Simplifying the Complexity- For the BeginnersBy: Nidhi Ralli Kapur
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Anyone can make the simple complicated. Let’s make complicated simple. - Inspired by thought of Charles Mingus
Adverse EventAdverse event (AE) : Any adverse change in health or side effect that occurs while thepatient is receiving the Treatment.Serious Adverse event (SAE): is defined as any Adverse Event occurrence that at any doseresults• in death• Is life threatening• requires inpatient hospitalization or prolongation of existing hospitalization• results in persistent or significant disability/incapacity• is a congenital anomaly/birth defect, or• requires intervention to prevent permanent impairment or damage.
How the Cycle Works… Someone falls He Goes to Doctor Prescribes ill the doctor the medicine/ Treatment This medicine/ treatment prescribed could have been already Launched in Market or could be still under surveillance i.e. in Clinical Trials•If still under Clinical Trial, Patient and his family should be duly informed and Informed Consent Document should be signed by them.•To Be in a clinical Trial specific Terms & Conditions apply. 5
Different Scenarios…Scenario A: Treatment Yet to come in the Market: Under Clinical Trial Known As Adverse Event Adverse Event Capturing for Clinical Trials (Phase 1, 2 and 3) Into Clinical Trials Into Pharmacovigilance Known as Adverse Event Capturing for Pharmacovigilance Process 6
Different Scenarios…Scenario B: Treatment Already in the Market Known As Adverse Event Adverse Event Capturing for Clinical Trials (Phase 4, Compassionate Trials)- Optional* Into Clinical Trials Into Pharmacovigilance Known as Adverse Event Capturing for Pharmacovigilance Process •If Manufacturing Company is conducting trial under this category. 7
Definition Clinical trials are a set of procedures in medical research conducted to allow safety and efficacy data to be collected for health interventions. These trials can take place only after satisfactory information has been gathered on the quality of the non-clinical safety, and Health Authority/ Ethics Committee approval is granted in the countrywhere the trial is taking place. Pharmacovigilance (abbreviated PV or PhV) is the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term side effects of medicines.
Significance of Reporting Adverse EventsRegulatory Agencies stresses on capturing of this data:• To enhance Patient Safety• To keep records of efficacy• Provide optimal information to users• Identifying New Information about hazards associated with medicines• Evaluates Changes in Benefits and Risks• Monitor impact of Action Taken• Identify Previously unknown Hazards
NotificationFollowing refers to the FIRST Notification of occurrence of Adverse Events: In Clinical Trial,- By Doctors/ Investigators • Adverse Event should be reported as soon as possible to Sponsor •Serious Adverse Event should be reported within 24 hours of its information received. Via CRF, eCRF or SAE forms. In Pharmacovigilance- By Doctors, Patients, Literature Review, etc. • Adverse Event or Serious Adverse Event should be reported as soon as information is received. Via SAE forms provided by Manufacturing Companies, Regulatory Agencies (e.g.: CIOMS, Medwatch), Teleservices, website Portals.
Case Flow Capture in MedicalCollect Data Database Review ReportFrom various Capture the Casesources like Medical insight Reporting the in databases on case dataLiterature, cases toSpontaneous captured RegulatoryReporting etc Agencies
Notifications to Regulatory AgencySUSAR (Suspected Unexpected Serious Adverse Reaction) : To be submitted to the national competent authority within 15 days of occurrence 7 days in case of death or life-threateningICSR (Individual Case Submission Reports): It includes case safety reports for both pre and post approval periods and covers both adverse drug reaction and adverse event reports. Expedited Reporting: Notification (submission) designated format to the appropriate Regulatory Authorities in compliance with the parameters and timelines specified by legislation and local regulatory guidelines. An expedited report would be a Report meeting the criteria for rapid transmission to a Competent Authority. PSUR (Periodic Safety Update Report): An overview of the safety of the product and includes all ADRs reported in the period since the last PSUR, - together with a summary of the registration status of the product worldwide, - actions taken for safety reasons, - the worldwide usage of the product and an analysis .
Minimum Criteria For Reporting• An identifiable patient • age (or age category, e.g., adolescent, adult, elderly) • gender • initials • date of birth • name or patient identification number•A suspect medicinal product• An identifiable reporting source• Name or initials, address or qualification• At least one event13
Final OutcomeRegulatory AgenciesThe agencies review the data to find out• Good v/s bad• To decide if : (i) drug should be launched or not (ii) keep the drug in the Market or withdraw itSponsorSignal Detection• The data of the drug is fetched and compare with same family of drugs for the new probability of• Adverse Events, known as Signal.• Once found these are verifies for causality and effectiveness and if result is positive:• A new clinical trial for the drug is Filed. Also Before Launch, a comprehensive AE Record sheet is created known as: Company Core Data Sheet (CCDS) This document is prepared by the Marketing Authorization Holder and contains, in addition to safety information, material relating to indications, dosing, pharmacology and other aspects of the product. It’s same as the small sheet of paper you get in packing of Cough Syrups etc 14
Impact: Unsafe Drug in Market• Fourth leading cause of death in the United States• 2 million fatal adverse drug reactions• 350,000 hospital administrations• Drug withdrawalsConsequences of Drug Withdrawals• Lost revenue• Litigation expenses• Reduced share price• Tarnished company imageThe annual economic cost of adverse drug events is estimated to be more than $75 billion (Johnson & Bootman,1995) 15
GlossaryCase: Every Adverse Event Reported to Pharmaceutical Company or Regulatory Agency during the PV process is known as Case.CRF: Case Report Form. Used in Clinical Trials to report the data of Patients by Physicians to Sponsor Pharmaceutical Companies.CIOMS: Council for International Organizations of Medical Sciences. It generally refers to Adverse Event Reporting form issued by this organization.Compassionate Trials: Trials conducted on same family of drugs to find the comparative resultsE2B: Standard for reporting ICSRs to Regulatory agencieseCRF: electronic CRFsLiterature Review: Any AE or SAE that seems possible after the Literature review of drug and related dataICSR: Individual Case Safety Reports
GlossaryMedwatch: It is Food and Drug Administrations reporting system for an adverse event. (Ref: Wikipedia)Spontaneous Reporting= Reporting of AE or SAE by doctors to Sponsor or Pharma Company, post marketing of drugRegulatory Agency: A regulatory agency (also regulatory authority, regulatory body or regulator) is a public authority or government agency responsible for exercising autonomous authority over some area of human activity in a regulatory or supervisory capacity. (Ref: Wikipedia)Signal : Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previouslyPhases of Clinical Trials:1= Determine the metabolic and pharmacological actions and the maximally tolerated dose2= Evaluate effectiveness, determine the short-term side effects and identify common risks for a specific population and disease3= Obtain additional information about effectiveness on clinical outcomes and evaluate the overall risk-benefit ratio in a demographically diverse sample4= Monitor ongoing safety in large populations and identify additional uses of the agent that might be approved by the FDA
About the Author Experience Have a total experience of 6+ years in various streams of Clinical Research. It includes extensive experience of 4 years on Clinical Data Validation, etc on both Paper and Electronic data capture. For the last 2 years have been working in Pharmacovigilance CoE (Center of Excellence) team in TCS. Papers & Research Work Presented the Research Paper in the ‘Indian Council of Medical Research’ Symposium on the Prevalence of a G6PD Deficiency in India & its Possible treatments‘ Poster Presentation at ‘National Seminar on Biotechnology’ on Language Gene. (http://in.linkedin.com/pub/nidhi-ralli-kapur/13/3a2/2b3)