1、 Guidance for Industry E2E Pharmacovigilance Planning U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) April 2005 ICH Guidance for Industry E2E Pharmacovigilance Planning Addit
2、ional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http:/www.fda.gov/cder/guidance/index.htm Office of Communication,
3、 Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 http:/www.fda.gov/cber/guidelines.htm. (Tel) Voice Information System at 800-835-4709 or 301-827-1800 U.S. Department of Health and H
4、uman Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) April 2005 ICH Contains Nonbinding Recommendations TABLE OF CONTENTS I. INTRODUCTION (1, 1.1) . 1 A. Background (1.2)2 B. Scope of the Guidance (1.3).2 II. SA
5、FETY SPECIFICATION (2) 3 A. Elements of the Specification (2.1) .4 1. Nonclinical (2.1.1) .4 2. Clinical (2.1.2).4 B. Summary (2.2)6 III. PHARMACOVIGILANCE PLAN (3) 6 A. Structure of the Pharmacovigilance Plan (3.1) .7 1. Summary of Ongoing Safety Issues (3.1.1) 7 2. Routine Pharmacovigilance Practi
6、ces (3.1.2) .7 3. Action Plan for Safety Issues (3.1.3)8 4. Summary of Actions To Be Completed, Including Milestones (3.1.4) .8 B. Pharmacovigilance Methods (3.2) 8 IV. REFERENCES (4) 10 ANNEX PHARMACOVIGILANCE METHODS 11 Contains Nonbinding Recommendations 1Guidance for Industry1E2E Pharmacovigilan
7、ce Planning This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of
8、 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION (1, 1.1
9、) 2This guidance is intended to aid in planning pharmacovigilance activities, especially in preparation for the early postmarketing period of a new drug (in this guidance, the term drug denotes chemical entities, biotechnology-derived products, and vaccines). The main focus of this guidance is on a
10、safety specification and pharmacovigilance plan that might be submitted at the time of license application. The guidance can be used by sponsors to develop a stand-alone document for regions that prefer this approach or to provide guidance on incorporation of elements of the safety specification and
11、 pharmacovigilance plan into the Common Technical Document (CTD). The guidance describes a method for summarizing the important identified risks of a drug, important potential risks, and important missing information, including the potentially at-risk populations and situations where the product is
12、likely to be used that have not been studied preapproval. It proposes a structure for a pharmacovigilance plan and sets out principles of good practice for the design and conduct of observational studies. It does not describe other methods to reduce risks from drugs, such as risk communication. The
13、guidance takes into consideration ongoing work in the three regions and beyond on these issues. 1This guidance was developed within the Expert Working Group (Efficacy) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) a
14、nd has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2004. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies
15、 of the European Union, Japan, and the United States. 2Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2004. Contains Nonbinding Recommendations 2This guidance does not cover the entire scope of pharmac
16、ovigilance. It uses the World Health Organization (WHO) definition of the term pharmacovigilance as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems.” This definition encompasses the use of pharmacoe
17、pidemiological studies. FDAs guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are
18、cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. A. Background (1.2) The decision to approve a drug is based on its having a satisfactory balance of benefits and risks within the conditions specified in the product labeling. Th
19、is decision is based on the information available at the time of approval. The knowledge related to the safety profile of the product can change over time through expanded use in terms of patient characteristics and the number of patients exposed. In particular, during the early postmarketing period
20、, the product might be used in settings different from clinical trials and a much larger population might be exposed in a relatively short timeframe. Once a product is marketed, new information will be generated, which can have an impact on the benefits or risks of the product; evaluation of this in
21、formation should be a continuing process, in consultation with regulatory authorities. Detailed evaluation of the information generated through pharmacovigilance activities is important for all products to ensure their safe use. The benefit-risk balance can be improved by reducing risks to patients
22、through effective pharmacovigilance that can enable information feedback to the users of medicines in a timely manner. Industry and regulators have identified the need for better and earlier planning of pharmacovigilance activities before a product is approved or a license is granted. This ICH guida
23、nce has been developed to encourage harmonization and consistency and prevent duplication of effort and could be of benefit to public health programs throughout the world as they consider new drugs in their countries. B. Scope of the Guidance (1.3) The guidance could be most useful for new chemical
24、entities, biotechnology-derived products, and vaccines, as well as for significant changes in established products (e.g., new dosage form, new route of administration, or new manufacturing process for a biotechnology-derived product) and for established products that are to be introduced to new popu
25、lations or in significant new indications or where a new major safety concern has arisen. Contains Nonbinding Recommendations 3The purpose of this guidance is to propose a structure for a pharmacovigilance plan and a safety specification that summarizes the identified and potential risks of the prod
26、uct to be addressed in the plan. The guidance is divided into the following sections: Safety specification Pharmacovigilance plan Annex Pharmacovigilance Methods It is recommended that company pharmacovigilance experts get involved early in product development. Planning and dialogue with regulators
