FDA News: Forceful steps for Opioid Crisis, Cybersecurity Workshop

FDA BRIEF: Week of May 22, 2017


FDA Commissioner Asks Staff for ‘More Forceful Steps’ to Stem the Opioid Crisis

By: Scott Gottlieb, M.D., Commissioner. @SGottliebFDA

Dr. Scott Gottlieb

Highest initial priority is reduce epidemic of opioid addiction; Establishing Opioid Steering Committee

  • Explore and develop additional FDA tools to answer following questions
  • ? Mandatory education for health care professionals: appropriate prescribing recommendations, identify abuse risk, treat addicted patients
  • ? Additional risk management to tailor prescription of opioid doses
  • ? Proper policy framework  for risk of abuse and misuse


Public Workshop – Cybersecurity of Medical Devices: A Regulatory Science Gap Analysis

Hosted by FDA, National Science Foundation (NSF) and Department of Homeland Security, Science and Technology (DHS, S&T)


  • Examine opportunities for FDA engagement with new and ongoing research
  • Catalyze collaboration among stakeholders to identify regulatory science challenges
  • Discuss innovative strategies to address those challenges
  • Encourage proactive development of analytical tools, processes, and best practices





FDA Supplemental Approvals: ACTEMRA, KEYTRUDA

FDA BRIEF: Week of May  22, 2017

FDA approved

ACTEMRA (tocilizumab) injection


SUPPLEMENTAL INDICATION:  Treatment of giant cell arteritis (GCA) in adult patients


  • Giant cell arteritis is a form of vasculitis causing inflammation of blood vessels
  • Standard treatment involves high doses of corticosteroids tapered over time
  • First FDA approved therapy specific to vasculitis


  • Breakthrough Therapy, Priority Review
  • Subcutaneous Actemra previously approved for treatment of moderate to severely active rheumatoid arthritis
  • Intravenous Actemra previously approved for treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis


  • Single, randomized, double-blind, multicenter study, n=251 patients with active GCA, 2 SC doses of ACTEMRA vs. 2 different placebo control groups (pre-specified prednisone-taper regimen), 2-week blinded period, followed by a 104-week open-label extension
  • Primary efficacy endpoint: Proportion of patients achieving sustained remission from Week 12 through Week 52; defined as absence of GCA symptoms, normalization of inflammatory laboratory tests, tapering prednisone use
  • Sustained remission: 56.0% and 3.1% s. 14.0% and 17.6%


  • Generally consistent with known safety profile
  • Boxed Warning: Serious infections.


KEYTRUDA (pembrolizumab) injection


SUPPLEMENTAL INDICATION:  Treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

  • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan


  • MSI-H and dMMR tumors contain abnormalities that affect proper DNA repair
  • Tumors with these biomarkers commonly found in colorectal, endometrial, gastrointestinal cancers, cancers in breast, prostate, bladder, thyroid gland etc
  • First FDA approval based on common biomarker rather than the location in the body where the tumor originated


  • Previous approvals: Metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, urothelial carcinoma
  • Accelerated approval:  Based on tumor response rate and durability of response. Continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials


  • 5 uncontrolled, open-label, multi-cohort, multi-center, single-arm trials; patients with MSI-H or dMMR solid tumors 2 doses of KEYTRUDA, 15 cancer types, n=149, 24 months
  • Major efficacy outcome measures: Objective Response Rate (ORR) assessed by blinded independent central radiologists’ (BICR), RECIST 1.1, Duration of Response (DOR)
  • Complete or Partial Response: 39.6%,  DOR of 6 mo. for 78% responders


  • Common side effects: Fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation and nausea
  • Serious conditions: Immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis


Image credits: FDA, Genentech, Merck


FDA Supplemental Indication Approvals: KALYDECO, KEYTRUDA

FDA News: Week of May 15, 2017

FDA approved

KALYDECO (ivacaftor) tablets, oral granules

Vertex Pharmaceuticals

SUPPLEMENTAL INDICATION: Treatment of cystic fibrosis (CF) in patients age 2 years and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.


