Updated Orange Book, Patent/Exclusivity FAQs

Orange Book 2.0  New Look, New Features

Orange Book

identifies drug products approved on the basis of safety and effectiveness by the FDA under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and related patent and exclusivity information.  LEARN

Patent Submission Date

date on which FDA receives patent information from NDA holder (21 C.F.R. 314.53(d)(ii)(5) LEARN

Orange Book Update

search results and drug listings now show patent submission dates where available;  may help generic drug manufacturers determine earliest date for marketing LEARN

Patent vs. Exclusivity

Patent– granted by US Patent and Trademark Office anytime during drug development;  encompass a wide range of claims.

Exclusivity– granted per FD&C Act. delays and prohibitions on approval of competitor drugs; for NDA and ANDA holders;  promote balance between new drug innovation and  generic drug competition LEARN

Image credit: FDA

FDA Marketing Authorizations: NUCLEUS COCHLEAR Telehealth, RxSIGHT Lens, MSK-IMPACT Tumor Profiling Assay, JULUCA, HEMLIBRA



NUCLUES COCHLEAR IMPLANT telemedicine platform

Cochlear Americas

INDICATION FOR USE: Remote feature for follow-up programming sessions for the Nucleus Cochlear Implant System through a telemedicine platform. The remote programming feature is indicated for patients who have had six months of experience with their cochlear implant sound processor and are comfortable with the programming process


  • 58,000 cochlear implants have been implanted in adults and 38,000 in children
  • Designed to produce useful hearing sensations for severe to profound hearing loss, by electrically stimulating nerves inside the inner ear
  • Often require regular programming visits with an audiologist
  • First telehealth option to program cochlear implants remotely


  • Product Code : MCM


  • Clinical study, n=39, aged 12 or older, with cochlear implant for at least one year
  • One in-person programming session and two remote programming sessions
  • Endpoint:  Speech perception tests showed no significant difference between in-person and remote programming
  • Endpoint: Patients’ self-assessment of hearing speech in presence of other sounds,  sense direction, distance and motion of sound
  • Endpoint: Cybersecurity measures for remote interaction


  • Telehealth as a service option in healthcare systems today- hospital networks, CMS




INDICATION FOR USE:   Reduction residual astigmatism to improve uncorrected visual acuity after removal of the cataractous natural lens by phacoemulsification and implantation of the intraocular lens in the capsular bag, in adult patients

  • With pre-existing corneal astigmatism of  ≥ 0.75 diopters
  • Without pre-existing macular disease

The system also reduces the likelihood of clinically significant residual spherical refractive errors


  • Refractive errors  common following cataract surgery; corrected with glasses, contact lenses or refractive surgery
  • First system to make small adjustments to artificial lens’ power after cataract surgery to improve visual acuity without glasses


  • Product Code: PZK


  • The RxSight Intraocular lens (IOL)  made of unique material that reacts to UV light delivered by Light Delivery Device, 17-21 days after surgery
  • Three or four light treatments over a period of 1-2 weeks


  • Randomized clinical study, n=600, Light Adjustable Lens vs. commercially available monofocal lens
  • Endpoint: Improvement of about one additional line down the vision chart, for distance vision without glasses vs. conventional IOL
  • Endpoint: Reduction in astigmatism in 75% patients

IMPACT tumor profiling test 

Memorial Sloan Kettering Cancer Center

INDICATION FOR USE: Qualitative in vitro diagnostic test that uses targeted next  generation sequencing of formalin-fixed paraffin-embedded tumor tissue matched with  normal specimens from patients with solid malignant neoplasms to detect tumor gene  alterations in a broad multi gene panel. The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product. MSK-IMPACT is a single-site assay performed at Memorial Sloan Kettering Cancer Center


  • NGS technologies can examine hundreds, if not millions, of DNA variants at a time
  • By identifying what genetic mutations are present in tumor, test results can provide useful insight for best treatment
  • Established Class II regulatory pathway for review of other NGS-based tumor profiling tests


  • Accreditation of the New York State Department of Health (NYSDOH) as an FDA third-party reviewer of in vitro diagnostics, including tests similar to IMPACT
  • NGS-based tumor profiling tests by NYSDOH do not need 510(k) clearance

GENERIC DEVICE TYPE:  Next generation sequencing (NGS) based tumor profiling test

  • Qualitative in vitro diagnostic test intended for NGS analysis of tissue specimens from malignant solid neoplasms to detect somatic mutations in a broad panel of targeted genes to aid in the management of previously diagnosed cancer patients by qualified health care professionals


  • High accuracy: > 99%  and capable of detecting a mutation at a frequency of approximately 5 %  (range of 2-5%)
  • Detection of certain molecular changes (microsatellite instability): concordant >92% across multiple cancer types in 175 cases vs. traditional detection methods



JULUCA (dolutegravir and rilpivirine) tablets

GlaxoSmithKline (ViiV)

INDICATION:  Treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions  associated with resistance to the individual components of JULUCA


  • Estimated 1.1 million people in US living with HIV
  • Limiting number of drugs in HIV treatment regimen can help reduce toxicity


MECHANISM OF ACTION:  Fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir and rilpivirine


  • 2 open-label, 148-week, randomized, multicenter, parallelgroup, non-inferiority trials, n=1,024 adult HIV–1-infected subjects; randomized 1:1 to continue current
    antiretroviral regimen or switched to JULUCA
  • Endpoint: HIV-1 RNA <50 copies/mL – Similar (95%)


  • Most common side effects: Diarrhea and headache
  • Serious side effects: Skin rash and allergic reactions, liver problems, depression or mood changes


Image result for hemlibra logoHEMLIBRA (emicizumab-kxwh) injection

Genentech, Inc.

