Market Authorizations: ARIKAYCE, clonoSEQ Assay, XOFLUZA

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ARIKAYCE (amikacin liposome inhalation suspension) oral
inhalation  

with LAMIRA nebulizer system 

Insmed, Inc

INDICATION: LIMITED POPULATION: Adults, who have limited or no alternative  treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy.

As only limited clinical safety and effectiveness data for ARIKAYCE are currently available, reserve ARIKAYCE for use in adults who have limited or no alternative treatment options. This drug is indicated for use in a limited and specific population of patients.

ADDRESSING UNMET NEED: 

  • Need to encourage the development of drugs to treat resistant infections
  • First approval under Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) to  spur development of drugs targeting infections that lack effective therapies

MECHANISM OF ACTION: Antibacterial drug

EFFICACY:

  •  Randomized, controlled clinical trial, n=336 patients with refractory  MAC lung disease, ARIKAYCE plus a background regimen or background regimen alone
  • Surrogate efficacy endpoint: Culture conversion (3 consecutive monthly negative sputum cultures) by Month 6
  • 29% with Arikayce vs.  9% without Arikayce

 SAFETY

  • Boxed Warning: Increased risk of respiratory conditions including hypersensitivity pneumonitis, bronchospasm, exacerbation of underlying lung disease, hemoptysis
  • Common side effects: Dysphonia, cough, ototoxicity, upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.

REGULATORY PATHWAY: NDA

  • Fast Track, Breakthrough Therapy, Priority Review, Accelerated Approval, Qualified Infectious Disease Product (QIDP) designations
  • Accelerated approval requirements :Randomized, double-blind, placebo-controlled clinical trial to describe clinical benefit in patients with nontuberculous mycobacterial (NTM) lung disease caused by MAC

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clonoSEQ Assay

Adaptive Biotechnologies

INDICATION FOR USE:  In vitro diagnostic that uses multiplex polymerase chain reaction (PCR) and next-generation sequencing (NGS) to identify and quantify rearranged IgH (VDJ), IgH (DJ), IgK, and IgL receptor gene sequences, as well as translocated BCL1/IgH (J) and BCL2/IgH (J) sequences in DNA extracted from bone marrow from patients with B-Cell acute lymphoblastic leukemia (ALL) or multiple myeloma (MM).

The clonoSEQ Assay measures minimal residual disease (MRD) to monitor changes in burden of disease during and after treatment. The test is indicated for use by qualified healthcare professionals in accordance with professional guidelines for clinical decision-making and in conjunction with other clinicopathological features.

The clonoSEQ Assay is a single-site assay performed at Adaptive Biotechnologies Corporation.

ADDRESSING UNMET NEED:

  • Determining whether patient has residual cancer cells remaining after treatment provides information on how well patient responded to therapy and how long remission may last
  • Highly sensitive test available to measure minimal residual disease in ALL or multiple myeloma patients can help providers manage their patients’ care
  • FDA applying novel regulatory approaches to make sure rapidly evolving NGS tests are accurate and reliable

GENERIC DEVICE TYPE: DNA-based test to measure minimal residual disease in hematological malignancies

  • Prescription in vitro diagnostic device that identifies and quantifies specific nucleic acid sequences within human tissues to estimate the percentage of cells that harbor the specific sequence(s). The test is intended to be used as an aid to measure Minimal residual disease to assess the change in burden of disease during Monitoring of treatment. The test is indicated for use by qualified healthcare professionals in accordance with professional guidelines for clinical decision-making, in conjunction with other clinicopathological features.

CLINICAL VALIDITY: 

  • Retrospective analysis of samples obtained from three previously conducted clinical studies- N=273 patients with ALL, N=323 patients with multiple myeloma (ongoing), N=706 patients with multiple myeloma
  • ALL: MRD level correlated with event-free survival
  • Multiple myeloma: MRD level correlated with progression-free survival

RISKS & MITIGATIONS:

  • Incorrect test results: General controls and special controls 
  • Incorrect interpretation of test results: General controls and special controls

REGULATORY PATHWAY: De Novo request

  • Regulation Number: 21 CFR 866.6100
  • Regulatory Class: Class II
  • Product Code: QDC

CLASSIFICATION ORDER


 

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XOFLUZA (baloxavir marboxil) tablets

