FDA news and Views: Quality Overall Summary, Third Party Review Metrics, Rogue Online Pharmacies, State of CDER, Warning for illegal, unapproved opioid cessation products

FDA BRIEF: Week of January 22, 2018

Quality Overall Summary (QOS) of all quality-related information provided in NDA, ANDA, BLA

  • Considering adjustments to QOS format to improve efficiency

CDER new white paper describes key considerations for QOS preparation:

  • Explaining product and process development in a patient-focused context
  • Effectively summarizing the overall control strategy
  • Guiding the regulator through the submission
For information[email protected].


510(k) Third Party Review Metrics

510 (k) Accredited Persons Program created to improve efficiency and timeliness

  • FDA accredits Third Parties to conduct 510(k) primary review
  • Third Party 510(k) submission goes through four different stages
    • Stage A – Reviews sponsor submission and sends recommendation to FDA
    • Stage B – FDA reviews submission to ensure Third Party has submitted
      all information needed to make final decision
    • Stage C (Optional) – Third Party reviews FDA’s request for additional
      information and notifies 510(k) submitter
    • Stage D – FDA reviews additional information and makes final decision.

Accredited Organizations: AABB, CMSI: Center for Measurement Standards of Industria, NYSDOH: New York State Department of Health, NIOM: Nordic Institute of Dental Materials, RTS: Regulatory Technology Services, LLC, TPRG: Third Party Review Group, LLC, TUV: TUV SUD America Inc

Review Metrics:
Capture.JPG READ

Buying from Online Pharmacies

Rogue online pharmacies

  • No valid prescription required
  • Do not have U.S. state-licensed pharmacist to answer questions
  • Low prices seem too good to be true
  • Send spam or unsolicited email offering cheap medicine
  • Located outside of US or ship worldwide.

Sell dangerous products with compromised safety and effectiveness

  • Under dosage or over dosage
  • Incorrect active ingredient
  • Addition of unsafe ingredients
  • Incorrect storage

Shop Safely Online


Capture.JPGPodcast: State of CDER 

Podcast: State of CDER 2018Transcript


FDA, FTC warn companies for selling illegal, unapproved opioid cessation products using deceptive claims

FDA +  FTC joint warning letters to marketers and distributors of 12 opioid cessation products

  • Health fraud for illegally marketing unapproved products with claims about treatment of opioid addiction and withdrawal
  • Products have not been demonstrated to be safe or effective
  • May keep patients from seeking appropriate, FDA-approved therapies
  • Making unsubstantiated therapeutic claims is violation of the Federal Trade Commission Act

 Have requested responses from each of the companies within 15 working days

  • Specific actions taken to address each concern
  • Failure to correct violations may result in law enforcement action such as seizure or injunction


Image credit: FDA







How can you tell if an online pharmacy is operating legally? The U.S. Food and Drug Administration’s BeSafeRx web page can help you identify and avoid rogue online pharmacies.

The FDA has several tips for buying medicines online safely. Read more here.


FDA News & Views: CDRH Accomplishments and Priorities, Clinical Trial Information Transparency, Expediting Military Products, Supervisory Review of CDRH Decisions, Complex Generic Drugs, Enforcement Reports, Compounding Priorities, Orally Inhaled and Nasal Drug products

FDA BRIEF: Week of January 15, 2018


Capture.JPGCDRH 2016-2017 Accomplishments and 2018-2020 Strategic Priorities 

Achievement of strategic priorities for 2016-2017

  • National Evaluation System for Medical Devices (NEST): Framework for the incorporation of real-world evidence into regulatory decision making
  • Partner with Patients: Established Patient Engagement Advisory Committee, increased use of patient reported outcomes in clinical studies, patient preference  patient preference studies in decision making
  • Promote Culture of Quality and Organizational Excellence CDRH staff formal quality training and certifications, PMA Critical-to-Quality Pilot Program to streamline the pre-market approval process

Foster innovation to spur the development of safer, more effective technologies, assure timely patient access

  • Annual number of approved devices has steadily

Three strategic priorities for 2018-2020: Holistic approaches to improvement

  • Employee Engagement, Opportunity, and Success. Recognize connection between taking care of FDA employees and achieving FDA vision
  • Simplicity. Streamline policies, processes, programs, approaches e.g. Total Product Life Cycle approach to integrates our pre-market, post-market surveillance, Least Burdensome principle
  • Collaborative Communities. Foster public and private sector Collaborative Communities,  advancement of smart regulation and rise of ‘Patient Scientists’

2016-2017 Accomplishments

2018-2020 Strategic Priorities

business person

Capture.JPGNew steps to enhance transparency of clinical trial information to support innovation and scientific inquiry related to new drugs 

Enhance transparency around FDA drug approval decisions by better informing of  clinical study reports (CSRs) to scientists, providers, and patients

  • Current approach- Summaries in [email protected] database
  • New pilot program –  Post portions of clinical trial-related summaries from the pivotal trials that were submitted to the FDA by drug’s sponsor on [email protected]
  • Include study report body, protocol and amendments, and statistical analysis plan for pivotal studies
  • New website

