reporting req for meds

7/27/2019 Reporting Req for Meds

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GUIDANCE FOR INDUSTRY

SAFETY REPORTING REQUIREMENTS FOR

REGISTERED MEDICINAL PRODUCTS

APRIL 2011


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Guidance for Industry Safety Reporting Requirements for Registered Medicinal Products April 2011

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TABLE OF CONTENTS

1 Introduction . 3

1.1 Purpose & scope ... 3

1.2 Background 3

2 Responsibilities of product licence holder.. 3

3 Reporting requirements ... 4

3.1 Spontaneous suspected AR reports .. 4

3.1.1 Fatal or Life-threatening Spontaneous Suspected AR reports 43.1.2 All other serious spontaneous suspected AR reports ... 53.1.3 Contents of suspected AR reports .... 5

3.1.4 Follow-up reports ..... 53.1.5 AR reporting forms ... 53.1.6 Local non-serious AR reports & overseas AR reports ... 63.1.7 Reports from consumers . 6

3.2 Scientific literature & other post-marketing safety information ... 6

4 Reporting requirements in special situations 6

4.1 The period between submission for registration & the granting of a productlicence . 6

4.2 Unregistered medicinal products ........ 74.3 Lack of efficacy .. 74.4 Reporting of outcomes of use during pregnancy . 7

4.5 Drug overdoses . 7

5 Periodic safety update report (PSUR) .. 8

5.1 Reporting requirements .... 85.2 Content of PSUR ... 8

6 Update of regulatory authority or company actions taken for safety reasons. 9

Annex I Summary of safety reporting requirements .... 10

Annex II (a) AR and Vaccine Adverse Event reporting forms ... 11

Annex II (b) General instructions for filling up the AR reporting form ...... 15

Annex III Periodic safety update report submission form . 16

Annex IV Glossary ... 17


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1 INTRODUCTION

1.1 PURPOSE & SCOPE

The purpose of this document is to guide product licence holder on the submission of

relevant safety information to the Vigilance Branch of the Health Products Regulation Group

(HPRG) of the Health Sciences Authority (HSA).

This guidance applies to product licence holder who is responsible for introducing registered

medicinal products into Singapore. It addresses the types of documents to be submitted, the

timelines and the requirements for reporting safety information of medicinal products. The

topics covered include the following:

Spontaneous suspected adverse reaction (AR) reports

AR 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 at

risk, 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 ARs 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 product licence holder.

2 RESPONSIBILITIES OF PRODUCT LICENCE HOLDER

The product 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 ARs should be

established.


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The product licence holder should also appoint a person responsible for matters relating to

product safety. It is the responsibility of the product licence holder to contact the Vigilance

(VB) Branch, HPRG, 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 HPRG.

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 product licence holder is responsible for reporting suspected ARs to the HPRG and

should keep a record of, or have access to, all reports of suspected ARs that are received

from all sources including healthcare professionals, published / unpublished studies and

reports.

3.1 SPONTANEOUS SUSPECTED AR REPORTS

A spontaneous report is a clinical observation that originates outside of a formal study. An AR

is suspected if either the reporting person or the product licence holder believes there is a

possible causal relationship between the adverse reactions and medicinal products in

question. Spontaneous reports of suspected ARs should be reported to the Vigilance Branch,

HPRG, even if the product licence holderdoes not agree with the reporters 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 product licence holder has reasons

to suspect a causal association.

3.1.1 FATAL OR LIFE-THREATENING SPONTANEOUS SUSPECTED AR REPORTS

All fatal or life-threatening spontaneous ARs occurring in Singapore should be reported to the

Vigilance Branch, HPRG as soon as possible but no later than 7 calendar days after first

knowledge by the product licence holder, followed by as complete a report as possible within

8 additional calendar days.
http://www.hsa.gov.sg/docs/contactinfor.dochttp://www.hsa.gov.sg/docs/contactinfor.doc


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3.1.2 ALL OTHER SERIOUSSPONTANEOUS SUSPECTED AR REPORTS

All other serious spontaneous ARs occurring in Singapore should be reported to the Vigilance

Branch, HPRG as soon as possible and no later than 15 calendar days after first knowledge

by the product licence holder. The clock for reporting starts as soon as any personnel of the

product licence holder, including sales representatives, is made aware of the ARs.

3.1.3 CONTENTS OF SUSPECTED AR REPORTS

The AR reports should be as complete as possible and contain essential information to

facilitate assessment.

The minimum information required for the submission of an initial AR report are:

An identifiable patient,

An identifiable reporting source,

One or more adverse reaction(s), and

One or more suspected medicinal product(s).

The product 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 product 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.

3.1.4 FOLLOW-UP REPORTS

To assist in the evaluation of the AR 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).

