Changing Requirements for Devices//Device Constituent Parts in Combination Products

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1 Changing Requirements for Devices//Device Constituent Parts in Combination Products Dan Wozinski, RPH, MBA Sanofi

2 Disclaimer The content and viewpoints of this presentation are mine alone and not those of those of Sanofi

3 Outline FDA requirements 21 CFR part 4 Current requirements versus future requirements GMP and the Quality System FDA versus other countries Assessing device complaints with an adverse event Assessing causality to the device constituent part Trending and signal detection Evaluating risk for combination products

4 FDA Requirements

5 Post-marketing Safety Reporting for Combination Products 21 CFR part 4, subpart B - Post-marketing Safety Reporting for Combination Products (as of today, still a proposed rule) 5-Day Report (803.53(a))- MDR Reportable event necessitates remedial action to prevent an unreasonable risk of substantial harm to the public health or FDA has made a written request 30-Day Device Malfunction Report ( (b)(3)(ii)) information reasonably suggests the device has malfunctioned and that device or similar device would likely cause or contribute to death or serious injury if it were to recur 15-Day Alert Report (314.80(c)(1) and (e) and (c)(1) and (e) adverse experience is serious and unexpected (special considerations for how the product was approved) 3-Day Field Alert (314.81(b)(1)) certain types of problems with the drug such as distribution problems, contamination, chemical/physical changes/deterioration, etc. Expedited Blood Fatality Report ( )

6 Current Good Manufacturing Practice Requirements for Combination Products Final Rule Effective July 22, 2013 Provides that all constituent parts must be manufactured in accordance with the CGMP requirements that apply to them if they were not part of a combination product. Compliance with either CGMP for drugs (210/211) or QSR (820) will satisfy many, but not all, of the CGMP requirements If you are a combination product manufacturer using CGMPs, you must now also include Quality System Requirements: 21 CFR Management Responsibility 21 CFR Design Controls 21 CFR Purchasing Controls 21 CFR Corrective and Preventive Action 21 CFR Installation 21 CFR Servicing

7 Complying with QSR for a combo product registered approved under an NDA Process must be in place to identify and evaluate complaints, adverse events and other quality or product related issues related to the device constituent part Processes should be performed in a consistent manner and at periodic intervals Evaluations and assessments should be performed by trained and qualified personnel Process should evaluate the risk to the patient, user, bystander Determine if mitigation is necessary Determine what corrective/prevention action is required Implement the action/correction Evaluate the success or failure of those actions It is managements responsibility to oversee the process Process should be continuous throughout the life of the product

8 EU Requirements Good practice guide on risk minimization and prevention of medication errors (18 November 2015) 5.1 General principles of risk management planning and the tools used Continuous throughout the life-cycle of the product Requires Pharmacovigilance planning to monitor and further characterize risk, planning and implementation of risk minimization activities and measurements of the success of these activities Defects and device failures (pre-authorization) A combination product is covered under the pharmaceutical legislation However, in addition, the relevant essential requirements in Annex I of the Medical Device Directive 93/42/EEC also apply with respect to safety and performance related features of the device Compliance with harmonized standards is recommended. Applicants should systematically assess risks throughout development Medical errors resulting in harm during post-authorization use For device-related medication errors, MAHs should investigate whether the reports are substantiated, are isolated examples or are batch-wide and batchspecific

9 Japan PMDA requires device reporting for all Drug/Device Combination products approved after November Death Serious Event Potential for serious event For DDC products approved prior to this date, manufacturers are expected to follow new regulation by November 2016

10 Assessing complaints with an adverse event for the device constituent part

11 Process Complaint/adverse event management is an important tool for CAPA Complaint management involves the entire system from people receiving the call/complaint all the way up to management Complaint management system must have a well structured process for identifying, evaluating and investigating complaints and adverse events Data collection should support evaluation of both the drug and device constituent part including information on handling/usage, performance of the device, etc. Complaint management system should include a process for delivering information to the right people at the right time Determined by risk, priority, urgency Must determine when issue need to be escalate to management

12 Complaints and Adverse events The nature of the combination drug/device products create a challenge for assessment and in determining whether the device part caused or contributed to the adverse event Often requires data from multiple sources to be reviewed simultaneously Data from different databases (AEs versus Complaint data) CAPA information Trending reports Sales data

13 Analysis Qualitative analysis Medical assessment of individual cases or clusters Technical analysis of cases Quantitative analysis Periodic/ad hoc Risk assessment Trending

14 Causality to the device Evaluation of device causality should include: Complete documentation of complaint/adverse event Necessary to perform complete and adequate follow-up with reporter Investigation of complaint/adverse event Product sample analysis/retention sample analysis Did device meet specification? Were instructions followed? Root cause analysis As it related to the complaint/adverse event caused by the device History of previous cases of similar complaints/adverse events/root causes Trending can identify unforeseen causalities and risks Signal detection methodology Medical assessment Specification of the device

15 Causality to the device It is extremely important to document any assessment on causality to the device including: Any deliberations Sources of data Expert opinions Technical investigation Etc. Medical judgments or statements alone are not always sufficient to determine and document causality!!

16 Adverse events Essential to evaluate causality to the device to determine risk to patient or user Adverse event, cause or contributed to by the device, could be the result of: Failure/malfunction of the device Design flaws Instructions for use Human factors or user error Side effect of the device Procedural complications Complications from set-up/installation

17 Adverse event analysis Severity Each adverse event is assigned a severity based on defined criteria Examples of severity criteria: Death Life-threatening Medically significant (i.e. hospitalization, requires medical/surgical intervention) Non-serious Negligible Refer to ISO Standard 14971:2009 Application of risk management to medical devices

18 Signal detection Signal detection Quantitative Trending Changes in number of cases over time Changes in rate of cases per sales/distribution Qualitative Changes in severity or nature of adverse events/complaints Signals can identify device issues unseen in individual cases Unidentified quality issues Instructions for use issues

19 Risk Risk = combination of the probability of occurrence of harm and the severity of that harm Risk = f {O,S} Harm = physical injury or damage As a general rule, we do not want to create additional risk of harm to a patient, user or bystander in using the device component

20 Risk assessment Quantifies risks bases on frequency and severity Quantifies individual risks Helps determine acceptability Determines need for CAPA Reassess after CAPA is completed

21 Risk Chart Green = acceptable Yellow = as low as reasonably possible Red = unacceptable, must mitigate

22 Quality System Complaints, adverse events, findings, root cause assessment and trending Risk management procedures What are the risks, severity, occurrence rate estimation, acceptability Quality System Feedback, e.g. Management Review; Period assessment reports and Trending Analysis Correction and prevention Re-evaluation

23 Questions?