Background
The 2011 Canadian Cancer Research Alliance (CCRA) report on the State of Cancer Clinical Trials In Canada identified the magnitude of the threat to the conduct of oncology clinical trials. The Report noted that with falling performance metrics, increasing complexity and workload, and an increasingly onerous regulatory environment, clinical trials were at risk, and observed that “Without clinical trials, the outcomes of cancer patients will not continue to improve”. The report recommended engaging with Health Canada and other key stakeholders to foster agreement in appropriate interpretations of the Health Canada Food and Drug Regulations and ICH Good Clinical Practice (GCP) guidelines.
The Initiative to Streamline Clinical Trials (ISCT) Working Group, formed in 2012 to address the CCRA recommendations, includes members who are experts in clinical trial conduct across many therapeutic areas. The primary objective of the ISCT was to develop specific, pragmatic and practical interpretations of current regulations, laws and guidelines, in order to facilitate, rather than limit, Canadian clinical trials, by expanding on recommendations such as those of the CCRA and OECD. During the discussions, it became apparent that changes to certain regulations or laws interpretations were also desirable.
The focus of ISCT encompassed academic clinical trials of drugs and/or biologics which are required to be, or interpreted as required to be conducted under a Clinical Trials Application. Academic trials are defined as trials where the regulatory sponsor of the clinical trial is not a commercial for-profit organization such as a pharmaceutical company or contract research organization (CRO).
The ISCT Recommendations were finalized in February 2014. The Recommendations are summarized below in a tabular format. Each recommendation was categorized as being feasible within the current regulatory framework, or if it was felt that changes to existing regulations or laws were required, as recommended. The complete document can be downloaded from this site. In many sections, sample documents or checklists will be available and will also be downloadable.
The final Recommendations of the ISCT are provided here to all participants as well as academic groups and investigators in Canada. Place links to the Recommendations on your websites if appropriate and ensure your members are aware of the Recommendations.
A summary of the recommendations is provided below for your convenience.
We hope that you will agree to provide your contact details so we can evaluate which area/s of the Recommendations have been implemented and also assess the impact of the Recommendations on the conduct of academic clinical trials in Canada by means of annual surveys.
Summary of Recommendations
CTA and Safety Reporting
Feasible
OECD framework and recommendations should be adopted and implemented in Canada within the existing regulatory framework
Appropriately justified standard –of-care drugs do not require a CTA
Consistent interpretation of risk and maintenance of a database of decisions
Consider a joint academia-regulatory initiative is recommended where consensus interpretations can be made
Only risk-based, relevant and justified processes for safety reporting and concomitant medication collection should be planned
For lower risk trials, limit expedited SAE collection to related and unexpected events, and consider collecting only AEs, and grade/severity of events, of interest
Recommended
If needed, amend regulations to allow standard-of-care drugs to be considered low risk and OECD Category A
Drug Accountability and Labelling
Feasible
Drugs used in a clinical trial, for which a CTA has not been filed (Category A trials), should be managed as commercial drugs and standard pharmacy/dispensing practices/policies followed.
Category B drugs which are commercially available, for which a CTA has been filed, should be managed as commercial drugs and standard pharmacy practice followed; trial-specific drug accountability logs are required only for drugs specifically labeled as clinical trial supply.
On-site monitoring of drug/pharmacy is rarely required for category A and B trials where commercial stock is used.
Monitoring
Feasible
ISCT is in agreement with recommendations of the FDA and the OECD with respect to implementation of a risk-based approach to monitoring
Central monitoring of selected critical study parameters and data elements should be the primary strategy for academic trials
Limited on-site monitoring may be appropriate for higher-risk Category B trials and for some Category C trials. The monitoring plan should allow for risk based adaptation of monitoring depending on deviations or data trends identified throughout the course of the trial
Risk based and justified monitoring plans should be summarized in the protocol or an appendix allowing review and approval by Health Canada during the CTA review process
Equipment and Facilities
Feasible
“Research equipment” for clinical trials should be defined as equipment used solely for the purpose of a clinical trial and unrelated to the delivery of standard-of-care. The responsibility for maintenance and calibration of such equipment rests with the Institution.
