Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis

In an evaluation of medicines approved by the European Medicines Agency 2000 to 2010, Ruben Duijnhoven and colleagues find that the number of patients evaluated for medicines approved for chronic use are inadequate for evaluation of safety or long-term efficacy. Background: At the time of approval of a new medicine, there are few long-term data on the medicine's benefit–risk balance. Clinical trials are designed to demonstrate efficacy, but have major limitations with regard to safety in terms of patient exposure and length of follow-up. This study of the number of patients who had been administered medicines at the time of medicine approval by the European Medicines Agency aimed to determine the total number of patients studied, as well as the number of patients studied long term for chronic medication use, compared with the International Conference on Harmonisation's E1 guideline recommendations. Methods and Findings: All medicines containing new molecular entities approved between 2000 and 2010 were included in the study, including orphan medicines as a separate category. The total number of patients studied before approval was extracted (main outcome). In addition, the number of patients with long-term use (6 or 12 mo) was determined for chronic medication. 200 unique new medicines were identified: 161 standard and 39 orphan medicines. The median total number of patients studied before approval was 1,708 (interquartile range [IQR] 968–3,195) for standard medicines and 438 (IQR 132–915) for orphan medicines. On average, chronic medication was studied in a larger number of patients (median 2,338, IQR 1,462–4,135) than medication for intermediate (878, IQR 513–1,559) or short-term use (1,315, IQR 609–2,420). Safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least 6 and 12 mo in 46.4% and 58.3% of new medicines, respectively. Among the 84 medicines intended for chronic use, 68 (82.1%) met the guideline recommendations for 6-mo use (at least 300 participants studied for 6 mo and at least 1,000 participants studied for any length of time), whereas 67 (79.8%) of the medicines met the criteria for 12-mo patient exposure (at least 100 participants studied for 12 mo). Conclusions: For medicines intended for chronic use, the number of patients studied before marketing is insufficient to evaluate safety and long-term efficacy. Both safety and efficacy require continued study after approval. New epidemiologic tools and legislative actions necessitate a review of the requirements for the number of patients studied prior to approval, particularly for chronic use, and adequate use of post-marketing studies. Background: Before any new medicine is marketed for the treatment of a human disease, it has to go through extensive laboratory and clinical research. In the laboratory, scientists investigate the causes of diseases, identify potential new treatments, and test these interventions in disease models, some of which involve animals. The safety and efficacy of potential new interventions is then investigated in a series of clinical trials—studies in which the new treatment is tested in selected groups of patients under strictly controlled conditions, first to determine whether the drug is tolerated by humans and then to assess its efficacy. Finally, the results of these trials are reviewed by the government body responsible for drug approval; in the US, this body is the Food and Drug Administration, and in the European Union, the European Medicines Agency (EMA) is responsible for the scientific evaluation and approval of new medicines. Why Was This Study Done?: Clinical trials are primarily designed to test the efficacy—the ability to produce the desired therapeutic effect—of new medicines. The number of patients needed to establish efficacy determines the size of a clinical trial, and the indications for which efficacy must be shown determine the trial's duration. However, 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 physicians 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 chronic (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 twelve months, respectively, before approval. But are these guidelines being followed? In this database analysis, the researchers use data collected by the EMA to determine how many patients are exposed to new medicines before approval in the European Union and how many are exposed for extended periods of time to medicines intended for chronic use. What Did the Researchers Do and Find?: Using the European Commission's Community Register of Medicinal Products, the researchers identified 161 standard medicines and 39 orphan medicines (medicines to treat or prevent rare life-threatening diseases) that contained new active substances and that were approved in the European Union between 2000 and 2010. They extracted information on the total number of patients studied and on the number exposed to the medicines for six months and twelve months before approval of each medicine from EMA's European public assessment reports. The average number of patients studied before approval was 1,708 for standard medicines and 438 for orphan medicines (marketing approval is easier to obtain for orphan medicines than for standard medicines to encourage drug companies to develop medicines that might otherwise be unprofitable). On average, medicines for chronic use (for example, asthma medications) were studied in more patients (2,338) than those for intermediate use such as anticancer 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 twelve months in 46.4% and 58.4% of new medicines, respectively. Finally, 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 twelve months. What Do These Findings Mean?: These findings suggest that although the number of patients studied before approval is sufficient to determine the short-term efficacy of new medicines, it is insufficient to determine safety or long-term efficacy. Any move by drug approval bodies 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, which likely would be unacceptable to patients and healthcare providers. Nevertheless, the researchers suggest that a reevaluation of the study size and long-term data requirements that need to be met for the approval of new medicines, particularly those designed for long-term use, is merited. 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. Additional Information: Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001407.