FDA Guidances, Federal Register: Periodic Benefit-Risk Evaluation, CLIA

FDA BRIEF: Week of July 18, 2016

fda guidances



FORMAT, CONTENT, CONSIDERATIONS for Periodic Benefit-Risk Evaluation Report (PBRER)

  • Analysis of new or emerging information on the risks and benefits – appraisal of  product’s overall benefit-risk profile
  • Relevant new safety information since international birth date (IBD)


  • Single PBRER for an Active Substance
  • PBRERs for Fixed-Dose Combination Product
  • Products Manufactured and/or Marketed by More Than One Company
  • Reference Information
  • Level of Detail
  • Efficacy/Effectiveness
  • Benefit-Risk Evaluation
  • Periodicity and PBRER Data Lock Point
  • IBD and Data Lock Point
  • Managing Different Submission Frequencies
  • Time Interval Between Data Lock Point and Submission
  • Format and Presentation


  • Introduction
  • Worldwide Marketing Approval Status
  • Actions Taken in the Reporting Interval for Safety Reasons
  • Changes to Reference Safety Information
  • Estimated Exposure and Use Patterns
  • Data in Summary Tabulations
  • Summaries of Significant Safety Findings From Clinical Trials During the Reporting Interval
  • Findings From Non-Interventional Studies
  • Information From Other Clinical Trials and Sources
  • Nonclinical Data
  • Literature
  • Other Periodic Reports
  • Lack of Efficacy in Controlled Clinical Trials
  • Late-Breaking Information
  • Overview of Signals: New, Ongoing, or Closed
  • Signal and Risk Evaluation
  • Benefit Evaluation
  • Integrated Benefit-Risk Analysis for Approved Indications





  • Description of features that make it ‘simple’
  • Hazard analysis
  • Poential sources of error
  • Design and results of flex studies
  • Fail-safe and Failure Alert mechanisms
  • Validation studies
  • Clinical tests for test accuracy by intended operators

COST FOR WAIVER : $350,000

  • Clinical study costs: Site selection, qualification, protocol review, execution



FDA Approvals: QUANTIDE X Kit, CARTIVA Implant

FDA BRIEF: Week of July 18, 2016

FDA approved


Asuragen, Inc., Austin, TX, USA


In vitro nucleic acid amplification test for the quantitation of BCR-ABL1 and ABL1 transcripts in total RNA from whole blood of diagnosed t(9;22) positive Chronic Myeloid Leukemia (CML) patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2. The QuantideX qPCR BCR-ABL IS Kit is a reverse transcription-quantitative PCR performed on the Applied Biosystems 7500 Fast Dx Real-Time PCR Instrument and is intended to measure BCR-ABL1 to ABL1, expressed as a log molecular reduction (MR value) from a baseline of 100% on the International Scale, in t(9;22) positive CML patients during monitoring of treatment with Tyrosine Kinase Inhibitors (TKIs).

The test does not differentiate between e13a2 or e14a2 fusion transcripts and does not monitor other rare fusion transcripts resulting from t(9;22). This test is not intended for the diagnosis of CML.


  • CML rare disease due to a genetic abnormality that produces the BCR-ABL gene (also known as the Philadelphia Chromosome) not found in normal cells
  • 8,220 estimated new CML cases in 2016; 1,070 estimated deaths
  • Need for BCR-ABL testing as a tool for clinicians to manage CML treatment

REG PATHWAY: De Novo, Regulation Number: 21 CFR 866.6060,  Class II, Product Code: OYX. First nucleic acid-based quantitation test for use during treatment of CML patients

DESCRIPTION: Kit uses blood specimens from patients with CML to measure the amount of BCR-ABL, which can be used to estimate the amount of leukemia cells in a patient when treated with BCR-ABL targeted therapies.


  • Study using banked samples across three U.S. clinical laboratories (n=98)
  • Significant difference in patient outcomes who achieved reduced levels of BCR-ABL from targeted therapy from those who did not

RISKS: False negative results, False positive results,  Lack of traceability of results



CARTIVA  Synthetic Cartilage Implant

Cartiva, Inc., Alpharetta, GA, USA


INDICATION FOR USE: Treatment of patients with painful degenerative or post-traumatic arthritis (hallux limitus or hallux rigidus) in the first metatarsophalangeal joint with or without the presence of mild hallux valgus


  • PMA, Product code PNW
  • Positive recommendation by  CDRH Orthopaedic and Rehabilitation Devices Panel
  • Need for post-approval study to demonstrate long-term durability of implant, long-term safety (up to 5 years)


  • Polymer-based biomaterial implant
  • Viscoelastic hydrogel material conducive to replacing focal areas of damaged cartilage, providing pain reduction, and maintaining range of motion
  • Molded cylindrical implant of polyvinyl alcohol and saline that is placed into the metatarsal head in the first metatarsophalangeal (MTP) joint via press-fit implantation
  • Biocompatible material is widely used in other approved medical devices, such as contact lenses
  • Short and minimally invasive implantation procedure
  • Does not regrow or replace cartilage


  • Non-inferiority (15% margin), Single prospective, randomized, controlled multi-center trial (n=202, UK, Canada),  CARTIVA SCI vs. arthrodesis, subjects with painful degenerative or post-traumatic arthritis
  • Composite primary endpoint reflecting pain, function, and safety: Visual Analog Scale (VAS) to assess pain, Foot and Ankle Ability Measure (FAAM) to assess function, absence of major complications and subsequent surgical interventions,  24-month postoperative visit
  • Pain decrease: 89% with Cartiva SCI vs greater pain reduction in control
  • Function improvement and maintenance: >  98% with Cartiva SCI
  • Radiographic success: 100% with Cartiva SCI
  • Freedom from Subsequent Secondary Surgical Interventions: 90% with Cartiva


  • Device related adverse event at 24 months : 15.1% with Cartiva vs. 8.0%
  • Serious device related adverse event at 24 months:  7.2%; vs 4.0%
  • Bony Reaction, Heterotopic Ossification