  • CF affects cells that produce mucus, sweat and digestive juices; rare disease that affects about 30,000 people in US
  • Expanded indication triples the number of rare gene mutations that the drug can now treat
  • Many rare mutations have small patient populations precluding clinical trials
  • Alternative approach, based on precision medicine, to identify certain gene mutations that are likely to respond to Kalydeco


  • Approval based, in part, on the results of laboratory testing, used in conjunction with evidence from earlier human clinical trials
  • Pathway for adding additional rare mutations of the disease based on laboratory data
  • Serves as an example of how successful patient-focused drug development can provide greater understanding about disease
  • Cystic Fibrosis Foundation maintains 28,000-patient registry, including genetic data, for research


  • Evidence from laboratory-based in vitro assay data
  • Previous approval covered 10 different mutations; efficacy against 23 additional mutations based on stringent criteria
  • Good understanding of the disease, thorough knowledge of clinical aspects of disease, data on thousands of CF patients and their mutations
  • Existing large efficacy and safety database, well-established risk/benefit profile
  • Solid understanding of the drug’s mechanism of action
  • In vitro data also able to identify types of CFTR mutations  NOT responsive to drug


  • Common side effects: Headache; upper respiratory tract infection,  abdominal pain; diarrhea; rash; nausea; and dizziness.
  • Risks: Elevated transaminases, pediatric cataracts


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KEYTRUDA (pembrolizumab) injection



  • Treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy
  • Treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

REG PATHWAY: sNDA, Priority Review, Breakthrough Designation

  • Regular approval for locally advanced or metastatic urothelial carcinoma with progression during or following platinum-containing chemotherapy
  • Accelerated approval for locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy
  • Accelerated approval based on tumor response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials


Previously Treated Urothelial Carcinoma: Multicenter, randomized, active-controlled trial, n=270, patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy; KEYTRUDA vs. investigator’s chemotherapy choice

  • Major efficacy outcomes: Overall survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR) assessed by BICR per RECIST 1.1
  • Median OS: 10.3 vs. 7.4 months (p=0.004)
  •  ORR:  21% vs. 11%, (p=0.002)
  • No statistically significant difference in PFF

Cisplatin Ineligible Patients with Urothelial Carcinoma: Multicenter, open-label, single-arm trial, n=370, patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy

  • Major efficacy outcome measures: ORR according to RECIST 1.1, Duration of Response (DOR)
  • ORR: 28.6% (95% CI 24, 34), median DOR not reached (range 1.4+, 17.8+ months)


  • Most common adverse reactions: Fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash
  • Serious adverse reactions: Immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, and endocrinopathies


Image credits: Vertex, Google

FDA News: New Commissioner’s Remarks, Reducing Preventable Medication Harm, Conformity Assessment Accreditation, Sunscreens

FDA BRIEF: Week of May 15, 2017


Dr. Gottlieb’s First Remarks to FDA Staff

Remarks by Commissioner Scott Gottlieb, M.D. at FDA All Hands Meeting

  • People’s lives depend on what FDA does
  • Great promise with scientific advances to make regulatory process more modern and efficient
  • Immediate challenge – opioid abuse and FDA’s role in minimizing use
  • Also help address challenge of prohibitive drug pricing – even though FDA does not have a direct role
  • Overall, need for risk-based, patient-centric, science-based approach and maintaining  gold standard for regulatory science and independent, science-led decision-making


Safe Use blog image

Reducing Preventable Harm from Medications: Too Big for FDA to Do Alone

By: John J. Whyte, M.D., M.P.H. , Director of Professional Affairs and Stakeholder Engagement, CDER 

Harm from medications also may come from known risks that could have been prevented

  • 1.5 million preventable adverse drug events occur each year
  • Prescribers and other providers struggle with intricacies of health care system
  • Patients have difficulty following detailed directions
  • Manufacturers need careful packaging and labeling to avoid confusion

