When good medicine goes bad

pharmafile | September 9, 2004 | Feature | |   

Those of you who have worked long enough in the pharma industry to collect your first payslip will have realised that it is one of the most regulated industries in the world. If this were the automobile industry marketing a new car, there would be so many warnings that a man with a red flag would walk in front of motorists.

What I want to discuss is not new, but it is something that will probably affect you, no matter what part of the industry you work in, and may help you understand the subtle changes that are developing.

In recent years, mainly as a result of a European document, lovingly referred to as volume 9, the rules about handling adverse events for marketed and pre-marketed drugs have been brought together and become more pervasive than you can imagine.

If you are in the business of marketing or selling licensed medicines, some of this will be a royal pain, but if you ignore the jargon it becomes apparent that what is really going on is a way of unifying what is done to protect the public not only from the industry, but from themselves. The current legislation and its interpretation is a brave, new attempt to improve those aspects of public health relating to unwanted and unexpected consequences of using medicines.

Avoiding public health disasters

It's useful to go back into history and remember the infamous episodes when the pharma industry was accused of putting profits before people. The big one was the thalidomide disaster of 1962.

By contemporary standards, the story is unthinkable. A British company licensed a medicine called thalidomide from a German company – the drug was a sedative positioned for prescribing to pregnant females who needed help sleeping.

I have seen the adverts in an old medical journal and the impression is that not only were pregnant females targeted but it was considered safe. This contrasts sharply with contemporary thinking and advertising for medicines in general where the treatment of pregnancy-related problems is perceived as a marketing nightmare.

The basic problem was that the pre-clinical testing of thalidomide was insufficient, even by today's standards. It rapidly became apparent that use of thalidomide in pregnancy was associated with phocomelia in the children born to these women. Phocomelia most dramatically manifests itself as gross deformities of the limbs, and these sufferers are now in their 40s.

They are seen on the television quite frequently at the moment, as there is renewed interest in thalidomide in other indications, where there is no satisfactory alternative treatment.

It was in response to this public health disaster and in an attempt to avoid a repeat, that the current legislation (in the UK this was the Medicines Act 1968) and advisory body, the Committee on Safety of Medicines, arose.

Unfortunately there have been other well-publicised problems with the safety of marketed medicines. Some time after its marketing launch the cardiovascular therapy Eraldin (practolol) was found to be causally associated with a sinister oculo-muco-cutaneous syndrome, which resulted in a highly useful selective beta-blocker being withdrawn from the market for routine use in 1976.

More recently, terodiline, an effective treatment for incontinence, was withdrawn from the market when it was discovered that its use was associated with potentially fatal cardiac arrhythmias in susceptible patients. This, despite the fact that it had showed a satisfactory profile in a Prescription Event Monitoring (PEM) study by the Drug Safety Research Unit in Southampton, involving almost 12,500 patients who had received the medication.

It was only when the PEM group looked at their data and discovered that there was an excess of fainting and funny-turns, compared to a control group, that it realised that the information was there but not easily visible.

These are just a few historical examples that show that, even with forward planning, sometimes good medicines turn out to be associated with problems. It is not only older products that are suddenly associated with unexpected problems, but without a structured way for continually monitoring the safety of marketed medicines, the industry cannot succeed in keeping the balance of benefit to risk in favour of the patient and the market.

MHRA inspections to become mandatory

A hot topic at the moment is that the MHRA is carrying out a programme of pharmacovigilance inspections of UK marketing authorization holders for medicines (prescription and over-the-counter) and will be looking for evidence of compliance with pharmacovigilance regulations.

The current regulations are contained within volume 9 of the European regulations for medicinal products for human and veterinary use, and this can be found as a large acrobat file on the eudra website (www.eudravigilance.org).

Suffice to say, that this document is hard work, but the MHRA has made it quite clear that it expects all licence holders to be aware of these regulations and understand their obligation to comply with them.

They have appointed pharmacovigilance inspectors who will do exactly what their title suggests and ensure marketing authorization holders comply. So far, several companies have volunteered (at their own expense) to be inspected, clearly demonstrating their houses were in order.

This year, however, a programme of mandatory inspections will begin, and when an inspector calls (there will usually be a notice period) they will not just be paying lip service to the regulations. The MHRA has made it crystal clear that they regard the safety of medicines as an important item on the public health agenda.

