FDA News: CDER Warning Letters, Information Technology Progress

FDA BRIEF: Week of Feb 19, 2018

CaptureCDER Warning Letters

Provided by CDER Freedom of Information Office (FOI)

  • Some have been redacted or edited to remove confidential information
  • Matters may have been subject to subsequent interaction between FDA and the recipient that may have changed the regulatory status

Types of Letters



PDUFA VI Information Technology Goals and Progress

Goal of improving predictability and consistency of electronic submission process

  • Electronic Submission Documentation
  • Electronic Submission and System Status
  • Electronic Submission Gateway (ESG) Target Timeframes, Milestones and Notifications

Enhance transprency and accountability of electronic submission and data standards activities

  • IT Public Meetings
  • Electronic Submissions Performance Metrics
  • Data Standards


Image credit: FDA


FDA Soundcast: KYMRIAH, first CAR-T cell immunotherapy


KYMRIAH, CAR-T cell immunotherapy- an entirely new treatment approach for patients with cancer FDA Approvals: KYMRIAH, MYLOTARG, VABOMERE, Benznidazole

  • Produced by taking patient’s blood sample, isolating T lymphocytes, and genetically engineering those T-cells to express a new chimeric receptor that recognizes CD19 on their leukemia and normal B-cells
  • Engineered T-cell should recognize and kill B-cells, including the malignant cells


Image credit: FDA

Market Authorization: ContaCT, ERLEADA, BANYAN Brain Trauma Indicator, APTIMA HBV Quant Assay





Notification-only, parallel workflow tool for use by hospital networks, trained clinicians to identify and communicate images of specific patients to a specialist, independent of standard of care workflow.

Uses an artificial intelligence (AI) algorithm to analyze images for findings suggestive of a prespecified clinical condition and to notify an appropriate medical specialist of these findings in parallel to standard of care image interpretation. Identification of suspected findings is not for diagnostic use beyond notification. Specifically, the device analyzes CT angiogram images of the brain acquired in the acute setting, and sends notifications to a neurovascular specialist that a suspected large vessel occlusion has been identified and recommends review of those images. Images can be previewed through mobile application.

Images that are previewed through the mobile application are compressed and are for informational purposes only and not intended for diagnostic use beyond notification. Notified clinicians are responsible for viewing non-compressed images on a diagnostic viewer and engaging in appropriate patient evaluation and relevant discussion with a treating physician before making care-related decisions or requests. ContaCT is limited to analysis of imaging data and should not be used in-lieu of full patient evaluation or relied upon to make or confirm diagnosis.


  • First approved Clinical Decision Software to analyze computed tomography (CT) results that may notify providers of stroke potential
  • 795,000 in U.S. have stroke each year; causes serious and irreversible damage
  • Software device notifies specialist earlier thereby decreasing the time to treatment


  • Computer-aided triage software using AI algorithm to analyze images for stroke indicators
  • Designed to analyze brain CT images
  • Send text notification to neurovascular specialist if suspected large vessel blockage
  • Involve specialist sooner with algorithm automatically notifying specialist concurrently with first-line provider who is conducting standard review of images
  • Specialist still needs to review images on clinical workstation


  • Retrospective study of 300 CT images
  • Brain large vessel blockage detection: Algorithm image analysis and notification vs.  performance of two trained neuro-radiologists
  • Real-world evidence used with clinical study to demonstrate neurovascular specialist notification sooner in cases of suspected blockage


  • 21 CFR 892.2080
  • Regulation Name: Radiological Computer Aided Triage and Notification Software
  • Class II, Product Code: QAS

GENERIC DEVICE TYPE:  Radiological computer aided triage and notification software

  • Image processing device intended to aid in prioritization and triage of radiological medical image
  • Notifies designated list of clinicians of the availability of time sensitive radiological medical images for review based on computer aided image analysis of those images performed by the device
  • Does not mark, highlight, or direct users’ attention to a specific location in original image
  • Does not remove cases from a reading queue
  • Operates in parallel with standard of care, which remains default option for all cases


