On February 5, 2013, the MHRA put out an update bulletin on its “Compliance Report”. The Compliance Report from the MHRA began around 2009 when they moved to a risk based pharmacovigilance (PV) inspection process. The MHRA was one of the first of the drug agencies to move to this concept. Many other agencies, including the FDA, have now also moved to risk based inspections.
The Compliance Report is a document that UK Marketing Authorisation Holders (MAHs) are “encouraged” to complete and file every two years with the MHRA. The first one was requested in 2011. The next one, just announced by this MHRA bulletin, will be released in November, 2013 using a revised format and contents. It is filled out and submitted electronically on an Excel spreadsheet. It will cover the 2013.
First, a little background on risk based inspections. The MHRA uses information submitted by the MAH as well as the MAH’s previous inspection history, organization change and the “results of intelligence” (MHRA’s term) to determine the amount of “control” an organization has. This is a numerical score. Then a numerical risk score is calculated from the Compliance Report and other information. The risk score is subtracted from the control score and the final number is called the “risk assessment score”.
The MHRA ranks these scores and inspections will be prioritized and carried out based on these scores: the worst scoring companies will get inspected more quickly.
The MHRA notes that the submission of the Compliance Report by MAHs is not mandatory. But then they drop the bomb! “However, MAHs should be aware that failure to submit a completed report will be assessed as a high-risk answer to all questions.” So if you don’t submit the report you get the worst score and will be high on the audit list for the year!
When an MAH gets selected for an inspection, they must complete another MHRA document known as the “Summary of Pharmacovigilance Systems”. This is a very detailed and tough document created by folks who understand how pharma companies work and “where the skeletons are buried”! We’ll discuss this document in a later posting.
The information on Risk Based Inspections is available on the MHRA website at https://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodPharmacovigilancePractice/Riskbasedinspections/index.htm
The actual 2011 Compliance Report spreadsheet that MAHs fill in is available at: https://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con044102.xls
Now let’s look at the Compliance Report using the 2011 edition. It will likely be updated for 2013 as the MHRA indicates probably touching more on the internet and social media – but we shall see in November.
Points are given for each section. The higher (worse) the point score, the more risk .
Section 1 is demography and asks about the location of the MAH. They want, in particular, a principal contact person.
Sections 2 and 3 are a listing of the MAH’s marketed products in the UK. For small companies this is easy to fill in but for large companies, it may not be that easy for the safety department to fill in completely. Sometimes many different formulations, strengths and preparations are marketed unbeknownst to the drug safety group. The safety or regulatory people filling out the Compliance Form should be sure to include all products marketed (actually this probably means approved products even if not actually sold or marketed). The MAH name and number are required for each. The MHRA notes: “This licence information is present within the MHRA, but can be populated by the MAH to give a complete risk assessment value.” One might wonder whether this is a “test” to be sure the MAH’s record keeping is complete!
Section 4 requires UK Market Authorisations for central, mutual recognition/decentralized and national approval as well as the different types of UK authorizations including Prescription Only (POM) and other (P and GSL) classifications. In particular, the black triangle products (newly licensed, new combination of active substances, a new route of administration or drug delivery, a significant new indication or new patient population) are to be listed. Based on this, a risk number up to 25 points is assigned based on the number of black triangle and POM products.
The next section covers changes in UK MAs (approvals). They ask whether there has been an increase in MAs in the last year. If the number increased by 40% or more the MAH gets 10 points, if over 30% five points and if over 20% two points.
Section 4 asks for the number of pharmacovigilance activities done in the last year and includes the following. Each category can score up to 5 points:
- QPPV – 5 points if < 1 QPPV
- Medical Information (MI) (UK only) – number of UK origin queries – 5 points if over 20 activities per full time employee (FTE) per day, 3 if under one per day and 5 points if there are activities but no FTEs!
- Quality Complaint Handling (UK only) – number of UK origin complaints – same points as MI above
- Case Processing (worldwide) – number of initial spontaneous cases – 5 points if 8 activities per day per FTE, 3 points if under 0.1 per day. If no FTEs 5 points.
- PSUR Production (Worldwide) – number of PSURs, bridging and addenda reports – 5 points if 1 per month per FTE, 3 if under 1 per quarter. If no FTEs then 5 points.
