RGD and MLDB have received financial support from the Medicines Evaluation Board (MEB) under the Regulatory Science collaboration between the MEB and Utrecht University for the submitted work. SMJMS is employed by the MEB. AWH is a member of the Dutch Medicines Evaluation Board but received no funding. AWH was not involved in the decision about the funding. AdB and JMR have no relationship with the MEB. The department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, of which AdB is the chair and RGD and MLDB are employees, has received unrestricted research funding from the Netherlands Organisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board (CVZ), the Royal Dutch Pharmacists Association (KNMP), the private-public funded Top Institute Pharma (
Conceived and designed the experiments: RGD MLDB. Performed the experiments: RGD. Analyzed the data: RGD AdB AWH MLDB. Contributed reagents/materials/analysis tools: RGD. Wrote the first draft of the manuscript: RGD. Contributed to the writing of the manuscript: RGD JMR SMJMS AdB AWH MLDB.
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.
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.
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).
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.
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.
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.
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.
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.
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Clinical studies conducted during the development of new medicines are generally designed to show efficacy under strict conditions and are performed in relatively small and selected patient populations
Although guidelines on the number of patients to be studied are in place, there are no formal European Union requirements for study size and length of follow-up in studies prior to the approval of new medicines. The size of an individual study and the total clinical development programme are mainly, if not entirely, driven by the statistical power needed to establish efficacy. The duration of trials is also determined by the indication for which efficacy must be proven and is rarely continued longer than strictly needed.
For the safety evaluation of medicines developed for chronic treatment of non-life-threatening diseases, the European Medicines Agency (EMA) and its United States counterpart, the Food and Drug Administration, use guidance on patient exposure and the length of time participants are studied based on the International Conference on Harmonisation (ICH) E1 guideline
The aim of this study was to review the number of patients exposed to new medicines before approval in the EU (main outcome), with a special focus on long-term exposure for medicines intended for chronic use.
The publicly available Community Register of Medicinal Products of the European Commission was used to identify all products approved in the EU through the “centralised procedure” between 1 January 2000 and 31 December 2010, including those that were subsequently withdrawn or suspended
European public assessment reports (EPARs) are publicly available on the EMA's website
The intended use of medications was assessed based on the official indication at approval. With this indication as a reference, intended treatment duration was classified as chronic, intermediate, or short term by R. G. D. and M. L. D. B. Any discrepancies were resolved in discussion with A. d. B. Examples of chronic use included asthma and HIV medication, intermediate length of use included anticancer treatment, and short-term use included antimicrobial medication and most analgesics and diagnostic agents.
For all medicines intended for chronic use we extracted additional information on the number of patients who had received treatment for at least 6 mo and at least 12 mo. If no (reliable) information on the number of exposed patients could be obtained, patient exposure was categorised as missing. In some EPARs the number of patients treated with the study medication for 12 mo was reported, whereas use for at least 6 mo was not reported. In such cases the number of participants with 12-mo use was imputed as 6-mo use.
In addition, information was obtained on special authorisation status (orphan status, exceptional circumstances, and conditional approval) where applicable. Products were categorised as orphan medicines if the EMA's Committee for Orphan Medicinal Products had granted them official EU orphan status; all other medicines were categorised as “standard medicines”.
Based on the total number of patients exposed before approval, all products were divided into one of the following five groups: less than 500 patients, 500 to 1,000 patients, 1,000 to 2,000 patients, 2,000 to 5,000 patients, and more than 5,000 patients. To assess long-term use before approval, the numbers of participants studied for at least 6 mo and for at least 12 mo were calculated. The cutoff values used for the number of patients required in long-term studies were chosen according to the clinical safety guideline: at least 300 for 6-mo use and at least 100 for 12-mo use
The non-parametric Wilcoxon two-sample test was used to determine whether there was a statistically significant difference in the number of participants studied for medicines still on the market versus those withdrawn from the market as of 4 November 2011.
We identified 200 newly approved medicines in the period 2000–2010, of which 161 were standard (non-orphan) medicines (80.5%) and 39 were official orphan medicines (19.5%). The specific medicines and number of patients studied are listed in Dataset S1.
The median number of total patients studied per medicine was 1,708 (interquartile range [IQR] 968–3,195) for standard medicines and 438 (IQR 132–915) for orphan medicines (
Results for standard (non-orphan) medicines are presented by intended length of use of the products (chronic, intermediate, or short-term) and as one group (sub-total). Boxplots present the 50th percentile, i.e., the median value is given, with the interquartile range (25th and 75th percentiles) indicated by the box, the 2nd and 98th percentiles indicated by the horizontal bars of the whiskers, and outliers indicated by individual circles. The total number of patients studied (
Orphan medicines generally had small numbers of patients in clinical studies; 31 (79.5%) of the products had been used by fewer than 1,000 patients. Eight orphan medicines had been tested in more than 1,000 patients (plerixafor, mecasermin, rufinamide, trabectedin, sorafenib, ziconotide, anagrelide, and imatinib).
