e2a

Clinical Safety Data

Management: Definitionsand Standards forExpedited Reporting

ICH-E2AMarch 1995

TABLE OF CONTENTS

I.II.

INTRODUCTION...............................................1DEFINITIONS AND TERMINOLOGY ASSOCIATED WITH CLINICAL

SAFETY EXPERIENCE..........................................2A.

Basic Terms..............................................21.2.3.B.C.III.

Adverse Event (or Adverse Experience)...................3Adverse Drug Reaction (ADR)...........................3Unexpected Adverse Drug Reaction......................4

Serious Adverse Event or Adverse Drug Reaction................4Expectedness of an Adverse Drug Reaction.....................5

STANDARDS FOR EXPEDITED REPORTING......................6A.

What Should be Reported....................................61.2.B.

Single Cases of Serious, Unexpected ADRs................6Other Observations...................................7

Reporting Time Frames.....................................81.2.3.

Fatal or Life-Threatening Unexpected ADRs................8All Other Serious, Unexpected ADRs.....................8Minimum Criteria for Reporting..........................8

C.D.E.

How to Report.............................................9Managing Blinded Therapy Cases.............................9Miscellaneous Issues......................................101.

Reactions Associated with Active Comparator or Placebo

Treatment..........................................10

2.3.F.

Products with More Than One Presentation or Use.........10Post-study Events...................................11

Informing Investigators and Ethics Committees/Institutional Review

Boards of New Safety Information............................11

IV.REFERENCE.................................................11

KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED REPORTS OFSERIOUS ADVERSE DRUG REACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . Attachment 1

GUIDELINE FOR INDUSTRY1

CLINICAL SAFETY DATA MANAGEMENT:DEFINITIONS AND STANDARDS FOR EXPEDITED

REPORTING2

I.

INTRODUCTION

It is important to harmonize the way to gather and, if necessary, to take actionon important clinical safety information arising during clinical development. Thus,agreed definitions and terminology, as well as procedures, will ensure uniformGood Clinical Practice standards in this area. The initiatives already undertakenfor marketed medicines through the CIOMS-1 and CIOMS-2 Working Groups onexpedited (alert) reports and periodic safety update reporting, respectively, areimportant precedents and models. However, there are special circumstances

This guideline was developed within the Expert Working Group (Efficacy) of the

International Conference on Harmonisation of Technical Requirements for Registrationof Pharmaceuticals for Human Use (ICH) and has been subject to consultation by theregulatory parties, in accordance with the ICH process. This document has beenendorsed by the ICH Steering Committee at Step 4 of the ICH process, October 27,1994. At Step 4 of the process, the final draft is recommended for adoption to theregulatory bodies of the European Union, Japan and the USA. This guidance waspublished in the Federal Register on March 1, 1995 (60 FR 11284) and is applicable toboth drug and biological products. In the past, guidelines have generally been issuedunder § 10.90(b) [21 CFR 10.90(b)], which provides for the use of guidelines to stateprocedures or standards of general applicability that are not legal requirements but thatare acceptable to FDA. The agency is now in the process of revising §10.90(b). Therefore, this guideline is not being issued under the authority of §10.90(b), and itdoes not create or confer any rights, privileges or benefits for or on any person, nordoes it operate to bind FDA in any way. For additional copies of this guideline contactthe Executive Secretariat Staff, HFD-8, Center for Drug Evaluation and Research,7500 Standish Place, Rockville, MD 20855, 301-594-1012. An electronic version ofthis guideline is also available via Internet by connecting to the CDER FTP server(CDVS2.CDER.FDA.GOV) using the FTP protocol.

The time frames and definitions in this guideline differ from those in the Code of

Federal Regulations [21 CFR 314.80]. Until the regulations are revised, the timeframes and definitions in the CFR should be followed.

