1. Pharmacovigilance in clinical trials
Victoria Nambasa
Manager Pharmacovigilance
National Drug Authority

2. Outline Importance of Pharmacovigilance Key definitions
Reporting timelines
Gaps and opportunities

3. What is Pharmacovigilance?
Pharmacovigilance is concerned with the detection, assessment and prevention of adverse reactions to drugs.
The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problem (WHO, 2004)

4. Why Pharmacovigilance in CT?
Majority of safety information considered prior to market authorization is derived from controlled clinical trial.
The goals of adverse event monitoring
Protect subjects in clinical study
Protect future patients by determining risk benefit and risk factors once a product is marketed
Protect future patients by allowing new drugs to be made available

5. Key Definitions Adverse Event
ICH E6: “An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.”
21CFR part (a) “Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”

6. Definition-2 An Unexpected Reaction:
An adverse reaction, the nature or severity of which is not consistent with description on the reference safety information(IB for CT), market authorization, or expected from the characteristics of the drug.

7. Definition -3
Seriousness- is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning. serves as a guide for defining regulatory reporting obligations
results in death,
is life-threatening
requires inpatient hospitalisation or results in
prolongation of existing hospitalisation,
results in persistent or significant disability/incapacity
is a congenital anomaly/birth defect,
is a medically important event or reaction

8. Who is monitoring? The IRB/IEC The Investigator
safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects
The Investigator
Ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial.
should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.

9. Investigator-2 All SAEs should be reported immediately to the sponsor.
except for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting
Comply with the applicable regulatory requirement (s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/ IEC.

10. Who is monitoring-3 The Sponsor: – Monitoring of the site
– Expedited reporting of individual reports (CIOMS or MedWatch etc)
Narrative Unblinding
– Ongoing Safety Evaluation

11. Sponsor –site monitoring
– Verify that: “Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.” – Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).

12. Systematic systems for monitoring safety(CIOMS Working Group VI, 2005)
Planning
Prior to study.
Ensure protocol includes detailed safety outcome measures if specific safety issues are anticipated e.g lab, ECG.
For trails involving special groups, details of outcome measure is important and how it will be obtained.
Establish medical monitoring plan
During the study
After completion
Procedures(roles and responsibilities, frameworks for decision making, implementation of risk mitigation measures?

13. Systematic systems for monitoring safety-2
People
Project management
Data access
Milestones

14. Reporting requirements for adverse events in clinical trials
Expedited reporting.
The purpose of expedited reporting is to make regulators, investigators, and other appropriate people aware of new, important information on serious reactions.
The purpose is to ensure the safety of trial subjects and allow rapid reaction should the conduct of the trial need to change

15. Reporting requirements-2
Most countries have a legislative basis for the expedited reporting of potential Adverse Events/ Drug Reactions (ADRs)
• Local requirements can differ substantially, but the basic premise and definitions are generally applicable
Largely based upon the definitions in ICH-E2A
Data also form the part of the body of evidence used for benefit:risk assessment at Marketing Authorisation Application (MAA).

16. What is subject to expedited reporting
Individual case safety reports (ICSRs):
– Generally require the presence of four valid elements as a minimum
– Identifiable patient (usually provided through Clinical Trial IDs)
– Identifiable reporter (Investigator)
– A suspect drug or drugs
– An event
Usually only SUSARs. However, depending on the product and any specific safety concerns or other AEs of special interest could also be reported , at the request of HAs

17. What is subject to expedited reporting-2
Other safety information
– Safety information from other observations that could change the benefit: risk evaluation for the product or affect the safety or trial subjects, e.g., increased frequency of expected events, important preclinical findings, etc
– In EU also includes events related to the protocol design and procedure.

18. Timelines SUSAR • Other information to be reported expeditiously:
– Fatal and life threatening: 7 days
– All other SUSARS: 15 days
– Follow up information: 15 days after receipt
– Ethic committees, IRBs, investigators: also to be notified
Uganda, PI reports within 48 hours to the sponsor
Sponsor to the RA within 7 days
• Other information to be reported expeditiously:
– Any change to benefit risk: e.g., Increased frequency or severity,important pre-clinical findings

19. Gaps existing Failure to report SAE
Failure to honor reporting timelines
Incomplete or insufficient narratives for reported SAEs.
Lack of comprehensive Pharmacovigilance plans in protocols.

20. Thank you