Facey Karen, Granados Alicia, Guyatt Gordon, Kent Alastair, Shah Nilay, van der Wilt Gert Jan, Wong-Rieger Durhane
Evidence Based Health Policy Consultant,
Global Medical Affairs,EVD. Genzyme a Sanofi Company and Autonomous University of Barcelona.
Int J Technol Assess Health Care. 2014 Oct;30(4):416-22. doi: 10.1017/S0266462314000464. Epub 2014 Nov 19.
Rare diseases are often heterogeneous in their progression and response to treatment, with only a small population for study. This provides challenges for evidence generation to support HTA, so novel research methods are required.
Discussion with an expert panel was augmented with references and case studies to explore robust approaches for HTA evidence generation for rare disease treatments.
Traditional RCTs can be modified using sequential, three-stage or adaptive designs to gain more power from a small patient population or to focus trial design. However, such designs need to maintain important design aspects such as randomization and blinding and be analyzed to take account of the multiple analyses performed. N-of-1 trials use within-patient randomization to test repeat periods of treatment and control until a response is clear. Such trials could be particularly valuable for rare diseases and when prospectively planned across several patients and analyzed using Bayesian techniques, a population effect can be estimated that might be of value to HTA. When the optimal outcome is unclear in a rare disease, disease specific patient reported outcomes can elucidate impacts on patients' functioning and wellbeing. Likewise, qualitative research can be used to elicit patients' perspectives, with just a small number of patients.
International consensus is needed on ways to improve evidence collection and assessment of technologies for rare diseases, which recognize the value of novel study designs and analyses in a setting where the outcomes and effects of importance are yet to be agreed.
罕见病在其进展和对治疗的反应方面往往具有异质性，可供研究的人群规模较小。这为生成支持卫生技术评估（HTA）的证据带来了挑战，因此需要新的研究方法。
通过参考资料和案例研究对与专家小组的讨论进行补充，以探索用于生成罕见病治疗HTA证据的可靠方法。
传统的随机对照试验（RCT）可以采用序贯、三阶段或适应性设计进行改进，以便从小规模患者群体中获得更大的效力，或使试验设计更具针对性。然而，此类设计需要保持随机化和盲法等重要设计方面，并在分析时考虑到所进行的多次分析。单病例试验采用患者内随机化来测试治疗和对照的重复周期，直至明确出现反应。此类试验对于罕见病可能特别有价值，并且当对若干患者进行前瞻性规划并使用贝叶斯技术进行分析时，可以估计出对HTA可能有价值的群体效应。当罕见病的最佳结局不明确时，针对特定疾病的患者报告结局可以阐明对患者功能和福祉的影响。同样，定性研究可用于获取患者的观点，且仅需少量患者。
需要就改善罕见病技术证据收集和评估的方法达成国际共识，这种共识应认识到在重要结局和效应尚未达成一致的情况下新颖研究设计和分析的价值。
