Good Pharmacovigilance Practices

In this post we will learn about Good Pharmacovigilance Practices which includes its background, good reporting practices, Characters of good report forms, Developing a case series as well as Pharmacovigilance plan and Pharmacoepidemiology.

Introduction to Good Pharmacovigilance Practices

Good pharmacovigilance practices provide guidance to industry on good pharmacovigilance practices and pharmacoepidemiologic assessment of observational data regarding drugs, including biological drug products (excluding blood and blood components). Specifically, this document provides guidance on:

• Safety signal identification
• Pharmacoepidemiologic assessment and safety signal interpretation, and
• Pharmacovigilance plan development.

Food and Drug Administration (FDA’s) guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidance’s describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance’s means that something is suggested or recommended, but not required.

Background

This guidance has been prepared by the PDUFA III Pharmacovigilance Working Group, which includes members from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.

For ease of reference, this guidance uses the term product or drug to refer to all products (excluding blood and blood components) regulated by CDER and CBER. Similarly, for ease of reference, this guidance uses the term approval to refer to both drug approval and biologic licensure.

PDUFA III’s Risk Management Guidance Goal

On June 12, 2002, Congress reauthorized, for the second time, the Prescription Drug User Fee Act (PDUFA III). In the context of PDUFA III, FDA agreed to satisfy certain performance goals. One of those goals was to produce guidance for industry on risk management activities for drug and biological products. As an initial step towards satisfying that goal, FDA sought public comment on risk management.

Specifically, FDA issued three concept papers. Each paper focused on one aspect of risk management, including

• Conducting premarketing risk assessment,
• Developing and implementing risk minimization tools, and performing post marketing pharmacovigilance and
pharmacoepidemiologic assessments.

In addition to receiving numerous written comments regarding the three concept papers, FDA held a public workshop on April 9 – 11, 2003, to discuss the concept papers. FDA considered all of the comments received in developing three draft guidance documents on risk management activities. The draft guidance documents were published on May 5, 2004, and the public was provided with an opportunity to comment on them until July 6, 2004. FDA considered all of the comments received in producing the
final guidance documents.

Overview of the Risk Management Guidances

Together, risk assessment and risk minimization form what FDA calls risk management. Specifically, risk management is an iterative process of:

• Assessing a product’s benefit-risk balance,
• Developing and implementing tools to minimize its risks while preserving its benefits,
• Evaluating tool effectiveness and reassessing the benefit-risk balance, and
• making adjustments, as appropriate, to the risk minimization tools to further improve the benefit-risk balance.

This four part process should be continuous throughout a product’s lifecycle, with the results of risk assessment informing the sponsor’s decisions regarding risk minimization.

Reviewing the recommendations provided in the Guidance

When reviewing the recommendations provided in this guidance, sponsors and applicants should keep the following
points in mind:

• Many recommendations in this guidance are not intended to be generally applicable to all products.

Industry already performs risk assessment and risk minimization activities for products during development and marketing. The Federal Food, Drug, and Cosmetic Act (FDCA) and FDA implementing regulations establish requirements for routine risk assessment and risk minimization (see e.g., FDA requirements for professional labeling, and adverse event monitoring and reporting).

As a result, many of the recommendations presented here focus on situations when a product may pose a clinically important and unusual type or level of risk. To the extent possible, we have specified in the text whether a recommendation is intended for all products or only this subset of products.

• It is of critical importance to protect patients and their privacy during the generation of safety data and the development of risk minimization action plans. During all risk assessment and risk minimization activities, sponsors must comply with applicable regulatory requirements involving human subject’s research and patient privacy.

• To the extent possible, this guidance conforms to FDA’s commitment to harmonize international definitions and standards as appropriate. The topics covered in this guidance are being discussed in a variety of international forums. We are participating in these discussions and believe that, to the extent possible, the recommendations in this guidance reflect current thinking on related issues.

• When planning risk assessment and risk minimization activities, sponsors should consider input from health care participants likely to be affected by these activities (e.g.,from consumers, pharmacists and pharmacies, physicians, nurses, and third party payers).

