FDA Debrief: CDRH Veteran Amputee Device Workshop, October 31, 2016

limb

KEY Concepts

  • Use / Assess TPLC (Total Product Life Cycle)
  • Engagement to improve patient experience – better understand patient preference and patient input
  • Include amputee preference in B/R assessment

DR. VIVEK PINTO:  Branch Chief, PMDB

  • Non-invasive prosthetic devices are generally Class I Exempt devices
  • Must comply with general controls: Components for prosthetic limbs, Assembled systems
  • TPLC
    • Novel prosthetics – less knowledge about safety and effectiveness : Greater premarket purview
    • Customary prosthetics- history of safety and effectiveness – Greater postmarket purview

DR. KIMBERLY KONTSON, OSEL

  • Functional Outcome measures
  • Patient-centered, Clinically-meaningful test methods
  • DARPA haptics, VR platform 

Q/As & DISCUSSION TOPICS

  • IoT/Interoperability: Data/Specification? Include in label what is / is not compatible
  • Differences in classification of ‘similar’ devices: FR publishes reviews, FDA will note to increase transparency
  • Patients vs Physician measures of performance: Website for tests used by physicians?
  • Lack of readily available information of approves/cleared prosthetics
  • Johns Hopkins University Patient Preference methods: Incorporate patient & caregiver voice : Facts vs Values, Measuring choices
  • LIM innovations: Optimal Socket design , R&D approach to incorporate user feedback: Improve comfort stds, Understanding patient journey post-amputation, connected tech to prosthetics, moderated interviews
  • FDA-CMS considerations upfront

VA Amputation Society (ASoc) Clin perspectives on amputation care

    • Enhance quality and consistency of amputation care
    • Prosthetic dissatisfaction and abandonment
    • Tech advances outpaces research

Prosthesis prescription considerations

  • Must be based on the Veteran not the available technology
  • Prosthetic education and training essential to successful outcomes
  • Greater need for highly specialized teams with advanced technology

SLIDES

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MATx App for Opioid Use Disorder

WHAT: Free App to  support practitioners who provide medication-assisted treatment (MAT), as well as those who plan to do so in the future.

WHY: 80% of Americans with opioid use disorder do not receive treatment

HOW: 

  • Information on FDA approved treatment approaches and medications
  • Buprenorphine prescribing guide
  • Clinical support tools – treatment guidelines, ICD-10 coding, working with special populations
  • Access to critical helplines and SAMHSA’s treatment locators.

LEARN

FDA News: Opioid Use, Cannabis Use Disorder, Targeted Therapies

FDA BRIEF: Week of November 21, 2016FDA Voice


Opioid Question Collage (600x600)

PATIENT CONSIDERATIONS FOR OPIOID USE

Opioid use approved FDA to treat certain kinds of acute and chronic pain; also have very serious side effects.

Points to consider by patient:

  • Length of treatment
  • Reduction of potential side effects
  • History of addiction
  • Concomitant medications
  • Storage, Disposal, Sharing
  • Rx for Naloxone

READ


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CLINICAL TRIAL ENDPOINTS FOR CANNABIS USE DISORDER (CUD)

ISSUE:  4 M individuals in CUD; projected to increase

ENDPOINT CHOICES: What matters to people with CUD?  measurable/standarizable?changes linked to clinical benefits?

FDA TOOLS: Guidances on innovative approaches, Drug Development Tools,  Critical Path Innovation Meetings

READ


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TARGETED THERAPIES

FOR RARE DISEASES AND DISEASE SUBSETS : Natural History Data, Biomarker Use, Clinical Trial Design

CASE STUDIES: Lumizyme, Carbaglu, Cholbam,  Glucarpidase

  • Highly plausible mechanistic hypothesis
  • Natural history data on untreated patients
  • Highly plausible biomarkers
  • Serious unmet medical need
  • Relatively large treatment effect

READ


 

FDA Approvals: DARZALEX, XULTROPHY, SOLIQUA, REALTIME ZIKA

FDA BRIEF: Week of November 21, 2016

FDA approved


DARZALEX (daratumumab) injection

Janssen Biotech of Horsham, PA, USA

Image result for darzalex

INDICATION: In combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.

UNMET NEED:

  • 26,850 new cases of multiple myeloma and 11,240 related deaths in US in 2016
  • Blood cancer resulting in weakened immune system, bone or kidney problems
  • Need for tretament options for patients resistant to other therapies

REG PATHWAY: NDA, Breakthrough Designation, Priority Review, Orphan Drug Designation, Accelerated Approval program

  • Accelerated approval in 11/2015 for multiple myeloma monotherapy

MECHANISM OF ACTION: Binds to CD38 and inhibits CD38 expressing tumor cell growth by inducing apoptosis

EFFICACY:

  • 2 randomized, open-label trials (n=569, 498)  DARZALEX  added to standard therapies
  • Endpoint: Progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria
  • 61-63% reduction in risk of disease progression or death for patients treated with DARZALEX
  • Complete/partial reduction tumor burden: 29% – 36%, avg duration:  7.4 months
SAFETY:
  • Warnings and Precautions: Neutropenia and thrombocytopenia
  • Most frequently reported adverse reactions : Infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasm, cough and dyspnea. The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3004 were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, peripheral sensory ions of the DARZALEX label.

