ZEPATIER Clinical Pharmacology Card

ZEPATIER™ (elbasvir and grazoprevir) tablets

Mechanism of Action A fixed-dose combination of elbasvir and grazoprevir which are direct-acting antiviral agents against the hepatitis C virus
Pharmacodynamics (PD) At therapeutic concentration, both elbasvir and grazoprevir do not prolong QTc to any clinically relevant extent
Pharmacokinetics (PK) Elbasvir pharmacokinetics were similar in both healthy and HCV-infected subjects and were approximately dose-proportional over the range of 5-100 mg once daily. Grazoprevir oral exposures are approximately 2-fold greater in HCV-infected subjects as compared to healthy subjects. Grazoprevir pharmacokinetics increased in a greater than dose-proportional manner over the range of 10-800 mg once daily in HCV-infected subjects.

Elbasvir median Tmax is at 3 hours (range of 3 to 6 hours); grazoprevir median Tmax is at 2 hours (range of 30 minutes to 3 hours) in HCV-infected subjects. Steady-state Cmax for elbasvir and grazoprevir are 121 ng/mL and 165 ng/mL, respectively. Corresponding values for AUC24 are 1920 ng.hr/mL and 1420 ng.hr/mL, respectively.

Elbasvir AUC0-inf and Cmax decreases by approximately 11% and 15%, respectively with high fat food in healthy subjects, whereas AUC0-inf and Cmax of grazoprevir increases by approximately 1.5-fold and 2.8-fold, respectively. These differences in elbasvir and grazoprevir exposure are not clinically relevant; therefore, ZEPATIER may be taken without regard to food.

Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively.

The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.

The primary route of elimination of elbasvir and grazoprevir is through feces with almost all (greater than 90%) of radiolabeled dose recovered in feces compared to less than 1% in urine. Elbasvir and grazoprevir are partially eliminated by oxidative metabolism, primarily by CYP3A. No circulating metabolites of either elbasvir or grazoprevir were detected in human plasma

PK-PD Analysis Not reported
Population PK Elbasvir and grazoprevir AUCs are estimated to be 16% and 45% higher, respectively, in subjects at least 65 years of age

Elbasvir and grazoprevir AUCs are estimated to be 50% and 30% higher, respectively, in females compared to males

Elbasvir and grazoprevir AUCs are estimated to be 15% and 50% higher, respectively, for Asians compared to Caucasians. Population pharmacokinetics estimates of exposure of elbasvir and grazoprevir were comparable between Caucasians and Black/African Americans

Special Populations Exposure differences of elbasvir and grazoprevir in HCV-infected subjects with renal impairment with or without hemodialysis are not clinically relevant.

Relative to non-HCV-infected subjects with normal hepatic function, no clinically relevant differences in elbasvir AUC values were observed in non-HCV-infected subjects with mild, moderate, or severe hepatic impairment. Elbasvir steady-state AUC was similar in HCV-infected subjects with compensated cirrhosis compared to HCV-infected, non-cirrhotic subjects.

Relative to non-HCV-infected subjects with normal hepatic function, grazoprevir AUC values were higher by 1.7-fold, 5-fold, and 12-fold in non-HCV-infected subjects with mild, moderate, and severe hepatic impairment, respectively. Grazoprevir steady-state AUC values were higher by 1.65-fold in HCV-infected subjects with compensated cirrhosis compared to HCVinfected, non-cirrhotic subjects.

Drug Interactions See drug interaction studies in Section 12.3 of the link below


Source : https://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf


HALAVEN Clinical Pharmacology Card

HALAVEN™ (eribulin mesylate) Injection

Mechanism of Action Exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.
Pharmacodynamics (PD) Effect of HALAVEN on the QTc interval was assessed in patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.
Pharmacokinetics (PK) Linear PK with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2

 Eribulin eliminates primarily in feces as unchanged drug

 Human plasma protein binding ranged from 49% to 65%

 No accumulation observed with weekly administration

PK-PD Analysis Not evaluated
Population PK Gender, race, and age do not have a clinically meaningful effect on the PK of eribulin
Special Populations Lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment
Drug Interactions No drug-drug interactions are expected with CYP system or P-gp

