News & Views: 24th FDA Commissioner, Drug importation from Canada, Center of Excellence for drug compounding, Acute pain opioid prescribing, Generic drug pricing, Operation Vapor Lock, Naloxone and opioid overdose, 2019-2020 Flu season

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Stephen Hahn, MD, confirmed as the 24th FDA Commissioner

  • Radiation Oncologist with Residency at the National Cancer Institute
  • Professor at University of Pennsylvania
  • Chief Medical Executive at MD Anderson Cancer Center

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Steps to lower U.S. prescription drug prices

Allow importation of certain prescription drugs shipped from Canada

  • Purpose of proposed rule is to lower prices and reduce out of pocket costs
  • Foreign seller, licensed by Health Canada and registered with FDA, to purchase directly from manufacturer
  • US importer, subject to the supply chain security requirements, to buy directly from foreign seller
  • Importer arranges for statutorily prescribed testing for authenticity, degradation, and other requirements by a qualifying US laboratory
  • Post-importation requirements including adverse event, medication error, field alert to manufacturer and to FDA

NPRM


CaptureImproving quality of compounded drugs

Novel approaches to reduce risks with production practices of outsourcing facilities 

  • Establishing Compounding Quality Center of Excellence to enhance collaboration among and provide educational programs for outsourcing facilities
  • Three main areas of focus: in-person, online education and trainings, conference to exchange ideas and best practices, market research help inform FDA on key issues

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Capture.JPGCapture.JPGNational Academies of Sciences, Engineering, and Medicine (NASEM) report on framing opioid prescribing guidelines for acute pain

FDA contracted NASEM for evidence-based guidelines for opioid analgesic prescribing for acute pain. NASEM recommendations are:

  • Develop an analytic framework (e.g., Figure above ) to develop and assess evidence base for clinical practice guidelines (CPG)
  • Outpatient opioid prescribing CPGs should explicitly state patient populations  (e.g., adults versus children) and contextual aspects (e.g. setting, prescriber type, prior treatments)
  • To determine optimal opioid prescribing strategies, examine not only intermediate outcomes (e.g. pills prescribed, unused, long-term opioid use), but also the short- and long-term health outcomes (e.g. mortality, overdose, opioid use disorder, pain, and function)
  • Well-designed observational and quality improvement initiatives helpful for evaluating the effects of opioid prescribing strategies on health outcomes
  • CPGs should be implemented by governmental (federal, state, and local) and nongovernmental entities
  • Prioritized surgical and medical indications listed for CPG development
  • State the role of opioid alternatives as first-line therapies, specify any other interventions, including nonopioid interventions, used to relieve pain

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Capture.JPGGreater Generic Competition and Lower Generic Drug Prices

  • New analysis showing greater competition among generic drug makers associated with lower generic drug prices
  • With six or more competitors,  price reductions of >95% compared to brand prices before generic entry
  • FDA helping bring greater efficiency and transparency to generic drug review process to encourage competition

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Capture.JPGOperation Vapor Lock seized sale of  illicit THC vaping cartridges 

FDA and DEA have seized 44 websites advertising the sale of illicit THC vaping cartridges 

  • Website advertising under various brand names with information indicating sale items would be considered a controlled substance under federal law
  • Some websites solely to fraudulently obtain payments without intending to mail product

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Capture.JPGHaving Naloxone on Hand Can Save a Life During an Opioid Overdose

Naloxone is a life-saving drug that, when sprayed into the nose or injected, quickly reverses the powerful effects of opioids during an overdose

  • Expanded availability by allowing consumers to get directly from pharmacist, by putting a “standing order”
  • Need to recognize opioid overdose and use Naloxone
  • Will not harm if no opioids in system
  • Discuss Naloxone when getting opioid prescription

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Capture.JPG2019-2020 Influenza season

Flu vaccine lots that have been released by FDA and are available for distribution by the manufacturers

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Image credit: FDA

Medicines and Driving

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Some Medicines and Driving don’t Mix

  • Some prescription and nonprescription medicines have side effects and cause reactions that may make it unsafe to drive (e.g.opioid pain relievers, anti-anxiety, anti-seizure drugs, antipsychotic, antidepressants, codeine)
  • Cannabidiol (CBD) products and driving can be dangerous
  • Some sleep medicines can impair even the next morning
  • Allergy medicines can affect ability to drive

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Image credit: FDA

Drug Authorizations: OXBRYTA and ADAKVEO for sickle cell, XCOPRI for partial-onset seizures, CALQUENCE for leukemia/lymphoma, GIVLAARI for acute hepatic porphyria

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OXBRYTA (voxelotor) tablets

Global Blood Therapeutics

INDICATION FOR USE: Treatment of sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older.

ADDRESSING UNMET NEED: Treatment option for 100,000 people in the U.S., and the more than 20 million globally, who live with this debilitating blood disorder

MECHANISM OF ACTION: Hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs) – increasing the affinity of Hb for oxygen

EFFICACY:

  • Randomized, double-blind, placebo-controlled, multicenter trial, n=274 patients with sickle cell disease, OXBRYTA vs. placebo
  • Endpoint: Hb response rate defined as a Hb increase of >1 g/dL from baseline to Week 24
  • 51.1% (OXBRYTA) vs. 6.5% (placebo),  (p < 0.001); no outlier subgroups observed

SAFETY:

  • Common side effects: Headache, diarrhea, abdominal pain, nausea, fatigue, rash and pyrexia

REGULATORY PATHWAY: NDA

  •  Accelerated Approval, Fast Track designation. Orphan Drug designation
  • Accelerated approval requirements: Phase 3, randomized, doubleblind, placebo-controlled trial in pediatric patients (age 2 years to < 15 years) with Sickle Cell Disease , long-term (5 years) followup

LABEL


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ADAKVEO (crizanlizumab-tmca) injection

Novartis

INDICATION FOR USE: Reduce the frequency of vasoocclusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease.