• There are points of overlap among the three guidance’s.

We have tried to note in the text of each guidance when areas of overlap occur and when referencing one of the other guidance’s might be useful.

The Role of Risk Management, Pharmacovigilance and Pharmacoepidemiology

• Risk assessment during product development should be conducted in a thorough and rigorous manner; however, it is impossible to identify all safety concerns during clinical trials. Once a product is marketed, there is generally a large increase in the number of patients exposed, including those with co-morbid conditions and those being treated with concomitant medical products. Therefore, post marketing safety data collection and risk assessment based on observational data are critical for evaluating and characterizing a product’s risk profile and for making informed decisions on risk minimization.

• This guidance document focuses on pharmacovigilance activities in the post-approval period. This guidance uses the term pharmacovigilance to mean all scientific and data gathering activities relating to the detection, assessment, and understanding of adverse events. This includes the use of pharmacoepidemiologic studies. These activities are undertaken with the goal of identifying adverse events and understanding, to the extent possible, their nature, frequency, and potential risk factors.

• Pharmacovigilance principally involves the identification and evaluation of safety signals. In this guidance document, safety signal refers to a concern about an excess of adverse events compared to what would be expected to be associated with a product’s use. Signals can arise from post marketing data and other sources, such as preclinical data and events associated with other products in the same pharmacologic class.

It is possible that even a single well documented case report can be viewed as a signal, particularly if the report describes a positive recalling or if the event is extremely rare in the absence of drug use. Signals generally indicate the need for further investigation, which may or may not lead to the conclusion that the product caused the event. After a signal is identified, it should be further assessed to determine whether it represents a potential safety risk and whether other action should be taken.

Identifying and describing Safety Signals

Good pharmacovigilance practice is generally based on acquiring complete data from spontaneous adverse event reports, also known as case reports. The reports are used to develop case series for interpretation.

Good Reporting Practices

Spontaneous case reports of adverse events submitted to the sponsor and FDA, and reports from other sources, such as the medical literature or clinical studies, may generate signals of adverse effects of drugs.

The quality of the reports is critical for appropriate evaluation of the relationship between the product and adverse events. FDA recommends that sponsors make a
reasonable attempt to obtain complete information for case assessment during initial contacts and subsequent follow-up, especially for serious events, and encourages sponsors to use trained health care practitioners to query reporters. Computer assisted interview technology, targeted questionnaires, or other methods developed to target specific events can help focus the line of questioning.

When the report is from a consumer, it is often important to obtain permission to contact the health care practitioner familiar with the patient’s adverse event to obtain further medical information and to retrieve relevant medical records, as needed. FDA suggests that the intensity and method of case follow-up be driven by the seriousness of the event reported, the report’s origin (e.g., health care practitioner, patient, literature), and other factors.

FDA recommends that the most aggressive follow-up efforts be directed towards serious adverse event reports, especially of adverse events not known to occur with the drug.

Characteristics of a good Case report

Now let’s see elements of Good case reports which include:

1. Description of the adverse events or disease experience, including time to onset of signs or symptoms;

2. Suspected and concomitant product therapy details (i.e., dose, lot number, schedule, dates, duration), including over-the-counter medications, dietary supplements, and recently discontinued medications;

3. Patient characteristics, including demographic information (e.g., age, race, sex), baseline medical condition prior to product therapy, co-morbid conditions, use of concomitant medications, relevant family history of disease, and presence of other risk factors;

4. Documentation of the diagnosis of the events, including methods used to make the diagnosis;

5. Clinical course of the event and patient outcomes (e.g., hospitalization or death);

6. Relevant therapeutic measures and laboratory data at baseline, during therapy, and subsequent to therapy, including blood levels, as appropriate;

7. Information about response to dechallenge and rechallenge; and

8. Any other relevant information (e.g., other details relating to the event or information on benefits received by the patient, if important to the assessment of the event).