INDICATION: Routine prophylaxis to prevent or reduce the frequency of bleeding
episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors


  • New option for reducing the frequency or preventing bleeding episodes
  • Important part of disease management for patients with hemophilia


  • Priority Review, Breakthrough Therapy designation, Orphan Drug designation

MECHANISM OF ACTION:  Bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis


  • An adult and adolescent trial  and a pediatric trial (HAVEN 2)
  • Randomized, multicenter, open-label, n= 109 adult and adolescent males with hemophilia, emicizumab-kxwh prophylaxis s. no prophylaxis
  • Endpoint: Annualized bleeding rate (ABR) 2.9 (95% CI; 1.7, 5.0) vs. 23.3 (95% CI: 12.3, 43.9), p<0.0001
  • Improvements in patient-reported hemophilia-related symptoms and physical functioning with prophylaxis
  • Single-arm, multicenter, open-label, n=23 pediatric males
  • ABR for treated bleeds was 0.2 (95% CI: 0.1, 0.6). ABR for all bleeds was 2.9 (95% CI: 1.8, 4.9)


  • Most common adverse reactions:  Injection site reactions, headache, and arthralgia
  • Cases of thrombotic microangiopathy and thrombotic events
  • Boxed warning: Thrombotic microangiopathy and thrombotic events


Image Credits:Cochlear Americas, RxSight, Memorial Sloan Kettering Cancer Center, GSK, Genentech




FDA News and Views: NGS and Tumor Profiling, Regenerative Therapy Guidances, FDA Hiring and Diversity, Office of Criminal Investigation, Generic Abuse-Deterrent Opioids

FDA BRIEF: Weeks of November 13 and 20, 2017

CaptureCDRH Approach to Tumor Profiling Next Generation Sequencing (NGS) Tests

Marketing authorization of two tumor profiling NGS tests

  • Thermo Fisher Scientific’s Oncomine Dx Target Test1 and MSK-IMPACT2
  • Real-world application of precision oncology

Three-Tiered approach for reporting biomarkers

  • Level 1: Companion Diagnostics
  • New Level 2: Cancer Mutations with Evidence of Clinical Significance
  • Level 3: Cancer Mutations with Potential Clinical Significance
  • A Fluid Approach to Reporting within Levels 2 and 3


Capture.JPGBig Day for Regenerative Therapy

Comprehensive policy framework for development and oversight of regenerative medicine products, including novel cellular therapies

  • Builds upon the FDA’s existing risk-based regulatory approach
  • Proposes efficient, science-based process to ensure safety and effectiveness
  • Risk-based framework for enforcement actions against significant safety concerns

Two final guidance documents and Two draft guidance documents


CaptureFDA Workforce and Diversity Plan

FDA challenged with building and retaining diverse, talented, dedicated workforce

  • Building stronger workforce by key process improvements in hiring and retention
  • Congress authorized new resources and authorities for talented workforce

FDA Hiring Initiative

  • Comprehensive evaluation of our hiring practices and procedures
  • Assess current challenges and provide roadmap for future
  • Initial Assessment of FDA Hiring and Retention report
  • Hiring pilot to modernize and streamline hiring practices; use new IT tools and eliminating unnecessary processes
  • Digital and social media tools for modern recruitment and outreach techniques

FDA Diversity and Inclusion Strategic Plan

  • Cultivate and promote diverse, inclusive culture
  • Promote continuous learning and discussion of diversity and inclusion topics
  • Recruit qualified candidates of different backgrounds, experiences, talents
  • Leverage every individual’s perspectives, passions, and background;  positive
    impact on innovation



Capture.JPGRemarks by Commissioner Gottlieb at FDA Office of Criminal Investigation Meeting

 Office of Criminal Investigations’s (OCI) nationwide presence

  • To advance FDA’s criminal law enforcement operations
  • To address criminal wrongdoing involving FDA-regulated products
  • Key to stopping dangerous counterfeit, unapproved, misbranded medical products into domestic supply chain

Comprehensive approach to President’s declaration of opioid crisis a public health emergency

  • Issuing guidance to encourage development of therapies to treat opioid addiction
  • Encouraging widespread use of existing, safe, effective FDA approved therapies to help combat addiction
  • Requirement for opioid manufacturers make training available to prescribers, potentially making them mandatory
  • Guidances to develop abuse deterrent opioids and non-addictive alternatives in the treatment of pain
  • Careful balancing of risks and benefits  when making approval decisions or market withdrawals

Dealing with bad actors that see addiction as an opportunity for profit

  • Using regulatory authorities and pursuing criminal charges
  • Will require manufacturers to  follow FDA market withdrawal notices e.g. Endo
  • Aggressive steps to identify and disrupt affirmative misconduct
  • Criminal enforcement actions in recent months e.g. Insys
  • Build cases against individuals who tamper with opioids at pharmacies, hospitals
  • Taking further action relating to a botanical substance known as kratom due to risks of abuse, addiction, and death
  • Increasing OCI’s Cybercrime Investigations Unit, Strategic Intelligence Unit, and Intelligence Analysis Branch



