ROLE OF PHARMACOVIGILANCE IN CLINICAL TRIALS

REGULATORY AFFAIRS
FIRST SEMESTER M.PHARM

1. ROLE OF PHARMACOVIGILANCE IN CLINICAL TRIALS PRESENTED BY : AKHILA A 1 st YEAR M PHARM PHARMACEUTICS NGSMIPS

2. CONTENTS INTRODUCTION PHARMACOVIGILANCE IN CLINICAL TRIALS STAKEHOLDERS IN CLINICAL TRIAL SAFETY EXPEDITED ADR REPORTING IN EU, INDIA, US PHARMACOVIGILANCE PROGRAM IN INDIA CONCLUSION REFERENCES

3. INTRODUCTION PHARMACOVIGILANCE : Known as Drug safety. According to WHO, Pharmacovigilance is defined as “the pharmacological science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”. Removes of approved and licensed products from the market because of clinical toxicity, which is caused by adverse drug reactions in the body. Aims : To improve patient care and safety. To contribute to assessment of benefit, harm and effectiveness of medicine. To promote rational and safe use of medicine.

4. CLINICAL TRIALS: Clinical trials are research studies which describes process of new medical approaches and their actions in public. These are the experiments or observations done in clinical research. Aims: To evaluate the safety and efficacy of experimental drug relative to its adverse drug reactions. To license the process of new drug. Advantages of conducting Clinical trials in India: Ongoing support and cooperation from the government, Lower cost, Availability of good infrastructure.

5. DRUG SAFETY MONITORING: Randomized clinical trials need to be monitored. Data and safety monitoring : Process for reviewing accumulated outcome data from an ongoing clinical study to ensure safety , validity and scientific merit of the study. Medical monitoring is increasing every year. These can be performed by a licensed physician with experience in clinical development and those who are capable of reviewing adverse events. Need to be responsible for identifying safety signals and responsible for data analysing which influence the medical outcome. They track patients safety throughout the trial.

6. PHARMACOVIGILANCE IN CLINICAL TRIALS Pharmacovigilance begins with clinical trials that provides data on the benefits and risks of a drug. Pharmacovigilance analysis conducted in Phase I, Phase II, and Phase III clinical trials gives drug companies data on the drug’s safety profile.

7. Key stakeholders in clinical trial safety: Ensuring safety in clinical trials is a shared responsibility across the following key stakeholders. Clinical Trial Subject Investigator Clinical Trial Sponsor Safety Monitoring Boards Ethics Committee Regulatory Agency

8. Clinical Trial Subject A clinical trial subject is an individual who participates in a clinical trial, either as a recipient of the investigational and products or as a control. Investigator An investigator is a person responsible for the conduct of a clinical trial, at a trial site. If a trial is conducted by a team of individuals at right side, the investigator is responsible leader of the team and may be called the principal investigator. Clinical trial sponsor An individual, company, institution or organisation which takes responsibility for the initiation, management and for financing of a clinical trial. Independent data monitoring committee It is a committee that may be established by the sponsor to assess at intervals of the programs of clinical trials, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.

9. Ethics Committees (EC) / Institutional Review Board (IRB) An independent body (a review board or a committee, institutional, regional, national), constituted of medical professionals and non-medical member, whose responsibility is to ensure the protection, safety, and well-being of human subjects involved in a trial and to provide protection among other things, reviewing and approving / providing favourable opinion on trial protocol. Regulatory agencies Regulatory agencies are bodies having power to regulate. As per ICH GCP guidelines, regulatory authority review submitted clinical data and conduct inspections. They are also referred to as competent authorities.

10. EXPEDITED REPORTING IN THE EUROPEAN UNION, INDIA AND THE UNITED STATES Expedited reporting is accelerated reporting of certain types of adverse drug reactions (ADRs) that may have a greater impact on safety and hence, may require rapid reporting and subsequent analysis. Typically, expedited reporting refers to cases of ADRs that are both serious and unexpected. Adverse Drug Reaction (ADR): D efined as all noxious and unintended response to the medicinal products related to any dose. Adverse reactions are a subset of all suspected adverse reaction when there is reason to conclude that the drug caused the event.