Reducing preventable harm from medications is a big part of FDA’s mission

  • Hosting a one-day public meeting  “Safe Use Symposium: A Focus on Reducing Preventable Harm From Drugs in the Outpatient Setting.”
  • Meeting with all stakeholders to discuss sources of preventable harm from drugs in outpatient setting


Accreditation Scheme for Conformity Assessment Pilot Program

Voluntary consensus standards establish safety & performance criteria for medical device design and manufacturing

  • Support claims of safety and quality in FDA premarket review
  • Sponsors include a `Declaration of Conformity” to attest to standards


  • Appropriate use of FDA recognized consensus standards not consistently applied
  • Require substantial specialized knowledge to interpret and apply correctly

Addressing Challenge

  • FDA and Industry to establish an FDA Accreditation Scheme for Conformity
    Assessment (ASCA) Program
  • Recognize accredited testing laboratories that evaluate medical devices according to FDA standards
  • Ease industry regulatory burden by allowing them to use recognized accredited test laboratories to ensure accurate conformance with the consensus standard
  • FDA requesting comments on proposal by June 30


Family walking on the beach. Mom says: Boys! You have sunscreen on now, but don't forget you need to reapply every 2 hours while we're at the beach. If you're in and out of the water, we'll need to reapply more often.  Boys say: Ok mom!

Sunscreen: FDA Regulated Product

Sunscreen is an FDA-regulated product, for protection from sunburn, skin cancer, early skin aging and other risks of sun overexposure 

Sun protection factor (SPF) in Label

  • Indicates level of sunburn protection: Amount on UVB and UVA radiation to cause sunburn with sunscreen vs without
  • Higher SPF values (up to 50) provide greater sunburn protection
  • “Broad Spectrum SPF [value]” in label indicate protection from both

Other Label Information  

  • List of acceptable active/inactive ingredients
  • Expiration dates based on stability testing
  • Ex-US products may not have same label standards as FDA


Image credits: FDA


FDA BRIEF: Week of May 8, 2017

FDA approved

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RADICAVA (edaravone) intrvenous infusion

Mitsubishi Tanabe Pharma America

INDICATION:  Treatment of amyotrophic lateral sclerosis (ALS)


  •  ALS is rare disease; attacks and kills nerve cells controlling voluntary muscles leading to paralysis
  • 12,000-15,000 Americans have ALS; most  die from respiratory failure within 3-5 years


  • Leveraged data from Japanese trials
  • Orphan drug designation



  • 6-month, randomized, double-blind study, n =137 Japanese patients with ALS, RADICAVA vs. placebo
  • Primary efficacy endpoint: Change in the ALS Functional Rating Scale – Revised (ALSFRS-R) total scores from baseline at week 24
  • Decline in ALSFRS-R scores from baseline significantly less in the RADICAVA-treated patients (p=0.0013)


  • Most common adverse reactions: Bruising (contusion), gait disturbance
  • Serious risk: Hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug


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BAVENCIO (avelumab)

EMD Serono

SUPPLEMENTAL INDICATION: Treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:

  • Have disease progression during or following platinum-containing chemotherapy
  • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy


  • Accelerated approval, Priority review
  • Approved based on tumor response and duration of response
  • Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials


  • Open-label, single-arm, multi-center study, n=242 patients with locally advanced or metastatic UC with disease progression
  • Efficacy outcome measure: Confirmed overall response rate (ORR) using RECIST criteria, duration of response (DOR); followed for minimum of both 13 weeks and 6 months
  • ORR: For at least 13 weeks : 13.3% (n=30), 6 weeks 16.1% (n=26)
  • Median time to response: 2.0 months


  • Most frequent serious adverse reactions: Urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestinal obstruction, and pyrexia
  • Most common adverse reactions: fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection


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KEYTRUDA (pembrolizumab) injection



  • Most common AEs : Fatigue, nausea, constipation
  • Most common grade 3-4 adverse reactions: Fatigue, dyspnea, nausea, vomiting, diarrhea, and rash
  • Most common adverse reaction: Acute kidney injury
  • Immune-mediated adverse reactions: Pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis


Picture of the device, highlighting upper esophageal pouch, oral catheter, magnet, stomach, gastric catheter, and gastronomy site.

