Drug and Vaccine Authorizations: EVENITY for osteoporosis, DENGVAXIA for Dengue, MAVYRET for Hep C in children, BENLYSTA in SLE, TIBSOVO for AML, VYNDAQEL/VYNDAMAX for cardiomyopathy, RUZURGI for LEMS

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EVENITY (romosozumab-aqqg) injection, for subcutaneous use 

Amgen

INDICATION FOR USE: Treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy
Limitations of Use : Anabolic effect wanes after 12 monthly doses of therapy. Therefore, the duration of EVENITY use should be limited to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered

ADDRESSING UNMET NEED:
  • > 10 million US women osteoporosis; weakened bones likely to fracture
  • Approval provides women with postmenopausal osteoporosis with high risk of fracture with a new treatment

MECHANISM OF ACTION: Monoclonal antibody that inhibits action of sclerostin, a regulatory factor in bone metabolism; increases bone formation and, to a lesser extent, decreases bone resorption

EFFICACY:
  • 2 randomized, double-blind studies, placebeo and alendronate controlled respectively, n>11,000 women with postmenopausal osteoporosis
  • Endpoints: Risk of a new fracture in spine (vertebral fracture): 73% lowered risk vs. placebo, maintained over the second year of trial when Evenity.  50% lowered risk vs. two years of alendronate alone
  • Evenity followed by alendronate reduced risk of fractures in other bones (nonvertebral fractures) vs. alendronate alone
SAFETY:
  • Boxed Warning: Potential risk for myocardial infarction, stroke and cardiovascular death
  • Common side effects: Joint pain, headache, injection site reactions
REGULATORY PATHWAY: BLA
  • Pediatric assessments: Waived; do not apply to population
  • Postmarketing requirements: Cardiovascular safety

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DENGVAXIA (Dengue Tetravalent Vaccine, Live) Suspension for Subcutaneous Injection

Sanofi Pasteur

INDICATION FOR USE: indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4. DENGVAXIA is approved for use in individuals 9 through 16 years of age with laboratory-confirmed previous dengue infection and living in endemic areas
Limitations of use: Not approved for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown; Safety and effectiveness have not been established in individuals living in dengue non-endemic areas who travel to dengue endemic areas

ADDRESSING UNMET NEED:

  • FDA committed to working with CDC and WHO to combat public health threats
  • Approval is important step toward reducing impact of virus in endemic US regions

MECHANISM OF ACTION: Elicits dengue-specific immune responses against four dengue virus serotypes

EFFICACY:

  • Three randomized, placebo-controlled studies, n=35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and Asia Pacific region, 9-16 years of age
  • Endpoint: Symptomatic virologically-confirmed dengue (VCD); DENGVAXIA 76%  effective in preventing VCD in individuals who previously had laboratory- confirmed dengue disease

SAFETY: 

  • Most commonly reported side effects: Headache, muscle pain, joint pain, fatigue, injection site pain and low-grade fever

REGULATORY PATHWAY: BLA

  • Priority Review and a Tropical Disease Priority Review Voucher
  • Postmarketing Study Requirement/Commitments: Safety and effectiveness in children 2 to < 9 years of age

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MAVYRET (glecaprevir and pibrentasvir) tablets

AbbVie

INDICATION FOR USE: Treatment of adult and pediatric patients 12 years and older or weighing at least 45 kg with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A)

ADDRESSING UNMET NEED:  First treatment for all genotypes of hepatitis C in pediatric patients

MECHANISM OF ACTION: Fixed-dose combination of glecaprevir and pibrentasvir, which are direct-acting antiviral agents against the hepatitis C virus

EFFICACY:

  • Open-label study, n=47  adolescent subjects 12 -< 18 years  with genotype 1, 2, 3 or 4 HCV infection without cirrhosis or with mild cirrhosis, 8 or 16 weeks.
  • 100% had no virus detected in blood 12 weeks after finishing treatment, suggesting  infection had been cured

SAFETY:

  • Adverse reactions observed were consistent with those observed in adults
  • Most commonly reported adverse reactions: Headache and fatigue

REGULATORY PATHWAY: Supplemental NDA

  • Initial US approval (NDA) in adult patients in 2017

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BENLYSTA (belimumab) intravenous infusion

GlaxoSmithKline

INDICATION FOR USE: Treatment of patients aged 5 years and older with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy

ADDRESSING UNMET NEED:

  • First treatment for pediatric patients with Systemic Lupus Erythematosus (SLE)
    • Benlysta has been approved for use in adult patients since 2011

EFFICACY:

  • International, randomized, doubleblind, placebo-controlled, 52-week, n=93  pediatric patients with a clinical diagnosis of SLE
  • Primary efficacy endpoint: SLE Responder Index (SRI-4) at Week 52; numerically higher patients achieving a response in SRI-4 with BENLYSTA vs. placebo

SAFETY:

  • Warning for mortality, serious infections, hypersensitivity and depression
  • Most common side effects: Nausea, diarrhea and fever, infusion reactions