  • Detailed description of notification and triage algorithms
  • Detailed description of pre-specified performance testing protocols and dataset(s) used to assess whether the device will provide effective triage
  • Performance testing
  • Appropriate software documentation
  • Labeling


  • Failure to prioritize images for review with positive findings may result in incorrect and/or delayed patient management
  • Positive notifications may result in deprioritization of review of images from other patients
  • Misuse to analyze images (unintended patient population, incompatible imaging
    hardware and image acquisition)
  • Device failure leading to absence, delay, incorrect results
  • Inappropriate use of triage and notification outputs
  • Mitigated by general and special controls


  • Precedence for CMS qualification of Clinical Decision Support Mechanisms


Capture.JPGERLEADA (apalutamide) tablets


INDICATION: Treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC)


  • Prostate cancer is second most common form of cancer in men;  161,360 men diagnosed-26,730 expected to die of disease
  • 10 to 20 % cases are castration-resistant; up to 16% show no evidence of metastasis  at the time of castration-resistant diagnosis
  • First approval based on endpoint of metastasis-free survival

MECHANISM OF ACTION: Androgen Receptor (AR) inhibitor,  inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription


  • Single multicenter, double-blind, clinical trial, n= 1,207 patients with NM-CRPC,  ERLEADA vs placebo
  • Major efficacy outcome: Metastasis-free survival (MFS), time to metastasis (TTM), progression-free survival (PFS) and overall survival (OS)


  • Significant improvement in MFS: 40.5 months vs 16. 2 months, HR=0.28, CI: 0.23, 0.35;p<0.0001


  • Most common adverse reactions : Fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema


  • Pediatric requirements waived


  • CMS covers prostate CA drugs
  • Novel and clinically meaningful endpoint could secure favorable coverage and pricing


CaptureBANYAN Brain Trauma Indicator

Banyan Biomarkers, Inc.


In vitro diagnostic chemiluminescent enzyme-linked immunosorbent assay (ELISA). Assay provides semi-quantitative measurement of the concentrations of ubiquitin Cterminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in human serum, and is used with the Synergy 2 Multi-mode Reader.

The assay results obtained from serum collected within 12 hours of suspected head injury are used, along with other available clinical information, to aid in the evaluation of patients 18 years of age and older with suspected traumatic brain injury (TBI, Glasgow Coma Scale score 13-15). A negative assay result is associated with the absence of acute intracranial lesions visualized on a head CT (computed tomography) scan.

The Banyan BTI is for prescription use only.


  • 2.8 million TBI-related emergency department visits, hospitalizations, deaths in US
  • Need for innovative testing technologies that minimize health impacts
  • Supports FDA Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging
  • Blood-testing option for TBI/concussion is a new tool, modernizing standard of and  likely reduce CT scans performed

GENERIC DEVICE TYPE: Brain trauma assessment test

  • Consists of reagents used to detect and measure brain injury biomarkers in human specimens
  • Measurements aid in evaluation of patients with suspected mild traumatic brain injury in conjunction with other clinical information to assist in determining the need for head imaging per current standard of care


  • Multi-center, prospective clinical study, n=1,947 individual blood samples from adults with suspected TBI/concussion
  • Comparison TBI/concussion blood tests results vs CT scan results
  • Prediction: 97.5% accuracy (presence of lesions),  99.6% accuracy (absence of lesions


  • Approval in <6 months as part of its Breakthrough Devices Program
  • 21 CFR 866.5830
  • Regulation Name: Brain trauma assessment test
  • Class II, Product Code: QAT


  • Performance testing including clinical testing
  • Labeling


  • Inaccurate test results that provide false positive or false negative results
  • Failure to correctly interpret test results can lead to false positive or false negative results
  • Mitigated by general and special controls


Capture.JPGAPTIMA HBV Quant Assay

Hologic, Inc


In vitro nucleic acid amplification test for the quantitation of hepatitis B virus (HBV) DNA in human plasma and serum on the fully automated Panther® system.