Add  ClinicalTrials.gov identifier number (NCT #) to FDA summaries

  • Easier to associate clinical trial listings on ClinicalTrials.gov to FDA communications about specific drugs, including product labeling and advisory committee meeting materials


Image result for DoD logoFDA and DoD launch program to expedite availability of medical products for the emergency care of American military personnel

Joint program with Health Affairs to prioritize efficient development of safe and effective medical products intended to save lives of American military personnel

  • Better understand military’s medical needs for deployed personnel
  • Give highest level of attention to and expedite its review of priority DoD medical products
  • Provide ongoing technical advice for rapid development and manufacturing
  • Take closer look at products currently under development to determine opportunities to expedite availability

FDA and Health Affairs to hold workshops to discuss scientific and clinical development


Capture.JPGInternal Agency Review of Decisions; Requests for Supervisory Review of Certain Decisions Made by CDRH

Implement regulations regarding internal agency supervisory review of certain CDRH decisions related to conform to FDASIA and the Cures Act

  • Provide transparency for internal and external stakeholders on supervisory review of decisions
  • Give requesters new predictability through binding deadlines on “significant decisions”
  • Codify types of decisions that are considered “significant decisions”

Following decisions being proposed as significant decisions – “517A decisions”

  • 510(k): Not substantially equivalent; Substantially equivalent
  • PMA/HDE: Not approvable; Approvable; Approval; Denial
  • Breakthrough Devices: Expedited access pathway, Grant, Denial
  • IDE: Disapproval, Approval
  • Failure to reach agreement on protocol
  • “Clinical Hold” determinations


Capture.JPGStatement from FDA Commissioner Scott Gottlieb, M.D. responding to GAO report and updating FDA’s ongoing efforts to increase access to complex generic drugs

U.S. Government Accountability Office (GAO) published report titled “Generic Drugs: FDA Should Make Public Its Plans to Issue and Revise Guidance on Nonbiological Complex Drugs.

  • GAO studied issues related to FDA’s review and approval of “nonbiological complex drugs”
  • Recommendation for FDA — announce plans to issue or revise related guidances

FDA Actions

  • Drug Competition Action Plan: Promoting competition and access, to generics
  • Focus GDUFA resources to aid generic drug developers of complex products
  • Issued four general guidance documents covering complex generics

Looking forward

  • Develop additional guidance for clarifying “sameness” requirements for ANDAs
  • Specific guidance on drug-device combination products


Capture.JPGNew policy steps for strengthening public warning and notification of recalls

FDA to improve recall processes to help ensure product safety

  • Recalls remove potentially unsafe products quickly and efficiently
  • Draft guidance describes public warning and notification of recalled products
  • Gives industry clear direction on communication of recalls and empower consumers by providing timely and accurate information

FDA Enforcement Report

  •  Listing of all recalls monitored by  FDA. You can read more about the changes the FDA made to its Enforcement Report in today’s blog


Capture.JPG2018 Compounding Policy Priorities Plan

2018 Compounding Policy Priorities Plan to implement federal compounding laws and advance public health mission

  • In accordance with Drug Quality and Security Act (DQSA)
  • Recognizes  importance of compounders’ role in access to quality drugs
  • Tailor policies for traditional compounding pharmacies and outsourcing facilities

2018 Priorities

  • Risk-Based Approach to Manufacturing Standards for Outsourcing Facilities
  • Restricting Compounding of Drugs that are Essentially Copies of FDA-Approved Drugs
  • Regulating Compounding from Bulk Drug Substances
  • Solidifying FDA’s Partnership with State Regulatory Authorities
  • Finalization of Biological Products Guidance and Clarifying Other Policies on Activities that Compounders Undertake
  • Compliance


Capture.JPGLocally-Acting Orally Inhaled and Nasal Drug Products 


Demonstration of Bioequivalence (BE) for locally-acting orally inhaled and nasal drug products  presents a unique challenge

  • FDA guidance to measure bioavailability under NDA and BE under ANDA
  • Increased understanding of complex interactions between formulation, manufacturing, and device

Better characterization, tools/methods to investigate  BE and product specific outcomes

  • Orally Inhaled Drug Products
  • Locally Acting Nasal Products


Image credits: FDA, DoD


FDA Marketing Authorizations: FLUARIX, LYNPARZA, GILOTRIF, REMOVE System

Image result for fluarix logoFLUARIX QUADRIVALENT (Influenza Vaccine) Suspension for Intramuscular Injection


INDICATION: Active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. Approved for use in persons aged 3 years and older


  • Randomized, double-blind, active-controlled, safety, immunogenicity, and noninferiority trial, FLUARIX QUADRIVALENT (n = 791) vs. comparator trivalent influenza vaccine (FLUARIX, TIV-1, n = 819 or TIV-2, 426 n = 801), age 3-17 years
  • Endpoint: % achieving seroconversion.  Non-Inferiority achieved


  • Injection site adverse reactions:  pain, redness, swelling
  • Systemic adverse events: drowsiness, irritability, loss of appetite, fatigue, muscle aches, headache, arthralgia, gastrointestinal symptoms


  • Initial approval in 2012
  • Extended to age range to include children 6 to 35 months of age


  • Vaccine product codes as well as some common administration codes associated with immunization



LYNPARZA (olaparib) tablet

AstraZeneca Pharmaceuticals

SUPPLEMENTAL INDICATION: Indicated in patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic


  • Approximately 20-25% patients with hereditary breast cancers and 5-10%  have a BRCA mutation
  • First treatment for breast cancer with a certain inherited gBRCAm HER2-negative metastatic breast cancer
  • Patients selected for treatment based on an FDA-approved genetic test – BRACAnalysis CDx.

