Pharmacovigilance Regulations

Contents
1. International Conference on Harmonization (ICH)     
2. Council for International Organization for Medical Sciences (CIOMS)
3. USA
4. India
5. Japan
7. List of Regulatory Authorities

International Conference on Harmonization (ICH)

• ICH consists of representatives of the regulatory authorities in the EU, Japan and US, with representatives of the corresponding industry regional organizations and Health Canada and WHO as observers.

• ICH establishes guidelines applicable to the EU, US and Japan through a series of expert working groups.

• There is a stepwise development of the guidelines. At Step 4, there is consensus internationally and at Step 5, an agreement by the regulators that they will introduce the guidelines into legislation, although there may be some divergence when these are actually put into effect in the different regions

Types of Guidelines

• Q-Quality guidelines: Harmonization achievements in the Quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.

• S-Safety guidelines: ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like carcinogenicity, genotoxicity and reprotoxicity. A recent breakthrough has been a non-clinical testing strategy for assessing the QT interval prolongation liability: the single most important cause of drug withdrawals in recent years.

• E-Efficacy Guidelines: The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety, and reporting of clinical trials. It also covers novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/genomics techniques to produce better targeted medicines.

• M-Multidisciplinary guidelines: Those are the cross-cutting topics which do not fit uniquely into one of the Quality, Safety and Efficacy categories. It includes the ICH medical terminology (MedDRA), the Common Technical Document (CTD) and the development of Electronic Standards for the Transfer of Regulatory Information (ESTRI).

Efficacy ICH guidelines

• E1: The extent of population exposure to Assess Clinical Safety for drugs intended for long term treatment of non-life threatening conditions

• E2A: Clinical safety data management: definitions and standards for expedited reporting

• E2B(R3): Clinical safety data management: Data Elements for transmission of individual case safety reports

• E2C(R2): Periodic Benefit-Risk Evaluation Reports 

• E2D: Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting

• E2E: Pharmacovigilance Planning

• E2F: Development Safety Update Report

• E3: Structure and Content of Clinical Study Reports

• E4: Dose-Response information to support drug registration 

• E5(R1): Ethnic factors in the acceptability of foreign Clinical Data

• E6: Good Clinical Practice

• E7: Studies in support of special populations: Geriatrics 

• E8: General Considerations for Clinical Trials

• E9: Statistical Principles for clinical trials

• E10: Choice of control group and related issues in clinical trials 

• E11: Clinical investigations of medicinal products in pediatric population 

• E12: Principles for clinical evaluation of new Antihypertensive drugs 

• E15: Definitions for genomic biomarkers, pharmacogenomics, genomic data and sample coding categories

• E16: Biomarkers related to drug or biotechnology product development: Context, structure and format of qualification submissions 

• E17: General Principles for planning and design of Multi-Regional Clinical trails 
• E18: Genome sampling and management of Genomic Data

Safety ICH guidelines

• S1: Rodent Carcinogenicity studies for human pharmaceuticals 

• S1A: Need for carcinogenicity studies of pharmaceuticals 

• S1B: Testing for Carcinogenicity of pharmaceuticals 

• S1C(R2): Dose Selection for Carcinogenicity studies of pharmaceuticals 

• S2: Guidance on genotoxicity testing and data interpretation for pharmaceuticals intended for human use 

• S3A: Note for guidance on toxicokinetics: The assessment of systemic exposure in toxicity studies

• S3B: Pharmacokinetics: Guidance for repeated dose tissue distribution studies 

• S4: Duration of chronic toxicity testing in animals (rodent and non-rodent toxicity testing)

• S5 (R2): Detection of toxicity to reproduction for medicinal products and toxicity to male fertility 

• S6(R1): Preclinical safety evaluation of biotechnology-derived pharmaceuticals 

• S7A: Safety pharmacology studies for human pharmaceuticals 

• S7B: The Non-clinical evaluation of the potential for delayed ventricular repolarization (QT Interval prolongation) by human pharmaceuticals 

• S8: Immunotoxicity studies for human pharmaceuticals

• S9: Nonclinical evaluation for Anticancer pharmaceuticals 

• S10: Photosafety evaluation of pharmaceuticals

The guidelines related to Pharmacovigilance are

• E2A: Clinical safety data management: Definitions and standards for expedited reporting

• E2B: Electronic reporting of adverse events

• E2C: Periodic benefit- risk evaluation report (PBRER)

• E2D: Post-approval safety data management: Definitions and standards for expedited reporting

• E2E: Pharmacovigilance planning

• E2F: Development Safety Update Report (DSUR)

• M1: Medical dictionary for Regulatory activities

• M4: The Common Technical Document (i.e. the international registration dossier)

Council for International Organizations of Medical Sciences (CIOMS)

• CIOMS  s a body set up under World Health Organization and UNESCO. It has developed a series of guidelines on pharmacovigilance, drawn up by a committee of volunteers from Industry, regulatory authorities, WHO and others.

• Whilst CIOMS guidelines are very influential they are not “official” regulatory guidelines, have no legal force and generally just provide a consensus on good practices and new methodologies.

• The main guidelines concern

  • • The international reporting form (CIOMS I)

    • Periodic safety update reports (CIOMS II)

    • Core data sheets (CIOMS III)

    • Benefit-risk assessments (CIOMS IV)

    • Practical issues in Pharmacovigilance (CIOMS V)

    • Clinical trial safety data (CIOMS VI)

    • Development safety update reports (CIOMS VII)

 

European Medicines Agency (EMA)

Laws

There are EU laws – regulations and directives – on the one hand, and national laws on the other. An EU regulation, when it comes into effect, is in force in all the Member States of the European Union. An EU directive, however, must first be enacted in national law in each EU Member State, within a specified time-frame. In addition to those national laws that promulgate the EU directives, there may also be national laws that concern Pharmacovigilance.