LABEL


XULTOPHY  (insulin degludec and liraglutide injection), for subcutaneous use 

Novo Nordisk, Bagsvaerd, Denmark

Image result for xultophy

INDICATION:  combination of insulin degludec and liraglutide; indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 50 units daily) or liraglutide (less than or equal to 1.8 mg daily).

Limitations of Use: Not for  first-line therapy , not studied in patients with pancreatitis, not for use  with any other product containing liraglutide/GLP-1 receptor agonist,  not for patients with type 1 diabetes mellitus/ diabetic ketoacidosis, not studied in combination with prandial insulin.

REG PATHWAY: NDA with REMS of Communication Plan

EFFICACY:

  • 3 randomized, parallel and active-controlled, n=1393, 26 weeks duration; subjects converting from liraglutide, from any basal insulin, from insulin glargine
  • Endpoint: Reduction in HbA1c from baseline
  • 1.31% for XULTOPHY vs. 0.36% for liraglutide
  • 1.94% for XULTOPHY vs. 1.05% for insulin degludec
  • 1.67% for XULTOPHY vs. 1.16% for insulin glargine

SAFETY:

  • Boxed Warning: Risk of Thyroid Cell tumors
  • Adverse Reactions: Pancreatitis, Hypoglycemia, Acute Kidney Injury, Hypersensitivity and Allergic Reactions, Hypokalemia

LABEL


SOLIQUA  (insulin glargine and lixisenatide injection), for subcutaneous use

Sanofi-Aventis U.S. LLC; Bridgewater, NJImage result for soliqua

INDICATION: Combination of insulin glargine and lixisenatide; indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) or lixisenatide.

Limitations of Use: Not studied in patients with pancreatitis, not for use in combination with any other product containing lixisenatide/GLP-1 receptor agonist, for use in patients with type 1 diabetes mellitus/ diabetic ketoacidosis, not studied in patients with gastroparesis, not studied in combination with prandial insulin.

REG PATHWAY: NDA with Post Marketing Requirements

EFFICACY:

  • Randomized, 30-week, activecontrolled, open-label, 2-treatment arm, parallel-group, multicenter study, n=736, SOLIQUA vs. insulin glargine, 30 weeks
  • Endpoint:  reduction in HbA1c from baseline
  •  -1.1% for SOLIQUA vs. -0.6% for insulin glargine

SAFETY: Anaphylaxis and Serious Hypersensitivity Reactions, Pancreatitis, Hypoglycemia, Acute Kidney Injury, Hypokalemia

LABEL


ABBOTT  RealTime ZIKA assay

Abbott Molecular Inc, Des Plaines, IL, USA

Image result for Abbott RealTime Zika assay

INTENDED USE: In vitro reverse transcription-polymerase chain reaction (RT-PCR) assay for the qualitative detection of RNA from the Zika virus in serum, EDTA plasma, and urine (collected alongside a patient-matched serum or plasma specimen) from individuals meeting CDC Zika virus clinical criteria (e.g., clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., history of residence in or travel to a geographic region with active Zika virus transmission at the time of travel, or other epidemiologic criteria for which Zika virus testing may be indicated), by laboratories in the United States that are certified under CLIA

REG PATHWAY: Emergency Use Authorization

DEVICE DESCRIPTION:

  • Abbott mSample Preparation System
  • Abbott RealTime ZIKA Amplification Reagent Kit
  • Abbott RealTime ZIKA Control Kit
  • Internal Control

BIOLOGICAL PRINCIPLES:

  • RT-PCR to generate amplified product from the RNA genome of the Zika virus in human serum, plasma, urine
  • Dual target assay
  • Zika unrelated RNA sequence introduced into each specimen, processed and amplified by RT-PCR – serves as internal control (IC)
  • RealTime ZIKA assay detects the Zika virus and IC through target-specific fluorescent-labeled oligonucleotide probe

Labeling


 

LASIK Quality of Life Collaboration Project

Image result for LASIK Quality of Life Collaboration Project

WHAT:  LASIK Quality of Life Collaboration Project (LQOLCP) to understand potential risk of severe problems from LASIK

WHY: Develop tool to assess patients with difficulties with usual activities and identify predictors

WHO:  FDA, National Eye Institute and Department of Defense

HOW: Patient-Reported Outcomes with LASIK (PROWL) studies

  • visual symptoms before and after their LASIK surgery
  • impact of symptoms on performing usual activities

LEARN

 

FDA News: Orphan Disease R&D, Mouse Model for Zika, FDA-CMS Shared Responsibility

FDA BRIEF: Week of Nov. 14, 2016

FDA Voice


Orphan Disease R & D Has a Home at FDA

John J. Whyte, MD, MPH, Director, Professional Affairs and Stakeholder Engagement, FDA