Reports of Medication Errors

For reports of medication errors, good case reports also include full descriptions of the following, when such information is available:

1. Products involved (including the trade (proprietary) and established (proper) name, manufacturer, dosage form, strength, concentration, and type and size of container);

2. Sequence of events leading up to the error;

3. Work environment in which the error occurred; and

4. Types of personnel involved with the error, type(s) of error, and contributing factors.

5 Patient outcomes may not be available at the time of initial reporting. In these cases, follow-up reports can convey important information about the course of the event and serious outcomes, such as hospitalization or death.

Developing a Case Series

FDA suggests that sponsors initially evaluate a signal generated from post marketing spontaneous reports through a careful review of the cases and a search for additional cases.

Additional cases could be identified from the sponsor’s global adverse event databases, the published literature, and other available databases, such as FDA’s Adverse Event Reporting System (AERS) or Vaccine Adverse Events Reporting System (VAERS), using thorough database search strategies based on updated coding terminology (e.g., the Medical Dictionary for Regulatory Activities (MedDRA)).

When available, FDA recommends that standardized case definitions (i.e., formal criteria for including or excluding a case) be used to assess potential cases for inclusion in a case series.7 In general, FDA suggests that caselevel review occur before other investigations or analyses. FDA recommends that emphasis usually be placed on review of serious, unlabeled adverse events, although other events may warrant further investigation.

Assessing Case Reports

As part of the case-level review, FDA suggests that sponsors evaluate individual case reports for clinical content and completeness, and follow up with reporters, as necessary. It is important to remove any duplicate reports. In assessing case reports, FDA recommends that sponsors look for features that may suggest a causal relationship between the use of a product and the adverse event, including:

1. Occurrence of the adverse event in the expected time (e.g., type 1 allergic reactions occurring within days of therapy, cancers developing after years of therapy);

2. Absence of symptoms related to the event prior to exposure;

3. Evidence of positive dechallenges or positive rechallenge;

4. Consistency of the event with the established pharmacological/toxicological effects of the product, or for vaccines, consistency with established infectious or
immunologic mechanisms of injury;

5. Consistency of the event with the known effects of other products in the class;

6. Existence of other supporting evidence from preclinical studies, clinical trials, and/or pharmacoepidemiologic studies; and

7. Absence of alternative explanations for the event (e.g., no concomitant medications that could contribute to the event; no co- or pre-morbid medical conditions).

Confounded cases are common, especially among patients with complicated medical conditions. Confounded cases (i.e., cases with adverse events that have possible
etiologies other than the product of concern) could still represent adverse effects of the product under review.

FDA recommends that sponsors carefully evaluate these cases and not routinely exclude them. Separate analyses of unconfounded cases may be useful.

Individual Case Report

For any individual case report, it is rarely possible to know with a high level of certainty whether the event was caused by the product. To date, there are no internationally agreed upon standards or criteria for assessing causality in individual cases, especially for events that often occur spontaneously (e.g. stroke, pulmonary embolism).

Rigorous pharmacoepidemiologic studies, such as case-control studies and cohort studies with appropriate follow-up, are usually employed to further examine the potential association between a product and an adverse event. FDA does not recommend any specific categorization of causality, but the categories probable, possible, or unlikely have been used previously.

8. If a causality assessment is undertaken, FDA suggests that the causal categories be specified and described in sufficient detail to understand the underlying logic in the classification. If the safety signal relates to a medication error, FDA recommends that sponsors report all known contributing factors that led to the event. A number of references are available to assist sponsors in capturing a complete account of the event.

9. FDA recommends that sponsors follow up to the extent possible with reporters to capture a complete account of the event, focusing on the medication use systems (e.g., prescribing/order process, dispensing process, administration process). This data may be informative in developing strategies to minimize future errors.

Summary Descriptive Analysis of a Case Series

In the event that one or more cases suggest a safety signal warranting additional investigation, FDA recommends that a case series be assembled and descriptive clinical information be summarized to characterize the potential safety risk and, if possible, to identify risk factors. A case series commonly includes an analysis of the following:

1. The clinical and laboratory manifestations and course of the event;

2. Demographic characteristics of patients with events (e.g., age, gender, race);

3. Exposure duration;

4. Time from initiation of product exposure to the adverse event.

5. Doses used in cases, including labeled doses, greater than labeled doses, and overdoses;

6. Use of concomitant medications;

7. The presence of co-morbid conditions, particularly those known to cause the adverse event, such as underlying hepatic or renal impairment;

8. The route of administration (e.g., oral vs. parenteral);

9. Lot numbers, if available, for products used in patients with events; and

10. Changes in event reporting rate over calendar time or product life cycle.

Use of Data Mining to identify Drug-Event combinations

At various stages of risk identification and assessment, systematic examination of the reported adverse events by using statistical or mathematical tools, or so-called data mining, can provide additional information about the existence of an excess of adverse events reported for a product.

