FDA NOTES: MDUFA IV Discussions, CDRH Early Feasibility Studies

FDA BRIEF: Week of May 23, 2016

MDUFA

Stakeholders present : Alliance for Aging Research, Duke University, National Center for Health Research, Alliance for Aging Research, National Coalition for Cancer Survivorship, National Health Council , American College of Cardiology, American Association of Neurological Surgeons, FasterCures, JDRF, Women’s Health Research, Pew Charitable Trusts, National Organization for Rare Disorders, Research!America, National Alliance on Mental Illness, Avalere Health

Current status of proposals:

  • Core infrastructure of Quality System critical for establishing consistency and long-term stability
  • Key innovation initiatives: Real World Evidence (RWE) and Digital Health
  • Additional dialogue needed : De Novos and Presubmissions
  • FOCUS TOPIC: Establishing National Evaluation System for Medical Devices and impact on  user fee negotiations
    • Goal to establish collaboration leveraging data from registries, medical claims, electronic health records, and potentially other source
    • RWE leveraged for premarket and postmarket regulatory decisions
    • Additional time and cost develop necessary infrastructure and coordinating center
    • Funding sources: Congressional budget, private-sector, or both
    • User fee investment for better quality registries for premarket regulatory decision-making, nest clinical trials in registries to reduce cost of evidence generation

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EFS.JPG

  • CDRH Learn Module updated  Early Feasibility Studies for Medical Devices to include a new section on the Device Evaluation Strategy
  • Describes and justifies the appropriate testing to support initiation of a clinical study
  • Processes for FDA engagement

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FDA Approvals: PROBUPHINE, AXUMIN, EPI PROCOLON

FDA BRIEF: Week of May 23, 2016

FDA approved

 

PROBUPHINE (Buprenorphine) Implant

Titan Pharmaceuticals Inc. San Francicso, CA and Braeburn Pharmaceuticals, Princeton, NJ, USA

INDICATION: Maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product

UNMET NEED

  • Opioid abuse and addiction have taken a devastating toll
  • Need for new innovative treatment options to regain control
  • Implant a better option that currently available pill or film
  • Medication-assisted treatment (MAT) options  important component of the FDA’s opioid action plan
  • One of three top priorities for the DHHS’  Initiative to reduce prescription opioid and heroin related overdose, death and dependence.

REG PATHWAY: NDA

MECHANISM OF ACTION: Buprenorphine is a partial agonist at the muopioid receptor and an antagonist at the kappa-opioid receptor. Implant provides constant, low-level dose for six months

EFFICACY:

  • Single randomized double-blind, double-dummy study (n=176), subjects meeting criteria for opioid dependence  and  clinically stable on  sublingual buprenorphine, PROBUPHINE vs sublingual buprenorphine
  • Endpoint: Detect opioid use, over the 6-month treatment period, measured by urine screening and self-reporting of illicit opioid use
  • 63% PROBUPHINE vs 64% sublingual  buprenorphine

SAFETY:

  • Boxed warning:  Risk of implant migration, protrusion, expulsion and nerve damage
  • Common side effects: Implant-site pain, itching, and redness, headache, depression, constipation, nausea, vomiting, back pain, toothache and oropharyngeal pain

LABEL


AXUMIN  (fluciclovine F 18) injection for PET imaging 

Blue Earth Diagnostics, Ltd., Oxford, UK

INDICATION:  For PET in men with suspected prostate cancer recurrence based on elevated blood prostate specific antigen (PSA) levels following prior treatment.

UNMET NEED:

  • Prostate cancer second leading cause of death from cancer
  • In suspected cancer recurrence cases, accurate staging important in improving management and outcomes.
  • Need for imaging tests to determine location of recurrent cancer when PSA is at very low levels

REG PATHWAY: NDA

MECHANISM OF ACTION: Fluciclovine F 18, synthetic amino acid transported across mammalian cell membranes by transporters  LAT-1 and ASCT2, which are upregulated in prostate cancer cells. Fluciclovine F 18 taken up to a greater extent in prostate cancer cells vs. surrounding normal tissues.

EFFICACY:

  • 2 studies in men with suspected recurrence of prostate cancer based on rising PSA levels following radical prostatectomy and/or radiotherapy
  • Study 1 (n=105): Comparison of AXUMIN scans vs  prostate biopsy. Consistent with on-site reads
  • Study 2 : 96 AXUMIN vs  C11 choline scan. Agreement between readings
  • Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.

