Many more health agencies are now doing pharmacovigilance inspections compared to years gone by. There are many reasons for this including the obvious ones of protecting the public health and ensuring that the company is following the laws, regulations and (unofficially) best practices. Other, less obvious reasons include generating fees (many agencies though not FDA charge the companies they inspect a pretty penny for inspections), and politics.
It is sometimes hard to know what will be cited as deficiencies or observations. Of course, one must follow the regulations but in many cases the regulations are obscure. The EU regulations (Good Pharmacovigilance Guidelines) are rather detailed whereas the US FDA regulations are less so. Canada falls somewhere in the middle in my view.
In February 2013 Health Canada’s Health Products and Food Branch Inspectorate released an interesting document entitled “Risk Classification of Good Pharmacovigilance (GVP) Observations” GUI-0063. See https://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0063_gvp-eng.php In this document Health Canada (HC) gives details on what risks they look for and how they classify them. Although this is limited to Canada, the contents are very generalizable to inspections done by all agencies. So for that reason we will go through this. Such clarity is not found in information supplied by other agencies around the world.
Firstly, HC will assign an overall rating to a company following an inspection:
Compliant (C) – “… the regulated party has demonstrated that the activities it conducts are in compliance with the Food and Drugs Act and its associated Regulations. A “C” rating does not mean that there are no observations or corrective actions required.”
Non-Compliant (NC) – “…the regulated party has not demonstrated that the activities it conducts are in compliance with the Food and Drugs Act and its associated Regulations.”
Note that there can be small observations found at an HP audit and corrective actions (CAPAs) required but that the company can still get an overall C rating.
Next HC describes risk ratings which is the “meat” of this document. These ratings are detailed in Appendix B of the document. A summary outline is presented below. See the document for more details:
Risk 1 (Critical) Observations:
Definition: “A situation that may produce an immediate or latent health risk as a result of the absence of drug safety information. Observations that involve fraud, misrepresentation are… are also considered critical.”
Examples:
- No expedited reports: No Canadian serious expected or unexpected ADRs are reported to HC. No foreign serious unexpected ADRs are reported to HC.
- Change in benefit-risk: The MAH did not notify Health Canada of a significant change in the risks and benefits of the drug.
- Issue-related summary report: not submitted.
- Unavailable records: No ADR reports were available.
- Falsification: Evidence of falsification or misrepresentation of records.
- No written ADR records: No records of ADR reports or reports of domestic unusual failure in efficacy of new drugs were available.
Comment: Note that there are not too many critical findings. As in the EU and US, expedited reporting that is not done is a critical observation as are changes in the benefit risk assessment that are not reported. Lack of record keeping or the inability to produce records are also critical findings. Note that periodic reporting is not mentioned here because, interestingly, HC does not require periodic reporting for all drugs as the FDA and EU do. They are submitted only upon request.
- Risk 2 (Major) Observations:
Definition: A situation of incomplete drug safety information that may result in a latent health risk.
Examples:
- Bad complaint handling: Lack of or inadequate system for complaint handling.
- No SOP for expedited reporting:
- Lack of adequate systems and processes for expedited reporting:
- Recording & tracking: All suspected ADRs are not recorded and/or tracked appropriately.
- Bad coding
- Expedited reporting: ADRs are not evaluated or assessed to determine whether they qualify for expedited 15-day reporting
by a qualified health care professional.
- Case nullification: No documented rationale and/or unavailable records for nullifying case reports
- Duplicates: Duplicate ADR case reports are nullified without the proper approval.
- Follow-Up: ADR reports are not re-evaluated upon receipt of follow-up information.
- Not all expedited reports are sent to HC.
- Late expedited reports.
- No SOP for literature searching.
- No internal PV audits: of all departments that may receive ADR reports or that are involved in PV activities.
- PV head not qualified.
- Case assessor not qualified.
- Delegation of PV activities to insufficiently qualified persons.
- Insufficient training &/or no training records for PV personnel resulting in related GVP
deviations.
- Consultants or contractors not qualified.
- Safety exchange agreements: Lack of adequate contractual agreement in place to specify the processes by which an exchange of safety information, including timelines and regulatory reporting responsibilities, are taking place between the MAH/importer and its partners.
- Non validated computer systems used for PV.
- Annual summary reports (ASR) not done.
- Non-submission of case reports & ASRs when requested by HC.
- No SOP for ASRs.
- Changes recommended by HC for subsequent ASRs not done.
- ASR preparation out-sourcing: No contractual agreement in place.
- Signal detection: No or inadequate SOP.
- Old/obsolete labeling used for the assessment of expectedness.
- No SOP for preparation of an issue-related summary requested by HC.
- SOP on ADR record maintenance: Lack of or inadequate procedure.
- Archiving: Not all records of serious ADR reports and ASRs are maintained. Not kept for at least 25 years
- Unavailable SADR records during an audit.
- Complaints: Lack of or incomplete records.
- Data privacy & security: No restricted access to records.
- Domestic efficacy failure: Not all records available. Not all cases were submitted to HC. Reported later than 15 days. Lack of or inadequate procedure. Cases not kept for 25 years. Suspected cases not evaluated for
expedited reporting or not evaluated by a qualified health care
professional.
Comment: Lots of major observations which are fairly consistent with FDA and the EU. Poor quality, bad records, missing records, non-validated computer systems, no or poor signal detection, literature searches, SOPs, bad data security, using out of date labeling, training, follow up, product complaint procedures, archiving, ASRs. Also having unqualified people doing PV, late cases, poor coding etc.
HC also reserves the right to upgrade a major to a critical finding.
Risk 3 (Other/Minor) Observations:
- No comprehensive procedure and system for ADRs, ASRs & data retention.
- Deficient systems for ADRs are present. Systems and processes for the receipt, handling, evaluation and reporting of ADRs are deficient.
- Bad documentation of determining if a case is an expedited report. Justification not documented to show an ADR is not an expedited report.
- Follow up not sought.
- Reportability decision-making process not appropriately documented.
- Late follow up submissions.
- No documentation of literature searches.
- Training: Inadequate training records. Insufficient written training program.
- No organizational charts.
- Incomplete contractual agreements for PV activities.
- IT: Inadequate or incomplete validation of computerized systems. No periodic backups of the computerized systems.
- ASRs do not include all appropriate case line listings, are incomplete or the ASR procedure incomplete or inadequate.
- Issue related summary report incomplete or inadequate.
- ADR files incomplete.
- New drugs: Assessments of failure in efficacy are not appropriately documented.
No real surprises here.
Summary & Conclusions
This is an excellent document in which Health Canada spells out the actual and detailed requirements of what must be in place for pharmacovigilance to get a “compliant” rating. This is entirely consistent with the FDA and EU and the observations they make at inspections. Similar requirements can be gleaned from public documents available from FDA, the EU and member states (particularly the MHRA).
HC is to be commended for clearly publishing the rules up front. There should be no surprises when an HC inspector finds some of these issues and cites them in the inspection report.
The message here to companies is that this is the necessary minimum that needs to be in place for pharmacovigilance, whether in-sourced or out-sourced, whether domestic or global. Although this is primarily written for post-approval (authorized) drugs, it can equally apply to the principles, procedures and requirements that must be in place for clinical trial pharmacovigilance and drug safety with various additions and subtractions for items that apply in that setting.
This checklist should be used by internal and external quality and compliance auditors when doing PV gap analyses, audits and mock inspections.
We have been warned.
