Guidance for Industry-Development and Use of Risk Minimization Action Plans

J:\!GUIDANC\6359OCC.doc 03/22/05 Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment 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) March 2005 Clinical Medical J:\!GUIDANC\6359OCC.doc 03/22/05 Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment Additional 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 or Office of Communication, 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 Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) March 2005 Clinical Medical Contains Nonbinding Recommendations J:\!GUIDANC\6359OCC.doc 03/22/05 TABLE OF CONTENTS I. INTRODUCTION..............................................................................................................................................1 II. BACKGROUND ................................................................................................................................................1 A. PDUFA III’S RISK MANAGEMENT GUIDANCE GOAL.......................................................................................2 B. OVERVIEW OF THE RISK MANAGEMENT GUIDANCES.......................................................................................2 III. THE ROLE OF PHARMACOVIGILANCE AND PHARMACOEPIDEMIOLOGY IN RISK MANAGEMENT.........................................................................................................................................................3 IV. IDENTIFYING AND DESCRIBING SAFETY SIGNALS: FROM CASE REPORTS TO CASE SERIES.........................................................................................................................................................................4 A. GOOD REPORTING PRACTICE ...........................................................................................................................4 B. CHARACTERISTICS OF A GOOD CASE REPORT..................................................................................................5 C. DEVELOPING A CASE SERIES............................................................................................................................6 D. SUMMARY DESCRIPTIVE ANALYSIS OF A CASE SERIES....................................................................................7 E. USE OF DATA MINING TO IDENTIFY PRODUCT-EVENT COMBINATIONS ...........................................................8 F. SAFETY SIGNALS THAT MAY WARRANT FURTHER INVESTIGATION ..............................................................10 G. PUTTING THE SIGNAL INTO CONTEXT: CALCULATING REPORTING RATES VS. INCIDENCE RATES ................10 V. BEYOND CASE REVIEW: INVESTIGATING A SIGNAL THROUGH OBSERVATIONAL STUDIES....................................................................................................................................................................12 A. PHARMACOEPIDEMIOLOGIC STUDIES .............................................................................................................12 B. REGISTRIES ....................................................................................................................................................15 C. SURVEYS........................................................................................................................................................16 VI. INTERPRETING SAFETY SIGNALS: FROM SIGNAL TO POTENTIAL SAFETY RISK................17 VII. BEYOND ROUTINE PHARMACOVIGILANCE: DEVELOPING A PHARMACOVIGILANCE PLAN .......................................................................................................................................................................18 Contains Nonbinding Recommendations J:\!GUIDANC\6359OCC.doc 03/22/05 Guidance for Industry1 Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment This guidance represents the Food and Drug Administration's (FDA's) 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 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 This document provides guidance to industry on good pharmacovigilance practices and pharmacoepidemiologic assessment of observational data regarding drugs, including biological drug products (excluding blood and blood components).2 Specifically, this document provides guidance on (1) safety signal identification, (2) pharmacoepidemiologic assessment and safety signal interpretation, and (3) pharmacovigilance plan development. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. BACKGROUND 1 This guidance has been prepared by the PDUFA III Pharmacovigilance Working Group, which includes members from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 2 For ease of reference, this guidance uses the term product or drug to refer to all products (excluding blood and blood components) regulated by CDER and CBER. Similarly, for ease of reference, this guidance uses the term approval to refer to both drug approval and biologic licensure. Paperwork Reduction Act Public Burden Statement: This guidance contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3520). The collection(s) of information in this guidance were approved under OMB Control No. 0910-0001 (until March 31, 2005) and 0910-0338 (until August 31, 2005). Contains Nonbinding Recommendations J:\!GUIDANC\6359OCC.doc 03/22/05 2 A. PDUFA III’s Risk Management Guidance Goal On June 12, 2002, Congress reauthorized, for the second time, the Prescription Drug User Fee Act (PDUFA III). In the context of PDUFA III, FDA agreed to satisfy certain performance goals. One of those goals was to produce guidance for industry on risk management activities for drug and biological products. As an initial step towards satisfying that goal, FDA sought public comment on risk management. Specifically, FDA issued three concept papers. Each paper focused on one aspect of risk management, including (1) conducting premarketing risk assessment, (2) developing and implementing risk minimization tools, and (3) performing postmarketing pharmacovigilance and pharmacoepidemiologic assessments. In addition to receiving numerous written comments regarding the three concept papers, FDA held a public workshop on April 9 – 11, 2003, to discuss the concept papers. FDA considered all of the comments received in developing three draft guidance documents on risk management activities. The draft guidance documents were published on May 5, 2004, and the public was provided with an opportunity to comment on them until July 6, 2004. FDA considered all of the comments received in producing the final guidance documents. 