Plasma may be prepared in ethylenediaminetetraacetic acid (EDTA), anticoagulant citrate dextrose (ACD) solution, and plasma preparation tubes (PPTs). Serum may be prepared in serum tubes and serum separator tubes (SSTs). Specimens are tested using the fully automated Panther system for sample processing, amplification, and quantitation. Specimens containing HBV genotypes A, B, C, D, E, F, G, and H are validated for quantitation in the assay.

The Aptima HBV Quant assay is intended for use as an aid in the management of patients with chronic HBV infections undergoing HBV antiviral drug therapy. The assay can be used to measure HBV DNA levels at baseline and during treatment to aid in assessing viral response to treatment. The results from the Aptima HBV Quant assay must be interpreted within the context of all relevant clinical and laboratory findings. Assay performance for determining the clinical stage of HBV infection has not been established. Clinical performance characteristics have been established for individuals treated with tenofovir disoproxil fumarate or entecavir.

The Aptima HBV Quant assay is not approved for use as a screening test for the presence of HBV DNA in blood or blood products or as a diagnostic test to confirm the presence of HBV infection


  • Hepatitis B is a liver infection caused by HBV; transmitted through infected blood, semen, or other body fluid
  • Risk for chronic infection is related to age at infection: ~ 90% of infected infants become chronically infected, vs. 2%–6% of adults
  • Chronic Hepatitis B infection can lead to cirrhosis or liver cancer


  • In vitro nucleic acid amplification test with real time transcription-mediated amplification (TMA) technology on Panther system
  • Standardized to the 3rd WHO International Standard for Hepatitis B Virus
  • Three main steps which all take place in a single tube on the Panther system: (1) target capture, (2) target amplification by TMA, (3) detection of amplification products (amplicon) by fluorescent labeled probes


  •  Effectiveness demonstrated when used for the quantitation of HBV DNA in human plasma and serum and serum separation tubes for management of patients undergoing treatment.
  • Clinical performance evaluated in ethnically diverse population representative of intended use population
  • Accurately measures viral load in patient at baseline and at intervals during antiviral therapy
  • Should benefit physician and patients in management of chronic HBV infected individuals undergoing antiviral therapy when used according to the directions for use in labeling


  • Product Code: MKT


  • CMS has determined that screening for HBV infection  is reasonable and necessary for the prevention or early detection
  • Will cover screening for HBV infection with FDA approved/cleared laboratory tests, used consistent with FDA approved labeling and in compliance with CLIA regulations Decision memo


Image credit: Viz.AI, Banyan, Janssen, Hologic


FDA News: 2017-2018 Flu Vaccine, Rapid Flu Tests, Warfarin INR Test Meters, Funding for Innovation, Advancing Neurological Treatments, External Stakeholder Meeting Requests

Week of February 12, 2018

CaptureEfficacy of the 2017-2018 influenza vaccine

2017-2018 Seasonal flu has been widespread with high rates of hospitalization 

  • Caused by one strain of influenza A called H3N2, with another strain of influenza A called H1N1 and strains of influenza B contributing to lesser extents
  • Viruses can change genetic make-up rapidly during course of single year
  • Questions raised about how flu vaccine efficacy; initial report of 36%

Select strains for next season’s flu vaccines

  • Convene Vaccines and Related Biological Products Advisory Committee
  • Collaboration with WHO, CDC, NIH, other federal partners to address full spectrum of measures for optimal protection
  • Select most appropriate flu strains, provide seed viruses and quality control reagents to manufacturers, ensure quality of manufacturing process
  • Analyze CMS databases covering millions of individuals for signals
    • Better effectiveness with cell-based vs egg-based vaccine



CLIA-Waived Rapid Flu Test Facts

Available Rapid flu tests have demonstrated acceptable clinical performance

  • Antigen-based rapid flu tests (rapid influenza diagnostic tests or RIDTs)
  • Nucleic acid-based rapid molecular flu tests

Performance Levels for antigen-based RIDTs

  • Reclassified  into class II to improve overall quality of flu testing
  • Prompted  by poor sensitivity resulting in misdiagnosed cases, even death.
  • Established special controls for assuring accuracy, reliability and clinical relevance