FLOURISH Pediatric Esophageal Atresia Device

Wilson-Cook Medical 

INDICATION FOR USE:  For use in pediatric patients, up to one year of age, with esophageal atresia without a tracheoesophageal fistula (TEF) or for whom a TEF has been closed as a result of a prior procedure. This device should be used only when the gap between the upper and lower portions of the esophagus is less than 4 centimeters apart.


  • 1 in every 2,500 babies born with esophageal atresia; birth defect causing gap in esophagus
  • Condition cannot feed normally, also have a tracheoesophageal fistula, breathing inteference
  • First non-surgical option to treat this birth defect

REG PATHWAY: Humanitarian Device Exemption


  • 2 catheters  with a magnet at its tip
  • One inserted through mouth and other through stomach
  • Magnetic ends attract one another and pull ends of esophagus together; surrounding tissue grows together


  • Implanted in 16 patients
  • All had successful joining of esophagus within 3-10
  • However, 13 of 16 patients developed anastomotic stricture requiring balloon dilation procedure, a stent or both to repair


  • Contraindicated in infants with existing tracheoesophageal fistula or who have esophageal segments that are more than 4 centimeters apart
  • Potential complications: Ulceration, tissue irritation, gum irritation
  • Potential long-term complication: Gastroesophageal reflux


Image credits: FDA, Google

FDA News: 23rd Commissioner, Clinical Trial Protocol Template, Depression Treatments, Continuous Manufacturing

FDA BRIEF: Week of May 8, 2017

Image result for scott gottlieb fda images

Meet Scott Gottlieb, M.D., Commissioner of Food and Drugs

Dr. Scott Gottlieb was sworn in as the 23rd FDA Commissioner on May 11

  • Physician, medical policy expert, public health advocate
  • Previously served at FDA and CMS
  • Senate appointment to serve on Federal Health Information Technology Policy Committee


FDA and NIH Release Final Template for Clinical Trial Protocols

NIH-FDA Joint Leadership Council issued protocol template for drugs and medical devices:
  • Describing trial objectives, trial design, methodology, statistical considerations, and trial organization
  • Standard protocol format to facilitate review by regulators and others (e.g., institutional review boards)
  • Following ICH E6 Good Clinical Practice guidelines
  • Contributing to important time and money-saving efficiencies


FDA Device Approvals, Classifications: POWERLOOK Software, ASTRON Pulsar Stent, OCULEVE Tear Stimulator

FDA BRIEF: Week of May 8, 2017

FDA approved

Image result for iCAD PowerLook® Tomo Detection Software

PowerLook® Tomo Detection Software

iCAD Inc. Nashua, NH, USA

INDICATION FOR USE: Software device intended to be used concurrently by radiologists while reading GE Senoclaire breast tomosynthesis exams. The system detects up to five soft tissue densities (masses, architectural distortions and asymmetries) in the 3D tomosynthesis images. The detections are blended with the standard 2D synthetic image and the computer assisted detection (CAD)-enhanced 2D synthetic image is viewed on a mammography review workstation.

The CAD-enhanced 2D synthetic image assists radiologists in identifying densities (masses, architectural distortions and asymmetries) that may be confirmed or dismissed by the radiologist in the digital breast tomosynthesis (DBT) images.


