Dan Jones

On 27 September this year, US President George W. Bush signed into law a revised version of the Prescription Drug User Fee Act (PDUFA), which provides greater funds to significantly broaden and upgrade the FDA’s drug safety programme. The hope is that such funds will help tackle the long-standing problems of severe adverse drug reactions (ADRs), which cause between 3–6% of US hospital admissions, and have been estimated to result in upwards of 100,000 deaths annually in the US alone.

Clinical trials provide a first-line of defence against clearly unsafe drugs, but their capacity to pick up danger signals is limited by

several factors. First, investigational drugs are administered in a very controlled manner in clinical trials. Second, patients are often unrepresentative of the wider population that will eventually take the drug, who might also suffer from additional conditions and be on other medications, points out Susan Jick, Associate Professor of Epidemiology and Biostatistics at Boston University School of Public Health, and member of the Boston Collaborative Drug Surveillance Program (BCDSP).

Another problem is the limited possibility of detecting rarer adverse events in clinical trials, given the number of patients involved — often 1,500–2,000. “If a serious ADR occurred in 1 in 5,000 patients

that would be enough to take it off the market,” says Sir Alasdair Breckenridge, Chairman of the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). “Yet the chances of seeing this in a Phase III trial are small.”

Drug safety surveillance is, as a result, largely a post-marketing issue. A key element of pharmacovigilance in both the US and Europe is a variety of voluntary reporting systems that enable both health-care professionals and the public to report potential ADRs. In the UK, the MHRA and the Commission on Human Medicines run the Yellow Card Scheme, through which information about suspected ADRs can be submitted electronically. To date, the scheme

Keeping vigilant about drug safetyHow might increased funding and new initiatives help tackle the challenges of collecting and monitoring data on the safety of prescription drugs?

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has collected more than 500,000 reports. The US FDA has a similar system, known as MedWatch, and doctors and patients can also contact drug manufacturers directly, often through dedicated hotlines, to flag up safety concerns, which the company is obligated to pass on to regulators.

These spontaneous reporting systems, although valuable for providing signals about drug safety, are not up to the task of modern pharmacovigilance. “The current systems were conceived at a time when we only had a handful of drugs and when drugs were introduced into the market much more slowly,” says Janet Woodcock, Deputy Commissioner for Operations at the FDA. “They are unable to pick up on all the long-term outcomes of using new medications.”

Working out the risk of ADRs from spontaneous reports is impossible because the denominator of the equation — how many people took the drug — is missing. There is also a major problem with under-reporting, with some studies suggesting that just 10% of ADRs are reported through these channels. “Clearly, this is a pretty haphazard system,” says Breckenridge, while acknowledging its utility.

One way to overcome these problems is through drug registers that all patients prescribed a given drug sign up to for subsequent monitoring. For example, the schizophrenia therapy clozapine can cause a dangerous drop in white blood cell count, and so pharmacists wait for the results of regular blood counts before filling new prescriptions for patients. “This is a way of having the drug on an active register and using it to screen for ADRs,” says Breckenridge.

The increased development of easily accessible and searchable e-health records, which document drug treatments and visits to physicians and hospital, is also providing new opportunities for pharmacovigilance. “The emergence of e-health records creates ways to look into drug safety that we never had before,” says Woodcock.

One of the largest such databases of patient information from primary care physicians is the UK’s General Practice

Research Database (GPRD), which contains information on ~13 million patients, including 3.4 million active patients. Databases such as GPRD enable researchers to conduct pharmaco-epidemiological studies to tease out the links between drugs and potential ADRs. Jick and fellow pharmaco-epidemiologists at BCDSP have, for instance, used the enormous amount of data in GPRD to shed light on the relative risks of different antidepressants in producing suicidal behaviour, an issue notoriously confounded by the fact that the very people who receive antidepressants — the depressed — are the most likely to commit suicide.

A recently announced initiative also hopes to capitalize on the information captured by e-health records. In August, the University of Miami Miller School of Medicine (UMMSM) and Humana Inc. — a health-care insurance provider — launched a pharmacovigilance initiative. Humana brings to the table data on 11 million people, 70% of whom are taking a prescription drug. As Humana pays the bills for all prescriptions, as well as physician and hospital bills, it has details of all treatments and ailments, affording a rich opportunity to pick up danger signals and conduct pharmaco-epidemiological studies.

“This initiative will be driven scientifically by the university, which is establishing an advisory board of physicians, pharmacists and biostatisticians whose clinical knowledge and expertise will provide early signals on which areas or outcomes should be addressed,” says John Hanna, Director of Health Services Research at Humana. As a case in point, Hanna cites the example of the diabetes drug rosiglitazone (Avandia; GlaxoSmithKline), which in a recent meta-analysis was linked to an increased risk of myocardial infarction (NEJM 356, 2457–2471; 2007). “So should we look at the relationship between diabetes drugs and heart disease generally or that one drug to heart disease?” asks Hanna. “This is the kind of question the board will help us address.”

In fact, the initiative is now looking at the effects of oral diabetes drugs as a group, and, as new drugs become available, will follow selected targets, says William O’neill, Executive Dean for Clinical Affairs at UMMSM. One such target drug is rimonabant (Acomplia; Sanofi–Aventis), which is already approved in Europe. “If and when this starts being prescribed in the US we’ll be able to use this registry to see if there are any signals of adverse events,” says O’neill.

Other drug-safety-related programmes are also springing up. September saw the launch of another public–private partnership,

one that aims to collect and combine genetic information and data on drug responses to identify genetic markers predictive of ADRs. The International Serious Adverse Events Consortium (SAEC), chaired by Arthur Holden, comprises seven large pharmaceutical companies who will provide millions of dollars in funding, and two academic institutions in Britain with access to tissue samples for the studies. SAEC will initially look at potential genetic variation underlying a rare drug-related skin condition called Stevens–Johnson syndrome, and in a second study, drug-induced liver injury.

Back at the FDA, the increased funds provided by the revised PDUFA will help regulators monitor drug safety more effectively. “We’re going to improve our databases for spontaneous reporting, increase staffing, and collaborate more closely with others in using e-health records and other electronic data to study pharmacovigilance,” says Woodcock. “The strategic long-term issue,” she adds, “is monitoring drug safety in emerging health-care databases — the methodologies for interrogating these databases to aid pharmacovigilance are not well worked out.” As BCDSP’s Jick cautions, “There are a lot of data in these systems; if you don’t know what you’re doing you can make a real mess of it.”

looking to the future, Breckenridge also sees risk-management plans playing a greater role in understanding the risks of drugs and taking appropriate action in response. “These say what is known about the safety of the medicine, what isn’t known, what needs to be found out, and how this will be achieved, as well as suggesting whether patient-education programmes might be required,” says Breckenridge. In Europe, all licensed drugs require a risk-management plan and, after the new PDUFA bill, selected drugs in the US will as well. “We’ve been talking about risk-management plans for 20 years, but previously we’ve not been able to enforce them — now they are increasingly becoming part of the licensing requirement.”

The emergence of e‑health records creates ways to look into drug safety that we never had before.

There are a lot of data in these systems; if you don’t know what you’re doing you can make a real mess of it.

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