New EU Draft Guideline on Pharmacovigilance Inspections “We are here to help you…”

What is this about?:

In late June 2012 the EMA released its “Module III” on PV inspections.  This is a draft guideline due to be finalized by year end with public consultation from June 27 to August 24. It describes how the EU and member states (MS)will do drug safety/PV inspections.

Why do I need to know this?:

If your company, partner, vendor, client etc. handles adverse events and other safety data from EU patients you or they are liable to being inspected by the EU.  Your premises, records, documents and PV system master file are all subject to inspection – whether in the EU or not.

In a nutshell:

EU MSs responsible for central and non-centrally approved products are responsible to ensure that the laws and regulations governing safety in the EU are complied with.

There will be 1) routine inspections and re-inspections scheduled according to a risk based approach and 2) pre-authorization (approval) inspections in support of the Marketing Authorization request and 3) for cause inspections triggered by non-compliance (real or suspected) or high risks from specific products.

These inspections are done to ensure that the company has a PV system in place or is establishing one that will cover the EU.  In addition, if there is a history of non-compliance, problematic previous inspections or information from other health agencies, an inspection may be done before drug approval.  In addition, if there are risk minimization activities or specific safety issues an inspection may be done.

Inspection triggers include late or poor quality expedited or periodic reports, inconsistencies between reports, non-compliance in the past, communication to the public without prior or simultaneous notification of the health agency, failure to provide information to competent authorities when requested, problems with Risk Management Plans, delays in carrying out obligations , CAPAs, problems found in GMP, GLP, GCP inspections at that company, problems found in inspections done by other agencies (e.g. FDA) etc.  A bad inspection may result in non-approval, a delay till the problems are rectified or imposition of certain conditions in the MA.

The inspection results will be sent to the inspectee for comment and corrective and preventive actions must be taken.  Data will be shared with the Pharmacovigilance Risk Assessment Committee (PRAC).  the Committee for Medicinal Products for Human Use (CHMP) and the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh).

Inspections may be announced (the usual case) or unannounced.  They may be done on site or remotely by phone, internet or other means, particularly if the company is located outside the EU.

Companies must do inspection planning and be ready for an inspection at any time.  They should understand that high-risk situations are likely to precipitate an inspection sooner rather than later.  These high risk situations include drugs with an RMP or post authorization safety studies (PASS), products with high sales volumes, products with limited alternatives in the market, a company that has never been inspected, a company with many products on the market or no previous drugs on the market, problems in other inspectable GXP areas, a recent merger or acquisition, a company that outsources some or all PV activities, a new or changed PV database, new PV service providers or changes at the service providers themselves, PV system master file delegation etc.

The scope:

The inspection can be broad and cover:

• Individual case safety reports (ICSRs): receipt, handling, processing reporting both internally, with partners and out-sourcers, case assessment, follow up, outcome determination, record keeping etc.
• PSURs: completeness, accuracy, timeliness, format
• Ongoing safety evaluations (signal detection): methodology, sources,  follow up, implementation of commitments in the RMP and elsewhere etc.
• Clinical trial & non-interventional trial case reporting (SUSARs), IBs, labeling etc.
• The PV System and master file: QPPV, the PV System Master File, staff training, qualifications, experience, Quality Systems, IT, contracts with partners, vendors etc.

Corrective Action & Preventive Action Plans are obligatory and must be done until the plan is completed.  The health agency(ies) doing the inspection will review, approve and track the CAPA.  The inspection data and responses will be shared within the EU (and possibly elsewhere).

To protect the public health, the agencies may implement specific requirements on the inspectee similar to US actions: education, re-inspection, warning letters, public naming and shaming, urgent safety restrictions, label changes, variation of the MA, suspension of the MA (that is, removal from the market), delaying new MA applications under review, penalties, fines and even possible criminal prosecution with possible imprisonment.

The guideline then goes on to discuss the internal EU mechanisms and requirements for the member states, the EMA, the PRAC, the CHMP and the CMD(h).  For details on these arcane workings, the reader is referred to the guideline itself.

Inspectee obligations:

Always be inspection ready, have the PV System Master File available for the inspections within 7 calendar days, ensure the sites that might be inspected will allow the inspection, have the staff and data available.

Fees:

The health authorities will charge for the inspection.  In the past these fees can reach the equivalent of tens of thousands of dollars per inspection.  Travel costs of the inspectors must also be covered by the inspectee.

Transparency:

The inspection conduct, outcome and follow up will be made public!

Read it for yourself:

https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129243.pdf

Comment:

This guideline formalizes the system that is in place in several countries already, most particularly the UK.  As the inspecting agency stands to collect significant fees there are clear monetary incentives in addition to public health protection motives.  It is likely that many if not most of the member states, particularly the bigger and more influential ones will gear up and do many more inspections than they do now.  The companies subject to inspection must be ready to respond to multiple inspections (hopefully not more than one at a time) from governments and, of course, vendors, clients and partners.  Infractions will be publicized and may thus trigger further inspections and possibly lawsuits in certain jurisdictions. How this will play out remains to be seen since the EMA is inviting public input on this guideline.