  • Class III, Product Code: MYN


  • Software in conjunction with the GE Senoclaire and mammography review workstation create a CAD-enhanced 2D synthetic image
  • Allow radiologists to review tomosynthesis images more quickly without a statistically significant decrease in performance
  • Detects soft tissue densities (masses, architectural distortions and asymmetries)
  • Blending algorithm processes CAD detections from  3D planes and merges into GE’s existing 2D volume preview
  • Software uses pattern recognition technology to identify potential regions of interest
  • Enhancement step to project 3D structure onto the V-Preview image


  • Pivotal Reader Study was a retrospective, multi-reader, multi-case study
  • Average radiologist performance with CAD noninferior to performance using GE DBT images without CAD enhanced 2D V-Preview images
  • Average AUC increased by 0.009 (95% CI: -0.012, 0.030; non-inferiority p < 0.01), from 0.841 without CAD to 0.850 with CAD
  •  Average radiologist reading time was improved with CAD


  • Aid in the interpretation of existing DBT images
  • Does not modify the existing DBT image acquisition process nor alter native DBT images
  • Use of the software does not directly involve the patient
  • Risk is increased false positives or false negatives


Pulsar-18 Image

ASTRON Pulsar Stent System

Biotronik, Inc, Oswego, OR, USA

INDICATION FOR USE: The Astron Pulsar and Pulsar-18 stent systems are indicated for use to improve luminal diameter in patients with symptomatic de novo, restenotic or occlusive lesions located in the superficial femoral or proximal popliteal arteries, with reference vessel diameters from 3.0 to 6.0 mm and total lesion lengths up to 190 mm.


  • Class III, Product Code : NIP


  • Self-expanding stent loaded on an over-the-wire (OTW) delivery system
  • Delivery system consists of inner shaft and outer shaft
  • Safety tab prevents accidental stent release
  • Black release marker that indicates completion of stent deployment, ends with a Luer port
  • Stent mounted between inner shaft and outer shaft between two radiopaque markers to facilitate fluoroscopic visualization and positioning across lesion
  • Guide wire to facilitate advancement of the delivery system toward and through lesion


  • Prospective, non-randomized, multi-center study with two treatment cohorts, iliac lesion treatment and superficial femoral artery (SFA) or proximal popliteal artery (PPA) lesion treatment
  • Primary effectiveness endpoint: Stent patency at 12 months as evidenced by peak systolic velocity ratio (PSVR)<2.4 from duplex ultrasound (DUS)
  •  Pre-specified endpoint not met : Primary patency rate numerically above performance goal; however the 95% lower confidence bound not met
  • Kaplan Meier analysis and imputed analysis for missing data supported primary patency rates similar to the observed rate; secondary endpoints met


  • Primary safety endpoint: Freedom from composite rate of procedure- or stent-related Major Adverse Events at 30 days post-index procedure : 99.7%, 95%
  • Higher than performance goal of 88% (p<0.001)




Image result for Oculeve Intranasal Tear Neurostimulator

OCULEVE Intranasal Tear Stimulator 

Oculeve Inc (Allergan), Dublin, IRELAND

INDICATION FOR USE: Provides temporary increase in tear production during neurostimulation in adult patients.

REG PATHWAY: De Novo request

  • Regulation Number: 21 CFR 886.5300
  • Regulation Name: Tear Electrostimulation Device
  • Regulatory Classification: Class II
  • Product Code: PQJ

GENERIC DEVICE TYPE: Tear electrostimulation device is a non-implantable, electrostimulation device intended to increase tear production


  • Tissue damage due to over-stimulation/understimulation or mechanical injury, device breakage:  Non-clinical performance testing, Software verification, validation and hazard analysis, Electrical, thermal, and mechanical safety testing, Labeling
  • Pain, headache, or discomfort: Non-clinical performance testing, Electrical, thermal, and mechanical safety testing, Labeling
  • Adverse tissue reaction: Biocompatibility, Labeling
  • Infection : Labeling
  • Electrical shock or burn: Electrical, thermal, and mechanical safety testing, Software verification, validation and hazard analysis, Labeling
  • Interference with other devices: Electromagnetic compatibility testing, Software verification, validation and hazard analysis, Labeling

Classification Order

Image sources: iCAD, Biotronik, Google



FDA BRIEF: Week of May 8, 2017

FDA approved

Image result for Device imfinzi

IMFINZI (durvalumab) injection

AstraZeneca. Wilmington, DE, USA

VENTANA PD-L1 (SP263) Assay

Ventana Medical Systems, Inc., Tucson, AZ, USA

INDICATION: Treatment of patients with locally advanced or metastatic urothelial carcinoma who:

  • have disease progression during or following platinum-containing chemotherapy
  • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum containing chemotherapy.