Source : http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/201532lbl.pdf

Opioid Warnings: Label Restrictions, Abuse Deterrence Guidance

FDA Brief: Week of Mar 21, 2016




Enhanced warnings for immediate-release (IR) opioid pain medications related to risks of misuse, abuse, addiction, overdose and death


  • Continuing effort to educate prescribers and patients about the potential risks related to opioid use
  • Class-wide safety labeling changes for IR opioid pain medication
    • New boxed warning : serious risks of misuse, abuse, addiction, overdose, death
    • Safety risk additional information


Draft Guidance on Abuse Deterrence Evaluation of Generic Oral Opioids


  • For approval with ‘abuse deterrence’ in labeling
  • Assessment of
    • Routes of abuse
    • Comparative in vitro studies and others(multiple strengths, PK)
    • Data analysis
    • Additional studies – Mechanical manipulation, Abuse by injection, ingestion, insufflation, smoking



FDA Voice: Human Factors and Combination Products

FDA Brief: Week of Mar 21, 2016


FDA Voice


Addressing Issues Relating to Combination Products: Human Factors (HF)


Jill Hartzler Warner, J.D., Associate Commissioner for Special Medical Programs

Thinh Nguyen, Director, Office of Combination Products

  • Combination products combine a drug, device, and/or biological product

May be physically or chemically combined; co-packaged; or separately distributed with specific labeling for combined use

  • If medical device constituent – HF engineering important for safe and effective use

Study how people interact with technology, how design of user interfaces affects  quality, experience, and outcomes of interaction

  • Feb 2016, draft guidance on HF studies (posted in BLOG )
    • timing and sequencing
    • new studies to qualify product changes
    • simulated vs actual use
    • FDA requirements
  • FDA seeking comments on draft








FDA Brief: Week of Mar 21, 2016

FDA approved


ANTHIM (obiltoxaximab) injection

Elusys Therapeutics, New Jersey, USA

Indication: In adult and pediatric patients

  •  For  treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs
  • For prophylaxis of inhalational anthrax due to B. anthracis when alternative therapies are not available or not appropriate [see Indications and Usage

Unmet Need:

  • Rare disease caused by breathing spores of bacterium Bacillus anthracis
  • Bacterial toxins produce massive and irreversible tissue injury and death
  • Potential bioterrorism threat

Reg Strategy: BLA, approved under the FDA’s Animal Rule, Developed in in conjunction with the U.S. DHHS Biomedical Advanced Research and Development Authority (BARDA)

Mechanism of Action: Monoclonal antibody that neutralizes toxins produced by B. anthracis.

Efficacy:   Rabbits (2 studies) and cynomolgus macaque (2 studies) as it is not feasible or ethical  for human studies; with systemic anthrax; placebo controlled

  • Survival : Significant improvement (p<0.01-0.001)  in survival relative to placebo
  • Survial (in combination with antibiotics) : Further improvement
  • Survival (prophylaxis treatment): 100%

Safety: 320 healthy human volunteers.

  • Boxed Warning: Hypersensitivity, Anaphylaxis
  • Most frequently reported side effects: Headache, itching (pruritus), upper respiratory tract infections, cough, nasal congestion, hives, and bruising, swelling and pain at the infusion site.


TALTZ (ixekizumab) injection

Eli Lilly, Indiana, USA

Indication:  Treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Unmet Need:

  • Autoimmune disorder, with a family history, between ages of 15 and 35
  • Thick, red skin with flaky, silver-white scales
  • Need for treatment option to  relieve the skin irritation and discomfort

Reg. Strategy: BLA, Standard review

Mechanism of Action: Humanized immunoglobulin G subclass 4 monoclonal antibody (mAb) Antibody binds to protein (interleukin -17A) that causes inflammation.

Efficacy:  3 multicenter, randomized, double-blind, placebo-controlled trials, n= 3866, 12 weeks. In 2 trials, subjects also randomized to etanercept for 12 weeks.

  • Greater clinical response than placebo in the 2 co-primary endpoints
  • Psoriasis Area and Severity Index (PASI) 75% reduction:
  • Static Physician Global Assessment (sPGA) 2-pt improvement


  • Medication Guide on greater risk of an infection
  • Serious allergic reactions and inflammatory bowel disease
  • Most common side effects: Upper respiratory infections, injection site reactions and fungal (tinea) infections.