ADDRESSING UNMET NEED: First targeted therapy approved for sickle cell disease, specifically inhibiting selectin, a substance that contributes to cells sticking together and leads to vaso-occlusive crisis- a painful condition

MECHANISM OF ACTION: Humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.

EFFICACY:

  • 52-week, randomized, multicenter, placebo-controlled, double-blind study, n=198 patients with sickle cell disease, any genotype, ADAKVEO vs placebo
  • Endpoint: Annual rate of vaso-occlusive crisis (VOC) to a healthcare visit
  • Median annual rate of 1.63 visits (ADAKVEO) vs. 2.98 visits (placebo)
  • 36%  on Adakveo did not experience VOC during the study, delayed the time of first VOC experience

SAFETY:

  • Common side effects: Back pain, nausea, pyrexia, arthralgia
  • Need to monitor patients for infusion-related reactions,  interference with automated platelet counts or platelet clumping

REGULATORY PATHWAY: BLA

  •  Priority Review and Breakthrough Therapy designation, Orphan Drug designation
  • Postapproval requirements: Further evaluation of immune mediated safety

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XCOPRI® (cenobamate tablets)

SK Lifesciences

INDICATION FOR USE: Treatment of partial-onset seizures in adult patients

ADDRESSING UNMET NEED: New option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life

MECHANISM OF ACTION: Precise mechanism unknown; demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents

EFFICACY:

  • Two multicenter, randomized, double-blind, placebo-controlled studies, N=655 adult patients
  • Endpoint: % change from baseline in seizure frequency per 28 days in the treatment period
  • 55.6%  reduction (XCOPRI 200 mg) vs 21.5% reduction (placebo), p< 0.0001

SAFETY:

  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),  shortening of the QT interval and ventricular fibrillation – dose needs to be titrated
  • Increased risk of suicidal thoughts or behavior and other neurological adverse reactions
  • Most common side effects: Somnolence (sleepiness), dizziness, fatigue, diplopia (double vision), headaches

REGULATORY PATHWAY: NDA

  • Contains cenobamate – (Controlled substance schedule to be determined after review by the Drug Enforcement Administration
  • Required pediatric assessments

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CaptureCapture.JPGCALQUENCE® (acalabrutinib) capsules

AstraZeneca

INDICATION FOR USE: treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

EFFICACY & SAFETY:

  • Two randomized, actively controlled trials in patients with CLL
  • Endpoint:  Progression-free survival (PFS) as assessed by independent review; significantly improved in both acalabrutinib arms, p<0.0001
  • Most common adverse reactions: Anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, diarrhea

REGULATORY PATHWAY: Supplemental NDA

  • First approved in 2017 
  • This review conducted under Project Orbis, framework for concurrent submission and review by FDA, the Australian Therapeutic Goods Administration, and Health Canada
  • FDA review used the Real-Time Oncology Review (RTOR) and Assessment Aid pilot programs, to sreamline data submission, Priority Review and Breakthrough Therapy designation

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CaptureGIVLAARI (givosiran) injection

Alnylam Pharmaceuticals

INDICATION FOR USE: Treatment of adults with acute hepatic porphyria (AHP)

MECHANISM OF ACTION: Double-stranded small interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes;  leads to reduced circulating levels of neurotoxic intermediates aminolevulinic acid
(ALA) and porphobilinogen (PBG), factors associated with attacks and other disease manifestations of AHP

EFFICACY: 

  • Randomized, double‑blind, placebo‑controlled, multinational trial, n=94 patients with AHP, GIVLAARI vs placebo
  • Endpoint: Rate of porphyria attacks requiring hospitalizations, urgent healthcare visit, or intravenous hemin administration at home
  • 1.9 (95% CI:1.3,2.8) with GIVLAARI vs, 6.5 (95% CI:4.5, 9.3) with placebo
  • 70% (95% CI: 60%, 80%) fewer porphyria attacks with GIVLAARI

SAFETY:

  • Most common adverse reactions: Nausea and injection site reactions
  • Warnings for anaphylactic reactions, hepatic and renal toxicities, and injection site reactions

REGULATORY PATHWAY: NDA

  • Priority Review, Orphan product, Breakthrough Therapy designations
  • Postmarketing commitments: Trial in pediatric patients age greater than or equal to 12 years to less than 17 years with AHP

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Image credit: Global Blood Therapeutics, Novartis, SK Lifesciences, AstraZeneca, Alnylam

 

 

CURE ID crowdsourcing App for novel uses of existing medicines

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 CURE ID app for health care professionals to report novel uses of existing medicines for patients with difficult-to-treat infectious diseases

Allow clinical community to report experiences treating difficult-to-treat infectious diseases with novel uses of existing FDA-approved drugs

  • Focus on infectious diseases lacking adequate treatments, neglected tropical diseases, emerging infectious drug-resistant threats
  • Collects simple case report form from caregivers about experience using an approved product for an unapproved use
  • Organizes and analyzes data fast for promising new uses for existing drugs
  • Collaboration between FDA and the National Center for Advancing Translational Sciences (NCATS), NIH

https://cure.ncats.io

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Image credit: FDA