Gayatri Rao, MD, JD, Director, Office of Orphan Products Development, FDA

LISTEN


FDA Research on Zika Virus Vaccines and Therapeutics

Neonatal mouse model provides a new platform for Zika virus research

  • New mouse model developed by FDA for exploring activity of Zika vaccines/therapeutics
  • C57BL/6 mouse strain susceptible to Zika, develops neurological symptoms and eventually recover from disease

PLoS Publication


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  • Acknowledges ‘ fragmentation’: FDA approval/clearance vs. approval for coverage and payment
  • States shared sources of evidence for both Agencies while still applying the most appropriate criteria to their decision making
  • Clarified differing FDA and CMS standards:
    • FDA: Product approval or clearance, based on  “substantial evidence”
    • CMS: Coverage approval based on  “reasonable and necessary”
  • Recommends early involvement of health systems and payers to help to understand and address the kinds of evidence needed to incorporate the new product into practice
  • Highlights several FDA-CMS initiatives to facilitate gathering adequate evidence for both Agencies
  • Provides perspectives on ‘personalized medicine’

 

 

FDA Approvals: INTRAROSA

FDA News: Week of November 14, 2016

FDA approved


Intrarosa

EndoCeutics Inc. Quebec, CANADA

INDICATION: Steroid indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA), due to menopause.

UNMET NEED:

  • Decline of estrogen during menopause cause condition known as VVA
  • Pain during sexual intercourse one of the most frequent symptoms of VVA
  • Need for treatment option forrelief of dyspareunia caused by VVA

REG PATHWAY: NDA

  • Prasterone, also known as dehydroepiandrosterone (DHEA), included in some dietary supplements
  • Efficacy/safety of those products not established for diagnosing, curing, mitigating, treating or preventing disease

MECHANISM OF ACTION:  Inactive endogenous steroid  that is converted into active androgens and/or estrogens; mechanism of action not fully established.

EFFICACY:

  • Four 12-week placebo-controlled trials and one 52-week open-label trial; INTRAROSA vs. placebo
  • 4 co-primary endpoints: most bothersome moderate to severe symptom of dyspareunia, the percentage of vaginal superficial cells, the percentage of parabasal cells, and vaginal pH
  • Overall, reduced severity of pain experienced during sexual intercourse

SAFETY: Most common adverse reactions: vaginal discharge, abnormal Pap smear

LABEL


FDA Guidances: Medical Device Reporting, Patient Connection Program, Neurological Devices IDE, Botanical Product Review

FDA BRIEF: Week of November 7, 2016fda guidances


device-reporting

For: Reporting and record-keeping requirements

  • manufacturers of medical devices
  • device-related adverse events
  • malfunctions

Scope:

  • Regulations and Basic Requirements
  • Manufacturer Reporting Requirements
  • Written Procedures, Recordkeeping and Public Disclosure
  • Specific Issues and Situations
  • Questions Concerning Completion of the MDR Report

Webinar: Nov 30th INFORMATION

READ


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CDRH Patient & Care-Partner Connection program (P&CC)

  • tied to one of CDRH’s strategic priorities to “Partner with Patients
  • build upon efforts at conducting meaningful patient engagement
  • also committed to engaging with family or care-partners who are integral to patient care and disease management

Seeking comments from interested persons FDA-2016-N-3462

General

  • Potential barriers to inclusion
  • What can FDA do to avoid or remedy
  • Appropriate and effective FDA engagement
  • Title appropriateness “Patient and Care-partner Connection”; other suggestions

Inclusion

  • Appropriate organizations for partnership
  • Barriers to effective communication between FDA, partner organizations, patients, and care-partners
  • Approaches for FDA engagement with underserved, underrepresented communities

Communication

  • Appropriate  lines of questioning
  • Positively and/or negatively viewed characteristics
  •  Preferred methods or qualities of communication

READ


ide

For: Neurological medical devices designed to slow, stop, or reverse disease progression

To: Provide general study design considerations

Overview:

  • Biological Markers and Clinical Endpoints : Biomarker Tests, Clinical Outcome Assessments
  • Trial Designs: Study Approaches and Limitations
  •  Investigational Plans
  • Safety
  • Benefit-Risk Considerations
  • Informed Consent Documents
  • Labeling : Indications for Use, Warnings and Precautions

READ


botanical

For: IND/NDA review process for botanical drug products and role of Botanical Review Team (BRT)

To: Ensure review quality and consistency

General:  BRT designated member of review team, provides pharmacognosy review, participate in submission meetings

Application Reviews: Regulatory business project managers, BRT, CMC and biopharmaceutics team members, clinical pharmacology review, nonclinical pharmacologist/toxicologist, clinical reviewers from OND and the statistical reviewers

Postapproval Activities and Surveillance

READ


 

 

FDA Approvals: VEMLIDY, SELZENTRY pediatrics, ReEBOV Antigen Rapid Test, OPDIVO for SCCHN

FDA BRIEF: Week of Nov 7, 2016

FDA approved


VEMLIDY (tenofovir alafenamide) tablets

Gilead Sciences, Foster City, CA, USA

Image result for vemlidy

INDICATION:  Treatment of chronic hepatitis B virus infection in adults with compensated liver disease

UNMET NEED:

  • Chronic hepatitis B is a life-threatening illness
  • Affects up to 2.2 million people in the US

REG PATHWAY: SNDA (also marketed as Descovy)

MECHANISM OF ACTION: nucleoside analog reverse transcriptase inhibitor, inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain-termination.