Shionogi & Co, Genentech USA

INDICATION:  Treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

ADDRESSING UNMET NEED:

  • First new antiviral flu treatment with novel mechanism of action approved by FDA in nearly 20 year
  • Provides an important, additional treatment option

MECHANISM OF ACTION: Prodrug that is converted by hydrolysis to baloxavir that inhibits endonuclease activity of the polymerase acidic protein required for viral gene transcription resulting in inhibition of influenza virus replication

EFFICACY:

  • Two randomized controlled clinical trials, n=1,832 patients,  Xofluza, vs. placebo, or vs. another antiviral flu treatment (oseltamivir) within 48 hours of experiencing flu symptoms
  • Primary endpoint: Time to alleviation of all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue)
  • Statistically significant shorter time to alleviation of symptoms vs placebo
  • No difference in time to alleviation of symptoms vs. oseltamivir

SAFETY:

  • Most common adverse reactions: Diarrhea and bronchitis

REGULATORY PATHWAY: NDA

  • Priority Review
  • Required Pediatric Assessments: Studies in from birth – < 12 months  and from 12 months to <12 years of age with acute uncomplicated influenza
  • Material Threat Countermeasure (MCM) Priority Review Voucher – Denied
    • no form of influenza is listed as a material threat

LABEL


Image credits: Insmed, Adaptive Biotechnologies, Shionogi/Genentech

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FDA News and Views: SUPPORT Law for Substance Use Disorder, Global Crackdown on Illegal Drug Websites, ClinicalTrials.gov Civil Money Penalties, Standing with Pittsburgh’s Jewish Community

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Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act

President signed into law the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act

  • Require certain opioid packaging for shorter durations of use,  reduce number of 30-day prescriptions, address problem of excess supply
  • Require opioids be dispensed with mail-back pouch or other safe disposal option
  • Promote development of evidence-based opioid prescribing guidelines for treating acute pain resulting from specific conditions or procedures
  • Support developing pain drugs that are not addictive, as well as better understanding of safety/efficacy profile of existing opioids

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Global operation to crack down on websites selling illegal, potentially dangerous drugs; including opioids

Action against target 465 websites illegally selling dangerous, unapproved versions of opioid, oncology, antiviral prescription drugs to U.S. consumers

  • Global cooperative effort, led by Interpol
  • Target illegal online pharmacies that knowingly and unlawfully distribute illicit drugs both on the surface and dark web
  • Consumers at risk by individuals who put financial gains above patient safety
  • Information on how to buy medicine safely online: BeSafeRx: Know Your Online Pharmacy

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Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank

Civil money penalties for violating 42 CFR Part 11, to submit registration
and/or results information to the ClinicalTrials.gov data bank 

  • Identification of violators
  • Circumstances for seeking civil money penalty
  • Procedures for seeking civil money penalty

Civil money penalties may be assessed for

  1. failing to submit required clinical trial registration
  2. submitting false or misleading information to the ClinicalTrials.gov data bank
  3. failing to submit required certification to FDA
  4. knowingly submitting a false certification to FDA

Maximum penalties not more than $10,000 for all violations adjudicated in single proceeding, if a violation is not corrected within 30 days – not more than $10,000 for each day that violation continues 

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♥ we stand with the Tree of Life Synagogue and with the Jewish community of Pittsburgh ♥


Image credits: FDA, Interpol

News and Views: Organs-on-Chips, DTC promotional labeling/advertisements, Critical Mitochondrial Functions of Cancer Cells, FDA-DHS coordination for Cybersecurity Threats, Cybersecurity Guidance, Targeted Therapies innovation, Fall 2018 Unified Agenda

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Organs-On-Chips for Radiation Countermeasures

Organs-on-chips mimic the structure, function, interactions between living tissues within human organs on chips

Use for development of medical countermeasures (MCMs)

  • Develop models of radiation damage in lung, gut, and bone marrow organs-on-chips
  • Use models to test candidate medical countermeasures to treat such damage

Understand how sex differences impact body’s response to MCMs for radiological and nuclear preparedness

  • Assess differences in sex-specific responses to radiation exposure and chemotherapeutic agents
  • Effect of MCMs on that response in the bone marrow chip

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Presenting Quantitative Efficacy and Risk Information in Direct-to-Consumer Promotional Labeling and Advertisements