2017-2018 Flu Season

  • Earlier than usual flu season with high incidence of flu cases
  • Manufacturers’ marketing forecasts may have underestimated needs
  • Some manufacturers have ramped up production



Capture.JPGWarfarin INR test meters 

INR test meter is portable, battery-operated meter, to monitor patient response to warfarin (brand names Coumadin and Jantoven)

  • Medical Device Reporting (MDRs) of adverse events of inaccurate results
  • Need to update information provided to patients, caregivers, and health care providers to safe and effective use

Updates include

  • Correct use: how to take blood from a fingerstick, how to make sure meter working properly
  • Information for health care providers: Medical conditions that could affect test results, recommendations for confirming test results
  • How to report problems with INR test meters



New FDA funding to promote innovation and broaden patient access through competition

  • Foster development of therapeutics and diagnostics for unmet medical needs
  • Advance drug and device competition
  • New domestic industries – pharmacy outsourcing facilities
  • Create modern, domestically-based manufacturing

I. Promote Domestic Manufacturing

  • Development of efficient regulatory pathways for personalized medicines and novel technologies – such as cell- and gene-based therapies, vaccines
  • Continuous manufacturing platforms to ramp up on short notice
  • Return product manufacturing to domestic sites, foster job creation

II. Robust and Reliable Source of Compounded Products

  • Create “Center of Excellence on Compounding for Outsourcing Facilities”
  • Wider availability of reliable compounded drugs meeting GMP

III. Advance Medical Device Manufacturing and Quality

  • Voluntary program for certification of manufacturers
  • Facilitate manufacturing innovation, investment in new production methods/ materials, lead to better medical products
  • Work collaboratively with industry, patients, providers and payers to develop parameters

IV. New Medical Data Enterprise

  • Advance use of Real-World Evidence to better inform patient care, provide more efficient, robust lower-cost ways to develop clinical data
  • Expanded use of natural language processing to speed recognition and remediation of emerging safety concerns
  • Cover data gaps in the Sentinel and NEST systems

V. Digital Health Technology Industry and Framework for Reliable Post-Market Oversight

  • New paradigm to market lower-risk products without FDA premarket review and market higher-risk products with streamlined FDA review
  • Validate quality of a firm’s software design and firm’s methods for certifying the quality and reliability of its underlying software performance
  • Create Center of Excellence on Digital Health to recognize third-party certifiers,  support cybersecurity unit

VI. Modern Science-Based Principles for New Drug Development 

  • Build knowledge management system and portal
  • Build on evolving information, decisions, gaps in policies and pathways, consistent responses to regulatory questions, prevent delays in response to innovations

VII. Medical Products Targeted to Rare Diseases

  • Develop clinical trial networks to understand natural history and clinical outcomes
  • Initial focus would be on rare and ultra-rare diseases to address challenges in clinical trial recruitment

VIII. Modernize Generic Drug Development 

  • Create new review platform for data-based assessment
  • Improve clarity for generic sponsors, reviews more efficient, increasing first-cycle approvals



Advancing development of novel treatments for neurological conditions

Symptoms and progression of neurological diseases vary significantly across patients, within patients, across organ systems

  • Urgent need for new medical treatments
  • Need to modernize multiple aspects of regulatory programs

CDER team-based modern approach

  • Integrate expert knowledge across different fields,  different stages of product life cycle toward a common public health goal
  • Piloting streamlined process for writing science-based, disease-based guidance documents

Duchenne Muscular Dystrophy and Related Dystrophinopathies

  • Support from Parent Project Muscular Dystrophy with scientific and patient input from DMD community

Amyotrophic Lateral Sclerosis

  • Support from ALS Association guidance funded by “ice bucket challenge”

Early Alzheimer’s Disease

  • Innovative approaches to studying very early disease before onset of dementia, use of sensitive cognitive screening, imaging tests, or biomarkers


  • Innovative approaches to clinical trial design for acute migraine

Partial Onset Seizures

  • Rigorous approach based on extrapolation of effectiveness adult patients to pediatric patients

External Stakeholder Meeting Request (ESMR) system

Meetings between stakeholders and CDER promote effective two-way communication to improve drug development and safety

