1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE H ARMONISED T RIPARTITE G UIDELINE ICH C S AFETY D LINICAL M ANAGEMENT : ATA D EFINITIONS AND S TANDARDS FOR E XPEDITED EPORTING R E2A Current Step 4 version dated 27 October 1994 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the reg ulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.
2 E2A Document History New First Codification History Date Codification November 2005 24 E2A E2A Approval by the Steering Committee under Step 2 and June release for public consultation. 1993 Current Step 4 version 27 E2A E2A and Step 4 Approval by the Steering Committee under October recommendation for adoption to the three ICH 1994 regulatory bodies.
3 C S AFETY D ATA M ANAGEMENT : LINICAL D E XPEDITED R EPORTING TANDARDS FOR EFINITIONS AND S ICH Harmonised Tripartite Guideline Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 27 October 1994, this guideline is recommended for adoption to the three regulatory parties to ICH I. INTRODUCTION ther and, if necessary, to take action on It is important to harmonise the way to ga ing during clinical development. Thus, important clinical safety information aris agreed definitions and terminology, as well as procedures, will ensure uniform Good Clinical Practice stand ards in this area. The initiatives already undertaken for marketed medicines through the CIOMS-1 and CIOMS-2 Working Groups on fety update reporting, respectively, are expedited (alert) reports and periodic sa ver, there are special circumstances important precedents and models. Howe pment, especially in the early stages involving medicinal products under develo and before any marketing experience is available. Conversely, it must be recognised that a medicinal product will be under various stages of development and/or marketing in different countries , and safety data from marketing experience will ordinarily be of interest to regulators in countries where the nal-only (Phase 1, 2, or 3) status. For medicinal product is still under investigatio well-advised to regard pre-marketing and this reason, it is both practical and post-marketing clinical safety re porting concepts and practices as interdependent, while recognising that re sponsibility for clinical safety within reside with different departments, regulatory bodies and companies may depending on the status of the product (investigational vs. marketed). There are two issues within the broad subj ect of clinical safety data management that are appropriate for harmonisation at this time: (1) the development of standard definiti ons and terminology for key aspects of clinical safety reporting, and (2) the appropriate mechanism for handlin g expedited (rapid) reporting, in the investigational (i.e., pre-approval) phase. The provisions of this guideline should be used in conjunction with other ICH Good Clinical Practice guidelines. II. DEFINITIONS AND TERMINOLOGY ASSOCIATED WITH CLINICAL SAFETY EXPERIENCE A. Basic Terms Definitions for the terms adverse event (or experience), adverse reaction, and unexpected adverse reaction have previously been agreed to by consensus of the more than 30 Collaborating Centres of th e WHO International Drug Monitoring Centre (Uppsala, Sweden). [Edwards, I.R., et al, Harmonisation in Pharmacovigilance. Drug Safety 10(2): 93-102, 1994.] Although those definitions can pertain to situations involving clinical investigations, some minor modifications are necessary, especially to accommodate the pre-approval, development environment. 1
4 Clinical Safety Data Management The following definitions, with input from the WHO Collaborative Centre, have been agreed: 1. Adverse Event (or Adverse Experience) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory findin g, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. 2. Adverse Drug Reaction (ADR) pre-approval clinical experience with a new medicinal product or its new In the c dose(s) may not be established: usages, particularly as the therapeuti all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. ucts" means that a causal relationship The phrase "responses to a medicinal prod between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. marketed medicinal products , a well-accepted definition of an adverse Regarding drug reaction in the post-marketing se tting is found in WHO Technical Report 498  and reads as follows: A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function. The old term "side effect" has been used in various ways in the past, usually to also positive (favourable) effects. It describe negative (unfavourable) effects, but is recommended that this term no longer be used and particularly should not be regarded as synonymous with adve rse event or adverse reaction. 3. Unexpected Adverse Drug Reaction An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational medicinal product). (See section III.C.) B. Serious Adverse Event or Adverse Drug Reaction ts may occur which, if suspected to be During clinical investigations, adverse even medicinal product-related (adverse drug reactions), might be significant enough to lead to important changes in the way the medicinal product is developed (e.g., change in dose, population, needed monitoring, consent forms). This is particularly true for reactions which, in th eir most severe forms, threaten life or function. Such reactions should be reported promptly to regulators. 2