By applying data mining techniques to large adverse event databases, such as FDA’s AERS or VAERS, it may be possible to identify unusual or unexpected product-event combinations warranting further investigation.

Data mining can be used to augment existing signal detection strategies and is especially useful for assessing patterns, time trends, and events associated with drug-drug interactions. Data mining is not a tool for establishing causal attributions between products and adverse events.

Methods of Data Mining

The methods of data mining currently in use usually generate a score comparing which includes following three elements

• The fraction of all reports for a particular event (e.g., liver failure) for a specific drug (i.e., the “observed reporting fraction”) with
• The fraction of reports for the same particular event for all drugs (i.e., “the expected reporting fraction”).
• This analysis can be refined by adjusting for aspects of reporting (e.g., the reporting year) or characteristics of the patient (e.g., age or gender) that might influence the amount of reporting. In addition, it may be possible to limit data mining to an analysis for drugs of a specific class or for drugs that are used to treat a particular disease.

The score (or statistic) generated by data mining quantifies the disproportionality between the observed and expected values for a given product-event combination. This score is compared to a threshold that is chosen by the analyst. A potential excess of adverse events is operationally defined as any product-event combination with a score exceeding the specified threshold. Applying data mining to large databases (such as AERS), it is not unusual for a product to have several product-event combinations with scores above a specified threshold.

The lower the threshold, the greater the likelihood that more combinations will exceed the threshold and will warrant further investigation.

Safety Signals that may warrant further Investigations

FDA believes that the methods described above will permit a sponsor to identify and preliminarily characterize a safety signal.

The actual risk to patients cannot be known from these data because it is not possible to characterize all events definitively and because there is invariably under-reporting of some extent and incomplete information about duration of therapy, numbers treated, etc.

Safety signals that may warrant further investigation may include, but are not limited to, the following:

1. New unlabeled adverse events, especially if serious;
2. An apparent increase in the severity of a labeled event;
3. Occurrence of serious events thought to be extremely rare in the general population;
4. New product-product, product-device, product-food, or product-dietary supplement interactions;
5. Identification of a previously unrecognized at-risk population (e.g., populations with specific racial or genetic
predispositions or co-morbidities);
6. Confusion about a product’s name, labeling, packaging, or use;
7. Concerns arising from the way a product is used (e.g., adverse events seen at higher than labeled doses or in populations not recommended for treatment);
8. Concerns arising from potential inadequacies of a currently implemented risk minimization action plan (e.g., reports of
serious adverse events that appear to reflect failure of a Risk MAP goal); and
9. Other concerns identified by the sponsor or FDA.

Investigating a Signal through Observational studies

FDA recognizes that there are a variety of methods for investigating a safety signal. Signals warranting additional investigation can be further evaluated through carefully designed nonrandomized observational studies of the product’s use in the “real world” and randomized trials. The Premarketing Guidance discusses a number of types of randomized trials, including the large simple safety study, which is a risk
assessment method that could be used either pre- or postapproval.

This document focuses on three types of non-randomized observational studies:

(1) Pharmacoepidemiologic studies,
(2) Registries, and
(3) Surveys.

By focusing this guidance on certain risk assessment methods, we do not intend to advocate the use of these approaches over
others. FDA encourages sponsors to consider all methods to evaluate a particular safety signal. FDA recommends that sponsors choose the method best suited to the particular signal and research question of interest. Sponsors planning to evaluate a safety signal are encouraged to communicate with FDA as their plans progress.