Steps to promote development of generic versions of opioids formulated to deter abuse

Opioids with abuse-deterrent formulations (ADFs) intended to make abuse, such as crushing, snorting, dissolving, more difficult or less rewarding

  • Approved 10 opioid drugs with these properties
  • But low uptake- learning curve, low awareness,prescribing uncertainty, price

FDA plans to permanently transition older formulations to ADFs

  • Improve access to the newer formulations through generic competitors
  • Final guidance on development of generic versions of approved ADF opioids
  • Developing appropriate, improved testing methodologies for evaluating abuse deterrence for both brand name  and generic opioid drug products
  • Flexible, adaptive approach to the evaluation and labeling of ADF opioids
  • Determining effectiveness of ADF products  in  real-world setting
  • Better understanding the attitudes and beliefs of health care professionals and those who are prescribed these products


Image credit: FDA

Influenza Virus Vaccine: 2017-2018 Season


Influenza Virus Vaccine: 2017-2018 Season

  • Trivalent vaccines contain the following:
    • an A/Michigan/45/2015 (H1N1) pdm09-like virus
    • an A/Hong Kong /4801/2014 (H3N2)-like virus
    • a B/Brisbane/60/2008-like virus (B/Victoria lineage).
  •  Quadrivalent vaccines contain additional B/Phuket/3073/2013-like virus (B/Yamagata lineage)
  • Flu vaccine lots that have been released and available for distribution by manufacturers


Image credit: FDA

FDA Device, Combination Product Authorizations: XW-100 ANALYZER, ABILIFY MYCITE, NSS-2 BRIDGE

Capture.JPGXW-100 Automated Hematology Analyzer

Sysmex America, Inc.

INTENDED USE:  For use in patients 2 years of age and older who require a whole blood cell count and white blood cell differential.

Test results can be used with other clinical and laboratory findings to provide early alerts of patients with serious conditions such as severe anemia (low red blood cell or hemoglobin count) and agranulocytosis (low white blood cell count), who require additional testing.

Not intended to diagnose or monitor patients with primary and/or secondary hematologic diseases, including oncology and critically ill patients.

REGULATORY PATHWAY: Dual Submission pathway – 510(k)) and CLIA Waiver

  • Original 510(k) clearance (2015) for use at patient’s point-of-care
  • CLIA Waiver: Simple operator instructions and number of hematology parameters reduced to 12
  • Dual clearance based on substantially equivalence to  2015 model + demonstration ease of use and low risk of false results when used by untrained operators
  • Regulation No. 864.5220
  • Product Code: GKZ


  • 15 µL venous blood to provide CBC with three-part differential
  • White Blood Cell Count (WBC), Red Blood Cell Count (RBC), Hemoglobin (HGB),  Hematocrit (HCT), Mean Corpuscular Volume (MCV), Platelet Count (PLT), Neutrophil Count (NEUT#), Lymphocyte Count (LYM#), Other White Blood Cell Count (Other WBC#), Neutrophil Percentage (NEUT%), Lymphocyte Percentage (LYM%), Other White Blood Cell Percentage (Other WBC%)


  • 582 samples collected from patients 2 to 92 years old.
  • Comparison of XW-100 test results: non-medical personnel in CLIA-waived settings  vs. hematology analyzer in accredited clinical laboratory
  • Accurate testing effectively conducted by untrained personnel following manufacturer’s instructions for use

Capture.JPGABILIFY MYCITE (aripiprazole with sensor) tablets

Otsuka Pharmaceuticals, Proteus Digital Health


Drug-device combination product comprised of aripiprazole tablets embedded with Ingestible Event Marker (IEM) sensor to track drug ingestion, is indicated for :
• Treatment of adults with schizophrenia
• Treatment of bipolar I disorder
• Adjunctive treatment of adults with Major Depressive Disorder

Limitations of Use:
• Ability to improve patient compliance not been established
• Use to track drug ingestion in “real-time” or emergency not recommended


  • Being able to track ingestion of medications prescribed for mental illness
  • New technology might benefit patients and prescribers


  • Abilify : NDA first approved in 2002 to treat schizophrenia
  • Ingestible sensor: De Novo order in 2012
  • Required Postmarketing Pediatric Studies:  Human factors usability studies in schizophrenia, bipolar I disorder, irritability associated with autistic disorder


  • Aripiprazole tablet embedded with IEM sensor
  • Patch (wearable sensor) that detects signal from IEM sensor after ingestion and
    transmits data to smartphone
  • APP – to display information for the patient
  • Web-based portal for healthcare professionals and caregivers


  • Safety and efficacy of aripiprazole tablets for the treatment of adults with schizophrenia, acute treatment of adults with manic and mixed episodes associated with Bipolar I disorder, and adjunctive treatment of adults with major depressive disorder  established based on prior adequate and well-controlled trials of aripiprazole tablets
  • Ensuring  compatibility with their specific smartphone and downloading APP; facilitated by the healthcare provider
  • Skin irritation with patch


  • Only select number of health plans and providers
  • Learnings for prescribers, health plans, and Otsuka for implementing broader access


Capture.JPGNSS-2 BRIDGE Neurostimulation System

Innovative Health Solutions, Inc.