2

1

involving medicinal products under development, especially in the early stagesand before any marketing experience is available. Conversely, it must be

recognized that a medicinal product will be under various stages of developmentand/or marketing in different countries, and safety data from marketingexperience will ordinarily be of interest to regulators in countries where the

medicinal product is still under investigational only (Phase 1, 2, or 3) status. Forthis reason, it is both practical and well-advised to regard premarketing andpost-marketing clinical safety reporting concepts and practices as

interdependent, while recognizing that responsibility for clinical safety withinregulatory bodies and companies may reside with different departments,depending on the status of the product (investigational vs. marketed).There are two issues within the broad subject of clinical safety datamanagement that are appropriate for harmonization at this time:

the development of standard definitions and terminology for key aspectsof clinical safety reporting, and

the appropriate mechanism for handling expedited (rapid) reporting, in theinvestigational (i.e., pre-approval) phase.

The provisions of this guideline should be used in conjunction with other ICHGood Clinical Practice guidelines.II.

DEFINITIONS AND TERMINOLOGY ASSOCIATED WITH CLINICALSAFETY EXPERIENCEA.

Basic Terms

Definitions for the terms adverse event (or experience), adverse reaction,and unexpected adverse reaction have previously been agreed to byconsensus of the more than 30 Collaborating Centers of the 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 involvingclinical investigations, some minor modifications are necessary,

especially to accommodate the pre-approval, development environment.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 andwhich does not necessarily have to have a causal relationship withthis treatment.

An adverse event (AE) can therefore be any unfavorable andunintended sign (including an abnormal laboratory finding, for

example), symptom, or disease temporally associated with the useof a medicinal product, whether or not considered related to themedicinal product.2.

Adverse Drug Reaction (ADR)

In the pre-approval clinical experience with a new medicinal

product or its new usages, particularly as the therapeutic dose(s)may not be established:

all noxious and unintended responses to a medicinal

product related to any dose should be considered adversedrug reactions.

The phrase \"responses to a medicinal products\" means that acausal relationship between a medicinal product and an adverseevent is at least a reasonable possibility, i.e., the relationshipcannot be ruled out.

Regarding marketed medicinal products, a well-accepted definitionof an adverse drug reaction in the post-marketing setting is foundin WHO Technical Report 498 [1972] and reads as follows:

A response to a drug which is noxious and unintended andwhich occurs at doses normally used in man forprophylaxis, diagnosis, or therapy of disease or formodification of physiological function.

The old term \"side effect\" has been used in various ways in thepast, usually to describe negative (unfavorable) effects, but alsopositive (favorable) effects. It is recommended that this term nolonger be used and particularly should not be regarded assynonymous with adverse event or adverse reaction.3.

Unexpected Adverse Drug Reaction

An adverse reaction, the nature or severity of which is notconsistent with the applicable product information (e.g.,

Investigator's Brochure for an unapproved investigationalmedicinal product). See section III.C.

B.

Serious Adverse Event or Adverse Drug Reaction

During clinical investigations, adverse events may occur which, ifsuspected to be medicinal product-related (adverse drug reactions),might be significant enough to lead to important changes in the way themedicinal product is developed (e.g., change in dose, population, neededmonitoring, consent forms). This is particularly true for reactions which,in their most severe forms, threaten life or function. Such reactionsshould be reported promptly to regulators.

Therefore, special medical or administrative criteria are needed to definereactions that, either due to their nature (\"serious\") or due to thesignificant, unexpected information they provide, justify expeditedreporting.

To ensure no confusion or misunderstanding exist of the differencebetween the terms \"serious\" and \"severe,\" which are not synonymous,the following note of clarification is provided:

The term \"severe\" is often used to describe the intensity (severity)of a specific event (as in mild, moderate, or severe myocardialinfarction); the event itself, however, may be of relatively minormedical significance (such as severe headache). This is not thesame as \"serious,\" which is based on patient/event outcome oraction criteria usually associated with events that pose a threat toa patient's life or functioning. Seriousness (not severity) serves asa guide for defining regulatory reporting obligations.

After reviewing the various regulatory and other definitions in use orunder discussion elsewhere, the following definition is believed toencompass the spirit and meaning of them all:

A serious adverse event (experience) or reaction is any untowardmedical 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 anevent which hypothetically might have caused death if itwere more severe.