  • Patient Satisfaction question, “My overall well-being has improved since the beginning of the study?”
  • “strongly agree” or “agree” was 76% and 74% at 12 and 24 mo. with Cartiva SCI




FDA Views: TransAtlantic Cooperation, PDUFA VI

FDA BRIEF: Week of July 18, 2016



Addressing Global Challenges through Transatlantic Cooperation


Howard Sklamberg, J.D., Deputy Commissioner for Global Regulatory Operations and Policy

Mary Lou Valdez, Associate Commissioner for International Programs

Donald Prater, Director of FDA’s Europe Office

Howard Sklamberg

Lou Valdez

Donald Prater

MEETING: FDA – EU regulatory counterparts and stakeholders meeting

DISCUSSION: Several topics

  • Globalization of suppliers and distributors;
  • Keeping pace with risk-based allocation of inspection resources
  • Complexity of the global supply chain and the need to collaborate on enforcement
  • Progress being made on the Mutual Reliance Initiative
  • Pharmaceutical GMP inspection
  • Interaction among FDA’s Europe, China, and India offices and regulatory counterparts in the EU and Governments of China and India

Transatlantic cooperation is vitally important to address the challenges and opportunities of a globalized marketplace.  READ



  • Represents FDA’s discussions with the regulated industry and public stakeholders
  • Formal tracked performance goals for timely access to safe, effective, and innovative drug products for patients


  • FDA Review Performance Goals
  • Enhanced Review Transparency And Communication
  • First Cycle Review Management
  • Review Of Proprietary Names
  • Major Dispute Resolution
  • Clinical Holds
  • Special Protocol Question Assessment And Agreement
  • Meeting Management Goals
  • Regulatory Science And Expediting Drug Development
  • Regulatory Decision Tools
  • Modernization of  Drug Safety System


  • Resource Capacity Planning , Time Reporting, Financial Transparency And Efficiency


  • Hiring System Infrastructure, Hiring Staff Capacity And Capability, Goals, Comprehensive  Assessment Of Hiring And Retention


  • Predictability And Consistency Of Electronic Submission Processes, Electronic Submission And Data Standards Activities



Medical Device Interoperability


WHAT:  FDA position and guidance on medical device interoperability  – ability to safely, securely, and effectively exchange and use information among one or more devices, products, technologies, or systems.

WHY:  Interoperable devices with the ability to share information across systems and platforms can:

  • Improve patient care,
  • Reduce errors and adverse events
  • Encourage innovation.

WHO: CDRH – along with  hospitals, health care providers, manufacturers, standards development organizations, and other interested parties to promote medical device interoperability.


FDA Guidances: Electromagnetic Compatibility, Companion Diagnostic

FDA BRIEF: Week of July 11, 2016

fda guidances



  • Electrically-powered devices: AC (mains) powered devices, battery powered devices, and active implantable devices
  • EMC: Ability of device to function safely and effectively in its intended electromagnetic environment, including immunity to electromagnetic disturbance (interference), without introducing excessive electromagnetic disturbances (emissions) that might interfere with other devices.
  • Relevant information for PMA/510(k)/HDE/De Novo

Relevant Information:

  • Environments
  • Testing summary
  • Specifications
  • Pass/Fail criteria
  • Device functions tested
  • Device performance during testing
  • Standard’s allowances
  • Specification deviations
  • Labeling and evidence of compliance
  • Changes or modifications




  • In vitro companion diagnostic (IVD) device:  Provides information that is essential for the safe and effective use of a corresponding therapeutic product
  • General principles for codevelopment for contemporaneous marketing authorization for therapeutic product and corresponding IVD

Relevant Information:

  • Regulation: Risk Assessment, IDE Requirements, Submission
  • Prospective Codevelopment Planning: Analytical validation, intended uses, prototypes, prescreening
  • Therapeutic Product Clinical Trial Design: Early/Late, prognostic and predictive markers, prospective-retrospective approaches, identifying intended populations
  • Late Therapeutic Product Development: Training samples vs. validation samples,  effect of changes, bridging studies,  SPA,
  • Planning for Contemporaneous Marketing Authorizations : Coordinating review timelines, shipment, verification
  • Labeling






FDA Classifications: Insomnia Thermal System, Metallic Biliary Stent System

FDA BRIEF: Week of July 11, 2016



Neurological Devices: Classification of Thermal System for Insomnia


Product : Cereve Sleep System

Classification: Class II special controls.

Codification: 21 CFR 882.5700

Risks and Mitigations: 

Table 1--Thermal System for Insomnia Risks and Mitigation Measures
            Identified risk                     Mitigation method
Adverse skin reaction..................  Biocompatibility Assessment.
Electromagnetic Interference with Other  Electromagnetic Compatibility
 Devices.                                 Testing.
Electrical Safety (e.g., shock)........  Electrical Safety Testing.
Thermal Injury.........................  Non-clinical Performance
                                         Software Verification,
                                          Validation, and Hazard


Gastroenterology-Urology Devices: Metallic Biliary Stent System for Benign Strictures


Product :  WallFlex Biliary Rx Fully Covered Stent System

Classification: Class II special controls.

Codification: 21 CFR 876.5011

Risks and Mitigations: 

Table 1--Metallic Biliary Stent System for Benign Strictures Risks and
                           Mitigation Measures
            Identified risk                     Mitigation measure
Adverse tissue reaction................  Biocompatibility Evaluation.
Infection..............................  Sterilization Validation.
                                         Shelf Life Validation.
Bile duct obstruction..................  Clinical Performance Testing.
  Stent migration......................  Non-clinical Performance
  Stent does not resolve obstruction...  Shelf Life Validation.
  Stent cannot be placed...............  Labeling.
  Expansion/compression forces.
Trauma to bile ducts...................  Clinical Performance Testing.

[[Page 45231]]

  During stent deployment..............  Non-clinical Performance
  During removal.......................  Shelf Life Validation.
  Due to stent migration...............  Labeling.
  During stent indwell.
  Inability to safely remove stent.....
  Expansion/compression forces.........



