At present, there is just one approved therapy for patients with mitochondrial diseases in Europe, another in Japan, and none in the United States. These facts reveal an important and significant unmet need for approved therapies for these debilitating and often fatal disorders. To fill this need, it is critical for clinicians and drug developers to work closely with regulatory agencies. In the United States, mitochondrial disease patients and clinicians, the United Mitochondrial Disease Foundation, and pharmaceutical industry members have engaged with the Food and Drug Administration to educate each other about these complex and heterogeneous diseases and about regulatory requirements to obtain approvals for novel therapies. Clinical development of therapies for rare diseases has been facilitated by the 1983 US Orphan Drug Act (ODA) and similar legislation in Japan and the European Union. Further legislation and regulatory guidance have expanded and refined regulatory flexibility. While regulatory and financial incentives of the ODA have augmented involvement of pharmaceutical companies, clinicians, with patient advocacy groups and industry, need to conduct natural history studies, develop clinical outcome measures, and identify potential supportive surrogate endpoints predictive of clinical benefit, which together are critical foundations for clinical trials. Thus, the regulatory environment for novel therapeutic development is conducive and offers flexibility for mitochondrial diseases. Nevertheless, flexibility does not mean lower standards, as well‐controlled rigorous clinical trials of high quality are still required to establish the efficacy of potential therapies and to obtain regulatory agency approvals for their commercial use. This process is illustrated through the authors' ongoing efforts to develop therapy for thymidine kinase 2 deficiency.

中文翻译：

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线粒体疾病新疗法开发的监管环境

目前，欧洲只有一种获批治疗线粒体疾病的疗法，日本有另一种，美国没有。这些事实揭示了对这些使人衰弱且通常致命的疾病的批准疗法的重要且显着未满足的需求。为了满足这一需求，临床医生和药物开发人员与监管机构密切合作至关重要。在美国，线粒体疾病患者和临床医生、联合线粒体疾病基金会和制药行业成员已与食品和药物管理局合作，就这些复杂和异质性疾病以及获得新疗法批准的监管要求进行相互教育。1983 年美国孤儿药法案 (ODA) 以及日本和欧盟的类似立法促进了罕见疾病疗法的临床开发。进一步的立法和监管指导扩大和完善了监管灵活性。虽然官方发展援助的监管和财务激励措施增加了制药公司的参与，但临床医生需要与患者倡导团体和行业一起进行自然史研究，制定临床结果测量，并确定预测临床益处的潜在支持性替代终点，这些共同是临床试验的重要基础。因此，新疗法开发的监管环境是有利的，并为线粒体疾病提供了灵活性。然而，灵活性并不意味着降低标准，因为仍然需要进行严格控制的高质量临床试验来确定潜在疗法的功效并获得监管机构对其商业用途的批准。通过作者不断努力开发胸苷激酶 2 缺乏症的疗法来说明这一过程。