MECHANISM OF ACTION:  Poly (ADP-ribose) polymerase (PARP) inhibitor


  • Open-label study (n=302) patients with gBRCAm HER2-negative metastatic breast cancer, LYNPARZA vs. healthcare provider’s choice of chemotherapy. Tested with the BRACAnalysis CDX to confirm deleterious or suspected deleterious gBRCAm status
  • Major efficacy outcome measure: Progression Free Survival (PFS)  assessed by blinded independent central review using RECIST version 1.1
  • PFS Number of events: 163 (80%) vs. 71 (73%), p=0.0009


  • Common side effects: Anemia), neutropenia, leukopenia, nausea, fatigue, vomiting, nasopharyngitis, respiratory tract infection, influenza, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation and inflammation and sores in the mouth
  • Severe side effects:  Myelodysplastic syndrome/acute myeloid leukemia, pneumonitis
  • Cause harm to a developing fetus and newborn baby


  • Priority Review
  • First approved in 2014 to treat certain patients with ovarian cancer


  • No Medicare coverage for previously approved indication (specialty product); high copay



GILOTRIF (afatinib) tablets

Boehringer Ingelheim Pharmaceutical

SUPPLEMENTAL INDICATION:  First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test.
Limitation of Use: Safety and efficacy have not been established in patients whose tumors have resistant EGFR mutations

MECHANISM OF ACTION: Covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling


  • In NSCLC patients harboring non-resistant EGFR mutations (S768I, L861Q, and/or G719X) other than exon 19 deletions or exon 21 L858R substitutions enrolled in one of three clinical trials – pooled analysis
  • Non-resistant EGFR mutations identified using either Sanger sequencing or by  therascreen EGFR RGQ PCR Kit.
  • Confirmed overall response rate: 66% .
  • Among the 21 responders, 52% had response duration of ≥12 months and 33% had response duration  ≥18 months


  • Most common adverse reactions: Diarrhea, rash/acneiform dermatitis, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritis


  • Priority Review and Orphan Drug Designation
  • Initial approval in 2013 for treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
  • This approval broadens the patient population


  • 100% of Medicare Part D and Medicare Advantage plan coverage; Tier 5 (non-preferred brand-name drugs)
  • Restrictions: Quantity limits, Prior Authorization




Ovesco Endoscopy AG


The remOVE System consists of the DC Impulse and the DC Cutter Set.
The remOVE DC Impulse is a medical electrical device for fragmentation of OTSC® (endoscopic device for effective treatment of hemorrhage and acute or chronic wall defects in the GI tract) and FTRD® (endoscopic device for full-thickness resection of colorectal wall lesions) clips made by Ovesco Endoscopy AG for the digestive tract.
The remOVE DC Cutter Set is a set of instruments for use in flexible endoscopy. It consists of a bipolar DC instrument for the fragmentation of OTSC (endoscopic device for effective treatment of hemorrhage and acute or chronic wall defects in the GI tract) and FTRD (endoscopic device for full thickness resection of colorectal wall lesion) clips from Ovesco Endoscopy AG, a pair of forceps and a cap for removal of these fragmented clips.

GENERIC DEVICE TYPE: Endoscopic electrosurgical clip cutting system

Prescription device that applies electrical energy to fragment metallic clips, which are devices placed in the digestive tract to close gastrointestinal perforations, hemorrhages, or perform resection.
The system includes instruments that are then used to remove the fragmented clips from the digestive tract.


  • Unintended tissue damage (burns, perforations, bleeding):  Animal performance testing, Non-clinical performance testing, Electrical and thermal safety testing, Usability testing, Labeling
  • Electromagnetic interference / Electrical shock: Electromagnetic compatibility testing, Electrical safety testing, Labeling
  • Adverse tissue reaction: Biocompatibility evaluation
  • Infection: Sterilization validation, Shelf life testing, Labeling


  • Regulation Number: 21 CFR 876.4310
  • Regulation Name: Endoscopic electrosurgical clip cutting system
  • Regulatory Class: Class II
  • Product Code: QAG




Image credits: GSK, AstraZeneca, Boehringer Ingelheim, Ovesco

FDA Guidances: IND communications, PDUFA Formal Meetings, Medical Device Accessories, Class I Unique Device Identification