3.1.5 AR REPORTING FORMS

The product licence holder can submit the AR report to the Vigilance Branch (VB), HPRG,

using the reporting form prescribed by the unit (see Annex II) or the CIOMS I form. The AR

reporting form can be downloaded fromhttp://www.hsa.gov.sg/adr_form. The completed AR

reports can be sent via mail, fax or email to the VB. Online AR reporting is also

available athttp://www.hsa.gov.sg/ae_online
http://www.hsa.gov.sg/adr_formhttp://www.hsa.gov.sg/adr_formhttp://www.hsa.gov.sg/adr_formhttp://www.hsa.gov.sg/ae_onlinehttp://www.hsa.gov.sg/ae_onlinehttp://www.hsa.gov.sg/ae_onlinehttp://www.hsa.gov.sg/ae_onlinehttp://www.hsa.gov.sg/adr_form


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3.1.6 LOCAL NON-SERIOUS AR REPORTS & OVERSEAS AR REPORTS

Local spontaneous reports of non-serious ARs and AR reports occurring outside of

Singapore need not be reported to the HPRG 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).

3.1.7 REPORTS FROM CONSUMERS

Consumers should be encouraged to seek medical attention and get the attending healthcare

professional to report the AR. 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 product licence holder should attempt to obtain as much information

from the consumer. If the adverse reaction is serious, the product 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 Vigilance Branch (indicating

on the reporting form that it is a consumer report).

3.2 SCIENTIFIC LITERATURE & OTHER POSTMARKETING SAFETY INFORMATION

As soon as the product licence holder is aware of any scientific / medical literature or

information from unpublished / published study reports, surveys, registries that could change

the risk-benefit balance of the registered product, this should be communicated to the

Vigilance Branch within 15 calendar days after first knowledge by the product licence holder.

A copy of the relevant report should be provided. If the report is not in English, submission of

a summary or translation in English is required.

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 Pharmaceuticals &

Biologics Branch (PBB), Pre-marketing Division , HPRG.


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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 to HSA. 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 or 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

of serious unexpected ARs that are not mentioned in the proposed Singapore package insert

and have not been submitted previously.

4.2 UNREGISTERED MEDICINAL PRODUCTS

The product licence holder importing medicinal products which are not registered with the

HPRG, other than those for use in clinical trials, should report all suspected cases of local

serious ARs to the Vigilance Branch if the information is made available to them. The product

licence holder should follow the requirements for AR 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 Vigilance Branch within 15 calendar

days after first knowledge by the product licence holder. The underlying principle is that if amedicinal product 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 product licence holder is aware that its product which is not recommended

for use during pregnancy has been consumed by a pregnant patient, the product 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 product licence holder must submit the AR report to the Vigilance Branch within

15 calendar days after first knowledge by the product licence holder.

4.5 DRUG OVERDOSES

The product licence holder need not report cases of drug overdoses.


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5 PERIODIC SAFETY UPDATE REPORT (PSUR)

5.1 REPORTING REQUIREMENTS

PSURs may be requested for selected registered medicinal products. If requested, PSURs

are required to be submitted to the Vigilance Branch, Vigilance, Compliance and

Enforcement Division, HPRG, 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.

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 HPRG 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 HPRG upon request. In the event of a

major safety concern, the HPRG 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 athttp://www.ich.org.
http://www.ich.org/http://www.ich.org/http://www.ich.org/http://www.ich.org/


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6 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 safety issues, the product licence

holder must inform the Vigilance Branch promptly, as soon as the product licence holder is

made aware of these issues.

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 product licence holder. Refer to the Guidelines on Product Defect Reporting

and Recall Procedures issued by the Enforcement Branch (EB), HPRG.

Removal of approved indications by reference regulatory agencies*

Failure to obtain a product licence renewal due to safety reasons

Dissemination of Dear Healthcare Professional Letter related to safety issues

The Vigilance Branch should be notified no later than 7 calendar days from the first receipt of

information by the product 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 product 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 product

licence holder arising from safety issues should be discussed with HPRG at an early stage.

For enquiries on this document, please refer to:Vigilance Branch, Health Products Regulation Group

Health Sciences Authority

11 Biopolis Way

#11-03, Helios

Singapore 138667

Tel: (65) 6866 3538; Fax: (65) 6478 9069

Email:[email protected]

* Reference regulatory agencies refer to US FDA, UK MHRA, Australia TGA, EU EMEA and Health Canada.
mailto:[email protected]:[email protected]:[email protected]:[email protected]


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ANNEX I

SUMMARY OF SAFETY REPORTING REQUIREMENTS

The summary of the reporting requirements is shown in the table below (for the detailedrequirements, please refer to the relevant sections of the guidance document):

Types of

information

Description Reporting timeframe Submit

to

Local reports(spontaneous)

Section 3

Fatal or life-threatening ARs No later than 7 calendardays after first knowledgeby the product licenceholder, followed by ascomplete a report aspossible within 8 additionalcalendar days.

