Pharmacovigilance in clinical trials Victoria Nambasa Manager Pharmacovigilance National Drug Authority

Outline Importance of Pharmacovigilance Key definitions Reporting timelines Gaps and opportunities

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)

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

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 part312.32 (a) “Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”

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.

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

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.

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.

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

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).

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?

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

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

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).

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

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.

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

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.

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