EFFICACY:

  • 2 randomized, double-blind, active-controlled studies,  48-week data, N=425 and N=873, patients  not allowed to receive other nucleosides, nucleotides, or interferon
  • VEMLIDY vs Tenofovir Disoproxil Fumarate (Viread)
  • Primary Endpoint: Proportion of subjects with plasma HBV DNA levels below 29 IU/mL at Week 48.
  • Additional endpoints:  Proportion of subjects with ALT normalization, HBsAg loss and seroconversion, and HBeAg loss and seroconversion
  • Noninferior to Viread

SAFETY:

  • Boxed Warning: Risks of lactic acidosis/severe hepatomegaly with steatosis and post-treatment severe acute exacerbation of hepatitis B
  • Commonly reported adverse events: Headache, abdominal pain, fatigue, cough, nausea and back pain

LABEL


SELZENTRY (maraviroc)

Image result for selzentry

INDICATION:  SELZENTRY is indicated in combination with other antiretroviral agents for the treatment of only CCR5 tropic human immunodeficiency virus type 1 (HIV 1) infection in patients 2 years of age and older weighing at least 10 kg.

FORMULATIONS:  20 mg/mL oral solution,  25 mg and 75 mg tablets
EFFICACY/SAFETY:
  • Open-label, multicenter trial,  2-<18 years old, infected with only CCR5 tropic HIV 1; dosing based on body sruface area and concomitant  potent CYP3A inhibitors and/or inducers.
  • At 48 weeks, 48% achieved plasma HIV-1 RNA less than 48 copies per mL; 65% achieved plasma HIV-1 RNA less than 400 copies per mL
  • Mean CD4+ cell count (percent) increase from baseline to Week 48 was 247 cells per mm3 (5%).
  • Safety profile through 96 weeks was similar to that for adults

ReEBOV™ Antigen Rapid Test for Ebola Zaire Virus
Corgenix Inc, Broomfield CO, USA
Zalgen Labs, Germantown, MD
INTENDED USE: Intended for circumstances when use of a rapid Ebola virus test is determined to be more appropriate than use of an authorized Ebola virus nucleic acid test, which has been demonstrated to be more sensitive in detecting the Ebola Zaire virus.
REG PATHWAY:  Emergency Use Authorization
DESCRIPTION:
  • Point-of-care test – self-contained, disposable dipstick-format lateral flow test that includes an internal process Control Lin
  • Ebola Zaire virus antigen, VP40 protein, present in the specimen, to bind nanoparticles labeled with antigen specific antibodies
  • . As the specimen and nanoparticles flow across the device membrane, immobilized Ebola Zaire virus antigenspecific antibody absorbs the nanoparticle immune- to generate chromogenic signal

LABEL


OPDIVO (nivolumab) Injection
Bristol-Myers Squibb, Princeton, NJ, USA
Image result for opdivo images
SUPPLEMENTARY INDICATION:  Treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy
EFFICACY:
  • International, multi-center, open-label, randomized trial  (n=240), OPDIVO vs  Investigator’s Choice of chemotherapy, patients with recurrent or metastatic SCCHN with disease progression
  • Primary Endpoint: Overall Survival (OS)
  • Statistically significant and clinically meaningful improvement in OS : Hazard Ratio 0.7 [95% CI: 0.52, 0.92]; p=0.0101
  • Estimated median OS: 7.5 mo, vs 5.1 mo.
SAFETY:
  • Serious adverse reactions occurred:  Pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.
  • Most common adverse reactions: Cough and dyspnea

FDA News: Penicillin in WWII, Cochlear Implants, AADE/FDA Twitter Chat

FDA BRIEF: Week of November 7, 2016

FDA Voice


The Race to bring Penicillin to the Troops in WWII

John SwannBy: John P. Swann, Ph.D., FDA Historian 

75 years ago..

The strain of Penicillium notatum that Fleming discovered at St. Mary’s Hospital in LondonFDA, academic, commercial, nonprofit, and governmental institutions raced to provide penicillin to WWII troops

  • Difficult to purify, scale up
  • US and Britain developed production modifications to increase yield by 100 fold
  • FDA technicians certified potency, absence of fever-producing contaminants, toxicity, sterility, and optimum moisture for stability
  • Participating firms increased purity and production for civilian needs as well

READ


Cochlear Implants: A Different Kind of ‘Hearing’

Cochlear implant

  • External part (behind the ear) + internal part (surgically placed under skin)
  • Magnet holds external system in place next to the implanted internal system
  • Receives sound, processes it, sends small electric currents to auditory nerve which signals brain
  • Can use as early as 18 m0.

FDA Regulation : Designated as Class III devices

Future:  Sophisticated technologies to minimize background noise, increase the noise-to-sound ratio, pairing with another cochlear implant or a hearing aid in other ear.

