FDA Approvals: Zepatier®, Halaven®

FDA Brief: Week of Jan 25, 2016

FDA approved


merck 1.JPGmerck 2.JPG

ZEPATIER, (fixed dose combination product of elbasvi and grazoprevir) tablets

Merck , Whitehouse Station, New jersey, USA

Indication : With or without ribavirin for treatment of chronic HCV genotypes 1 or 4 infection in adults

Unmet Need :

  • Hepatitis C can lead to diminished liver function or liver failure
  • Most infected people asymptomatic until liver damage becomes apparent
  • 3 million Americans are infected with HCV, of which genotype 1 is the most common and genotype 4 is one of the least common
  • The approval provides another oral treatment option for patients with genotypes 1 and 4 HCV infections without requiring use of interferon.

Reg Pathway : Breakthrough Therapy designation, Priority Review

Mechanism of Action: Direct-acting antiviral agents against the hepatitis C virus


  • Six studies(n=1,373), open label and double-blind, with or without ribavirin, with or without cirrhosis, 12-16 weeks
  • Sustained virologic response (SVR) 12 weeks post-treatment : 94-97 % (genotype-1) and 97-100 % (genotype-4)
  • To maximize SVR rates :  Label provides recommendations regarding length of treatment with or without ribavirin specifically tailored to the characteristics of the patient and their virus


  • Warning : Elevations of liver enzymes
  • Most common side effects: Fatigue, headache, nausea. With ribavirin, anemia and headache.



HALAVEN  ( eribulin mesylate ) injection

Eisai, Woodcliff Lake, New Jersey, USA


Indication : Unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.

Unmet Need:

  • Liposarcoma is a  Soft Tissue Sarcoma(STS) in fat cells
  • STS most common in the head, neck, arms, legs, trunk and abdomen
  •  12,000 cases of STS diagnosed in US
  • Need for therapy with survival benefit

Reg Pathway : sNDA, Orphan Drug designation, Priority Review

Mechanism of Action : Inhibits growth phase of leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.


  • Single open-label, randomized, active-controlled trial (n=446.), patients with unresectable, locally advanced or metastatic liposarcoma or leiomyosarcoma, at least two prior systemic chemotherapies (containing anthracyclis) , Halaven vs dacarbazine
  • Overall Survival : Statistically significant improvement (p=0.011)
  • Progression-free survival: No significant difference in overall population
  • No evidence of with advanced or metastatic leiomyosarcoma


Safety :

  • Most common Serious Adverse Reactions: Neutropenia, Pyrexia
  • Most frequent Adverse Reactions leading to Discontinuation: Fatigue, thrombocytopenia.
  • Most common Adverse Reactions: Fatigue, nausea, alopecia, constipation, peripheral neuropathy, abdominal pain, and pyrexia

FDA Voice on Clinical Trial Diversity

FDA Brief: Week of Jan 25, 2016

FDA Voice

2016: The Year of Diversity in Clinical Trials

By: Robert M. Califf, M.D., FDA’s Deputy Commissioner for Medical Products and Tobacco

  • Increasing diversity in clinical trials is a priority for FDA
  • Research participants need to be representative of patients who will use product
  • FDASIA Section 907 :
    • evaluate underrepresented groups e.g. elderly, women, racial/ethnic
  • FDA Activities:
    • Drug Trial Snapsots  publication on clinical trial demographic information
    • Office of Minority Health tools for clinical trial participation
    • Office of Women’s Health’s Diverse Women in Clinical Trials initiative
    • Better estimates of treatment effects for diverse populations
    • Obtain patient’s perspective
    • Office of External Affairs plans to publish a consumer update



Women’s Health Research Roadmap

FDA Brief: Week of Jan 25, 2016

OWH Vision

A Strategy for Science and Innovation to Improve The Health of Women

By FDA Office of Women’s Health (OWH)

Research Priority Areas

  1. Advance Safety and Efficacy: Advance the safety and efficacy and reduce the toxicity of FDA-regulated products used by women
  2. Improve Clinical Study Design and Analyses: Improve clinical study design and conduct to better identify and evaluate possible sex differences related to FDA-regulated products
  3. Novel Modeling and Simulation Approaches: Evaluate and promote the adoption of novel modeling and simulation approaches that can aid in regulatory evaluation of FDA-regulated products
  4. Advances in Biomarker Science: Develop tools and methods that can help identify, evaluate, and qualify predictive or prognostic clinical and non-clinical biomarkers and surrogate endpoints
  5. Expand Data Sources and Analysis: Identify, develop, and evaluate data sources and efficient techniques for data mining, data linkage, and large data set analysis that can be used to assess the postmarket toxicity or the safety and effectiveness of FDA-regulated products
  6. Improve Health Communications: Develop, evaluate, and use tools and methods to foster the creation and easy availability of clear and useful information about FDA-regulated products used by women to help women and their health care professionals make informed health-related decisions
  7. Emerging Technologies: Support the identification of sex differences related to the use of emerging technologies




FDA focus on French Biotrial Phase 1 Tragedy

FDA Brief : Week of Jan 25, 2016


Drug Information Update-FDA works with regulatory partners to understand French-based Biotrial phase 1 clinical study

  • Conferring with European regulators regarding the tragic phase 1 clinical study, conducted by Biotrial that resulted in 1 death and 4 neurological injuries
  • BIA 10-2474 is inhibitor of fatty acid amide hydrolase (FAAH), an enzyme involved in cell function in the nervous system
  • FDA is collecting and reviewing safety information pertinent to FAAH inhibitors in US and will work with sponsors, patients, investigators to ensure safety