FDA BRIEF: Week of July 11, 2016

FDA approved



InSightec, Dallas, TX, USA

INDICATION FOR USE: In patients with essential tremor whose tremors cannot be treated using medication. Patients must be at least 22 years old. The designated area in the brain responsible for the movement disorder symptoms (ventralis intermedius) must be identified and accessible for targeted thermal ablation by the ExAblate device.


  • Essential tremor, also called benign essential tremor, is the most common form of tremor
  • Several million Americans, usually those over age 40, are affected by the condition
  • If medications fail, treatment with surgery (thalamotomy) or deep brain stimulation to destroy thalamus that controls some involuntary movements.
  • Need for new treatment option that could help them to avoid more invasive surgical treatments



  • Magnetic resonance image-guided focused ultrasound (MRgFUS) system
  • Non-invasively destroys tiny areas of brain tissue
  • The ultrasound treatment applied in incremental increases in energy called sonications until  satisfactory result is achieved


  • Double-blind control trial (n=76) patients with essential tremor, not responded to medication therapy
  • ExAblate Neuro treatment vs. fake treatment (crossed over to treatment group after 3 mo.)
  •  3 mo post-procedure. : 50 % improvement tremors and motor function (composite tremor/motor function score) vs. no improvement/ slight worsening
  • 12 mo post-procedure : 40%  percent improvement compared to baseline.


  • Adverse events consistent with thalamotomy surgery: Numbness/tingling of  fingers, headache, imbalance/unsteadiness, loss of control of body movements (ataxia) or gait disturbance
  • Other effects possibly related to MR-guided focused ultrasound treatment: Tissue damage in an area other than the treatment area, hemorrhage in the treated area requiring emergency treatment, skin burns with ulceration of the skin, skin retraction and scar formation and blood clots.


XIIDRA (lifitegrast)  ophthalmic solution 

 Shire, Lexington, MA, USA

INDICATION:  Treatment of the signs and symptoms of dry eye disease (DED).


  • DED  – Eye does not produce adequate tear volume or tears are not of correct consistency
  • ~ 5% population (age 30-40), 10-15% (age >65); more common in women
  • Can lead to pain, ulcers or scars in cornea
  • Need for new treatment option

REG PATHWAY: NDA, Standard review


  • Binds to the integrin lymphocyte function-associated antigen-1 (LFA-1) with cognate ligand intercellular adhesion molecule-1 (ICAM-1)
  • ICAM-1 may be overexpressed in DED


  • Four  12-week, randomized, multi-center, double-masked, vehicle-controlled studies (n=1181); minimal signs (i.e., Corneal Fluorescein Staining (CFS) and non-anesthetized Schirmer Tear Test (STT)) and symptoms (i.e., Eye Dryness Score (EDS) and Ocular Discomfort Score (ODS)) severity scores at baseline
  • DED Symptoms:  Eye dryness Score (EDS) using visual analogue scale (VAS);  larger EDS reduction with Xiidra
  • DED Signs:  Dry Eye Disease Inferior fluorescein corneal staining score (ICSS); larger reduction in ICSS favoring Xiidra

SAFETY: Most common side effects: Eye irritation, discomfort or blurred vision, unusual taste sensation (dysgeusia).



Abbott Medical Optics, Santa Ana, CA, USA

INDICATION FOR USE: For  cataract patients with an extended depth-of-focus, which helps improve their sharpness of vision (visual acuity) at near, intermediate and far distances.


  • >20 %  Americans will have cataracts by  age  65
  • IOLs mainstay of cataract treatment
  • Need for new option for better vision across a broader range of distances

DEVICE DESCRIPTION: 4 toric models, reduction of residual refractive astigmatism or imperfections in the curvature of the eye


  • Randomized clinical trial comparing (n=200) , Tecnis Symfony IOL vs.  monofocal IOL
  • Endpoints: Visual acuity at near, intermediate and far ranges, contrast sensitivity
  • Intermediate distance: 77 % with good vision (20/25) vs. 34%
  • Near distance : Read two additional, progressively smaller lines with Tecnis
  • Distance vision: Comparable

SAFETY: Worsening of or blurred vision, bleeding or infection.

HUMULIN R U-500 insulin dedicated SYRINGE


  • Humulin R U-500 insulin vial has been available with no dedicated device for delivery since 1994
  • Dedicated syringe for the administration of Humulin R U-500 insulin
  • Only device approved for use with U-500 insulin vial
  • Humulin R U-500 insulin vial label will be updated to remove the dose conversion information for U-100 and tuberculin syringes


FDA Views: Clinical Pharmacology White Papers, Clinical Trial Diversity

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FDA Collaborates on White Papers for Improving Innovative Drug Development

 FDA’s Office of Clinical Pharmacology (OCP)  + Duke-Robert J. Margolis, MD, Center for Health Policy expert working group

Improving Productivity in Pharmaceutical Research and Development: The Role of Clinical Pharmacology

Enhancing clinical pharmacology tools and methods for improving efficiency of  development process and body of evidence

Utilization of Quantitative and Systems Pharmacology (QSP) and Model-Informed Drug Development (MIDD) potentially can:

  • Lower the risk inherent in early-stage decision-making
  • Positively address the late-stage attrition trends in development
  • Ensure right investigational compound is hitting right target in right patient

Facilitating Biomarker Development: Strategies for Scientific Communication, Pathway Prioritization, Data-Sharing, and Stakeholder Collaboration

Highlights key priority areas to advance biomarker development and precision medicine Challenges include:

  • Lack of consistent and coherent set biomarker definitons and uses
  • Confusion on regulatory pathways for biomarker acceptance
  • Data standards
  • Rigor in data practices
  • Improved collaboration in data sharing between interested stakeholders.
  • Lack of coordination and prioritization of limited public and private resources


Be A Champion for Clinical Trial Diversity

by: Dr. Jonca Bull,  Assistant Commissioner for Minority Health, Office of Minority Health

Jonca Bull, M.D., is Director of FDA’s Office of Minority Health

FDA launching campaign to encourage minority participation in clinical trials

It supports FDA’s initiative: “The Year of Clinical Trial Diversity.”