CINQAIR (reslizumab) infusion

Teva, Pennsylvania, USA

Indication:  Add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype

Unmet Need:

  • > 22 million in U.S. have asthma, > 400,000 asthma-related hospitalizations/yr
  • Need for another treatment option


Reg Strategy: BLA, Standard review

Mechanism of Action: Humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology in murine myeloma cells. Reduces blood eosinophils that contribute to asthma.

Efficacy: 4 randomized, double-blind, placebo-controlled studies (n=981), 52 weeks, 12 years of age and older

  • Frequency of asthma exacerbations:  Significant reduction
  • Time to first attack: Significantly longer
  • Improvement in Lung Function (FEV1): Improved




  • Can cause serious side effects including allergic (hypersensitivity) reactions
  • Most common side effects: Anaphylaxis, cancer, muscle pain



 Xalkori (crizotinib) capsules

Pfizer, New York, USA

Indication:  Treatment of patients with metastatic non small-cell lung cancer (NSCLC) whose tumors are ROS1-positive (previously approved for NSCLC with anaplastic lymphoma kinase (ALK)-positive tumors)

Unmet need:

  •  221,200 new diagnoses and 158,040 deaths in US in 2015
  • Difficult to treat, different mutations, some of which are rare
  • Need for treatment option for rare and difficult to treat ROS-1 gene mutation

Reg. Strategy:  SNDA, Breakthrough Therapy designation, Priority Review, Orphan Drug designation

Efficacy: Single, multicenter, single-arm study (n=50), histologically-confirmed advanced NSCLC with a ROS1 rearrangement

  • Objective Response Rate: 66%
  • Duration of Response: 18.3 mo.


  • Serious side effects: Liver problems, life-threatening or fatal lung inflammation, abnormal heartbeats, vision loss
  • Most common side effects: Vision disorders, nausea, diarrhea, vomiting, swelling (edema), constipation, liver problems (elevated transaminases), fatigue, decreased appetite, upper respiratory infection, and dizziness and numbness or tingling in the hands or feet



Medical Device Bans



WHAT: Total prohibition on the current and future sales, distribution, and manufacturing of a medical device

WHY:  Analyzing and weighing the risks and benefits the device poses to individuals. Can ban a device without actual proof of illness or injury, and only needs to find that a device has the potential to present the required degree of risk based on all available data and information

WHEN: Acts on this authority very rarely. Until 2016, the FDA banned only one other medical device, prosthetic hair fibers. In 2016, FDA proposed ban on powdered gloves on the unreasonable and substantial risk of illness or injury to exposed individuals

HOW: Notice of proposed rulemaking is published in the Federal Register



FDA Voice: Patient Advocacy Roadmap, FDA-NIH Template

FDA brief: Week of Mar 14, 2016

FDA Voice

A ‘Roadmap’ for Navigating Patient Advocacy

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

Help patient advocates gain a better understanding of FDA and ways to effectively advocate and engage with the Agency

  • Discussion on labeling, generic drugs, and providing input to FDA
  • Review programs including drug approval processes, expanded access, and FDA’s role in patient focused drug development (PFDD)



FDA and NIH Release a Draft Clinical Trial Protocol Template for Public Comment

By: Peter Marks, M.D., Ph.D., Director, CDER 

Key scientific priority to improve efficiency and save time/cost of clinical trials by  developing better organized, high-quality protocols

  • Clinical trial standards defined in:

International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practice: Consolidated Guidance (drugs)

International Organization for Standardization (ISO) Clinical Investigation of Medical Devices for Human Subjects — Good Clinical Practice  ISO 14155:2011 (devices)

  • NIH-FDA Joint Leadership council launched project to develop a template for clinical trial protocol for IND (drug) and IDE (device) studies
  • FDA collaboration with industry groups like TransCelerate to help ensure consistency for the medical product development community
  • NIH and FDA are seeking public comment on the draft template (posted in blog)