Best Practices For Communication between IND Sponsors and FDA During Drug Development


  • Describe best practices and procedures for timely, transparent, effective communications between IND sponsors and FDA
    • May facilitate earlier availability of safe and effective drugs


  • Philosophy regarding timely interactive communication
  • Scope of appropriate interactions
  • Types of advice
  • General expectations FDA response timing
  • Best Practices and Communication Methods
    • Formal Meetings
    • Written Correspondence from FDA
    • Sponsor Submissions
    • Acknowledging Receipt of Communications
    • Email Between FDA and Sponsors
    • General Telephone Calls Between FDA and Sponsors
    • Faxes Between FDA and Sponsors
    • Use of Out-of-Office Messages by FDA and Sponsors

Resources for Sponsors

  • Guidances, Policy and Procedures, Basics for Industry, Interactive Media, Presentations, Labeling and Approvals, Rules and Regulations, Scientific Research Results, Code of Federal Regulations

Additional Contacts

  • CDER : Biomarker Qualification Program, Controlled Substance Staff , Division of Drug Information, Division of Pediatric and Maternal Health, Emerging Technology Team, Enhanced Communication Team, Import/Export, Office of Pharmaceutical Quality, Ombudsman, Rare Diseases Program, Small Business and Industry Assistance Program, Therapeutic Biologics and Biosimilars Staff
  • CBER : Manufacturers Assistance and Technical Training,  Ombudsman
  • Office of Special Medical Programs: Advisory Committee Oversight and Management Staff, Office of Combination Products, Office of Good Clinical Practice,  Office of Orphan Products Development, Office of Pediatric Therapeutics



Formal Meetings Between FDA ad Sponsors or Applicants of PDUFA Products


  • Discuss principles of good meeting management practices (GMMPs)
  • Describe standardized procedures for requesting, preparing, scheduling, conducting, documenting formal meetings


  • Meeting Types : Type A, Type B Meeting, Type B (EOP),  Type C
  • Meeting Formats
  • Meeting Requests
  • Assessing and Responding to meeting requests: Denied, Granted
  • Meeting Package: Submission timing, Copies, Content
  • Preliminary Responses
  • Rescheduling and Canceling
  • Meeting Conduct
  • Meeting Minutes



Medical Device Accessories – Describing Accessories and Classification Pathways


  • Describe policy concerning classification of accessories
  • Application of policy to devices that are commonly used as accessorie
  • Explain what devices considered an “accessory”
  • Describes processes to allow requests for risk- and regulatory control-based classification


  • Accessory: Finished device intended to support, supplement, and/or augment the
    performance of one or more parent devices
  • Component: [A]ny raw material, substance, piece, part, software, firmware, labeling, or assembly which is intended to be included as part of finished,
    packaged, and labeled device
  • Finished Device: [A]ny device or accessory to any device that is suitable for
    use or capable of functioning, whether or not it is packaged, labeled, or sterilized
  • Parent Device: Finished device whose performance is supported, supplemented, and/or augmented by one or more accessories

Accessory Classification Policy

  • Is the article an accessory?
    • Supports : Performance of parent device by enabling or facilitating performance according to its intended use
    • Supplements: Performance of parent device if it adds new function or new way of using the parent device, without changing intended use
    • Augments: Performance of parent device by enabling more safe or effective use
  • What are risks of accessory when used as intended with the parent device(s)
  • What regulatory controls necessary to provide reasonable assurance of safety
    and effectiveness

Accessory Classification Process

  • Accessory Requests
  • Classification of New Accessory Types through the De Novo Process




  • Describe enforcement of  Unique Device Identification (UDI) System
  • For Class I and unclassified devices  other than implantable, life-supporting or life-sustaining (I/LS/LS) devices
  • Does not intend to enforce standard date formatting, labeling, and GUDID data submission requirements
  • Does not intend to enforce direct mark requirements

Compliance Dates




FDA News and Views: 2017 Medical Product Innovation, Many “Firsts” for 2017 Drug Approvals, Opioid Cough and Cold medicines Safety Labeling

FDA BRIEF: Week of January 8, 2018

Dr. Scott Gottlieb

Reflections on a Landmark Year for Medical Product Innovation and Public Health Advances and Looking Ahead to Policy in 2018

Inspiring year of advances in both medicine and public health

  • A Record Year for New Innovation
  • Modernizing FDA’s Regulatory Programs
  • Promoting Drug Competition
  • New Steps to Combat Addiction
  • New Steps to Combat Addiction
  • Improving our Stewardship of Vital Drugs
  • Protecting and Empowering Consumers

pie chart of approvals

Chart of device approvals

2017 generics approvalsREAD


Many “Firsts” for CDER’s 2017 Drug Approvals Reflect Innovation and Enhanced Patient Care

Approved new treatments for patients with rare diseases

  • Batten disease
  • Chagas disease
  • Hemophilia A with inhibitors

Novel “Firsts” in treating

  • Liver cancer in almost a decade
  • Sickle cell diseasein almost 20 years
  • Giant cell arteritis
  • Cytokine release syndrome
  • Chronic graft versus host disease after a bone marrow transplant
  • Marginal zone lymphoma
  • Eosinophilic granulomatosis with polyangiitis
  • Erdheim-Chester Disease

