Evaluating medicines: let’s use all the evidence

As a requirement for marketing approval, the benefits and risks of medicines are evaluated in formal clinical trials. However, these trials are not necessarily representative of the way medicines are used by consumers. Currently we rely on voluntary reporting schemes to detect adverse events that may occur after marketing, when a much larger patient population is exposed to a medicine.

We describe here the limitations of the current system of monitoring medicines and propose an updated method that takes advantage of the capabilities of information technology, existing data resources and statistical methodologies. Australia is well provided with quality data to support this approach — an approach that is gaining increasing support overseas.1-3

Historically, procedures for establishing the effectiveness of medical treatments have been suboptimal, with many commonly used treatments still awaiting rigorous evaluation.4 The safety of many medicines has largely been taken on faith, on the assumption that claimed benefits outweigh (un)known risks. In the early 1960s, the connection between thalidomide and severe birth defects was observed;5 this was a potent catalyst for clinicians and regulators to consider systems for monitoring drug safety.

The urgent need for increased medicines surveillance has been recently argued by international bodies, such as the International Society for Pharmacoepidemiology, and considered as a component of the new requirements for postmarketing epidemiological studies by the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. Similar discussions are underway locally as legislation is developed for the upcoming Australia New Zealand Therapeutic Products Authority.11

An optimal postmarketing surveillance system should assess all available information about the performance of medicines, drawing on worldwide pre- and postmarketing trials and voluntary reporting, with the addition of findings from regular, systematic and ongoing evaluation using linked observational data.1,7,8,12-14 A number of centres in several countries are already performing high-class pharmacoepidemiological studies of this type.15-19

The utility of linked observational data is well illustrated by the aftermath of the worldwide withdrawal of the cyclooxygenase-2 inhibitor rofecoxib (Vioxx) in response to concerns that the medicine increased heart attack risk. The international literature has since carried a series of over 20 controlled observational and cohort studies evaluating the excess risk associated with use of rofecoxib and related drugs in the United States, Canada and Europe.20 All but two studies employed linked observational data (or linked electronic medical records), permitting rapid evaluation of potential harms. Had these data been analysed cumulatively as soon as they became available (as would occur in a routine surveillance system), rofecoxib might have been withdrawn earlier. A recent meta-analysis of controlled observational studies has indicated that diclofenac has a similar risk profile.21

Australia, as a fortuitous consequence of a complex multi-jurisdictional health care funding system, is replete with observational health care data in linkable databases. They describe the vast majority of health care encounters across the nation, including doctor visits, medicine dispensing, hospital admissions, deaths, and various disease registries. Recent work has shown the practicality of bringing these data together for active monitoring of the outcomes of new drugs while they are being used in the “real world”.22-24 Specific methodologies have been developed to support pharmacoepidemiological analysis of these large datasets.25,26 Encouraging progress has been made over the past few years to improve access to these health datasets. A major linked data resource is now available in Western Australia and a similar resource is being developed in New South Wales.27 To ensure ethical and appropriate use of these data, a nationally accepted protocol has been designed to guarantee both strong privacy protection and accurate linkage.28 While these data have some known limitations and biases, they portray actual practice in use of medicines — and their long-term consequences. With the adoption of appropriate case-inclusion criteria, most of the biases in these data can be controlled.29 Although there are as yet no overseas examples of “routine” medicines monitoring, there have been useful studies based on ad-hoc linkages of medicines and health-outcomes data.30,31

Our preferred approach would support the stated regulatory goals of Australia’s National Medicines Policy.32,33 We propose a staged introduction, incorporating the following features:

• Establish a pharmacoepidemiology data analysis centre, with staff trained in data management, epidemiology, statistics, and, in particular, the use of linked data. The centre would require start-up funding but should ultimately be supported by registration fees from medicine manufacturers or sponsors. It would logically be based within the TGA, but the work could be contracted to external bodies. It may be appropriate to run a pilot program based on data from WA.

• All applications for new chemical entities would continue to be evaluated by the TGA; however, initial provisional approval would provide a “Caution – New Medicine” rating for the drug and have expanded requirements for periodic review.

• Periodic review would be based on accumulated adverse drug reaction reports, recent drug studies, and commissioned Australian observational studies using the linked databases.

• Provisional approval could be upgraded once significant market experience is gained; for example, a medicine could be given a “gold” safety rating after achieving an agreed benchmark.

• Progressive assessment of existing medicines could be introduced as evaluation resources and expertise become available.

• Timely provision of appropriate observational data should be secured under agreements with federal and state government data custodians. These data should be linked according to accepted protocols to ensure adequate privacy protection.

• Provisionally registered medicines should be eligible for Pharmaceutical Benefits Scheme listing to ensure sufficient uptake for adequate postmarketing evaluation.

We call for more practice-based evidence, to ensure that medicines earn their reputation in the marketplace. A conservative approach should be adopted until sufficient evidence is available to provide confidence in a medicine’s safety and efficacy. Granting a provisional safety rating for initial approval is consistent with this philosophy and allows experience gained over time to be incorporated into the ongoing evaluation of all medicines through the process of periodic review.

Australia is ideally placed to introduce an updated 21st century pharmacovigilance system. Commonwealth infrastructure support is available for this work,34,35 and the system could use and benefit from information that has been dutifully collected for many years. Such a system could provide a model for other countries to follow.