  • Need diverse pool of research participants—racial and ethnic minorities, women, even the elderly –  to ensure safety for everyone
  • Health disparities important — diseases that occur more frequently or appear differently in non-white populations
  • Clinical trials participants need to more closely mirror the patients who will ultimately use the medicine
  • Campaign includes educational aids such as videos, a blog, and an infographic

Watch and share videos and other educational aids (more in this blog)


FDA News: 30 years @ CDER, ZIKA Action, National Evaluation System

FDA BRIEF: Week of July 11, 2016




Director's Corner - 30 years at FDA

Breakthroughs in Drug R&D

  • Recombinant proteins
  • Monoclonal antibodies
  • Genetics and Molecular Medicine

Breakthroughs in Drug Regulation & Review

  • Accelerated approvals
  • Safety review
  • Rise of Clinical Pharmacology
  • Breakthrough Therapy program

Next Revolutionary Innovation

  • In CBER – gene therapy

Sustaining Innovation in Drug R&D

  • Basic Science – engine to drive a new understanding
  • Translational Science – biomarkers
  • Responsive Regulation – in keeping with the scientific advances

Long-Range Forecast – 30 yrs from now……

  • Splintering of diseases into molecular subtypes
  • Rise of precision medicine
  • Better diagnostics
  • Disease Prevention
  • Targeted Treatments


FDA Takes Action against Zika Virus

Robert Califf, M.D., Commissioner , Luciana Borio, M.D.,  Acting Chief Scientist

Robert Califf

Dr. Lu Borio

Alliance with World Health Organization and ANVISA (Brazilian Health Regulatory Agency) taking important steps to rapidly respond and minimize impact of  Zika virus outbreak.

Engagement with commercial and government developers, including the NIAID and BARDA on medical product development

  • Protecting Tissues and the Blood Supply
  • Supporting Diagnostic Development
  • Strategies to Suppress Mosquito Population
  • Facilitating Medical Product Development



Jeffrey Shuren, MD., JD. Director, CDRH

Robert Califf, MD, Commissioner

New technologies and methods to meet CDRH standards for

  • Reasonable assurance of Safety and Effectivenes (RASE)
  • Safe and Appropriate Use

National Evaluation System engaging all stakeholders to enable FDA to facilitate development and interpretation of more informative data essential for policy making and clinical decisions for individuals and populations.

Quickly detect and understand context of medical technology issues as they arise

Efficient system that rewards innovation that leads to better health outcomes, creating powerful incentives for continuous improvement and accelerating access to technologies that patients and physicians can use with the assurance of safety, efficacy, and a well-characterized balance of benefit and risk.


FDA News: Precision Medicine, Next Gen Sequencing Guidances

FDA BRIEF: Week of   July 4, 2016 

FDA advances Precision Medicine Initiative by issuing draft guidances on next generation sequencing-based tests

In support of the President’s Precision Medicine

Two draft guidances for next generation sequencing (NGS)

  • New technology to scan a person’s DNA to detect genomic variations for risk of disease
  • Conventional diagnostics provide limited  measure of disease/conditions
  • NGS can examine millions of DNA variants at a time

Regulatory Perspective

  • Encourage innovation while assuring NGS-based tests are accurate and useful
  • Adherence will offer flexible and adaptive regulatory oversight
  • Ensure Precision Care –  is only as good as the tests that guide diagnosis and treatment
  • Draft guidances  important step in the development of NGS-based tests
  • Encouraging public comments during the 90-day comment period.


Scope: Content and standards in providing oversight for whole exome human DNA sequencing (WES) or targeted human DNA sequencing NGS-based tests

Recommendations: Designing, developing, and validating NGS-based tests for germline diseases

Classification: Class II and potentially exempting them premarket notification;  longer-term goal to establish special controls for 510(k)

Key Elements:

Test Design Considerations .

  • Indications for Use Statement(s) of the Test
  • Specific User Needs for the Test
  • Specimen Type
  • Interrogated Regions of the Genome
  • Performance Needs
  •  Components and Methods

Test Performance Characteristics

  • Accuracy
  • Precision (Reproducibility and Repeatability) .
  • Limit of Detection (LoD)
  • Analytical Specificity

Test Run Quality Metrics

  • Coverage (Read Depth and Completeness)
  • Test Run Metrics and Performance Thresholds




  • Whether a genetic variant database could support NGS-based test validity in  premarket submission
  • Using curated databases using expert human interpretation for test developers to rely on clinical evidence from FDA-recognized public genome databases to support clinical claims

Recommendations: Recognition of Publicly Accessible Genetic Variant Databases

  • Database Procedures and Operations .
  • Data Quality
  • Curation, Variant Interpretation and Assertions
  • Professional Training and Conflicts of Interest

Process: Genetic Variant Database Recognition

  •  Submission for Recognition
  • FDA Review
  • Maintenance of FDA Recognition
  • Use of Third Parties
  •  Use of Data and Assertions from Recognized Genetic Variant Databases









FDA Approvals: ABSORB stent, OTC DIFFERIN Gel, SUREPATH & COBAS for HPV screen

FDA BRIEF: Week of July 4, 2016

FDA approved


ABSORB GT1™ Bioresorbable Vascular Scaffold (BVS) System 

Abbott Vascular in Santa Clara, CA, USA

Image of the device.

INDICATION FOR USE: Temporary scaffold that will fully resorb over time and is indicated for improving coronary luminal diameter in patients with ischemic heart disease due to de novo native coronary artery lesions (length is less than or equal to 24 millimeters mm) with a reference vessel diameter of greater than or equal to 2.5 mm and less than or equal to 3.75 mm.