INDICATION FOR USE: Percutaneous nerve field stimulator (PNFS) system, that can be used as an aid to reduce the symptoms of opioid withdrawal, through application to branches of Cranial Nerves V, VII, IX and X, and the occipital nerves identified by transillumination


  • Innovative new way to address epidemic of opioid addiction
  • Additional help  to live lives of sobriety with medically assisted treatment

REGULATORY PATHWAY: De Novo Request, to expand use

  • Regulation Number: 21 CFR 882.5896
  • Regulation Name: Percutaneous nerve stimulator for substance use disorders
  • Regulatory Class: Class II
  • Product Code: PZR
  • Prior (2014) clearance of EAD (electro auricular device)for use in acupuncture
GENERIC TYPE OF DEVICE: Percutaneous nerve stimulator for substance use disorders
  • Device that stimulates nerves percutaneously to aid in the reduction of withdrawal symptoms associated with substance use disorders


  • Small electrical nerve stimulator placed behind patient’s ear
  • Battery-powered chip emits electrical pulses to stimulate branches of certain cranial nerves
  • Stimulations may provide relief from opioid withdrawal symptoms


  • Single-arm clinical study, n=73, undergoing opioid physical withdrawal
  • Endpoint: Clinical opiate withdrawal scale (COWS) score
  • COWS reduction of at least 31 %  within 30 minutes of device use
  • Transitioned to medication assisted therapy: 88% after 5 days of device use


  • Adverse tissue reaction – Biocompatibility evaluation, Labeling
  • Electrical, mechanical, or thermal hazards leading to user discomfort or injury –
    Electromagnetic compatibility testing, Electrical, mechanical, and thermal safety testing, Non-clinical performance testing, Software verification, validation and hazard analysis, Labeling
  • Infection Sterility testing- Shelf life testing, Labeling

Image credit: Sysmex, Otsuka, Innovative Health Solutions


FDA approved

Capture.JPGZELBORAF (vemurafenib) Tablet

 Hoffmann-La Roche, Inc./Genentech, Inc.

INDICATION: Treatment of patients with Erdheim-Chester Disease (ECD) with BRAF
V600 mutation


  • ECD is slow-growing blood cancer that originates in the bone marrow; very limited life expectancies
  • Rare cancer with no approved therapies
  • Application of knowledge of underlying genetic characteristics of certain malignancies to other cancers


  • First approval in 2011 for wild-type BRAF melanoma
  • Priority Review, Breakthrough Therapy, Orphan Drug


  • Open-label, multicenter, single-arm, multiple cohort study, patients ≥ 16 years of age with non-melanoma BRAF V600 mutation–positive diseases, n=22
  • Endpoint: Best overall response rate maintained on two occasions at least four weeks apart, assessed by RECIST v 1.1
  • Responders: 54.5%, Complete Response in 1, Partial Response in 11, Median time to response of 11 months


  • Severe side effects: Development of new cancers,  growth of tumors in patients with BRAF wild-type melanoma, hypersensitivity reactions, severe skin reactions, heart abnormalities (QT prolongation), liver damage, photosensitivity, severe reactions in the eye, immune reactions,  kidney failure, thickening of tissue in hands and feet, harm to fetus
  • Common side effects: Arthralgia, maculo-papular rash, alopecia; fatigue; change in the heart’s electrical activity (prolonged QT interval) and papilloma


  • ICD-10-CM: E88.89
  • NDC: 10-digit and 11-digit
  • Codes not all-inclusive; appropriate codes can vary by patient, setting of care and payer


Capture.JPG ALECENSA (alectinib)


 Hoffmann-La Roche, Inc./Genentech, Inc.

INDICATION:  Treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test

REGULATORY PATHWAY: sNDA, Fulfillment of postmarketing requirement

  • Breakthrough therapy designation
  • Accelerated approval in 2015, for second line treatment of ALK-positive metastatic NSCLC


  • Open-label, randomized, active-controlled, multicenter study, patients with  ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay, ALECENSA vs. crizotinib, n=303
  • Major efficacy outcome: Progression-free survival (PFS) determined RECIST v1.1
  • Other: Time to CNS progression, objective response rate (ORR) , duration of response (DOR), overall survival (OS)
  • Improvement in PFS: Hazard ratio  0.53 (95% CI: 0.38, 0.73; p<0.0001)
  • Estimated median PFS: 25.7 months vs. 10.4 months
  • Time to cause-specific CNS also significantly improved
  • Confirmed ORR : 79% vs. 72%


  • Most common adverse reactions: Fatigue, constipation, edema, myalgia, and anemia


  • Diagnosis: ICD-10-CM: C34.00—C34.02, C34.10—C34.12, C34.2, C34.30—C34.32, C34.80—C34.82, C34.90—C34.92
  • Codes are not all-inclusive; appropriate codes can vary by patient, setting of care and payer


Capture.JPGPREVYMIS (letermovir) tablets and injection


INDICATION:   Prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT)


  • >27,000 allogeneic HSCTs/year worldwide (8,500 transplants in US); 65-80%  recipients previously exposed to CMV and at high risk for CMV infection
  • First drug indicated to help prevent CMV infection and disease in adults who have been exposed to CMV and have received HSCT