1. Premarketing Risk Assessment (Premarketing Guidance) 2. Development and Use of Risk Minimization Action Plans (RiskMAP Guidance) 3. Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance) B. Overview of the Risk Management Guidances Like the concept papers and draft guidances that preceded them, each of the three final guidance documents focuses on one aspect of risk management. The Premarketing Guidance and the Pharmacovigilance Guidance focus on premarketing and postmarketing risk assessment, respectively. The RiskMAP Guidance focuses on risk minimization. Together, risk assessment and risk minimization form what FDA calls risk management. Specifically, risk management is an iterative process of (1) assessing a product’s benefit-risk balance, (2) developing and implementing tools to minimize its risks while preserving its benefits, (3) evaluating tool effectiveness and reassessing the benefit-risk balance, and (4) making adjustments, as appropriate, to the risk minimization tools to further improve the benefit-risk balance. This four- part process should be continuous throughout a product’s lifecycle, with the results of risk assessment informing the sponsor’s decisions regarding risk minimization. When reviewing the recommendations provided in this guidance, sponsors and applicants should keep the following points in mind: • Many recommendations in this guidance are not intended to be generally applicable to all products. Industry already performs risk assessment and risk minimization activities for products during development and marketing. The Federal Food, Drug, and Cosmetic Act (FDCA) and FDA implementing regulations establish requirements for routine risk assessment and risk minimization (see e.g., FDA requirements for professional labeling, and adverse Contains Nonbinding Recommendations J:\!GUIDANC\6359OCC.doc 03/22/05 3 event monitoring and reporting). As a result, many of the recommendations presented here focus on situations when a product may pose a clinically important and unusual type or level of risk. To the extent possible, we have specified in the text whether a recommendation is intended for all products or only this subset of products. • It is of critical importance to protect patients and their privacy during the generation of safety data and the development of risk minimization action plans. During all risk assessment and risk minimization activities, sponsors must comply with applicable regulatory requirements involving human subjects research and patient privacy.3 • To the extent possible, this guidance conforms with FDA’s commitment to harmonize international definitions and standards as appropriate. The topics covered in this guidance are being discussed in a variety of international forums. We are participating in these discussions and believe that, to the extent possible, the recommendations in this guidance reflect current thinking on related issues. • When planning risk assessment and risk minimization activities, sponsors should consider input from health care participants likely to be affected by these activities (e.g., from consumers, pharmacists and pharmacies, physicians, nurses, and third party payers). • There are points of overlap among the three guidances. We have tried to note in the text of each guidance when areas of overlap occur and when referencing one of the other guidances might be useful. III. THE ROLE OF PHARMACOVIGILANCE AND PHARMACOEPIDEMIOLOGY IN RISK MANAGEMENT Risk assessment during product development should be conducted in a thorough and rigorous manner; however, it is impossible to identify all safety concerns during clinical trials. Once a product is marketed, there is generally a large increase in the number of patients exposed, including those with co-morbid conditions and those being treated with concomitant medical products. Therefore, postmarketing safety data collection and risk assessment based on observational data are critical for evaluating and characterizing a product's risk profile and for making informed decisions on risk minimization. 3 See 45 CFR part 46 and 21 CFR parts 50 and 56. See also the Health Insurance Portability and Accountability Act of 1996 (HIPAA) (Public Law 104-191) and the Standards for Privacy of Individually Identifiable Health Information (the Privacy Rule) (45 CFR part 160 and subparts A and E of part 164). The Privacy Rule specifically permits covered entities to report adverse events and other information related to the quality, effectiveness, and safety of FDA-regulated products both to manufacturers and directly to FDA (45 CFR 164.512(b)(1)(i) and (iii), and 45 CFR 164.512(a)(1)). For additional guidance on patient privacy protection, see http://www.hhs.gov/ocr/hipaa. Contains Nonbinding Recommendations J:\!GUIDANC\6359OCC.doc 03/22/05 4 This guidance document focuses on pharmacovigilance activities in the post-approval period. This guidance uses the term pharmacovigilance to mean all scientific and data gathering activities relating to the detection, assessment, and understanding of adverse events. This includes the use of pharmacoepidemiologic studies. These activities are undertaken with the goal of identifying adverse events and understanding, to the extent possible, their nature, frequency, and