2016 CDER Guidances, CDRH Interoperable Devices, Neurological Devices Reclassification

FDA Brief: Week of Jan 25, 2016

fda guidances


New & Revised Draft Guidances CDER is Planning to Publish During Calendar Year 2016


Advertising, Biopharmaceutics, Clinical/Antimicrobial,  Clinical/Medical, Clinical Pharmacology,  Clinical/Statistical,  Electronic Submissions,  Labeling, Pharmaceutical Quality/CMC,  Pharmaceutical Quality/Manufacturing Standards (CGMP), Pharmacology/Toxicology,  Procedural,


  • Health Care Economic Information in Promotional Labeling and Advertising
  • Treatment/Prevention of Anthrax, Attachment to HIV-1 Infection, Bacterial Vaginosis, Chronic Hepatitis C Virus Infection, Recurrent Herpes Labialis, Vulvovaginal Candidiasis, Allergic Rhinitis,  Exocrine Pancreatic Insufficiency,  Rare Diseases,  Nonallergic Rhinitis, Ulcerative Colitis
  • Patient Reported Outcomes for Varicose Vein burden, COPD
  • Adaptive Clinical Trial Design, Meta-Analysis for Safety
  • Post-marketing Safety reporting



Design Considerations and Pre-market Submission for Interoperable Medical Devices

  • Interconnectivity of  medical devices characterized as  “interoperability.”
  • Interoperability – Ability of two or more products, technologies or systems to exchange information and use of exchanged information
  • Highlights:
    •  designing systems
    •  performance testing and risk management activities
    • specifying functional, performance, and interface characteristics in labeling


Neurological Devices; Reclassification of Cranial Electrotherapy Stimulator  (CES)

Intended To Treat Insomnia and/or Anxiety : Class III to II – 510(k)

Intended To Treat Depression : PMA

Recalssification based on deliberations of  2012 Panel meeting,  reclassification petitions  and  new information that there is sufficient information to establish special controls to mitigate risks.





NINLARO® (ixazomib) Capsule for Patients with Multiple Myeloma

A reversible proteasome inhibitor, preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.

Pharmacodynamics (PD) Did not prolong the QTc interval at clinically relevant exposures
Pharmacokinetics (PK) Approximately 58% absolute bioavailability (median Tmax of 1 hour) in patients.

A 28% and 69% decreased in ixazomib AUC and Cmax, respectively, following the administration of NINLARO with a high-fat meal

AUC increased in a dose proportional manner over a dose range of 0.2 to 10.6 mg (i.e., 0.05 to 2.65 times the approved recommended dosage)

Accumulation approximately 2-fold

Systemic clearance was approximately 1.9 L/h and terminal half-life (t1/2) was 9.5 days

Extensive metabolism with both non-CYP and CYP enzymes contributing to ixazomib metabolism. At higher than clinical concentrations (in vitro), CYP3A4 is predominant (42%)

Plasma protein binding was approximately 99%.

Approximately 62% of the administered radioactivity was excreted in the urine (< 3.5% as unchanged drug) and 22% in the feces

PK-PD Analysis Did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients
Population PK There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m2), or race on the clearance of ixazomib
Special Populations PK of ixazomib was similar in patients with normal hepatic function and in patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1-1.5 x ULN and any AST)


PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min). Mean AUC was 39% higher in patients with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal function.

Drug Interactions Co-administration of ixazomib with rifampin decreased ixazomib Cmax by 54% and AUC by 74%


Co-administration of ixazomib with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib


Ixazomib is a low affinity substrate of P-gp, but is not expected to cause transporter-mediated drug-drug interactions.

Source : http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf


NUCALA Clinical Pharmacology Card


NUCALA® (Mepolizumab) for subcutaneous (SC) injection for Severe Asthma Aged 12 Years and Older


Mechanism of Action Interleukin-5 (IL-5) antagonist monoclonal antibody (IgG1 kappa), responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils
Pharmacodynamics (PD) Blood eosinophils decreased in a dose-dependent manner for doses 12.5 mg SC, 125 mg SC, 250 mg SC
Pharmacokinetics (PK) Exhibited approximately dose-proportional pharmacokinetics over a dose range of 12.5 to 250 mg. in subjects with asthma

 Accumulation approximately 2-fold at steady state

 Approximately 80% is absorbed following SC administration in the arm

 Central volume of distribution of mepolizumab in patients with asthma is estimated to be 3.6 L for a 70-kg individual

 Mean terminal half-life ranged from 16 to 22 days

Proteolytic enzymatic degradation that is widely distributed in the body

PK-PD Analysis Have not been reported
Population PK There was no significant effect of race and gender on mepolizumab clearance

There was no significant effect of age on mepolizumab clearance, ranging in age from 12 to 82 years

Special Populations No clinical trials have been conducted to investigate the effect of renal impairment or hepatic impairment on the pharmacokinetics of mepolizumab
Drug Interactions No formal drug interaction studies have been conducted

Source : http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125526Orig1s000Lbl.pdf


FDA Brief, Week of Jan 18, 2016


Oncology Drug Approvals: Year in Review

2015 Office of Hematology and Oncology Products (OHOP) approvals & expedited review programs.

Richard Pazdur, M.D., Director of the Office of Hematology and Oncology Products


  • 16 new molecular entities (NMEs): non-small-cell lung cancer, colorectal cancer, breast cancer, melanoma, renal cancer, pancreatic cancer
  • Multiple Myeloma advances: Darzalex (daratumumab), Empliciti (elotuzumab), Ninlaro (ixazomib), and Farydak (panobinostat)
  • Biosimilar products: Zarxio (filgrastim-sndz) a bone marrow stimulant, Unituxin dinutuximab), for pediatric high-risk neuroblastoma