  • Coronary heart disease is responsible for about 370,000 deaths/yr
  • Caused by cholesterol-containing deposit build up and narrowing of coronary arteries
  • Treatment by  angioplasty to widen the artery using a metal stent; however, scar tissue formation within the stent can cause restenosis
  • Drug-eluting stents temporarily release a drug to combat restenosis
  • Need for new treatment option for an absorbable device rather than a permanent metallic coronary stent

REG PATHWAY:. PMA. Positive FDA Circulatory Devices Panel voting.


  • Fully absorbable stent mounted on balloon dilatation catheter
  • Made of absorbable polymer, poly(L-lactide) (PLLA), with a thin coating of the absorbable polymer poly(D,L-lactide) (PDLLA) containing the drug everolimus
  • Contains two (2) platinum marker beads, one (1) embedded at each end
  • Absorbable stent is placed into a blood vessel (coronary artery) during angioplasty to help keep the coronary artery open
  • Stent dissolves and will be absorbed by the body in approximately three (3) years, leaving behind only the platinum markers.


  • Single randomized clinical trial (n=1,322), ABSORB vs. XIENCE metallic stent, 5 year followup
  • Endpoint: Combined rate of cardiac death, heart attack at year 1:  7.8%  vs 6.1%
  • Rate of blood clot formatio: 1.5%  vs. 0.7%
  • Importance of vessel sizing to identify arteries that are appropriate for Absorb implantation
  • Overall, clinical outcomes comparable to XIENCE


  • Adverse events associated with procedure:  Allergic reactions to materials in the device or medications used during the procedure, allergic reaction to the drug everolimus, infection or irritation at the catheter insertion site, internal bleeding, the development of abnormal connections between arteries and veins, embolism, or other coronary artery complications that may require medical intervention and that could lead to death.

LABEL: Not yet posted


DIFFERIN Gel 0.1% (adapalene),  topical gel

Galderma Laboratories, L.P., Fort Worth, TX, USA

INDICATION : For the over-the-counter (OTC) treatment of acne, for use in people 12 years of age and older.


  • Millions of  adolescents to adults suffer from acne
  • Need for access to a new safe and effective OTC option


  • Originally approved in 1996 as prescription product for acne vulgaris treatment in patients 12 years of age
  • Now approved to be made available OTC


  • Safety and efficacy initially established based on 5 clinical trials
  • Post-marketing safety data  accrued from 1996-2016
  • Consumer studies (label comprehension study, self-selection study, actual use trial) – Can appropriately select and use product
  • Maximal use trial – Drug absorption through acne-affected skin when applied daily over a large surface area (face, shoulders, upper back and chest) : Limited absorption

LABEL: Not posted

SUREPATH Preservative Fluid  with COBAS HPV Test 

SurePath Preservative Fluid, Becton Dickinson and Company, Franklin Lakes, NJ, USA

Cobas HPV Test, Roche Molecular Systems, Basel, SWITZERLAND



INDICATION FOR USE: Use with cervical cell samples obtained for a Pap test to screen women age 30 and older for Human Papilloma Virus (HPV) in order to determine whether additional follow-up and diagnostic procedures are needed. Roche cobas HPV Test with SurePath indicated in women age 21 and older who have already had an abnormal Pap test result (borderline cellular cytology) in order to determine whether additional follow-up and diagnostic procedures are needed. The test with SurePath is also able to detect high-risk HPV genotypes 16 and 18 in the same populations of women.


  • HPV infections are the most common sexually-transmitted infections
  •  HPV genotypes 16 and 18 cause approximately 70% cervical cancers worldwide
  • 12,990 new cases and 4,120 deaths in US in 2016
  • Need for  HPV test to be used with cervical cells obtained for a Pap test and collected in SurePath Preservative Fluid
  • Need for specific instructions for laboratories to process cervical samples collected in SurePath Preservative Fluid to minimize the risk of false negative results.


  • Cobas HPV Test, when used with samples collected into SurePath Preservative Fluid, demonstrated to be safe and effective for cervical cancer screening
  • Comparable performance to specimens collected into ThinPrep PreservCyt Solution, another type of cell collection media
  • FDA approval includes triage of ASC-US (Atypical Squamous Cells of Undetermined Significance) Pap cytology results and adjunct testing with Pap cytology for women 30 years of age and older

LABEL: Not posted



FDA BRIEF: Week of June 27, 2016

FDA approved

EPCLUSA (sofosbuvir and velpatasvir) tablet

Gilead Sciences, Inc., CA, USA


INDICATION: Treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection : (i) without cirrhosis or with compensated cirrhosis  (ii) with decompensated cirrhosis for use in combination with ribavirin


  • ~75% Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small numbers of patients are infected with genotypes 4, 5 or 6
  • ~ 75 to 85% cases become chronic
  • Need for management and treatment option for a wider scope of  chronic HCV

REG PATHWAY: NDA, Priority Review

MECHANISM OF ACTION:  Fixed-dose combination of sofosbuvir and velpatasvir which are direct-acting antiviral agents against hepatitis C virus


  • Several studies


  • Serum HCV RNA values measured using COBAS AmpliPrep/COBAS Taqman HCV test
  • Primary Endpoint: Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment
  • Relapse: HCV RNA greater than or equal to LLOQ during the post-treatment period
  • On-treatment virologic failure: Breakthrough, rebound, or non-response
  • >90% patients receiving Epclusa had no virus detected in the blood 12 weeks after finishing treatment, suggesting the patients’ infections had been cured


  • Warning- Serious slowing of heart rate (symptomatic bradycardia) and cases requiring pacemaker intervention
  • Most common side effects of Epclusa include headache and fatigue



Revision Optics, Inc. of Lake Forest, CA, USA

INDICATION FOR USE:  Intrastromal implantation to improve near vision in the non-dominant eye of phakic, presbyopic patients, 41 to 65 years of age, who have manifest refractive spherical equivalent of (mrse) +1. 00 diopters (d) to -0. 50 d with less than or equal to 0. 75 d of refractive cylinder, who do not require correction for clear distance vision, but who do require near correction of +1. 50 d to +2. 50 d of reading add.