FDA Guidances: Zika transmission, IND/IDE Clinical Protocol Template

FDA Brief: Week of Mar 14, 2016

fda guidances


zika_GzikaGuidance : To reduce risk of transfusion-tranmission of Zika Virus

  • For blood establishments that collect whole blood and blood components for donor screening, donor deferral and product management
  • Zika is an arbovirus; transmitted to humans primarily by mosquito, intrauterine, perinatal and sexual transmission have been reported
  • Risk of transmission by blood transfusion is considered likely based on case reports, viremia, pre-symptomatic periods, positive blood donation reports
  • Recommendations provided for
    • For Areas without Active Transmission
    • For Areas with Active Transmission
    • Post-Donation Information and Product Management
    • Product Disposition and Labeling


Q&A for Guidance

  • Answers to common questions from blood establishments
  • To assist blood establishments in implementing the guidance recommendations



  • Clinical Trial Protocol Template for  IND trials (drugs) or IDE trials (Devices)
  • For trials supported by the National Institutes of Health (NIH)
  • Investigators  strongly encouraged to use template; meets ICH standards
  • For Public Comment



FDA Approval: INDEGO Exoskeleton

FDA Brief: Week of Mar 14, 2016

FDA approved



INDEGO Powered Lower Extremity Exoskeleton

Parker Hannifin Corporation,  US


Intended Use : Powered Exoskeleton

Indication for Use:  

Orthotically fits to the lower limbs and the trunk

Enable individuals with spinal cord injury at levels T7 to L5 to perform ambulatory functions with supervision of a specially trained companion in accordance with the user assessment and training certification program.

The device is also intended to enable individuals with spinal cord injury at levels T4 to T6 to perform ambulatory functions in rehabilitation institutions in accordance with the user assessment and training certification program.

Not intended for sports or stair climbing.

Reg Pathway: Class II 510(k), Predicate – ReWalk™

Device Description: 

  • Wearable powered exoskeleton
  • Snap‐together components-lumbar/hip, right & left upper leg, right & left lower leg
  • Hip component houses rechargeable battery pack, central processor, Bluetooth
  • Upper leg component houses two motors, embedded sensors and controllers
  • Microprocessors receive sensor signals on posture and tilt to control motion
  • Visual cues (LED lights)  and vibratory feedback inform therapist and patient
  • Indego controls self‐contained, crutches or walker used solely for stability
  • Users can  sit‐to‐stand and stand‐to‐sit, walk along even or uneven terrain
  • Physical therapist can configure, operate, monitor device via wireless application
  • Via Bluetooth connection,  gait speed and step length/height can be modified
  • Utilized in multiple indoor and outdoor locations within rehab/personal setting


  • Clinical study (n=40)  for assessing the mobility of persons with Spinal Cord Injury (SCI), 27 study sessions
  • Timed Up‐and‐Go (TUG) Test : 39 subjects completed with minimal assistance
  • Walking speed (Ten Meter Walk Test) :  0.38 m/s ± 0.08 m/s
  • Sustained walking: 38 subjects completed single‐session walk of 600 m
  • Level of assistance:  All subjects capable of managing all tested terrains
    and scenarios
  • Subject effort for basic level‐ground walking: “very light exercise”, “light exercise”


  • Minor instances of bruising, redness, abrasion, swelling; attributed to improper fitting or improper padding
  • No Unanticipated Adverse Events (UAE).




FDA Guidances and Legislation: Patient Reported Outcome in COPD, Pediatric Study Plan, MEDTECH Act

FDA Brief: Week of Mar 7, 2016

fda guidances


COPD guidance

  • Drug Development Tool (DDT) : Clinical Outcome Assessment (COA) for Patient-reported outcome (PRO) instrument for Chronic Obstructive Pulmonary Disease (COPD)
  • For exploratory use  to measure respiratory symptoms in patients with stable COPD
  • Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary : E-RS: COPD
  • E-RS: COPD total score qualified for exploratory use as a PRO instrument to measure respiratory symptoms of stable COPD in clinical studies
  • Additional development work needed to further assess measurement properties, including ability to detect clinically meaningful change, treatment effect on reducing respiratory symptoms from baseline levels



PSP guidance

  • Provide information on submission of initial pediatric study plan (iPSP) and amendments
  • Addresses:
    • Who must submit
    • When it must be submitted
    • What should be included
    • What should be included in amendment
    • Use of template