SAFETY

  • Radioactive drug; should be handled with appropriate safety measures
  • Commonly reported adverse reactions: Injection site pain, redness, and a metallic taste in the mouth

LABEL


 

EPI PROCOLON

Epigenomics AG, Berlin, GERMANY 

INDICATION FOR USE: Qualitative in vitro diagnostic test for the detection of methylated Septin 9 DNA  associated with the occurrence of colorectal cancer (CRC)

REG PATHWAY: PMA, Priority Review because first of a kind device that uses breakthrough technology. Device Code: PHP

  •  Molecular and Clinical Genetics Advuisory Panel voted to approve;  indicated in a second-line setting, post-approval study to evaluate the programmatic performance

DEVICE DESCRIPTION:

  • In vitro polymerase chain reaction (PCR) assay for the qualitative detection of methylated Septin 9 DNA isolated from  patient plasma
  • 3 components: Epi proColon Plasma Quick Kit, Epi proColon Sensitive PCR Kit, Epi proColon Control Kit
  • Plasma Quick Kit: Extraction, purification and conversion of DNA from plasma.
  • Sensitive PCR Kit: Amplify and detect the methylated Septin 9 (mSEPT9) target region and a control region in the β-actin gene (ACTB) in one PCR reaction
  • Colon Control Kit: Test validity of each run

EFFECTIVENESS:

  • Study 1: 68.2% sensitivity, 80.0% specificity vs colonoscopy results
  • Study 2: 73.3% sensitivity, 81.5% specificity vs. colonoscopy results
  • Study 3:  Based on  recommendations from advisory committee – to evaluate adherence in a study population with a history of non-compliance.  99.5% of the study population underwent screening with Epi proColon
  • Patient perspective assessment: Epi proColon provides an option for adults  unable or unwilling to undergo routine CRC screening tests

SAFETY:

  • Erroneous device results could delay detection of CRC
  • False positive results could lead to an increased number of colonoscopies

LABEL

 

FDA Approvals: LENVIMA, OPDIVO, TECENTRIQ+VENTANA Assay

FDA BRIEF: Week of May 16, 2016

FDA approved

LENVIMA® (lenvatinib) capsules

Eisai Inc. Woodcliff Lake, New Jersey, USA

INDICATION: in combination with everolimus for the treatment of patients with advanced Renal Cell Carcinima following one prior anti-angiogenic therapy.

REG PATHWAY: Supplemental NDA, approved prior to PDUFA goal date. Breakthrough Therapy Designation,  Priority Review

MECHANISM OF ACTION: Receptor tyrosine kinase (RTK) inhibitor, inhibits activities of vascular endothelial growth factor (VEGF) receptors, and other  RTKs implicated in pathogenic angiogenesis, tumor growth, and cancer progression

EFFICACY:

  • Single, multicenter study (n=153), advanced or metastatic RCC, previously received anti-angiogenic therapy; LENVIMA +everolimus vs LENVIMA monotherapy
  • Primary Endpoint: Investigator-assessed Progression Free Survival (PFS), RECIST 1.1
  • Median PFS: 14.6 mo. vs 5.5 mo.
  • Overall Survival: 25.5 mo. vs 15.4 mo.

OS

SAFETY:

  • Most common adverse reactions:  Diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, bleeding events, and proteinuria.

OPDIVO  (nivolumab) injection

Bristol-Myers Squibb, Princeton, New Jersey, USA

INDICATION: Teatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin

REG. PATHWAY: Supplemental BLA for new Indication. Opdivo first approved in 2014.  Breakthrough Therapy Designation,   Orphan Drug status,  Priority Review, Accelerated Approval Program. Approved  prior to PDUFA goal date.

MECHANISM OF ACTION: Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Can contribute to inhibition of active T-cell immune surveillance of tumors.

EFFICACY:

  • Two open-label studies (n=95), OPDIVO as single agent, in patients with cHL after failure of autologous HSCT and post-transplantation brentuximab vedotin
  • Included patients regardless of their tumor PD-L1 status
  • Endpoints: Objective response rate (ORR)  by independent radiographic review committee, duration of response (DOR)
  • ORR= 65% (95% CI: 55%, 75%), 58% partial remission,  7% complete remission
  • Median time-to-response: 2.1 months (range: 0.7 to 5.7 months)
  • Median DOR : 8.7 months.
  • Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials

SAFETY:

  • Most common adverse reactions: Fatigue, upper respiratory tract infection, cough, pyrexia,diarrhe
  • Additional common adverse reactions: Rash, pruritus, musculoskeletal pain, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, arthralgia, dyspnea, infusion-related reactions, and hypothyroidism or thyroiditis
  • Immune-mediated adverse reactions: Rash, pneumonitis, hepatitis, hyperthyroidism, colitis
  • Serious adverse reactions:  Pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reaction, rash
  • “Warning and Precaution” for complications of allogeneic HSCT

LABEL


TECENTRIQ (atezolizumab) injection

 Genentech, San Francisco, California, USA

VENTANA  PD-L1 (SP142) assay 

Ventana Medical Systems, Tucson, Arizona, USA.

Positive UC tissue stained with PD-L1 (SP142) assay, 10x

INDICATION: Treatment of locally advanced or 4 metastatic urothelial carcinoma who:

  • Have disease progression during or following platinum-containing chemotherapy
  • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

UNMET NEED:

  •  Urothelial carcinoma most common type of bladder cancer
  • 76,960 new cases of bladder cancer and 16,390 deaths from the disease in 2016
  • First FDA-approved PD-L1 inhibitor

REG PATHWAY: BLA. Breakthrough Therapy Designation, Priority Review, Accelerated Approval

MECHANISM OF ACTION:   Binds to PD-L1 and blocks interactions with both PD-1 and B7.1 receptors – releases inhibition of the immune response, including activation of the anti-tumor immune response.