REGULATORY PATHWAY: sBLA, Priority review

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TIBSOVO (ivosidenib) tablets

Agios Pharmaceuticals

RealTime IDH1 Assay

Abbott

INDICATION FOR USE: Treatment of newly-diagnosed acute myeloid leukemia (AML)  with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adult patients who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy

ADDRESSING UNMET NEED: First-line treatment for AML with IDH1 mutation

EFFICACY:

  • Open-label, single-arm, multicenter clinical trial, n=28 (newly-diagnosed AML with IDH1 mutation detected by Abbott RealTimeTM IDH1 Assay
  • Endpoints: Rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, conversion rate from transfusion dependence to transfusion independence
  • CR+CRh :42.9%, 41.2% achieved transfusion independence lasting at least 8 weeks

SAFETY:

  • Boxed Warning for Differentiation Syndrome which may be life-threatening or fatal
  • Adverse reactions: Diarrhea, fatigue, edema, decreased appetite, leukocytosis, nausea, arthralgia, abdominal pain, dyspnea, differentiation syndrome and myalgia

REGULATORY PATHWAY: sNDA

  • Used Real-Time Oncology Review pilot program
  • Priority Review and Orphan Product designation
  • Postmarketing requirement: Determine safe dose in mild, moderate and severe hepatic impairment

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VYNDAQEL (tafamidis meglumine) and VYNDAMAX (tafamidis) capsules 

FoldRx (Pfizer subsidiary)

INDICATION FOR USE: Treatment of cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization

ADDRESSING UNMET NEED:

  • Transthyretin-mediated amyloidosis is rare, debilitating, often fatal disease
  • Approval an important advancement in treatment of cardiomyopathy caused by transthyretin-mediated amyloidosis

MECHANISM OF ACTION: Selective stabilizer of TTR;  slows dissociation into monomers, the rate-limiting step in the amyloidogenic process

EFFICACY:

  • Multicenter, international, randomized, double-blind, placebo-controlled study
    n=441 patients with wild type or hereditary ATTR-CM
  • Endpoints: All-cause mortality and frequency of cardiovascular-related hospitalizations
  • Significant reduction (p=0.0006) in all-cause mortality and frequency of
    cardiovascular-related hospitalizations with Vyndaqel / Vyndamax group

SAFETY:

  • No drug-associated side effects identified
  • May cause fetal harm when administered to pregnant woman

REGULATORY PATHWAY: NDA

  •  Fast Track, Priority Review and Breakthrough Therapy designations
  • Orphan Drug designation

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RUZURGI (amifampridine) tablets 

Jacobus Pharmaceutical Company

INDICATION FOR USE: Treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age

ADDRESSING UNMET NEED:

  • LEMS is a rare autoimmune disorder affecting connection between nerves and muscles
  • First approved treatment for LEMS specifically in children

MECHANISM OF ACTION: Broad spectrum potassium channel blocker

EFFICACY:

  • Randomized, double-blind, placebo-controlled withdrawal study
  • Primary measure of efficacy: Change in Triple Timed Up and Go test (3TUG)  and self-assessment scale for LEMS-related weakness
  • Less impairment with Ruzurgi; greater perceived weakening with placebo

SAFETY: 

  • Most common side effects: Burning or prickling sensation (paresthesia), abdominal pain, indigestion, dizziness and nausea
  • Seizures in patients without a history of seizures

REGULATORY PATHWAY: NDA,  Priority Review and Fast Track designations, Orphan Drug designation

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Image credits: Amgen, Sanofi, AbbVie, Agios, GSK, Pfizer, Jacobus

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News & Views: CDRH reorg implementation, Deep Learning and patient safety, Patient Preference Information, CMS reimbursement for novel devices, Biologics development, Addressing health disparities, Safer prescribing of psychoactives with opioids, Marketed Device safety measures, Warnings for insomnia drugs,

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Team-Based Approach to Medical Device and Radiological Product Evaluation and Quality

Operationalizing  Office of Product Evaluation and Quality (OPEQ)

  • Identifying, Resolving, and Communicating Safety Issues — Faster and Better
  • Informing New Product Approvals with Latest Safety Data
  • Advancing Safer and More Effective Innovative Technologies
  • Enhancing Evidence Generation Throughout the Total Product Life Cycle
  • Fostering Employee Engagement, Opportunity, and Success

CDRH Directory


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Capturing Patient Experience Through Deep Learning

  • FDA developing computational approaches to use deep learning, a form of artificial intelligence (AI), to extract  adverse events of drugs and therapeutic biologics (using standard MedDRA terms) automatically from NDAs
  • Patient narratives in NDAs used to train a neural network to make correct MedDRA coding decisions using diverse natural language processing (NLP)
  • Development of user-friendly tool to check MedDRA  coding accuracy of previous submissions, such as adverse event reports from drug developers

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Using Patient Preference Information (PPI) in Medical Device Evaluation

PPI defined as

  • Qualitative/Quantitative assessments of relative patient desirability or acceptability of specified alternatives or choices among outcomes or other attributes
  • Clarify what benefits and risks are most important to patients
  • Impact premarket clinical study design, benefit-risk assessments, postmarket evaluation