  • To help external, non-industry stakeholders more easily request meetings with CDER
  • Mechanism for communicating, sharing ideas to improve efficiency and advance medical product development
  • ESMR system to improve value and efficiency of stakeholder meetings
  • Professional Affairs and Stakeholder Engagement (PASE) Staff facilitate meeting

 Image credit: FDA

Market Authorizations: BIKTARVY, ZYTIGA, RADIOGENIX system


BIKTARVY (bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF)) tablet


INDICATION: Complete regimen for the treatment of HIV-1 infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of

MECHANISM OF ACTION: Fixed dose tablet of antiretroviral drugs:

  • bictegravir (BIC) : Integrase strand transfer inhibitor
  • emtricitabine (FTC): HIV nucleoside analog reverse transcriptase inhibitor
  • tenofovir alafenamide : Acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate


  • 2 trials each in (a) adults with no antiretroviral treatment history and (b) virologically suppressed adults, n=2,415
  • Met primary objective of non-inferiority at 48 weeks across all four studies
  • No partients  failed Biktarvy with treatment-emergent virologic resistance
  • No patients discontinued Biktarvy due to renal adverse events, no cases of proximal renal tubulopathy or Fanconi syndrome
  • Most common adverse reactions: Diarrhea, nausea and headache.


  • Required postmarketing studies in pediatrics


  • Patient Assistance programs: Gilead’s U.S. Advancing Access® program
  • Working closely with the AIDS Drug Assistance Programs (ADAP) Crisis Task Force to provide discounts to state ADAPs



ZYTIGA (abiraterone acetate) in combination with prednisone


INDICATION:  For metastatic high-risk castration-sensitive prostate cancer (CSPC)


  • Placebo controlled international clinical trial, n=1,199 patients, placebo controlled
  • Patients in both arms received gonadotropin releasing hormone or had bilateral orchiectomy
  • Major efficacy endpoint: Overall Survival. Median OS not estimable in ZYTIGA arm vs. 34.7 months in placebo arm, p<0.0001
  • Median time-to-initiation of chemotherapy: Not reached in ZYTIGA arm vs. 38.9 in  placebo arm, p<0.0001


  • Adverse reactions:  Hypertension, hot flush, hypokalemia, increased alanine aminotransferase or aspartate aminotransferase, headache, urinary tract infection, upper respiratory tract infection, and cough


  • Priority Review; approved more than a month ahead of due date
  • Postmarketing commitment: Overall survival analysis
  • Initial approval in 2011 for patients with metastatic castration-resistant prostate cancer (CRPC)
  • Expanded indication in 2012 for patients with metastatic CRPC


  • 100% of Medicare Part D and Medicare Advantage plans coverage; quantity limits and prior authorization
  • Tier 5- Non-preferred brand-name drug



RADIOGENIX System (technetium Tc-99m generator )

NorthStar Medical

INDICATION FOR USE: Technetium Tc-99m generator used to produce sterile, non-pyrogenic Sodium Pertechnetate Tc-99m injection. Sodium Pertechnetate Tc-99m injection is indicated for use in the preparation of FDA approved diagnostic radiopharmaceuticals

Sodium Pertechnetate Tc-99m injection is also indicated:

In Adults for:

  • Thyroid Imaging
  • Salivary Gland Imaging
  • Urinary Bladder Imaging (direct isotopic cystography) for detection of vesicoureteralreflux
  • Nasolacrimal Drainage System Imaging (dacryoscintigraphy)

In Pediatric Patients for:

  • Thyroid Imaging
  • Urinary Bladder Imaging (direct isotopic cystography) for the detection of vesicoureteralreflux


  • Broad collaboration across FDA, Nuclear Regulatory Commission (NRC) and  industry
  • Tc-99m plays vital role in nuclear imaging studies for wide range of uses, including cancer and cardiology
  • Used > 80 percent of routine medical imaging procedures
  • Stable supply chain is critical due to limited shelf life
  • Approval restores U.S. ability to domestically supply a critical medical diagnostic tool for the first time in 30 years

MECHANISM OF ACTION: Pertechnetate ion distributes in the body similarly to iodide ion, but is not organified. In contrast to the iodide ion, the pertechnetate is released unchanged from the thyroid gland.