  • Breakthrough Therapy and Orphan Drug designation

MECHANISM OF ACTION: Antiviral drug against CMV


  • Multicenter, double-blind, placebo-controlled, adult CMV-seropositive recipients
    [R+] of an allogeneic HSCT, PREVYMIS vs. placebo, n= 565
  • Primary efficacy endpoint: Incidence of clinically significant CMV infection through
    Week 24 post-transplant (prophylaxis failure)
  • Proportion of subjects who failed prophylaxis: 38% vs. 61%


  • Contraindicated with pimozide and ergot alkaloids and in patients receiving pitavastatin or simvastatin when co-administered with cyclosporine.
  • Most common side effects: Nausea, diarrhea, vomiting, swelling in the arms and legs, cough, headache, tiredness and stomach (abdominal) pain


CaptureADCETRIS (brentuximab vedotin)

Seattle Genetics

INDICATION: Treatment of primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therap


  • Breakthrough Therapy Designation, Orphan Designation, and Priority Review
  • Initial approval in 2011


  • Randomized, open-label, multicenter clinical trial, patients with MF or pcALCL withe prior therapy, n=131, ADCETRIS vs physician’s choice of methotrexate or bexarotene
  • Endpoint: Improvement in objective response rate lasting 4 months (ORR4), complete response (CR) rate, and progression-free survival (PFS)
  • ORR4: 56% vs 12% (p<0.001)
  • CR: 16% vs 2% (p=0.007)
  • PFS: Estimated hazard ratio of 0.27, p<0.001, median PFS of 17 mo.


  • Boxed Warning:  Progressive multifocal leukoencephalopathy (PML)
  • Most common adverse reactions: Anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue, and neutropenia

 CaptureMEPSEVII (vestronidase alfa-vjbk) injection

Ultragenyx Pharmaceutical, Inc.

INDICATION: Treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome


  • MPS VII is an extremely rare, progressive condition that affects most tissues and organs; impacts less than 150 patients worldwide
  • First drug to be apprived for MPS VII


  • Fast Track designation, Orphan Drug designation, Rare Pediatric Disease Priority Review Voucher
  • 12th rare pediatric disease priority review voucher issued by the FDA
  • Postmarketing REquirement: Long term risk of immunogenicity, pre- and post-natal development study, measurement of PD marker


  • Clinical trial and expanded access protocols, n=23 , 5 months to 25 years of age
  • Dosin every two weeks for up to 164 weeks
  • Efficacy endpoint : Six-minute walk test in ten patients
  •  Mean difference in distance walked relative to placebo: 18 meters, continued improvement and stabilization
  • Marked improvement in pulmonary function in 2 patients
  • Most common side effects: Infusion site reactions, diarrhea, rash and anaphylaxis

 Image Credit: Hoffmann La-Roche, Merck, Seattle Genetics, Ultragenyx


FDA Guidances: 510(k) for Device/Software Changes, DDI Studies, Breakthrough Devices Program, De Novo Process and Review, Sharing Patient-Specific Information

fda guidances


Deciding When to Submit a 510(k) for a Change to an Existing Device

510(k)s for changes to a legally marketed device should consider Quality System (QS) regulation

  • For some types of changes submission of new 510(k) not required
  • Reliance on existing QS requirements is the least burdensome approach

Guiding Principles

  • Changes made with intent to significantly affect safety or effectiveness
  • Initial risk-based assessment
  • Unintended consequences of changes
  • Use of risk management
  • Role of testing in evaluating effect on safety and effectiveness
  • Evaluating simultaneous changes
  • Appropriate comparative device and cumulative effect of changes
  • Documentation requirement
  • 510(k) submissions for modified devices
  • Substantial equivalence determinations


  • Labeling Changes
  • Technology, Engineering, and Performance Changes
  • Materials Changes
  • Technology, Engineering, Performance, and Materials Changes for In Vitro Diagnostic Devices
  • Considerations for Risk-Based Assessments of Modified Devices



Deciding When to Submit a 510(k) for a Software Change to an Existing Device

When software (including firmware) change to medical device may require 510(k)

  • Enhance predictability, consistency, transparency of the “when to submit”
  • Provide a least burdensome approach, regulatory framework, policies, practices

Guiding Principles

  • Changes made with intent to significantly affect safety or effectiveness
  • Initial risk-based assessment
  • Unintended consequences of changes
  • Use of risk management
  • Role of testing in evaluating effect on safety and effectiveness
  • Evaluating simultaneous changes
  • Appropriate comparative device and cumulative effect of changes
  • Documentation requirement
  • 510(k) submissions for modified devices
  • Substantial equivalence determinations

Additional guidance

  • Use flowchart in concert with the Guiding Principles
  • With multiple changes, use all applicable parts of flowchart and companion text, including the Guiding Principles



Clinical Drug Interaction Studies — Study Design, Data Analysis, and Clinical Implications

Conduct of clinical studies to evaluate Drug-Drug Interaction (DDI) potential

  • Timing and design of clinical studies
  • Interpretation of study results
  • Options for managing DDIs in patients

Goals of studies to determine

  • Whether investigational drug alters pharmacokinetics of other drugs
  • Whether other drugs alter pharmacokinetics of investigational drug
  • Magnitude of changes in pharmacokinetic parameters
  • Clinical significance of observed or expected DDIs
  • Appropriate management strategies for clinically significant DDIs