- Signal Detection (Worldwide) – number of potential signals or trends detected in house – Scoring similar to PSURs above
- Signal Evaluation (Worldwide) – number of signals with a formal evaluation performed including risk benefit analyses including requests from competent authorities – scoring similar to Signal Detection above
- Submission of Safety Variations for UK labeling – number submitted – Scoring 5 if over 2 per month per FTE, 3 if under 1 per year and if no FTE’s 5.
Section 5 covers compliance with expediting reporting and PSUR submission. There are four categories and timeliness of submissions must be calculated:
- Spontaneous cases from the UK
- Spontaneous cases from the rest of the EU
- Spontaneous cases from outside the EU
- Clinical trial cases
- PSURs
For each of these four categories 5 points if submissions are less than 92% on time, 3 points if less than 98% and no points if >98%.
Note: This is the first time that I’ve seen any regulatory agency actually give an acceptable on time score for expedited reporting: >98%!
Section covers staff turnover.
- QPPV: how many in the past 2 years and how many were contractors? Five points if more than 30%, 3 points if more than 10%, zero if 10% turnover.
- Medical Information (MI) (UK only) – number of UK origin queries – Five points if more than 30%, 3 points if more than 10%, zero if 10% turnover.
- Case Processing (worldwide) – number of initial spontaneous cases – Five points if more than 30%, 3 points if more than 10%, zero if 10% turnover.
- PSUR Production (Worldwide) – number of PSURs, bridging and addenda reports – Five points if more than 30%, 3 points if more than 10%, zero if 10% turnover.
- Signal Detection (Worldwide) – number of potential signals or trends detected in house – Five points if more than 30%, 3 points if more than 10%, zero if 10% turnover.
Section 7 covers contracts and agreements. The number of in-licensing, distribution and co-marketing/co-licensing agreements is required. Ten points if greater than half of the total number of licenses are in this category, 5 points if greater than ½ and otherwise zero.
Section 8 covers outsourcing of PV activities including: Medical Information, Quality Complaints, Literature Searching, Case Processing, Electronic Reporting, PSURs, Signal Detection, Signal Evaluation, Variation Submission and Database Maintenance and Support. Three points each if outsourced and not audited, 1 point if outsourced and audited, otherwise zero. Databasing is the exception with one point for outsourcing and zero for not outsourcing. The message here is that outsourcing is really not bad (only one risk point) but you really need to audit your vendors and outsourcers.
Section 9 is Risk Management Plans (RMPs) and asks for the number of EU/EMA RMPs and the number of RMPs which contain a requirement for additional non-routine PV activities or risk minimization measures. Ten points if more than one RMP with non-routine PV activities, 5 points if one such RMP.
Section 10 covers Quality Management Systems and asks whether procedures (SOPs) are in place, whether there is documented evidence of training, whether the activity has ever been audited and whether the outputs from activities are retained or not. The activities covered are same as in Section 8 above: Medical Information, Quality Complaints, Literature Searching, Case Processing, Electronic Reporting, PSURs, Signal Detection, Signal Evaluation, Variation Submission and Database Maintenance and Support. Three or 5 points for a no answer to any of the questions in each category. Maximum points possible from this section are 42.
Finally, section 11 covers Product Related Safety Issues and asks the following questions:
- How many products have been withdrawn for safety reasons anywhere in the world in the last year?
- How many products had urgent safety restrictions in the past year?
- How many products have been formally referred to the CHMP for safety reasons in the past year?
- How many safety variations were initiated by the company in the previous year.
Details on each are required and the risk scores for each question are 5 points if more than 1 three points if one.
The total number of points possible for the report is 241 and this is highest (worst) possible risk score a company can have.
Comments: This was designed by folks who clearly understand the strong and weak points of doing drug safety. It is complete and hits the key areas. In particular they ask questions about volume (cases processed per person); they prefer FTEs to consultants; they expect you to have complete and detailed records; they expect quality systems and audits and more. In a nutshell, they expect the MAH to be in full control of its drug safety systems and processes. In my experience the inspectors from the MHRA are experienced and use these sheets and the Summary of PV Systems to do thorough and detailed inspection.
So the message here is to be sure your company really is in control of drug safety and pharmacovigilance. Not every health agency in the world goes into such detail but almost all of them now (including FDA) are doing risk based inspections and analyses of companies.
Suggestion: Even if you are not marketing in the UK, fill out this report and see what your company’s score is! Use the spreadsheet at the URL above. If you get a bad score, think about making some changes.
