IINVESTIGATOR'S brochure and its articles
- 1. PRESENTED BY:- NAIBEDYA KUMAR BRANCH:- M.PHARM, PHARMACEUTICS REG. NO:- 2361611009 SUBJECT:-REGULATORY AFFAIRS SUBJECT CODE:- MPH 104T DATE OF PRESENTATION:-18/01/24 SCHOOL OF PHARMACEUTICAL SCIENCES SHIKSHA ‘O’ANUSANDHAN DEEMED TO BE UNIVERSITY A Deemed to be University declared U/S 3 of the UGC Act, 1956 Khandagiri Square, Bhubaneswar 751030, Odisha, India www.soauniversity.ac.in INVESTIGATOR’S BROCHURE
- 2. INTRODUCTION:- 1. Investigator brochure is a collection of the clinical and non-clinical data on the investigational products that are relevant to the study of the product in human subjects. 2. IB is a comprehensive document summarizing the information about the investigational products obtained during clinical trials. 3. The information should be presented in a short, simple, objective. 4. IB is prepared by the sponsor who also controls the distribution of the document. 5. 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 IB to the responsible IRB/IEC (Institutional Review Board/Institutional Ethics Committee).
- 3. PURPOSE OF I.B:- ➢Its purpose is to provide information to the Investigators and others involved in the trial such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. IB contains Summary of Data and Guidance for the Investigator: 1. Provide the investigator with a clear understanding of the possible risks and adverse reactions, details of tests, observations, and precautions that may be needed for a clinical trial. 2. The information should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product. 3. It should also provide treatment for possible overdose and adverse drug reactions. 4. The IB should be reviewed annually.
- 4. GENERAL CONSIDERATION:- 1. Title page ➢Sponsor's name: ➢ Product: ➢ Research Number: ➢Name(s): Chemical, Generic (if approved) &Trade Name(s). ➢Edition Number: ➢Release Date: ➢Replaces Previous Edition Number: ➢Date 2. Confidentiality statement: ➢The sponsor may include a statement instructing the investigator to treat the IB as a confidential document for the sole information and use of the investigator’s team and the IRB/IEC(Institutional Review Board/Institutional Ethics Committee).
- 6. Contents of IB:- I. Table of Contents II. Summary III. Introduction IV. Physical, chemical and pharmaceutical properties & and formulation V. Nonclinical studies VI. Effect on humans VII. Summary of Data and Guidance for the Investigator
- 8. 2. Summary:- ▪ A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product. 3. Introduction:- ▪Contains the chemical name (generic and trade name when approved), all APIs, pharmacological class, the rationale for performing research of the investigational products, and the anticipated prophylactic, therapeutic, or diagnostic indication(s). ▪Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product. 4. Physical, Chemical, and Pharmaceutical Properties and Formulation:- ▪A description should be provided of the investigational product substance (the chemical and/or structural formula(e)), and brief summary should be given of the physical, chemical, and pharmaceutical properties. To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) used. ▪Instructions for the storage and handling of the dosage form(s) should also be given. ▪ Any structural similarities to other known compounds should be mentioned.
- 9. 5. Nonclinical studies:- The information provided may include the following, as appropriate, if known/available: ▪Species tested ▪ Number and sex of animals in each group ▪Unit dose ▪Dose interval ▪Route of administration ▪Duration of dosing ▪Information on systemic distribution ▪ Duration of post-exposure follow-up Results, including the following aspects: ▪Nature and frequency of pharmacological or toxic effects ▪ Severity or intensity of pharmacological or toxic effects ▪Time to onset of effects ▪Reversibility of effects ▪ Duration of effects ▪ Dose response Nonclinical Pharmacology • The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. • This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavourable and unintended effects on humans
- 10. 5.1 Nonclinical Pharmacology:- ➢A summary of the pharmacological aspects of the investigational product and, its significant metabolites studied in animals, should be included. ➢Such a summary should incorporate studies that assess potential therapeutic activity (e.g., efficacy models, receptor binding, and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect). 5.2 Pharmacokinetics and Product Metabolism in Animals:- ➢A summary of the pharmacokinetics and biological transformation and disposition (getting a drug into its appropriate position in the body and in an appropriate concentration) of the investigational product in all species studied should be given. ➢ Absorption and the local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological effects in animal species.
- 11. 5.3 Toxicology:- ➢ The study of the adverse effects of chemicals on animals is described under the following headings where appropriate:- ➢ Single dose ➢ Repeated dose ➢ Carcinogenicity ➢ Special studies (e.g. irritancy and sensitization) ➢ Reproductive toxicity ➢ Genotoxicity (mutagenicity) ➢6. Effects on Humans:- ➢A thorough discussion of the known effects of the investigational product(s) in humans should be provided, including information on:- ▪Pharmacokinetics, metabolism, pharmacodynamics, dose-response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided.
- 12. 6.1Pharmacokinetics and Product Metabolism in Humans:- ➢A summary of information on the pharmacokinetics of the investigational product should be presented, including the following: ▪Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and elimination). ▪Bioavailability of the investigational product using a reference dosage form. ▪Population subgroups (e.g., gender, age, and impaired organ function). ▪Interactions (e.g., product-product interactions and effects of food). ▪ Other pharmacokinetic data (e.g., results of population studies performed within a clinical trial(s). 6.2 Safety and Efficacy:- ➢A summary of information should be provided about the investigational product's safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in human subjects. ➢Important differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed. ➢The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products.
