Medical Matters: Lines need to be re-drawn in the study of efficacy and safety of new drugs

A lot of time, expense and effort go into developing a new drug. From the original laboratory discovery through animal testing to human trials can take years. Eventually, either the Food and Drugs Administration (FDA) or the European Medicines Agency (EMEA) gives its approval and the medication appears on the market.

But while these clinical trials are designed to demonstrate a drug’s efficacy and its initial tolerance in humans, they have major limitations when it comes to safety measured in terms of patient exposure and length of follow-up.

Identifying adverse effects of drugs generally requires the drug to be taken by more patients than are required to show efficacy, so the information about adverse effects is often relatively limited at the end of clinical testing.

Consequently, when new medicines are approved, their benefit-risk ratios are often poorly defined, even though doctors need this information to decide which treatment to recommend to their patients. For the evaluation of risk or adverse effects of medicines being developed for the long-term treatment of non-life-threatening diseases, current guidelines recommend that at least 1,000-1,500 patients are exposed to the new drug and that 300 and 100 patients use the drug for six and 12 months, respectively, before approval.

So I was interested to see a Dutch study, published last month in the open access journal PLOS, which looked at all drugs approved by the EMEA between 2000 and 2010. Researchers identified 200 newly approved medicines in the period 2000-2010, of which 161 were standard medicines and 39 were official orphan medicines (the name given to drugs used to treat rare, life-threatening diseases).

Orphan medicines
The average number of patients studied before approval was 1,708 for standard medicines and 438 for orphan medicines. On average, medicines for chronic use – to treat asthma, for example, were studied in more patients (2,338) than those for intermediate use such as anti-cancer drugs (878), or short-term use such as antibiotics (1,315). The safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least six and 12 months in 46 per cent and 58 per cent of new medicines, respectively. Among the 84 medicines intended for chronic use, 72 were studied in at least 300 patients for six months, and 70 were studied in at least 100 patients for 12 months.


The findings suggest that although the number of patients studied before approval is sufficient to determine the short-term efficacy of new drugs, it is not enough to determine safety or long-term efficacy. The problem is that any move by drug regulators to require pharmaceutical companies to increase the total number of patients exposed to a drug, or the number exposed for extended periods of time to drugs intended for chronic use, would inevitably delay the entry of new products into the market.

Unpopular move
Such a move would be unpopular with patients and healthcare professionals. But the researchers suggest a re-evaluation of the study size and long-term data requirements that need to be met for the approval of new medicines. They also stress the need for continued study of both the safety and efficacy of new medicines after approval and the importance of post-marketing studies that actively examine safety issues.

Meanwhile, many of the thousands of medicines given to children have never been tested on them. Many drugs used in children have only ever been licensed for adult use, with paediatricians and other doctors exercising their right to prescribe drugs “off-label” in order to use a particular medication in a child under 12.

It is estimated that more than 50 per cent of medicines used to treat children in Europe have not been appropriately tested. This means the doctor cannot be sure the medicine will be effective; he will be somewhat uncertain as to the appropriate dose and cannot accurately predict what side effects the child may suffer.

Sounds like a case of EMEA “heal thyself”.