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CHAPTER

10

The EU Qualified Person for Pharmacovigilance

For companies with products registered in the European Union, the Directive 2010/84/EU requires that there be a “Qualified Person for Pharmacovigilance” (QPPV). This is a critical role and function within the company. The concept of a QPPV is most interesting: a named individual (and backup) takes corporate and personal responsibility for the functioning of drug safety and pharmacovigilance (PV) for every company that has a Marketing Authorization (MA) in the EU.

Introduction

There is no direct counterpart in the US, Canada, or many other countries. However, as of mid-2018, more than 70 jurisdictions, some within the EU, had adopted the role of a qualified or responsible person for pharmacovigilance. The EU QPPV functions at the EU level. Others operate at the country level. In the EU, all local QPPVs must report to the EU QPPV. The position and requirements are defined in Directive 2010/84/EU and Good Pharmacovigilance Practice (GVP) Module I. The EU QPPV must be designated (and, thus, a quality PV system must be in place) at the time of submission of an MAA. Note that the QPPV is not responsible for manufacturing issues; there is a separate QP for manufacturing.

Directive 2010/84/EU and GVP Module I note the following:

Each company must submit a summary of the applicant’s pharmacovigilance system master file (PSMF) which shall include the following elements:

Proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance;

The Member State(s) in which the qualified person resides and carries out his/her tasks; and

The contact details of the qualified person.

The MAH should have permanently and continuously at his disposal a QPPV residing and operating in the EU or EEA with 24/7 availability.

One QPPV per PV system in a company is required, but one single QPPV may have oversight of several PV systems. There could be a qualified deputy also residing in the EEA. The name and contact information must be provided to EMA/member states.

Some member states require a named person/national QPPV, too. This person may or may not be the same as the EU QPPV.

The QPPV should be appropriately qualified, with documented experience in all aspects of pharmacovigilance. If the QPPV is not medically qualified (i.e., an MD), access to a medically qualified person should be available 24/7.

The EU QPPV has multiple responsibilities:

Establishing and maintaining/managing the MAH’s pharmacovigilance system;

Ensuring that a PSMF is in place and up to date (some jurisdictions also have local requirements for the equivalent of a local or regional PSMF, which must be consistent with the EU PSMF);

Ensuring that all ARs (including literature searches) are collected, collated, and accessible at least at one point within the EU;

Preparing ICSRs and synthesis reports (PSURs/PBRERs, RMPs, benefit–risk assessment, etc.) and company-sponsored post-authorization safety/efficacy studies (PASS & PAES);

Evaluating continuously the overall pharmacovigilance system, including in particular, during the post-authorization period;

Having oversight of signal detection and risk management, including PASS/PAES and risk minimization measures (routine and non-routine measures);

Being aware of any new information about benefit–risk assessments for all registered drugs;

Ensuring that any request from the health agency is answered fully and promptly.

Note: GVP Module I specifies “The QPPV may delegate specific tasks, under supervision, to appropriately qualified and trained individuals, for example, acting as safety experts for certain products, provided that the QPPV maintains system oversight and overview of the safety profiles of all products. Such delegation should be documented.”

The QPPV should have oversight of the PV system, including and, therefore, “sufficient authority to influence the performance of the quality system and the pharmacovigilance activities and to promote, maintain and improve compliance,” i.e., authority over:

The organization of the Drug Safety department, processes, tools, and performance/compliance;

The needed measures for signal detection and risk management activities, including benefit–risk assessments;

The decision to take for variations, urgent safety restrictions, and communication to patients and healthcare professionals;

Partnerships.

The MAH, as well, has responsibilities to the following:

Support the QPPV and ensure appropriate processes, resources, communication mechanisms, and access to all sources of relevant information in place for the QPPV.

Ensure full documentation of all procedures and activities of the QPPV.

Implement mechanisms for the QPPV to be kept informed of emerging safety and risk–benefit issues including clinical trials and contractual agreements.

Ensure the QPPV has the authority to implement changes to the MAH’s PV system to maintain compliance.

Ensure the QPPV has input into Risk Management Plans and the preparation of regulatory action in response to emerging safety concerns.

Ensure the presence of back-up procedures (e.g., in case of non-availability of personnel, AE database failure, failure of other hardware or software with impact on electronic reporting and data analysis).

Note: The MAH may transfer/outsource PV activities to another person or organization. A detailed and clear written contract must be in place documenting such transfers and outsourcing. The contracted person or organization should implement QA/QC and allow auditing by the MAH. It is possible to outsource the EU QPPV function but the ultimate responsibility for all PV obligations always resides with the MAH.

