This article explores the circumstances under which providers and patients should

This article explores the circumstances under which providers and patients should be able to attempt drugs or combinations for indications for which we still lack formal clinical trials. approved can be used alone or in combination for many others the core question of expanded access is: Under what circumstances should providers and patients be able to attempt drugs or combinations for indications for which we still lack formal clinical trials? At the outset let us stipulate that we consider this question only as it pertains to off-protocol use of these drugs (i.e. use outside of clinical trials) and for patients who have exhausted all proven therapies. When clinical trials are an option we encourage their enrollment and the ethics of such trials has been extensively discussed. But outside of trials few articles have tackled the off-protocol use of drugs for unapproved uses although authors have recognized that this is a key challenge in clinical medicine [1] and such use is common. It must also be remembered Canertinib that off-label use often pertains to cancer drugs with annual costs in Canertinib excess of $100 0 [2]; thus financial implications of this use are large. As an example one of us recently faced the question of whether for a patient with relapsed refractory multiple myeloma it was permissible to treat with daratumumab a monoclonal antibody approved as single agent in Mouse monoclonal to 4E-BP1 combination with pomalidomide-a combination that has demonstrated relative safety in phase I trials but lacks phase II or phase III efficacy results (i.e. no proof that the combination is better than either agent alone). These kinds of Canertinib questions are frequently encountered in clinical oncology although reliable statistics are absent. For patients with relatively good performance status who are interested in pursuing more treatment but who have exhausted recommended options many Canertinib oncologists attempt single drugs or combinations that are not yet vetted. We believe that a pragmatic framework can aid in such decisions. While we admit there is no canonical answer for what is best we believe consideration of three factors may frame this topic. These factors are safety efficacy and cost and are depicted in Figure 1. Figure 1. Decision-making model for off-protocol use of the novel treatment combination of daratumumab and pomalidomide in clinical oncology. * For compelling but still hypothesis-generating subgroups and relatively low toxicity interventions. Safety It should be remembered that novel drugs and their combinations may have unexpected safety signals. For example vemurafenib a small molecule inhibitor of BRAF and ipilimumab an antibody against an immunologic checkpoint are individually active in BRAF V600E mutant metastatic melanoma but the combination demonstrated adverse hepatic toxicity in 66%-75% of patients when combined in a phase I study requiring the trial to be halted [3]. Notably this toxicity could not have been predicted because the drugs have distinct (and non-interacting) mechanisms of action and non-overlapping toxicities. Thus clinicians must consider that safety exists on a continuum with drugs or combinations for which either no safety data exist (i.e. no phase I trials) phase I trial data exist and show relative Canertinib safety at usual doses or phase I trial data exist and confirm toxicity (e.g. the case of vemurafenib and ipilimumab). In all cases where phase I trial data demonstrate toxicity precluding further drug development or are absent we do not believe combinations should be attempted irrespective of cost. Efficacy The majority of cancer drug approvals are based on a surrogate endpoint which may or may not predict improved survival or quality of life-true patient-centered efficacy endpoints. Moreover just 8% of National Comprehensive Cancer Network guidelines are based on level I evidence [4]. For these reasons it is incredibly common that oncologists have to make treatment recommendations for patients while lacking strong evidence that our choices either improve survival or quality of life [1] over placebo [2] or other available standards of care. In some cases however randomized trials may have been performed and the results may be positive or negative. In the latter case (well-done negative randomized trials) we believe that insurers should not be asked to pay for refuted treatments. For example societal payers should not pay for sorafenib in the adjuvant setting of hepatocellular cancer. In some cases of contradicted practices with severe toxicity no provider should offer the treatment regardless of patient desire.