5 Clinical Safety Data Management Therefore, special medical or administrative criteria are needed to define reactions that, either due to their natur e ("serious") or due to the significant, unexpected information they provid e, justify expedited reporting. To ensure no confusion or misunderstanding of the difference between the terms synonymous, the following note of "serious" and "severe," which are not clarification is provided: The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the tively minor medical significance (such event itself, however, may be of rela as severe headache). This is not the same as "serious," which is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or fun ctioning. Seriousness (not severity) serves as a guide for defining re gulatory reporting obligations. and other definitions in use or under After reviewing the various regulatory discussion elsewhere, the following definition is believed to encompass the spirit and meaning of them all: A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: * results in death, * is life-threatening, NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. * requires inpatient hospitalisation or prolongation of existing hospitalisation, * results in persistent or significant disability/incapacity, or * is a congenital anomaly/birth defect. be exercised in deciding whether Medical and scientific judgement should expedited reporting is appropriate in othe r situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the pa tient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dy scrasias or convulsions that do not result in hospitalisation; or developmen t of drug dependency or drug abuse. C. Expectedness of an Adverse Drug Reaction The purpose of expedited reporting is to make regulators, investigators, and other appropriate people aware of ne w, important information on serious reactions. Therefore, such reporting will generally involve events previously unobserved or undocumented, and a guideline is needed on how to define an event as "unexpected" or "expected" (exp ected/unexpected from the perspective of 3
6 Clinical Safety Data Management previously observed, not on the basis of what might be anticipated from the pharmacological properties of a medicinal product). As stated in the definition (II.A.3.), an "unexpected" adverse reaction is one, the nature or severity of which is not consis tent with information in the relevant nts are amended, expedited reporting is source document(s). Until source docume required for additional occu rrences of the reaction. The following documents or circumstances will be used to determine whether an adverse event/reaction is expected: 1. For a medicinal product not yet ap proved for marketing in a country, a rve as the source document in that company's Investigator's Brochure will se country. (See section III.F. and ICH Guideline for the Investigator's Brochure.) ion on specificity or severity of a 2. Reports which add significant informat R constitute unexpected events. For known, already documented serious AD example, an event more specific or more severe than described in the Investigator's Brochure would be consider ed "unexpected". Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis. III. STANDARDS FOR EXPEDITED REPORTING A. What Should be Reported? 1. Single Cases of Serious, Unexpected ADRs All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting. This app lies to reports from spontaneous sources and from any type of clinical or epidem iological investigation, independent of design or purpose. It also applies to cases not reported dire ctly to a sponsor or regulatory authority-generated ADR manufacturer (for example, those found in rce of a report (investigation, spontaneous, registries or in publications). The sou other) should always be specified. e serious but expected will ordinarily be Expedited reporting of reactions which ar so inappropriate for serious events from inappropriate. Expedited reporting is al clinical investigations that are consider ed not related to study product, whether the event is expected or not. Similarly, non-serious adverse reactions, whether expected or not, will ordinarily not be subject to expedited reporting. Information obtained by a sponsor or manufacturer on serious, unexpected tted on an expedited basis to appropriate reports from any source should be submi regulatory authorities if the minimum criteria for expedite d reporting can be met. See section III.B. Causality assessment is required for clinical investigation cases. All cases judged by either the reporting health care pr ofessional or the sponsor as having a reasonable suspected causal relationship to the medicinal product qualify as ADRs. For purposes of reporting, ad verse event reports associated with marketed drugs (spontaneous reports) usually imply causality. 4
7 Clinical Safety Data Management Many terms and scales are in use to describe the degree of causality (attributability) between a medicinal product and an event, such as certainly, definitely, probably, possibly or likely rela ted or not related. Phrases such as "plausible relationship," "suspected causality," or "causal relationship cannot be ruled out" are also invoked to describe cause and effect. However, there is currently no standard international nome nclature. The expression "reasonable causal relationship" is meant to convey in general that there are facts (evidence) or arguments to suggest a causal relationship. 