information transmission from the product owner to the licence holder. Where the licence holder has entered into relationships with another company for the marketing of, or research on, the suspected product, the timeframe for regulatory submission should be no longer than 15 calendar days from first receipt by either the licence holder or that company.

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

3.1.1

February 2005

CONTENTS OF SUSPECTED ADR REPORTS

The ADR reports should be as complete as possible and contain essential information to facilitate assessment.

The minimum information required for the submission of an initial ADR report are: An identifiable patient, An identifiable reporting source, One or more adverse reaction(s), and One or more suspected medicinal product(s). The licence holder should include the name, profession and place of practice of the person making the report to facilitate the detection of duplicate reports. The licence holder may comment on whether there is a causal association between the suspected product(s) and adverse reaction(s) and should provide the explanation on which the causality assessment is made. 3.1.2

FOLLOW-UP REPORTS

To assist in the evaluation of the ADR reports, additional information not available at the time of the initial report should be provided in the form of follow-up reports within 15 calendar days of receipt of new information. The reports should be clearly labelled as follow-up reports (with appropriate cross-referencing). 3.1.3

ADR REPORTING FORMS

The licence holder can submit the ADR report to the Pharmacovigilance (PV) Unit, CDA, using the reporting form prescribed by the unit (see Annex II) or the CIOMS I form. The ADR reporting form can be downloaded from http://www.hsa.gov.sg/adr_form. The completed ADR reports ca n b e sen t vi a m a il , fa x o r email to the PV Unit. Online ADR reporting is also available at http://www.hsa.gov.sg/adr_online. 3.1.4

LOCAL NON-SERIOUS ADR REPORTS & OVERSEAS ADR REPORTS

Local spontaneous reports of non-serious ADRs and ADR reports occurring outside of Singapore need not be reported to the CDA on a regular basis, but should be made available upon request or prepared as line-listings in a Periodic Safety Update Report (if one is required, see section 5).

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

3.1.5

February 2005

REPORTS FROM CONSUMERS

Consumers should be encouraged to seek medical attention and get the attending healthcare professional to report the ADR. This is in recognition of the difficulties posed by the lack of medical details and clinical information for consumer reports. When a consumer is unwilling or unable to do this, the licence holder should attempt to obtain as much information from the consumer. If the adverse reaction is serious, the licence holder should obtain from the consumer voluntary informed consent to contact the treating healthcare provider or relevant information e.g. medical documentation. When there is a reason to suspect a causal association, a report must be submitted to the PV Unit (indicating on the reporting form that it is a consumer report). 3.2

SCIENTIFIC LITERATURE & OTHER POST-MARKETING SAFETY INFORMATION As soon as the licence holder is aware of any scientific / medical literature or information from unpublished study reports, surveys, registries that could change the risk-benefit balance of the registered product, this should be communicated to the PV Unit within 15 calendar days. A copy of the relevant report should be provided. If the report is not in English, submit a summary or translation in English.

4

REPORTING REQUIREMENTS IN SPECIAL SITUATIONS There are some situations that are not covered directly by the reporting requirements detailed in section 3.

4.1

THE PERIOD BETWEEN SUBMISSION FOR REGISTRATION & THE GRANTING OF A PRODUCT LICENCE In the period between submission for registration and the granting of a product licence, it is the responsibility of the applicant to ensure that any new safety information which may impact the benefit to risk balance of the product is immediately submitted to the Product Evaluation & Registration Branch (PER), CDA. What constitutes a change to the benefit to risk balance is a matter of judgement for the applicant but an applicant may be required to justify a decision not to report. For example, another report of a well-known adverse reaction would not be significant, but a report of an unexpected or new serious suspected reaction with good evidence of a causal relationship, or where there is suspicion of a change in the frequency of severity of a known effect, would be considered relevant to the evaluation. Similarly, results from studies which impact on the assessment of efficacy would be significant. The applicant is required to submit a tabulation

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

of serious unexpected ADRs that are not mentioned in the proposed Singapore package insert and have not been submitted previously. 4.2

UNREGISTERED DRUGS The licence holder importing drugs which are not registered with the CDA, other than those for use in clinical trials, should report all suspected cases of local serious ADRs to the PV Unit if the information is made available to them. The licence holder should follow the requirements for ADR reporting as set out in section 3 and indicate that the suspected product reported is exempted from registration.

4.3

LACK OF EFFICACY Local reports of lack of efficacy should be reported to the PV Unit within 15 calendar days. Lack of efficacy is considered an adverse reaction. The underlying principle is that if a drug fails to produce the expected pharmacological or therapeutic benefit, there may be an adverse outcome for the patient, including a worsening of the condition for which the medication is being taken.

4.4

REPORTING OF OUTCOMES OF USE DURING PREGNANCY In the event that a licence holder is aware that its product which is not recommended for use during pregnancy has been consumed by a pregnant patient, the licence holder should follow-up with the doctor on the pregnancy outcome. If a pregnancy results in a serious or an abnormal outcome which the reporting doctor considers might be due to the product, the licence holder must submit the ADR report to the PV Unit within 15 calendar days.

