Biologics are essential to oncology care. As patents for older biologics begin to expire, the United States is developing an abbreviated regulatory process for the approval of similar biologics (biosimilars), which raises important considerations for the safe and appropriate incorporation of biosimilars into clinical practice for patients with cancer. The potential for biosimilars to reduce the cost of biologics, which are often high-cost components of oncology care, was the impetus behind the Biologics Price Competition and Innovation Act of 2009, a part of the 2010 Affordable Care Act. In March 2011, NCCN assembled a work group consisting of thought leaders from NCCN Member Institutions and other organizations, to provide guidance regarding the challenges health care providers and other key stakeholders face in incorporating biosimilars in health care practice. The work group identified challenges surrounding biosimilars, including health care provider knowledge, substitution practices, pharmacovigilance, naming and product tracking, coverage and reimbursement, use in off-label settings, and data requirements for approval.

The co-crystal X-ray structures of two isomeric α-ketooxazole inhibitors (1 (OL-135) and 2) bound to fatty acid amide hydrolase (FAAH), a key enzymatic regulator of endocannabinoid signaling, are disclosed. The active site catalytic Ser241 is covalently bound to the inhibitors' electrophilic carbonyl groups, providing the first structures of FAAH bound to an inhibitor as a deprotonated hemiketal mimicking the enzymatic tetrahedral intermediate. The work also offers a detailed view of the oxyanion hole and an exceptional "in-action" depiction of the unusual Ser-Ser-Lys catalytic triad. These structures capture the first picture of inhibitors that span the active site into the cytosolic port providing new insights that help to explain FAAH's interaction with substrate leaving groups and their role in modulating inhibitor potency and selectivity. The role for the activating central heterocycle is clearly defined and distinguished from that observed in prior applications with serine proteases, reconciling the large electronic effect of attached substituents found unique to this class of inhibitors with FAAH. Additional striking active site flexibility is seen upon binding of the inhibitors, providing insights into the existence of a now well-defined membrane access channel with the disappearance of a spatially independent acyl chain-binding pocket. Finally, comparison of the structures of OL-135 (1) and its isomer 2 indicates that they bind identically to FAAH, albeit with reversed orientations of the central activating heterocycle, revealing that the terminal 2-pyridyl substituent and the acyl chain phenyl group provide key anchoring interactions and confirming the distinguishing role of the activating oxazole.

A series of C4 substituted α-ketooxazoles were examined as inhibitors of the serine hydrolase fatty acid amide hydrolase in efforts that further define and generalize a fundamental substituent effect on enzyme inhibitory potency. Thus, a plot of the Hammett σ m versus -log K i provided a linear correlation (R 2 = 0.90) with a slope of 3.37 (ρ = 3.37) that is of a magnitude that indicates the electronwithdrawing character of the substituent dominates its effects (a one unit change in σ m provides a >1000-fold change in K i ).Fatty acid amide hydrolase (FAAH) 1,2 is the enzyme that serves to hydrolyze endogenous lipid amides 3,4 including anandamide (1a) 5 and oleamide (1b), 6 Figure 1. Its distribution is consistent with its role in degrading and regulating such signaling fatty acid amides at their sites of action. 3 Although it is a member of the amidase signature family of serine hydrolases, for which there a number of prokaryotic enzymes, it is currently the only characterized mammalian enzyme bearing the family's unusual Ser-Ser-Lys catalytic triad. 7,8 Due to the therapeutic potential of inhibiting FAAH 9 especially for the treatment of pain, 10 inflammation, 11 or sleep disorders, 12 there has been increasing interest in the development of selective and potent inhibitors of the enzyme. 9 Early studies shortly following the initial discovery and characterization of FAAH led to the demonstration that the endogenous sleepinducing molecule 2-octyl α-bromoacetoacetate is an effective FAAH inhibitor, 13 the disclosure of a series of nonselective, reversible inhibitors bearing an electrophilic ketone (e.g., trifluoromethyl ketone-based inhibitors), 14,15 and the reports of a set of irreversible inhibitors 16 (e.g., fluorophosphonates and sulfonyl fluorides). To date, two classes of inhibitors have been disclosed that provide opportunities for the development of inhibitors with therapeutic potential. One class is the reactive aryl carbamates and ureas 17-24 that irreversibly acylate a FAAH active site serine. 25 A second class is the α-ketoheterocycle-based inhibitors 26-29 that bind to FAAH via reversible hemiketal formation with an active site serine. Many of these latter competitive inhibitors are not only potent and extraordinarily selective for FAAH versus other mammalian serine hydrolases, but members of this class have been shown to be efficacious analgesics in vivo. 28In the course of these latter studies, we disclosed a fundamental substituent effect in which a well-defined correlation between the electronic character of a para substituent (Hammett σ p ) and the inhibitor potency (−log K i ) was observed. 27 Thus, the inhibitor potency was found to *Corresponding author: email boger@scripps.edu. Whereas the former para substituents are directly conjugated with the electrophilic carbonyl, the meta substituents would exert their effects through their inductive electron-withdrawing properties. Moreover and although intuitive expectations might suggest that such a nonconjugated substituent effect might...

Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decision-making is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility from clinical, scientific, and coverage policy standpoints. The NCCN Molecular Testing Work Group identified challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence.

The quality of patient care varies based on numerous factors, such as health care setting, geographic location, access to medications, insurance coverage, and treatment protocols. Recently, the issue of whether use of clinical pathways can reduce costs and inappropriate variability in care has been the subject of much debate. As clinical treatment guidelines and pathways are increasingly deployed in oncology practice, they have a growing impact on the quality of treatment and how it is delivered. To fulfill the current need to discuss the use of pathways and clinical treatment guidelines in oncology and to address how patient care is impacted by their use, the National Comprehensive Cancer Network convened the NCCN Oncology Policy Summit: Equity in Cancer Care-Pathways, Protocols, and Guidelines. The summit was a forum to discuss the use and implementation of pathways, including how much flexibility pathways should allow in care, pathways' impact on public and private health insurance benefit design, what data is used to select pathway regimens and protocols, and ultimately what impact pathways may have on variation in care. The use and implementation of clinical treatment guidelines in practice was also explored from a variety of perspectives.