  • Impressive metric: 6 approvals using expedited review programs in Nov. 2015
  • Accelerated Approval: ‘Frequently’ used based upon a surrogate endpoint reasonably likely to predict a clinical benefit, e.g. overall survival
  • Priority Review:  Granted after NDA submission For serious and life-threatening diseases and provides significant improvement in safety or effectiveness over available therapy. Reduces NDA review times from 12 mo (standard) to 8 mo
  • Breakthrough therapy: Granted at IND stage. For expediting development of drugs for serious and life-threatening with preliminary clinical evidence. More dynamic interaction with sponsors to expedite development


  • Development of “targeted agents” – Greater effectiveness in a specific population and may generally have a more favorable benefit-risk profile
  • Breakthrough therapy designations – High response rates substantially better than available therapy


  • Review team and high standards of review quality
    • OHOP’s oncologists practicing physicians : medical, pediatric oncologists, radiation oncologists, oncology nurses, physician assistants, and oncology pharmacists
    • In addition, statisticians, basic scientists examining clinical pharmacology and toxicology, chemists reviewing manufacturing
  • External Engagement:
    • Advocacy groups and professional organizations
    • Other Agency centers, offices and National Cancer Institute
    • Ex-US regulators to share ideas and concerns
    • Expansion of “patient voice” initiative



FDA clarification of Flibanserin approval – after 2 rejections !

  • Careful evaluation of efficacy endpoints and clinical meaningful improvement, safety concerns and benefit/risk framework
  • Required additional Phase 3 studies as well as Clin Pharm/ Drug interaction studies
  • Considered generalizability of Ph 3 outcomes to all women likely to be prescribed
  • Factored in external feedback on HSDD’s on women’s sense of identity, emotional well-being, relationships
  • Risk evaluation and mitigation strategy with “elements to assure safe use” (REMS-ETASU) to ensure benefits outweigh increased risk of hypotension and syncope with alcohol
  • Risk management with labeling – Warning and Medication Guide
  • Required post-approval trials with enhanced pharmacovigilance to take further actions if needed



FDA approved

novartisArzerra (ofatumumab)  


Indication: Extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive chronic lymphocytic leukemia (CLL).

Reg Pathway: sBLA, Priority Review


  • Single randomized, open-label  (n=474), patients with  complete or partial response after at least two lines of prior therapy, ofatumumab vs . observation
  • Event rate (progressed or died) : 33% vs. 51%
  • Investigator-assessed median Progression Free Survival : 29.4 mo. vs. 15.2 mo. (p<0.0001)



  • Most common adverse reactions: infusion reactions, neutropenia and upper respiratory tract infection
  • Most common serious adverse reactions: Pneumonia, pyrexia and neutropenia (including febrile neutropenia)


evis exera

EVIS EXERA II TJF-Q180V duodenoscope

with design modifications intended to reduce infection risk

Olympus medical Systems, Center Valley, PA

Intended Use:  Olympus TJF-Q180V duodenoscope with modifications to the device’s design and labeling intended to help reduce the risk of bacterial infections

Unmet Need:

  • Duodenoscopes  have been associated with the transmission of infectious agents, including antibiotic-resistant infections
  • Need to improve safety of duodenoscopes by reducing  risk of fluid leakage into the elevator channel, which in turn can reduce patient exposure to bacteria and other potential infections

Design Modifications:

  • Elevator channel sealing mechanism to create a tighter seal and reduce the potential for leakage of patient fluids and tissue into the closed elevator channel
  • Conduct annual inspections of each scope in use by facilities to identify any wear and tear on the elevator channel sealing mechanism or the presence of attached debris at the scope’s tip, which would require replacement of the potentially contaminated parts.

Reg Pathway:  510(k) for design modifications

  • 2014 FDA letter : Need for remarket notification for the “closed” elevator channel model which had never been cleared for marketing
  • 2015 FDA Safety Communication : Validated instructions for cleaning and disinfecting of TJF-Q180V while the 510(k) under review
  • Voluntary recall of the original TJF-Q180V model from health care facilities and make needed repair
  • Post market surveillance and Annual reporting

fda guidances


Implanted Blood Access Devices for Hemodialysis

  • Reclassifying implanted blood access devices for hemodialysis, which were preamendments Class III devices, into Class II (special controls) and subject to premarket notification.- requiring 510(k) Submission





Sterility Information for 510(k) Submissions for ‘Sterile’ Devices

  • Clarification of information regarding sterilization processes for 510(k)s for devices labeled as ‘sterile’
  • ‘Sterile’ –  subject to industrial terminal sterilization processes based on microbial inactivation
  • Describes ESTABLISHED and NOVEL methods





Director’s Corner Podcast

WHO: Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research.

WHAT: Discussion of major events of the past year and priorities for 2016.


LINK to Podcast



SBIA Chronicles

WHO: CDER Small Business and Industry Assistance

WHAT:  Best Communications Practices with FDA

WHY: Communication between FDA and sponsors during product development and at critical junctures ultimately facilitate earlier availability of safe and effective drugs to the American public.





WHO:  AIDSinfo is releasing HIV/AIDS Guidelines app for iOS and Android devices.