11. Classification of ADR: Mild Drug can be continued without any treatment. e.g., Occurrence of drowsiness while on therapy with anti-allergic medications. ii. Moderate Drug was changed or stopped; reaction require treatment e.g., Occurrence of hypokalaemia while on diuretic therapy.   iii. Severe These may be life-threatening and requires a discontinuation of the drug therapy. e.g., Occurrence of QT prolongation or drug-induced liver failure

12. Serious Adverse Events (Experience) or Serious Adverse Reaction (SAR): An SAE or SAR is any untoward medical occurrence that at any dose: Results in death Is considered life-threatening. Requires inpatient hospitalization or prolongation of existing hospitalization. Results in persistent or significant disability/ incapacity Is a congenital anomaly/ birth defect.

13. Unexpected Adverse Drug Reaction: An adverse reaction, the nature or severity of which is not consistent with the applicable product information. In other words, it is considered unaffected if it is not listed in the investigators brochure or is not listed at the specificity or severity that has been observed. Suspected Unexpected Serious Adverse Drug Reaction (SUSAR): An adverse event that is serious, possible casually related to a medicinal product and is considered unexpected as per the investigator’s brochure. A SUSAR requires expedited reported to most of the regulatory agencies.

14. Reporting Process for Expedited Reporting Of Serious Adverse Event (Experience) (SAE) or Serious Adverse Reaction (SAR): These reporting process starts from the awareness of the occurrence of the serious adverse events at the clinical trial site. The investigator has to report SAR (usually within 24 hours) to the sponsor. The sponsor, depending on the regulations, may have to report the same to the concerned regulatory agencies SAR may also have to be reported to the ethics Committee (IRB) by either the sponsor or by the investigator depicts the sponsor or by the investigator depicts the reporting process for an SAR.

15. Usually there are two types of expedited clinical trials: 15 days reports where the sponsor has to report SUSARs to the regulatory agency to the ethics committee within 15 calendar days of the information reaching the sponsor. 7 days reports that are subsets of the 15-day report, where in the sponsor has to report fatal or life-threatening SUSARs to the regulatory agency and to the ethics committee 7 calendar days of the information reaching the sponsor.

16. EUROPEAN UNION Responsibility of the investigator: The investigator should report all serious adverse events immediately to the sponsor except for those that the protocol or investigator brochure identifies as not requiring immediate reporting. The immediate reports shall be followed by detailed, written reports. The timeline of immediate reporting should allow the sponsor to take the appropriate measures to address potential new risks in clinical trial. Therefore, the immediate report should be made within a very short period of time and should not exceed 24 hours following the knowledge of the serious adverse event.

17. Responsibility of the sponsor The sponsor should report all suspected, unexpected, Serious Adverse Drug Reactions (SUSAR) that are fatal or life-threatening as soon as possible to the competent authorities and to the ethics committee and in any case no later than 7 calendar days Relevant follow-up information should be subsequently communicated within an additional 8 days. The other SUSAR should be reported to the competent authorities and to ethics committee as soon as possible but within the maximum of 15 days of the first knowledge by the sponsor. The sponsor also has the responsibility to inform all the investigators in the clinical trials about SUSARs.

18. INDIA Responsibility of the investigator Investigator shall report all serious and unexpected adverse events to the sponsor within 24 hours and to the ethics committee that accorded approval to the study protocol within 7 working days of their occurrence. The report of the serious adverse events, after due analysis shall be forwarded by the investigator to the license authorities , chairman of the ethics committee and the head of the institution where the trial has been conducted within 14 calendar days of the occurrence of serious adverse event. In case if the investigator fails to report any serious adverse events within the stipulated period, he shall have to furnish the reason for the delay to this satisfaction of the licensing authority along with the report of serious adverse events,

19. Responsibility of the sponsor: Any report of the serious adverse event, after due analysis shall be forwarded by the sponsor to the licensing authority as, chairman of the ethics committee and the head of the institution where the trial has been conducted within 14 calendar days of the occurrence of the serious adverse effects. Responsibility of the Ethics committee: In case of serious adverse event occurrence to the clinical subjects, the ethics committee shall forward its report on the Serious Adverse event, after due analysis, along with its opinion on the financial compensation, if any, to be paid by the sponsor or his representative, whosoever had obtained permission from the licensing authority as referred to in clause (b) of rule 21 for conducting the clinical trial to the licensing authority within a specified time frame of the occurrence of the serious adverse event .

20. UNITED STATES Responsibilities of the investigator: The investigator should immediately report to the sponsor any serious adverse events, whether or not considered drug-related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event. The US FDA is a cognizant of the fact that it may take investigator a short period of time to compile information about the event, but they expect the information to the immediately reporting to the sponsor. The investigator shall also promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others.

