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International Conference on Harmonization (ICH)

This chapter summarizes the purpose of the International Conference on Harmonization (ICH) and the reports issued by the various working groups related to drug safety. These reports have been used as the basis for creating certain safety regulations in North America, Europe, Japan, and elsewhere. They are worth taking the time to review online or in this chapter. Keep in mind that not all proposals from the ICH were adopted nor were the adopted proposals necessarily taken directly and without change by national regulatory authorities.

The documents in question are:

• E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
  
• E2B(R3): Maintenance of the Clinical Safety Data Management, including the Maintenance of the Electronic Transmission of Individual Case Safety Reports Message Specification
  
• E2C: Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs
  
• E2CA Addendum to E2C: Periodic Safety Update Reports for Marketed Drugs
  
• E2D: Postapproval Safety Data Management: Definitions and Standards for Expedited Reporting
  
• E2E: Pharmacovigilance Planning

They can be found at Web Resource 37-1.

E2A combines many concepts from the Council for International Organizations of Medical Sciences (CIOMS) I and CIOMS II documents covering the development of standard definitions and terminology for safety reporting and the appropriate mechanism for handling expedited (alert) reporting. This document was originally developed to cover primarily the investigational phase of drug development, but its concepts have been extended to cover postmarketing (approved) drugs also (see document E2E below).

The definitions and recommendations for expedited reporting developed in this document have largely been accepted throughout the world. However, some of the recommendations have been tried and withdrawn (e.g., increased frequency reporting in the United States), inconsistently applied (e.g., breaking the blind), or never applied (reporting an expedited case to all open Investigational New Drug Applications [INDs]).

Definitions

Adverse event or adverse experience (AE): “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.”

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 adverse drug reactions. For marketed products: 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.”

Unexpected ADR: “An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator Brochure for an unapproved investigational medicinal product).” Note that this applies to nonmarketed drugs. This definition was extended to marketed drugs in E2E (see below).

“Serious” and “severe”: The terms serious and severe are differentiated. The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such 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 functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

Serious: “A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.”

“Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious.” Note that “cancer” and “overdose” have been removed. These terms appeared in various pre-1995 definitions of “serious.”

What Should Be Reported to Regulatory Authorities as Expedited Reports?

All ADRs that are both serious and unexpected are subject to expedited reporting. This applies to reports from spontaneous sources and from any type of clinical or epidemiologic investigation, independent of design or purpose.

• Note that this means all adverse reactions (i.e., causally related to the drug) that are serious and unexpected. Thus, it requires all three categories (causality, seriousness, and unexpectedness) for clinical trial cases. Although not explicitly stated in this document, for postmarketing cases the causality is implied (i.e., all spontaneous reports are presumed to be causally related), and thus only two criteria need to be examined: seriousness and expectedness.
  
• No international standard exists for causality classification.
  
• An increased frequency of a known serious ADR should be reported in an expedited fashion.
  
• A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in a life-threatening disease.
  
• A major safety finding from a newly completed animal study.

Reporting Time Frames

• Fatal or life-threatening ADRs: 7 calendar days by phone or fax followed 8 calendar days later with an expedited 15-day report.
  
• Other serious unexpected ADRs: 15 calendar days after the first knowledge by the sponsor that the case meets the minimum criteria for reporting.

Minimum Criteria for Reporting

• An identifiable patient
  
• A suspect medicinal product
  
• An identifiable reporting source
  
• An event or outcome that is serious and unexpected and, for clinical trial cases, a reasonable suspected causal relationship

Follow-up information should be sought and reported as soon as it becomes available. The CIOMS I form should be used to report the cases. (Note: Now with electronic transmission E2B transmissions are required in most jurisdictions).

Managing Blinded Cases

This report recommends that, although it is advantageous to retain the blind for all patients before study analysis, when a serious adverse reaction is reportable on an expedited basis, the blind should be broken only for that specific patient by the sponsor even if the investigator has not broken the blind. The blind should be maintained where possible for the personnel in the company responsible for the analysis and interpretation of the results. There may be circumstances where not breaking the blind is desirable, and in these circumstances, an agreement with the regulatory authorities should be pursued.

Other Issues

• For reactions with comparators, the sponsor is responsible for deciding whether to report the case to the other manufacturer or to the appropriate regulatory agencies. Placebo events do not normally need to be reported.
  
