TABLE OF CONTENTS
1.INTRODUCTION
Opening words
Objectives in contract
Context within which objectives are interpreted
2. WHERE WE ARE NOW
2.1THE REGULATORY ENVIRONMENT
Current regulations
Overview of Canada, Europe, USA, ICH.
Definitions
AE, ADR, SADR, SUADR.
Commentary
2.2VIEWS FROM THE FIELD
Literature survey and summary of opinions about issues related to AERs
2.3ISSUES AND OPPORTUNITIES
Identify the central issues through a “life cycle” from initial observation to actions taken, and the opportunities for addressing them.
3.LOOKING FORWARD
3.1PRINCIPLES AND OBJECTIVES FOR AN OCSI SYSTEM
3.2OPTIONS
Establish options for consideration under the headings of:
Stakeholder responsibilities and accountabilities
Managing ongoing clinical safety information
Ensuring dialogue and operational interactions between stakeholders
Situate options within “life cycle”
4.RECOMMENDATIONS AND CONCLUSIONS
1. INTRODUCTION (Good first draft)
Draft of Feb 26
Protection of research subjects and patients in clinical trials under Health Canada’s regulatory mandate depends in part on timely, accurate and effective responses to ongoing clinical safety information. We proposed this study to Health Canada because we had concluded from our own experience and many conversations and reports that the present management of ongoing clinical safety information imposes heavy workloads, especially on REBs, that are not justified by their impact on patient safety. We believed that the central issue was lack of clarity in the definition of roles and responsibilities of, and communications between, the major players (sponsors, qualified investigators, research institutions, research ethics boards (REBs) and regulators) in meeting their shared responsibilities to research subjects, patients, and Canadians in general.
The objectives of this contract are stated as:
“The work will result in a document that will serve as the basis for drafting policy options on ongoing safety information in a form that can be used by Health Canada and all interested stakeholders and clients such that the following will be taken into consideration:
The respective roles and responsibilities of the five major groups of players in the area (sponsors, REBs, Health Canada, qualified investigators and institutions);
Mechanisms for managing ongoing clinical safety information in clinical trials that effectively and efficiently help protect research subjects and also respect the needs of the various players;
Mechanisms for developing open and continuing effective dialogue and operational interaction between the major players, and especially between Health Canada and REBs/qualified investigators/institutions in addressing issues of ongoing clinical safety information.”
We envisage these objectives within the context of:
Protecting research subjects;
Effectiveness and efficiency;
Respect for Canadian and International policies and requirements;
Expressing and implementing the shared and individual rights, responsibilities, accountabilities, liabilities etc. of researchers, sponsors, institutions and REBs;
Meeting legal requirements and responsibilities.
2. WHERE WE ARE NOW
2.1THE REGULATORY ENVIRONMENT (Reasonable first draft)
Current Regulations
In Canada, the US and Europe, regulations require sponsors to inform the regulator and REBs about all serious and unexpected adverse drug reactions related to a trial. (See summary for Canada, Europe, USA and ICH, Appendix 1.) Of note are the following:
Canada
Regulations mandate the filing of adverse drug reactions to the regulator, but not to REBs. However, the draft Guidance Document (17/08/01) states that serious unexpected adverse drug reactions should be reported simultaneously to the REBs, but provide no information as to what is expected of the REB.
Europe
Sponsors are obliged to report all serious unexpected adverse drug reactions to the Ethics Committee, but there is no regulatory requirement for REB assessment and monitoring.
United States
Adverse drug reactions must be reported to the IRBs; the mechanism of assessment and monitoring of clinical safety information appears to be a decision of the IRB.
International Conference On Harmonization: Good Clinical Practice
REB procedures include a specific clause requiring investigators to report serious and unexpected adverse drug reactions to the REB. The sponsor is obliged to report serious and unexpected adverse drug reactions to REBs only where required by regulators.
Definitions (reasonable first draft)
The regulations and ICH documents contain the following definitions related to adverse events and drug reactions
Adverse event (AE): Any adverse occurrence in the health of a clinical trial subject who is administered a drug, that may or may not be caused by the administration of the drug, and that includes an adverse drug reaction.
Adverse drug reaction (ADR): Any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.
Serious adverse drug reaction (SADR): An ADR that requires in-patient hospitalization or prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life threatening or that results in death.
Serious unexpected adverse drug reaction (SUADR): An SADR that is not identified in nature, severity or frequency in the risk information set out in the investigator’s brochure or on the label of the drug.
Commentary
These broad definitions may not be sufficiently precise for effective and efficient interpretation in operational terms. For example:
“Serious” sets a very high threshold. Many trials deal with treatments for conditions that do not envisage such serious outcomes. Should the term “serious” be scaled in a manner that is proportionate to the level of harms set out in the consent information?
The reference to “hospitalization” may not provide a consistent standard of concern. Health care in Canada has changed considerably since the definitions of adverse events set out in ICH E2a, b, c were developed in the mid 1990s. Hospitalization now is affected not only by the severity of the adversity, but also by factors such as the patient’s frailty, social support structures, or availability of beds.