21. Responsibilities of the sponsor The sponsor must notify FDA in all participating investigators in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting as follows.

22. PHARMACOVIGILANCE PROGRAM IN INDIA Pharmacovigilance Program in India was initiated and introduced by the Indian regulatory authority (Central Drug Control Standard Organization). Ministry of Health and Welfare under DCGI under CDSCO started with an aim to protect the public health safety. This is working under Steering Committee.

23. Mission of PvPI: To safeguard the health of the Indian population by ensuring that the benefits of use of medicine outweigh the risks associated with its use. Vision of PvPI: To improve the patient safety and welfare in Indian population by monitoring the drug safety and thereby reducing the risks associated with the use of medicine.

24. Objective of PvPI: To develop a national-wide system for patient safety monitoring. To determine and examine the new signal (ADR) from the reported cases. Examine benefit-risk ratio of marketed medications. To create awareness among healthcare professionals about the importance of ADR reporting in India. Arise as a national centre of excellence for pharmacovigilance activities.

25. Who can report What to report Whom to report Healthcare professionals (clinicians, dentist, pharmacist, nurses, and others) can report suspected adverse drug reaction. Pharmaceutical companies can also send ICSRs specific for their product to NCC. All types of suspected ADRs irrespective of whether they are known or unknown, serious and non-serious, frequent or rare. Although pharmacovigilance is primarily concerned with pharmaceutical medicines, adverse reactions associated with drugs used in traditional medicines (e.g., herbal remedies) should also be considered   Use the ‘Suspected Adverse Drug Reaction Reporting Form’ which is available on the official website of IPC ( www.ipc.gov.in ) as well as CDSCO ( www.cdsco.nic.in ) to report any ADR. A reporter who is not a part of AMC can submit the ICSR to the nearest AMC or directly to the NCC. Performance and Effectiveness of PV system :

26. PvPI phases: It is a 5-year program and it consists of totally 5 phases. Initial phase (2010-2011) Expansion and consolidation phase (2011-2012). Expansion and maintenance phase (2012-2013) Expansion and optimization phases (2013-2014) The excellence phases (2014-2015).

27. Initial phase Developing systems and procedure Enrolment of 40 medical institute Start data collection from AEFI (Adverse Events following Immunization) ii. Expansion and consolidation phase Linkage with UMC, Sweden Identify gaps and address via proper training Training of PV software supply by UMC, WHO  iii. Expansion and maintenance phase Enrolment of additional hundred medical institute Software development and validation Zonal workshop of drug safety public awareness  

28. iv. Expansion and optimization phase Training of PV human resources. Newsletter publication of drug safety Enrol additional 100 medical colleges v. Excellence phase Create Centre of Excellence for Pharmacovigilance in Asia Pacific

29. Communication under PvPI

30. Committees of NCC: Steering Committee Working Group Quality Review Panel Signal Review Panel Core Training Panel Different modes of communications used in PvPI: Press and Media Communication Website Newsletter

31. CONCLUSION Pharmacovigilance is the only way to ensure the safety of the drug throughout the life cycle. Now it is considered as user-friendly network for reporting the adverse events. Hence by determining the adverse reaction we can make an alternative solution in order to overcome the adverse events and hence it can be recovered

32. REFERENCES Mohanta G P, Manna P K. Textbook of Pharmacovigilance Concepts and Practice. 2 nd ed. Hyderabad: PharmaMed Press, 2020; P: 1-8, 12-26. Charylu R N, Jose J. Pharmaceutical Regulatory Science. Pune: Nirali Prakashan , 2021; P: 4.21-4.24. Baweja H. Textbook of Clinical Research. Punjab: S Vikas and Company, 2021; P: 136- 149, 214- 221. Tripathi D K, Shukla S S , Pandey R K. Textbook of Pharmacovigilance. 2 nd ed. Pune: Nirali Prakashan , 2021; P:1.11-1.114. ICH website: www.ipc.gov.in (accessed on 6 febrauary 2022) Jaani M, Nagasamy V D, Pharmacovigilance- A Master key for Drug Safety. J. Pharm. Sci. & Res. Vol. 11(5), 2019, 1963-1970. Chin R, Bairu M. Global Clinical Trials Playbook. Chapter 13. Pharmacovigilance and Risk Management, 2012; P: 141-159. Anusha L, Aashrita M, Sridhar R. A review of Pharmacovigilance and its importance. World J Pharm Pharm Sci. 2017; Volume 6, Issue 1, 300-310.

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