2. Other Observations There are situations in addition to single case reports of "serious" adverse events communication to regulatory authorities; or reactions that may necessitate rapid appropriate medical and scientific judgement should be applied for each situation. In general, information that might materially influence the benefit- that would be sufficient to consider risk assessment of a medicinal product or changes in medicinal product administration or in the overall conduct of a clinical investigation represents such situations. Examples include: ase in the rate of occurrence which is a. For an "expected," serious ADR, an incre judged to be clinically important. b. A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening disease. c. A major safety finding from a ne wly completed animal study (such as carcinogenicity). B. Reporting Time Frames 1. Fatal or Life-Threatening Unexpected ADRs ming so as to require very rapid Certain ADRs may be sufficiently alar where the medicinal product or indication, notification to regulators in countries formulation, or population for the medi cinal product are still not approved for marketing, because such reports may lead to consideration of suspension of, or ns program. Fatal or life-threatening, other limitations to, a clinical investigatio unexpected ADRs occurring in clinical investigations qualify for very rapid reporting. Regulatory agencies should be notified (e.g., by telephone, facsimile transmission, or in writing) as soon as possible but no later than 7 calendar days a case qualifies, followed by as complete after first knowledge by the sponsor that a report as possible within 8 additional calendar days. This report must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar medicinal products. 2. All Other Serious, Unexpected ADRs Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must be filed as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting. 5
8 Clinical Safety Data Management 3. Minimum criteria for reporting aluation of a case report may not be Information for final description and ev available within the required time fr ames for reporting outlined above. ial reports should be submitted within Nevertheless, for regulatory purposes, init the prescribed time as long as the fo llowing minimum criteria are met: an identifiable patient; a suspect medicinal product; an identifiable reporting source; and an event or outcome that can be identified as serious and unexpected, and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. Follow-up information should be actively sought and submitted as it becomes available. C. How to Report The CIOMS-I form has been a widely a ccepted standard for expedited adverse event reporting. However, no matter what the form or format used, it is important that certain basic information/data elements, when available, be included with any expedited report, whether in a tabular or narrative presentation. The listing in Attachment 1 addresses those data elements regarded as desirable; if all are not available at the time of expedited reporting, efforts should be made to obtain them. (See section III.B.) All reports must be sent to those regula tors or other official parties requiring them (as appropriate for the local situation) in countries where the drug is under development. D. Managing Blinded Therapy Cases When the sponsor and investigator are b linded to individual patient treatment (as in a double-blind study), the occurrence of a serious event requires a decision on whether to open (break) the code for th e specific patient. If the investigator breaks the blind, then it is assumed the sponsor will also know the assigned treatment for that patient. Although it is advantageous to retain the blind for all patients prior to final study analysis, when a serious adverse reaction is judged mmended that the blind be broken only reportable on an expedited basis, it is reco en if the investigator has not broken the for that specific patient by the sponsor ev blind. It is also recommended that, when possible and appropriate, the blind be maintained for those persons, such as biometrics personnel, responsible for analysis and interpretation of results at the study's conclusion. There are several disadvantages to maintaining the blind under the circumstances described which outweigh the advantages. By retaining the blind, placebo and comparator (usually a marketed product) cases are filed unnecessarily. When the blind is eventua lly opened, which may be many weeks or months after reporting to regulators , it must be ensured that company and regulatory data bases are revised. If the event is serious, new, and possibly related to the medicinal product, then if the Investigator's Brochure is updated, notifying relevant parties of the new information in a blinded fashion is inappropriate and possibly misleading. Mo reover, breaking the blind for a single patient usually has little or no significant implications for the conduct of the clinical investigation or on the analysis of the final clinical investigation data. However, when a fatal or other "serious" outcome is the primary efficacy endpoint in a clinical investigation, the integrit y of the clinical investigation may be compromised if the blind is broken. Under these and similar circumstances, it 6
9 Clinical Safety Data Management th regulatory authorities in advance may be appropriate to reach agreement wi concerning serious events that would be treated as disease-related and not subject to routine expedited reporting. E. Miscellaneous Issues 1. Reactions Associated with Active Comparator or Placebo Treatment cide whether active comparator drug It is the sponsor's responsibility to de reactions should be reported to the other manufacturer and/or directly to appropriate regulatory agencies. Sponsors must report such events to either the manufacturer of the active control or to appropriate regulatory agencies. Events associated with placebo will usually not satisfy the criteria for an ADR and, therefore, for expedited reporting. 