WHAT: Provides mobile access to the  federally approved HIV/AIDS medical practice treatment guidelines.

WHY:  To provide Health Care Providers mobile access to up-to-date HIV information at the point of care—even when Internet connection is unavailable

HOW: AIDSinfo to download the free Guidelines app to your device

FDA Brief, Week of Jan 11, 2016

CDRH Priorities


  • Establish a National Evaluation System for medical devices : To successfully harness from the diverse set of real-world evidence in an efficient manner
    • Increase access to real-world evidence to support regulatory decision-making
    • Increase use of real-world evidence to support regulatory decision-making
  • Partner with Patients; interact with patients as partners and work together to advance the development and evaluation of innovative devices, and monitor the performance of marketed devices
    • Promote a culture of meaningful patient engagement by facilitating CDRH interaction with patients
    • Increase use and transparency of patient input as evidence in decision-making
  • Promote a culture of quality and organizational excellence; manufacturer’s ability to design and make high-quality, safe and effective devices and CDRH’s ability to provide the necessary oversight to assure devices on the market are high-quality, safe and effective 
    • Strengthen culture of quality within CDRH
    • Strengthen product and manufacturing quality within medical device ecosystem



FDA Voice

Progress and Collaboration on Clinical Trials

Barbara D. Buch, M.D, . Chair of the 907 Steering committee and the Associate Director for Medicine in FDA’s Center for Biologics Evaluation and Research

Based on Congress’s directive in Section 907 of FDASIA, FDA looking more closely at sex, age, and race/ethnicity data collected in clinical trials.

Three priorities:

  • improving the quality and comprehensiveness of demographic subgroup data collection, reporting and analysis
  • identifying and eliminating barriers for increased participation in clinical trials
  • improving the transparency of subgroup data.


  • Public meeting on this topic on February 29.
  • Guidances : Integrated Summary of Effectiveness: Guidance for Industry & Evaluation of Sex-Specific Data in Medical Device Clinical Studies
  • Supportive Programs across FDA’s Divisions and Offices : Office of Minority Health (OMH), CDER, CDRH
  • Updated Medwatch Forms to standardize collection of demographic information


  • OWH and NIH collaborative workshop on importance of diversity
  • Availability of demographic data through ‘Drug Trials Snapshots’
  • FDA and Johns Hopkins University co-sponsored clinical trials workshop on Safety and Efficacy for a Diverse Population


  • Language Access Plan Working Group to address needs of under-represented subpopulations
  • CBER transparency pilot program for open access to demographic information from BLAs
  • CDRH modified templates for certain medical devices to ensure inclusion of demographic information


CDER conversations

Compendium of CLINICAL OUTCOME ASSESSMENTS (COAs) to promote the use of patient-focused outcome measurement in drug development

Elektra Papadopoulos, M.D., MPH, Acting Associate Director, Clinical Outcome Assessments Staff, Office of New Drugs, CDER, FDA


What is patient-focused outcome measurement about?

Understanding of the impact of a disease on the people who have it, and what they value most in terms of alleviating symptoms

How does patient input influence the choice of outcome measures in drug development?

Patient input into the selection of outcomes that are meaningful to them can profoundly influence drug development by ensuring the patient voice is captured.

What is a clinical outcome assessment and how are COAs captured in drug development?

COAs are captured using four types of COA measures: patient-reported, clinician-reported, observer-reported, and performance outcome measures.

What are patient-reported outcomes?

Patient-reported outcomes (PROs) are outcomes that are based on reports coming directly from the patient about how he or she feels or functions as a result of treatment. PROs may not always be feasible or appropriate depending on the particular context, and other types of COAs may be utilized.

What is the COA Compendium? And what is its purpose?

Table describing use of COAs in drug development related symptoms) and support labeling claims

Designed to be used as a starting point when considering the use of COAs in clinical trials

Why is this COA Compendium important and what does it mean for patients?

Tool to foster patient-focused drug development mission and  to see knowledge gaps

Is FDA encouraging drug companies to consider using PROs in trials that support approval of a drug?


Will this compendium be an all-conclusive list of COAs?

No – this is a pilot. Hope to get public comment to expand scope.

Where can people find the COA Compendium?

Federal Register notice seeking review and comment on the content and format of the compendium

What type of information are you hoping to obtain?

Seeking public feedback on the utility, approach for development, suggestions for future approaches to expand scope of COA Compendium




Clinical Outcome Assessment (COA) Compendium


  • Describes clinical outcome assessments to support labeling claims
  • Identifies clinical outcome assessments qualified for potential use
  • Recognizes ongoing qualification projects


  • Not a comprehensive list
  • Sponsors strongly encouraged to seek advice from the relevant Office of New Drug (OND) review division early in drug development
  • Inclusion in COA Compendium does not equate to an FDA endorsement


  • CDER’s DDT COA Qualification Program
  • Drug Labeling Approved From 2003 to 2014 (New Molecular Entity (NME) labeling)


  • Importance of collaborative development of COAs in response to unmet measurement needs
  • Provides regulatory conclusion on specific COA, specific interpretation and application in regulatory review
  • Inclusion of labeled COA serve as additional resource


  • Table alphabetically listing conditions or diseases
  • Six Columns :
    • Disease Condition
    • Indication and/or Claim(s) Description
    • Outcome of Interest
    • COA (COA Type)
    • COA Context of Use
    • COA Qualification Information


  • Not a comprehensive list
  • Not a replacement for FDA interactions or supersede existing guidances

