Tuesday , September 26 2023



Pharmacovigilance plan especially in preparation for the early postmarketing period of a new drug .  Pharmacovigilance Plan that might be submitted at the time of licence application. Pharmacovigilance plan can be used by sponsors to develop a stand-alone document for regions that prefer this approach Pharmacovigilance Plan into the Common Technical Document (CTD).

WHO definition of ‘pharmacovigilance’ is “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems.”

The purpose of Pharmacovigilance Plan  is to propose a structure for a Pharmacovigilance Plan, and a Safety Specification that summarises the identified and potential risks of the product to be addressed in the Plan. The guideline is divided into the following sections:
• Safety Specification;
• Pharmacovigilance Plan;
• Annex – Pharmacovigilance Methods.

Here we discussed in details about Pharmacovigilance Plan

Structure of the Pharmacovigilance Plan
Summary of Ongoing Safety Issues
Routine Pharmacovigilance Practices
Action Plan for Safety Issues
Summary of Actions to be Completed, Including Milestones
Pharmacovigilance Methods
Design and Conduct of Observational Studies


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The Safety Specification is a summary of the important identified risks of a drug, important potential risks, and important missing information.It include the populations potentially at-risk  and outstanding safety questions which warrant further investigation to refine understanding of the benefit-risk profile during the post-approval period.

The Safety Specification can be built initially during the pre-marketing phase and, at the time approval is sought, it should reflect the status of issues that were being followed during development.

The Common Technical Document (CTD), especially the Overview of Safety [2.5.5], Benefits and Risks Conclusions [2.5.6], and the Summary of Clinical Safety [2.7.4] sections, includes information relating to the safety of the product, and should be the basis of the safety issues identified in the Safety Specification.

The length of the document will generally depend on the product and its development program.

Elements of the Specification
The elements of the Safety Specification that are included a guide,additional elements, depending on the nature of the product and its development program.
The focus of the Safety Specification should be on the identified risks, important potential risks, and important missing information. The following elements should be considered for inclusion.

The non-clinical safety findings that have not been adequately addressed by clinical data, for example.
• Toxicity (including repeat-dose toxicity, reproductive/developmental toxicity, nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity etc.);
• General pharmacology (cardiovascular, including QT interval prolongation; nervous system; etc.);
• Drug interactions;
• Other toxicity-related information or data.

Limitations of the safety database (e.g., related to the size of the study population, study inclusion/exclusion criteria) should be considered, and the implications of such limitations with respect to predicting the safety of the product in the marketplace should be explicitly discussed.

The world-wide experience should be briefly discussed, including:
• The extent of the world-wide exposure;
• Any new or different safety issues identified;
• Any regulatory actions related to safety.

Populations not Studied in the Pre-Approval Phase
The implications of this with respect to predicting the safety of the product in the marketplace should be explicitly discussed (CTD 2.5.5). Populations to be considered should include (but might not be limited to):
• Children;
• The elderly;
• Pregnant or lactating women;
• Patients with relevant co-morbidity such as hepatic or renal disorders;
• Patients with disease severity different from that studied in clinical trials;
• Sub-populations carrying known and relevant genetic polymorphism;
• Patients of different racial and/or ethnic origins.

Adverse Events (AEs) / Adverse Drug Reactions (ADRs)
list the important identified and potential risks that require further characterisation or evaluation. Specific references should be made to guide a reviewer to where clinical safety data are presented (e.g., relevant sections of the CTD 2.5.5 and 2.7.4).

  1. Identified risks that require further evaluation
    More detailed information should be included on the most important identified AEs/ADRs, which would include those that are serious or frequent and that also might have an impact on the balance of benefits and risks of the product. This information should include evidence bearing on a causal relationship, severity, seriousness, frequency, reversibility and at-risk groups, if available. Risk factors and potential mechanisms should be discussed.
  2. Potential risks that require further evaluation
    Important potential risks should be described in this section. The evidence that led to the conclusion that there was a potential risk should be presented. It is anticipated that for any important potential risk, there should be further evaluation to characterise the association.

Identified and Potential Interactions, Including Food-Drug and Drug-Drug Interactions
Identified and potential pharmacokinetic and pharmacodynamic interactions should be discussed. For each, the evidence supporting the interaction and possible mechanism should be summarised, and the potential health risks posed for the different indications and in the different populations should be discussed.

The epidemiology of the indication(s) should be discussed. This discussion should include incidence, prevalence, mortality and relevant co-morbidity, and should take into account whenever possible stratification by age, sex, and racial and/or ethnic origin. Differences in the epidemiology in the different regions should be discussed (because the epidemiology of the indication(s) may vary across regions), if this information is available.
In addition, for important adverse events that may require further investigation, it is useful to review the incidence rates of these events among patients in whom the drug is indicated (i.e., the background incidence rates).

