PV Inspection Update

Sep 20, 2016
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

As always, a hot topic that pharmaceutical companies are always concerned about involves pharmacovigilance inspections by health authorities (HAs). Detailed information about inspections of other companies is often hard to find as the information is usually privileged and unavailable or, if it is available, it must be obtained through Freedom of Information requests. It’s rarely posted on HA websites.

One exception to this is the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA).  They are fairly forthcoming about inspections on their Good PV Practice website.

They have an excellent overview with further details on types of inspections, how to prepare for an inspection, how the inspection is done, how the findings are graded and what you must do to respond. The link to “Responding to Inspection Findings” is an excellent Powerpoint presentation which is applicable to any PV inspection, not just those from the MHRA. The Good PV Practice site also includes the fees which are charged for PV inspections and which are quite high. The basic rate is £2635 (~$3500) per day with further fees for additional inspectors, pre-inspection preparation, travel, report preparation and issue resolution. Inspections can thus run tens of thousands of dollars!

One piece of news that was just published on this website notes that the “Compliance Report” that was more or less obligatory for pharmaceutical companies to prepare and submit to the MHRA has been dropped. This report, which was very detailed and complicated to prepare, was used by the MHRA to decide which companies with MAs should be inspected as a higher priority. This information was used to make risk-based assessments looking for companies where PV problems might be expected to occur and thus be a high priority target for an inspection. The MHRA now feels it can obtain this information from other sources though they retain the right to request this information from companies if they feel they need it.

Another section of the MHRA website on PV inspections is the PV Inspection Metrics Report. This is a section that describes the activities of the Inspectorate Unit of the MHRA listing their inspections and, importantly, their findings. The latest report covers April 2014 to March 2015.

Here are some of the key findings:

MHRA Inspections

Twenty-five innovative pharmas were inspected as well as 20 generic companies totaling 45.  Fifteen were of companies not previously inspected and 21 were follow-up inspections of which ten were triggered by critical findings in earlier inspections.  This works out to roughly one inspection a week.

Findings

There were 27 critical findings, 169 major and 155 minor findings.

Innovative company findings had, on average, about 0.5 critical, 3 major and 4 minor findings.  Generic houses had, again on average, nearly 1 critical, nearly 4 major and 2.5 minor findings.  Thus, except for minor findings, there were more observations found in generic houses than innovative companies.

Critical Findings

The critical findings run roughly as follows:

  • Maintenance of Reference Safety Informatio 29%
  • Signal Management 26%
  • MAH Oversight 11%
  • Quality System 11%
  • Risk Management System 7%
  • PSUR Production, ICSR Management, Submission of false and misleading information <4% each

It is interesting to compare this to findings in earlier years. In the 2011/2012 report for critical findings, the category of Reference Safety Information was still the largest at 37% with Signal Generation at 11%. There was no category noted of risk management.

In the 2009/2010 report again Reference Safety Information was the most frequent finding at 22% with Signal Generation at 14%. This was the first year the Inspectorate started reporting findings publicly.

Over time, the average number of critical findings has varied from 0.7 to 0.1 per inspection.  Interestingly the higher values were found in the earlier periods in 2006 and 2007 dropping down to about 0.1-0.2 from 2009 through early 2012 and then rising again from 2012 to in 2014/2015. The latest totals are nearly as high as the worst case in 2006.  It is not clear why this trend has reversed.

Major Findings

In 2014/2015 the major findings were much more scattered with 19 topic areas noted. The largest was Signal Management and ICSR Management each at 15% followed by Quality Systems at 14% and Reference Safety Information at 11%.

In 2009/2010 the major findings were related primarily to spontaneous case processing (20%), PSUR production (17%), QPPV (9%) and signal generation (9%). Thus we see that companies largely corrected their “mechanical” issues on case processing and PSUR production.

The number of major findings associated with the PV Master File (PSMF) decreased from the earlier inspection period by 45%. The combined number of critical and major findings from the previous period also dropped though, as noted above, the critical findings increased.

MHRA Conclusions

The MHRA notes the rise in critical findings and discusses briefly the two key areas of findings.

Reference Safety Information. The primary issues here were failures and delays in the submission of safety variations to update safety sections of SmPCs and PILs.

The signal management area was noted to include problems in failure to conduct signal detection activities, failure to incorporate all available data into signal detection activities, significant delays in completing signal evaluation and failure to address major findings from previous inspections (persistent non-compliance).  Some of these failures to complete signal work-ups resulted in delays in updating SmPCs and PILs.  That is, they had a “measurable impact” as the MHRA calls it.

Comments

So what are we to make of this?

Firstly, the MHRA continues to perform inspections at the rate of roughly one a week.  Key targets are never-previously-inspected companies and re-inspections where previous critical findings were noted.  So if your company has a UK/EU MA and has never been inspected or has a “bad track record” from one or more previous inspections, you should be ready for another inspection.  Unlike the US FDA, most EU inspections are announced in advance giving some preparation time (usually weeks to a couple of months at most).  Unannounced inspections in the EU though are indeed sometimes performed.

Secondly, if there are any findings from previous inspections or if there are any open CAPAs (or non-existent CAPAs where there should be CAPAs), then the company should immediately rectify the problems.  As always, findings and actions should be carefully documented.  If any promises or commitments were made to the MHRA (or any HA for that matter), you should be meticulous in ensuring that they are completed in a correct and timely manner.

Thirdly, it is fairly clear now that the “mechanical” aspects of PV (data collection, processing of SAEs and expedited reports, preparation of PSURs and PSMFs) seem to have been largely mastered by the pharmaceutical companies.  There are fewer findings in these processing areas.  Rather now, the bigger problems are in risk management and in signaling.  One can argue, in my view correctly, that the entire goal of PV is to find the safety issues with products and update the labeling (reference safety information) as rapidly and as scientifically as possible.  That is, the goal here is not collecting mounds of SAEs and AEs but rather figuring out what really matters and what doesn’t to the treatment and health of patients.  Prescribers and patients must be made aware of new safety information as soon as possible.

This clearly is harder to do than merely collecting data.  It requires formal processes within companies that receive, analyze, investigate and report on safety data in a continuous manner.  Clear mechanisms in companies must exist to rapidly investigate new safety issues, analyze and escalate them to empowered senior management for timely safety decisions.  This means one or more safety committees in the company which slice, dice and aggregate data and then pass the key findings up to the senior committee for a decision (e.g. label change, product recall or withdrawal, etc.).  All these mechanisms must be documented in SOPs and minutes kept of meetings and reviews.  A “signal list” should be kept, reviewed and updated as necessary.

Lastly, labeling/reference safety information continues to be a problem area.  It seems that companies sometimes delay or do not have adequate mechanisms to ensure that the RSI is kept up to date.  As these are really the key documents that prescribers and patients have, they must be kept up to date.

 

All of these issues have become much more complicated in the last decade as more and more operational tasks are being out-sourced to CROs, business partners and other vendors.  Similarly many small pharma companies rely on larger partners or CROs to do signaling and risk management.  There is nothing wrong with this at all, but this does not diminish the legal, regulatory and ethical obligations of the MA holder to be sure that patients taking their product are as fully informed as possible and that risks are mitigated.

So, if you haven’t been inspected recently (or ever) be ready.  If there are problems, fix them.  If you don’t have adequate RSI, signaling and risk management systems, put them in place.

 

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