Recent research on Direct-to-consumer (DTC) promotional labeling/advertisements for prescription and OTC drugs indicates

  • Consumers can recall and comprehend efficacy and risk information when it is provided quantitatively
  • Quantitative information can improve consumers’ accuracy in estimating the drug’s benefits and risks

Recommendations for presenting quantitative efficacy and risk information in DTC promotional materials: 

  • Probability information in terms of absolute frequencies, percentages, and relative frequencies
  • Formatting quantitative efficacy or risk information
  • Using visual aids to illustrate quantitative efficacy or risk information
  • Providing quantitative efficacy or risk information for the treatment group and the control group

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CDER Scientists Investigate Critical Cellular Functions That Can Be Targeted to Kill Cancer Cells

Scientists in the CDER Office of Pharmaceutical Quality studying biochemical reactions of cancer cells to certain drugs designed to penetrate mitochondria 

  • Mitochondria are  “powerhouses” of the cell
  • Drugs that selectively enter and damage the mitochondria of cancer cells are of interest
  • However, cancer cells may thwart this strategy by employing a multi-step process, called mitophagy
  • Understand how removal of damaged mitochondria by mitophagy contributes to drug resistance during chemotherapy

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FDA and DHS increase coordination of responses to medical device cybersecurity threats under new partnership

FDA and Dept of Homeland Security (DHS) signed memorandum of agreement to implement a new framework for addressing cybersecurity in medical devices

  • DHS will continue as central medical device vulnerability coordination center
  • DHS will continue to coordinate and enable information sharing between medical device manufacturers, researchers and the FDA
  • FDA will continue to engage with DHS and advise DHS regarding the risk to patient health and potential for harm posed by identified cybersecurity threats and vulnerabilities

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Draft Recommendations on Premarket Submissions for Management of Cybersecurity in Medical Devices

Provide recommendations regarding cybersecurity device design, labeling, and documentation  for devices with cybersecurity risk

  • General Principles & Risk Assessment
  • Designing a Trustworthy Device: Application of NIST Cybersecurity Framework
  • Labeling Recommendations for Devices with Cybersecurity Risks
  • Cybersecurity Documentation
  • Recognized Standards

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FDA’s new steps to modernize drug development, improve efficiency and promote innovation of targeted therapies

Focus on modernizing approach to design of clinical trials,  making drug development process efficient and less costly, while maintaining regulatory standards

  • New pilot program to encourage use of complex innovative trial designs, particularly in areas with small patient populations or unmet need
  • Use of  master protocols in oncology trials and one on the use of adaptive designs for clinical trials

Two new guidances

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Fall 2018 Unified Agenda: FDA’s New Regulatory Work to Advance Health and Safety

Federal government published Fall 2018 Unified Agenda,  on government’s top regulatory priorities including FDA priorities

  • Combating Nicotine Addiction and Preventing Use among Youth
  • Modernizing Nutrition Claims, Labels and Standards of Identity
  • Prioritizing Medical Device Innovation and Safety
  • Advancing Drug Safety, Accessibility and Affordability

DHHS/FDA List

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Image credit: FDA

Marketing Authorizations: Bose Hearing Aid, JIVI, LIBTAYO, VIZIMPRO

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BOSE HEARING AID

Bose Corporation

INDICATION FOR USE: To amplify sounds for individuals 18 years or older with perceived mild to moderate hearing impairment (hearing loss)

ADDRESSING UNMET NEED: 

  •  37.5 million adults aged 18 and over report having some trouble hearing without a hearing aid
  • First hearing aid authorized for marketing by the FDA that enables users to fit, program and control the hearing aid on their own, without assistance from a health care provider

DEVICE DESCRIPTION:

  • User-fitted wireless air conduction hearing aid
  • Captures sound vibrations through one or more microphones
  • Signal is processed, amplified, and played back through an earphone placed in the ear canal
  • Patients can adjust aid through mobile application on phone
  • Enables users to fit the hearing aid settings themselves, in real-time and in real-world environments without the assistance of a health care professional

EFFECTIVENESS & SAFETY:

  • Clinical data from 125 patients
  • Self-fitting of the Bose Hearing Aid comparable to those with professional fitting
    • Amount of amplification selected, speech in noise testing and overall benefit
  • Patients preferred those hearing aid settings over professionally-selected settings
  • Labeling to inform consumer when to consult a hearing health care professional

REGULATORY PATHWAY: De Novo request


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JIVI [antihemophilic factor (recombinant), PEGylated-aucl]

Bayer Healthcare

INDICATION FOR USE: For use in previously treated adults and adolescents (12 years of age and older) with hemophilia A (congenital Factor VIII deficiency) for: on-demand treatment and control of bleeding episodes; perioperative management of bleeding; and routine prophylaxis to reduce the frequency of bleeding episodes.