Requires inpatient hospitalization or prolongation of existinghospitalization,

Results in persistent or significant disability/incapacity, or Is a congenital anomaly/birth defect.

Medical and scientific judgment should be exercised in deciding whetherexpedited reporting is appropriate in other situations, such as importantmedical events that may not be immediately life-threatening or result indeath or hospitalization but may jeopardize the patient or may requireintervention to prevent one of the other outcomes listed in the definitionabove. These should also usually be considered serious.

Examples of such events are intensive treatment in an emergency roomor at home for allergic bronchospasm; blood dyscrasias or convulsionsthat do not result in hospitalization; or development of drug dependencyor 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 new, important information onserious reactions. Therefore, such reporting will generally involve eventspreviously unobserved or undocumented, and a guideline is needed onhow to define an event as \"unexpected\" or \"expected\"

(expected/unexpected from the perspective of previously observed, noton the basis of what might be anticipated from the pharmacologicalproperties of a medicinal product).

As stated in the definition (II.A.3.), an \"unexpected\" adverse reaction isone, the nature or severity of which is not consistent with information inthe relevant source document(s). Until source documents are amended,expedited reporting is required for additional occurrences of the reaction.The following documents or circumstances will be used to determinewhether an adverse event/reaction is expected:1.

For a medicinal product not yet approved for marketing in acountry, a company's Investigator's Brochure will serve as the

source document in that country. See section III.F. and ICHGuideline for the Investigator's Brochure.2.

Reports which add significant information on specificity or severityof a known, already documented serious ADR constitute

unexpected events. For example, an event more specific or moresevere than described in the Investigator's Brochure would beconsidered \"unexpected.\" Specific examples would be (a) acuterenal failure as a labeled ADR with a subsequent new report ofinterstitial nephritis and (b) hepatitis with a first report of fulminanthepatitis.

III.STANDARDS FOR EXPEDITED REPORTINGA.

What Should be Reported?1.

Single Cases of Serious, Unexpected ADRs

All ADRs that are both serious and unexpected are subject toexpedited reporting. This applies to reports from spontaneoussources and from any type of clinical or epidemiological

investigation, independent of design or purpose. It also applies tocases not reported directly to a sponsor or manufacturer (forexample, those found in regulatory authority generated ADR

registries or in publications). The source of a report (investigation,spontaneous, other) should always be specified.

Expedited reporting of reactions that are serious but expected willordinarily be inappropriate. Expedited reporting is also

inappropriate for serious events from clinical investigations that areconsidered not related to study product, whether the event is

expected or not. Similarly, nonserious adverse reactions, whetherexpected or not, will ordinarily not be subject to expeditedreporting.

Information obtained by a sponsor or manufacturer on serious,unexpected reports from any source should be submitted on anexpedited basis to appropriate regulatory authorities if the

minimum criteria for expedited reporting can be met. See sectionIII.B.

Causality assessment is required for clinical investigation cases. All cases judged by either the reporting health care professional orthe sponsor as having a reasonable suspected causal relationship

to the medicinal product qualify as ADRs. For purposes of

reporting, adverse event reports associated with marketed drugs(spontaneous reports) usually imply causality.

Many terms and scales are in use to describe the degree ofcausality (attributability) between a medicinal product and anevent, such as certainly, definitely, probably, possibly or likelyrelated 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 iscurrently no standard international nomenclature. The expression\"reasonable causal relationship\" is meant to convey in general thatthere are facts (evidence) or arguments to suggest a causalrelationship.2.

Other Observations

There are situations in addition to single case reports of \"serious\"adverse events or reactions that may necessitate rapid

communication to regulatory authorities; appropriate medical andscientific judgment should be applied for each situation. In

general, information that might materially influence the benefit-riskassessment of a medicinal product or that would be sufficient toconsider changes in medicinal product administration or in theoverall conduct of a clinical investigation represents suchsituations. Examples include:a.b.