EFFICACY:

  • Sngle, multicenter, open-label, two-cohort trial (n=310),   locally advanced or metastatic urothelial carcinoma
  • Tumor specimens evaluated prospectively using the Ventana PD-L1 (SP142) Assay
  • Primary Endpoint: Confirmed objective response rate (ORR) assessed by independent review facility (IRF) using RECIST v1.1 and duration of response (DOR).
  • All patients : 14.8% partial shrinkage of tumors, DOR 2.1->13.8 mo.
  • “Positive” for PD-L1 expression: 26% tumor response vs. 9.5% for “negative”
  • Continued approval contingent upon verification and description of clinical benefit in confirmatory trials

SAFETY:

  • Most common side effects: Fatigue, decreased appetite, nausea, urinary tract infection, fever (pyrexia) and constipation
  • Potential to cause infection and serious side effects from immune system effect

LABEL

FDA Voice: Precision FDA Competition, WebMD

FDA BRIEF: Week of May 16, 2016

Voice

FROM COMPETITION TO COLLABORATION: precisionFDA CHALLENGES

Taha Kass-Hout

Zevana Tezak

Elaine Johanson

 

 

 

 

 

Taha A. Kass-Hout, M.D., M.S., Chief Health Informatics Officer, Director Office of Health Informatics

Zivana Tezak, Ph.D., Associate Director, Science and Technology, Office of In Vitro Diagnostics and Radiological Health, CDRH

Elaine Johanson, precisionFDA Project Manager, Deputy Director Office of Health Informatics

  • precisionFDA : online, cloud-based, virtual research space
  • Allow external parties to collaborate on creating tools for “reading” DNA – next generation sequencing (or NGS)

2  COMPETITIONS

  • Consistency Challenge, Use informatics software to identify genetic variants and check for consistency in provided datasets of whole genome sequences from a known human sample, sequenced at two different sites. WINNERS to be announced soon
  • Truth Challenge, to identify genetic variants in one known and one unknown sample dataset

precision

 

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WebMD: Better information. Better health.

WebMD INTERVIEW: EXPERT Q&A: BOOSTING DIVERSITY IN CLINICAL TRIALS 

Jonca Bull, MD, Assistant Commissioner for Minority Health

John Whyte, MD, MPH, Director of Professional Affairs and Stakeholder Engagement, CDER

Importance of  diversity

  • Understand variability in drug response
  • Clinical trials enroll intended population (including elderly) and explore whether there might be a difference in drug response
  • Help physicians decision making

Improve diversity in clinical trials and overcome barriers to involvement

  • Using tools – social media, blogs, brochure for physicians
  • Working with sponsors, stakeholder groups, patient advocacy groups, health professional organizations
  • Improve improve clinical trials – minority physicians involvement, recruitment by mobile van
  • Consider whole clinical trial enterprise: simplify enrollment, target underserved and underrepresented.

Ensure safety and efficacy of drugs for everyone

  • Important to acknowledge clinical trials never encompass entire range of patients
  • Monitor post-approval drug safety after approval- men vs women, age above and below 65, race

Ensure patient safety during clinical trials

  • Institutional review boards
  • Data monitoring safety boards
  • Trials on hold if safety concerns
  • Report death, serious adverse events in a timely manner

Information on participating in  clinical trial

www.clinicaltrials.gov.

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FDA Guidances: Device Post-Market Surveillance, Electronic Health Records

FDA BRIEF: Week of May 16, 2016

fda guidances

Surveillance.JPG

STATUTORY CRITERIA

  • Food and Drug Modernization Act (FDAMA), 1997, amended section 522 of Safe Medical Devices Act for postmarket surveillance for a class II or class III device:
    • failure would cause serious adverse health consequence
    • have significant use in pediatric populations
    • implanted in the human body for more than one year
    • intended to be life-sustaining/supporting

IMPLEMENTATION

  • Surveillance Plans: Agreement by FDA an Manufacturer
  • Surveillance Reports:  Interim/Final Format and Content, possible FDA actions
  • Postmarket Surveillance Status Determination
  • Failure to Comply with Postmarket Surveillance Requirements
  • Public Disclosure of Postmarket Surveillance Plan Information and Reports.

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522

WEBPAGE


 

EHR

 

ELECTRONIC HEALTH RECORD  IN FDA-REGULATED CLINICAL INVESTIGATIONS

  • Assist sponsors, clinical investigators, CROs, IRBs
  • For clinical investigations of drugs, biologics, devices, combination products

RECOMMENDATIONS

  • Whether and how to use
  •  Interoperability with supporting electronic systems
  • Data quality and the integrity
  • Inspection, recordkeeping, record retention requirements

BEST PRACTICES

  • ONC-Certified Health Information Technology
  • Data Modifications
  • Audit Trails
  • Informed Consent
  • Privacy and Security of Data

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522 Postmarket Surveillance Studies

522

 

WHAT:  Design, Tracking, Oversight, Review of studies mandated under section 522, Federal Food, Drug and Cosmetic Act