FDA seeking public feedback 
FDA will host Webinar


fda guidances


CDRH Draft Guidance on Cybersecurity

  • Recommendations for monitoring, identifying and addressing cybersecurity vulnerabilities and exploits as part of medical device management
  • General principles for Pre-Market and Post-Market considerations, essential clinical performance
  • Risk management based on exploitability of the cybersecurity vulnerability, and health impact severity if the vulnerability were to be exploited
  • Remediating and Reporting vulnerabilities including controlled and uncontrolled risks to essential clinical management
  • Content for PMA Periodic Reports including description of vulnerability, sponsor conclusion and description of changes made
  • Elements of an Effective Postmarket Cybersecurity Program : Identify, Protect/Detect, Protect/Respond/Recover
  • To be discussed at the Jan 2021 FDA Workshop on Cybersecurity





POCA – Phonetic and Orthographic Computer Analysis

  • Part of CDER, Office of Surveillance and Epidemiology (OSE), Division of Medication Errors Prevention and Analysis (DMEPA)’s mission to prevent medication errors due to proprietary name confusion
  • POCA is a web application to determine written and phonetic similarities between proposed drug names using advanced algorithms
  • Compares a drug name against multiple drug names found in several different “data sources” contained in the software
  • FDA is providing zip files to download and install to help Sponsor evaluate potemtial proprietary names vs FDA database. – ‘Drugs @ FDA’ and ‘RxNorm’





drug links

WHAT : Drug Industry -specific resources pages focused on information that serves as a guide to key information




WHAT : CELP serves as a liaison between the FDA and the cardiovascular and endocrine health professional and patient communities. CELP encourages and supports active participation in forming FDA regulatory policies that promote healthy dietary and nutrition practices and advance the safety and effectiveness of human medical products that treat diabetes, hypertension, heart disease, and obesity.

WHO : Your organization can collaborate with FDA

HOW : Phone: 301-796-8460, [email protected]



Mechanism of Action

Fixed-dose combination of antiretroviral drugs elvitegravir (EVG), boosted by the CYP3A inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide(TAF)

Pharmacodynamics (PD)

Effect on QT interval is not known

Pharmacokinetics (PK)

Median Tmax: EVG: 4 hours; COBI: 3 hours; FTC: 3 hours; TAF: 1 hour

Food Effect: EVG AUC was increased by 34% and 87% when GENVOYA was co-administered with a light meal and high fat meal, respectively. No clinically meaningful food effect on COBI, FTC or TAF was observed.

Median Terminal half-lives: EVG: 12.9 hours; COBI: 3.5 hours ; FTC: 10 hours; TAF: 0.51 hours

Metabolism: EVG: CYP3A (major) and UGT1A1/3 (minor): COBI: CYP3A (major) and CYP2D6 (minor): FTC: Not significantly metabolized; TAF: Cathepsin A (major), carboxylesterase 1 (minor), and CYP3A (minimal)

Excretion: FTC is excreted renally; TFV (the primary metabolite of TAF) is excreted renally; EVG and COBI metabolites are primarily eliminated in feces

Plasma protein binding: EVG: ~99%;  COBI: ~98% ; FTC: <4%; TAF: ~80%

PK-PD Analysis

No exposure-response relationships for safety or efficacy were identified for any of the components of GENVOYA at the approved recommended dosage.

Population PK

No dosage adjustment is recommended based on race or gender

Special Populations

No dosage adjustment is recommended based on creatinine clearance ≥30 mL/min, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, or age ≥12 to ≤75 years.

Renal Impairment: GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL/min.

Hepatic Impairment: GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

Drug Interactions

GENVOYA can alter the concentration of drugs metabolized by CYP3A or CYP2D6.

Coadministration of GENVOYA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events, and drugs that may lead to reduced efficacy of GENVOYA and possible resistance, such as potent CYP450 inducers.

Coadministration of GENVOYA is not recommended with rifabutin, rifapentine, salmeterol, and/or colchicine in patients in patients with renal or hepatic impairment.

Consider alternatives to the coadministration of GENVOYA with oxcarbazepine, systemic dexamethasone, and/or inhaled/nasal fluticasone.

Consider alternatives to the coadministration of GENVOYA with contraceptive patch, vaginal ring, injectable contraceptives, and oral contraceptives containing progestogens other than norgestimate.

Dose reduction may be necessary for sedative/hypnotics, neuroleptics, midazolam, and beta blockers when coadministered with GENVOYA.

Specific dosage regimens are required for phosphodiesterase-5 inhibitors, colchicine, and bosentan when coadministered with GENVOYA.

Initiate with the lowest starting dose of atorvastatin when coadministered with GENVOYA and titrate carefully while monitoring for safety.

Separate GENVOYA and antacid administration by at least 2 hours.

The maximum daily dosage of ketoconazole or itraconazole should not exceed 200 mg per day when coadministered with GENVOYA. Assessment of benefit/risk is recommended to justify use with voriconazole.



