As everyone who deals with the EU and the UK in drug safety knows, the EMA issued a new set of Good PV Guidelines to replace (largely) Volume 9A. These are more than “guidelines” in the US sense where guidelines represent FDAs current thoughts on the matters addressed but are not binding. In the EU, these guidelines are binding.
The Summary of PV Systems is a document that is prepared before an MHRA PV inspection of a sponsor, vendor, MAH etc. It is a long and detailed document sent electronically (CD, DVD etc.) some six or so weeks before the inspection describing the PV/drug safety system in place at that company. This is quite different from the way FDA handles inspections where no upfront information is requested or required from the company.
With the PV Guidelines a new document the Pharmacovigilance Systems Master File (PSMF) has been created which covers most of what the SPS and DDPS cover. One might have thought that these two older reports would no longer be needed now that a master document exists that must be up to date and immediately available to the EMA and member states.
Yet this is not the case in the UK. The SPS remains in place and is still required before an MHRA inspection even though the PSMF is also used. It is necessary to be familiar with the for any company that has an MA in the UK.
But there is another, perhaps even more important reason to go over this document. The SPS forces the writer to describe and detail the entire PV system in place in that company. This then serves as a type of “internal audit” of the company’s PV system. If everything is well in place as described in this document then the company will clearly have a very adequate PV system and should pass the MHRA inspection with flying colors. If some items are not in place, it can serve as a type of “gap analysis” which can be used to prepare a Corrective Action, Preventive Action (CAPA) plan.
This document should be prepared, if used as a tool for an internal “gap analysis” along with the Compliance Report which was summarized in a previous Bart’s Corner posting. Together these two documents (or the relevant parts of these documents) will give you a fairly good idea of how well your drug safety/PV system compares to the requirements of the health authorities.
Here is a quick review of the components of the SPS.
Section 1: Company Information. Contact information for the company and, in particular for the Qualified Person for Pharmacovigilance (QPPV). Other names used by the company if they have product licenses (MAs) in other corporate names. This will not necessarily be obvious to the drug safety department and they will most likely have to do a little digging with legal and finance to come up with this information. Also required is the number of licenses (MAs) held in the UK and in the EU (centralized products).
Section 2. Company Structure & Operating Model. A brief description of the holding or parent company, world-wide subsidiaries, therapeutic areas and product portfolio – both investigational and marketed products, recent mergers and acquisitions and their impact on PV. This too may not be evident to the PV department and some corporate searching may be needed.
A succinct overview of to how PV is managed. Examples are given of the type of description wanted including this one:
Company X has one main PV site where the following are performed: data entry of ADR reports, preparation of PSURs, preparation of RMPs, signal generation, and answering all global safety related enquiries from regulator authorities. Expedited submissions to the EMA are managed by the global site. The global site monitors compliance with reporting timeframes for expedited and PSUR submissions.
Local subsidiaries are responsible for maintaining a local database/tracking sheet, forwarding individual ADRs to the main site for data entry, submitting domestic and non-domestic ADR reports to their respective authority on an expedited basis, and submitting PSURs to their respective authority within 60 days of data lockpoint.
Section 3. PV System. This is a summary of the PV activities done by the sites in the UK and the global PV department. It is meant to summarize how the company ensures that all regulatory requirements are met. Topics addressed should include:
- A summary of the PV activities done by other departments that interface with PV such as medical information, regulatory, quality etc.
- The process for spontaneous & clinical trial ADR management from receipt to data entry, review and expediting (if appropriate). Use flow diagrams.
- Details of compliance monitoring that is performed.
- Management and monitoring of clinical trial drug safety including data reconciliation.
- The process for PSUR preparation & submission.
- The QPPV and functions.
- Processes for signal generation, trend analysis and label changes.
- Risk Management Plans.
They want to understand PV at the company: who, what, when, where, how and why.
Section 4. Computer Systems used for PV. The present situation is described for all PV systems both global and local. There should be details of the computer systems/databases for all AEs (spontaneous, trial, solicited etc.). Detail should include:
- Commercial vs customized in-house (or “bespoke” the charming UK word for custom built)
- Validation status and where the documents are located
- Version details
- Details of the groups who maintain & support the systems
- Databases used to track and capture ADR reports including medical information and enquiry systems. Use diagrams if appropriate.