  • Timing, Types, Design and conduct of DDI sudies
  • Stand-Alone and Nested Prospective DDI Studies
  • CYP-Mediated Interactions
  • Transporter-Mediated Interactions
  • Reporting and Interpretations
  • Labeling recommendations


Capture.JPGBreakthrough Devices Program

Breakthrough Devices Program for certain medical devices for life-threatening or irreversibly debilitating diseases or conditions


  • Expedites development, assessment, FDA review, while preserving statutory standards
  • Supersedes the Expedited Access Pathway (EAP)


  • Program Principles
  • Program Features
  • Designation Request
  • Designation Review Process
  • Designation Withdrawal



Manufacturers Sharing Patient-Specific Information from Medical Devices with Patients Upon Request

Patients play an active role in their own healthcare

  • May request personal information that has been recorded, stored, processed, retrieved, and/or derived from marketed medical device
  •  Sharing “patient-specific information”  upon request may assist in being more engaged with healthcare providers in making sound medical decisions

Categories of patient-specific information for sharing

  • Data healthcare provider inputs in device to record status and ongoing treatment
  • Information stored by device to record usage, alarms, or outputs (e.g., pulse oximetry data, heart electrical activity)
  • Case logs entered into device by healthcare provider



De Novo Classification Process (Evaluation of Automatic Class III Designation)

To provide guidance on the process for the submission and review of a De Novo classification request

  • for cases where there is no predicate device or has received an NSE determination on a 510(k) submission
  • specific device and device type is classified in class I or class II
  • publish a notice in the Federal Register announcing classification and controls necessary to provide reasonable assurance of safety and effectiveness



Acceptance Review for De Novo Classification Requests

To explain FDA procedures and criteria for acceptability for substantive review of De Novo classification request  

  • Making “Accept” or “Refuse to Accept” (RTA) decisions

De Novo Acceptance Review Policies and Procedures

  • Acceptance Review Policies and Procedures
  • FDA Review Clock
  • Notification of Acceptance Review Result
  • Refuse to Accept Principles

Checklist Acceptance Review

  • Organizational Elements
  • Elements of a Complete De Novo Request (RTA Items)
  • Applying the Checklist of RTA Items
  • Elements Marked as “Not Applicable” (N/A)
  • Adequacy of Information
  • Elements Marked “No”

Recommended Content Checklist

  • Purpose
  • Prior Submission(s) Relevant to the De Novo Request Under Review


  • Acceptance Checklist for De Novo Classification Requests
  • Recommended Content Checklist for De Novo Classification Requests



FDA News and Views: Pediatric Clinical Trials, Genetic Health Risk Testing, Shared REMS, Type 2 Diabetes CE Course

FDA BRIEF: Week of November 6, 2017


FDA Awards Funding to Support Pediatric Clinical Trials Research

Some 60%-90%  drugs used in children and neonates not approved for pediatric use

  • Failure in clinical trials
  • Could not complete study recruitment
  • FDA to facilitate the plan, start up, conduct, close out of clinical investigations

FDA award to Institute for Advanced Clinical Trials for Children (IACT for Children) and Duke University

  • $1 million to each awardee for this year under Global Pediatric Clinical Trials Network Cooperative Agreement
  • Leverage basic science research to support extrapolation from adult data
  • Understand maturation of metabolic pathways for modeling and simulation to optimize dosing strategies
  • Develop innovative trial designs to optimize data from multiple sources
  • Leverage and standardize all sources of information
  • Develop multiple types of biomarkers
  • Develop clinically meaningful short- and long-term efficacy and safety endpoints


FDA statement on implementation of agency’s streamlined development and review pathway for consumer tests that evaluate genetic health risksCapture.JPG

Genetic health risk (GHR) testing helps understanding of  individual risk for developing diseases

  • Make more informed lifestyle choices
  • Direct-to-consumer (DTC) access to GHR tests available
  • Opportunities for  detection of additional genetic conditions and diseases

GHR Testing has its own risks

  • Incorrect or misleading information leading to health choices without medical advice
  • Adaptive regulatory framework for unique  challenges of new technology
  • Balance efficient pathway to customer access without sacrificing FDA oversight

Flexible approach for regulating novel medical advances such as GHR

  • Lessons learned from authorization of  first DTC GHR and carrier screening tests (23andMe)
  • GHR tests to be exempted from premarket review under certain conditions
  • Manufacturers would have to come to FDA for a one-time review; no furtjer review of new tests
  • Established special controls  in a separate de novo classification order

READ23andMe label

Capture.JPGFDA statement on new steps to improve FDA review of shared Risk Evaluation and Mitigation Strategies to improve generic drug access

Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of the drug outweigh the risks

  • Medication Guide or patient package insert
  • Communication plan
  • “Elements to Ensure Safe Use” (ETASU) e.g. prescriber training, patient counseling

Use of shared REMS to prevent use as a tool to block generic competition

  • Encourage use of shared system between innovator and generic companies
  • Reduce  likelihood for branded drug companies to use existing REMS to slow generic competition
  • Streamline submission and review process for shared system REMS
  • Use of a single Drug Master File (DMF) for shared system REMS submissions


Leveraging Health Literacy and Patient Preferences to Reduce Hypoglycemia Events in Patients with Type 2 Diabetes