REG PATHWAY: Accelerated Approval

  • Based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials
  • Also approval for complementary diagnostic for the assessment of the PD-L1 protein in formalin-fixed, paraffin-embedded urothelial carcinoma tissue

MECHANISM OF ACTION:  Human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD80;  releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity


  • Multicenter, multicohort, open-label clinical trial, n=182 patients with locally advanced or metastatic urothelial carcinoma; had progressed while on or after a platinum-based therapy
  • Major efficacy outcome measures: Confirmed Objective Response Rate (ORR) according to RECIST v1.1 by Blinded Independent Central Review (BICR), and duration of response (DoR)
  • Responding patients: 31; 45% had ongoing responses of 6 months or longer, 16% had ongoing responses of 12 months or longer
  • Confirmed ORR: 26.3%  in 95 patients with a high PD-L1 score, 4.1% in 73 patients with a low or negative PD-L1 score


  • Most common adverse reactions: Fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection
  • Infection and immune-related adverse events: Pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, diabetes



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ALUNBRIG (brigatinib) tablets

Ariad Pharmaceuticals, Inc. (Takeda), Cambridge, MA, USA

INDICATION:  Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib

REG PATHWAY: BLA. Accelerated Approval, Breakthrough Therapy Designation, Orphan Drug Designation, Priority Review

  • Accelerated approval based on tumor response rate and duration of response
  • Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial

MECHANISM OF ACTION:  Tyrosine kinase inhibitor with in vitro activity against multiple kinases,  inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins, dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice


  • Two-arm, open-label, multicenter trial, n=222, patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on crizotinib, had documented ALK rearrangement based on an FDA-approved test  or a different test with adequate archival tissue to confirm ALK arrangement by the Vysis® ALK Break-Apart fluorescence in situ hybridization Probe Kit test. BRIGATINIB 90 mg or 180 mg
  • Major efficacy outcome measure: Confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) evaluated by an Independent Review Committee (IRC); Additional measures included Investigator-assessed ORR, duration of response (DOR), intracranial ORR, and intracranial DOR
  • ORR: 48% (90 mg), 53% (180 mg) with DOR of 13.8 months in both arms
  •  Intracranial ORR: 42% (90 mg), 67% (180 mg), DOR of at least 4 mo.


  • Most common adverse reactions: Nausea, diarrhea, fatigue, cough, headache
  • Most common serious adverse reactions: Pneumonia and ILD/pneumonitis
  • Fatal adverse reactions: Pneumonia, sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis, urosepsis


Image Source: Google

Drug, Cosmetic or Both?


Product’s Intended Use determines regulation as Drug, Cosmetic, or Both 

  • Drugs:  Diagnosis, cure, mitigation, treatment, or prevention of disease and affect structure/function of body
  • Cosmetics: Rubbed, poured, sprinkled, sprayed on, introduced into, applied to human body for cleansing, beautifying, promoting attractiveness, or altering the appearance
  • Drug + Cosmetic:  Example – antidandruff shampoo
  • FDA does not recognize the term “cosmeceutical”


FDA News: AAMI Technical Information Report, Fraudulent Cancer Products

FDA BRIEF: Week of April 24, 2017

Logo of AAMI: Advancing Safety in Healthcare Technology

AAMI Technical Information Report on “Risk Management of Radio-frequency Wireless Coexistence for Medical Devices and Systems.”