- 13. 6.3 Marketing Experience:- ➢The IB should identify countries where the investigational product has been marketed or approved. ➢Any significant information arising from the marketed use should be summarized (e.g., formulations, dosages, routes of administration, and adverse product reactions). ➢The IB should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration. 7. Summary of Data and Guidance for the Investigator:- ➢This section should provide an overall discussion of the nonclinical and clinical data and should summarize the information from various sources on different aspects of the investigational product, wherever possible. ➢In this way, the investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials. ➢Where appropriate, the published reports on related products should be discussed. ➢This could help the investigator to anticipate adverse drug reactions or other problems in clinical trials
- 15. ARTICLE 1 Preclinical efficacy studies in investigator brochures: Do they enable risk-benefit assessment?:- Wieschowski S. et al., in the year 2019 Prepared a meta-research article on Preclinical efficacy studies in investigator brochures. To make a clinical trial ethical, regulatory agencies and institutional review boards have to judge whether the trial-related benefits (the knowledge gain) outweigh the trial-inherent risks. For early-phase human research, these risk–benefit assessments are often based on evidence from preclinical animal studies reported in so-called “investigator brochures.” ➢Objective: This analysis aims to investigate whether preclinical efficacy studies reported in investigator brochures provide sufficient information to enable a comprehensive risk-benefit assessment for early-phase clinical trials. ➢Methods: ▪Data source: Analyze a representative sample of investigator brochures for investigational new drugs (INDs) submitted to regulatory agencies. ▪Study design: The design is robust and relevant to the clinical trial(e.g., blinding, randomization, appropriate controls) ▪Methodology: The methods are clearly described and reproducible (e.g., sample size, outcome measures, statistical analysis) ▪Results: The results were presented comprehensively and transparently (e.g., data availability, effect size, reporting of negative findings)
- 16. ▪Analysis: Quantitatively: Calculating the proportion of brochures meeting specific criteria. Qualitatively: Analyzing the nature and severity of reporting deficiencies. ➢Results: ▪ Preliminary findings: Existing research suggests:- ▪A majority of brochures lack sufficient information for proper risk-benefit assessment. ▪Reporting often lacks crucial details about study design, methodology, and results. ▪Negative findings and limitations are rarely reported systematically. ▪Expected outcomes: This analysis will further quantify these findings and identify specific areas for improvement ➢Conclusion: ▪Preclinical efficacy studies in investigator brochures currently fall short of enabling a comprehensive risk-benefit assessment for early-phase clinical trials. Addressing these shortcomings through improved reporting, training, and regulatory oversight is crucial to ensure the ethical and efficient development of new drugs.
- 18. ARTICLE 2 Investigator brochures for phase I/II trials that lack information on the robustness of preclinical safety studies:- Soren Sievers. et al., in the year 2020 prepared an article on investigator brochures for phase I/II trials that lack information on the robustness of preclinical safety studies. This relies largely on preclinical animal studies addressing the safety and efficacy of treatments. These studies are reported in an Investigator’s Brochure (IB) to inform ethics review boards and regulatory authorities. The study investigated the extent, reporting quality and accessibility of preclinical safety studies (PCSSs) compiled in IBs. ➢ Objective: This analysis aims to investigate the extent to which investigator brochures for phase I/II clinical trials lack information on the robustness of preclinical safety studies. ➢Methods: ▪Data source: Analyzing a representative sample of investigator brochures for phase I/II trials approved by a specific regulatory agency or obtained from a research institution. ▪Study design: The design appropriate to assess the specific safety concerns of the drug (e.g., adequate species selection, dose range, relevant endpoints). ▪Methodology: The methods sound and adherent to Good Laboratory Practice (GLP) guidelines (e.g., randomization, blinding, quality control). ▪Reporting: The brochure provides sufficient details about the study conduct, analysis, and results (e.g., sample sizes, statistical methods, adverse event reporting).
- 19. ▪Analysis: Quantitatively: Calculating the proportion of brochures meeting specific robustness criteria. Qualitatively: Analyzing the nature and frequency of missing or inadequately reported information. ➢Results: Preliminary findings: Existing research suggests: ▪A significant proportion of brochures lack key information about the robustness of preclinical safety studies. ▪Missing details often pertain to study design, methodology, and reporting of limitations. ▪Inadequate information limits the ability to fully assess potential safety risks for participants in clinical trials. ▪Expected outcomes: This analysis will further quantify the extent of missing information and identify specific areas where robustness reporting is lacking. ➢Conclusion: ▪Investigator brochures for phase I/II trials often lack critical information about the robustness of preclinical safety studies. This gap in reporting hinders the ability to make informed decisions about the safety of new drugs and the ethics of conducting early-phase trials. Addressing this issue through improved reporting standards, training, and regulatory oversight is crucial to ensure the safety of participants and the responsible development of new drug
- 20. REFERENCE:- ➢Wieschowski S, Chin WW, Federico C, Sievers S, Kimmelman J, Stretch D. Preclinical efficacy studies in investigator brochures: do they enable risk–benefit assessment?. PLoS biology. 2018 Apr 5;16(4):e2004879. ➢Sievers S, Wieschowski S, Strech D. Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies. British Journal of Clinical Pharmacology. 2021 Jul;87(7):2723-31.