READ


AADE/FDA Chat

FDA News: Consumer Expenditure, Impetigo Treatment, Post-Marketing Commitments, National Cyber Security Awareness Month

FDA BRIEF: Week of October 31, 2016

Voice


Consumer expenditure on FDA regulated products: 20 cents of every dollar

By: Sheri Walker, Ph.D., FDA Senior Economist, and Clark Nardinelli FDA Chief Economist

20 cents pie chart

FDA-regulated products account for about 20 cents of every dollar of annual spending by U.S. consumers.

  • > $2.4 trillion in annual consumption (medical products, food, tobacco)
  • Based on expenditure data collected by the Bureau of Economic Analysis (BEA)

READ


impetigo and kids

How to Treat Impetigo and Control This Common Skin Infection

Causes: 

  • Staphylococcus aureus and Streptococcus pyogenes, bacteris found on skin
  • > 3 million cases in US every year
  • Prevalent in kids 2 – 6 years old: itchy red sores, itchy rash, fluid-filled blisters

Treatment:

  • Presription topical or oral antibiotics
  • NO over-the-counter (OTC) treatment

READ


Performance of Drug and Biologics Firms in Conducting Postmarketing Requirements (PMRs) and Postmarketing Commitments (PMCs) (FY 2013 and FY 2014)

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Postmarketing requirement (PMR): Drug study equired by statute or regulation to conduct after drug approval

Postmarketing commitment (PMC): Agreed post-approval study but not required by statute or regulation.

  • To assess a known serious risk or identify an unexpected serious risk
  • Study certain new drugs for pediatric populations
  • Verify and describe the predicted effect for accelerated approval
  • For approval on animal efficacy because human trials not ethical or feasible

CDER’s 2013-2014 Evaluation of PMRs & PMC Data

  • Similar  number of applicants and unique applications with PMRs/PMCs: more with drugs than biologics
  • Most applicants meeting annual reporting obligation
  • >50% PMRs for pediatric research
  • Majority of PMRs/PMCs progressing on schedule
  • Comparatively fewer PMRs/PMCs off schedule

READ


National Cyber Security Awareness Month: Understanding the Interdependencies of Medical Devices and Cybersecurity

By: Suzanne B. Schwartz, M.D., M.B.A., Associate Director for Science and Strategic Partnerships, CDRH
Suzanne Schwartz

FDA guidances for monitoring, identifying, and addressing pre- and post-approval cybersecurity vulnerabilities in medical devices

  • Life cycle approach to cybersecurity risk management – from early product development and extending throughout product’s lifespan
  • Collaborating with entities that discover threats or vulnerabilities
  • Developing appropriate solutions prior to vulnerabilities being publicly disclosed

FDA partnership with the National Health Information Sharing and Analysis Center (NH-ISAC), and the Medical Device Innovation, Safety, and Security Consortium (MDISS)

  • Rapid sharing of medical device vulnerabilities, threats, and mitigations within the hospital and health care ecosystem

READ


 

FDA De Novo Order: BD MAX

FDA BRIEF: Week of Oct 31, 2016

FDA approved


BD MAX Vaginal Panel

BD Diagnostics, USA, Canada

Image result for BD Max Vaginal Panel

INDICATION FOR USE: Automated qualitative in vitro diagnostic test for the direct detection of DNA targets from bacteria associated with bacterial vaginosis (qualitative results reported based on detection and quantitation of targeted organism markers), Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis from vaginal swabs in patients who are symptomatic for vaginitis/vaginosis. The test utilizes real-time polymerase chain reaction (PCR) for the amplification of specific DNA targets and utilizes fluorogenic target-specific hybridization probes to detect and differentiate DNA from Bacterial vaginosis markers, Candida spp.

INTENDED USE: The BD MAX Vaginal Panel is intended to aid in the diagnosis of vaginal infections in women with a clinical presentation consistent with bacterial vaginosis, vulvovaginal candidiasis and trichomoniasis.

REG PATHWAY: De Novo Request

  • Regulation Number: 21 CFR 866.3975
  • Regulation Name: Device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis
  • Regulatory Classification: Class II
  • Product Code: PQA, OUY, OOI, NSU

IDENTIFIED RISKS AND MITIGATION:

  • Incorrect identification or lack of identification of a pathogenic microorganism by the device can lead to improper patient management: General controls and special controls
  • Failure to correctly interpret test results: General controls and special controls
  • Special Controls:
    • Premarket notification submissions with detailed device description
    • Premarket notification submissions with performance characteristics
    • Premarket notification submissions of prospective clinical study
    • Premarket notification submissions of device software
    • Labeling requirements

ORDER

Regulatory Pharmaceutical Fellowship

Image result for Regulatory Pharmaceutical Fellowship clipart

WHAT: 2-year fellowship – Rotations with FDA’s CDER and Industry

WHY: Train selected candidates in one of three tracks focused on the medical and regulatory aspects of drug information dissemination, drug advertising and promotion, or medication safety

WHO: Jointly Sponsored by: FDA, Purdue University, Eli Lilly and Company, Janssen Scientific Affairs, LLC, and Johnson and Johnson

WHEN: Available Positions for 2017 – 2019

LEARN

Division of Drug Information (DDI)

FDA Logo, hands holding pills

WHAT: Division serving public by providing information on human drug products and drug product regulation by FDA

WHY: Timely communication of drug safety to Healthcare Professionals

HOW: Use social media to communicate the latest drug information.

