Pharmacovigilance slides with details on Medical Devices and PVAs in Clinical studies

Pharmacovigilance slides with details on Medical Devices and PV Agreements set-up in Clinical studies. Useful for healthcare professionals, education and interview preparation, career prospectus

1. Medical Devices and Pharmacovigilance Agreements (PVAs) in Clinical Trials

2. Agenda PV and Clinical trials Pharmacovigilance Agreements (PVAs) Medical Devices in Clinical Trials Closing remarks

3. PV and Clinical trials

4. Clinical Trials/Studies (FDA) people volunteer to help find answers to specific health questions when carefully conducted – the safest and fastest way to find new treatments/improve health conducted according to a plan (protocol) FDA works to ensure that people have reliable information before deciding whether to join a CT (informed consent) strict rules for the conduct of CTs to make sure that the study participants are treated as safely as possible new drug or device is safe and effective (Safety comes first)

5. Pharmacovigilance & Clinical Research PV begins with CTs that provide data on the benefits and risks continuous monitoring & evaluation of all adverse events during drug development assessing the safety of participants and evaluating the risk and benefit to determine whether the benefits outweigh the risks obtaining approval to market the new drug based on safety data safety data collected during CTs is not exhaustive – Post Marketing Surveillance

6. Pharmacovigilance in Clinical Research Reference Safety Information (RSI) Package Insert/Leaflet Contraindications Warnings on labeling (Safety) data collection in special situations Study termination (Safety/Benefit)

7. Pharmacovigilance Agreements (PVAs)

8. Pharmacovigilance Agreements What & Why? Background - a significant increase in the collaborations, partnerships, in licensing and out licensing Why?? to synergize on their specific expertise (e.g. manufacturing, API vs formulation, R&D, clinical trials, marketing, regulatory capabilities) Risk?? – PV/drug safety activities may either be overlooked/missed or duplicated. Solution – well drafted PVA (or SDEA) ensures regulatory compliance What? – a written agreement entered into by the parties to set forth the protocols and procedures for reporting adverse events and complying with regulatory requirements PVAs during clinical trails – Co-development arrangements; Service level agreements; Delegation of PV activities or supporting functions; Collaboration arrangement with not-for-profit organizations

9. Contents of PVA Maintenance of Global safety database. Literature review Case processing including medical assessment and follow up Reporting timeframes, notification and responsibilities Signal detection Preparation of (PSURs) and submission to various regulatory authorities Ongoing and planned clinical trials Archiving of PV documents Updating SmPC/ Package Inserts (PI), Patient info leaflets, company core safety information (CCSI) Development, review, evaluation and implementation of RMP Audits/Inspections; HA Questions/ queries Continuous benefit risk assessment Responsibilities for reporting to ethics committees/IRBs and investigators Handling of blinded reports and the unblinding Pharmacovigilance agreements should be drafted to clearly define who will be responsible for the following activities.

10. Contents of PVA PVAs must also include Appropriate contact details for each party (PV Head, QPPV, Signal, ICSR, PSUR) List of abbreviations used Definition of key terms Revision frequency and terms Translation responsibilities Partner audit clause Compliance clause Interesting to know Companies having handful of PVAs can manage manually Those having hundreds of PVAs might require PVA database for: tracking & managing PVAs/revisions fetching partner lists/contact lists to support operational teams routine reconciliations periodic contact verification of partners

11. PVAs – aptly recognized/maintained? Criticality – any lapse w.r.t. RA requirements may lead to hefty penalties or regulatory actions; questions the integrity of safety data/study reports/dossiers; missed signals! Why ignored?? collaborations are driven by business focusing on the commercial & financial aspects Best time to work on PVAs – while the business negotiations are ongoing Revisions required: (apart from periodic revisions) change in the legislation or regulatory requirements change in the business agreements/conditions/responsibilities change in product range and/or territories involved - regular communication/reconciliation b/w PV and business groups to ensure up-to-date PVAs