Pharmacoepidemiologic Studies

Pharmacoepidemiologic studies can be of various designs, including cohort (prospective or retrospective), case-control, nested case-control, case crossover, or other models. The results of such studies may be used to characterize one or more safety signals associated with a product, or may examine the natural history of a disease or drug utilization patterns. Unlike a case series, a pharmacoepidemiologic study which is designed to assess the risk attributed to a drug exposure has a protocol and control group and tests prespecified hypotheses.

Pharmacoepidemiologic studies can allow for the estimation of the relative risk of an outcome associated with a product, and some (e.g., cohort studies) can also provide estimates of risk (incidence rate) for an adverse event. Sponsors can initiate pharmacoepidemiologic studies at any time. They are sometimes started at the time of initial marketing, based on questions that remain after review of the premarketing data.

More often, however, they are initiated when a safety signal has been identified after approval. Finally, there may also be occasions when a pharmacoepidemiologic study is initiated prior to marketing (e.g., to study the natural history of disease or patterns of product use, or to estimate background rates for adverse events).

Describing methodologies for Pharmacoepidemiologic Studies

There are a number of references describing methodologies for pharmacoepidemiologic studies, discussing their strengths and limitations, and providing guidelines to facilitate the conduct, interpretation, and documentation of such studies.

Consequently, this guidance document does not comprehensively address these topics. However, a protocol for a pharmacoepidemiologic study generally includes:

•Clearly specified study objectives;
•A critical review of the literature; and
•A detailed description of the research methods, including:
•The population to be studied;
•The case definitions to be used;
•The data sources to be used (including a rationale for data sources if from outside the U.S.);
•The projected study size and statistical power calculations; and
•The methods for data collection, management, and analysis.

Depending on the type of pharmacoepidemiologic study planned, there are a variety of data sources that may be used, ranging from the prospective collection of data to the use of existing data, such as data from previously conducted clinical trials or large databases. In recent years, a number of pharmacoepidemiologic studies have been conducted in automated claims databases (e.g., HMO, Medicaid) that allow retrieval of records on product exposure and patient outcomes.

In addition, recently, comprehensive electronic medical record databases have also been used for studying drug safety issues.

Depending on study objectives, factors that may affect the choice of databases include the following:

•Demographic characteristics of patients enrolled in the health plans (e.g., age, geographic location);
•Turnover rate of patients in the health plans;
•Plan coverage of the medications of interest;
•Size and characteristics of the exposed population available for study;
•Availability of the outcomes of interest;
•Ability to identify conditions of interest using standard medical coding systems (e.g., International Classification of Diseases
(ICD-9)), procedure codes or prescriptions that could be used as markers;
•Access to medical records; and
•Access to patients for data not captured electronically.

For most pharmacoepidemiologic studies, FDA recommends that sponsors validate diagnostic findings through a detailed
review of at least a sample of medical records. If the validation of the specific outcome or exposure of interest using the
proposed database has been previously reported, FDA recommends that the literature supporting the validity of the
proposed study be submitted for review.

Developing a Pharmacovigilance Plan

For most products, routine pharmacovigilance (i.e., compliance with applicable post market requirements under the FDCA and FDA implementing regulations) is sufficient for post marketing risk assessment. However, in certain limited instances, unusual safety risks may become evident before approval or after a product is marketed that could suggest that consideration by the sponsor of a pharmacovigilance plan may be appropriate.

A pharmacovigilance plan is a plan developed by a sponsor that is focused on detecting new safety risks and/or evaluating already identified safety risks. Specifically, a pharmacovigilance plan describes pharmacovigilance efforts above and beyond routine post marketing spontaneous reporting, and is designed to enhance and expedite the sponsor’s acquisition of safety information. The development of pharmacovigilance plans may be useful at the time of product launch or when a safety risk is identified during product marketing. FDA recommends that a sponsor’s decision to develop a pharmacovigilance plan be based on scientific and logistical factors, including the following:

1. The likelihood that the adverse event represents a potential safety risk;
2. The frequency with which the event occurs (e.g., incidence rate, reporting rate, or other measures available);
3. The severity of the event;
4. The nature of the population(s) at risk;
5. The range of patients for which the product is indicated (broad range or selected populations only); and
6. The method by which the product is dispensed (through pharmacies or performance linked systems only).

