Balancing risk with benefit

IMB chief Pat O'Mahony talks to David Labanyi about what is involved in licensing medicines.

IMB chief Pat O'Mahony talks to David Labanyiabout what is involved in licensing medicines.

Within hours of this interview Pat O'Mahony, chief executive of the Irish Medicines Board, flew to Amsterdam for a meeting with heads of similar European agencies.

The meeting was about a project started during the Irish Presidency of the Commission to improve information sharing on adverse drug reactions across European pharmaceutical monitory bodies and impose a consistency of approach.

It is an example of the increasingly international nature of the IMB's work, further evidenced by O'Mahony's recent appointment as chairman of the European Medicines Agency (EMEA), the first Irish person to hold the role.

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One immediate issue facing the EMEA is a safety review of a painkiller which was recently suspended from the Irish market by the medicines board after it was linked to liver failure in nine patients, three of whom died.

Products containing nimesulide - which is manufactured in Mulhuddart, Co Dublin - and sold under the brand names Aulin, Mesulid and Mesine were recalled in May after the IMB suspended its licence pending an investigation.

The non-steroidal anti-inflammatory is for the treatment of arthritis and period pains and was used by more than 30,000 Irish people.

"We received new data from the National Liver Transplant Unit at St Vincent's Hospital in Dublin. They went back over files and found nimesulide was implicated in a substantial number of cases that we hadn't been aware of," O'Mahony says.

"Data from those new cases was enough to swing our decision and we have suspended this product pending a review of its safety."

This instance illustrates O'Mahony's view that there are no safe medicines. "Our job in the IMB is to balance the risk with the benefit. People will accept a different benefit/risk assessment depending on the severity of their disease."

A cancer drug which has been shown to prolong life but which also has significant side effects might be approved, he says.

Asked if the nimesulide case reveals weaknesses in the pharmacovigilance systems operated by the IMB and similar agencies - the product is licensed for use in 50 countries and remains available in many - O'Mahony says products are withdrawn because of an unexpected side effect or when the product is being used incorrectly.

"The instructions for the use of nimesulide were clear: use for the shortest possible time and it is contra-indicated for people with liver problems.

"We got 1,500 calls to our helpline in the four days after the product was withdrawn, 95 per cent of which were from the public. Some said they had been on the product for years."

If a product is recalled on the basis of a known risk there is a strong likelihood "it is being misused", he suggests.

He says prescribers are under severe pressure to be informed about a product and how it reacts with other medicines. "To do nothing is not an option when there is a patient in the surgery. At the end of the day, people make judgments, prescribe products and issues arise."

There have been 53 reports of liver-related adverse reactions with nimesulide, since it was licensed for use in the Republic in 1995 .

The EMEA is reviewing the IMB's report on the liver failures and will report next month on whether it considers the drug safe.

Monitoring adverse drug reactions (ADRs) is a core part of the IMB's remit and O'Mahony says there have always been drug recalls. "They just get more media attention now."

Most medicines are licensed only after successfully completing a series of clinical trials, typically on cohorts of 5,000-20,000 people.

"Undoubtedly it is the case that when you go from a group of 20,000 to 20 million you get some very rare additional safety issues that didn't arise in the trials.

"I am not denying that you will see some additional reactions in some products. That is what we do: we look for the 0.01 per cent of people who might have an adverse reaction."

O'Mahony accepts this means the initial months and years after a new medical product is licensed for use are effectively the final stages of the trial.

To perform its monitoring of ADRs, the IMB relies on reports from medical professionals and the public.

Each year the IMB receives about 2,000 such reports about patients in the State. It is currently redesigning its website to make reporting ADRs online simpler.

O'Mahony is quick to reject criticism in a recent Oireachtas Health Committee report on ADRs that suggested the public was unable to report an ADR directly to the IMB. "They can and we investigate every case," he says.

"The perception is also out there that the reporting of ADRs in Ireland by doctors is low but we are in the top eight in a list of WHO countries.

"We are always asking prescribers to report unusual or unexpected side effects."

To disperse this information on a European level the EMEA is developing an IT system called EudraVigilance for reporting and evaluating suspected adverse reactions.

Drug companies are also obliged under the terms of their licence to report ADRs to the IMB.

The IMB examines compliance with this requirement as part of its overall auditing of pharmaceutical manufacturers. Ireland is the second biggest net exporter of pharmaceuticals in the world.

The same Oireachtas report also criticised the reliance of the IMB on fees from pharmaceutical firms. It said such a payment system places the companies as "clients of the IMB", an incongruous position for an agency mandated to protect patients.

To counter this it suggests splitting the IMB in two, with one agency responsible for licensing and the other working on surveillance of approved products. It is not an approach O'Mahony supports, although the IMB board has discussed it.

He argues the fees for inspections and licensing do "not compromise us in any shape or form. We see ourselves as being involved with the product from the day the clinical trial is proposed right through to the end. We have all of the data and all of the expertise in one agency," he says.

"The fees are paid upfront and are transparent. It is the same model used by other medicines agencies. The IMB Act obliges us to be self-financing and we generate 80 per cent of our income from this source. The remainder comes from the department for very specific functions."

He also denies that by moving to eradicate a backlog of medicine licence applications the IMB was serving the needs of industry. "Some product applications were taking two years so we restructured and eradicated the backlog.

"If there is a product application, it usually follows there is a clinical need so the delays were denying patients access to products. It's not just facilitating the trade."

The IMB is preparing a detailed response to the issues raised in the Oireachtas Health Committee report. O'Mahony notes drily that the report contained submissions from a "very small number of people who are campaigning on specific issues".

The board is being given new responsibilities to add to its regulation of human and veterinary pharmaceuticals and medical devices.

The largely neglected role of monitoring cosmetics is transferring from the Department of Health and within the next few days the medicines board is to become responsible for monitoring pharmaceutical advertising and sponsorship campaigns.

"While the cosmetics are not medicines per se, we certify the small number of manufacturers here and look at safety issues in relation to usage. It is a huge area and there is a lot happening on a European level where a new set of directives is planned."

As with ADRs, the IMB will accept complaints from the public about health promotion or advertising campaigns.

The IMB is examining the industry's voluntary codes before introducing new regulations. Under these new powers the IMB can halt campaigns and launch prosecutions with penalties including fines and imprisonment.

International inspection is another growing area for IMB staff. These are carried out on behalf of the EMEA in countries which do not have the expertise to inspect new pharmaceutical factories. "We do five or six foreign missions a year. It is a growing part of our work," he says.