  • Did not require new clinical studies because it relied on safety and efficacy information and data from an already FDA-approved Tc-99m generator
  • Common side effects: Allergic reactions, including anaphylaxis


  • Complete response to FDA’s November 4, 2013, action letter
  • Exempt from pediatric requirements
  • Postmarking requirements: Evaluation of fluid path bioburden and final product endotoxins and sterility


 Image credits: Gilead, Janssen, NorthStar Medical


FDA News: NTP report on Radiofrequency Energy Exposure, CDER/CBER Data Standards, GAIN Report, Complete ANDA submissions, Kratom Abuse

FDA BRIEF: Week of February 5, 2018


Statement from Jeffrey Shuren, director CDRH: National Toxicology Program draft report on radiofrequency energy exposure

FDA ensures safety of electronic products that emit radiation (e.g. cell phones, TV)

  • Federal Communications Commission (FCC) standards +  other health agencies for scientific expertise

Recently released National Toxicology Program research on radiofrequency energy exposure in rodents

  • Male rats showed carcinogenic activity with radiofrequency energy exposure rate much higher than current safety standard
  • Equivocal/ambiguous evidence that whole body radiofrequency energy exposures in rats/mice actually caused cancer; additional unusual findings
  • FDA to participate in peer review of study
  • Public comment welcome Federal Register notice

FDA has reviewed many sources of scientific and medical evidence on possibility of adverse health effects from radiofrequency energy exposure

  • Not found sufficient evidence of adverse health effects or increase in events like brain tumors
  • Current safety limits for cell phones acceptable for protecting public health



CDER/CBER Data Standards Strategy FY2018-FY2022

Development, implementation, maintenance of comprehensive data standards program for pre- and postmarket regulatory review

  • With Stakeholder collaboration
  • Other Regulatory Authorities, Other Federal Agencies, Clinical Data Interchange Consortium (CDISC), Critical Path Institute, Health Level 7 (HL7), International Council on Harmonisation, International Organization for Standards, TransCelerate BioPharma, World Health Organization

Strategic Goals

  • More efficient, science-based pre-market review
  • Improve postmarket risk management strategies and pharmacovigilance
  • Improve quality and integrity of marketed products
  • Promote innovation in development and use of data standards
  • Effective communication and collaboration with stakeholders
  • Improve management and usability of  information



Generating Antibiotic Incentives Now (GAIN)  FY2012-FY2017

GAIN passed in 2012 to address public health threat of antibacterial drug resistance by stimulating new antibacterial and antifungal drug development

  • Qualified Infectious Disease Products (QIDP): Designation (147), Approval with Priority Review (12)
  • Review and revision of guidance documents for streamlined development, limited population pathway for antibacterial and antifungal drugs (LPAD)
  • Engagement to support development by public workshops and advisory committee meetings, collaborative partnerships, funding regulatory science research
  • Development and implementation of stewardship programs to slow and control spread of resistant infections



FDA Helping Generic Industry Submit Complete Applications

Improve Abbreviated New Drug Application (ANDA) submission and assessment process;~ 50% ANDAs required at least 3 review cycles

  • Guidance to industry
  • Establishing internal practices to help reduce review cycles

Good ANDA Submission Practices to address

  • Patent and Exclusivity Deficiencies
  • Labeling Deficiencies
  • Product Quality Deficiencies
  • Bioequivalence Deficiencies



Statement from FDA Commissioner Scott Gottlieb: Scientific evidence on presence of opioid compounds in kratom, underscoring its potential for abuse

Scientific tools, data, research on FDA’s concerns about kratom’s potential for abuse, addiction, and serious health consequences; including death