FDA + Association for the Advancement of Medical Instrumentation (AAMI) report

  • Applies to medical devices and medical electrical equipmen) that incorporate Radio Frequency (RF) wireless technology
  • Used to perform or control a medical function or to communicate medical data
  • Directly support the medical device’s intended use
  • In alignment with FDA Guidance on RF wireless technology

Provides consensus process for risk management of coexistence of wireless medical devices and systems with other wireless products

  • Includes implanted cardiac pacemakers and cardioverter defibrillators, numerous physiological monitoring devices, implantable neurostimulators, drug and insulin infusion devices, diagnostic imaging systems, and a wide range of other medical devices


image of fake cancer cures

FDA Takes Action Against Fraudulent Cancer Products

14 companies peddling bogus cancer cures have received warning letters from FDA

  • Untested and potentially dangerous products,  selling on the internet
  • Fraudulent products attempt to subvert compliance and enforcement efforts by changing the names of their products, their companies, and/or their websites

Fraudulent claims, Red Flags

  • Treats all forms of cancer
  • Miraculously kills cancer cells and tumors
  • Shrinks malignant tumors
  • Selectively kills cancer cells
  • More effective than chemotherapy
  • Attacks cancer cells, leaving healthy cells intact
  • Cures cancer

FDA response

  • Compliance and enforcement actions against unscrupulous companies
  • Consumer education to decrease demand



FDA BRIEF: week of April 24, 2017

FDA approved

Image result for Brineura use

BRINEURA (cerliponase alfa) injection, for intraventricular use

BioMarin Pharmaceutical Inc., Novato, CA

INDICATION:  To slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency


  • CLN2 disease is rare (2-4/100,000 live births) inherited disorder primarily affecting nervous system affecting essential motor skills
  • Individuals require wheelchair use by late childhood and typically do not survive past teenage
  • First drug for the treatment of this form of Batten disease


  • Priority Review, Breakthrough Therapy designation, Orphan Drug Designation,Rare Pediatric Disease Priority Review Voucher
  • Post-marketing Requirements: Observational post approval safety study to evaluate the long-term safety,  sensitive cellular uptake assay  to evaluate neutralizing capacity of anti-drug antibodies,  immunogenicity study

MECHANISM OF ACTION:  Enzyme replacement therapy. Active ingredient, cerliponase alfa, is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease.


  • Non-randomized single-arm dose escalation clinical study with extension in symptomatic pediatric patients with CLN2 disease, confirmed by TPP1 deficiency, 96 weeks, n=24, BRINEURA vs. natural history cohort
  • Primary endpoint: Motor domain of a CLN2 Clinical Rating Scale to assess disease progression; Scores from 3 (grossly normal) to 0 (profoundly impaired)
  • Descriptive Comparison: 21 (95%) did not decline vs 42 (50%) in natural history cohort
  • Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype:  Lesser decrease in motor function in treated patients


  • Most common adverse reactions: Fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure
  • Not to be administered if signs of acute intraventricular access device-related complications
  • Routinely test patient CSF samples to detect device infections


sidebar imageROXYBOND (oxycodone hydrochloride) tablets

Inspirion Delivery Sciences, KS, USA

INDICATION: For the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate

  • Limitations of Use:  Because of the risks of addiction, abuse, and misuse with opioids, reserve for use in patients for whom alternative treatment options have not been tolerated, have not provided adequate analgesia


  • First immediate-release opioid analgesic approved with labeling describing its abuse-deterrent properties consistent with the FDA’s Guidance


  • Schedule II
  • Post-marketing Requirements: Toxicology studies, Abuse and related clinical outcomes,  Formal observational studies to assess whether use result in a meaningful decrease in misuse and abuse, consequences, addiction overdose, death

MECHANISM OF ACTION: Full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses

  • Has physicochemical properties expected to make abuse via injection difficult – forms viscous gel when in contact with liquid
  • Not expected to deter oral abuse