FDA Brief, Week of Jan 4th, 2016

FDA Voice

2015: Another Strong Year for Patients in Need of New Drug Therapies

By: John K. Jenkins, M.D. Director of the Office of New Drugs, CDER


Strong year for novel new drug approvals:  45 novel new therapies vs. average of 28 over the previous nine years

  • Cancers : Multiple myeloma (4), lung, skin, breast, brain, colorectal, and other cancers.
  • Heart failure, high cholesterol, cystic fibrosis, irritable bowel syndrome
  • Rare Diseases

Approval Highlights

  • 36% : “First-in-class,” : Addyi, Bridion, Corlanor, Cosentyx, Darzalex, Empliciti, Entresto, Ibrance, Kanuma, Nucala, Orkambi, Praluent, Praxbind, Strensiq, Unituxin, Xuriden
  • 40% : rare or “orphan” diseases: Alecensa, Cholbam, Cotellic, Cresemba, Darzalex, Empliciti, Farydak, Kanuma, Lenvima, Natpara, Ninlaro, Orkambi, Portrazza, Praxbind, Repatha*, Strensiq, Tagrisso, Unituxin, Uptravi, Xuriden, Yondelis
  • First reversal agent for a blood thinner: Praxbind
  • 60% : Designated in one or more categories for Expedited Development and Review methods
    • Fast Track 31%
    • Breakthrough 22%
    • Priority Review 53%
    • Accelerated Approval 13%
  • 64% approved first in the US
  • 96% PDUFA goal dates met
  • 87% “first cycle” approval
  • Qualified Infectious Disease Product (QIDP, GAIN Act): 2


FDA 2015: A Look Back (and Ahead) – Part 2: Medical Product Safety and Oversight

By: Stephen M. Ostroff, M.D., Acting Commissioner of Food and Drugs

Reflection on FDA’s impact on medical product safety and oversight.

Responding to Ebola : Expediting availability of diagnostic tests, investigational therapeutics, vaccines;  investigating fraudulent products

Addressing Transmission of Infections from Duodenoscopes : Safety communication, public Advisory Committee meeting, Warning letters,  Postmarket surveillance studies on reprocessing in real-world clinical settings.

Compounding:  Policy documents, meetings with stakeholders, including pharmacy, physician, and consumer groups, and collaborations with state governments.

Addressing the Opioid Abuse Crisis:  Multipronged approach to balance availability of medical treatments vs tragic consequences of abuse and misuse. Guidance for development of abuse-deterrent opioid formulations, options for medication-assisted treatment of opioid-dependence, treat consequences of overdoses.


FDA approved


Integra Omnigraft Dermal Regeneration Matrix to treat diabetic foot ulcers

Integra LifeSciences Corporation of Plainsboro, New Jersey

Indication for Use : Treat certain diabetic foot ulcers that last for longer than six weeks and do not involve exposure of the joint capsule, tendon or bone, when used in conjunction with standard diabetic ulcer care.

Unmet need :

  • 29 million people in US diagnosed with diabetes; 25% will experience foot ulcer during their lifetime
  • Chronic diabetic foot ulcers associated with tissue and bone infections and result in 50,000 amputations each year.
  • Need for new innovation in diabetes care with the potential to improve the number of foot ulcers that heal

Reg Pathway : PMA Supplement

– PMA (1996) : Treatment of life threatening burn injuries when the use of a patient’s own skin for a graft was not possible

– PMA Supplement (2002) : Treat patients undergoing reconstructive surgery for burn scars when they cannot have skin grafts

Effectiveness :

  • Study, a multi-center, randomized, controlled, parallel group clinical trial conducted under an Investigational Device Exemption (IDE). Omnigraft  vs. standard of care (includes cleaning and covering the wound with a surgical bandage and keeping weight off of the foot with the ulcer)
  • 51 percent of patients treated with Omnigraft had healed ulcers after 16 weeks compared to 32 percent of patients treated with standard diabetic foot ulcer care alone

Safety :  Adverse events included infections, increased pain, swelling, nausea, and new or worsening ulcers


fda guidances


Draft Guidance : Hearing Aid Devices and Personal Sound Amplification Products

  • New efforts to balance patient safety vs encouraging advancements in hearing aid technology and patient access
  • Hearing aids often underutilized medical device
  •  Most hearing aids are Class I (low-risk);  possible modifications to regulation to a “decrease in cost and improvement in capability, convenience and use of assistive hearing devices.”
  • Public workshop :  “Streamlining Good Manufacturing Practices (GMPs) for Hearing Aids,” April 21, 2016 : Alternative regulatory models to accelerate innovation while enabling quality design and manufacturing
  • Re-opened Public Comment period on draft guidance: Through May 19, 2016





Noxafil (posaconazole)

  • Dosing errors when switching between different oral formulations of antifungal
  • Drug labels revised to indicate that the two oral formulations cannot be directly substituted for each other but require a change in doseP
    • Prescribers – Specify the dosage form, strength, and frequency
    • Pharmacists – Request clarification from prescribers when the dosage form, strength, or frequency not specified
    • Patients – Talk to their health care professional before switching


Surgical Mesh for the Transvaginal Repair of Pelvic Organ Prolapse

  • Strengthened data requirements for  to address safety risks
  • Two final orders to manufacturers and the public
    • Reclassify from class II (moderate-risk) to class III (high-risk)
    • Require manufacturers to submit PMA application for safety and effectiveness




  • Transparency – provide interested parties an unprecedented look into how FDA performs its work.
  • Results – highlights performance measures and results with relevance to the agency’s public health mission.
  • Accountability – requires senior managers to develop, track, and report performance measures that will improve the agency’s accountability to the public; holds the program offices accountable for their priorities, plans and results.
  • Credibility – encourages sharing of information about FDA performance which is essential for the agency’s credibility; provides the opportunity to submit suggestions which will be considered as part of the continuous improvement efforts.
  • Knowledge-sharing – enables the identification of common issues and interdependencies among program offices to improve FDA’s operational effectiveness through better collaboration and sharing of ideas.