  • Senate panel approved  legislation on clinical decision support (CDS) software
  • CDS represents a wide range of technologies, from common automated alerts and reminders to software that relays data to and from implanted devices
  • Commonly used CDS tools help providers with drug-prescribing decisions
  • MEDTECH Act Legislation bans FDA  from regulating certain categories of software, including CDS software and electronic health records
  • However, bill only exempts CDS if the software is designed to enable doctors to double-check the tool’s recommendation.
  • Thus, majority of the software affected by the MEDTECH legislation is very low risk





FDA Voice on Combination Products

FDA Brief: Week of Mar 7, 2016


FDA Voice


‘Leaning in’ on Combination Products


Nina L. Hunter, Ph.D.,  Associate Director for Science Policy in the Office of Medical Products and Tobacco

Rachel E. Sherman, M.D., M.P.H., Associate Deputy Commissioner in the Office of Medical Products and Tobacco

Combination Products:

  • Combine drugs, devices, and/or biological products
  • Include components from multiple regulatory categories (e.g., drug and device, drug and biologic, biologic and device, drug, device, and biologic) with distinct regulatory requirements
  • Review requires involvement of more than one FDA Center
  • Present regulatory, policy, and review management challenges

FDA Approach:

  • Improve overall efficiency, consistency, and predictability of combination product review
  • Launch Lean Management Process Mapping

Expected Outputs:

  • Baseline Map on existing sources of delay or redundancy
  • Identify metrics for success and to assess the impact of improvements
  • Future Map  on streamlined, efficient process that will eliminate previously identified delays and redundancies
  • Reflect FDA’s prior success with Lean Management


FDA Approvals: Idelvion (hemophilia B), Triggerfish (eye pressure), Xalkori (lung cancer)

FDA Brief: Week of Mar 7, 2016


FDA approved

IDELVION (coagulation Factor IX albumin fusion protein)

CSL Behring, King of Prussia, Pennsylvania, USA

Indication:  Children and adults with hemophilia B (congenital factor IX deficiency) for:

  • On-demand control and prevention of bleeding episodes
  • Perioperative management of bleeding
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes

Unmet need:

  • Rare inherited bleeding disorder; prevents normal clotting
  • Repeated episodes of potentially serious bleeding, mainly into the joints, which can be damaged by the bleeding
  • Need for another important therapeutic option for children and adults to prevent or control bleeding and reduce the bleeding episode frequency

Reg. Pathway: BLA, first coagulation factor-albumin fusion protein product to be approved

Mechanism of Action: Replace Factor IX, a naturally occurring clotting factor that is missing (functionally deficient) or defective in people with Hemophilia B


  • Two multicenter studies (n=90), adult and pediatric patients with Hemophilia B between 12 and 61 years of age
  • On-demand Control and Prevention of Bleeding Episodes: >90% Excellent/Good based on investigator assessed 4-point scale
  • Perioperative Management of Bleeding:  >80% assessed as excellent/good by investigator/surgeon
  • Routine Prophylaxis: 89% reduction in the annualized bleeding rate

Safety:  No safety concerns identified; most common side effect was headache.

Prescribing Information



  TRIGGERFISH (soft silicone contact lens) 

Sensimed AG, Lausanne, Switzerland

Intended Use: One-time use contact lens that may help practitioners identify the best time of day to measure a patient’s intraocular pressure (IOP).

Unmet Need:

  • Glaucoma, due to elevated IOP, leading cause of vision loss; 3 million Americans
  • IOP varies throughout the day; may not be abnormally high during eye exam
  • Elevated IOP is often associated with the optic nerve damage in glaucoma
  • Need for device to detect fluctuations in IOP

Reg. Pathway: De Novo premarket review

Device Description:

  • Sensor: Embedded in a soft silicone contact lens that detects tiny changes or fluctuations in an eye’s volume
  • Adhesive antenna: Worn around eye; receives data
  • Portable data recorder: Worn by patient;  transfers  data via Bluetooth to clinician’s computer
  • Shows the range of time during the day the pressure of the eye may be increasing.

Effectiveness: Several studies; association between device output and IOP fluctuation.