For an \"expected,\" serious ADR, an increase in the rate ofoccurrence which is judged to be clinically important.A significant hazard to the patient population, such as lackof efficacy with a medicinal product used in treatinglife-threatening disease.

A major safety finding from a newly completed animal study(such as carcinogenicity) .

c.

B.

Reporting Time Frames1.

Fatal or Life-Threatening Unexpected ADRs

Certain ADRs may be sufficiently alarming so as to require veryrapid notification to regulators in countries where the medicinalproduct or indication, formulation, or population for the medicinal

product are still not approved for marketing, because such reportsmay lead to consideration of suspension of, or other limitations to,a clinical investigation program. Fatal or life-threatening,

unexpected ADRs occurring in clinical investigations qualify forvery rapid reporting. Regulatory agencies should be notified (e.g.,by telephone, facsimile transmission, or in writing) as soon aspossible but no later than 7 calendar days after first knowledge bythe sponsor that a case qualifies, followed by as complete a reportas possible within 8 additional calendar days. This report shouldinclude an assessment of the importance and implication of thefindings, including relevant previous experience with the same orsimilar 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 than15 calendar days after first knowledge by the sponsor that thecase meets the minimum criteria for expedited reporting.3.

Minimum Criteria for Reporting

Information for final description and evaluation of a case reportmay not be available within the required time frames for reportingoutlined above. Nevertheless, for regulatory purposes, initialreports should be submitted within the prescribed time as long asthe following minimum criteria are met: an identifiable patient; asuspect medicinal product; an identifiable reporting source; and anevent or outcome that can be identified as serious and

unexpected, and for which, in clinical investigation cases, there isa reasonable suspected causal relationship. Follow-up informationshould be actively sought and submitted as it becomes available.

C.

How to Report

The CIOMS-I form has been a widely accepted standard for expeditedadverse event reporting. However, no matter what the form or formatused, it is important that certain basic information/data elements, whenavailable, be included with any expedited report, whether in a tabular ornarrative presentation. The listing in Attachment 1 addresses those dataelements regarded as desirable; if all are not available at the time ofexpedited reporting, efforts should be made to obtain them. See sectionIII.B.

All reports must be sent to those regulators or other official parties

requiring them (as appropriate for the local situation) in countries wherethe drug is under development.D.

Managing Blinded Therapy Cases

When the sponsor and investigator are blinded to individual patient

treatment (as in a double-blind study), the occurrence of a serious eventrequires a decision on whether to open (break) the code for the specificpatient. If the investigator breaks the blind, then it is assumed the

sponsor will also know the assigned treatment for that patient. Although itis advantageous to retain the blind for all patients prior to final studyanalysis, when a serious adverse reaction is judged reportable on anexpedited basis, it is recommended that the blind be broken only for thatspecific patient by the sponsor even if the investigator has not broken theblind. It is also recommended that, when possible and appropriate, theblind be maintained for those persons, such as biometrics personnel,responsible for analysis and interpretation of results at the study'sconclusion.

There are several disadvantages to maintaining the blind under thecircumstances described which outweigh the advantages. By retainingthe blind, placebo and comparator (usually a marketed product) casesare filed unnecessarily. When the blind is eventually opened, which maybe many weeks or months after reporting to regulators, it must beensured that company and regulatory data bases are revised. If the

event is serious, new, and possibly related to the medicinal product, thenif the Investigator's Brochure is updated, notifying relevant parties of thenew information in a blinded fashion is inappropriate and possibly

misleading. Moreover, breaking the blind for a single patient usually haslittle or no significant implications for the conduct of the

clinical investigation or on the analysis of the final clinical investigationdata.

However, when a fatal or other \"serious\" outcome is the primary efficacyendpoint in a clinical investigation, the integrity of the clinical investigationmay be compromised if the blind is broken. Under these and similarcircumstances, it may be appropriate to reach agreement with regulatoryauthorities in advance concerning serious events that would be treated asdisease-related and not subject to routine expedited reporting.E.

Miscellaneous Issues

1.