LEARN

Clin. Pharm. Card: TECENTRIQ

TECENTRIQ (atezolizumab) intravenous injection

Image result for tecentriq

Mechanism of Action Atezolizumab is a monoclonal antibody that binds to PD-L1 (programmed death- ligand 1) and blocks its interactions with both PD-1 (programmed cell death 1) and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of the immune response, including activation of the anti-tumor immune response without inducing antibody- dependent cellular cytotoxicity.
Pharmacodynamics (PD) Not reported.  
Pharmacokinetics (PK) The terminal half-life was 27 days

 After 6 to 9 weeks (2 to 3 cycles) of repeated dosing, the systemic accumulation in AUC, Cmax and Cmin were 1.91, 1.46 and 2.75-fold, respectively.

PK-PD Analysis Not reported.
Population PK Typical population clearance and volume of distribution at steady state were 0.20 L/day and 6.9 L, respectively.  

 In a post-hoc analysis, atezolizumab clearance was found to decrease over time, with a mean maximal reduction from baseline value of approximately 17.1% (CV% of 40.6%). However, the decrease in CL was not considered clinically relevant.

 

Specific Populations

 Age (21–89 years), body weight, gender, positive anti-therapeutic antibody (ATA) status, albumin levels, tumor burden, region or race, mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin < 1.0 to 1.5 × ULN and any AST), level of PD-L1 expression, or ECOG status had no clinically significant effect on the systemic exposure of atezolizumab.

 The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) or moderate or severe hepatic impairment (bilirubin > ULN and AST > ULN or bilirubin ≥1.0 to 1.5 × ULN and any AST) on the pharmacokinetics of atezolizumab is unknown.

Drug Interactions

 

The drug interaction potential of atezolizumab is unknown. 

Source: https://www.gene.com/download/pdf/tecentriq_prescribing.pdf

Clin. Pharm. Card: EPCLUSA

EPCLUSA Tablet (Sofosbuvir plus Velpatasvir)Image result for epclusa

Mechanism of Action It is a fixed-dose combination of sofosbuvir and velpatasvir which are direct-acting antiviral agents against the hepatitis C virus Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor and velpatasvir is an NS5A inhibitor.
Pharmacodynamics (PD) At a dose three times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent. At a dose five times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent.                  
Pharmacokinetics (PK) Tmax (median): Sofosbuvir: 0.5-1 hour; velpatasvir: 3 hours 

 Effect of high fat meal:  Sofosbuvir is up by 78% and velpatasvir is up by 21%.

 Plasma protein binding: Sofosbuvir: 61-65%; velpatasvir: greater than 99.5%

 Elimination Half-life (mean): Sofosbuvir: 0.5 hour; GS-331007 (Gilead Sciences- 331007; primary circulating nucleoside metabolite of sofosbuvir): 25 hours; velpatasvir: 15 hours

 Metabolism: Sofosbuvir: Cathepsin A, CES1, and HINT1; Velpatasvir: CYP2B6, CYP2C8, and CYP3A4 

 Elimination: The primary route of elimination is metabolism for sofosbuvir; passive and glomerular filtration and active tubular secretion for GS-331007; and biliary excretion (of unchanged drug) for velpatasvir.

PK-PD Analysis No exposure-response relationships for safety or efficacy were identified for either of the components of EPCLUSA at the recommended dosage.
Population PK Age had no clinically relevant effect on the exposure to sofosbuvir, GS-331007 or velpatasvir was reported in HCV-infected subjects (18 to 82 years).

 Race had no clinically relevant effect on the exposure of sofosbuvir, GS-331007 or velpatasvir was reported.

Gender had no clinically relevant effect on the exposure of sofosbuvir, GS-331007 or velpatasvir

Special Populations  No dosage adjustment of EPCLUSA is required for patients with mild or moderate renal impairment. The safety and efficacy of EPCLUSA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or end-stage-renal disease (ESRD) requiring hemodialysis.

 No dosage adjustment of EPCLUSA is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C).

Pediatric Patients

 

The pharmacokinetics in pediatric patients has not been established.
Drug Interactions Sofosbuvir and velpatasvir are substrates of drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are inducers of P-gp may decrease plasma concentrations of sofosbuvir and velpatasvir leading to reduced therapeutic effect of EPCLUSA. Use of these agents with EPCLUSA is not recommended.

Drugs that are moderate to potent inducers of CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine), CYP2B6, or CYP2C8 may decrease plasma concentrations of velpatasvir leading to reduced therapeutic effect of EPCLUSA. Use of these agents with EPCLUSA is not recommended.

 Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3. Coadministration of EPCLUSA with drugs that are substrates of these transporters may increase the exposure of such drugs. 

 Coadministration of EPCLUSA with atorvastatin is expected to increase the concentrations of atorvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse events, such as myopathy.