An assessment of risk and acceptability of institutional programs should be conducted prior to implementing a trial specific equipment maintenance process.
Requirements for maintenance of equipment designated as research should be documented appropriately and prospectively in the protocol or an appendix. Inspectors should use that agreed plan when conducting site inspections.
Delegation of Trial Related Duties
Feasible
Roles required as part of standard-of-care, or as part of care provided on an ad hoc basis, are not required to be documented as part of the trial delegation log (e.g. imaging, emergency room staff).
If a specific trial-related task requires a level of training beyond the usual scope of practice, or requires a specific professional to conduct the task, it will be stated in the protocol or in the operational documentation from the study sponsor. Otherwise, tasks can be delegated by the QI to an individual qualified to perform that task or process, and no additional training (other than study specific training) is required.
The delegation list, either the initial list or any modified version, should be created and maintained by the QI, or delegate, in a timely manner. Verbal authorization from the QI to begin a trial-related task is permissible, with the delegation log to be revised within an acceptable window, to be determined and prespecified by the sponsor. Sign-off of each change to the delegation list by the QI is not required if the task is delegated appropriately.
CVs and other documentation (e.g. financial disclosures) are only required for the QI and sub-investigators, provided that other staff, who are delegated tasks, are employees of the institution.
Validation of Electronic Systems
Feasible
An electronic system used as the permanent record for regulatory purposes needs to be validated for its intended use and records retained in accordance with the Regulations. Processes of the software development and deployment need to align with Software Development and System Operation Good Practices, and be appropriately documented.
The level of validation of the electronic system needs to be consistent with complexity, level of customization, and overall risk assessed.
Requirements and Policies related to the retention of records need to align with Institutional Policies where applicable.
Source Documents and Record Retention
Feasible
For documentation identified as requiring a review in the protocol, there should be a record that either the QI or sub-investigator has reviewed the protocol- defined out-of-range results.
The protocol should identify those data elements requiring source documentation, and sites can then declare the type of source documents (e.g. chart-based, e-record, a combination).
Investigators are not required to store electronic CRFs (eCRFs) after study completion if data have been collected through an electronic database. The sponsor will store these data.
Recommended
Record retention policies will be according to institutional policies. If the trial data are being used to support a marketing application, once all data are collected and quality assurance policies completed, on-site data storage need only follow institutional policies. The sponsor will keep these data for 10 years after marketing application submission. This will require a change to the Food and Drug Act.
Trial Costs
Feasible
CIHR funding guidelines and eligible expenses for clinical trials conducted under a Health Canada CTA must be aligned with Health Canada regulations to allow for the payment of essential expenses related to regulatory compliance. This would include regulatory support for CTA submissions, study monitoring and oversight activities, research ethics board fees, and clinical trial insurance.
Other
Feasible
Prior to an inspection would provide some context to the inspector on how the site operates (i.e. do other facilities participate in the research process).
Health Canada might consider a default period for approval of corrective action plans, where approval is understood after a default of 30 days.
ISCT recommends that training can be demonstrated by the following: certificates, CVs, minutes of meetings (with attendance), signed note to files, but that template documents should be provided that includes required sections (date, duration, trainer, agenda, and attendees). People need to be trained only on relevant areas and people performing standard-of-care processes (e.g. standard laboratory tests or administering standard –of-care chemotherapy) do not need trial specific training or to be on the delegation list unless the processes are trial specific.
The Health Canada website could be improved by the inclusion of a site map – specifically for Clinical Trials. The addition of an advanced search function would also allow for more appropriate hits.
Recommended
ISCT recognizes the complexity of organizational structures and processes within the Federal government and Health Canada, and the difficulty with ensuring consistency and efficiency across multiple organizational parts, especially with different reporting structures, which may be regional. Nonetheless, the impact of this on the academic research community is very costly (in terms of both dollars and resources). Clear, simple and consistent processes and interpretation, would significantly improve the access of Canadians to non-commercially driven trials, which have been proven to improve outcomes. This recommendation, in the opinion of ISCT, is critical.