ADDRESSING UNMET NEED:

  • Option for : On-demand treatment and control of bleeding episodes; Perioperative management of bleeding;  Routine prophylaxis to reduce the frequency of bleeding episodes.

MECHANISM OF ACTION: Site-specifically PEGylated recombinant antihemophilic factor [see Description (11)], temporarily replaces the missing coagulation Factor VIII. The site-specific PEGylation in the A3 domain reduces binding to the physiological Factor VIII clearance receptors resulting in an extended half-life and increased AUC

BENEFIT/RISK:

Benefits

  • On-demand JIVI is effective for treatment of and prevention of spontaneous or traumatic bleeding in patients with Hemophilia A
  • JIVI is effective in the perioperative setting for reduction of bleeding during surgery
  • JIVI is effective in patients over years of age

Risks

  • Hypersensitivity reactions and development of anti-PEG antibodies which resulted in loss of efficacy in patients <12 years of age
  • Risk of development of inhibitory antibodies is considered an expected adverse event

REGULATORY PATHWAY: BLA

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LIBTAYO (cemiplimab-rwlc) injection

Regeneron Pharmaceuticals

INDICATION:  Treatment of patients with metastatic cutaneous squamous cell
carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation

ADDRESSING UNMET NEED: 

  • First  approval of a drug specifically for advanced CSCC
  • CSCC is the second most common human cancer in the United States with an estimated annual incidence of approximately 700,000 cases
  • Immune checkpoint inhibitors targeting the the PD-1 / PD-L1 pathway for treating a variety of tumors, from bladder to head and neck cancer, and now advanced CSCC

EFFICACY:

  • Two open label clinical trials, n=108 patients (75 with metastatic disease and 33 with locally-advanced disease)
  • Primary endpoint: Objective response rate, or the percentage of patients who experienced partial shrinkage or complete disappearance of their tumor(s) after treatment
  • 47.2% patients had tumors shrink or disappear

SAFETY:

  • Severe and Fatal Immune-Mediated Adverse Reactions
  • Infusion-Related Reactions, Embryo-Fetal Toxicity
  • Common side effects: Fatigue, rash and diarrhea
  • Must be dispensed with a patient Medication Guide

REGULATORY PATHWAY: BLA

  • Breakthrough Therapy and Priority Review designations

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VIZIMPRO (dacomitinib) tablets

Pfizer

INDICATION FOR USE:  First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test

MECHANISM OF ACTION:  Irreversible inhibitor of the kinase activity of the human EGFR family (EGFR/HER1, HER2, and HER4) and certain EGFR activating mutations (exon 19 deletion or the exon 21 L858R substitution mutation)

EFFICACY:

  • Randomized, multicenter, open-label, active controlled trialm n= 452 patients with unresectable, metastatic NSCLC,  dacomitinib vs gefitinib
  • Significant improvement in progression-free survival; no improvement in overall response rate or overall survival were demonstrated
  • Median progression-free survival; 14.7 vs. 9.2 months p<0.0001

SAFETY:

  • Warnings & Precautions: Interstitial Lung Disease (ILD), Diarrhea, Dermatologic Adverse Reactions, Embryo-Fetal Toxicity

REGULATORY PATHWAY: NDA

  • Priority Review and Orphan Drug Designation
  • Postmarketing study:  Pharmacokinetic trial to determine an appropriate dose of dacomitinib to minimize toxicity in patients with severe hepatic impairment

LABEL


Image credit: Bose, Bayer, Regeneron, Pfizer

 

News and Views: CDRH 2019 guidances, ‘Gaming’ of Generics, Master Protocols, Antimicrobial Resistance, Medical Device Cybersecurity

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Medical device guidance documents intended to be published in 2019

To meet quantitative and qualitative goals intended to help get safe and effective medical devices to market more quickly