WHY: To ensure well-designed 522 postmarket surveillance studies, conducted effectively and efficiently in the least burdensome manner

WHEN: Since 2008

WHO: Division of Epidemiology , Office of Surveillance and Biometrics, CDRH

HOW: CDRH Internal Tracking System, PUBLIC WEBPAGE

LINK

Device Reviews: IMAGE READY, IMPELLA, FLUENCY, TRIDYNE

FDA BRIEF: Week of May 9, 2016

FDA approved

 

IMAGE READY MR CONDITIONAL PACING SYSTEM

Boston Scientific Corporation, St. Paul, MINNESOTA, USA

MRI

ingevity.JPG

INDICATION FOR USE:

Treatment of the following conditions:

  • Symptomatic paroxysmal or permanent second- or third-degree AV block, Symptomatic bilateral bundle branch block
  • Symptomatic paroxysmal or transient sinus node dysfunction with or without associated AV conduction disorders
  • Bradycardia-tachycardia syndrome
  • Neurovascular (vaso-vagal) syndromes

REG PATHWAY: PMA

DEVICE DESCRIPTION:

  • ImageReady System created specifically for use with MRI scans
  • Includes ACCOLADE™ MRI and ESSENTIO™ MRI pacemakers, as well as the new INGEVITY™ MRI pacing leads
  • Pacemaker design has minimized use of ferromagnetic materials, which can interact with the fields generated during a typical MRI scan, and circuits have been designed to tolerate voltages that may be induced during scans
  • Lead wire designed to reduce absorption of energy from MR Fields, thus minimizing subsequent heating
  • System for full body scan, with no thoracic exclusion zone

EFFECTIVENESS:

 INGEVITY study: Prospective, non-randomized study, n =1,036 patients,  patients with a single or dual chamber pacemaker

  • Primary Endpoints (3 mo. post-implant): Pacing Threshold at 0.5 ms pulse, Sensed Amplitude, Pacing Impedance
  • Met the pre-specified effectiveness endpoints at 3 months of follow-up

SAMURAI study: Prospective, global,open-label, two-group randomized to receive a protocol-required MRI scan (MRI Group) or not receive a scan (Control Group).

  • Primary Endpoints (pre and 1-mo. post MRI): Change in Pacing Threshold (at 0.5 ms pulse width),  Change in Sensed Amplitude
  • Performed acceptably while used in the MRI environment. The clinical study met the pre-specified effectiveness endpoints at the MRI + 1 month (3 months post-implant) follow-up.

SAFETY:

  • Suitable for longterm implant
  • Adverse event rates comparable to  other marketed  pace/sense leads

IMPELLA 2.5 SYSTEM
ABIOMED, Inc., Danvers, MASSACHUSETTS,  USA

impella

INDICATION FOR USE:

Temporary ventricular support devices intended for:

  • short term use (≤ 4 days for the Impella 2.5)
  • treatment of ongoing cardiogenic shock that occurs immediately (< 48 hours) following acute myocardial infarction or open heart surgery
  • intent is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function

REG. PATHWAY: Supplemental PMA  to expand indication for use to include cardiogenic shock. Original PMA approved March 2015. Classification: OZD

DEVICE DESCRIPTION:

  • Catheter consist of micro-axial rotary blood pump mounted on a 9F drive catheter,  connected to external controller -Automatic Impella Controller (AIC).
  • 4 different Impella support Catheters to accommodate range of cardiac flow requirements and implant techniques
  • Catheter placed with cannula inflow located in left ventricle and outflow located in ascending aorta
  • AIC generates signals power drive motor of Catheter and provides user interface
  • AIC also incorporates disposable Impella Purge Cassette system fluid pressure barrier
  • AIC qualified for use for patient transport by trained healthcare professionals

EFFECTIVENESS:

  • Prospective, singlearm study, n=18 (RECOVER I) (+  Impella Registry, comparative analysis vs approved surgical Ventricular Assist Device, VAD, literature review)
  • Primary Endpoint: Survival to:
    • Recovery defined as 30-day survival post-explant or hospital discharge
    • Bridge-to-other-therapy
  • Survival met in 88% of the cases
  • Consistent and reproducible hemodynamic support
  • Rapid wean of patients off of inotropes and pressors

K-M death

SAFETY:

  • 2 serious adverse events : hemolysis, infection; both resolved
  • Overall profile favorable vs approved VAD.

FLUENCY PLUS ENDOVASCULAR STENT GRAFT 

Bard Peripheral Vascular, Inc. Tempe, ARIZONA, USA

stent

INDICATION FOR USE: Treatment of in-stent restenosis in the venous outflow of hemodialysis patients dialyzing by either an arteriovenous (AV) fistula or AV graft and for the treatment of stenosis in the venous outflow of hemodialysis patients dialyzing by an AV graft.