• When a drug has more than one presentation (e.g., different dosage forms, formulations, delivery systems) or uses (different indications or different populations), the expedited report should be reported to or referenced to all other product presentations and uses.
  

  NOTE: This is generally not the case currently. Reporting is usually to only one IND or premarketing dossier in most countries should multiple INDs or dossiers exist.

  
  
• Poststudy AEs are usually not collected or sought by sponsors but may nonetheless be reported to the sponsor by the investigator. These events should be treated as if they were study events and reported as expedited reports should they qualify to be such.

Two working groups were set up in the ICH to develop the means for the electronic transmission of individual case safety reports between or among companies and regulators, regulators and regulators, and companies and companies. This system would allow the (theoretical) replacement of paper-based submissions using MedWatch or CIOMS I forms. To do this, the data elements, fields, and contents of the electronic report needed to be rigidly standardized. There are two series of documents in question.

The first is the E2B documents, which were prepared by the medical representatives and specified data elements for the transmission. The second is the M2 documents, prepared by the informatics representatives, which provide technical specifications for structured messaging; electronic data interchange; data definitions to incorporate structured data formats (e.g., SGML); security to ensure confidentiality, data integrity, authentication, and nonrepudiation; documents to handle heterogeneous data formats; and physical media for storage and transferability of data.

Several documents were issued and the nomenclature is a bit confusing.

The terminology here has been confusing as there have been multiple other names for earlier versions of these documents, including E2B(R), E2B(M), and others. The documents were first developed in 1997 and finalized (more or less) in 2001. The R3 document includes experience gained over the last several years but has not been formally adopted by all countries.

There are several initiatives under way that aim to standardize data transmission of health data, including individual case safety reports (ICSRs), of which E2B is the current standard. Ultimately, it is expected that the HL7 requirements will encompass ISO, local regional requirements, and ICH requirements. The other groups include ISO (International Standards Organization) and HL7 (see Chapter 8). The R2 document is the current document used globally.

• E2B(R3): Revision of the E2B(R2) ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports
  
• E2B(R2): Maintenance of the Clinical Safety Data Management, including Data Elements for Transmission of Individual Case Safety Reports (previously called E2B(M))
  
• M2: Electronic Standards for the Transfer of Regulatory Information (ESTRI)

Personnel involved in drug safety should be familiar at a high level with the E2B documents; in addition, the informatics personnel supporting them should be familiar with M2. The contents of the E2B transmissions determine to a certain degree how data are handled and stored in a company’s database. For example, decisions must be made on whether to code laboratory data as free text or as structured fields.

We briefly review here the data elements of the E2B documents. The goal of the E2B document is to provide all the data elements needed to comprehensively cover complex reports regardless of source, destination, and databases at either end of the transmission. Not all cases have all data elements. Thus, simple cases have few elements transmitted, and complex cases have many or most of the elements transmitted. The E2B transmission concepts can be used for pre- and postapproval AEs/ADRs. Currently, E2B is primarily used for expedited reporting.

Structured data are strongly recommended and are available for AE terms and other elements using the Medical Dictionary for Regulatory Activities (MedDRA). However, structured vocabularies for other elements (e.g., drug names) are not yet available, finalized, or agreed on. The E2B document also allows for unstructured text (e.g., narratives) to be transmitted and, in some cases, allows data to be transmitted as structured or unstructured data (e.g., laboratory values).

There are two sections to a transmission. The first is the header, which contains technical information, and the second is the data elements, in two parts: first, the administrative and identification information, and, second, the case information. The data elements are described briefly here.

A1. Identification of the case safety report

• Case unique identifier number and MedDRA version
  
• Source country; country where the AE occurred
  
• Date of transmission
  
• Type of report (spontaneous, study, other)
  
• Seriousness
  
• Date of latest information
  
• List of other documents held by sender
  
• Expedited report?
  
• Other identifying numbers for the case (e.g., local health authority numbers)

A2. Sources

• Reporter name, address, profession
  
• Literature reference
  
• Clinical study information (name, type, study number)

A3. Sender Information

• Type: company, regulatory authority, healthcare professional, World Health Organization, and so on
  
• Sender identifier, address, e-mail, and so on

B1. Patient characteristics

• Identifier, age, date of birth, age at reaction onset, weight, height, sex
  
• Medical and drug history and concurrent conditions (either structured or as free text)
  
• Death information
  
• Parent–child report information

B2. Reaction(s)/event(s): This is a repeating section so that a new section can be created for each reaction/event.