“Drug reactions” vs “adverse events” operate at both the sponsor and the research site levels. Identifying an AE as an ADR requires clinical judgement, especially when the blind is retained. Confusion exists in the reporting process between ADRs and adverse events that occur in the natural course of the illness.
“Unexpected” also should include consideration of frequencies. At this time, there is no demand for urgent reporting of serious but expected ADRs or AEs. Can frequent unfavourable outcomes occur without the requirement for timely management, whether they result from lack of efficacy or from adverse events?
The Investigator’s Brochure is also important, but there is variability in how needed changes, and new relevant information, are communicated to REBs, and how the consent process should be modified.
2.2 VIEWS FROM THE FIELD (Not yet drafted)
This section (to be drafted) is intended as a brief literature survey on the present handling of adverse event reports, and a summary of opinions heard in discussions.
2.3ISSUES AND OPPORTUNITIES
(First draft that indicates intended format but needs a lot more thought)
The key to management of ongoing clinical safety information lies in the collection and analysis of data and its conversion to useful information, and the use of the resulting information. The central issue is that each stakeholder have the information that they need to make the decisions that are needed in the appropriate timescale. Since the stakeholders are interdependent in this regard. Each depends on the others, and each influences the other in many ways. The result is a matrix of expectations and obligations for management of data and information.
We seek to identify the major issues, and the opportunities for addressing them, by linking them to the various stages, in a multi-centre clinical trial, of the “life cycle” of an adverse event, from its observation through its collation with other events, to the decisions that are taken. A supplementary graphic representation assists this interpretation.
Research planning and start up
The steps under this heading include:
Sponsor develops trial, recruits trial sites, QIs;
QI submits proposal to REB;
REB reviews, modifies, approves protocol;
REB informs QI, institution;
Institution/QI contracts with sponsor
Sponsor starts trial in each centre in turn.
Issues:
Workability/usefulness of regulations / guidance for OCSI reporting?
Definition of categories of adverse events
Sensitivity to expected harms
Sensitivity to patient expectations
Identification of adverse events anticipated in the trial – red flags
Is a standard format feasible – useful
Links to experience with similar molecules
Anticipated frequencies
Criteria for reporting of adverse events
Reporting requirements for data and side effects
Is a standard format feasible – useful
Requirements – criteria for stopping rules - data monitoring mechanisms
Is a standard format feasible – useful
Opportunities:
Redefine requirements for adverse event reporting to reflect changing expectation of public and patients, and changing health care environments and expectations
Test feasibility/usefulness of more standardized approaches to adverse event reporting
Guidance on needs/criteria/requirements for stopping rules, DSMBs etc.
Data collection and reporting to sponsor
The steps under this heading include:
Patient suffers an adverse event:
Local research team records event
QI assesses event against criteria of expectedness and seriousness
QI reports event to local REB and to sponsor
Issues
Recognition and recording of the event on site.
Patient observation data
Laboratory data
Local/central labs
Classification of event against categories
Necessary for further actions
Affected by expectedness, seriousness,
Reporting to REB
What? Timeframes?
REB responses?
Reporting to sponsor
Timeframes?
Depend on classification of expectedness and seriousness,
Opportunities
Electronic data collection and transmission mechanisms
Data analysis and information generation
The steps under this heading include:
Sponsor receives data from all trial sites
Sponsor analyses the data
Classifies each item (seriousness, unexpectedness)
Perhaps uses a review structure (e.g., DSMB)
Determines need to inform QI and/or regulator
Need, timeframes etc depends on classification
Issues
Sponsor categorization of data – expectedness/seriousness
Incorporation into OCSI databases (trial and molecule)
Data analysis
Timelines
? defer analysis of non-serious – expected events
Roles of DSMBs etc.
Decisions on:
What to inform trial sites, Health Canada
Recommendations on whether to amend/stop trial
Timelines
Opportunities
Electronic data management and analysis
Roles of DSMBs - independent surveillance body (e.g., DSMB)
Clarify what should be reported and to whom, and responsibilities
Useable information, not data. E.g., frequencies vs expectations
Require a recommendation to accompany reports
Trial site decision making
The steps under this heading include:
Sponsor provides information to QIs at each trial site
QI informs the REB
REB makes decision and informs QI
QI acts on information from REB for local patients
QI informs sponsor of REB decision
Issues
What information to provide
Expectedness/seriousness classifications
Timescales
Should the information come with a recommendation?
QI role in assessing/interpreting information for REB.
Ability/competence of REB to handle information
Quality of information/data/recommendation
Full or expedited REB review
Opportunities
Require information that can be used by the REB
REB refuse to accept/consider useless data
Require recommendations to accompany information
Central REB function to review
? link to DSMB function – but ? independence?
