The inspector calls

pharmafile | September 28, 2005 | Feature | Research and Development |   

I have become a pharmacovigilance bore within my company, a prophet of doom. It is worse than that, because for three months it became the main topic of conversation at home while we awaited and participated in a statutory pharmacovigilance inspection.

The problem is that if you were asked to identify those activities inside your pharmaceutical company that generated income, and even better, profit, you would be hard-pressed to put product safety on your list. In fact, at first glance, it is a parasitic sap on resources, slurping up money, and responding by telling you what you can't do. But despite the inherent risk-taking nature of sales and marketing departments in the industry, there is a sound logic. While the man in the street might be happy with the potential hazards of riding a motorbike, or playing a contact sport, when it comes to taking medicines, no level of personal risk seems to be acceptable. Consumers are risk-averse when it comes to using medicines.

Until recently, a number of companies had volunteered for specimen pharmacovigilance inspections which were presumably exercises by both the MHRA and the companies in getting a feel for what would happen when the system of statutory inspections went live.

Feedback from these voluntary exercises has been offered at several conferences, but one thing that seemed relevant was that the process seemed to involve large multinational companies with significant amounts of safety data from developmental and marketed drugs, and the personnel and resource to go with it. Perhaps the small companies were burying their heads in the sand, arguing 'we will deal with the problem when and if it occurs'. The statutory scheme has been in place since 2003, and by the middle of this year, over thirty inspections have been conducted that have included big and small companies. All UK marketing authorisation holders will be subject to inspection.

For Forest Laboratories, the call came in January of this year, when communications came from the MHRA telling us that the company would be inspected, whether we liked it or not. As a small organisation dealing with a seemingly minimal volume of adverse reaction information, it was difficult to understand what would be inspected.

Like other small companies, not involved in the development of new chemical entities, we are mainly focused on sales and marketing of existing products, and with a portfolio of products we think we know well, pharmacovigilance was seen as a minor activity. Examining the experiences of bigger companies seemed to be of limited value, as there simply were not the same resources available. All activities, of necessity fell within the remit of the existing personnel, and there appeared to be little point investing huge sums in computerised systems. As a result of attending MHRA organised meeting, and training, we started to implement systems consistent with the guidelines of Volume 9. In the event the inspection process helped us focus very sharply on the nature of our business, and our public health responsibilities.

What to expect if you have never had an inspection

With only about 30 inspections in the UK done on the date we were audited, the chances are you might not yet have received the call. If you are a manufacturing operation, the medicines inspectors are familiar figures but small marketing orientated companies may have little experience of being audited. The bottom line is that if you hold a marketing authorisation, then pharmacovigilance is part of your duty, and you can expect to be inspected.

The starting point for the inspection is the summary of pharmacovigilance systems (SPS). This is a short synoptic document of 25 pages or less, which give an overview of your company's pharmacovigilance systems. Fortunately, the MHRA supplied a template, and completing the document is fairly straightforward. The subsequent inspection is based on the systems that this document declares.

Central to the SPS is the Qualified Person for pharmacovigilance (QP). This is not the same as the QP who releases manufactured products (but in some circumstances could be the same). The QP for pharmacovigilance is a person defined in volume 9, who takes responsibility for a company's marketed products in the EEA. The buck stops at the QP, and consequently it is neither a sinecure nor token role. Ideally it should be a medical graduate working for the company, but can be a nominated contractor, or can be non-medical, as long as there is access to a suitably qualified and experienced medical opinion.

The QP function is part of the audit and he or she can expect to be quizzed about what they do and how they do it. The QP seemingly has theoretically unimaginable powers within apharmaceutical company, and hypothetically can overrule chief executives in matters of safety. Needless to say there should be evidence that the QP has received training in pharmacovigilance.

The SPS lists all the marketing authorisations that a company has, other organisations that the company has a relationship with that might have something to do with drug safety, and all relevant standard operating procedures. It is just possible that your company does not have an SPS yet. It is never too early to start, as one only starts to learn about missing bits of the system for pharmacovigilance when filling in the spaces. Relationships with other pharmaceutical companies are integral to the SPS, and if you are part of a multinational company, routes of communication may need to be shown, and the paths for flow of information must be documented.

Marketing authorisation holders also have to take responsibility for their export markets especially within the EU, and there should be evidence of how relationships work. It is interesting that the UK seems to have taken the lead in pharmacovigilance inspections, although it is enshrined within European law. Other EU territories seem somewhat lackadaisical in this respect, and it may be that except for the US, other countries may not treat requests for information, relevant to an inspection, with the sense of urgency that the inspectors cast over companies about to be audited. The SPS is an incredibly useful document, as it sets out in one convenient place what a pharmaceutical company thinks it should be doing in terms of safety information, and helps focus the mind.

Standard operating procedures (SOPs) form a very important part of carrying out drug safety duties, and surviving an inspection. Although not enshrined in legislation, it seems almost criminally reckless not to have SOPs for handling adverse events from marketed medicines, investigational products, PSUR production and customer complaints. Naturally these should all be volume 9 compliant, and many hours can be spent with the guidelines trying to read between the lines to interpret just how much you are intended to do.

One lasting impression that I have taken out of our inspection is that the more you can reduce the working day to a series of SOPs the less explanation has to be offered about how pharmacovigilance activities are conducted. If only all of life had guidelines that would keep you on the straight and narrow – an SOP means never having to say you're sorry (except to quality assurance officers).

