Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis
Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis
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DOI：
10.1371/journal.pmed.1001407
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发表时间：
2013-03-01
期刊：
影响因子：
15.8
通讯作者：
De Bruin, Marie L.
中科院分区：
文献类型：
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作者：
Duijnhoven, Ruben G.;Straus, Sabine M. J. M.;De Bruin, Marie L.
背景：在批准新药时，很少有关于药物获益-风险平衡的长期数据。临床试验旨在证明疗效，但在患者暴露和随访时间方面的安全性方面存在重大局限性。本研究对欧洲药品管理局批准药物时已使用药物的患者人数进行了研究，旨在确定研究的患者总数以及长期使用慢性药物的患者人数，并与人用药品注册技术要求国际协调会的E1指南建议进行比较。方法和结果：2000年至2010年期间批准的所有含有新分子实体的药物都被纳入研究，包括作为单独类别的孤儿药。提取批准前研究的患者总数（主要结局）。此外，确定了长期使用（6或12个月）慢性药物的患者数量。确定了200种独特的新药：161种标准药物和39种孤儿药。标准药物获批前研究的患者中位总数为1，708例（四分位距[IQR] 968- 3，195），孤儿药为438例（IQR 132-915）。平均而言，在更多患者中研究了慢性药物（中位数2，338，IQR 1，462 - 4，135），而不是中期（878，IQR 513- 1，559）或短期使用（1，315，IQR 609- 2，420）。在少于1,000例患者中研究了46.4%和58.3%的新药长期使用至少6个月和12个月的安全性和有效性。在84种长期使用的药物中，有68种（82.1%）符合6个月使用的指南建议（至少300名受试者研究6个月，至少1，000名受试者研究任何时间长度），而67（79.8%）的药物符合12个月患者暴露标准结论：对于长期使用的药物，上市前研究的患者数量不足以评估安全性和长期疗效。安全性和有效性都需要在批准后继续研究。新的流行病学工具和立法行动需要审查批准前研究的患者数量要求，特别是长期使用，以及充分使用上市后研究。
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.