 Serious symptomatic bradycardia has been observed when amiodarone is coadministered with a sofosbuvir-containing regimen (with another HCV direct acting antiviral). Therefore, coadministration of amiodarone with EPCLUSA may also result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with EPCLUSA is not recommended; if coadministration is required, cardiac monitoring is recommended.

 Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease systemic concentrations of velpatasvir.

Antacids: Separate antacid and EPCLUSA administration by 4 hours.

H2-receptor antagonists: H2-receptor antagonists may be administered simultaneously with or 12 hours apart from EPCLUSA at a dose that does not exceed doses comparable to famotidine 40 mg twice daily.

 Proton-pump inhibitors: Coadministration of omeprazole or other proton pump inhibitors is not recommended. If it is considered medically necessary to coadminister, EPCLUSA should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton pump inhibitors has not been studied.

Source http://go.usa.gov/xrjNd.

CDRH Industry Basics: Quality System & Management Controls

November 3, 2016

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MANAGEMENT CONTROLS

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Management is Core – ultimately responsible for entire Quality System (QS)

  • Involved, Engaged and Committed to the QS
  • Senior Employee with executive responsibilities
  • Harmonized with ISO and other global regulations

Implement Management Control Subsystem

  • Adequate resources
  • Ensure adequate and effective QS
  • Monitor QS and make necessary adjustments

Management Responsibilities to Establish & Maintain

  • Quality Policy
  • Effective organization structure
  • Appropriate responsibility and authority
  • Adequate resources
  • Appoint representatives
  • Management reviews
  • Establish Quality Plan
  • Establish QS Procedures

Conduct Internal Audit

  • Appropriate auditor, appropriate steps to address issues
  • Appropriate documentation

Personnel

  • With appropriate qualifications, training, background

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FDA NEWS: Device Data Collection by Hospitals, Opioid Action Plan Update, Abuse-Deterrent Opioids, Depression Treatment

FDA BRIEF: week of October 24, 2016

Voice


FDA is working with hospitals to modernize data collection about medical devices

By: Jeffrey Shuren, M.D., J.D., Director CDRH
Jeffrey Shuren

Hospital staff use a variety of medical devices, help identify new safety problems with devices,  use technologies in real-world setting of clinical practice

FDA improving work with hospitals to modernize and streamline data collection about medical devices – with focus on SAFETY

(1) Medical device reporting from hospitals

  • Must report device-related serious injuries/ device-related deaths to both FDA and the manufacture
  • However, this is passive surveillance

(2) MedSun (the Medical Product Safety Network) with hospitals

  • Understand and report on device use in the real-world environmen
  • But limited added value, unnecessary costs and resources
  • Not enforced universal reporting requirements

High-profile device safety issues occurring in hospitals in 2015

  • Inspections at 17 hospitals- related to spread of uterine cancer from use of morcellators or  contaminated duodenoscopes

Lessons learned from inspections

  • Didn’t submit required reports for deaths or serious injuries
  • Didn’t not have adequate procedures for reporting device-related death or serious injury events to FDA/manufacturers
  • Need better way to work with hospitals to get the real-world information

Next Steps to effectively work with hospitals

  • Participate in the National Evaluation System for health Technology NEST
  • Asses current reporting requirements
  • Use effective modern tools for surveillance
  • Public workshop to solicit input and advice on improving hospital-based surveillance systems
  • Work with the Association of American Medical Colleges and the American Hospital Association

READ


FDA’s Opioids Action Plan: A Midyear Checkup

By: Robert M. Califf, M.D., FDA Commissioner

Robert Califf

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FDA working with Surgeon General’s office (TurnTheTideRx campaign to address Opioid epidemic

Conducted tours of areas hard-hit by the opioid crisis in TN, WV, KY

Opioid education – including training during medical school and residency and greater public awareness far and wide – is a key component in fighting the opioid epidemic

FDA milestones so far include

  • Developing warning and safety information for immediate release opioids
  • Better understand long-term safety of using extended release/long acting opioids
  • Guidance on development of generics with abuse-deterrent formulations
  • Advice from National Academy of Science Engineering and Medicine on balance of patients needs vs. opioid misuse and abuse
  • Supporting increased access to naloxone
  • Launch competition to create Mobile App
  • Approve first implantable treatment for opioid dependence.

FDA will continue work for judicious and responsible use of opioids

READ


Key Facts about “Abuse-Deterrent” Opioids

By: Douglas C. Throckmorton, M.D., Deputy Center Director for Regulatory Programs, CDER

Douglas C. Throckmorton, M.D.

7 approved opioid formulations with abuse-deterrent (AD) properties

  • Tablets/Capsules designed to deter abusers from crushing them into a powder for swallowing, snorting or injecting to create a faster, more intense high.
  • Manufacturers submitted study data demonstrating products are expected to deter abuse.
  • Labeling clearly states the product’s abuse-deterrent properties

“Abuse-deterrent” (AD) vs.abuse-proof

  • AD will always have some potential for abuse
  • FDA requires further post-marketing evaluation of AD products

Generic abuse-deterrent development encouraged

REA


Depression: FDA-Approved Medications May Help
Depression -- FDA Medications Can Help

Treatment with Medication

Antidepressants:  Change neurotransmitters—primarily serotonin, norepinephrine, and dopamine—which are involved in regulating mood.