VB

All other serious ARs No later than 15 calendardays after first knowledge

by the product licenceholder.

Non-serious ARs Not required on a routinebasis.

-

Foreign reports(spontaneous)

Section 3

Serious ARs Not required on a routinebasis.

-

Non-serious ARs Not required on a routinebasis.

-

Periodic safetyupdate reports(PSURs)

Section 5

For selected products only 6 monthly for first 2 yearsafter marketing approval,then annually forsubsequent 3 years orharmonised according tointernational requirements.

PBB

Update ofregulatoryauthority orcompany actionstaken for safetyreasons

Section 6

Product withdrawal / product recall /product defect

Within 24 hrs after firstknowledge by the productlicence holder.

EB

Significant safety issues such as:

Removal of approved indicationsby reference agencies

Failure to obtain a product licencerenewal due to safety reasons

Dissemination of Dear HealthcareProfessional Letter related tosafety issues

Within 7 calendar days

from initiation of actions bythe relevant authority or byproduct owner.

VB

EB: Enforcement BranchPBB: Pharmaceuticals & Biologics BranchVB: Vigilance Branch


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ANNEX II (a)

HSA AR REPORTING FORM

Front


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Back


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Front


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Back


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ANNEX II (b)

GENERAL INSTRUCTIONS FOR FILLING UP THE AR REPORTING FORM

SECTION I - PARTICULARS OF PATIENT

The patients 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 REACTION (AR)

Date of onset of AR

If the date is not available, provide the best estimate of the date of first occurrence of AR.

Description of AR

Describe the nature of AR, its localisation, severity and characteristics.

Outcome attributed to the AR

Indicate the consequences of the AR for the patient (including the date of recovery or death ifavailable), using the worst of the different outcomes for multiple reactions.

Sequelae

Indicate the sequelae (any permanent complications or injuries as a result of the AR) if thisinformation 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, alsostate 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 bestestimate of date(s) of therapy.

Other concomitant drug(s)

Indicate whether the patient was on any other medication and provide a list of medicinal productsthat the patient has been given at the same time or 3 months before the onset of the AR.

Other relevant information

Provide any other relevant information that could help in the assessment of the temporalrelationship between the observed AR and suspected medicinal product(s). This includes pre-existing medical conditions, renal and hepatic functions, known allergies, pregnancy, smoking oralcohol use, reappearance of AR with same drug(s) upon rechallenge and relevant laboratoryresults. Attach additional pages if necessary.

SECTION III - MANAGEMENT OF REACTION

Indicate if the patient was hospitalised as a result of the AR and whether the AR was consideredserious. Indicate if any treatment was given for the management of the AR.

SECTION IV - PARTICULARS OF REPORTER

Indicate the companys name and contact number. Each report should also include the name,profession and practice address of the person making the AR report to the company. These areessential for verification and for further case follow-up if required.

Use NIL when no information is available. Additional information should be provided when availableat a later date. Please indicate that it is a follow-up report. Cross-referencing of follow-up reports isessential to facilitate the detection of duplicate reports.


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ANNEX IIIHEALTH PRODUCTS REGULATION GROUP, HEALTH SCIENCES AUTHORITY

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 thisreport (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 periodcovered 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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ANNEX IV

GLOSSARY

1. Adverse reaction (AR)

An adverse reaction to a health product means any adverse effect that is unintended and

occurs in association with the use or administration of the product at doses normally

used in man for the prophylaxis, diagnosis, or therapy of disease or for the restoration,

correction or modification of physiological function.

2. Causality assessment

Determination of whether there is reasonable possibility that the product is etiologically

related to the adverse 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 product licence holder in any country in the world.

6 Product 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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7 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 product licence

holder has a contract.

9 Serious adverse reaction (AR)

A serious adverse reaction to a health product means an adverse reaction that

results in a persons death.

threatens a persons life

results in a person being hospitalised as an in-patient or prolongs a

persons existing stay in hospital

results in a persons persistent or significant disability or incapacity.

results in a congenital anomaly or birth defect; or

is judged to be medically important even though the event might not be

immediately life-threatening or result in death or hospitalisation, but might

jeopardise the person or might require intervention to prevent one of the

other outcomes listed above.

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 asserious.

10. Spontaneous adverse reaction (AR) 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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Contact:

Vigilance BranchVigilance, Compliance & Enforcement Division

Health Products Regulation GroupHealth Sciences Authority

11 Biopolis Way, #11-03 HeliosSingapore 138667www.hsa.gov.sgTel: 6866 3538

Fax: 6478 9069

reporting req for meds

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