4.5

DRUG OVERDOSES The licence holder need not report cases of drug overdoses.

5

PERIODIC SAFETY UPDATE REPORT (PSUR)

5.1

REPORTING REQUIREMENTS PSURs may be requested for selected registered medicinal products. PSURs are required to be submitted to the Product Evaluation & Registration Branch (PER), CDA, 6-monthly for the first 2 years after marketing approval, after which they are to be submitted on a yearly basis for the subsequent 3 years. This timeframe may be varied in order to harmonise periodic safety updates internationally.

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

Data lock points may be set according to the international birthdate of the medicinal product. Each PSUR should cover the period of time since the last update report and should be submitted within 60 days of the data lock point. Where there are reasons to continue the safety monitoring of a particular product, the CDA may request for PSURs to be submitted after the initial 5 years of marketing approval. For other registered products, PSURs are not required to be submitted on a regular basis. However, PSURs or a summary report of safety data should be maintained for the first 5 years of marketing approval and made available to the CDA, within 30 calendar days upon request. In the event of a major safety concern, the CDA may request for PSURs or a summary report of safety data to be submitted within a shorter timeframe. Each PSUR submitted should be accompanied with the following: A copy of the most updated local package insert and patient information leaflet (if any). A PSUR submission form (see Annex III). The form includes an estimate of drug usage and/or patient exposure (e.g. local sales figures, patient-years exposed, number of prescriptions if available) in relation to the period covered in the PSURs. 5.2

CONTENT OF PSUR For guidance on the format and content of the PSURs, refer to the latest version of the International Conference on Harmonisation (ICH) on the Guidance for Industry E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs. This can be found at http://www.ich.org.

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UPDATE OF REGULATORY AUTHORITY OR COMPANY ACTIONS TAKEN FOR SAFETY REASONS In the event of any regulatory actions taken by other regulatory authorities or action(s) taken by the company i.e. product owner arising from significant drug safety issues, the licence holder must inform the PV Unit promptly as soon as the licence holder is made aware of these issues.

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

Significant safety issues are those which may influence the overall benefit and risk of the product such as: Product withdrawal / recall and product defects (The reporting timeline for the above is 24 hours upon receipt of information by the licence holder. Refer to the Guidelines on Product Defect Reporting and Recall Procedures issued by the Investigation & Surveillance (I&S) Unit, CDA.) Removal of approved indications by benchmarked regulatory agencies* Failure to obtain a product licence renewal due to safety reasons Dissemination of Dear Healthcare Professional Letter related to safety issues The PV Unit should be notified no later than 7 calendar days from the first receipt of information by the licence holder. The safety related reasons that led to these actions should be described and documentation appended where appropriate. Each notification should be accompanied with an assessment by the licence holder, of the significance of the regulatory action in the local context and recommendation(s) on follow-up action(s) to be undertaken locally. Any intention of voluntary local withdrawal / discontinuation of a registered medicinal product by the licence holder arising from safety issues should be discussed with CDA at an early stage.

For enquiries on this document, please refer to: Pharmacovigilance Unit Centre for Drug Administration Health Sciences Authority 11 Biopolis Way #11-03, Helios Singapore 138667 Tel: (65) 6866 3538; Fax: (65) 6478 9069 Email: [email protected]

* Benchmarked regulatory agencies refer to US FDA, UK MHRA, Australia TGA, EU EMEA and Health Canada

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

ANNEX I

SUMMARY OF SAFETY REPORTING REQUIREMENTS The summary of the reporting requirements is shown in the table below (for the detailed requirements, please refer to the relevant sections of the guidance document): Types of information

Description

Reporting timeframe

Submit to

Local reports (spontaneous)

Serious ADRs

Within 15 calendar days from first receipt by licence holder.

PV

Submit follow-up report(s) within 15 calendar days of receipt of new information.

Section 3

Non-serious ADRs

Not required on a routine basis.

-

Foreign reports (spontaneous)

Serious ADRs

Not required on a routine basis.

-

Section 3

Non-serious ADRs

Not required on a routine basis.

-

Periodic safety update reports (PSURs)

For selected products only

6 monthly for first 2 years after marketing approval, then annually for subsequent 3 years or harmonised according to international requirements.

PER

Product withdrawal / product recall / product defect

Within 24 hrs of receipt of information by licence holder.

I&S

Significant safety issues such as:

Within 7 calendar days from initiation of actions by the relevant authority or by product owner.