  • Presbyopia is loss of ability to change focusing power of eye
  • Bifocals, reading glasses common correction method
  • Corneal inlay surgery elective option
  • Need for new option for surgical, outpatient treatment of presbyopia



  • Made of soft, biocompatible hydrogel; bioengineered to facilitate the transport of nutrients and fluid to the eye
  • Corneal inlay that creates a prolate-shaped cornea, and easily placed under a femtosecond laser flap of non-dominate eye; resembles a tiny water droplet.
  • Inlay provides steeper surface to help eye focus on near objects or print
  • By reshaping the curvature of the cornea, the inlay corrects the refractive error that results in near vision problems.


  • Clinical trial , n=373
  • 92%  with 20/40 vision or better at near distances with the inlay-implanted eye 2 years post implantation.


  • May cause or worsen problems with glare, halos, foreign body sensation and pain
  • Risks: Infection, inflammation, dry eye,  retinal detachment, decrease in distance vision, corneal complications, epithelial ingrowth

Patient Information Brochure



Cepheid, Sunnyvale, CA, USA

INDICATION FOR USE: Intended as an aid in infection control to detect and differentiate the most prevalent carbapenemase gene families in isolates expressing resistance and can be used in conjunction with other clinical and laboratory findings. Although the Xpert Carba-R Assay tests for the most prevalent carbapenemase genes associated with resistance to carbapenem antibiotics, it does not detect the bacteria, carbapenemase activity or other possible non-enzymatic causes of carbapenem resistance. The Xpert Carba-R Assay tests only for genetic material.


  • Carbapenem antibiotics are widely used in hospitals to treat severe infections –  resistant organisms are commonly referred to as Carbapenem-resistant Enterobacteriaceae (CRE)
  • Current methods to identify CRE colonization are bacterial culture methods and susceptibility testing that may take up to four days
  • Need for  rapid test using specimen taken directly from patient – quick identification

REG PATHWAY: 510(K), Class II, Code: POK


  • Differentiates between KPC, NDM, VIM, IMP, and OXA-48 gene families, representing more than 90 different genes responsible for carbapenemase production
  • LIS connectivity enabling immediate implementation of infection control measures
  • Detection in  48 minutes.


  • Study using rectal swabs , n=755, patients in hospitals or long-term care facilities
  • Second study using rectal swabs, n=432, artificially prepared with specific concentrations of bacteria containing the genes detected by the test
  • Compared results from Xpert Carba-R Assay vs reference cultures and PCR sequencing
  • Similar performance between the Xpert Carba-R Assay and culture method.


  • Does not detect all types of carbapenemase genes
  • Labs continue to perform standard bacterial culture in conjunction with  Assay


FDA Voice: Oncology Center of Excellence, Richard Pazdur, Advisory Committee ‘Appearance’

FDA BRIEF: Week of June 27, 2016


Acting director of the FDA Oncology Center of Excellence

By : Robert Califf, MD, FDA Commissioner


FDA honored to be an integral part of the Vice President’s National Cancer Moonshot Initiative (“Cancer Moonshot”)

Creating Oncology Center of Excellence (OCE) – to  expedite development of novel combination products and support an integrated approach to tackle disease

FDA’s own Dr. Richard Pazdur,  chosen as director to serve as central point of engagement for oncology stakeholders, including patient-focused advocacy groups, professional associations, industry, academia and sister agencies such as NIH.

Will leverage thought leaders inside and outside Agency including center directors from CDER, CBER, CDRH


Leveraging the Power of Collaboration – FDA’s New Oncology Center of Excellence

By: Richard Pazdur, M.D., Acting Director, Oncology Center of Excellence


Honored to be selected by Commissioner Califf today as the acting director of OCE

OCE will combine skills of regulatory scientists and clinical oncology reviewers


Personal experiences at FDA:

  • Joined FDA from MD Anderson Cancer Center in  1999
  • Oncology products reviewed in different divisions within CDER
  • Director of Office of Hematology and Oncology Products (OHOP) created in 2005 to consolidate
  • Additional reorganization into disease-specific teams in 2011
  • Between 2010 – present, OHOP approved 61 NMEs with most approvals before deadline.
  • Wife Mary, an oncology nurse, died of ovarian cancer last November.

OCE will

  • Be collaborative
  • Incorporate patient view in regulatory decision-making
  • Support innovation and address multiple treatment and diagnostic options in the best interest of patients.



FDA Advisory Committee Members and ‘Appearance Issues’

By: Michael Ortwerth, Ph.D., Director of the Advisory Committee Oversight and Management Staff


  • FDA relies on advisory committees for independent scientific and technical expertise and advice on challenging public health issues
  • Members  appointed as “special government employees” (SGEs)
  • Subject to Federal conflict of interest laws and regulations
  • “Guidance for the Public, FDA Advisory Committee Members, and FDA Staff on Procedures for Determining Conflict of Interest and Eligibility for Participation in FDA Advisory Committees.” (2008) described requirements
  • “Appearance Issues.” not addressed
    • Interests and relationships creating appearance that they lack impartiality
    • Examples: Household member working with sponsor,  past financial interests, consulting
  • New Guidance for evaluating appearance issues
    • Ethical principles
    • FDA determination of potential issue
    • FDA makes final decision






FDA Guidances/Orders for Devices: Age/Race/Ethnicity, Availability/Compliance/Enforcement, Pediatric Extrapolation, Symbols in Labeling, Aesthetic Use Devices

FDA BRIEF: Week of June 27, 2016

fda guidances


For devices for which safety, effectiveness or benefit-risk profile expected to vary across subgroups

Applicable to 510(k), PMA, De Novo, HDE applications


  • Encourage collection of relevant age, race, ethnicity and associated covariates (e.g., body size, biomarkers, bone density, etc.)
  • Recommend analyses and interpretation of data
  • Specify expectations for reporting information in  summaries and labeling

Terminology & Need:

  • Age: Pediatric <22, Older subgroups 65- 261 74, ≥75 years –  often underrepresented in clinical trials
  • Race and Ethnicity: Categories describing sociocultural construct of US society – distinct lack of publicly reported race and ethnicity data for medical devices

