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M-07: Efficacy of Unapproved Drugs in Compassionate use in Comparison With Clinical Trial Results: A Systematic Review

Poster Presenter

      Mio Saito

      • PAREXEL Clinical Research Services
      • PAREXEL International Inc.


To compare the efficacy of unapproved drugs used in compassionate use (CU) programs in US, EU and, Japan, with the efficacy reported in the pivotal phase III trials for marketing authorization in those regions


We performed a systematic review of the literature of unapproved drug used under CU program conducted in US, EU and Japan. The primary efficacy endpoint reported in the CU program was compared with the efficacy endpoint reported in the pivotal phase III trials for marketing authorization


Literature search was conducted using PubMed, Embase, Cochrane, etc., including Japanese databases, with the keywords “compassionate use“ and “expanded access”. 1,826 titles were hit, and of those the ones unrelated to the CU clinical results were excluded by reviewing their titles and abstracts. In the second extraction, two independent reviewers reviewed 183 papers by full text reading, whether to meet the following criteria; (1) the therapeutic indication, posology and route of administration used in CU was the same in the pivotal clinical trials, (2) CU should be concerned with unapproved drugs and (3) medicines authorized by Centralized Procedure when the CU carried out in EU. The papers describing the CU using the same efficacy endpoint used in the corresponding pivotal trials for marketing authorization were adopted. The nine CU papers from EU and US were adopted for comparison. No Japanese CU report was extracted. Those CU programs included six anti-cancer drugs, trabectedine, vemurafenib, plerixafor, azacitidine, cabazitaxel, and lenalidomide, and one anti-hepatitis C virus drug, boceprevir. The endpoints used for anti-cancer drugs except for plerixafor were overall survival, progression-free survival and overall response. Three papers described the efficacy results of different plerixafor CU programs, which used the endpoint based on attainment of CD34+ cell count. The vemurafenib CU paper presented the results of two patient groups with/without brain metastasis. Better efficacy results were reported for the CU programs of plerixafor, trabectedine and lenalidomide than in the pivotal trials. The efficacy of vemurafenib (without brain metastasis) and another plerixafor CU were approximately the same as one reported in the pivotal trials. Less efficacy in the CU programs of boceprevir, azacitidine, cabazitaxel, and vemurafenib (with brain metastasis) and the other plerixafor CU program was reported than the one reported in the pivotal trials.


In the US, the CU system was officially established for the patients suffering from a disease for which no other satisfactory authorized treatment alternative exists and for who were unable to enter a clinical trial in 1987. In EU, Directive 89/341/EEC institutionalized the system in which the member states were able to distribute unapproved drugs from the humanitarian standpoint in 1989, and CU was legislated as the regulation in 2004. CU was also implemented in Japan in April 2016. However, it has not been studied whether the efficacy in CU program is comparable to the one in the corresponding pivotal phase III trials or not. In the present systematic review of CU program literature, five of nine CU programs presented better or equal efficacy compared with the ones reported in the pivotal trials. Since patient population under CU programs is rather small and generally worse in condition compared with those in clinical trials, the efficacy of CU programs seem unlikely to be comparable to the one in clinical trials. However, our result suggests that CU programs may be beneficial for the patients who suffer from a disease for which no satisfactory treatment alternative exists and who cannot enter a clinical trial if caution is sufficiently and deliberately exercised. We hope that such patients make use of CU system effectively. Additional authors: Shihori Furuhata, Nanae Tanemura, Hisashi Urushihara

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