potential risk factors. Pharmacovigilance principally involves the identification and evaluation of safety signals. In this guidance document, safety signal refers to a concern about an excess of adverse events compared to what would be expected to be associated with a product's use. Signals can arise from postmarketing data and other sources, such as preclinical data and events associated with other products in the same pharmacologic class. It is possible that even a single well- documented case report can be viewed as a signal, particularly if the report describes a positive rechallenge or if the event is extremely rare in the absence of drug use. Signals generally indicate the need for further investigation, which may or may not lead to the conclusion that the product caused the event. After a signal is identified, it should be further assessed to determine whether it represents a potential safety risk and whether other action should be taken. IV. IDENTIFYING AND DESCRIBING SAFETY SIGNALS: FROM CASE REPORTS TO CASE SERIES Good pharmacovigilance practice is generally based on acquiring complete data from spontaneous adverse event reports, also known as case reports. The reports are used to develop case series for interpretation. A. Good Reporting Practice Spontaneous case reports of adverse events submitted to the sponsor and FDA, and reports from other sources, such as the medical literature or clinical studies, may generate signals of adverse effects of drugs. The quality of the reports is critical for appropriate evaluation of the relationship between the product and adverse events. FDA recommends that sponsors make a reasonable attempt to obtain complete information for case assessment during initial contacts and subsequent follow-up, especially for serious events,4 and encourages sponsors to use trained health care practitioners to query reporters. Computer-assisted interview technology, targeted questionnaires, or other methods developed to target specific events can help focus the line of questioning. When the report is from a consumer, it is often important to obtain permission to contact the health care practitioner familiar with the patient’s adverse event to obtain further medical information and to retrieve relevant medical records, as needed. 4 Good reporting practices are extensively addressed in a proposed FDA regulation and guidance documents. See (1) Safety Reporting Requirements for Human Drug and Biological Products, Proposed Rule, 68 FR 12406 (March 14, 2003), (2) FDA guidance for industry on Postmarketing Reporting of Adverse Experiences, (3) FDA guidance for industry on E2C Clinical Safety Data Management: Periodic Safety Update Report (PSUR), (4) FDA guidance for industry on Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report. Contains Nonbinding Recommendations J:\!GUIDANC\6359OCC.doc 03/22/05 5 FDA suggests that the intensity and method of case follow-up be driven by the seriousness of the event reported, the report's origin (e.g., health care practitioner, patient, literature), and other factors. FDA recommends that the most aggressive follow-up efforts be directed towards serious adverse event reports, especially of adverse events not known to occur with the drug. B. Characteristics of a Good Case Report Good case reports include the following elements: 1. Description of the adverse events or disease experience, including time to onset of signs or symptoms; 2. Suspected and concomitant product therapy details (i.e., dose, lot number, schedule, dates, duration), including over-the-counter medications, dietary supplements, and recently discontinued medications; 3. Patient characteristics, including demographic information (e.g., age, race, sex), baseline medical condition prior to product therapy, co-morbid conditions, use of concomitant medications, relevant family history of disease, and presence of other risk factors; 4. Documentation of the diagnosis of the events, including methods used to make the diagnosis; 5. Clinical course of the event and patient outcomes (e.g., hospitalization or death);5 6. Relevant therapeutic measures and laboratory data at baseline, during therapy, and subsequent to therapy, including blood levels, as appropriate; 7. Information about response to dechallenge and rechallenge; and 8. Any other relevant information (e.g., other details relating to the event or information on benefits received by the patient, if important to the assessment of the event). For reports of medication errors, good case reports also include full descriptions of the following, when such information is available: 1. Products involved (including the trade (proprietary) and established (proper) name, manufacturer, dosage form, strength, concentration, and type and size of container); 2. Sequence of events leading up to the error; 3. Work environment in which the error occurred; and 4. Types of personnel involved with the error, type(s) of error, and contributing factors. 5 Patient outcomes may not be available at the time of initial reporting. In these cases, follow-up reports can convey important information about the course of the event and serious outcomes, such as hospitalization or death. Contains Nonbinding Recommendations J:\!GUIDANC\6359OCC.doc 03/22/05 6 FDA recommends that sponsors capture in the case narrative section of a medication error report all appropriate information outlined in the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) Taxonomy.6 Although sponsors are not required to use the taxonomy, FDA has found the taxonomy to be a useful tool to categorize and analyze reports of medication errors. It provides a standard language and structure for medication error-related data collected through reports. C. Developing a Case Series FDA suggests that sponsors initially evaluate a signal generated from postmarketing spontaneous reports through a careful review of the cas