Nanoparticles in Drug Development


Nanoparticle technologies have revolutionized the drug development process and change the landscape of the drug industry. Nanoparticles (NP) could improve the aqueous solubility, dissolution rate, and absorption of poorly water-soluble substances.

Addressing Pharmaceutical Unmet Need : Major issues associated with poorly water-soluble compounds are poor bioavailability, fed/fasted variation in bioavailability, lack of dose-response proportionality and that leads to suboptimal dosing, need a pharmacokinetic (PK) booster to enhance bioavailability, and noncompliance by the patient, i.e., inconvenience dosing schedules.

Characteristics: NP can be defined as solid particles with a size in the range of 10-1000nm. The increased surface area of NP will enhance the dissolution of poorly water soluble drug substances. The chance gravitational settling is less for NP  because of their small size and can be suspended easily in liquid formulation. The NP approach is suitable for highly potent compounds (low dose) but it is not practical when the dose requirement may be big. In recent years nanotechnology is gaining popularity by formulators for reformulating the old formulation of poorly soluble compounds. For marketed products requiring lifecycle extension opportunities, NP formulation strategies provide a means to develop a new drug-delivery platform with improved therapeutic outcome incorporating the existing drug, thus creating new avenues for addressing unmet medical needs.

Pharmaceutical Application : An increasing number of the drug candidates synthesized each year by pharmaceutical companies which may have poor water solubility and many of these promising compounds are rejected from development because traditional formulation approaches will not be able to improve bioavailability. Nanotechnology could rescue these compounds. For new chemical entities development, the nanotechnology can be of great value in preclinical pharmacokinetics and efficacy/ safety assessment studies in the early development phase. Drug formulation with NP could reduce or eliminate food-effect related variability resulting in no dosing restriction since NP improve the solubility of drug substances. There are several techniques to make drug NP out in the literature, e.g bottom-up (Precipitation methods), top-down etc.

Disposition : Enhancing solubility and dissolution rate of poorly soluble compounds correlates with improved PK profile since dissolution kinetics is the primary driving force behind the improved PK/ bioavailability of NP formulations of poorly water soluble compounds. The enhanced bioavailability should be translated to faster onset of action that may translate into improved therapeutic outcome.

Marketed products: Oral products developed using nanoparticle technology are in the market and listed below: Rapamune (Sirolimus); Emend (Aprepitant), TriCor (Fenofibrate), MegaceES (Megestrol). Avinaza (Morphine sulphate),  Focalin (Dexmethyl-phenidate HCl),  and Zanaflex (Trizanidine HCl) and the intravenous products: intravenous nutritional fat emulsion (Intralipid) and liposomal products (Doxil, AmBisome).

FDA BRIEF, Weeks of Dec 21st and Dec 28th, 2015



FDA Voice



FDA 2015: A Look Back (and Ahead) – Part 1: Medical Product Innovation

By: Stephen M. Ostroff, M.D.

 Reflection of  FDA’s  2015 accomplishments by  Acting Commissioner

Medical Product Approvals

  • > 40 approvals including 4 new treatments for multiple myeloma, 2 new drugs for heart failure, and several drugs for  rare or “orphan” diseases
  • Several important vaccines, including meningococcal disease, seasonal influenza vaccine for elderly, anthrax
  • Several innovative devices  including brain cancer, congenital heart disease
  • Speed and efficiency in both drug and device approvals

Amplifying the Patient Voice

  • Patient-Focused Drug Development initiative
  • Voice of the Patient report (drug)
  • Patient Preference Initiative (device)
  • Draft guidance, Patient Engagement Advisory Committee


  • First biosimilar approved
  • Several Guidances

Next Generation Sequencing Tests and Strengthening Clinical Trials

  • Growing ability to apply technologies of next generation sequencing and precision medicine
  • Precision Medicine Initiative, precisionFDA web platform
  • Refine clinical trial design and statistical methods of analysis to create more efficient studies with smaller patient populations, more focused therapies, and better outcomes


FDA Invites Patient Organizations to Take a Place at the Podium

By: Theresa M. Mullin, Ph.D.

Reflection on Patient-Focused Drug Development (PFDD) program by is Director of FDA’s Office of Strategic Programs

  • More first-hand knowledge from those most affected by the diseases
  • Better understand context for regulatory decision making
  • Committed to hold meetings for at least 20 disease areas & 24 disease-focused meetings 2017
  • Encourage patient organizations in conducting an externally-led PFDD meeting and keeping FDA informed



FDA approved


ardea    ZURAMPIC  (lesinurad)


Indication: In combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase (XO)  inhibitor alone

 Unmet need:

  • Gout is a painful form of arthritis caused by uric acid buildup
  • Need for new treatment option for controlling hyperuricemia for the long-term treatment of gout

Reg pathway: NDA Standard Review

Mechanism of Action: Inhibits transporter proteins functions involved in uric acid reabsorption in the kidney and reduces serum uric acid levels


  • 3 multicenter, randomized, double-blind, placebo-controlled studies, Patients with hyperuricemia and gout
  • Zurampic + XO inh (allopurinol or febuxostat) vs XO inh
  • N=511, 510, 516, Duration :  12 mo.
  • Superior lowering of serum uric acid to less than 6 mg/dL at 6 mo.