  • Public Health Assessment via Structural Evaluation (PHASE) methodology to use molecular structure to predict biological function
    • Analyzed chemical structures of 25 most prevalent compounds in kratom
    • All had structural similarities with controlled opioid analgesics, e.g. morphine derivatives
  • Analyzed chemical structure against software to determine biologic targets
    • 22 (including mitragynine) of 25 compounds bind to mu-opioid receptors
    • Top five most prevalent compounds (including mitragynine) activate opioid receptors (“opioid agonists”)
    • Some may bind to brain receptors and impact neurologic and cardiovascular functions – seizures and respiratory depression
  • 3-D image on how strongly they bind to biological targets
    • Comparable to scheduled opioid drugs

Learnings from reports of death associated with kratom

  • Monitoring the use of kratom for several years, with import alerts
  • Releasing reports of 36 deaths  underscoring serious and deadly risks
  • One new report of death with no known opioid use, except for kratom

Kratom should not be used to treat medical conditions, or as an alternative to prescription opioids

  • No evidence of safety and effectiveness


Image credit: FDA








FDA Drug Databases

Drug Approvals and Databases



FDA News and Views: OTC Loperamide Limitations, REMS Education Blueprint, Research Subjects Reimbursement

FDA BRIEF: Week of January 29, 2018


New steps to help prevent new addiction, curb abuse and overdose related to opioid products: OTC LOPERAMIDE

Unprecedented and novel action regarding OTC Loperamide (Brand Name Imodium A-D)

  • Approved to help control short-term symptoms of diarrhea, including Travelers’ Diarrhea
  • However, intentional misuse and abuse of loperamide has been increasing;  used as potential alternative to manage opioid withdrawal symptoms or to achieve euphoric effects of opioid use
  • Reports of serious heart problems and deaths

Loperamide packaging limitations and unit-of-dose packaging

  • Limited amount appropriate for use for short-term diarrhea per product label
  • Manufactures to implement changes in a timely fashion
  • Online retail web sites advised to take voluntary steps to limit distribution



Opioid REMS Education Blueprint

Blueprint for Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS) to ensure benefits outweigh risks

  • Core educational messages for health care providers for pain
  • Information on acute and chronic pain management, non-pharmacologic and pharmacologic treatments (non-opioid and opioid analgesic)
  • Education for safe and effective use

Revised FDA Blueprint contains

  • Core educational messages  to be included in educational programs developed under Opioid Analgesic REMS
  • Focus on fundamentals of acute and chronic pain management and contextual framework for safe prescribing
  • Directed to prescribers, pharmacists, and nurses, but also relevant for other HCPs who participate in pain management of pain


Capture.JPGPayment and Reimbursement to Research Subjects

Updates to the Payment for Research Subjects: Information Sheet

  • Reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging are acceptable

Image credit: SAMHSA, FDA

FDA Marketing Authorizations: LUTATHERA, REMODULIN Impant

FDA BRIEF: Week of January 22, 2018


LUTATHERA (lutetium Lu 177 dotatate) injection

 Advanced Accelerator Applications

INDICATION: Treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults


  •  First FDA Approval for a Peptide Receptor Radionuclide Therapy (PRRT) –  targeting molecule that carries radioactive component
  • Approved indication is a rare disease and unmet need in NET community

MECHANISM OF ACTION:  Binds to somatostatin receptors including malignant somatostatin receptor-positive tumors, and is internalized; beta emission from Lu 177 induces cellular damage


  • Randomized, multicenter, open-label, active-controlled trial, n=229, patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumor, LUTATHERA vs. high-dose long-acting octreotides
  • Major efficacy outcome measure: Progression free survival (PFS); additional efficacy outcome measures were overall response rate (ORR), duration of response, overall survival (OS), RECIST criteria


  • Median PFS was not reached for LUTATHERA vs. 8.5 mo. in octreotide (p<0.0001)
  • Efficacy in subset (n=360) of 1214 patients with GEP-NET tumors;  16% ORR  including 3 complete responses


  • Adverse Reactions:  Lymphopenia, increased GGT, vomiting, nausea, elevated AST,  increased ALT, hyperglycemia, hypokalemia
  • Myelodysplastic syndrome reported