12. Medical Devices in CTs In context to PV Reporting (Medical Device Regulation)

13. Some (key/unique) definitions Adverse device effect (ADE) any AE related to the use of an investigational medical device or a comparator Device deficiency (DD) any inadequacy in the identity, quality, durability, reliability, safety or performance of an investigational device, including malfunction, use errors or inadequacy in information supplied by the manufacturer Incident any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect Serious incident any incident that directly or indirectly led, might have led or might lead to any of the following: the death of a patient, user or other person the temporary or permanent serious deterioration of a patient's, user's or other person's state of health, a serious public health threat

14. Medical Devices in Clinical Investigations Clinical Trials/studies more commonly referred to as clinical investigations in the medical device industry Medical Device Coordination Group ( MDCG ) established by Article 103 of Regulation (EU) 2017/745 representatives from all Member States and chaired by a representative of the European Commission deals with key issues from the medical devices sector expertise divided in 13 subgroups, which respectively provide advice and draft guidance on their expertise field Clinical investigation and evaluation (CIE) – 1 of the 13 subgroups

15. Clinical investigation and evaluation Develops and promotes homogenous interpretation and implementation with regard to clinical evaluation and investigation also supports other working groups on CIE issues Topics of interest : common specifications in respect of the clinical investigation, evaluation and post-market clinical follow-up (PMCF) Guidance on safety reporting under the Medical Device Regulation (MDR) has been developed by the CIE

16. Clinical investigations of medical devices Pre-market clinical investigations covered by Articles 62 and 74(2) of the MDR conducted with : Non-CE (‘ conformité européenne’ meaning ‘ European conformity ’ ) marked devices CE marked devices used outside the intended use(s) covered by the CE-marking some studies covered by MDR Article 82 ( Other clinical trials ) Post-Market Clinical Follow Up (PMCF) investigations Other post-market clinical investigations due to national requirements following MDR Article 82 (no general requirement)

17. Recording & reporting of AEs The sponsor shall report, without delay to all Member States in which the CI is being conducted: any SAE that has a causal relationship with the investigational device, the comparator or the investigation procedure or where such causal relationship is reasonably possible ; any device deficiency that might have led to a SAE if appropriate action had not been taken, intervention had not occurred, or circumstances had been less fortunate; any new findings in relation to any event referred to in points (a) and (b)

18. Reporting Timelines For all reportable events which indicate an imminent risk of death, serious injury, or serious illness and that requires prompt remedial action for other patients/subjects, users or other persons or a new finding to it: Immediately, but not later than 2 CDs after awareness by sponsor (includes events that become alarming as a potential public health hazard and/or possibility of multiple deaths occurring at short intervals) Other reportable events or a new finding/update to it: Immediately, but not later than 7 CDs following the date of awareness by the sponsor In some cases, a different periodicity or modality may be agreed between the participating NCAs and the sponsor according to the investigation’s design and the pathology under clinical investigation

19. Closing remarks PV starts as early as CT but does not end with study endpoint PV has a plethora of sub-domains to learn & contribute (apart from Case Processing, Signal Detection, Medical Writing) PVAs and Medical Devices – gaining momentum owing to emerging landscape of global partnerships and recent/ongoing advances in medical device technologies PV is an ongoing clinical study which continues throughout the lifecycle of a drug , though PMS not as closely controlled as in CTs (my own understanding and believe)

20. Thank you

21. Back-up slides

22. Study termination Safety : The risks to human subjects unexpectedly outweigh the benefits because of unexpected severe adverse events. An example is drug manufacturer Bial's phase 1 clinical trial in healthy volunteers. (Chan S. 6 hospitalized, one of them brain-dead, after drug trial in France.  The New York Times  . January 15, 2016 http://www.nytimes.com/2016/01/16/world/europe/french-drug-trial-hospitalization.html?_r=0 ) Benefit:  The study hypothesis is unexpectedly proven early within predesignated criteria. Continuing to expose subjects in the inferior arm to additional potential risks or keeping them from benefitting from the therapies in the superior arm is hard to justify ethically.