The Potential Benefit of Expedited Development and Approval Programs in Precision Medicine.

BACKGROUND: Increased understanding of the molecular causes of disease has begun to fulfill the promise of precision medicine with the development of targeted drugs, particularly for serious diseases with unmet needs. The drug approval regulatory process is a critical component to the continued growth of precision medicine drugs and devices. To facilitate the development and approval process of drugs for serious unmet needs, four expedited approval programs have been developed in the US: priority review, accelerated approval, fast track, and breakthrough therapy programs. METHODS: To determine if expedited approval programs are fulfilling the intended goals, we reviewed drug approvals by the US Food and Drug Administration (FDA) between 2011 and 2017 for new molecular entities (NMEs). RESULTS: From 2011 through 2017, the FDA approved 250 NMEs, ranging from 27 approvals in 2013 to 46 in 2017. The NME approvals spanned 22 different disease classes; almost one-third of all NMEs were for oncology treatments. CONCLUSIONS: As these pathways are utilized more, additional legislative changes may be needed to re-align incentives to promote continued development of innovative drugs for serious unmet needs in a safe, efficacious, and affordable manner.

Effects of Delivering SLCO1B1 Pharmacogenetic Information in Randomized Trial and Observational Settings.

BACKGROUND: Outcomes of tailoring statin-type based on solute carrier organic anion transporterfamily member 1B1 ( SLCO1B1)pharmacogenetic toxicity information on patient, provider, and pharmacological outcomes are unknown. METHODS: The trial randomized 159 patients not taking statins because of prior statin myalgia 1:1 to receiving SLCO1B1 GIST (Genotype Informed Statin Therapy) versus usual care (UC) and followed for up to 8 months. The UC arm received their SLCO1B1 results post-trial. The primary outcome was statin adherence using the Morisky Medication Adherence Scale, which was assessed in those patients who reinitiated statins. Secondary outcomes assessed in all participants included statin reinitiation and LDLc (low-density lipoprotein cholesterol), within and post-trial. Using commercial laboratory data, serial LDLc were compared between 1907 patients receiving SLCO1B1 testing and propensity-matched, untested controls. RESULTS: Trial participants were 25% SLCO1B1*5 carriers. Statin adherence was similar between arms (Morisky Medication Adherence Scale in GIST versus UC, 6.8±1.5 versus 6.9±1.6, P=0.96). GIST led to more new statin prescriptions (55.4% versus 38.0%, P=0.04) and lower LDLc at 3 months (131.9±42.0 versus 144.4±43.0 mg/dL; P=0.048) with similar magnitude at 8 months (128.6±37.9 versus 141.0±44.4; P=0.12). SLCO1B1*5 carriers exhibited a greater drop in LDLc with GIST versus UC (interaction P=0.048). Post-trial, LDLc decreased in UC participants who crossed over to GIST compared with those allocated to GIST (-14.9±37.8 versus +9.0±37.3 mg/dL, P=0.03). Patients tested for SLCO1B1 though a commercial laboratory had a greater LDLc decrease ( P=0.04) compared with controls. CONCLUSIONS: Delivery of SLCO1B1 pharmacogenetic testing that addresses statin myalgia improved statin reinitiation and LDLc but did not improve self-reported statin adherence. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01894230.

Community pharmacists' experience with pharmacogenetic testing.

OBJECTIVE: Appendix 1 Statements of knowledge of correct medication use Appendix 2 Statements of self-efficacy of correct medication use Appendix 3 Statements of skills of correct medication use To characterize the experiences and feasibility of offering pharmacogenetic (PGx) testing in a community pharmacy setting. DESIGN: Pharmacists were invited to complete a survey about PGx testing for each patient who was offered testing. If the patient consented, pharmacists were also asked to complete a follow-up survey about the process of returning PGx testing results to patients and follow-up with the prescribing provider. SETTING: Community pharmacies in North Carolina from August through November 2014. PARTICIPANTS: Pharmacists at five community pharmacies. MAIN OUTCOME MEASURES: Patient consent for testing, time to introduce PGx testing initially and communicate results, interpretation of test results, and recommended medication changes. RESULTS: Of the 69 patients offered testing, 56 (81%) consented. Pre-test counseling typically lasted 1-5 minutes (81%), and most patients (55%) did not have any questions about the testing. Most pharmacists reported test results to patients by phone (84%), with discussions taking less than 1 minute (48%) or 1-5 minutes (52%). Most pharmacists believed the patients understood their results either very well (54%) or somewhat well (41%). Pharmacists correctly interpreted 47 of the 53 test results (89%). All of the incorrect interpretations were for patients with test results indicating a dosing or drug change (6/19; 32%). Pharmacists reported contacting the ordering physician for four patients to discuss results indicating a dosage or drug change. CONCLUSION: The provision of PGx services in a community pharmacy setting appears feasible, requiring little additional time from the pharmacist, and many patients seem interested in PGx testing. Additional training may be necessary to improve test result interpretation, as well as for communication with both patients and ordering physicians.

Adding pharmacogenetics information to drug labels: lessons learned.

The US Food and Drug Administration approved a revised package insert for two cancer drugs to include information about the increased risk of severe adverse events owing to enzyme deficiencies caused by genetic variants. The label revisions stopped short of recommending or requiring pharmacogenetic testing prior to or following an adverse event. Despite (or because of) the lack of specific recommendations, we believe the actions taken by US Food and Drug Administration will have implications for pharmacogenetics research, clinical integration, and other policy considerations. We review the reasons behind the cautious label changes and discuss some of the lessons that can be learned from these experiences.

BP1, a homeodomain-containing isoform of DLX4, represses the beta-globin gene.

In earlier studies we identified a putative repressor of the human beta-globin gene, termed beta protein 1 (BP1), which binds to two silencer DNA sequences upstream of the adult human beta-globin gene and to a negative control region upstream of the adult delta-globin gene. Further studies demonstrated an inverse correlation between the binding affinity of the BP1 protein for the distal beta-globin silencer sequence and the severity of sickle cell anemia, suggesting a possible role for BP1 in determining the production of hemoglobin S. We have now cloned a cDNA expressing the BP1 protein. Sequencing revealed that BP1 is a member of the homeobox gene family and belongs to the subfamily called Distal-less (DLX), genes important in early development. Further analysis showed that BP1 is an isoform of DLX4. BP1 protein has repressor function towards the beta-globin promoter, acting through the two beta-globin DNA silencers, demonstrated in transient transfection assays. Strong BP1 expression is restricted to placenta and kidney tissue, with no expression in 48 other human tissues. BP1 exhibits regulated expression in the human erythroid cell line MB-02, where its expression decreases upon induction of the beta-globin gene. BP1 is thus the first member of the DLX family with known DNA binding sites and a function in globin gene regulation.