In an age where new chemical entity drug development can average 15 years to complete and only 0.1% of drugs advance from early drug discovery to approval, a different approach is needed to address a pandemic like COVID-19.
“Drug repurposing” and the request of an Emergency Use Authorization (EUA) are two approaches that can address the speed of development during emergency situations.
通过药物重新施加策略，分析了具有最小的部分非临床和临床数据集的化合物，用于对新治疗靶标进行效用。其中一些化合物可能已经取得营销授权;其他人可能没有达到原始疗效基准，他们的发展被停产。在任何一种情况下，选择合适的化合物以便为新的给药和/或指示提供新的途径，可以显着降低开发成本并提高市场速度。
While drug repurposing can shorten the development timeline, it is still incumbent upon the sponsor to determine if the efficacy and safety profile of the candidate drug supports the new route of administration and indication before filing their IND or EUA request. The FDA’s guidance entitled “Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route“（2015），提供具体建议。
The concept of an EUA is described in “Emergency Use Authorizations of Medical Products and Related Authorities; Guidance for Industry and other Stakeholders“（2017）。The therapies for which an EUA can be requested include drugs (e.g., antivirals and antidotes), biological products (e.g., vaccines, blood products, and biological therapeutics), and devices (e.g., in vitro diagnostics and personal protective equipment) when there are no adequate, approved and available alternatives to address the subject unmet medical need. If granted, the EUA is a temporary measure put in place for national safety; an EUA does not circumvent the need to complete the standard IND and NDA/BLA or other processes to maintain long-term patient access to the product.
Incorporating scientific considerations for an EUA request
欧洲央行计划奠定了FDA改变标准审查和批准过程，以使涉及化学，生物，放射性和核（CBRN）药剂的未满足医疗需求的药物，包括新出现的传染病等Covid-19流行病。它还为评估这些药物适用于将进化的进展提供给人类试验的许多科学考虑。赞助商应考虑在考虑重新调整药物并要求EUA时考虑以下科学问题，如上所述FDA.’s Emergency Use Authorization of Medical Products and Related Authorities:
- 药物是否已经取得了营销批准？
- If not already approved, how much nonclinical and clinical data are available to support the safety and mechanism of action of the drug?
- Any information on safety associated with use in humans of this or related compounds should be submitted, including that from other than well-controlled clinical trials.
- Can the new therapeutic indication be effectively treated with the route of administration and dose/formulation for which safety and efficacy data were previously collected?
- 是否有关于产品的作用机制和适用于受试者疾病的强大数据？
- It is unlikely that comprehensive effectiveness data would be available for every EUA candidate. Therefore, authorization of an EUA will also depend on the circumstances of the CBRN emergency, as well as available knowledge about the product’s safety profile.
- 是关于药物的药理/有效性，药代动力学或毒性的数据，这些药物可用的药物可以有助于了解人类的潜在影响？
- 是来自动物疗效研究的数据可用于产品或正在开发的产品。Product Development Under the Animal Rule; Guidance for Industry” (2015)?
- 是药物的风险福利概况，用于新迹象相同或更好是最初开发的指示？
- FDA希望根据临床状况，替代诊断，预防或替代疗法（如果有的话）以及紧急情况或紧急威胁的具体情况来解释安全信息。
- 是否有关评估活动，有效性和剂量（例如，公布的案例报告，不受控制的试验，受控试验以及任何其他相关人类使用经验）有关的证据是有关的
- For drugs, is data available to support the proposed dosage for the intended use (including pharmacokinetics and pharmacodynamics data, and for vaccines or antibody therapies, immunogenicity and/or achievement of protective levels of relevant parameters of immunity)?
Preparing an integrated assessment for an EUA
The generation of a well-developed integrated assessment of the available data will be a key stepping stone in the pursuit of an EUA request. The content and format of the assessment will include many of the elements of a traditional IND application, including the submission of comprehensive study reports, tabulated group and individual data for both nonclinical and clinical studies with regulatory compliance status duly noted (GLP or GCP, respectively). The dossier will also include a comprehensive description of the available Chemistry Manufacturing and Control (CMC) data for the candidate drug.
If the assessment demonstrates that the existing dataset is fully supportive of the new indication, then it may be feasible to request an EUA based solely on the integrated assessment described above and a letter of cross reference granted by the holder of the previously approved marketing authorization.
If the new use of a previously approved drug poses a unique risk to the targeted patient population (e.g., inconsistent with the originator product), then information from additional in vitro studies, animal studies and clinical studies would be required before an EUA could be granted.
For repurposed drugs which did not achieve a prior marketing authorization, the FDA’s expectations for consideration of an EUA request will include submission of available in vitro and in vivo safety pharmacology, pharmacokinetic and toxicology data. As available, human safety information from clinical trials and individual patient experience must be provided. A comprehensive assessment of correlation between exposure and toxicity should be conducted for any nonclinical data submitted and use of modeling and simulation approaches to estimating human exposure are encouraged.
Regardless of the prior approval status of the drug, the FDA’s expectations for an EUA include the following, again from the documentEmergency Use Authorization of Medical Products and Related Authorities:
- A discussion of the candidate product’s known and potential risks and benefits based upon the integrated data assessment described above;
- 计划减轻风险或优化治疗益处的措施计划;
- A description of limitations, uncertainty and data gaps;
- A description of circumstances, if any, under which the product should not be used (e.g., contraindications);
- 在某种程度上已知，有关CBRN代理（实际上或潜在）所涉及的威胁的信息以及可能与评估风险和福利有关的涉及和预期的响应和运营考虑因素。
寻找药物开发伙伴
如果合作CRO,赞助商应该考虑到der a partner with end-to-end scientific and strategic tools and capabilities to provide guidance through the entire duration of the drug development process. Whether developing an NME or repurposing a previously evaluated drug, a partner should offer comprehensive services ranging from in vitro and animal efficacy models in which to evaluate candidates against corona viruses, the nonclinical development capabilities to conduct any necessary nonclinical bridging studies and the support of swift progression through the regulatory process to advance efficiently into the clinical investigations around your new therapy. With a goal in support of your drug repurposing efforts, a CRO should ultimately identify a scientifically sound yet time and resource efficient plan to progress your program into clinical trials.
了解Covance如何加速您的drug repurposingefforts during COVID-19.