Regulator decision making
The steps under this heading include:
Sponsor informs Health Canada
Health Canada decides its actions in light of new OCSI data
Health Canada informs sponsor
Sponsor informs trial sites of health Canada decision
Issues
The regulations require the sponsor to inform the regulator about serious adverse drug reactions
Opportunities
3. LOOKING FORWARD
3.1PRINCIPLES AND OBJECTIVES FOR AN OCSI SYSTEM
(Needs thought and fleshing out)
We envisage these objectives within the context of:
Protecting research subjects;
Effectiveness and efficiency;
Respect for Canadian and International policies and requirements;
Expressing and implementing the shared and individual rights, responsibilities, accountabilities, liabilities etc. of researchers, sponsors, institutions and REBs;
Meeting legal requirements and responsibilities.
3.2OPTIONS
(only first heading has been worked on. Other headings reflect contract objectives, but have not been thought about at all)
DEFINE STAKEHOLDER RESPONSIBILITIES AND ACCOUNTABILITIES
(Reasonable first draft)
General Responsibilities
The major participants in the shared responsibilities and intentions to research subjects and future patients with respect to management of adverse event reporting, analysis and decision-making are:
The Qualified Investigator
The Sponsor
The Research Ethics Board (REB)
The Research Institution
The Regulator
Because the Qualified Investigator and the Sponsor carry out the research, they share primary responsibility to the research subjects for the performance of the trial.
Though not mentioned in Health Canada’s regulations the research institution:
Employs or houses the Qualified Investigator
Provides the research environment
Has overall responsibility for patients in the institution
Establishes and mandates the Research Ethics Board
The REB and the regulator share responsibility for oversight of the research, the REB at the local level, and the regulator at the wider collective or national level.
Specific Responsibilities
With respect to management of ongoing clinical safety information, the specific responsibilities of the qualified investigator, the sponsor and the research ethics board should be as follows:
Sponsor
An individual, corporate body, institution or organization that conducts a clinical trial.
NB, Each clinical trial must have a sponsor who is responsible for the overall conduct of the trial. The sponsor is most frequently the company that manufactures the product under study. However, an academic investigator or a research funding organization can be the sponsor for a multi-centre or single centre trial; at one site in a particular trial, particularly for a single site trial, the sponsor and the QI may be the same person.
In this report, we regard the sponsor as including any clinical research organisation (CRO) that has been engaged to carry out the trial, and hence assign no separate responsibilities to CROs.
The Sponsor necessarily has overall responsibility for the trial, and for enabling the other participants to carry out their responsibilities effectively and efficiently. In particular, the sponsor should be responsible for all aspects of the management of the information accumulating in the trial, and for ensuring that the qualified investigators and the REBs (and the regulator) have the information and recommendations that they need in a usable form to make the decisions that they must take.
Hence, the sponsor should be responsible for:
-Setting out in the protocol reviewed by the REB effective plans and procedures for surveillance and management of AEs that are appropriate to the research protocol;
-Ensuring that the qualified investigator has the training needed to carry out the trial, and meets performance standards;
-Ensuring implementation of these plans and procedures in the trial;
- Collecting and keeping records on all AE reports;
-Analysing all AE reports in terms of whether they are ADRs, and whether these are SADRs or SUADRs;
-Communicating timely, relevant and useful information to the REB on a ongoing basis until the trial is completed;
-Communicating to the regulator information required by the regulations
-Communicating the recommendations on actions needed with respect to the trial;
Communicating the recommendations and the essential information behind them to the REBs and the regulator in a manner that can be assessed effectively and efficiently by them.
Qualified Investigator
The person responsible to the sponsor for the conduct of the clinical trial at a clinical trial site, who is entitled to provide health care under the laws of the province where that clinical trial site is located and ……
The Qualified Investigator should be responsible, in addition to all actions relating to the safety and rights of subjects at that site, for:
- Providing information on AEs to the sponsor
- Ensuring effective transfer of usable information on a timely basis between the sponsor and the REB.
Research Ethics Board
Approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being: ……………..
The REB is responsible for ensuring that the research at the local site is carried out under conditions of oversight that meet the requirements of the Canadian people.
The Research Ethics Board should be responsible for:
- Reviewing the plans proposed by the Sponsor for their appropriateness in managing reports of AEs, as a condition of allowing enrolment of subjects at that site;
- Assessing the recommendations and evidence from the sponsor in terms of implications for that trial site;
- Acting on that assessment as appropriate.
Institution
No functions for institutions are set out in the Regulations. However, in most industrial research projects, the institution receives overhead costs for the research project. In addition, neither the Qualified Investigator nor the Research Ethics Board can meet their mandated requirements or function effectively or responsibly without the direct or indirect involvement of the institution.
It should be noted that not all trial sites or QIs function within a formal institutional structure, and hence use REB and other resources that do not have a reporting relationship to a recognized authority. This situation has yet to be addressed effectively.
The Institution should be responsible for:
-Ensuring that the Qualified Investigator has the qualifications and expertise necessary for the research to be undertaken, especially when the research overlaps with patient care responsibilities in the institution;
-The qualifications required to perform a clinical trial are not just health professional and clinical trial methodological, but also involve a high level of understanding of relevant regulations and ethics. The institution has a responsibility to ensure that those involved in clinical research have the needed training and attitudes.