What to do before the inspection – meeting, meetings, meetings

The inspectors send an inspection plan before arrival, and this may detail individuals or functions that they want to interview. It is the usual culprits including medical information, the authors of PSURs, medical advisors and so on. One interesting aspect of the interviewing profile is that a sales representative (of the company's) will be invited for interview to check for their compliance with pharmacovigilance legislation.

Within each company there is a cadre of individuals (possibly even a team), who are well used to being on the receiving end of audits (eg, manufacturing inspections or clinical research audit) but there are many who might never normally be audited. However, for a pharmacovigilance inspection, individuals who have never been subjected to audit may suddenly find themselves in the limelight, and even with prior warning, this can come as a bit of a shock.

The pharmacovigilance inspectors are simultaneously professional, assiduous and relentless. Thus preparation will pay dividends. Apart from training those involved in the pharmacovigilance information trail, which should all have been performed and documented, there is a good case for taking advice. For those organisations that cannot afford the luxury of practice audits, taking third party advice on what to expect is money well spent. We took advice from a third party pharmacovigilance service provider, and it was worth every moment spent on the preparation. That is not to say that we were trying to obfuscate the audit process, but we maximised the opportunity to make sure we were as compliant with volume 9 as possible before the date.

The process involves the inspection of many relevant (and some seemingly less relevant) documents, and times spent reviewing documents, making sure they actually exist, are current, and non-contradictory is never wasted. The inspectors have the right to ask for any document and it is also wise to check that documents thought to exist actually do, and their location is known.

On the day

The dates for the inspection are pre-notified and agreed. We were typical of a small company, in that about three days were set aside for inspection of our systems. Companies should make availability of relevant personnel non-negotiable during these periods. The key individual is the QP for pharmacovigilance (and their deputy). As someone not used to the auditing process, I found it critically useful to have an experienced member of our quality assurance staff present not only to advise me about the general conduct of audits, but also to act as scribe to the meeting and observer so that training feedback could be given to me.

The inspection kicks off with an opening meeting during which the scope of the inspection is discussed, and the methods the MHRA use are explained. More inspectors are being appointed, and it would seem reasonable to expect that an inspection (as in our case) will involve a senior officer of the department and someone undergoing or completing their training.

We were told that we were undergoing a systems inspection but with a local viewpoint. We were asked about links with other subsidiaries/parent companies, and how pharmacovigilance systems interlinked.

Many of the topics discussed were self-evident, but questions were asked relating to areas where companies might not give excessive attention (alternatively, our interpretation of volume 9 was at fault, so it was our own stupid fault, but here they are anyway).

The inspectors asked about methods for documenting allegations or cases of inefficacy of products. I had naively thought that this was not a clear-cut safety issue, as efficacy is a given within a marketing authorisation. The inspectors were also not only concerned about warnings and precautions relating to pregnancy, but wanted to see systems relating to how reports of product usage during pregnancy that were against SmPC advice were handled, and what efforts were made to follow up and document the outcomes of pregnancy. One interesting problem raised was the conundrum that if a company fielded an enquiry as to whether a particular product was safe (for a particular patient) during pregnancy, did that signal that there had been use (even possibly inadvertent/contraindicated)? Thus a very high level of suspicion is necessary and the existence of systems is advised to cope with such scenarios.

At the end of the day

The final stages of an inspection include a closing meeting, at which the audit findings will be discussed. There should be no surprises at this stage, and the objective is to create a plan for action. Findings are classified, typically as critical, major and other (includes minor infractions). Critical and major defects in a pharmacovigilance system can invoke several consequences such as re-inspection or a warning letter.

To my mind the real issue is that a major finding can result in the suspension of a marketing authorisation or even criminal prosecution, and thus it seems self-evident that the role of the QP for pharmacovigilance is critical to a company. Not being able to demonstrate that a product is safe, or demonstrate that there are systems in place which confirm this (as far as is possible) is a sure route to commercial disaster.

Fortunately, while there is plenty of scope for being awarded a major defect (eg, failure to submit a PSUR on time), critical findings (eg, complete failure to document and report serious adverse events and follow them up) require a degree of meditated recklessness that brings its own reward. I have to say that the inspectors use a good helping of common sense at this point. The regulations are uniformly applied across the industry, irrespective of company size or product portfolio, but the nature of a company is taken into account when classifying findings, and one company's critical may become another company's major.

Recommendations will be made during the closeout meeting for improving systems, and a final report issued in writing. The company typically has 30 days to respond to the findings with their plan of action. By the time our inspection was completed, I realised that the agency requires MA holders to maintain standards of public health in relation to marketed medicines by having a demonstrably resilient system in place.

It is difficult to argue a case against the high standards required, and one only has to consider how companies react when bad news about drug safety breaks. Those that have all the facts in place, and can show that they have carefully considered each element of information will be best-placed to survive the inevitable onslaught.

Things you can do to make an audit work well:

1) Calmly, concisely and accurately respond to all queries from the agency before, during and after the inspection.

2) Do not even dream of telling anything but the complete truth – your lies will find you out and haunt you forever. The truth, however stupid, will be accepted, and the process will move on.

3) When assembling information before an audit, do not take no for an answer to a reasonable request for information within your company. A missing piece of the jigsaw will create a hunt (by the inspectors) for pieces you did not even know you had lost.

4) For those not experienced in audit, remember that anger and outrage have no part to play during the process – save it for later.

5) A plate of chocolate biscuits works wonders in times of stress – even for the inspectors.

6) If in doubt, ask for help from someone with experience.

7) Get trained to an adequate level for the job you have to perform.