  • Boxed Warning : Risk for acute kidney (renal) failure
  • Common Adverse Reaction : Headache, influenza, increased blood creatinine, and gastroesophageal reflux disease
  • Postmarketing Study : Renal and Cardiovascular safety



UPTRAVI (selexipag)


Indication : Treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH

Unmet Need:

  • PAH is high blood pressure in arteries connecting heart to lungs; can lead to limitations on exercise ability and shortness of breath
  • Need for additional treatment option for PAH patients

Reg Pathway : NDA – Standard review, Orphan Drug Designation

Mechanism of  Action:  Oral prostacyclin receptor agonist


  • Single multi-center, double-blind parallel group, N=1156, Uptravi vs Placebo, 1.4 yrs
  • Primary endpoint : Time to first occurrence of : death, hospitalization for PAH, PAH worsening,  initiation of parenteral prostanoid therapy or chronic oxygen therapy, other disease progression
  • 40% reduction (99% CI: p-value < 0.0001) of primary endpoint events vs placebo  – primarily due to reduction in hospitalization for PAH and reduction  disease progression events


  • Common Adverse Reaction : Headache, diarrhea, jaw pain, nausea, muscle pain (myalgia), vomiting, pain in an extremity, and flushing



FENIX  Continence Restoration System

Torax Medical Inc, Shoreview, Minnesota

Indication for Use: Treat fecal incontinence in patients who are not candidates for, or have previously failed, medical or other surgical options

Unmet Need:

  • Fecal incontinence caused by damage anal sphincter muscles; frequently underreported
  • Need for viable surgical option other non-invasive methods have failed

Reg Pathway: PMA, Humanitarian Device Exemption (HDE) process


  • 3 components: Implant, Anal Sphincter Sizing Tool, Introducer Tool
    • Implant : Titanium beads with magnetic cores; minimizes involuntary opening of anal canal
    • Sizing Tool : Associates anal sphincter size to appropriate implant
    • Introducer Tool : Guides sizing tool and implant into position


  • Study (n=35), evaluations before and after procedure and at 6 wks, 3 mo, 6 mo, 12 mo
  • Bowel diary to track fecal incontinence events & validated questionnaire (Fecal Incontinence Quality of Life Scales)
  • 50% reduction after 12 mo: 9 %  (fecal incontinence episodes), 54.3 % (fecal incontinence days), 37.1 % (urgent episodes)
  • Improvements in Quality of Life measures : depression, self-perception, embarrassment


  • Adverse Events : Pain, infection, impaction or defecatory disorder, device erosion, device removal/re-operation, and bleeding
  • Patients required register with MedicAlert Foundation


fda guidances.JPG


emerging signals

  • Need for FDA to notify the public about emerging signals that the Agency is monitoring or analyzing
  • Proposes criteria, timeframes, communication, follow-up for emerging signals that may impact benefit/risk
  • Emerging Signals : New adverse event, increase in severity/frequency,  new product-product interactions, device malfunctions, patient injuries,  reduction in benefit
  • FDA will assess of need for communication : Within 30 days of receipt of information
  • If yes, FDA will communicate using standardized format and provide updates


  • Electroconvulsive Therapy (ECT) Devices for Severe Major Depressive Episode associated with Major Depressive Disorder or Bipolar Disorder reclassified  into class II from class III
  • Guidance provides recommendations for complying with the special controls and for 510(k) information for special controls


  • Specific emerging technology review assigned to a group within CDER (Emerging Technology Team – ETT) to collaborate with sponsor to implement emerging manufacturing technology
  • IND, NDA, BLA, ANDA implementation– specific discussion meetings to present proposal and align on requirements


CDRH Fiscal Year 2016 (FY 2016) Proposed Guidance Development and Focused Retrospective Review of Final Guidance


A List

Final Guidance Topics

  • General Wellness Products
  • Medical Device Accessories
  • Benefit-Risk Factors to Consider when Reviewing IDE Submissions
  • UDI Direct Marking
  • Adaptive Design for Medical Device Clinical Studies
  • Incorporating Patient Preferences into Medical Devices Premarket Approvals, Humanitarian Device Exemptions, and De Novo Classifications
  • Applying Human Factors & Usability Engineering to Optimize Medical Device Design
  • Policy for Regulatory Oversight of Laboratory Developed Tests (LDTs)
  • Submission and Review of Sterility Information for Devices Labeled as Sterile
  • Use of ISO 10993-1, Biological Evaluation of Medical Devices Part I: Evaluation and Testing
  • Postmarket Surveillance Studies
  • Medical Device Reporting (MDR) for Manufacturers

Draft Guidance Topics

  • Medical Device Decision Support Software
  • Use of Symbols in Labeling
  • 510(k) Modifications
  • Software Modifications
  • 510(k) Third Party Review Program
  • Companion Diagnostics Co-Development
  • Use of Real-World Observational Patient Data to Support Decision Making for Medical Devices
  • UDI Convenience Kit
  • Public Notification of Emerging Postmarket Medical Device Signals

There is also a B List


HELPFUL LINKS : Drug Approvals and Databases



Clinical Investigator Inspection List (CLIIL)

WHAT : Names, addresses, pertinent information FDA inspections of clinical investigators

WHEN : August 1977-present,  updated quarterly





Bioresearch Monitoring Information System (BMIS)

WHAT : Clinical investigators, contract research organizations, and institutional review boards involved in IND studies, Based on information from 1572

WHEN : Updated quarterly





NEW OFFICE: Office of Dietary Supplement Programs (ODSP)

WHY : Need to take action against fraudulent supplements that can cause serious risk to consumer (e.g.  egregious benefit claims in treating serious diseases) or widespread economic fraud.

WHAT : Newly created; to enhance effectiveness of dietary supplement regulation

WHO : Under CFSAN, will work closely with CDER to help remove falsely labeled supplements