Safety: Temporary side effects were pressure marks from the contact lens, ocular hyperemia (red eyes) and punctate keratitis (irritation of the cornea)

xalkori Xalkori (crizotinib) capsules

Pfizer, New York, USA

Indication: Treatment of metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive.  (Crizotinib was first approved in 2011 for the treatment of patients whose tumors are anaplastic lymphoma kinase (ALK)-positive).


Reg. Pathway: Breakthrough Therapy Designation,  Priority Review, approved prior to PDUFA goal date


  • Single multicenter, single-arm trial (n=50), 25-77 yrs,  in patients with metastatic ROS1 rearrangement-positive NSCLC
  • Objective response rate (ORR), RECIST v1.0 , by independent radiology review: 66%
  • Duration of response: 18 months
  • Consistent with the safety profile of crizotinib
  • Most common adverse reactions: vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.


CDRH Experiential Learning Program

Experiential learning

WHAT: CDRH 2016 Experiential Learning Program (ELP)  to invite medical device industry, academia, and health care facilities to  participate in training program for FDA’s medical device review staff

WHY: CDRH staff training to

  •  understand policies, laboratory practices, and challenges with device development life cycle
  • enhance communication and facilitate the premarket review process.
  • understand current industry practices, innovative technologies, regulatory impacts, and regulatory needs

NOT a  compliance inspection

WHO: Medical device industry, academia, and health care facilities  can participate

HOW:  Submit electronic or written request for participation


FDA Leapfrog Guidance on Neurological Devices

FDA Brief: Week of Feb 29, 2016

fda guidances



  • Leapfrog guidance to provide initial recommendations for emerging medical device technologies that address an unmet medical need
  • For Neurological Devices intended to slow, stop, or reverse the effects of neurological disease e.g.  Alzheimer’s disease, Parkinson’s Disease, or Primary  Dystonia – addresses an important unmet need
  • Summarizes critical Clinical Study Considerations:
    • Biological Markers and Clinical Endpoints including Clinical Outcome Assessments
    • Trial Designs including approaches and limitations
    • Investigational Plan overview
    • Safety Assessments
    • Benefit -Risk Framework including knowledge from clinical, nonclinical and patient domains
    • Labeling including Indications for Use and Warnings/Precautions
  • Advises discusion with review Division via Pre-Submission program



FDA Perspective: Rare Diseases

FDA Brief: Week of Feb 29, 2016



Encouraging drug development for rare diseases

by: Jonathan Goldsmith, M.D., FACP, Associate Director for Rare Diseases in the Office of New Drugs

Challenges in rare disease drug development and steps to address


Rare Diseases : Affects < 200,000 people in the US. Approximately 7,000 different rare diseases, collectively affecting as many as 30 million people or about 10 percent of the U.S. population.

Orphan drug designation:  Instituted by 1983 Orphan Drug Act.Introduced financial incentives including 7 years of market exclusivity, waiver of a prescription drug user fee, and other tax benefits.

Orphan drug must still demonstrate safety and effectiveness through adequate and well-controlled studies.


  • Small size: Finding enough patients for studies, difficulty for medical practitioners to develop expertise
  • Restrictive clinical study design and replication. Large, placebo-controlled, randomized trials or repetition of even small trials are not always feasible
  • ‘Flexibility’ in regulatory evidence :  Requirements for drug approval, acceptability of end points, innovative statistical design
  • Natural history of disease progression : Poorly or incompletely understood.
  • Lack of support groups for many rare diseases

Increasing awareness – Rare Disease Day

  • US joined in 2009; 80 countries participate in event held annually on the last day of February
  • FDA’s Office of Orphan Products Development and CDER’s Rare Diseases Program present programmatic updates
  • Increased recognition of rare diseases from industry and the public

FDA supports orphan drug developers

  • Annual staff training and issues guidance document
  • Patient-focused drug development meetings
  • FDA Rare Disease Council to discuss rare disease issues

Working together for new therapies to treat rare diseases

  • FDA goal of increased access to quality drug treatments
  • Continued  collaboration with industry and other stakeholders
  • Maintain momentum spurred by the Orphan Drug Act and Rare Disease Day