A pharmacovigilance plan may be developed by itself or as part of a Risk Minimization Action Plan (Risk MAP), as described in the Risk MAP Guidance. Sponsors may meet with representatives from the appropriate Office of New Drugs review division and the Office of Drug Safety in CDER, or the appropriate Product Office and the Division of Epidemiology, Office of Biostatistics and Epidemiology in CBER regarding the specifics of a given product’s pharmacovigilance plan.

FDA believes that for a product without safety risks identified pre- or post-approval and for which at-risk populations are thought to have been adequately studied, routine spontaneous reporting will be sufficient for post marketing surveillance.

Pharmacovigilance Plan

A pharmacovigilance plan could include one or more of the following elements:
1. Submission of specific serious adverse event reports in an expedited manner beyond routine required reporting (i.e., as 15-day reports);
2. Submission of adverse event report summaries at more frequent, pre-specified intervals (e.g., quarterly rather than annually);
3. Active surveillance to identify adverse events that may or may not be reported through passive surveillance.

Active surveillance can be

(1) Drug based: identifying adverse events in patients taking certain products,
(2) Setting based: identifying adverse events in certain health care settings where they are likely to present for treatment (e.g., emergency departments, etc.), or
(3) Event based: identifying adverse events that are likely to be associated with medical products (e.g., acute liver failure);
4. Additional pharmacoepidemiologic studies (for example, in automated claims databases or other databases) using cohort, case-control, or other appropriate study designs (see section V);
5. Creation of registries or implementation of patient or health care provider surveys (see section V); and
6. Additional controlled clinical trials.

As data emerges, FDA recommends that a sponsor re-evaluate the safety risk and the effectiveness of its pharmacovigilance plan. Such re-evaluation may result in revisions to the pharmacovigilance plan for a product. In some circumstances, FDA may decide to bring questions on potential safety risks and pharmacovigilance plans before its Drug Safety and Risk Management Advisory Committee or the FDA Advisory Committee dealing with the specific product in question.

Such committees may be convened when FDA seeks:

(1) General advice on the design of pharmacoepidemiologic studies,
(2) Comment on specific pharmacoepidemiology studies developed by sponsors or FDA for a specific product and safety question, or
(3) Advice on the interpretation of early signals from a case series and on the need for further investigation in pharmacoepidemiologic studies. While additional information is being developed, sponsors working with FDA can take interim actions to communicate information about potential safety risks (e.g., through labeling) to minimize the risk to users of the product.

Good Pharmacovigilance Practice Regulations 2009

In exercise of the powers conferred on the Governing Council of the National Agency for Food and Drug Administration and Control (NAFDAC) by sections 5 and 29 of NAFDAC Act 1993 (as amended) and all the powers enabling it in that behalf, the Governing Council of NAFDAC with approval of the Honorable Minister of Health makes the following Regulations.

1. These regulations shall apply to authorize medicinal products for human and veterinary use and any pharmacovigilance activity connected therewith. These regulations shall apply to but are not limited to pharmaceuticals, nutriceuticals, and traditional, complementary and or alternative medicines, and vaccines, biological and medical devices.

2. No person shall manufacture or distribute any medicinal product except as prescribed in these and other regulations. Failure to comply with the provisions of these regulations shall be subject to regulatory action.

3. It shall be the responsibility of the marketing authorization holder and other person authorized to distribute medicinal
products to have permanently and continuously at his disposal an appropriately qualified person responsible for pharmacovigilance.