Other firsts that are not novel drug approvals 

  • Biosimilars to treat certain cancers
  • Immediate-release opioid product with properties intended to deter abuse
  • Once-monthly injectable buprenorphine product for opioid addiction
  • Cancer treatment based on a genetic feature rather than location
  • Treatment to help prevent recurrence of renal cell carcinoma
  • Complete regimen to treat HIV-1 that contains only two drugs, neither a nucleoside reverse transcriptase inhibitor, which can be detrimental to a patient’s kidneys, bones, and heart;
  • Drug with a sensor embedded in pill to track medication compliance
  • Short-acting “follow-on” insulin product




FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older

Safety labeling changes to limit the use of prescription opioid cough and cold medicines containing codeine or hydrocodone in children younger than 18 years old

  • Serious risks of these medicines outweigh potential benefits in population
  • Products will no longer be indicated for use to treat cough in pediatric population
  • Additional safety information for adult use – risks of misuse, abuse, addiction, overdose and death, and slowed or difficult breathing

Addressing epidemic of opioid addiction

  • Limit unnecessary exposure to opioids, especially in young children
  • Taking steps to help reassure parents that treating the common cough and cold is possible without using opioid-containing products
  • Guidances for Health care professionals and Parents and caregivers

List of Prescription Cough and Cold Medicines Containing Codeine

Active Ingredient(s)

Brand Name(s)

codeine, chlorpheniramine

Tuxarin ER, Tuzistra XR

codeine, phenylephrine, promethazine

Only generics available

codeine, promethazine

Only generics available

codeine, pseudoephedrine, tripolidine

Triacin C

List of Prescription Cough and Cold Medicines Containing Hydrocodone

Active Ingredient(s)

Brand Name(s)

hydrocodone, guaifenesin

FlowTuss, Obredon

hydrocodone, pseudoephedrine, guaifenesin

Hycofenix, Rezira

hydrocodone, chlorpheniramine

Tussionex Pennkinetic, Vituz

hydrocodone, chlorpheniramine, pseudoephedrine


hydrocodone, homatropine

Only generics available


Image credits: FDA


FDA News and Views: CDER standards program, Anti-aging Products, Enhancing Generic Drug Review and Availability, Smoking Cessation Products

FDA BRIEF: Week of Jan 1, 2018


CDER Data Standards Program Action Plan

Governing body for drug data standards

  • Provides quarterly updates on  current initiatives

Program Initiatives

  • Drug Development and Pre-Market Review
  • Drug Safety Performance and Promotion
  • Pharmaceutical Quality
  • Policy


Examples of claims cosmetics are allowed to make: Cleanses skin, Enhances beauty, Promotes attractiveness, Alters appearance. Examples of claims cosmetics may NOT make: Treats a disease, such as acne, eczema, or rosacea; Increases collagen; Revives cells.

Wrinkle Treatments and Other Anti-aging Products

Cosmetics – if:

  • Intended to make people more attractive e.g. moisturizing
  • Intended to make lines and wrinkles less noticeableby moisturizing the skin
  • Makeup or “primers” intended hide signs of aging
  • Must be safe when used according to product labeling
  • Does not require cosmetics to be approved by FDA

Drugs or Medical Devices – if:

  • Intended to affect the structure or function of the body, such as the skin
  • To remove wrinkles or increase the skin’s production of collagen
  • Will require marketing authorization by FDA based on effectiveness and safety

FDA concern: Product claims, marketed as cosmetics (skin care, anti-wrinkle, anti-aging) that involve supposed effects on the structure or function of the skin



Statement from FDA Commissioner Scott Gottlieb, M.D. on new steps to facilitate efficient generic drug review to enhance competition, promote access and lower drug prices

Continued implementation of the “Drug Competition Action Plan”

  • Reducing gaming by branded companies that can delay generic drug entry
  • Resolving scientific and regulatory obstacles to generics approval
  • Improving efficiency and predictability of  FDA’s generic review process

Releasing 2 documents:

Additional Steps:

  • Improve FDA practices and efficiency
  • Accelerate generic entry of complex generics e.g. metered dose inhalers
  • Take steps to minimize brand companies tactics to deter generics

Potential abuses of the citizen petition process

Restricting access to testing samples of branded drugs

Abuses of the single, shared system REMS negotiation process



FDA-approved smoking cessation products

Nicotine Replacement Therapy (NRT)

  • Nicotine primarily responsible for causing addiction
  • NRTproducts designed to wean smokers by supplying nicotine in controlled amounts while sparing from other chemicals found in tobacco products
  • Short time use to manage nicotine cravings and withdrawal
  • Available over the counter and by prescription

Over-the-counter NRTs 

  • Skin patches (also called “transdermal nicotine patches”)
  • Chewing gum (also called “nicotine gum”)
  • Lozenges (also called “nicotine lozenges”)
  • Important to follow the instructions on the Drug Facts Label (DFL) and User’s Guide

Prescription nicotine replacement therapy (prescription): Nicotrol

Smoking cessation products that do not contain nicotine (prescription): Chantix (varenicline tartrate) and Zyban (buproprion hydrochloride)



Image credit: FDA


FDA Device Market Authorizations: DERMAPACE System, VERSICE Deep Brain Stimulation, HEMOBLAST Bellows



Sanuwave, Inc.