• Verbatim term, MedDRA lower-level term, term highlighted by reporter
  
• Seriousness criterion
  
• Start and stop dates and outcome

B3. Tests and procedures (and their results) done to investigate

B4. Drug information

• Drug type (suspect, concomitant, interacting, blinded, etc.)
  
• Drug name, active ingredient
  
• Authorization (New Drug Application) holder and (New Drug Application) number
  
• Dose, start date, route of administration, indication for use, action taken
  
• Drug-reaction matrix for causality (to capture causality at the event level and a reporter and company causality)

B5. Narrative (clinical course, therapeutic measures, outcome, and additional relevant information)

• Reporter comments
  
• Sender’s diagnosis/syndrome and comments

This was adopted by ICH in November 1996. An addendum was published in 2003 and is summarized below. These documents give guidance on the format and content of safety updates, which need to be provided at intervals to regulatory authorities after products have been marketed. The guideline is intended to ensure that the worldwide safety experience is provided to authorities at defined times after marketing with maximum efficiency and avoiding duplication of effort.

PSURs have been adopted by many countries, including those in the European Union, Japan, Canada, and others. In the United States, they are not yet obligatory, but most NDA holders submit PSURs rather than the older NDA Periodic Reports. FDA is expected to make PSURs obligatory at some point soon. Companies wishing to submit PSURs in place of New Drug Application periodic reports must contact the FDA to obtain U.S. requirements and FDA consent for their submissions.

The general principles are as follows:

• One report for one active substance. The PSUR should cover all dosage forms, formulations, and indications. There may be separate presentations of data for different dosage forms or populations if appropriate. The PSUR should be a “stand-alone” document.
  
• For combination products also marketed individually, safety information may be done as a separate PSUR or included in the PSURs prepared for one of the components, with cross-referencing.
  
• The report should present data for the interval of the PSUR only, except for regulatory status information, renewals, and serious unlisted ADRs, which should be cumulative.
  
• The report should focus on ADRs. All spontaneous reports should be assumed to be reactions (i.e., possibly related). Reports should be from healthcare professionals. For clinical trial and literature reports, only those cases believed by the reporter and sponsor to be unrelated to the drug should be excluded.
  
• Lack of efficacy reports (which are considered to be AEs) should not be included in the tables but should be discussed in the “other information” section.
  
• Increased frequency reports for known reactions should be reported if appropriate.
  
• If more than one company markets a drug in the same market, each Marketing Authorization holder (MAH) is responsible for submitting PSURs. If contractual arrangements are made to share safety information and responsibilities, this should be specified.
  
• Each product should have an international birth date (IBD), usually the date of the first Marketing Authorization anywhere in the world. This date should be synchronized around the world for PSUR reporting such that all authorities receive reports every 6 months or at multiples of 6 months based on the IBD.
  
• The report should be submitted within 60 days of the data lock-point.
  
• The reference document for expectedness (“listedness” as opposed to “labeled-ness,” which refers to national data sheets such as the U.S. Package Insert) should be the company core data sheet (CCDS), the safety section of which is known as the company core safety information (CSI).
  
• The verbatim reporter term as well as standardized coding term (i.e., MedDRA, which was approved after E2C was finished) should be used.
  
• ADR cases should be presented as line listings and summary tabulations. That is, individual CIOMS I or MedWatch forms are not included.

The sections of a PSUR are as follows:

• Introduction
  
• Worldwide market authorization status
  
  
  
  • A table with dates of Market Authorization and renewals, indications, lack of approvals, withdrawals, dates of launch, and trade names
  
  
• Update of regulatory authority or MAH actions taken for safety reasons
  
• Changes to the Reference Product Information
  
  
  
  • The version of the CCDS in place at the beginning of the PSUR interval as the reference document. If there is a time lag between changes to the CCDS and local labeling, this should be commented on when submitting to that local health authority.
  
  
• Patient exposure
  
  
  
  • The most appropriate method should be used and an explanation for its choice provided. This includes patients exposed, patient-days, number of prescriptions, and tonnage sold.
  
  
• Presentation of individual case histories from all sources (except nonmedically confirmed consumer reports)
  
  
  
  • Follow-up data on previously reported cases should be presented if significant.
    