  • List of prioritized device guidance documents (the “A-list”);
  • List of guidances to be published as resources permit (the “B-list”)
  • Update website in a timely manner
  • Provide stakeholders an opportunity to provide feedback
  • Finalize, withdraw, reopen the comment period,

The ‘A’ List- Final Guidances

  • Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions
  • Unique Device Identification: Policy Regarding Compliance Dates for Class I and Unclassified Devices and Direct Marking of Inventory
  • Breakthrough Devices Program
  • Expansion of the Abbreviated 510(k) Program: Demonstrating Substantial Equivalence through Performance Criteria
  • The Least Burdensome Provisions: Concept and Principles
  • Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act
  • Clinical and Patient Decision Support Software
  • Multiple Function Device Products:  Policy and Considerations
  • Humanitarian Device Exemption (HDE) Program
  • Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program
  • The Special 510(k) Program

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New agency actions to further deter ‘gaming’ of the generic drug approval process by the use of citizen petitions

Drug Competition Action Plan for steps to increase competition and help facilitate entry of lower-cost affordable alternatives 

Address practices by branded firms to “game” system and extend monopoly

  • Make it hard for generic manufacturers to get access to  branded drug
  •  Use of citizen petitions (Section 505(q), FD&C Act)  to block generic entry

Revised draft guidance to allow for more efficient approach to 505(q) petitions and allow  reviewer resources on scientific reviews.

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Master Protocols- Efficient Clinical Trial Design Strategies to Expedite Development of Cancer Drugs and Biologics.

Design and conduct of clinical trials intended to simultaneously evaluate more than one investigational oncology drugs

  •  More than one cancer type within the same overall trial structure (master protocols) in adult and pediatric cancers
  • The recommended phase 2 dose (RP2D) has been established
  • Focus for continued discussions among FDA, pharmaceutical sponsors, academic community, public
  • Describes aspects of master protocol designs and trial conduct and related considerations, such as biomarker codevelopment, statistical analysis considerations

Types : Single Investigational Drug or Investigational Drug Combination Across Multiple Cancer Populations, Investigational Drugs or Investigational Drug Combination(s) in Single Cancer Type

Specific Design Considerations: Single Common Control Arm, Novel Combination of Two or More Investigational Drugs, Drugs Targeting Multiple Biomarkers, dding and Stopping Treatment Arms, Biomarker development

Statistical Considerations: Nonrandomized, Activity-Estimating Design, Randomized Designs., Adaptive/Bayesian Design, Biomarker-Defined Subgroups

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Antimicrobial Resistance Information from FDA

Antimicrobial resistance (AMR)—the ability of a microorganism (bacteria, virus, fungi, parasite) to resist the effects of a drug—is serious, complex, costly public health problem

  • At least two million people develop serious infections caused by AMR each year in US, the United States a, and at least 23,000 people die as a result. Combating AMR re

Proactively addressing complex challenges associated with growing threat of AMR by

  • Facilitating efficient product development: development of new antimicrobials, diagnostic tests, and vaccines
  • Promoting appropriate and responsible use of antimicrobials :promoting interventions to slow development of resistance
  • Supporting development and enhancement of tools for conducting surveillance:  better track, treat, or respond to AMR outbreaks
  • Advancing regulatory science:  translation of breakthrough discoveries in science and technology into innovative, safe, and effective medical products

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FDA’s efforts to strengthen the agency’s medical device cybersecurity program as part of its mission to protect patients

FDA working hard with various stakeholders to stay ahead of constantly evolving cybersecurity vulnerabilities

  • Created a Cybersecurity Working Group within CDRH
  • Guidance to establish framework to address cybersecurity regulatory considerations:  Premarket and Postmarket
  • Create shared responsibility with diverse stakeholders, including other government agencies, industry, health care delivery organizations, cybersecurity researchers
  • MITRE Corporation, with support from the FDA, released a Medical Device Cybersecurity Regional Incident Preparedness and Response Playbookdisclaimer icon.
  •  Memoranda of understanding with multiple stakeholder groups to create information sharing analysis organizations (ISAOs)
  • Participating with manufacturers in the DefCon Biohacking Village – Medical Device Hacking Lab in 2018
  • Issued Medical Device Safety Action Plan for advancing medical device cybersecurity

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Image credit: FDA