Reactions Associated with Active Comparator or PlaceboTreatment

It is the sponsor's responsibility to decide whether activecomparator drug reactions should be reported to the other

manufacturer and/or directly to appropriate regulatory agencies. Sponsors should report such events to either the manufacturer ofthe active control or to appropriate regulatory agencies. Eventsassociated with placebo will usually not satisfy the criteria for anADR and, therefore, for expedited reporting.

2.Products with More Than One Presentation or Use

To avoid ambiguities and uncertainties, an ADR that qualifies forexpedited reporting with one presentation of a product (e.g., a

dosage form, formulation, delivery system) or product use (e.g., foran indication or population), should be reported or referenced toregulatory 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 the

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 agiven product used in different indications or populations (singledose vs. chronic administration, for example). Thus,

\"expectedness\" may be product or product use specific, andseparate Investigator's Brochures may be used accordingly.

However, such documents are expected to cover ADR informationthat applies to all affected product presentations and uses. Whenrelevant, separate discussions of pertinent product-specific oruse-specific safety information will also be included.

It is recommended that any adverse drug reactions that qualify forexpedited reporting observed with one product dosage form or usebe cross referenced to regulatory records for all other dosageforms and uses for that product. This may result in a certainamount of overreporting or unnecessary reporting in obvious

situations (for example, a report of phlebitis on IV injection sent toauthorities in a country where only an oral dosage form is studiedor marketed). However, underreporting is completely avoided.

3.Post-study Events

Although such information is not routinely sought or collected bythe sponsor, serious adverse events that occurred after the patienthad completed a clinical study (including any protocol requiredpost-treatment follow-up) will possibly be reported by an

investigator to the sponsor. Such cases should be regarded forexpedited reporting purposes as though they were study reports. Therefore, a causality assessment and determination ofexpectedness are needed for a decision on whether or notexpedited reporting is required.

F.

Informing Investigators and Ethics Committees/Institutional ReviewBoards of New Safety Information

International standards regarding such communication are discussedwithin the ICH GCP Guidelines, including the addendum on \"Guideline forthe Investigator's Brochure.\" In general, the sponsor of a study shouldamend the Investigator's Brochure as needed, and in accord with anylocal regulatory requirements, so as to keep the description of safetyinformation updated.

IV.

REFERENCE

Federal Register. Vol.60, No. 40, Wednesday, March 1, 1995, pages 11284-11287.

Attachment 1

KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED REPORTS OF

SERIOUS ADVERSE DRUG REACTIONSThe following list of items has its foundation in several established precedents,including those of CIOMS-I, the WHO International Drug Monitoring Centre, andvarious regulatory authority forms and guidelines. Some items may not be relevantdepending on the circumstances. The minimum information required for expeditedreporting 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 asserious and unexpected and for which, in clinical investigation cases, there is areasonable suspected causal relationship. Attempts should be made to obtainfollow-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 medicinal product was prescribed ortested,

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 (including non-prescription/OTCmedicinal products) and non-medicinal product therapies, provide thesame information as for the suspected product.

4.

Details of Suspected Adverse Drug Reaction(s):

Full description of reaction(s) including body site and severity, as well asthe criterion (or criteria) for regarding the report as serious should begiven. In addition to a description of the reported signs and symptoms,whenever possible, attempts should be made to establish a specificdiagnosis 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),

Outcome: Information on recovery and any sequelae; what specific testsand/or treatment may have been required and their results; for a fataloutcome, cause of death and a comment on its possible relationship tothe suspected reaction should be provided. Any autopsy or otherpost-mortem findings (including a coroner's report) should also be

provided when available. Other information: anything relevant to facilitateassessment of the case, such as medical history including allergy, drugor alcohol abuse; family 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 received 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 inreporting company or institution,

Identifying regulatory code or number for marketing authorization dossieror clinical investigation process for the suspected product (for exampleIND or CTX number, NDA number),

Sponsor/manufacturer's identification number for the case (This numbershould be the same for the initial and follow-up reports on the samecase).