Agency has identified  Priority List of Patient Preference-Sensitive Areas

Parameters for patient preference-sensitive areas

  • Better understand full impact of disease and treatment options on patients
  • Patients may value benefits-risks  differently from healthcare professionals
  • Population-level differences in patient perspectives not well understood
  • Significant public health impact

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CMS comprehensive strategy to foster innovation for transformative medical devices 

Goal to get new innovations to  beneficiaries concurrent with FDA approval

  • Removing government barriers to innovation
  • Harmonizing CMS coverage, coding, and payment processes

Initiatives

  • CMS-FDA Parallel Review Program – FDA approval and CMS coverage on same day
  • Modernize payment policies for ‘Breakthrough Devices’ designation – waive  requirement for “substantial clinical improvement”
  • More frequent, semi-annual, opportunities to request HCPCS code
  • Consider commercial payments in determining payments for innovative Durable Medical Equipment (DME)
  • Reevaluiate guidelines for new hospital technology add-on payment (NTAP)
  • Enhance ease of billing for new technologies
  • New guidance on Local Coverage Decisions (LCD) – contractors not authorized to make coverage determinations to automatically non-cover any item or service

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Efforts to Advance the Development of Biologics

Biologics, regulated by CBER, are either living cells or tissues, or are made from them, such as stem cells and genetically engineered immune cells

  • Drugs: Includes blood components/derivatives, vaccines, allergenics, and cellular/gene therapies
  • Devices: In vitro diagnostic tests for screening blood supply, for manufacturing blood and tissue products
  • Safety and efficacy linked to quality and consistency of manufacturing

Cellular and Gene Therapy Approvals in 2018

  • LUXTURNA for heritable disorder that causes blindness: retinal dystrophy associated with mutations in the RPE65 gene
  • YESCARTA, CAR-T cell therapy  to treat adults with certain types of relapsed or refractory diffuse large B cell non-Hodgkin lymphoma

Vaccine and Blood Product Approvals in 2018

  • HEPLISAV-B, Hepatitis B vaccine to prevent infection caused by all known subtypes of hepatitis B virus in adults 18 of age and older
  • SHINGRIX, vaccine for shingles prevention in adults 50 years of age and older
  • COBAS Zika Test and the PROCLIEX Zika Virus Assay for Zika detection in human plasma

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Addressing Health Disparities Through Communication, Research, and Collaboration

Office of Minority Health and Health Equity (OMHHE) promotes and protects health of diverse populations and strives for health equity

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Preclinical Research to Achieve Safer Prescribing of Psychoactive Therapeutics for Patients Who Use Opioids

More than 30%  of deaths from opioids involve use of benzodiazepines, commonly used for anxiety or insomnia

  • Might worsen the respiratory effects of opioids in patients being treated for pain. To achieve this goal
  • Gaps in evidence needed for safer prescribing

FDA developing Preclinical Model to address gaps 

  • Rat study and predict interaction of psychoactive sedative drugs and opioids
  • Exposed to psychoactive drug with or without the opioid oxycodone
  • Determine respiratory effect and opioid-induced respiratory depression
  • Measurement of achieved blood concentrations over time to determine how to administer the drugs so that tested drug and opioid reach simultaneous peak levels

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Marketed Device Safety Measures

SURGICAL MESH for transvaginal repair of pelvic organ prolapse – Sales stopped 

  • FDA ordered all manufacturers of surgical mesh intended for transvaginal repair of anterior compartment prolapse (cystocele) to stop selling-distributing immediately
  • Manufacturers- Boston Scientific and Coloplast- have not demonstrated reasonable assurance of safety and effectiveness for these high risk  devices these devices

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SURGICAL STAPLERS- New steps to reduce risks

  • Large number of adverse events reports  including opening of staple line, malformation of staples, misfiring, difficulty in firing, failure of stapler to fire staple, misapplied staples
  • Increasing regulatory requirements from Class I (low risk) to Class II (moderate risk)
  • Require labeling to provide adequate information for use, including hazards, contraindications, information for safe and effective use

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BREAST IMPLANTS- New efforts to protect health and ensure safety

  • Weighing risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)
  • Improve labeling to communicated risk of BIA-ALCL, greater risk of BIA-ALCL with textured implants, and risk of developing systemic symptoms to women and health care professionals professionals

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Stronger warnings about rare but serious incidents related to certain prescription insomnia medicines

Rare, complex sleep behaviors specifically associated with use of eszopiclone (Lunesta), zaleplon (Sonata) and zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist)

  • Serious injuries because of sleep behaviors, including sleepwalking, sleep driving, and engaging in other activities while not fully awake (e.g. using a stove)
  • Have also resulted in deaths

Labeling updates

  • Boxed Warning –most prominent warning
  • Contraindication-strongest warning
  • Avoid use in patients who have previously experienced an episode of complex sleep behavior with eszopiclone, zaleplon, and zolpidem

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Image credit: FDA