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Investigation of Medicinal Product Dossier (IMPD) and Investigator Brochure (IB)

This document provides an overview of an Investigational Medicinal Product Dossier (IMPD) and Investigator Brochure (IB). It begins with background on the European Medicines Agency and drug approval process. It then describes the contents and objectives of an IMPD, which includes quality, manufacturing, and clinical data submitted as part of a clinical trial application. Next, it introduces the IB and lists components like the product description, nonclinical study results, effects in humans, and guidance for investigators. The document aims to define harmonized IMPD requirements for clinical trials involving multiple EU member states.

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Investigation of Medicinal Product Dossier (IMPD) and Investigator Brochure (IB) Guided by: Dr. Vidya Sabale Associate Professor Department of Pharmaceutics Presented by:- Tanvi D. Mhashakhetri M. Pharm 1st Sem Department of Pharmaceutics Dadasaheb Balpande College Of Pharmacy, Besa , Nagpur -440037 2022-23 1
Contents: • European Medicines Agency (EMA) • IMPD Introduction • Contents of IMPD • Objectives • Scope • Introduction of IB • General Consideration • Content of IB 2
European Medicines Agency (EMA) • It is a decentralized agency of the European union. • The Management Board is the European Medicines Agency’s integral governance Body. • The Agency is responsible for the scientific evaluation, supervision and safety monitoring of the medicines developed by pharmaceutical companies use in EU. • EMA protects public and animal health in 27 EU member states, as well as the countries of the European economic area , by ensuring that all medicines available on the EU market are safe, effective and of high quality. 3
History • European medical agency was found in 1995, has worked across the EU and globally to protect public and animal healty by assessing medicines to rigorous scientific standards and providing with independent, science-based informations on medicines. • EMA has 20 year track record of ensuring efficacy and safety of human and veterinary medicines across Europe, and promoting research and innovation in the developments of medicines. • In first two decades, the agency recommended the authorization of the total of 975 humans and 188 veterinary medicines. 4
Drug approval process There are two regulatory steps to go through before a drug is Approved to be marketed in the EU. There two steps are:- 1. Clinical trial application 2. Marketing authorization application • Clinical trial applications are approved at the member state level. Marketing authorization applications are approved at both the member state or centralized levels. • Qualified person has to certify that the investigation medicinal product (IMP) is manufactured according to GMP. • The component authority has the right to inspect the manufacturing facility for GMP compliance, the preclinical facility for GLP compliance and the clinical trial sites for GCP compliance. 5
Clinical Trial Application EU directive (April 2001) sets out the new rules and regulations for the approval and conduct of clinical trials in Europe. • A sponsor submits a clinical trial application to the competent Authority in each member state where the trials are to be conducted. • The competent Authority has 60 days to review and approve or reject the application. • Application is in prescribed forms and cover the proposed clinical trials protocol, manufacturing and quality controls on the drug and supporting data, such as: 1. Chemical,biological and pharmacological data 2. Non-clinical pharmacological and toxicological data 3. Previous human experience and clinical data 6
• Dossier A collection of documents about a particular person, event or subject e.g. patient’s medical record • Medicinal product dossier File containing detailed records about a particular drug product 7
Investigational Medical Product Dossier ( IMPD ) • The IMPD is the basic for approval of clinical trials by the competent authorities in the EU . • The clinical trial directive came in force, harmonizing the laws, regulations and administrative provisions of the member states relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use. • The directive introduced a harmonized procedure for the authorization to perform a clinical study in any one of the EU member states. • In addition, it defines the documentation to be submitted to the Ethics committee as well as the investigational medicinal product dossier (IMPD) to be submitted to the competents authority for approval. 8
IMPD: IMPDs are submitted as part of clinical trial application dossier. As the basic for approval of clinical trials by competent regulatory authorities within European Union. IND application are equivalent in U.S. Contents: subsequent trial documentation 1.Protocols 2.Informed consent forms 3.Investigator brochure 4.Study reports 5.Subject narratives 6.Risk management 7.safety update reports 9
The IMP dossier required will depend on many factor including: • Risk aspects • Nature of the product • State of development • Patient population • Nature and severity of the illness • Type and duration of the clinical trial itself 10
What is IMPD ? • The investigational medicinal product dossier (IMPD) is one of several pieces of investigational medicinal product (IMP) related data required whenever the performance of the clinical trial is intended in one or more European union member states. • The IMPD includes summaries of information related to the quality , manufacture and control of any IMP ( including reference product and placebo) , and data from non- clinical and clinical studies. Objectives : • Since clinical trials will often be designed as multi center studies, potentially involving different member states. • It is the aim of the guideline to defined harmonized requirements of the documentation to be submitted through the European community. 11
Scope • Guideline addresses the documentation on the chemical and pharmaceutical quality of IMPs containing chemically defined active substances, synthetic peptides, herbal substances herbal preparations and chemically defined radio active/radio labelled substances to be submitted to be competent authority for approval prior to beginning a clinical competent authority a clinical trials in humans. • It includes the requirements for IMPs to be tasted in phase I, phase II and phase III studies as well as the requirements for modified and unmodified comparator requirements for modified and unmodified comparator products and IMPs to be tested in generic bioequivalenvce studies and [and placebo products]. 12