INDICATION FOR USE: To provide acoustic pressure shockwaves in the treatment of chronic, full-thickness diabetic foot ulcers with wound areas measuring no larger than 16 cm2 , which extend through the epidermis, dermis, tendon, or capsule, but without bone exposure.

The dermaPACE System is indicated for adult (22 years and older), diabetic patients presenting with diabetic foot ulcers greater than 30 days in duration and is indicated for use in conjunction with standard diabetic ulcer care.


  • About 25 percent of people with diabetes will experience a foot ulcer in their lifetime; leading cause of lower limb amputations
  • Additional option for successfully treating and healing ulcer wounds may help prevent lower limb amputations


  • Extracorporeal shockwave device for treatment of chronic wounds is a prescription device that focuses acoustic shock waves onto the dermal tissue. The shock waves are generated inside the device and transferred to thevbody using an acoustic interface.


  • Two multi-center, randomized, double-blind studies, n= 336 diabetic patients receiving either usual care plus Dermapace System shock wave therapy vs. usual care plus non-working (sham) shock wave therapy
  • Both patient groups included those with poorly controlled and well-controlled blood glucose levels
  • Increase in wound healing at 24 weeks, 44% vs. 30% wound closure rate
  • Most common side effects: Pain, local bruising and numbness, migraines, nausea, fainting, wound infection, infection beyond the wound (cellulitis, osteomyelitis) and fever


  • Initial PMA submission not approved
  • Resubmission as De Novo
  • Regulation Number: 21 CFR 878.4685
  • Regulation Name: Extracorporeal shock wave device for treatment of chronic wounds
  • Regulatory Class: Class II
  • Product Code: PZL


  • Adverse tissue reaction – Biocompatibility evaluation
  • Infection – Reprocessing validation, Labeling
  • Inadequate healing – Labeling
  • Device failure / malfunction – Non-clinical performance testing, Electrical safety testing, Electromagnetic compatibility (EMC) testing, Use life testing, Software verification, validation, and hazard analysis, Labeling
  • Hearing loss – Non-clinical performance testing, Labeling



Capture.JPGVERCISE Deep Brain Stimulation (DBS) System

Boston Scientific Corporation

INDICATION FOR USE: In bilateral stimulation of the subthalamic nucleus (STN) as an adjunctive therapy in reducing some of the symptoms of moderate to advanced levodopa-responsive Parkinson’s disease (PD) that are not adequately controlled with medication.


  • At present there is no cure for PD
  • Additional surgical treatment option focused on management of symptoms that  best meets expectations and lifestyle
  • Adjunct to therapy towards reducing the motor complications of subjects with PD


  • Includes a Stimulator with DBS Leads for stimulation of selected targets (i.e., the subthalamic nucleus) in the brain.
  • DBS Extensions are used to connect the DBS Leads to the Stimulator implanted near the clavicle.
  • The Vercise DBS System utilizes current steering across eight contacts per DBS Lead,
    which is intended to provide precise positioning of stimulation.
  • The Stimulator is controlled by a handheld Remote Control, and can be programmed by a Clinician Programmer using the Bionic Navigator™ Software.
  • Periodically, the rechargeable Stimulator battery must be replenished with a radiofrequency (RF) charging device provided in the Charging Kit.


  • Study on bilateral DBS of the STN, n=160 pre-specified interim analysis; active vs control, 12 weeks
  • Primary endpoint: Mean change from baseline in mean number of waking hours per day with good symptom control and no troublesome dyskinesia as measured on the PD diary, with no increase in antiparkinsonian medications – mean difference of  3.03 ± 4.2 hours, p < 0.001
  • Secondary endpoints: UPDRS III scores in the stim on/meds off condition, PDQ-39, Modified Schwab and England, Global Impression of Change as assessed by clinician and Treatment Satisfaction
  • UPDRS III score: Mean 30% improvement (12.02 ± 11.42 points) was noted in UDPRS III scores (stim on/meds off)
  • Statistically significant improvement in quality of life: Based on PDQ-39 and modified Schwab and England scales


  • Infection: Most commonly reported serious adverse event associated with device-hardware/procedure


  • Device Generic Name: Stimulator, Electrical, Implanted, for Parkinsonian Tremor
  • Device Procode: NHL


  • DBS Devices assigned ICD-10 daignosis and procedure codes
  • HCPCS II Device Codes
  • Device C-Codes and Device Edits
  • CPT Procedure Codes
  • MS-DRG Assignments




Biom’Up SA

INDICATION FOR USE: In surgical procedures as an adjunct to hemostasis when control of minimal, mild, and moderate bleeding by conventional procedures is ineffective or impractical, except in neurosurgical, ophthalmic and urological procedures.