  • selective serotonin reuptake inhibitors (SSRIs): Prozac (fluoxetine), Celexa (citalopram), Paxil (paroxetine)
  • serotonin norepinephrine reuptake inhibitors (SNRIs): Effexor (venlafaxine), Cymbalta (duloxetine)
  • tricyclic antidepressants (TCAs): Elavil (amitriptyline), Tofranil (imipramine), Pamelor (nortriptyline)
  • monoamine oxidase inhibitors (MAOIs): Nardil (phenelzine) and Parnate (tranylcypromine)
  • Other: Remeron (mirtazapine), Wellbutrin (bupropion)

Antidepressant Effectiveness

  • Regular doses several weeks
  • Significant percentage may not respond to prescribed antidepressant; switching to a different medication or adding another medication can sometimes help treat symptoms
  • Some may not respond to medication

Common side effects

  • Nausea and vomiting
  • Weight gain
  • Diarrhea
  • Sleep disturbances
  • Sexual problems

READ

 

Approvals: KEYTRUDA, AMPLATZER

FDA BRIEF: Week of Oct 24, 2016

FDA approved


KEYTRUDA (pembrolizumab) injection

Merck and Co., Whitehouse Station, NJ

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INDICATION: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations

UNMET NEED: First FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer

REG. PATHWAY:

  • Breakthrough Therapy designation, Priority Review status, and previously granted Accelerated Approval
  • Current approval converts prior accelerated approval in second-line treatment of metastatic NSCLC patients to regular approval
  • Approved nearly two months before the PDUFA goal date

EFFICACY:

  • Two randomized, multicenter, open-label, active-controlled trial, patients with metastatic NSCLC, whose tumors had high PD-L1 expression [tumor proportion score (TPS) of 50% or greater] by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit , KEYTRUDA vs. chemotherapy, n=305, 1033
  • Statitically significant improvement in  in progression-free survival (PFS) and overall survival (OS)

SAFETY:

  • Most common side effects: Decreased appetite, fatigue, nausea, dyspnea, cough,  constipation
  • Rare but serious adverse events: Immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis

Label


 

AMPLATZER PFO Occluder – P120021

St. Jude Medical, Inc., Plymouth, MN, USA

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INDICATION FOR USE:  percutaneous transcatheter closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke.

UNMET NEED:

  • 25 to 30% Americans have a PFO
  • In some patients, PFO provides a path for a blood clot to travel to the brain, blocking a blood vessel resulting in a stroke
  • Patients with a cryptogenic stroke and  PFO may be at increased risk of second stroke
  • No FDA-approved heart occluder devices specifically indicated to close PFOs to reduce the risk of a recurrent stroke in patients with a prior cryptogenic stroke

REG. PATHWAY:

  • Device previously approved under humanitarian device exemption (HDE), but was voluntarily withdrawn in 2006 after FDA concluded target population > 4,000
  • New PMA, Device Code MLV

DEVICE DESCRIPTION:

  • Inserted through a catheter that is placed in a leg vein and advanced to the heart
  • Implanted close to the hole in the heart between the top right chamber (right atrium) and the top left chamber (left atrium)

EFFECTIVENESS AND SAFETY:

  • Single, prospective, randomized, multi-center, event driven trial, n=980,  device closure of a PFO (plus medical management) vs medical management alone
  • Primary effectiveness endpoint: Composite of recurrent nonfatal stroke, fatal ischemic stroke, or post-randomization mortality within 30 days post-implant or 45 days post-randomization
  • Secondary effectiveness endpoints: Absence of transient ischemic attack (TIA) and the rate of complete PFO closureat 6 months follow-up
  •  50% reduction in the rate of new strokes in participants using the Amplatzer PFO

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  • Adverse effects: Injury to the heart, irregular and/or rapid heart rate (atrial fibrillation), blood clots in the heart, leg or lung, bleeding and stroke.

Physician Label

FDA Facts: Abuse-Deterrent Opioid Medications

Image result for Abuse-Deterrent Opioid Medications

WHAT: FDA Website on FDA standards for Abuse-Deterrent (AD) opioid formulations

WHY:  To help drug makers expedite regulatory path to market as quickly as possible. FDA is taking a flexible, adaptive approach to the evaluation and labeling of potentially AD products.

WHICH:  FDA has approved the following extended-release/long-acting (ER/LA) opioids with AD labeling 
  • OxyContin
  • Targiniq ER
  • Embeda
  • Hysingla ER
  • MorphaBond
  • Xtampza ER
  • Troxyca ER

NO immediate-release products with FDA-approved AD labeling c

LEARN

Reporting Allegations of Regulatory Misconduct

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WHAT:  FDA reporting  of allegation of regulatory misconduct of medical device manufacturer or individuals marketing medical devices

WHY: Help FDA identify potential risks to patients, determine whether further investigation is warranted, and identify steps needed to address or correct violation

WHO: Anyone may file a complaint; identity or contact information will not be shared publicly

 

HOW: Allegations of Regulatory Misconduct Form, by email, or by regular mail.

LEARN