CDERLearn: Health Literacy and Patient Preferences to Reduce Hypoglycemia Events in Patients with Type 2 Diabetes

  • Free one-hour Continuing Education (CE) course for healthcare providers (physicians, pharmacists, nurses, and others)
  • Describe the prevalence of hypoglycemic events among patients with type 2 diabetes mellitus and risk factors leading to an event
  • Introduce methods of assessing health literacy and numeracy of patients and caregivers
  • Review effective ways to incorporate patient preferences into care plans and differentiate A1C target values for individuals
  • List the action steps to reduce the likelihood of a hypoglycemic event for a high-risk patient


Image credit: FDA, 23andMe, IACT



  • A searchable catalogue of nearly 500 profiles on research consortia. Learn more about their work – including mission, structure, data sharing, partners, and more – and connect with them
  • framework report that presents a series of questions for those seeking to create new collaborative efforts, expand existing ones, or re-orient early-stage programs
  • 2013 landscape analysis in Science Translational Medicine analyzing characteristics of 369 consortia around the world
  • Highlighted by CDER-FDA  as a comprehensive public resource for researchers seeking partners with similar interests and objectives







FDA BRIEF: Week of October 23 and October 30, 2017


Image of the device.

HEARTMATE 3™ Left Ventricular Assist System (LVAS)

Thoratec Corporation

INDICATION: Providing short-term hemodynamic support (e.g., bridge to transplant or bridge to myocardial recovery) in patients with advanced refractory left ventricular heart failure



  • HeartMate 3 left ventricular assist device (LVAD) and and external components
  • LVAD composed of implanted centrifugal blood pump, outflow graft with bend relief, apical cuff, and pump cable
  • LVAD connected via percutaneous cable (driveline) to microprocessor-based external System Controller
  • System Controller powered by either the Power Module (for hospital use) or the Mobile Power Unit that connects to the AC mains power, or by two batteries that the patient carries
  • System Controller performs all power handling and monitoring functions, including
    supplying power to the LVAD; communicating with the LVAD; storing system operating parameters; logging performance data; generating diagnostic information; producing visual and audible alarms; providing uninterrupted power to the LVAD during main power exchange; and displaying alarm messages, alarm history, and key operating parameters


  • Prospective, multicenter, randomized pivotal study comparing the HeartMate 3 LVAS with the HeartMate II LVAS; 1:1 randomization to either HeartMate 3 or HeartMate II.
  • At 6 months post implantation, 86% of patients in the HeartMate 3 arm achieved success in the composite primary endpoint as compared to 77% of patients in the HeartMate II arm demonstrating non-inferiority
  • Clinically significantly higher number of pump exchanges and urgent transplants in the HeartMate II arm (7.8%) as compared to the HeartMate 3 arm (0.7%)
  • Overall survival rate at 6-months post implantation was comparable between the HeartMate 3 (89%) and HeartMate II arms (87%)
  • Death (HeartMate 3: 11.3% vs. HeartMate II: 13.0%)
  • Major infection (37% vs. 30%)
  • Bleeding (30% vs. 37%)
  • Right heart failure (30% vs. 25%)
  • Cardiac arrhythmias (26% vs. 33%)
  • Respiratory failure (22% vs. 17%)
  • Renal dysfunction (11% vs. 9%)
  • Stroke (8% vs. 11%)
  • No suspected pump thrombosis events in the HeartMate 3 arm



Capture.JPGCALQUENCE (acalabrutinib) capsule

AstraZeneca Pharmaceuticals 

INDICATION: Treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy


  • MCL is a rare and fast-growing type of non-Hodgkin lymphoma; particularly aggressive cancer
  • New treatment option showing high rates of response for some patients


  • Priority Review, Breakthrough Therapy designation, Orphan Drug designation
  • Accelerated approval based on overall response rate; continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

MECHANISM OF ACTION:   Inhibitor of Bruton tyrosine kinase (BTK) leading to malignant B-cell proliferation and survival


  • Open-label, Phase 2 Study, n=124 patients with MCL who had received at least one prior therapy
  • Tumor responses assessed according to Lugano Classification for Non-Hodgkin’s lymphoma
  • Major efficacy outcome: Overall response rate (ORR) and the median follow-up was 15.2 months
  • 81% had complete or partial response (40 percent complete response, 41 percent partial response)


  • Serious side effects: Hemorrhage), infections, atrial fibrillation, additional cancers
  • Common side effects: Headache, diarrhea, bruising, fatigue, myalgia, anemia, thrombocytopenia, neutropenia


  • Limited distribution network via oncology pharmacy services
  • CALQUENCE Patient Savings Program to assist with out of pocket costs


(Photo: Business Wire)SOLIRIS (eculizumab) intravenous infusion


SUPPLEMENTAL INDICATION:  Treatment of adult patients with generalized Myasthenia Gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody positive


  • First new treatment in many years for MG; rare and chronic neuromuscular disorder
  • First monoclonal antibody approved for use in patients with MG


  • Risk Evaluation and Mitigation Strategy (REMS) requirements for serious and life-threatening meningococcal infections