  • Consists of hemostatic powder (HEMOBLAST™ Bellows Hemostatic Powder) supplied in an applicator system incorporating a bellows design
  • Powder is dry, sterilized, biocompatible, and non-pyrogenic. No intraoperative preparation, mixing, or heating is required. absorbs in vivo over a 4-week period
  • Powder composed predominantly of highly purified porcine collagen (with glucose) with smaller amounts of bovine chondroitin sulfate (CS) and human pooled plasma derived thrombin.
  • Bellows Applicator contains the Powder and is sterilized using gamma-sterilization
  • Nozzle Extension serves to assist in the delivery of the Powder, during surgery


  • Prospective, multicenter, single-arm pilot clinical investigation, to evaluate  Surface Bleeding Severity Scale (“SBSS”), n=31 undergoing orthopedic and abdominal surgeries with associated bleeding sites
  • Statistical superiority in achieving hemostasis at 3 and 6 minutes vs. standard of care
  • Safety  profile similar to standard of care

REGULATORY PATHWAY: Combination product, PMA

  • Regulation number: 878.4490
  • Product Code: PMX
  • Generic name: Absorbable Collagen Hemostatic Agent With Thrombin


  • Pending
  • Precedents for reimbursement for absorbable collagen hemostatic


Image credits: Sanuwave, Boston Scientific, Biom’Up


FDA approved


BOSULIF (bosutinib) tablets


SUPPLEMENTAL INDICATION:  Newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML).


  • Open-label, randomized, multicenter trial, n=487 patients with Ph+ newly-diagnosed CP CML, bosutinib 400 mg once daily vs. imatinib 400 mg once daily
  • Major efficacy outcome: Major molecular response (MMR) at 12 months, defined as ≤0.1% BCR ABL ratio on international scale (corresponding to ≥3 log reduction from standardized baseline) with a minimum of 3000 ABL transcripts as assessed by the central laboratory.
  • 47.2% (95% CI: 40.9, 53.4) vs. 36.9% (95% CI: 30.8, 43.0), p=0.0200


  • Most common adverse reactions: Diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, and increased aspartate aminotransferase


  • Priority Review, and Orphan Drug designation, Accelerated approval for supplemental application
  • Approval based on molecular and cytogenetic response rates;  continued approval may be contingent upon verification and confirmation of clinical benefit in an ongoing long-term follow up trial
  • First approval in 2012 for treatment of patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.


  • 100% of Medicare Part D and Medicare Advantage plans coverage
  • Tier 5 (specialty); Co-pay based on coverage stage
  • Patient Assistance programs



GIAPREZA (angiotensin II) injection

La Jolla Pharmaceutical Company

FIRST INDICATION: Increases blood pressure in adults with septic or other distributive shock


  • Shock can result in organ failure and death
  • Need for treatment options for critically ill hypotensive patients who do not adequately respond to available therapies

MECHANISM OF ACTION: Angiotensin II raises blood pressure by vasoconstriction and increased aldosterone release


  • Single double-blind study, n=321 adults with septic or other distributive shock, GIAPREZA vs.placebo
  • Primary endpoint: % of subjects with Mean Arterial Pressure (MAP) ≥ 75 mmHg or a ≥ 10 mmHg increase in MAP without an increase in baseline vasopressor therapy at 3 hours
  • 70% vs. 23%, p < 0.0001 (treatment effect of 47%)


  • Can cause dangerous blood clots with serious consequences (clots in arteries and veins, including deep venous thrombosis)
  • Prophylactic treatment for blood clots should be used


  • Priority Review
  • Required pediatric assessments


  • Available March 2018



CABOMETYX (cabozantinib) tablets


SUPPLEMENTAL INDICATION:  Treatment of patients with advanced renal cell carcinoma (RCC)


  • Single, randomized, open-label phase 2 multicenter study, n=157 patients with intermediate and poor-risk previously untreated RCC, Cabometyx vs. sunitinib
  • Endpoint: Estimated median progression-free survival (assessed by blinded independent radiology review committee)
  • 8.6 months (95% CI: 6.8, 14.0) vs. 5.3 months (95% CI: 3.0, 8.2),  p=0.0008


  • Most commonly reported adverse reactions: Diarrhea, fatigue, nausea, decreased appetite, hypertension, palmar-plantar erythrodysesthesia, weight decreased, vomiting, dysgeusia, and stomatitis
  • Most frequent grade 3-4 adverse reactions:  Hypertension, diarrhea, hyponatremia, hypophosphatemia, PPE, fatigue, ALT increased, decreased appetite, stomatitis, pain, hypotension, and syncope



  • Approval provides for treatment in first-line setting
  • Previous approval in 2016 for treatment of patients with advanced RCC who have received prior anti-angiogenic therapy


  • 100% of Medicare Part D and Medicare Advantage plans coverage
  • Tier 5 (specialty); Co-pay based on coverage stage
  • Patient Assistance programs