PV

Section 5 Update of regulatory authority or company actions taken for safety reasons Section 6

Removal of approved indications by benchmarked agencies Failure to obtain a product licence renewal due to safety reasons Dissemination of Dear Healthcare Professional Letter related to safety issues

I&S: PER: PV:

Investigation & Surveillance Unit Product & Evaluation & Registration Division Pharmacovigilance Unit

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

ANNEX II (a) HSA ADR reporting Form Front

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

Back

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

ANNEX II (b) GENERAL INSTRUCTIONS FOR FILLING UP THE ADR REPORTING FORM SECTION I - PARTICULARS OF PATIENT The patient’s identifiers include initials, record number, age, weight, gender and ethnic group. This information should be as complete as possible as they are used to identify duplicate reports. SECTION II - DETAILS OF ADVERSE DRUG REACTION (ADR) Date of onset of ADR If the date is not available, provide the best estimate of the date of first occurrence of ADR. Description of ADR Describe the nature of ADR, its localisation, severity and characteristics. Outcome attributed to the ADR Indicate the consequences of the ADR for the patient (including the date of recovery or death if available), using the worst of the different outcomes for multiple reactions. Sequelae Indicate the sequelae (any permanent complications or injuries as a result of the ADR) if this information is available. SUSPECTED DRUG(S) / CONCOMITANT DRUG(S) Suspected drug(s) Provide either the brand name (preferred) or active ingredient(s) of the medicinal product, also state the dose, frequency, route, start date, end date and indication for which the drug was given (batch numbers are important for vaccines). If the exact dates are unknown, provide the best estimate of date(s) of therapy. Other concomitant drug(s) Indicate whether the patient was on any other medication and provide a list of medicinal products that the patient has been given at the same time or 3 months before the onset of the ADR. Other relevant information Provide any other relevant information that could help in the assessment of the temporal relationship between the observed ADR and suspected medicinal product(s). This includes preexisting medical conditions, renal and hepatic functions, known allergies, pregnancy, smoking or alcohol use, reappearance of ADR with same drug(s) upon rechallenge and relevant laboratory results. Attach additional pages if necessary. SECTION III - MANAGEMENT OF REACTION Indicate if the patient was hospitalised as a result of the ADR and whether the ADR was considered serious. Indicate if any treatment was given for the management of the ADR. SECTION IV - PARTICULARS OF REPORTER Indicate the company’s name and contact number. Each report should also include the name, profession and practice address of the person making the ADR report to the company. These are essential for verification and for further case follow-up if required. Use ‘NIL’ when no information is available. Additional information should be provided when available at a later date. Please indicate that it is a follow-up report. Cross-referencing of follow-up reports is essential to facilitate the detection of duplicate reports.

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

CENTRE FOR DRUG ADMINISTRATION, HEALTH SCIENCES AUTHORITY

February 2005

ANNEX III

PERIODIC SAFETY UPDATE REPORT SUBMISSION FORM I

Product information

Brand name: Active ingredient(s): Local birthdate (Date of registration): II

PSUR information

International birthdate: Period covered by this report (data lock point): Total number of volume for current submission: III

Sale figures (Singapore)

Please indicate the local sales volume and/or estimated patient exposure for the same period covered in the PSUR.

IV

Company particulars

Company: Address: Name of personnel: Designation of personnel: Telephone number: Fax number: Email address: Signature / date: V

Comments

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

February 2005

ANNEX IV GLOSSARY 1.

Adverse drug reaction (ADR) A reaction which is noxious (harmful) and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or treatment of a disease, or for the modification of a physiological function.

2.

Causality assessment Determination of whether there is reasonable possibility that the product is etiologically related to the adverse drug reaction. Causality assessment includes assessment of temporal relationships, dechallenge / rechallenge information, association with (or lack of association with) underlying disease, presence (or absence) of a more likely cause, plausibility.

3.

CIOMS I form An adverse reaction reporting form developed by the Council for International Organisations of Medical Sciences (CIOMS), intended for notifying the regulatory authorities of countries other than the country where the report originated.

4.

Data Lock Point (cut-off date) The date designated as the cut-off date for data to be included in a periodic safety update report (PSUR).

5.

International birthdate (IBD) The date of the first marketing approval for a medicinal product granted to a licence holder in any country in the world.

6

Licence holder The company or legal entity responsible for introducing (one or more consignments of) a western medicinal product into the Singapore market, and which has been granted authorisation to do so by way of a product licence or import licence. This party is responsible for each consignment of the product that it has introduced into the market, and this responsibility extends to all aspects of the product including safety, quality and continued compliance with the conditions attached to the licence. The party must subject to the jurisdiction of the country that issued the authorisation, which normally means being physically located in that country.

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Guidance for Industry – Safety Reporting Requirements for Registered Medicinal Products

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February 2005

Periodic safety update report (PSUR) An integrated summary assessment of all adverse reaction reports, both serious and non-serious. It records information on medicinal product safety from different sources and is collated to allow for mutual exchange of safety data among regulatory authorities.

8

Product owner A company who is the legal / registered owner of the product formulation and/or the manufacturing process pertaining to the product, and with whom the licence holder has a contract.

9

Serious adverse drug reaction (ADR) A reaction is considered to be serious if it: is fatal. is life-threatening. results in persistent or significant disability / incapacity. requires in-patient hospitalisation or prolongs existing hospitalisation. results in birth defects. is medically significant. NB: The term life-threatening in the definition of ‘serious’ refers to an event in which the patient was at risk of death at the time of event; it does not refer to an event which hypothetically might have caused death if it were more severe. Medical judgement should be exercised in deciding whether a reaction is serious in other situations. Important adverse reactions that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise the patient should be considered as serious.

10.

Spontaneous adverse drug reaction (ADR) reports Also referred to as voluntary, unsolicited or anecdotal reports. It is a clinical observation that originates outside of a formal study.

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