  • Priority review, Orphan Drug Designation
  • Postmarketing Requirements: Safety analyses based on 5 and 10 yr followups, Overall Survival data
  • Complete Response Letter and Discipline Review Letter issued previously requesting additional data


  • Expanded Access Program
  • NETSPOT, another FDA-approved Molecular Nuclear Medicine from Advanced Accelerator,  granted Transitional Pass-Through status under “A-code” (A9587) for drug reimbursement
    • HCPCS “A Code” will be used on claims to private payers
  • However, UK medicines cost-effectiveness group, NICE, has published draft guidance not recommending LUTATHERA




INDICATIONS FOR USE:  For adult patients with Class I, II and III pulmonary arterial hypertension (PAH) receiving intravenous delivery of Remodulin.

Physicians prescribing this system for use with Remodulin must be familiar with the indications, contraindications, warnings, precautions, adverse events, and dosage and administration information described in the Remodulin drug labeling.

The Model 8551 Refill Kit is intended for use in refilling the Medtronic implantable  programmable infusion pumps with the exception of Medtronic MiniMed infusion pumps.


Consists of the following components:

  • Medtronic SynchroMed II 8637P Programmable Pump (the “pump”)
  • Medtronic 8201 Implantable Intravascular Catheter (the “catheter”)
  • Medtronic N’Vision 8840 Clinician Programmer with 8870 Application Card (the  “programmer”)
  • Remodulin (treprostinil) Injection stored in pump reservoir and, per a programmed prescription, moves through pump tubing, catheter port, and catheter to  intravascular delivery site
  • Programmer is handheld device for healthcare provider use only that is used to review and program pump parameters using telemetry, a radio frequency communication


  • Multi-center, prospective, single arm, non-randomized open label Investigational Device Exemption (IDE) clinical study, n=64, met the approved Remodulin indication, using approved concentrations, and approved intravenous route
  • Primary endpoint: Demonstrate safety when used with the Medtronic SynchroMed II Implantable Infusion System to deliver Remodulin
  • No effectiveness endpoint – effectiveness based on ability to provide accurate drug delivery
  • Clinical data, mathematical modeling, bench testing indicate that over the expected longevity of the pump, the accuracy ratio will decrease and plateau at ~ 0.8
  •  Primary safety objective met (p<0.0001); catheter revisions, early pump  replacement rates significantly less than literature reports


  • Device Generic Names: Pump, Infusion, Implanted, Programmable
    Implantable Intravascular Catheter, Clinician Programmer
  • Device Procode: LKK
  • Postmarketing requirements: Report on  pump failure analysis, validate the initial training program utilizing the to-be-marketed user interface, PAS reports


  • Existing codes and coverage for infusion pumps and associated parts
  • Information specific to this device not available


Image credit:  Advanced Accelerator Applications, Medtronic

Transparency at FDA

New platforms for analyzing and visualizing large, complex datasets

  • Harness data to advance the safe and efficient development of new therapies
  • Tailor clinical care to individual patient characteristics and preferences
  • Communicate information supporting regulatory decision-making to engender greater public confidence

Advance transparency without reducing incentives to innovate

  • FDA’s Data Dashboard: publicly available datasets, data visualization tools 
  • openFDA
    • APIs and full sets of downloadable FDA data files for adverse events, drug product labeling, recall enforcement reports
    • supports open source user community, sharing of source code and techniques for use through GitHub, Twitter, and StackExchange

New Steps to filter information and harness it into more usable knowledge

  • Greater transparency and efficiency in NDA and BLA reviews
  • Track product development in clinical trials posted on the ClinicalTrials.gov
  • Pilot (9 applications) to disclose key portions of Clinical Study Reports to decipher  key clinical evidence for approval decision
  • Add special identifier number to clinical trials registered through ClinicalTrials.gov  and link to FDA communications (e.g. labeling, advisory committee materials)
  • Explore possibility – under existing statutory authority- to release Complete Response Letters (CRLs) information directly relevant to patients

Technology, no matter how powerful, is always just a tool

  • Commitment to transparent, responsible, and science-based use to save and improve lives

FDA Commissioner Statement

Blueprint for FDA transparency