2. Products with More than one Presentation or Use To avoid ambiguities and uncertainties , an ADR that qualifies for expedited oduct (e.g., a dosage form, formulation, reporting with one presentation of a pr delivery system) or product use (e.g., for an indication or population), should be reported or referenced to regulatory filings across other product presentations and uses. It is not uncommon that more than one dosage form, formulation, or delivery system (oral, IM, IV, topical, etc.) of th e pharmacologically active compound(s) is under study or marketed; for these different presentations there may be some marked differences in the clinical safety profile. The same may apply for a given product used in different indications or populations (single dose vs. chronic administration, for example). Thus, "exp ectedness" may be product or product- Brochures may be used accordingly. use specific, and separate Investigator's cover ADR information that applies to However, such documents are expected to all affected product presentations and uses. When relevant, separate discussions of pertinent product-specific or use-sp ecific safety information will also be included. ug reactions that qualify for expedited It is recommended that any adverse dr reporting observed with one product dosage form or use be cross referenced to regulatory records for all other dosage forms and uses for that product. This may result in a certain amount of overrepo rting or unnecessary reporting in obvious situations (for example, a report of phlebiti s on IV injection sent to authorities in a country where only an oral dosage form is studied or marketed). However, underreporting is completely avoided. 3. Post-study Events Although such information is not routin ely sought or collected by the sponsor, serious adverse events that occurred after the patient had completed a clinical study (including any protocol-required po st-treatment follow-up) will possibly be reported by an investigator to the sponsor. Such cases should be regarded for expedited reporting purposes as though they were study reports. Therefore, a causality assessment and determination of expectedness are needed for a decision on whether or not expedite d reporting is required. 7
10 Clinical Safety Data Management F. INFORMING INVESTIGATORS AND ETHICS COMMITTEES/ INSTITUTIONAL REVIEW BOARDS OF NEW SAFETY INFORMATION International standards regarding such communication are discussed within the ICH GCP Guidelines, including the addendum on "Guideline for the Investigator's Brochure." In general, the sponsor of a study should amend the Investigator's Brochure as needed, and in accord with any local regulatory requirements, so as to keep the descri ption of safety information updated. 8
11 Clinical Safety Data Management Attachment 1 KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED REPORTS OF SERIOUS ADVERSE DRUG REACTIONS The following list of items has its foundation in several established precedents, including those of CIOMS-I, the WHO Inte rnational Drug Monitoring Centre, and various regulatory authority forms and guid elines. Some items may not be relevant mum information required for expedited depending on the circumstances. The mini reporting purposes is: an identifiable patient, the name of a suspect medicinal product, an identifiable reporting source, and an event or outcome that can be identified as serious and unexpected and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. Attempts should be made to obtain follow-up information on as many other listed items pertinent to the case. 1. Patient Details Initials Other relevant identifier (clinical investigation number, for example) Gender Age and/or date of birth Weight Height 2. Suspected Medicinal Product(s) Brand name as reported International Non-Proprietary Name (INN) Batch number Indication(s) for which suspect medici nal product was prescribed or tested Dosage form and strength Daily dose and regimen (specify units - e.g., mg, ml, mg/kg) Route of administration Starting date and time of day Stopping date and time, or duration of treatment 3. Other Treatment(s) For concomitant medicinal products (inc luding non-prescription/OTC medicinal products) and non-medicinal product therap ies, provide the same information as for the suspected product. 9
12 Clinical Safety Data Management 4. Details of Suspected Adverse Drug Reaction(s) body site and severity, as well as the Full description of reaction(s) including garding the report as serious should be given. In criterion (or criteria) for re addition to a description of the reported signs and symptoms, whenever possible, attempts should be made to establish a specific diagnosis for the reaction. Start date (and time) of onset of reaction Stop date (and time) or duration of reaction Dechallenge and rechallenge information Setting (e.g., hospital, out-patient clinic, home, nursing home) information on recovery and any Outcome: sequelae; what specific tests and/or treatment may have been required and their results; for a fatal outcome, cause of death and a comment on its possible relation ship to the suspected reaction should be provided. Any autopsy or other post-mortem findings (including a coroner's report) should also be provided when available. Other information: anything relevant to facilitate assessment of the case, such as medical history including allergy, drug or alcohol abuse; fam ily history; findings from special investigations. 5. Details on Reporter of Event (Suspected ADR) Name Address Telephone number Profession (speciality) 6. Administrative and Sponsor/Company Details Source of report: was it spontaneous, from a clinical investigation (provide details), from the literature (provide copy), other? Date event report was first rece ived by sponsor/manufacturer Country in which event occurred Type of report filed to authorities: initial or follow-up (first, second, etc.) Name and address of sponsor/manufacturer/company Name, address, telephone number, and FAX number of contact person in reporting company or institution Identifying regulatory code or number for marketing authorisation dossier or clinical investigation process for the su spected product (for example IND or CTX number, NDA number) Sponsor/manufacturer's identification num ber for the case (this number must be the same for the initial and follow-up reports on the same case). 10