Subgroup Participation : Overcome barriers to enrollment and utilize enrollment resources

Planning at IDE, Premarket and Postmarket Stages: For achieving appropriate enrollment, diverse study recruitment, study design analysis and interpretation, FDA submission



Framework for benefit and risk factors for compliance and enforcement efforts to maximize medical device quality and patient safety

Applies to diagnostic and therapeutic medical devices subject to, and exempt from, Premarket review

Patient Focused Benefit-Risk Assessments:

  • Authority to limit availability of violative medical devices with goal of protecting and promoting the public health
  • Consider short-term and long-term impact of non-compliance on benefit-risk profile  – including patient perspectives

Factors to Consider Regarding Benefit-Risk:

  • Benefit: Type, Magnitude, Likelihood, Duration, Patient Preference, Health Care Provider / Caregiver Considerations, Medical Necessity
  • Risk:  Severity, Likelihood, Duration, Inaccurate Results (diagnostics), Patient Tolerance, Risks for Health Care Provider / Caregiver
  • Additional Factors: Uncertainty, Mitigation, Detectability, Failure Mode, Scope of issue, Patient Impact, Preference for Availability, Firm Compliance Issues

FDA Decision-Making considerations:

  • Recall strategy  : Correction vs. Removal
  • FDA actions when continued access to nonconforming device needed during shortage
  • Best interest of  public health to grant variance from certain requirements identified during  PMA pre-approval inspection
  • Exercise enforcement discretion and not take immediate action
  • Adequacy of manufacturer’s proposed correction strategy
  • Issuing  Warning Letter or Untitled Letter  vs alternative, more informal approach


  • Benefit Assessments
  • Risk Assessments
  • Assessing potential decisions based on the Benefit-Risk Assessment Outcome




Leveraging relevant available clinical data may increase availability of medical devices for use in pediatric patients

Applicable to PMA, De Novo, HDE applications

Pediatric Medical Device Safety and Improvement Act (PMDSIA), 2007, specifically authorized the use of adult data to demonstrate pediatric effectiveness

“Extrapolation” refers to leveraging process where an indication for use in a new pediatric patient population can be supported by existing clinical data from a studied patient population


  • Provide roadmap for leveraging relevant existing clinical data
  • Explain appripriate circumstances for leverage existing clinical data
  • Outline approach to determine if extrapolation is appropriate
  • Describe statistical methodology that can be used to leverage the data in a way that i

Pediatric Age Ranges:

  • Neonates: from birth through the first 28 days of life
  • Infants: 29 days to less than 2 years
  • Children: 2 years to less than 12 years
  • Adolescents: aged 12 through 21 (up to but not including the 22nd birthday)

Full and Partial Extrapolation: Use directly or in combination with pediatric data (via statistical model)

Extrapolation for Effectiveness vs. Safety: Extrapolation for safety is expected to be rarer than extrapolation for effectiveness because of physiological differences  and lack of power of adult clinical studies  to provide comprehensive safety assessments

Pediatric Extrapolation Decision Process and Decision Tree: 

  • Similarity of existing adult response data/ population characteristics to pediatric
  • Quality of adult data – study design, data collection, measurement
  • Extrapolated data use to fairly and responsibly assess reasonable assurance of safety and effectiveness






  • Allow optional inclusion of graphical representations of information, or symbols, in labeling without adjacent explanatory text- “stand-alone symbols”
  • Use of symbols, accompanied by adjacent explanatory text continues to be permitted
  • Allow use of  “Rx only” or “℞ only” in labeling for prescription devices.



Classifying OTC Electrosurgical Devices for Aesthetic Use as Class II with special controls

            Identified risk                     Mitigation measure
Infection..............................  Cleaning Validation.
Adverse Tissue Reaction................  Biocompatibility.
Skin Overheating/Burn..................  Clinical Performance Testing.
                                         Non-clinical Performance
                                         Software Verification,
                                          Validation and Hazards
Electromagnetic Interference/Electrical  Electromagnetic Compatibility
 Shock.                                   Testing.
                                         Electrical Safety Testing.
Worsening Aesthetic Outcomes...........  Clinical Performance Testing.
Use Error..............................  Usability Study.
Failure to Identify Correct Population   Label Comprehension and Self-
 and Condition.                           Selection Study.



Mechanistic Oral Absorption Modeling and Simulation

Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation


FDA Public Workshop was hosted on May 19, 2016 by the US Food and Drug Administration (FDA) at its White Oak Campus in Silver Spring, MD. The workshop speakers were from the FDA, industry, and academia. The workshop was chaired by Dr. Liang Zhao, Director of Division of Quantitative Methods & Modeling Office of Research Standards Office of Generic Drugs.

The plenary sessions presenters were from FDA (Drs. John Duan, Xinyuan Zhang,  from industry (Drs. Filippos Kesisoglou (Merck), Jasmina Novakovic (Apotex ), Masoud Jamei  (Simcyp), Viera Lukacova (SimulationsPlus) and Thomas Eissing (Bayer Technology), and from academia (Dr. Gordon Amidon, University of Michigan).  Dr. Kathleen Uhl gave the opening remarks and Dr. Robert Lionberger gave the closing remarks.