  • Literature should be monitored and cases included. Duplicates should be avoided. If a case is mentioned in the literature, even if obtained also as a spontaneous or trial case, the citation should be noted.
    
  • If medically unconfirmed cases received from consumers are required to be submitted in the PSUR, they should be submitted as addenda line listings and summary reports.
    
  • Line listings should include each patient only once. If a patient has more than one adverse drug experience/ADR, the case should be listed under the most serious adverse drug experience/ADR, with the others also mentioned there. If appropriate, it may be useful to have more than one line listing for different dosage forms and indications. The headings for the listings are:
    
    
    
    • MAH reference number
      
    • Country where the case occurred
      
    • Source (trial, literature, spontaneous, regulatory authority)
      
    • Age and sex
      
    • Daily dose, dosage form, and route of suspected drug
      
    • Reaction onset date
      
    • Treatment dates
      
    • Description of the reaction (MedDRA code)
      
    • Patient outcome at the case level (resolved, fatal, improved, sequelae, unknown)
      
    • Comments (e.g., causality if manufacturer disagrees with reporter, concomitant medications)
  
  
• Line listings should include the following cases:
  
  
  
  • Spontaneous reports: all serious reactions, nonserious unlisted reactions.
    
  • Studies or compassionate use: all serious reactions (believed to be serious by either the sponsor or the investigator).
    
  • Literature: all serious reactions and nonserious unlisted reactions.
    
  • Regulatory authority cases: all serious reactions.
    
  • If nonserious, listed ADRs are required by some authorities, they should be reported as an addendum.
  
  
• Summary tabulations
  
  
  
  • Each line listing should have an aggregate summary that will normally contain more terms than patients. It may be broken down by serious and nonserious and listed and unlisted, as well as other breakdowns as appropriate. There should also be a summary for nonserious listed spontaneous reactions.
    
  • Data in summary tabulations should be noncumulative except for ADRs that are both serious and unlisted, for which a cumulated figure should be provided in the table.
  
  
• MAH analysis of individual case histories
  
  
  
  • This section may contain brief comments on individual cases. The focus here is on individual cases (e.g., unanticipated findings, mechanism, reporting frequency) and should not be confused with the global assessment as described below.
  
  
• Studies
  
  
  
  • All completed studies (nonclinical, clinical, epidemiologic), planned or in-progress studies, and published studies yielding or with potential to yield safety information should be discussed.
  
  
• Other information
  
  
  
  • Lack of efficacy information should be presented here.
    
  • Late-breaking information after database lock should be presented here.
  
  
• Overall safety evaluation
  
  
  
  • The data should be presented by system organ class and should discuss
    
    
    
    • A change in characteristics of listed reactions
      
    • Serious unlisted reactions, placing into perspective the cumulative reports
      
    • Nonserious unlisted reactions
      
    • Increased frequency of listed reactions
      
    • New safety issues
      
    • Drug interactions
      
    • Overdose and its treatment
      
    • Drug misuse or abuse
      
    • Pregnancy and lactation information
      
    • Experience in special patient groups
      
    • Effects of long-term treatment
  
  
• Conclusion

This section should indicate which safety data do not remain in accord with the previous cumulative experience and with the company CSI:

• Any action recommended or initiated
  
• Appendix: Company Core Data Sheet (CCDS)

The Addendum provides clarification and guidance on PSURs and addresses some new concepts not in E2C but reflecting current pharmacovigilance practice needs, including Proprietary Information (Confidentiality), Executive Summary, Summary Bridging Report, Addendum Reports, Risk Management Program, and Benefit–Risk Analysis.

• International Birth Dates (IBDs)
  
  
  
  • PSURs should be based on IBDs. To transition to a harmonized IBD, the MAH may submit its already prepared IBD-based PSUR plus (1) line listings and/or tabular summaries for the additional period (≤3 months if submitting a 6-month PSUR or ≤6 months if submitting a longer PSUR) with comments, or (2) an Addendum Report (see below) with the same duration limits as in (1).
    
  • In attempting to harmonize IBDs, it is possible that a drug will be on a 5-year cycle in one country and a 6-month cycle in another. If harmonization is not possible, the MAH and regulators should try to find a common birth month and day so that reports can be submitted on the same month and day whether every 6 months, yearly, or every 5 years. (Note that many regions have changed the frequency from 5 years to 3 years.)
  