Among the standard medicines, 90 (55.9%) of the 161 products had been studied in fewer than 2,000 patients in total, of which 20 (13.7%) were studied in fewer than 500. 52 (32.3%) products were studied in 2,000–5,000 patients, and 19 (11.8%) were studied in more than 5,000 (
Total Number of Patients | Standard Medicines | Orphan Medicines | Total | |||
Chronic | Intermediate | Short-Term | Sub-Total | |||
<500 | 6/84 (7.1%) | 6/27 (22.2%) | 8/50 (16.0%) | 20/161 (12.4%) | 21/39 (53.8%) | 41/200 (20.5%) |
500–1,000 | 4/84 (4.8%) | 9/27 (33.3%) | 10/50 (20.0%) | 23/161 (14.3%) | 10/39 (25.6%) | 33/200 (16.5%) |
1,000–2,000 | 23/84 (27.4%) | 10/27 (37.0%) | 14/50 (28.0%) | 47/161 (29.2%) | 7/39 (17.9%) | 54/200 (27.0%) |
2,000–5,000 | 38/84 (45.2%) | 1/27 (3.7%) | 13/50 (26.0%) | 52/161 (32.3%) | 1/39 (2.6%) | 53/200 (26.5%) |
>5,000 | 13/84 (15.5%) | 1/27 (3.7%) | 5/50 (10.0%) | 19/161 (11.8%) | 0/39 (0.0%) | 19/200 (9.5%) |
Total | 84/84 (100%) | 27/27 (100%) | 50/50 (100%) | 161/161 (100%) | 39/39 (100%) | 200/200 (100%) |
Percentages are column percentages.
The number of patients receiving medicines for short-term treatment before marketing authorisation varied considerably. Eight (16.0%) medicines had been studied in fewer than 500 patients, whereas five (10.0%) medicines had been studied in more than 5,000 patients, and 13 (26.0%) in 2,000–5,000 patients. Medicines intended for intermediate length of use were tested on the smallest number of patients before approval; 25 (92.4%) medicines were used by fewer than 2,000 patients. Within this category, 20 (74.1%) medicines were indicated for treatment of cancer. Medicines for chronic use were studied in larger numbers of patients during clinical development. In total, 51 (60.7%) of these products had been used by 2,000 or more patients, of which 13 (15.1%) had been studied in more than 5,000 patients.
Six medicines in our analyses had their marketing authorisation subsequently suspended or withdrawn. Medicines still on the market had been studied before approval in a median 1,694 patients (IQR 899–3,167), versus 2,161 patients (IQR 968–5,479) for suspended or withdrawn medicines; this difference was not statistically significant (
Among the 84 medicines intended for chronic use, 69 (82.1%) met the patient exposure recommendations for 6-mo use (at least 300 participants studied for 6 mo and at least 1,000 participants in total), and 67 (79.8%) of the medicines met the criteria for 12-mo patient exposure (at least 100 participants) (
Reference lines are added to indicate the minimum criteria from the ICH E1 guideline: 1,000 patients in total and 300 and 100 patients studied for 6 and 12 mo, respectively. Any products not meeting the ICH E1 guideline recommendations are shown in red.
Total Number of Patients | Number of Patients with 6-mo Use | Number of Patients with 12-mo Use | |||||||
<300 | 300–1,000 | >1,000 | Missing | <100 | 100–1,000 | >1,000 | Missing | ||
<1,000 | ( |
|
|
|
4/10 (40.0%) |
|
|
|
6/10 (60.0%) |
1,000–5,000 | ( |
|
30/61 (49.2%) | 28/61 (45.9%) | 1/61 (1.6%) |
|
39/61 (63.9%) | 16/61 (26.2%) | 3/61 (4.9%) |
>5,000 | ( |
|
0/13 (0.0%) | 11/13 (84.6%) | 1/13 (7.7%) |
|
3/13 (23.1%) | 9/13 (69.2%) | 1/13 (7.7%) |
Total | ( |
|
33/84 (39.3%) | 39/84 (46.4%) | 6/84 (7.1%) |
|
45/84 (53.6%) | 25/84 (29.8%) | 10/84 (11.9%) |
Percentages presented are row percentages for 6 and 12 mo use. Products with (1) a total number of patients studied of fewer than 1,000, (2) fewer than 300 studied for 6 mo, or (3) fewer than 100 studied for 12 mo do not meet the guideline criteria, and are shown in bold. For purposes of calculation and display, missing data were assumed to be in compliance with the recommended patient exposures.
Safety and efficacy of chronic use were studied in fewer than 1,000 individuals for 6 mo or more in 41 (48.8%) medicines, and for 12 mo or more in 49 (58.3%) medicines.