  • 26-week randomized, double-blind, parallel-group, placebo controlled,
    multicenter trial, n=125, SOLIRIS vs. placebo
  • Primary efficacy endpoint: The primary efficacy endpoint change from baseline  in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at Week 26
  • MG-ADL total scores:  -4.2 points in SOLIRIS vs.  -2.3 points in placebo (p=0.006)


  • Life-threatening and fatal meningococcal infections
  • Increased susceptibility to infections, especially with encapsulated bacteria
  • Frequently reported adverse events: Musculoskeletal pain


  • No public information for new indication


Image credit: Thoratec, Astra Zeneca, Alexion















































































































































































































FDA Approves New Indication for Soliris (Eculizumab) As Treatment for Myasthenia Gravis 
On October 23, 2017, FDA approved a new indication for Soliris (eculizumab),  Myasthenia Gravis who are anti-acetylcholine receptor antibody-positive. Soliris can lower the ability of the immune system to fight infections and therefore increases the chance of getting serious and life-threatening meningococcal infections. For more information, please read the medication guide, the Full Prescribing Label, or theapproval letter sent to the manufacturer.







PD-L1 IHC 22C3 pharmDx – P150013/S006

Image of PD-L1 IHC 22C3 pharmDx









Philips IntelliSite Pathology Solution (PIPS) DEN160056 Classification Order Decision Summary
MiSeqDx Universal Kit 1.0 DEN130042 Classification Order Decision Summary

2017 FDA Science Forum


2017 FDA Science Forum

  • Presentation of unique scientific research and collaborative efforts of 11,000 FDA scientists
  • Investigation and application of new science and emerging technologies to inform FDA’s regulatory decision-making and foster safe innovation
  • Concentrating on creating test methods and developing process knowledge to ensure safety and efficacy of products
  • FDA science is critical to product quality and safety


Image credit: FDA

FDA CDER Presentations Library


FDA CDER Presentations Library

  • CDER professionals participate in several meetings, conferences and workshops throughout the year
  • Topics can range from users fees, to drug advertising and marketing, to genomics, to over-the-counter products
  • Materials and overviews from some of those meetings are listed in the presentations library


Image credit: FDA

FDA News and Views: Opioid Packaging, Device Cybersecurity, Global Manufacturing Inspections, Marijuana Warnings, Health Literacy

FDA BRIEF: Week of October 30, 2017


Statement from FDA Commissioner Scott Gottlieb, M.D., on new strategies for addressing the crisis of opioid addiction through innovation in packaging, storage and disposal

Steps to reduce the scope and human tragedy of opioid addiction epidemic

  • New ways to work more creatively with public and private partners
  • Reduce exposure to opioid drugs
  • Proposer prescriptions and duration of treatment

Packaging innovations

  • Packaged in a manner that limits the number of pills dispensed
  • Easier to track the number of doses that have been taken
  • Improve storage and encourage prompt disposal
  • Allow health care providers, pharmacists or family members to monitor patient use of prescription opioids

public workshop, Dec. 11-12, 2017, to advance this issue


Thumbnail image of fact sheet.FDA’s Role in Medical Device Cybersecurity

Breach potentially impacting safety and effectiveness of a medical device can threaten patient health

  • CDRH coordinated approach of vigilance, responsiveness, resilience, and recovery
  • Total product lifecycle approach- starting at the product design phase to planning how to reduce the likelihood of future risks
  • Encouraging medical device manufacturers to proactively update and patch devices in a safe and timely manner
  • Need to balance protecting patient safety and promoting the development of innovative technologies and improved device performance
  • Published guidances for manufacturers
  • Planning  to address cybersecurity risks is as essential to the device development process as coming up with a novel new product

prevalent myths concerning FDA


Capture.JPGFDA takes unprecedented step toward more efficient global pharmaceutical manufacturing inspections 

FDA will recognize eight EU drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements

  • Austria, Croatia, France, Italy, Malta, Spain, Sweden, UK
  • Implementation of US-EU Mutual Recognition Agreement
  • Will now rely on the inspectional data obtained by these eight regulatory agencies

EU Commission determined (6/17) that the FDA “has the capability, capacity and procedures in place to carry out GMP inspections at a level equivalent to the EU.”

  • Enables the FDA and the EU to avoid duplication of drug inspections
  • Allows regulators to devote resources to other high risk manufacturing facilities



FDA warns companies marketing unproven products, derived from marijuana, that claim to treat or cure cancer

Increasing concern with cannabidiol (CBD) products claiming to treat or cure cancer

  • Marketed in a variety of product types e.g. oil drops, capsules, syrups, teas
  • Not approved for any indication
  • Substances containing marijuana components treated like any other products making unproven claims to shrink cancer tumor

Warning letters to four companies for unsubstantiated claims

  • Greenroads Health
  • Natural Alchemist
  • That’s Natural! Marketing and Consulting
  • Stanley Brothers Social Enterprises LLC


Health Literacy: Getting the Info You Need

Health literacy is the ability to get and understand information on health issues and medical services so that patients you can make informed decisions 

  • ~ 12%  US adults have skills to manage health and prevent disease
  • Difficult to improve their health

FDA Promotes Health Literacy

  • Plain language for clear communications
  • Patient package inserts,  instructions for use, and Medication Guides
  •  Drug Safety Communications
  •  Recalls and Withdrawals
  • Free online resources
  • FDA Patient Network
  •  FDA Consumer Updates


Image credits: FDA, EMA