Such qualified person shall reside in the country and shall be responsible for the following:

i) The establishment and maintenance of a pharmacovigilance system to ensure that any information about suspected adverse reactions which have been reported to the personnel of the company and to medical Representatives, is collected, collated, evaluated and forwarded to the Agency;
ii) Preparing reports as prescribed in section 7.
iii) Reply accurately, fully and promptly to any request made by the Agency for the provision of additional information necessary for the evaluation of the risks and benefits afforded by a medicinal product, including the provision of information about the volume of sales of the medicinal product concerned;
iv) Providing the Agency with any other information relevant to the evaluation of the risks and benefits of a medicinal product particularly information concerning post authorization safety studies including information regarding the validity of the withdrawal period or lack of expected efficacy.
v) The marketing authorization holder shall not communicate information relating to pharmacovigilance concerns to the general public in relation to its authorized medicinal products without prior approval by the Agency. The marketing authorization holder shall ensure that such information is presented objectively and is not misleading.
vi) Marketing authorization holders shall use internationally agreed terminology for reporting adverse reactions.

4. The marketing authorization holder and other person authorized to distribute medicinal products shall maintain detailed records of all suspected adverse reactions occurring within and outside Nigeria. These reactions shall be communicated as prescribed by the Agency.

5. A. The marketing authorization holder and other person authorized to distribute medicinal products shall keep records of all suspected serious adverse reactions which have occurred in Nigeria and brought to his attention and report same to the Agency not later than fifteen (15) days following the receipt of information.

B. In accordance with the required pharmacovigilance plan prescribed by the Agency, the marketing authorization holder shall record and report, not later than fifteen (15)days, all other suspected serious adverse reactions occurring in Nigeria which he is reasonably expected to have knowledge of.

6. The marketing authorization holder shall report to the Agency any action relating to their product safety that has been taken by a regulatory authority outside Nigeria, including the basis for such action, not later than three (3) working days of first knowledge.

7. a. Periodic safety update reports shall be submitted to the Agency.

b. Periodic safety update reports for new drug molecules in Nigeria shall be submitted within the first ten (10) years of marketing authorization, at least every six (6)months for the first two (2) years, annually for the three (3) following years, and every five (5) years, at the time of renewal of license.

c. Where a new medicinal product is already being marketed elsewhere, existing periodic safety update reports shall be submitted to the Agency not later than thirty days after submission of documents requesting for marketing authorization in Nigeria.

d. Where a medicinal product is listed, the marketing authorization holder shall submit periodic safety update report every six (6) months for the two (2) year listing period (provisional registration).

8. a The Agency shall establish a National Pharmacovigilance Centre which shall receive, collect, collate, document, follow-up, scientifically analyze and evaluate adverse reaction reports to generate useful information for patient safety.

b. Marketing authorization holders and health care professionals shall immediately report any adverse reaction associated with medicinal products as prescribed by the Agency.

c. The information collected within the system shall be maintained in a database and communicated to institutions, professionals and the public by the Agency as applicable.

9. a. A person who contravenes a provision of these regulations is guilty of an offence and liable on conviction:-

i. In the case of an individual, to imprisonment for a term not exceeding two years or to a fine not exceeding N50,000 or to both imprisonment and fine.
ii. In the case of body corporate, to a fine not exceeding N100, 000.

b. Where an offence under these Regulations is committed by a body corporate or firm or other association of individuals:-

i. Every director, manager, secretary or other similar officer of the body, corporate; or
ii. Every partner or officer of the firm; or
iii. Every trustee of the body concerned; or
iv. Every person concerned in the management of the affairs of the association; or
v. Every person who was purporting to act in a capacity referred to in paragraphs (i) to (iv), is severally guilty of that offence and liable to be proceeded against and punished for that offence in the same manner as if he had himself committed the offence unless he proves that the act or omission constituting the offence took place without his knowledge, consent or connivance.

Scope and Prohibition

These regulations shall apply to authorize medicinal products for human and veterinary use and any pharmacovigilance activity connected therewith. These regulations shall apply to but are not limited to pharmaceuticals, nutriceuticals, traditional and complementary medicines, and vaccines, biological and medical devices.

No person shall manufacture or distribute any medicinal product except as set forth in these regulations. Failure to comply with the provisions of these regulations shall be subject to regulatory action.

Summary

ISPE is committed to providing an unbiased scientific forum to consider the views of all parties with interests in the safety of therapeutically and as such is deeply committed to the advancement of risk management science generally and this proposed industry guidance specifically. The Society welcomes the opportunity for further collaboration with the FDA and its Centers on risk management and other related initiatives.

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