The principal EU laws concerning Pharmacovigilance are:

• Directive 2001/83, amended by Directive 2004/27. This concerns all medicinal products, although for Pharmacovigilance it is most relevant to products authorized by the national, mutual recognition and decentralized procedures. The Member States are the licensing authorities in these procedures.

• Regulation 726/2004. This concern centrally authorized products. The European Commission is the licensing authority for these products.

• Directive 2001/20. This is the Clinical Trials Directive and includes extensive coverage of Pharmacovigilance for interventional clinical trials pre- and post-authorization.

Guidelines

The EU laws make reference to guidelines drawn up by the European Commission which provide detail and interpretation. These guidelines are not considered to be voluntary – they are mandatory as far as companies are concerned. The guidelines are also directed at regulatory authorities, with detailed requirements for the way that they carry out Pharmacovigilance as well. They comprise:

• Volume 9A of the Rules Governing Medicinal Products in the European Community – for post-authorization Pharmacovigilance

• Volume 10 of the Rules Governing Medicinal Products in the European Community. This applies to clinical trials pre- and post-authorization and incorporates the guideline Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use

Volume 9: Pharmacovigilance guidelines

• Volume 9A: Pharmacovigilance for medicinal products for Human use

  • From July 2012, the volume 9A was replaced by good Pharmacovigilance guidelines (GVP) released by European Medicines Agency.

• Volume 9B: Pharmacovigilance for medicinal products for veterinary use

Good Pharmacovigilance Guidelines (GVP):

• Good Pharmacovigilance practices (GVP) are a set of measures drawn up to facilitate the performance of Pharmacovigilance in the European Union (EU).

• GVP apply to marketing-authorization holders, the European Medicines Agency and medicines regulatory authorities in EU Member States.

• The guideline on GVP is divided into chapters that fall into two categories:

• • modules covering major Pharmacovigilance processes;

  • Product- or population-specific considerations.

List of modules in GVP: 

• Module I: Pharmacovigilance Systems and their Quality Systems 

• Module II: Pharmacovigilance System Master File

• Module III: Pharmacovigilance Inspections

• Module IV: Pharmacovigilance Audits 

• Module V: Risk Management Systems

• Module VI: Collection, Management and Submission of Suspected Adverse Reactions to Medicinal Products 

• Module VI Addendum I: Duplicate management of suspected adverse reaction reports 
• Module VII: Periodic Safety Update Reports

• Module VIII: Post-Authorization Safety Studies

• Module VII Addendum I: Requirements and recommendations for the submission of information on non-interventional post-authorization safety studies

• Module IX: Signal Management

• Module IX Addendum I: Methodological aspects of signal detection from spontaneous reports of suspected adverse reactions

• Module X: Additional Monitoring

• Module XI: Public Participation in Pharmacovigilance (later moved to different page)

• Module XII: Continuous Pharmacovigilance, Ongoing Benefit-Risk Evaluation, Regulatory Action and Planning of Public Communication (later moved to different page)

• Module XIII: Incident Management (later moved to different page)

• Module XIV: Referral Procedures for Safety Reasons (later moved to different page)

• Module XV: Safety Communication

• Module XVI: Risk minimisation meastures: selection of tools and effectiveness indicators

• Module XVI Addendum I: Educational materials

List of Product- or population-specific considerations

• I: Vaccines for prophylaxis against infections diseases
• II: Biological medicinal products
• IV: Paediatric population

US: United States Food Drug Administration

• Prescription Drug User Fee Act (PDUFA )

• Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic assessment.

India

• Pharamcovigilance Programme of India (PVPI): The National Pharmacovigilance Program (NPVP) was inaugurated on 23 November, 2004 at New Delhi.

• The program is coordinated at Central Drug Standard Control Organization (CDSCO) office

• Under the program

  • • 25 peripheral Centers,

    • 5 Regional Centers and

    • 2 Zonal Centers were established

Japan: Ministry of Health and Labour Welfare (MHLW) and PMDA

• The Ministry of Health, Labor and Welfare is one of the cabinet level Ministries in the Japanese government.

• This government body provides regulations on maximum residue limits for agricultural chemicals in foods, basic food and drug regulations, standards for foods, food additives, etc.

Important Drug Regulatory Authorities:

Sr.No	Country	Regulatory Authority
1	Australia	Therapeutic Goods Administration (TGA)
2	Brazil	ANVISA Pharmacovigilance Unit (Federal Agency) CVS Pharmacovigilance Unit (Local Agency – Sao Paulo State)
3	Canada	Health Canada
4.	China	China Food and Drug Administration
5.	France	ANSM( AgenceNationale de SécuritéduMédicament et des produits de Santé) Also local Health authorities such as CRPV
6.	Germany	BundesinstitutfuerArzneimittel und Medizinprodukte (BfArM)or also known as Federal Institute for Drugs and Medical Devices
7	India	Drugs Controller General (India)
8.	Italy	Italian Pharmaceutical Agency  Ministry of Health
9.	Hong Kong	Department of Health: Pharmaceutical Services
10.	Japan	Pharmaceuticals and Medical Devices Agency (PMDA) Ministry of Health Labour and Welfare
11.	New Zealand	New Zealand Medicines and Medical Devices Safety Authority
12.	Singapore	Health Sciences Authority (HSA)
13.	Sweden	Medical Products Agency (MPA)
14.	UK	Medicines and Healthcare products Regulatory Agency (MHRA)
15.	US	U.S. Food and Drug Administration (US FDA)

Note: In European Union, there are many local health authorities for single country eg. France.