REG PATHWAY : Supplement PMA to add stenosis treatment. Original PMA approved June 2014

DEVICE DESCRIPTION:

  • Flexible, self-expanding endoprosthesis comprised of expanded polytetrafluoroethylene (ePTFE) encapsulating a Nitinol stent framework
  • Nitinol, an alloy, can be processed to assume a pre-defined final configuration upon exposure to body temperature
  • Four radiopaque tantalum markers on each end facilitating stent graft placement
  • Nitinol stent encapsulated with ePTFE  except graft ends

EFFECTIVENESS:

  • Randomized, prospective, multi-center clinical trial (RESCUE); also leveraged data from original PMA
  • Primary endpoint: Access Circuit Primary Patency (ACPP) at 6 m0.
  • ACPP rate significantly higher (p<0.001) in FLUENCY arm vs. control
  • Secondary Endpoint: Post-Intervention Lesion Patency (PLP) at 6 mo.
  • PLP significantly higher (p<0.001) in the FLUENCY arm vs. control

SAFETY:

  • Similar to original PMA; included in Labeling

 

TRIDYNE VASCULAR SEALANT

 Neomend, Inc. Irvine, CALIFORNIA, USA 

tridyne

INDICATION FOR USE: use in aortic surgery when adjunctive measures to achieve hemostasis are required by mechanically sealing areas of leakage

REG PATHWAY: PMA, Code NBE

DEVICE DESCRIPTION:

  • Single-use, formed by mixing (1) Human Serum Albumin (HSA) and (2)  synthetic crosslinking component of polyethylene glycol (PEG)
  • Delivery system used to deliver hydrogel at intended treatment site

EFFECTIVENESS:

  • Prospective, multicenter, randomized, single-blind (subject), superiority clinical study, n=156, TRIDYNE vs. Control for intraoperative bleeding control after thoracic surgery
  • Primary endpoint: Time to hemostasis (TTH)
  • TTH : Significantly lower with TRIDYNE, 124.3 sec vs 377.8 sec, p< 0.0001
  • Higher proportion of patients in TRIDYNE arm  achieved immediate hemostasis,  hemostasis within 5 min,  hemostasis within 10 min

SAFETY:

  • Deaths: 2 in TRIDYNE vs. 1 in Control. Not considered device related
  • No major differences in adverse events between groups

 

FDA Updates: Translational Science, MDUFA Reauthorization Discussions

FDA BRIEF: Week of May 9, 2016

director corner.JPG

Director’s Corner Podcast – Talking Translational Science

Overview of translational science and how it can speed development and review of innovative new therapies

  • Translational science: Activities to translate discoveries in  laboratory to human products
  • Drug development hampered without appropriate translational science assessments
  • Example: Rare Disease Drug Development requires Natural History studies to adequately design clinical studies
  • CDER Programs : Biomarker Qualification Program, Critical Path Innovation Meetings etc.

PODCAST


MDUFA.JPG

Discussion on:

  • Pre-Submissions: Performance projections, options to address growing inventory
  • De Novo Requests: FDA resource constrained to complete reviews in a timely manner; options to reduce working inventory, achieve stability, improve performance
  • Patient Input: Potential deliverables and metrics, selection process, governance, participation  rules for user fee-funded public-private projects
  • Quality Management: Feedback from AdvaMed, MDMA, MITA
  • Workload Adjustment: Description of components, submission types, review efforts, scenarios
  • Real World Evidence: Potential deliverables, metrics, governance models, data sharing
  • Digital Health: Previous proposal, potential deliverables and metrics
  • Third Party Premarket Review: Previous proposal, potential deliverables and metrics

Next Steps: Industry to provide counter proposals at next negotiation meeting

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FDA 3D Printing Webpage

 

3D web

3D Printing of Medical Devices

 WHAT: New webpage on 3D printed medical devices (e.g. orthopedic and cranial implants, surgical instruments, dental restorations such as crowns, external prosthetics). FDA has cleared more than 85 3D printed medical devices!

WHO:  CDRH

HOW: FDA standards discussed in presentations, workshops and a new guidance posted in this blog

LINK

FDA Guidances: Hepatitis C, Additive Manufacturing (3D Printing), Infectious Disease Next-Gen Sequencing, SPA

FDA BRIEF: Week on May 9, 2016

fda guidances

Hepatitis

  • Clinical development of direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C (CHC)
  • Each marketing application must contain at least one active-controlled comparative trial

General Drug Development Considerations:

  • Nonclinical Virology Development Considerations (Mechanism of action, Antiviral activity in cell culture, Cytotoxicity and mitochondrial toxicity, Antiviral activity in animal models, Combination antiviral activity, Resistance and cross-resistance
  • General Considerations for Phase 1 and Phase 2 Development (Phase 1a/first-in-human trials, Phase 1b (proof-of-concept), Phase 2 trials with combination DAA regimens
  • Drug Development Population
  • Efficacy Considerations
  • Safety Considerations

Phase 3 Efficacy Trial Considerations:

  • Trial Design (Treatment-naïve, non-DAA treatment-experienced,DAA treatment-experienced)
  • Trial Population
  • Entry Criteria (Assessment of cirrhosis, HCV genotype considerations, DAA treatment experience)
  • Randomization, Stratification, and Blinding
  • Specific Populations (HIV-1/HCV co-infected, decompensated cirrhosis and pre- or post-transplants, pediatric, advanced chronic kidney disease)
  • Dose Selection
  • Efficacy Endpoints
  • Trial Procedures and Timing of Assessments
  • Statistical Considerations (Analysis populations, Efficacy analyses, Noninferiority margin, Handling of missing data, Interim analyses and data monitoring committees, Statistical analysis plan)
  • Accelerated Approval (Subpart H) Considerations