A few Dr. Zhao’s presentation slides were on:

  • M&S Impact Various Regulatory Activities in OGD (4/1/15 to 4/1/16)
  • PBPK in Applications for Generics
  • Number of Compounds Assessed Using Absorption Modeling
  • PBPK Applications in NDA: Current Status
  • Drug labels with dosing recommendations informed by PBPK


Dr. Duan’s presentation title was The Application of Mechanistic Oral Absorption Model in Biopharmaceutics Review”. Highlights of presentation were:

His presentation outline slide described an overview, covering

  • Patient first initiative in drug development
  • Biopharmaceutics Team growth
  • Predictions help decision making

Current status, covering

  • Current practice
  • Dissolution spec setting
  • Set clinically relevant product specs
  • Risk assessment

PBPK Future App

  • Meet the challenge
  • Information in regulatory submission
  • Product life cycle management


Dr. Zhang’s presentation title was OGD Experience and Efforts on Oral Absorption Modeling and Simulation”. Highlights of presentation were:

Update on Absorption Modeling and Simulation in OGD

  • Innovative Model for Future Product Development

Case Examples:

  • Evaluate the impact of slow dissolution in a specific pH condition on BE (warfarin sodium tablets)
  • Evaluate the PPI impact on BE (prasugrel HCl tablets, fingolimod capsules)

Summary slides had following points:

  • OGD has routinely applied mechanism-based absorption modeling and simulation to address various issues raised in regulatory activities.
  • OGD is actively improving the science of predictions for oral solid dosage forms.
  • OGD is willing to collaborate with internal and external stakeholders to advance the application of mechanism-based absorption modeling and simulation in drug product development and regulatory review.

Dr. Kesisoglou’s presentation title was Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: An Industry Perspective”. A few presentation slides were on:

  • Current status of absorption modeling in formulation development
  • Case studies
    • Formulation development and achlorhydric simulations
    • Dissolution impact on PK and BE projections
    • Multimedia dissolution and BE projections
    • Projection of API form change and population simulations
    • Food effect projection for a BCS I compound
    • Absorption modeling-based IVIVC for IR tablet
    • Conclusions and future directions


Dr. Novakovic’s presentation title was ”Modeling and Simulations for Development and Bioequivalence Evaluation of a Generic Drug Product”. Highlights of presentation were:

Roles of PBPK modeling and simulation

Early development

  • Reference List Drug (RLD) characterization;
  • Establishing Quality Target Product Profile (QTPP);
  • Formulation design and product development of to achieve bioequivalence

Life-cycle and Quality Risk Management (QRM)

  • Bio-indicative dissolution test conditions and clinically meaningful specification limits;
  • Bio-study waiver for the additional strengths and SUPAC;
  • Critical material attributes (CMA) and boundaries for a rate–controlling excipient;

Summary slide had the following points:

  • At early product development stage PBPK modeling is a proven toll to characterize RLD, facilitate product development to define formulation strategy and achieve bioequivalence;
  • During life-time cycle management, QRM is ensured by implementing adequate controlled strategies (i.e. test methods and specification limits);
  • Controlled strategy, established to ensure BE, is developed based on PBPK modeling;
  • PBPK Modeling and Simulation is a powerful but underused tool to facilitate development and ensure QRM of a generic drug product.


Dr. Amidon’s  presentation title was ” Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence (BE) Evaluation ”.


Dr. Jamei presentation title was ” Mechanistic Modeling and Simulation of Oral Drug Absorption: Opportunities and Challenges”. A few presentation slides were on:


IVIVE (in vitro-in vivo extrapolation )-Linked PBPK absorption modelling

Physiologically-based IVIVC (PB-IVIVC)

Bioequivalence and PBPK modelling


Dr. Lukacova’s presentation title was ”Incorporating Mechanistic Modeling & Simulation to Assist with Formulation Development”. Highlights of presentation were:


  • Why Modeling & Simulation?
  • Overview of Mechanistic Simulation Models
  • Predicting in vivo absorption & PK

Applications in Generic Product Development

  • Generating IVIVCs
  • Performing virtual bioequivalence trials and establishing dissolution specifications
  • Understanding food effects

A successful biowaiver case study


Summary slide was:

  • A mechanistic, physiologically-based absorption/PK model was constructed in GastroPlus and validated across three dose levels (50, 100, and 300 mg) using in vivo data collected from tablets manufactured with non-particle-engineered API.
  • Parameter sensitivity analysis showed that mean particle size would be the main property that determines whether formulations are likely to be bioequivalent, regardless of dose.
  • Virtual bioequivalence trial simulations showed that, for a sufficiently powered study, the population-derived Cmax and AUC values would be bioequivalent between the tablets manufactured with non-particle-engineered (NPE) vs. new-particle-engineered (PE) API, regardless of the dose.
  • Regulatory agencies approved the sponsor’s biowaiver application


Dr. Eissing’s  presentation title was ” PK-Sim for Mechanistic Oral Absorption Modeling and Simulation and More”. A few presentation slides were on:

  • Introduction: PBPK modeling with PK-Sim & MoBi
  • Oral absorption and dissolution modeling
    • Concept
    • Examples
    • Implementation


  • Examples shown for how to model different formulations and their oral absorption in PK-Sim/MoBi to better understand PK
  • PK-Sim is a PBPK tool with a focus on flexibility and transparency, together with MoBi leaving a lot of room for problem specific solutions


Dr. Kesisoglou’s presentation title was ”OrBiTo: Innovative Tools for Oral Biopharmaceutics”. Highlights of presentation were:


  • Programme vision, mission and objectives
  • Members of the OrBiTo consortium
  • OrBiTo Work Packages
    • Aims and deliverables
    • Highlights of progress to date
  • Integration of dissolution in PBPK models

Objective slide described:

  • Define the critical physicochemical, formulation and physiological factors that determine oral drug product performance.
  • Develop both experimental and theoretical models which can be used to robustly predict the in vivo performance of formulated drug products.
  • Fully leverage industrial knowledge and experience through pooling existing physicochemical, in vitro characterization, preclinical and clinical data to assess the reliability of currently available prediction methods and to underpin the development of new modelling and simulation tools.

Physicochemical tools – Understanding the API


  1. Provide a range of in vitro physico-chemical tools and in silico models that can assess the API’s key molecular properties important for in vivo performance, including excipient interactions
  2. Provide the information gained by use of tools, defined in objective 1, for a subset of the OrBiTo database to establish a Drug Development Decision Tree, expanding the DCS and facilitating drug formulation selection and optimising the dosage form design process
  3. Integrate knowledge and results obtained from physico-chemical studies and models in WP1 with “In vitro tools – understanding the formulation” (WP2).
  4. Serve as physico-chemical parameter input for integrated modelling and predictive tools developed in WP4 (PBPK modelling).