If you work for a reasonably big company there will almost certainly be an individual or group of employees who do nothing else but look after the information about the safety of a company medicines, both before and after marketing authorization.

There are many companies, however, that are too small to dedicate a department to drug safety. They may also be dealing with older products with less turnover that generate almost no drug safety problems; such companies may go from year to year never hearing anything about problems with their products.

Designated qualified person needed

Despite this the MHRA has indicated it will treat everyone the same and within each organization there will be a designated, qualified person responsible for pharmacovigilance:  their responsibilities will include the establishment and maintenance of an information system for suspected adverse reactions; the submission of adverse reaction reports to the competent authority (ie, the licensing authority); and the preparation and submission of periodic safety update reports documenting the ongoing safety issues and indicating the suitability to continue marketing a product.

New guidelines to affect everyone

It is an ill wind that will do no one any good and a thriving industry of contractors has appeared who will take on this thankless task. For those of you sitting comfortably outside the medical/regulatory arena, you might be thinking that this has nothing to do with you; you could not be more wrong.

Firstly, there are already guidelines in place (part of the prescription medicines code of practice of the ABPI) which give direction about salesforce members reporting suspected adverse reaction information passed to them in the course of their activities to their companies. This has now also been enshrined within volume 9, and makes reporting mandatory.

In addition, the salesforce not only becomes responsible for this reporting, but also accountable. The new regulations mean that if there is a pharmacovigilance inspection, the competent agency will not only check that systems are in place, but may also want to track adverse events that have been reported such as those that might come in a periodic safety update report. It may sound surprising but it is entirely within the remit of the competent authority to interview a salesforce member who had reported an event and that person will be expected to be familiar with their obligations.

Advice given at a recent meeting hosted by the MHRA, was that salesforce members should retain for their own records any written notes as well as any typed memoranda or e-mails sent to head office about product safety.

Training and systems need to be in place

Companies need to have a system in place, and there should be training given to salesforce members, ideally validated and recorded in a training log.

The training process does not stop there: individuals that hear about a suspected adverse reaction report first should be trained in the company's pharmacovigilance procedure; they should be fully aware of the information flow and the significance of that information.

They are not being asked to judge or evaluate adverse event information, but they are going to have to be able to recognise a product-related issue that needs action by the person(s) responsible for pharmacovigilance.

What changes will companies need to make?

The key question is what changes will companies need to make? For the bigger companies used to developing major new chemical entities there will be few, except those related to the impact of pharmacovigilance inspections.

For smaller companies, and those not used to receiving adverse reaction reports, the changes implied in volume 9 may come as a bit of a culture shock.

In the first instance pharmacovigilance systems will have to be put into place detailing how the company will deal with information about their licensed products, and a pharmacovigilance qualified person (usually medically qualified and employed by the company) will need to be identified and advised of their responsibilities and duties. This may be contracted out, but the competent authority has to be aware of this.

Once this is done, it may be that products previously thought of as clean as a whistle start to reveal themselves as having an undercurrent of adverse events that just never made it to the right people's attention. Companies can expect a visit from the inspector in due course.

The current indications are that inspections may be event driven, and if a licensed medicine is seen to be associated with a previously poorly recognised problem, that may trigger an inspection. But it is more likely that if evidence comes to light of non-compliance with current legislation, there will be an inspection and enforcement. Non-compliance will be judged on a case-by-case basis, and initially the MHRA may only invoke a name and shame ethos but this may change.

Companies judged by the same set of rules

The problem that really exists is that this is an even playing field, where companies may be judged by the same set of rules.

It is self-evident that for smaller product holders, it is questionable whether it will be worthwhile implementing a pharmacovigilance programme, when there may be nothing to show for it at the end of several years except a huge bill.

Similarly, it is difficult to evaluate the value to inspectors of finding out that a small organization with a small product fails to see the importance of volume 9.

One thing the MHRA has made clear is that deliberate non-compliance with legislation, failure to improve performance and standards once instructed to; or failure to notify a competent authority of a change in the risk of a product will be viewed very seriously and could even result in the suspension of a marketing authorization. You have been warned.