Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.1 ~David Sackett (1996)
This quote, from one of the gurus of evidence-based medicine, highlights the link between the systematic evaluation of scientific evidence on effects of medical treatments, and applying this evidence to patient care decisions – taking into account both clinical expertise and patient needs. Evidence-based medicine is not simply applying scientific evidence. It requires an assessment and interpretation in light of individuals’ health needs and preferences.
Although the first randomised controlled trials in medicine date from the 1950s, for many years there was no way to understand the body of information produced by drug trials and other forms of medical research. Writing in 1979, Archie Cochrane said:
It is surely a great criticism of our profession that we have not organised a critical summary, by specialty or subspecialty, adapted periodically, of all relevant randomised controlled trials.2
The Cochrane Collaboration (www.cochrane.org) was subsequently formed in 1992 and started its work looking at the effectiveness of obstetric interventions, as this was an area in which some interventions with substantial evidence of benefit were underused and others with little scientific basis remained widespread. The Cochrane Collaboration is an international network of more than 28 000 researchers from over 100 countries with different review groups based on clinical specialties. It helps healthcare providers, policy-makers, patients and their advocates and carers make well-informed decisions about health care by preparing, updating, and promoting the accessibility of Cochrane systematic reviews. A strength is the focus on methodological rigour, and Cochrane reviews are often seen as the ‘gold standard’ in systematic review. Over 5000 reviews have been published online in the Cochrane Database of Systematic Reviews (part of The Cochrane Library). The Collaboration also prepares the largest collection of records of randomised controlled trials in the world, called CENTRAL (published as part of The Cochrane Library).
The work of the Cochrane Collaboration and other evidence-based groups has grown significantly over the last 20 years. In 1981 there were only three meta-analyses indexed on Medline, in 1986 only 26. By 2011 the number had grown to around 8000.
Has the evidence-based movement been captured by commercial interests? Despite the rapid growth in the scale of activity to develop robust systematic review processes and procedures, there is a fundamental block in terms of limitations in the clinical trial evidence on the effects of new medicines. The requirements that manufacturers must meet to bring a new drug to market differ substantially from the clinical questions that physicians and patients face in order to understand a medicine’s place in therapy and decide whether or not to use it.
Studies of new pharmaceuticals are to a large degree shaped by regulatory requirements in order to obtain market approval. Currently, premarket randomised controlled trials are predominantly placebo controlled – or if not, they are non-inferiority trials. The latter are studies that are designed to test whether the drug is no worse than an existing treatment within a prespecified margin. Postmarketing surveillance data are mainly derived from observational studies. Regulators are becoming more interested in postmarketing safety surveillance, but there are no set standards for the rigour of the design of such studies.
Because most drug trials are designed and sponsored by the manufacturer, they are designed to present the drug in the best possible light and publication of all of the trial information is optional. When a drug becomes available there is usually no information on:
- the effects in vulnerable population groups (because they will have been excluded from trials)
- long-term or less frequent effects
- clinical outcome efficacy (short-term surrogate outcomes are often used)
- comparative effectiveness and safety.
There is no requirement for manufacturers to prove that their products are at least as safe as existing drugs. This has meant that some new drugs have turned out to have a worse safety profile than existing drugs. For example, the most frequent serious adverse event associated with use of combined oestrogen and progestogen-containing oral contraceptives is venous thromboembolism. However, when a new oral contraceptive comes to market the manufacturer does not need to show that their newer pill has a lower or similar rate of venous thromboembolism to existing alternatives. Several newer oral contraceptives have been found to cause more venous thromboembolism than other oral contraceptives, including the drospirenone-containing products Yaz and Yasmin.3,4
In a regulatory environment without a requirement to establish an advantage in order to get a new drug to market, many new drugs are no more effective than existing alternatives. This overview is from La Revue Prescrire, a French independent drug bulletin that evaluates every new approved drug for its readership of over 30 000 practitioners.
The figure covers all new drugs and indications reviewed by La Revue Prescrire from 2002 to 2011.5 Over half were judged to be ‘me too’ drugs – i.e. nothing new. Around 7% had solid evidence of an advantage over existing drugs (whether major or minor). In around 15% of new drug reviews there was evidence of poor effectiveness or safety compared to drugs already on the market.