For example, if condition X is an important adverse event in patients who are treated with drug Y for disease Z, then it is useful to review the incidence of condition X in patients with disease Z who are not treated with drug Y; this is the background rate of condition X among patients with disease Z. Information on risk factors for an adverse event (condition X) would also be useful to include, if available.

Pharmacological Class Effects
The Safety Specification should identify risks believed to be common to the pharmacological class.
At the end of the Safety Specification a summary should be provided of the:
• Important identified risks;
• Important potential risks;
• Important missing information.
Sponsors are encouraged to summarise specific ongoing safety issues on an issue-by-issue basis,

The Pharmacovigilance Plan should be based on the Safety Specification.  The Plan would normally be developed by the sponsor and can be discussed with regulators during product development, prior to approval (i.e., when the marketing application is submitted) of a new product, or when a safety concern arises post-marketing. It can be a stand-alone document but elements could also be incorporated into the CTD.

Structure of the Pharmacovigilance Plan
The structure can be varied depending on the product in question and the issues identified in the Safety Specification.
Summary of Ongoing Safety Issues
At the beginning of the Pharmacovigilance Plan a summary should be provided of the:
• Important identified risks;
• Important potential risks;
• Important missing information.

Routine Pharmacovigilance Practices
Routine pharmacovigilance should be conducted for all medicinal products. This routine pharmacovigilance should include the following:
• Systems and processes that ensure that information about all suspected adverse reactions that are reported to the personnel of the company are collected and collated in an accessible manner.
• The preparation of reports for regulatory authorities:

  1. Expedited adverse drug reaction (ADR) reports.
  2. Periodic Safety Update Reports (PSURs).

• Continuous monitoring of the safety profile of approved products including signal detection, issue evaluation, updating of labeling, and liaison with regulatory authorities;
• Other requirements, as defined by local regulations.

Action Plan for Safety Issues
The Plan for each important safety issue should be presented and justified according to the following structure:
• Safety issue
• Objective of proposed action(s).
• Action(s) proposed.
• Rationale for proposed action(s).
• Monitoring by the sponsor for safety issue and proposed action(s).
• Milestones for evaluation and reporting.
Any protocols for specific studies can be provided in the CTD section Other Clinical Study Reports or other sections as appropriate (e.g., Module 4 if the study is a non-clinical study).

Summary of Actions to be Completed, Including Milestones
An overall Pharmacovigilance Plan for the product bringing together the actions for all individual safety issues should be presented.
It is recommended that milestones for completion of studies and other evaluations, and for submission of safety results, be included in the Pharmacovigilance Plan. In developing these milestones one should consider when:

• Exposure to the product will have reached a level sufficient to allow potential identification/characterisation of the AEs/ADRs of concern or resolution of a particular concern; and/or

• The results of ongoing or proposed safety studies are expected to be available.

These milestones might be aligned with regulatory milestones (e.g., PSURs, annual reassessment and license renewals) and used to revise the Pharmacovigilance Plan.

Pharmacovigilance Methods
The best method to address a specific situation can vary depending on the product, the indication, the population being treated and the issue to be addressed. The method chosen can also depend on whether an identified risk, potential risk or missing information is the issue and whether signal detection, evaluation or safety demonstration is the main objective of further study.

When choosing a method to address a safety concern, sponsors should employ the most appropriate design. The Annex provides a summary of the key methods used in pharmacovigilance. This is provided to aid sponsors considering possible methods to address specific issues identified by the Safety Specification. This list is not all-inclusive, and sponsors should use the most up-to-date methods that are relevant and applicable.

Design and Conduct of Observational Studies
In observational studies, the investigator “observes and evaluates results of ongoing medical care without ‘controlling’ the therapy beyond normal medical practice.”

Before the observational study a protocol should be finalized for  Pharmacovigilance Plan with under guidance  of relevant disciplines (e.g., pharmacovigilance experts, pharmacoepidemiologists and biostatisticians) and also discussed with the regulatory authorities before the study starts.

A study report after completion, and interim reports if appropriate, should be submitted to the authorities according to the milestones within the Pharmacovigilance Plan.

Study protocols should, Contains as a minimum

Study aims


Methods to be used,

Plan for analysis.

The final study report should accurately and completely present the study objectives, methods, results, and the principal investigator’s interpretation of the findings.

It is recommended that the sponsor follow good epidemiological practice for observational studies
The highest possible standards of professional conduct and confidentiality should always be maintained and any relevant national legislation on data protection followed




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About Pharmaceutical Guidanace

Ms. Abha Maurya is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 18 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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