27、should also start long before license application. A safety specification and pharmacovigilance plan can also be developed for products already on the market (e.g., new indication or major new safety concern). The plan could be used as the basis for discussion of pharmacovigilance activities with re
28、gulators in the different ICH regions and beyond. For products with important identified risks, important potential risks or important missing information, the pharmacovigilance plan should include additional actions designed to address these concerns. For products for which no special concerns have
29、 arisen, routine pharmacovigilance as described in section III.A.2 (3.1.2) of this guidance should be sufficient for postapproval safety monitoring, without the need for additional actions (e.g., safety studies). During the course of implementing the various components of the plan, any important eme
30、rging benefit or risk information should be discussed and used to revise the plan. The following principles underpin this guidance: Planning of pharmacovigilance activities throughout the product life-cycle Science-based approach to risk documentation Effective collaboration between regulators and i
31、ndustry Applicability of the pharmacovigilance plan across the three ICH regions II. SAFETY SPECIFICATION (2) The safety specification should be a summary of the important identified risks of a drug, important potential risks, and important missing information. It should also address the populations
32、 potentially at-risk (where the product is likely to be used), and outstanding safety questions that warrant further investigation to refine understanding of the benefit-risk profile during the postapproval period. This safety specification is intended to help industry and regulators identify any ne
33、ed for specific data collection and also to facilitate the construction of the pharmacovigilance plan. The safety specification can be built initially during the premarketing phase and, at the time approval is sought, it should reflect the status of issues that were being followed during development
34、. 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 saf
35、ety specification. Sponsors should support the safety specification with Contains Nonbinding Recommendations 4references to specific pages of the CTD or other relevant documents. The safety specification can be a stand-alone document, usually in conjunction with the pharmacovigilance plan, but eleme
36、nts can also be incorporated into the CTD. The length of the document will generally depend on the product and its development program. Appendices can be added if it is considered important to provide a more detailed explanation of important risks or analyses. A. Elements of the Safety Specification
37、 (2.1) It is recommended that sponsors follow the structure of elements provided below when compiling the safety specification. The elements of the safety specification that are included are only a guide. The safety specification can include additional elements, depending on the nature of the produc
38、t and its development program. Conversely, for products already on the market with emerging new safety concerns, only a subset of the elements might be relevant. The focus of the safety specification should be on the identified risks, important potential risks, and important missing information. The
39、 following elements should be considered for inclusion. 1. Nonclinical (2.1.1) Within the Specification, this section should present nonclinical safety findings that have not been adequately addressed by clinical data, for example: Toxicity (including repeat-dose toxicity, reproductive/developmental
40、 toxicity, nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity, etc.) General pharmacology (cardiovascular, including QT interval prolongation; nervous system; etc.) Drug interactions Other toxicity-related information or data If the product is intended for use in special populations, cons
41、ideration should be given to whether specific nonclinical data needs exist. 2. Clinical (2.1.2) a. Limitations of the human safety database Limitations of the safety database (e.g., related to the size of the study population, study inclusion/exclusion criteria) should be considered, and the implica
42、tions of such limitations with respect to predicting the safety of the product in the marketplace should be explicitly discussed. Particular reference should be made to populations likely to be exposed during the intended or expected use of the product in medical practice. The worldwide experience s
43、hould be briefly discussed, including: The extent of the worldwide exposure Any new or different safety issues identified Any regulatory actions related to safety Contains Nonbinding Recommendations 5b. Populations not studied in the preapproval phase The specification should discuss which populatio
44、ns have not been studied or have only been studied to a limited degree in the preapproval 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
45、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 ra
46、cial and/or ethnic origins c. Adverse events (AEs)/adverse drug reactions (ADRs) This section should list the important identified and potential risks that require further characterization or evaluation. Specific references should be made to guide a reviewer to where clinical safety data are present
47、ed (e.g., relevant sections of the CTD 2.5.5 and 2.7.4). Discussion of risk factors and potential mechanisms that apply to identified AEs/ADRs should draw on information from any part of the CTD (nonclinical and clinical) and other relevant information, such as other drug labels, scientific literatu
48、re, and postmarketing experience. Identified risks for 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 prod
49、uct. 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. These AEs/ADRs should usually call for further evaluation as part of the pharmacovigilance plan (e.g., frequency in normal conditions of use, severity, outcome, at-risk groups). Potential risks for further evaluation Important potential risks should be described in this section. The evidence that led to the conclusion th