FDA providing $2 million in new grants for natural history studies in rare diseases

  • FDA Orphan Products Grants
  • AIM to collect data on how specific rare diseases progress in individuals over time (‘Natural History’) so that knowledge can inform and support product development and approval
    • Characterize natural history
    • Identify subpopulations
    • Develop and/or validate clinical outcome measures, biomarkers and companion diagnostics





FDA Brief: Week of Feb 29, 2016


FDA approved



Center for Disease Control (CDC)

Intended Use:  qualitative detection of Zika virus IgM antibodies in human sera or cerebrospinal fluid that is submitted alongside a patient-matched serum specimen, collected from individuals meeting CDC Zika virus clinical criteria and/or CDC Zika virus epidemiological criteria.

  • For use in CDC qualified laboratories as a part of a multi-test algorithm
  • For presumptive identification of IgM antibodies to Zika virus
  • Confirmation requires additional CDC testing using the CDC-issued algorithm
  • Results cannot be used as the sole basis of patient management decisions and must be combined with clinical observations, patient history, epidemiological information, and other laboratory evidences.

Reg pathway: Emergency Use Authorization

Mechanism of Action: IgM antibody capture enzyme-linked immunosorbent assay for the in vitro qualitative detection of Zika virus-specific IgM antibodies in human sera and other authorized specimen types

Criteria for Issuance of Authorization

  • The Zika virus can cause Zika virus infection, a serious or life-threatening disease orcondition to humans infected with the virus
  • Totality of scientific evidence available to FDA, Zika MAC-ELISA may be effective in diagnosing Zika virus infection when positive or equivocal results are further tested by CDC or by authorized laboratories
  • Known and potential benefits of the Zika MAC-ELISA for diagnosing Zika virus infection outweigh the known and potential risks of such product when tested CDC standards
  • There is no adequate, approved, and available alternative to the emergency use of the Zika MAC-ELISA for diagnosing Zika virus infection.

Conditions of Authorization for CDC

  • Distribution only to authorized laboratories
  • HCP, Pregnant women and patient fact sheets on CDC website
  • Inform and set standards for authorized laboratories
  • Tack adverse events and report to FDA





Secretary of Health and Human Services (HHS) issued notice authorizing the emergency use of in vitro diagnostic tests for detection  and/or diagnosis of Zika virus infection




ODEFSEY (emtricitabine, rilpivirine, and tenofovir alafenamide),  fixed-dose combination tablet

Gilead Sciences, Foster City, CA

Indication:  Complete regimen for treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY

Reg Strategy:  505(b),  Gilead Access Program

Mechanism of Action:

  • Emtricitabine: Inhibits activity of HIV-1 reverse transcriptase
  • Rilpivirine: Reverse transcriptase inhibitor and inhibits HIV-1 replication
  •  Tenofovir Alafenamide (TAF): Inhibits HIV-1 replication through incorporation into viral DNA

Clinical Data: 

Bioequivalence study demonstrating

  • Similar exposure of emtricitabine and TAF as Genvoya®
  • Similar exposure of rilpivirine as Edurant® (rilpivirine 25 mg).

Safety, efficacy and tolerability supported by  clinical studies in a wide range of patients with HIV.

Approved label


FDA Medical Devices Research Programs



WHAT: Medical Devices Research Program aim to ensure patients have access to high quality, safe and effective medical devices.

WHY: Advance regulatory science of developing new tools, standards and approaches to assess the safety, efficacy, quality, and performance of medical devices and radiation-emitting products.

HOW: Laboratory and field research in the areas of physical, life, and engineering sciences as well as epidemiological research in postmarket device safety. Collaborations with academia, healthcare providers, other government agencies and industry.


FDA Commissioner’s Fellowship Program


Comm Fello

WHAT: FDA’s Commissioner’s Fellowship Program Class of 2016

WHEN: Accepting applications from April 1 – May 12, 2016

WHY: FDA invites outstanding health care professionals, scientists, and engineers to apply to its two-year Fellowship Program, where they will receive regulatory science training and the chance to conduct cutting-edge research on targeted scientific, policy, or regulatory issues under the mentorship of an FDA senior scientist.

Questions? E-mail [email protected]hhs.gov