Practicalities

The QPPV is a responsible and very challenging position. The person must be involved and have real influence in the safety system of the company. He or she must be knowledgeable and able to discuss, at least at a high level, particularly during a governmental inspection, the PV system in place globally, including standard operating procedures (SOPs); working documents; quality assessment/quality control (QA/QC); databases in use for drug safety, privacy, and security issues; all products marketed in the EEA and where they are sold outside of Europe; global licensing; distribution; co-marketing; agency commitments; compliance status and key performance indicators (metrics); signal identification; analysis and workup mechanisms in place; specific signals and safety issues pending globally; the risk management system and business continuity/crisis management plans in place; post-marketing trials under way, and new indication trials for marketed drugs; safety training; and issues with health authorities (HAs).

He or she must review and sign Periodic Safety Update Report (PSURs/PBRERs) and other PV documents submitted to HAs. To succeed in this position, communication across the organization is critical! Good communication skills are needed to link the QPPV with management, drug safety, the rest of the organization, the European Medicines Agency (EMA) and member state HAs, deputy and national QPPVs, and so forth. There must be a formal job description, and many companies also have a formal, written contract with the QPPV. The person, often a medical doctor (MD), should have senior management’s ear.

Many companies, particularly small companies and generic houses, will outsource the QPPV to a Clinical Research Organization (CRO) or consultant. Although this is legal and feasible, the company and the QPPV must take the job seriously. Some QPPVs at CROs may be performing this function for 15 or more clients! Whether this is practical and wise is debatable. All delegation, both within the company and outsourced, must be rigidly and carefully documented. The specific delegated functions must be written down and all parties must sign off. Note that all companies with MAs must have a QPPV. This includes generics, over-the-counter products, and so forth. No exceptions.

The EU QPPV is not required to be part of the PV team. He/she can have a non-PV position with oversight of the PV organization and performance. In such circumstances, it is best to have the EU QPPV at least at the same hierarchy level of the head global PV.

Note: The CMO or the head global PV can also be the EU QPPV.

Frequent QPPV Inspection Findings by the EMA

No QPPV or interim measures (change of QPPV, no backup procedures for absence, etc.);

More than one QPPV per PV System or unclear organization;

Not resident or operating in the EEA;

No job description;

Failure to notify Competent Authorities of QPPV details;

Lack of 24/7 coverage;

Inadequate oversight of the pharmacovigilance system (ICSRs, PSURs/PBRERs, RMPs, PASS, PAES, safety profile of products, audits and inspections, QA & QC, database(s));

Lack of training or experience;

No or inadequate training of drug safety staff;

Roles and responsibilities not formally defined (especially important if parts of role are delegated); and

Inadequate access to medically qualified personnel.

Penalties can be severe and can include fines of up to 5% of the MAH’s EU sales, with further penalties if the problems are not promptly corrected. Civil and criminal penalties for the MAH and the QPPV are possible.

Frequently Asked Questions

Q: Why would anyone want to do this job?

A: Good question, and I’m not sure I have a good answer. Perhaps a combination of responsibility, power, the desire to have a meaningful job that makes an impact, a good salary (though some say they could never be paid enough to do this job), visibility, and the like. For people who like and accept being empowered (and who really are empowered), and who like playing a fascinating role with interactions in all areas and in all levels of the company and with health authorities, this can be a marvelous job. Until something bad happens. Then the stress level rises and it truly becomes a 24/7 job, particularly in the age of the internet, with instant communications and media knowledge of problems. Word of problems and misbehavior travels quickly.

Q: Why would anyone not want to do this job?

A: Good question also! As specified before, such responsibilities could become a 24/7 job with real and stressful roles and responsibilities, particularly if the QPPV does not have the full support of the company. As icing on the cake, two legal consequences must be emphasized: First, even after the EU QPPV transitions to new responsibilities or a different organization, he or she will still be responsible for a safety issue that occurred during his or her tenure as EU QPPV. Any decision/measure, taken (or not taken) during the EU QPPV tenure can be challenged at any time and that individual will be committed “forever”. In other words, one can be prosecuted ten, twenty or more years after leaving the EU QPPV post. Second, as an EU QPPV and in case of a major safety issue, you can face criminal charges. In such a situation, it would be too late if you did not, before the issue arises or at the start of your QPPV tenure, secure a commitment of well-financed legal support from the MAH. Many EU QPPVs have tried to include such a protective statement in their contract, but most often, the company is reluctant to accept ... Have fun!

Q: What do I do if I am QPPV but not empowered and cannot get management to act on the appropriate needs, resources, and safety issues?

A: Quit. First, do your utmost to convince management that this is serious business and certain things must be done. You may need to get allies to make the case (e.g., the regulatory and legal colleagues in the company or an outside auditor). Point out the key sections from the EU Regulations. Document fully in writing everything you have done and everyone notified (and when), all items, actions, resources, and so forth, that you have requested, plus the responses. Always do and say the right thing and document it. Give it a reasonable attempt and length of time to get actions and corrections. It helps to have a forceful type-A personality. If all fails, update your CV and get a new job. You’ll sleep better and your gastric acid and blood pressure will return to normal.