  • Evaluate ability of abuse-deterrent technology to reduce abuse potential
  • In vitro laboratory manipulation, extraction, and syringeability studies; In vivo intranasal clinical abuse potential study
  • Human Abuse Potential Study: Randomized, double-blind, double-dummy, placebo-controlled, single-dose four-way crossover study, n=29, non-dependent recreational opioid users with history of intranasal drug abuse
  • Endpoint: Abuse potential of crushed intranasal ROXYBOND tablets vs. crushed intranasal oxycodone immediate release tablets
  • Drug liking and willing to take drug again measured on visual analog scale (VAS)
  • Statistically significantly lower drug liking and take drug again (Emax) scores with ROXYBOND

SAFETY: Boxed Warning for Addiction, Abuse and misuse, life threatening respiratory depression, accidental ingestion, neonatal opioid withdrawal syndrome, Cytochrome P450 interactions, risks from concomitant use with benzodiazepines or other CNS depressants.


RYDAPT (midostaurin) capsules

Novartis Pharmaceuticals, East Hanover, NJ, USA

LEUKOSTRAT CDx FLT3 Mutation Assay

Invivoscribe Technologies Inc., San Diego, CA, USA


  • Acute Myeloid Leukemia: In combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by FDA approved test (LeukoStrat CDx FLT3 Mutation Assay)
  • Systemic Mastocytosis: Treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL)


  • 19,930 people diagnosed with AML in 2016; 10,430 were projected to die of disease
  • First targeted therapy to treat patients with AML, in combination with chemotherapy
  • Ability to detect gene mutation with diagnostic test helps identification of specific patients who may benefit from treatment


  • Priority Review, Fast Track (for the mastocytosis indication) and Breakthrough Therapy (for the AML indication) designations
  • Post-marketing Requirements: Worldwide Pregnancy Surveillance Program

MECHANISM OF ACTION: Inhibits multiple receptor tyrosine kinases, FLT3 receptor signaling and cell proliferation, induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Can inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.


  • Randomized, double-blind placebo-controlled trial, n=717 patients with newly-diagnosed FLT3-mutated AML; RYDAPT RYDAPT  in combination with daunorubicin /cytarabine
  • Primary Endpoint: Overall Survival (OS), date of randomization until death by any cause;  Hazard Ratio 0.77; 95% CI 0.63, 0.95; 2 sided p=0.016
  • Single-arm, open-label, multicenter trial, n=116 in patients with ASM, SM-AHN, and MCL, RYDAPT as single agent
  • Primary Endpoint: Confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles
  • Confirmed major or partial responses: 46 of 73 patients with KIT D816V mutation, 7 of 16 with wild-type or unknown status, 21 of 32 having prior therapy for SM


  • Common side effects:  Febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia and upper respiratory tract infection
  • Patients with pulmonary toxicity should stop treatment
Image result for stivarga

STIVARGA (regorafinib) tablets 

Bayer, Whippany, NJ, USA

SUPPLEMENTAL INDICATION: Treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

  • HCC originates in the liver and is the most common form of liver cancer
  • 40,710 people will be diagnosed; 28,920 will die
  • First FDA-approved treatment for a liver cancer in almost a decade

REG PATHWAY: Supplemental NDA

  • Priority Review, Orphan Drug Designation

MECHANISM OF ACTION:  Inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity


  • International, multicenter, randomized (2:1), doubleblind, n=760 patients with previously-treated metastatic colorectal cancer, STUVARAG vs placebo
  • Major efficacy outcome: Overall survival (OS); additional efficacy outcome measures included progression-free survival (PFS) and overall tumor response rate
  • Number of Deaths:  275 (55%) vs. 157 (62%), p=0.0102
  • Number of Deaths or Progressions: 417 (83%) vs. 231 (91%), p<0.0001
  • Common side effects: Pain, hand-foot skin reaction, fatigue, diarrhea, decreased appetite, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash and nausea
  • Serious risks: Hepatotoxicity, infections, hemorrhage, gastrointestinal perforation or fistula, dermatologic toxicity, hypertension, cardiac ischemia and infarction, reversible posterior leukoencephalopathy syndrome, wound healing complications


Photo Sources: Google, Novartis, Inspirion, Bayer