PERJETA (pertuzumab)


SUPPLEMENTAL INDICATION:  In combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease


  • Single multicenter, randomized, double-blind, n= 4804 patients with HER2-positive early breast cancer with primary tumor excised prior to randomization, PERJETA vs placebo
  • Efficacy outcome: Invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause
  • Intent to Treat population: 7.1% (n=171) vs. 8.7%, p=0.047
    • In patients with hormone receptor negative disease:  8.2% vs. 10.6%
    • In patients with node positive disease: 9.2% vs. 12.1%
  • Overall survival data are not yet mature


  • Adverse reactions:  Diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting
  • Most common grade 3-4 adverse reactions: Neutropenia, febrile neutropenia, diarrhea, neutrophil count decreased, anemia, white blood cell count decreased, leukopenia, fatigue, nausea, and stomatitis


  • Fulfills post-marketing requirement for 2013 accelerated approval
  • First approval in 2012 for use in combination with trastuzumab and docetaxel for  HER2-positive metastatic breast cancer with no prior therapy
  • Accelerated approval in 2013 as neoadjuvant treatment


  • 70% of Medicare Part D and Medicare Advantage plan coverage
  • Tier 5 (specialty); Co-pay based on coverage stage
  • Patient Assistance programs


Image credit: DailyMed, La Jolla

FDA News and Views: Patient Engagement Collaborative, Case for Quality Pilots, Medical Device Accessories, Malfunction Reporting

FDA BRIEF: Weeks of Dec 22 and 29

FDA Voice

You Spoke, FDA Listened: New Patient Engagement Collaborative, Call for Nominations 

Patient Engagement Collaborative (PEC)

  • Patients who have personal disease experience
  • Caregivers who support patients
  • Representatives from patient groups who have direct or indirect disease experience
  • Joint endeavor between the CTTI and FDA

PEC forum to discuss

  • More meaningful patient engagement in medical product development
  • Incorporating various perspectives into regulatory decision-making processes
  • Builds on existing  Patient Focused Drug Development (drugs, biologics)  and the Patient Preference Initiative (medical devices)
  • Modeled after the European Medicines Agency’s Patients’ and Consumers’ Working Party

Nomination ProcessREAD


Case for Quality Pilot Activities

Case for Quality

  • Allows FDA identify device manufacturers consistently producing high-quality devices
  • Focus FDA resources helping other manufacturers raise quality level
  • Identify and promote practices supporting consistent quality manufacturing, and align regulatory, enforcement, compliance approaches

1. Premarket Approval (PMA) Critical-to-Quality Pilot Program

  • PMA device manufacturers meeting participation criteria to engage with FDA early in review process of new applications
  • Proactive engagement to develop critical-to-quality characteristics and controls  and a focused inspectional approach
  • Streamline the premarket approval process while assuring quality system
  • FDA to forego pre-approval inspection, instead conduct post-approval inspection

2. Voluntary Medical Device Manufacturing and Product Quality Pilot Program

  • Third-party teams certified by Capability Maturity Model Integration (CMMI) Institute to conduct quality system maturity appraisals of device manufacturers
  • Drive continuous improvement and organizational excellence
  • Engage early with CDRH and submit baseline metrics before and during appraisal to monitor progress
  • FDA to forego conducting surveillance and preapproval inspections

3. Digital Health Software Precertification (Pre-Cert) Program

  • Modern and tailored approach for software iterations and changes
  • Enable companies demonstrate their embedded culture of quality and organization excellence (CQOE)
  • FDA to learn, adapt, adjust key elements based on program effectiveness

4. Digital Health Entrepreneurs-in-Residence Program

  • Entrepreneurs work intensively with FDA Digital Health Unit staff to iteratively develop and test key conceptual elements of  software precertification program

5. Medical Device Single Audit Program (MDSAP)

  • Global approach to auditing and monitoring manufacture of medical devices
  • MDSAP recognized Auditing Organization to conduct single regulatory audit of manufacturer to satisfy requirements of multiple regulatory authorities : US, Australia, Brazil, Canada, Japan, WHO, EU



Medical Device Accessories

Intended Use : Finished device intended to support, supplement, and/or augment performance of one or more parent devices

Accessory Classification Request: Written request for appropriate classification

Classification of New Accessory Type: Submitted together with the parent device submission or submitted separately as De Novo Classification Request

  • Submit necessary information, based on Least Burdensome principles, to establish  risk profile of accessory when used as intended with parent device
  • Class II must include an initial draft proposal for special controls,

FDA Consulation: Prior to Accessory Classification Request – through Pre-Submission



Voluntary Medical Device and Combination Products Malfunction Summary Reporting

Manufacturer reporting of certain device malfunction medical device reports (MDRs) in summary form

  • Streamlining malfunction reporting
  • Permitting manufacturers of devices in certain product codes to report malfunctions on a quarterly basis and in a summary format
  • Reflecting FDA’s findings from pilot program to study summary reporting formats for malfunction MDRs.


Image credits: FDA