Other Considerations: Nonclinical Safety, PK/PD, Clinical Virology, Expanded Access considerations

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3D.JPG

  • Leapfrog guidance on 3-dimensional (3D) printing to share initial thoughts on emerging technologies
  • Additive manufacturing (AM) builds an object by iteratively building 2-dimensional (2D) layers and joining each to the layer below, allowing device manufacturers to rapidly alter designs without the need for retooling and to create complex devices built as a single piece
  • Guidance outlines considerations for testing and characterization for devices that include at least one AM fabrication step.

Design and Manufacturing Considerations

  • Software Workflow
  • Material controls
  • Post processing
  • Process validation and Acceptance Activities
  • Quality Data

Device Testing Considerations

  • Device Description
  • Mechanical Testing Dimensional Measurements
  • Material Characterization
  • Cleaning and Sterilization
  • Biocompatibility
  • Labeling considerations

DEADLINE for comments: Aug 8, 2016

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3D webFDA has launched  3D Printing Web Content


Idisease

  • Infectious Disease Next Generation Sequencing Based Diagnostic Devices – Infectious Disease NGS Dx devices employimg employing targeted or agnostic sequencing approaches
  • Use: Diagnostic aid for microbial infection and in selecting appropriate therapies
  • NGS technology: Rapid, actionable detection of clinically important pathogenic organisms in human specimens e.g., urine, blood, cerebrospinal fluid, stool, sputum
  •  Systems Approach:  Use a “one system” approach for evaluation – from sample collection through the output of clinically actionable data using methods from the  systems science discipline
  • FDA-ARGOS database: Validated regulatory-grade microbial genomic sequence entries
  • Guidance summarizes
    • BENEFIT-RISK ASSESSMENT
    • DEVICE DESCRIPTION
    • DEVICE VALIDATION
    • DEVICE MODIFICATION
    • COMPARATOR DATABASE QUAITY CRITERIA

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SPA

  • Special Protocol Assessment (SPA) provides for protocol evaluation trials prior to initiation
  • Process for sponsors and FDA to reach agreement on key design elements of clinical/animal studies
  • Sponsors: Submit specific questions about protocol design, scientific, regulatory requirements
  • FDA : Issues SPA Letter including assessment of protocol, agreement or nonagreement, abnd responses to questions
  • SPA agreement : FDA Concurrence with adequacy and acceptability of specific critical protocol design elements that meet regulatory 33 requirements for approval
  • However, existence of SPA agreement does not guarantee FDA filing and approval of NDA
  • Guidance summarizes
    • ELIGIBLE PROTOCOLS AND GENERAL INFORMATION
    • PROCEDURES FOR SUBMISSION OF A REQUEST
    • CONTENT OF A REQUEST AND SUBMISSION MATERIALS
    • FDA ASSESSMENT PROCESS
    • SPONSOR OPTIONS AFTER RECEIPT OF NONAGREEMENT SPA LETTER
    • DOCUMENTATION
    • CHANGES IN OR RESCISSION OF SPECIAL PROTOCOL ASSESSMENT AGREEMENTS
    • DISPUTE RESOLUTION

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ODEFSEY Clinical Pharmacology Card

 

ODEFSEY® (emtricitabine, rilpivirine, and tenofovir alafenamide) tablets for oral use 

Mechanism of Action ODEFSEY is a fixed dose combination of antiretroviral drugs emtricitabine (FTC), rilpivirine (RPV), and tenofovir alafenamide (TAF).
Pharmacodynamics (PD) Higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in ODEFSEY) prolonged the QTc interval.  TAF at the recommended dose and at a dose approximately 5 times the recommended dose did not affect the QT/QTc interval and did not prolong the PR interval. The effect of FTC on the QT interval is not known
Pharmacokinetics (PK) Tmax:  4 h (RPV). 3 h (FTC) and 1 h (TAF)

 Cmax (multiple dose, mcg/mL):  2.1 (FTC), NA (RPV) and 0.16 (TAF)

 AUCtau (mcg.h/mL):  11.7 (FTC), 2.2 (RPV) and 0.21 (TAF)

Ctrough (mcg/mL):  0.10 (FTC), 0.08 (RPV) and NA (TAF)

 Food Effect (high fat meal):  72% increased of AUC ( RPV). No change (FTC) and 53% increased of AUC (TAF).

 Protein Binding (% bound):  about 9 (RPV), <4 (FTC) and 80 (TAF)

 Metabolism: by CYP3A (RPV), not significantly metabolized (FTC) and by Cathepsin A, hepatocytes, and minimal CYP3A (TAF).

 Elimination: by  metabolism (RPV), by glomerular filtration and active tubular secretion (FTC) and by metabolism (TAF)

Exposure-Response Relationship Pediatric subjects 12 to less than 18 years of age, antiretroviral HIV-1-infected, had comparable PK of RPV to those in HIV-1 infected adults. There was no impact of body weight on RPV PK in pediatric subjects.
 