  
• Summary Bridging Reports
  
  
  
  • A summary bridging report integrates two or more PSURs to cover a specific time period for which a single report is requested. Thus, two 6-month PSURs could be used to create a summary bridging report to cover the full year or 10 6-month reports to cover a 5-year PSUR. The bridging report does not contain new data but briefly summarizes the data in the shorter reports. The report should not contain line listings but may have summary tables.
  
  
• Addendum Reports
  
  
  
  • An addendum report is used when it is not possible to synchronize PSURs for all authorities requiring submissions. The addendum report is an update to the most recently completed PSUR. It should be used when more than 3 months for a 6-month PSUR and more than 6 months for a longer PSUR. It is not intended as an in-depth report (which will be done in the next regularly scheduled PSUR). It should contain an introduction, any changes to the CSI, significant regulatory actions on safety, line listings, and summary tabulations and a conclusion.
  
  
• Restarting the Clock
  
  
  
  • For products in a long-term PSUR cycle (e.g., 5 years), the return to a 6-month reporting schedule may occur if a new clinically dissimilar indication is approved, a previously unapproved use in a special population is approved, or a new formulation or route of administration is approved. Restarting the reporting clock should be discussed with the regulatory authorities.
  
  
• Time Interval Between Data Lock-Point and the Submission
  
  
  
  • The MAH has 60 days to prepare a submission after the data lock-point. An issue that arose was review and comment by the regulatory authority(ies), which took a long time to do and was sent back to the sponsor at a date very close to the submission of the following PSUR. If this review contains new requirements or other obligations for the MAH, the MAH may not be able to adequately complete the additional analyses requested in time for the next PSUR. Hence, the Addendum notes that the regulatory authority will attempt to send comments to the MAH
    
    
    
    • As rapidly as possible if any issues of noncompliance with format and content are noted.
      
    • As rapidly as possible and before the next data lock-point if additional safety issues are identified that may require further analysis in the next PSUR. Such analyses could also be submitted as a separate stand-alone report instead of in the next PSUR.
  
  
• Additional Time for Submissions
  
  
  
  • In rare circumstances, the MAH may request an additional 30 days to submit a PSUR. This might occur if there is a large number of case reports and there is no new safety issue, if issues are raised by the authorities in the previous PSUR for which additional time is needed for further analysis for the next PSUR, or if issues needing further analysis are identified by the MAH.
  
  
• Reference Safety Information
  
  
  
  • The MAH should highlight differences between the CSI and the local product-labeling in the cover letter accompanying the PSUR.
    
  • For 6-month and 1-year PSURs, the CSI in effect at the beginning of the period should be used as the reference document.
    
  • For PSURs longer than 1 year, the CSI in effect at the end of the period should be used as the reference document for PSURs and Summary Bridging Reports.
  
  
• Other Issues
  
  
  
  • The title page of the PSUR should have a confidentiality statement because proprietary information is contained in the report.
    
  • An executive summary should be included right after the title page in each PSUR.
    
  • Patient exposure data
    
    
    
    • It is acknowledged that these data are often difficult to obtain and not always reliable. If the exposure data do not cover the full period of the PSUR, extrapolations may be made. A consistent method of exposure calculations should be used over time for a product.
    
    
  • Individual case histories
    
    
    
    • Because it is impractical to summarize all cases as narratives, the MAH should describe the criteria used to describe the cases summarized.
      
    • The section should contain selected cases, including fatalities, presenting new and relevant safety information and grouped by medically relevant headings or system organ class.
    
    
  • Consumer listings
    
    
    
    • If required by regulators, consumer listings should be done in the same way that other listings and summary tabulations are prepared.
    
    
  • The “comments” field
    
    
    
    • This field should be used only for information that helps to clarify individual cases.
    
    
  • Studies
    
    
    
    • This section should contain only those company-sponsored studies and published safety studies (including epidemiology studies) that produce findings with potential impact on safety. The MAH should not routinely catalogue or describe all studies.
    
    
  • The “other information” section
    
    
    
    • Risk management programs may be discussed in this section.
      
    • When a more comprehensive safety or risk–benefit analysis has been done separately, a summary of the analysis should be included here.
      
    • Discussion and analysis for the “Overall Safety Evaluation” section should be organized by system organ class and not by listedness or seriousness.

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