• The IMPD includes summaries of information related to the quality, manufacture and control of the investigational medicinal product, data from non clinical studies and from its clinical use. • An overall risk benefit assessment, critical analyses medicinal of the non clinical and clinical data in relation to the potential risks and benefits of the proposed study have to be part of the IMPD. • In certain situations e.g. where the investigational medicinal product has already been authorized as a medicinal product in one of the EU member states or where clinical studies with the IMP have already been approved by a member state, a simplified IMPD will be sufficient. 13
Procedure : 14
Investigator’s Brochure ( IB ) : • Investigator brochure is a collection of the clinical and non-clinical data of the investigational product that are relevant to the study of the product in human subject. • IB is a comprehensive document summarizing the information about the investigational product obtained during a clinical trials. •The information should be presented in a short, simple, objective, and non-promotional form that enables a clinical or potential investigator to understand it. • IB is prepared by the sponsor who also controls the distribution of the document. • The sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator and investigators are responsible for providing the up-to-date to the responsible IRB ( Institutional Review Board ) / IEC( Institutional Ethics Committee) . 15
General Considerations Title page 1. Sponsor name 2. The identity of each investigational product (i.e., research number, chemical or approved generic name, and trade name where legally permissible and desired by the sponsor). 3. The release date. 4. Confidential statement Confidential statement The sponsor may wish to include a statement instructing the investigator to treat the IB as a confidential document for the sole information and use of the investigators team and the IRB 16
Contents of IB The investigator brochure should include : 1. Table of contents 2. Summary :-preferably not exceeding two pages . Should highlighting the significant physical, chemical, pharmaceutical, pharmacological, pharmacokinetic, metabolic and clinical information available that is relevant to the stage of clinical development of the investigational product(IP). 3. Introduction :- A brief introductory statement should be provided that contains – • The chemical name ( and generic and trade name ) of the investigational product. • All active ingredients • The investigational product 17
• Pharmacological class and its expected position within this class • Therapeutic or diagnostic indication. • The introductory statement should provide the general approach to be followed in evaluating the investigational product. 4. Description of investigational product (IP) :- • A brief summary should be given of the relevant physical, chemical , and pharmaceutical properties. • A discription of formulation to be used, including excipients, should be provided and justified if clinically relevant. • Instructions for the storage and handling of the dosage form should also be given. 18
5. Nonclinical Studies The result of all relevant nonclinical pharmacological ,toxicology, pharmacokinetic and investigational prouct metabolism studies should be provided in summary form. The information provided may include:- • Species tested • Number and gender of animal in each group • Unit dose (e.g., mg/kg) • Dose interval • Route of administraton • Duration of dosing • Information on systemic distribution • Duration of post-exposure follow up 19
Result including following aspects:- • Nature and frequency of pharmacological or toxic effect • Severity or intensity of pharmacological or toxic effects. • Time to onset of effects • Duration of effects • Dose response (A) Non-clinical pharmacology A summary of the pharmacological aspect of the investigational product, its significant metabolites studied in animal should be included. (B) Pharmacokinetic and product metabolism in animal • A summary of the pharmacokinetic and biological transformation and deposition of the investigational product in all species studied should be given. •Single dose 20
• Repeated dose • Carcinogenicity • Special studies (e.g., irritancy and sensitization ) • Reproductive toxicity • Mutagenicity Effects in Humans Introduction :- Effects of the investigational product in humans should be provided, including information on pharmacokinetc, metabolism , pharmacodynamics, and dose response, safety, efficacy, and other pharmacological activities. (A) Pharmacokinetics and product metabolism in Humans- A summary of information on the pharmacokinetics of the Investigational product should be presented. • Pharmacokinetics ( including metabolism , absorption, plasma protein binding, distribution and elimination ). • Bioavailability of the investigational product using a reference dosage form . 21
• Population subgroups. (e.g., gender, age , and impaired organ function). Interactions (e.g., effect of food ). • Other pharmacokinetic data (e.g., result of population studied performed within clinical trial). B) Safety and Efficacy A summary of information should be provided about the investigational products ( including metabolites), safety, pharmacodynamics, efficacy and dose response that were obtained from preceding trial in humans ( healthy volunteer / patient ). C) Marketing Experience • The IB should identify countries where the investigational product has been marketed or approved. • The IB should also identify all the countries where the investigational product did not receive approval/ registration for marketing . 22
6. Summary of Data and Guidance for the Investigator • This section should provide an overall discussion of the nonclinical and clinical data of IP. • IB provide the investigator a clear understanding of - The possible risk - Adverse reaction - Observation &precaution needed for the clinical trial. 23
References : 1. Richard A. Gaurino , M.D., New Drug Approval Process , Fifth Edition, 2. http;//www.imp-dossier.eu/ 24
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