Six (7.1%) medicines had been used by fewer than 300 patients for a minimum of 6 mo. 33 (39.3%) medicines had been tested in 300 to 1,000 patients, and 39 (46.4%) medicines had been tested in more than 1,000 patients, both for a minimum of 6 mo. For six (7.1%) medicines, information on the number of patients included in long-term studies was missing in the EPAR.
For 45 (53.6%) medicines, 100 to 1,000 patients had been studied for at least 12 mo, and 25 (29.8%) products had been studied in over 1,000 patients. For four medicines (4.8%), fewer than 100 patients had been studied for at least 12 mo. Data on 12-mo use was missing in 10 (11.9%) EPARs.
To our knowledge no recent research has systematically assessed the number of patients and volunteers exposed to new medicines before approval. A previous study of product licence applications in the UK between 1987 and 1989 by Rawlins and Jefferys showed that the median number of individuals exposed to new active substances in premarketing studies was 1,480 (range 129–9,400) for successful applications, and 1,052 (range 43–15,962) for unsuccessful applications
The aim of the ICH E1 guideline on data requirements for medicines for long-term use is to assure at least a minimum of experience and knowledge of long-term efficacy and safety before approval. Overall, 1,000 to 1,500 patients in total, and a minimum of 300 and 100 treated for at least 6 and 12 mo, respectively, are required. Results from our study show that the minimal requirements are met by approximately 80% of new medicines approved for chronic use in the EU.
Although increasing the number of patients exposed to a medicine before approval could be justified, especially for medicines intended for long-term use, the requirement could delay new products entering the market. In the current era, in which patients and healthcare providers demand more rapid access to new medicines, this would not be acceptable for most stakeholders in the field. Furthermore, randomised controlled trials sufficiently large to accurately assess long-term safety and effectiveness are expensive, and epidemiological studies in the post-marketing phase may be more suitable.
As an example, in the meta-analysis by Nissen and Wolski published in 2007 on myocardial infarction in users of rosiglitazone, myocardial infarction incidence was approximately 36 per 10,000 patients in the control group, with rosiglitazone use incurring an estimated increased risk (odds ratio) of 1.43
For a clinical trial to reveal a relative risk of 1.43 with statistical significance (a power of 80% and α of 0.05%, see
Relative Risk | Incidence of the Outcome in the Study | |
1∶5,000 | 1∶1,000 | |
2.0 | 117,697 | 23,511 |
2.5 | 61,025 | 12,187 |
3.0 | 39,228 | 7,832 |
5.0 | 14,707 | 2,934 |
7.5 | 7,888 | 1,572 |
10 | 5,323 | 1,059 |
However, for chronic medications, the clinical safety guidelines require too few patients to be studied long term. The possibility of detecting long-term adverse events from follow-up of only 300 patients for 6 mo or 100 patients for 12 mo, as required in the current ICH E1 guideline, is insufficient. It would be more sensible to move towards a minimum targeted long-term study size of 1,000 to 1,500 patients, comparable to the overall study size now required
Knowledge of a medicine's benefit–risk profile, including its effectiveness in clinical practise and associated adverse effects, should only increase over time and with increasing use. Clinical use outside the restrictive environment of trials may be the only way to achieve a full understanding of the safety profile
RMPs have become an important tool to progressively extend the knowledge of the safety of newly approved medicines
Post-marketing observational pharmacoepidemiological studies are essential, even though confounding in observational data may be impossible to eliminate completely. RMPs and other pharmacovigilance activities do not overcome the problems due to insufficient statistical power and the need for large study sizes to detect less common adverse effects in clinical trials (as discussed above for the case of rosiglitazone). Signals of adverse effects require formal and adequately powered observational studies before the issue can be quantified and addressed.
Regulator-driven post-marketing studies are possible in both the US
Recently, new approaches in regulation have been proposed by means of “adaptive licensing”
A re-evaluation of the requirements regarding study size and long-term data for approval of new medicines seems to be merited. Such a discussion should involve healthcare providers, patients, and academia, as well as industry and regulators, and should include debate on the level of acceptable uncertainty, especially for adverse events and the long-term outcomes for chronic medication.
The numbers of individuals studied before approval of new medicines in Europe from 2000 to 2010 are comparable to the study sizes for medicines approved in UK in the 1980s, and are generally adequate to assess only short-term efficacy. For most approved medicines intended for chronic use, the number of patients studied before marketing is insufficient to study safety and long-term efficacy. In light of new scientific and legislative tools to monitor benefits and risks in clinical use, discussion of the long-term exposure requirements for approval of medicines, particularly for medicines intended for chronic use, seems warranted.
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European Medicines Agency
European public assessment report
International Conference on Harmonisation
interquartile range
risk management plan