- Historical situation: a summary of the legacy databases used to collect, collate and evaluate information about ADRs over the last 5 years.
This information too is not necessarily immediately available to the drug safety group and will require some hunting. The legacy information going back 5 years may be hard to find even in the IT department!
Section 5. Quality Management System. This includes:
- Does the company intend to maintain the PV system (not just computers but the whole system) in its current state for the next 6 months? If not, what is planned.
- Who is responsible for conducting audits of the company’s PV system? How long are the audits kept and where are they?
The messages here are that the company has to have a quality management system and has to do or have done audits of the PV system(s).
Section 6. Training Records. Describe the training record system and where the records are kept. Also include CVs and job descriptions.
Section 7. Archiving. Describe the archiving activities for PV documents. If out-sourced, give information.
- Organization charts with names & titles for the PV department(s) locally and globally and for the Medical Information department. If out-sourced the information on this.
- Up to date CV & job description of the QPPV.
- A list of all MAs with active ingredients noted, trade names, whether marketed or not, method of approval (national, central, mutual recognition).
- Reference member state in the EU.
- Black triangle status if any.
- The 5 products that generated the greatest number of ADR reports last year
- A list of all ongoing phase I, II and III company sponsored clinical trials with at least one site in the EU.
- A global list of all ongoing post-authorization clinical studies (interventional and non-interventional).
- The SOP on SOPs.
- A list of all the global, regional and local PV procedural documents (e.g. policies, SOPs, work instructions).
- A list of all procedural documents that relate to PV used by other departments (e.g. Medical Information, Quality, Regulatory).
- Compliance with expedited reporting of spontaneous reports including a breakdown per month of total number of ADRs reports (serious & non-serious) received by the company globally and locally, total number of ADR reports submitted as expedited reports, total number of late reports, number of late reports as a percentage of the total number of expedited reports submitted.
- Compliance with all PSURs due 60 days after data lock point for the last two years by product, data lock point and date submitted.
- Third party agreements (e.g. co-licensing, co-marketing, distribution, in or out licensing) and other service providers such as CROs doing PV or medical information. Provide a list of all agreements with these 3rd parties locally and globally for marketed and investigational products. Details of all PV activities that are out-sourced
- Details of any products that have been withdrawn anywhere in the world in the last 5 years due to safety reasons with date of withdrawal, country, and the nature of the safety issue.
- Details of all urgent safety restrictions (that is, label changes to restrict use, dose, addition of warnings etc.).
- Copies of all procedural documents relating to clinical trial & spontaneous case processing, follow up of individual cases, reporting of expedited reports to the health agencies, monitoring of compliance for 7 and 15 day reports, PSUR preparation and submission, signal detection and trend analysis, enquiry handling.
This document requires an enormous amount of work to compile, particularly if the company is a medium to large global pharma. Much of this data is siloed and hard to find. When this document has to be prepared in 4 or 5 weeks for an upcoming inspection, it can be a very painful “crisis” situation.
So several lessons can be drawn:
- Any company that does trials or markets products in the UK (or anywhere in the EU) and elsewhere including the US, will have to supply some or all of these details to inspectors and should have this document ready. It should be in a fairly up to date state requiring only an update since its last preparation or revision.
In the EU there is usually a month or so given to prepare this information and load it onto electronic media to send to the agency. It may be in this form for the UK, in a similar form (though not necessarily all in English) for other EU member state agencies. In the US, although a formal mass of information like this is not required to be submitted, most everything in this document is fair game for the FDA inspector.
For companies not in the EU directly, their partners in the EU may ask for this information if they are being inspected. And they may not give you much time to gather it.
- For companies that have no EU exposure at all (even indirectly) it is still worth preparing these documents (the SPS and Compliance Report) as an exercise in internal auditing. This is a checklist of what is required for a good PV department.
- It is also worth noting that the EU (and FDA) requirements have changed and have gotten somewhat more complex since the original preparation of this document. Note that it does not address social media and the internet nor does it emphasize out-sourcing which has grown enormously in the past few years. So keep in mind that these documents will surely be more complex and detailed when they are revised.
The bottom line conclusion is that the regulatory agencies are paying more and more attention to the details of PV. Not just checking MedWatch/CIOMS I forms and PSURs but also the inner workings of the system, the quality of the data and whether “bad things” are being picked up in signaling. Failure in these areas will lead to shame, public censure, penalties and even loss of MAs.