Population PK

Renal Impairment:  No clinically relevant changes in mild impirment (RPV), exposure was higher in moderate impairment and no clinically relevant changes (TAF).

 No dosage adjustment is recommended based on race or gender for FTC, RVP or TAF.

 Hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure of RPV.

Special Populations Hepatic Impairment:  Not studied (FTC), exposure was 47% higher in mild hepatic impairment and 5% higher in moderate hepatic impairment (RPV) and no clinically relevant changes (TAF).

Age did not have a clinically relevant effect on exposures of TAF up to 75 years of age. RVP and FTC have not been fully evaluated in the elderly..

Drug Interactions RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV.

 Drugs that strongly affect Pgp activity (e.g., cyclosporine) may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF which may lead to loss of therapeutic effect of ODEFSEY and development of resistance. Co-administration of ODEFSEY with other drugs that inhibit Pgp may result in increased absorption and plasma concentrations of TAF and possible adverse events.

 Co-administration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV.

Source: http://www.gilead.com/~/media/files/pdfs/medicines/hiv/odefsey/odefsey_pi.pdf?la=en

FDA APPROVAL: NUPLAZID, KRYPTOR,

FDA BRIEF: WEEK OF MAY 2, 2016

FDA approved

 

Nuplazid

NUPLAZID (pimavanserin) tablets

Acadia Pharmaceuticals, San Diego, California, USA

INDICATION:  Treatment of hallucinations and delusions associated with Parkinson’s  disease psychosis

UNMET NEED: 

  • ~ 50,000 Americans diagnosed with Parkinson’s disease each year
  • Hallucinations or delusions can occur ~in as many as 50 percent of patients
  • Can be profoundly disturbing and disabling

REG PATHWAY: Breakthrough therapy designation, Priority Review

MECHANISM OF ACTION:  Exact mechanism unknown. Could be mediated through combination of inverse agonist and antagonist activity at serotonin 5-HT2A and  5-HT2C receptors.

EFFICACY:

  • Single 6-week, randomized, placebo-controlled, parallel-group study. (n=199)
  • Primary Endpoint: Parkinson’s Disease -adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), at 6 weeks; measured by central, independent, and blinded raters
  • Superior to placebo in decreasing frequency and/or severity of hallucinations and delusions

Nu_efficacy

SAFETY:

  • Boxed Warning: An increased risk of death associated with the use  (same as other atypical antipsychotic drugs)
  • Most common side effects: Swelling, usually of the ankles, legs, and feet due to the accumulation of excessive fluid in the tissue; nausea; and abnormal state of mind

LABEL


kryptor

BRAHMS

B·R·A·H·M·S PCT sensitive KRYPTOR

B·R·A·H·M·S GmbH, part of Thermo Fisher Scientific, Berlin, GERMANY

INDICATIONS FOR USE

  • Immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma
  • Intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of Intensive Care Unit (ICU) admission for progression to severe sepsis and septic shock
  • Also to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all cause mortality

REG PATHWAY: De Novo, Class II, Code PMT

DEVICE DESCRIPTION:

  • pipetting module
  • reading module
  • external bottles for fluidic system
  • external PC
  • handheld barcode scanner
  • software

EFFECTIVENESS:

  • Prediction of 28-d cumulative all-cause mortality in patients with severe sepsis/septic shock (n=858). PCT levels measured on Days 0, 1, 4
  • Percent change in PCT level over Day 4 significantly associated with 28-d cumulative mortality;
  • Stratification by hospital location gave significant correlation
  • Mortality Risk and Prognostic Accuracy base don initial PCT levels determined

RISKS (MITIGATION): Improper patient management

  • False positives/negatives (Special Controls including detailed Instructions for Use, Labeling)
  • Incorrect interpretation (Special Controls including Labeling, website with ‘PCT change calculator’)
  • Manual Calculation error of final results (Labeling)

 

FDA Views: Parkinson’s Patient Voice, EvGen II FDA Voice

FDA BRIEF: Week of May 2, 2016

 

PFDD_Parkinson

  • Part of FDA’s Patient-Focused Drug Development initiative
  • Obtain input from patients, caretakers,patient representatives on : (1) Effects of Parkinson’s disease that matter most to patients and (2) Patients’ perspectives on treatments for Parkinson’s disease.

Key Themes

  • Progressive, devastating disease: Difficulty of living with the unexpected onset and progression of symptoms – bradykinesia, dyskinesia, tremor, dystonia, sleep disturbances, cognitive impairment, fatigue, and constipation.
  • Impacts all aspects of patients’ lives: Severe limitations in performing at work, caring for self and family, and maintaining relationships and emotional toll
  • Complexity of disease management: Selection of options, timing, pill burden, adjustments to daily changes in symptoms
  • Using combination of drug and non-drug treatments. For optimal symptom management
  • Need for medications for delaying symptom onset or slowing symptom progression 

READ


 

FDA Voice

 

EvGen Part II:

Building Out a National System for Evidence Generation

shermancaliff

Rachel E. Sherman, M.D., M.P.H., Associate Deputy Commissioner

Robert M. Califf, M.D., Commissioner 

 

EvGen Part I posted previously in this  blog

Need to remove barriers to data sharing

  • Common approach for data presentation, reporting and analysis
  • Transparent rules of engagement across all stakeholders
  • Output public good and readily accessible to all stakeholders.

Vision for EvGen

  • Common attributes for drug/biologic/device reviews: Characterization of individuals and populations and associated clinical outcomes
  • Secondary use(s) of data in related fileds

Examples of Related Initiatives

  • Sentinel Initiative
  • National Patient-Centered Clinical Research Network (PCORnet)
  • NIH Health Care Systems Research Collaboratory
  • Reagan-Udall Foundation Innovation in Medical Evidence Development and Surveillance (IMEDS) Evaluation Program
  • National Device Evaluation System (NDES)

More in future postings

READ

 

 

 

FDA Updates: Expanded Access Navigator, Marijuana Regulation

FDA BRIEF: Week of April 25, 2016

marijuana.JPG

 

CENTRAL MESSAGES

  •  FDA supports scientific and rigorous assessment of marijuana
  • Current information on safety, efficacy and reliability is not good enough
  • FDA will support needed scientific research to characterize therapeutic promise

FDA HAS MULTIPLE ONGOING ACTIVITIES

  • Providing scientific advice on risks
  • Supporting rigorous scientific research into therapeutic value
  • Taking appropriate actions related to the marketing of products

FDA WILL CONTINUE TO SUPPORT DEVELOPMENT

  • Specific new drugs that are safe, effective, and manufactured to a high quality
  • Grounded in rigorous scientific research  to determine appropriate use
  • Efficient processes to speed availability to American public

READ


reagen-Udall

  • Creation of an EXPANDED ACCESS (EA) NAVIGATOR to provide information on the request process for individual patient access to investigational drugs, where no Expanded Access Program (EAP) has been established
  • The proposal describes the Navigator scope, functions and anticipated outcomes.
  • Navigator will provide educational content : individual patient access to drugs and biologics, FDA, IRB, manufacturer roles, information for healthcare providers, how EA fits into the drug development, clinical trial, and FDA approval processes

READ


CDEReCATS, CDRH Emergency Use Authorizations

CDEReCATS

WHAT: New electronic system to request a Certificate of Pharmaceutical Product (CPP) online as an alternative to a paper submission

WHO: CDER

WHY:  Possible reduction in certificate processing time, a guided step-by-step application process, real-time validation of data, and e-mail notifications of status updates

HOW: Electronic submission procedures guide

LINK


Emergency use

 

WHAT: Listing of  current and terminated Emergency Use Authorizations that make available diagnostic and therapeutic medical devices

WHO : CDRH

WHY: To diagnose and respond to public health emergencies

LINK


 

FDA Approvals: CABOMETYX, ESOPHAGEAL COOLING DEVICE

FDA BRIEF: Week of April 25, 2016

 

FDA approved


cabomatyx

CABOMETYX  (Cabozantinib)

Exelixis Inc.,  South San Francisco, California, USA

INDICATION:  Treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy

REG PATHWAY: Breakthrough Therapy Designation, Fast Track, and Priority Review; approved prior to the Priority Review deadline of June 22, 2016

MECHANISM OF ACTION: Inhibits the tyrosine kinase activity of receptors involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

EFFICACY:

  • Single pivotal, randomized (1:1, (N=658)), open-label, multicenter study, CABOMETYX vs. everolimus, in patients with advanced RCC woith 1 prior therapy
  • Primary outcome: Progression-free survival (PFS) : 7.4 mo. vs. 3.8 mo. (p<0.0001)
  • Overall Survival  : 21.4 mo. vs. 16.5 mo. (p<0.0001)

OS.JPG

SAFETY:

  • Most common serious adverse events: Abdominal pain, pleural effusion, diarrhea, nausea
  • Most common adverse reactions: Diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, hypertension, vomiting, weight decreased, constipation

cool

ESOPHAGEAL COOLING DEVICE
Advanced Cooling Therapy, Inc., Chicago, Illinois, USA

INDICATION: Thermal regulating device, intended to:

  • connect to a Gaymar Medi-Therm III Conductive Hyper/Hypothermia System to control patient temperature
  • provide gastric decompression and suctioning

REG PATHWAY: De Novo, Class II

DEVICE DESCRIPTION:

  • Silicone tube with three lumens that is placed in the esophagus
  • Control’s patient’s temperature, while simultaneously maintaining access to the stomach to allow gastric decompression and drainage
  • Modulation and control of patient temperature achieved by connecting to  external heat exchanger and circulating temperature controlled fluid

CLINICAL DATA:

  • 16 patients, from centers outside US where device is approved
  • Data summaries of therapeutic cooling, maintenance of target temperature, eventual rewarming
  •  Cooled and eventually rewarmed patients resuscitated from cardiac arrest
  • Duration of temperature management: 24-36 hrs
  • No evaluation whether hypothermia improved cardiac arrest outcomes