FDA Brief, Week of September 21, 2015

FDA Voice

Seeing is believing: Making clinical trial statistical data from medical product testing easy to understand

  • Trick to tell clear, compelling stories – Creating tables and graphs that aren’t dense
  • Tool for Public from Safety Graphics Working Group  : Web-based, step by step process for graphical designs for reporting clinical trial safety data
  • Designs clearly illustrate statistical data representing a wide variety of  adverse effects observed during clinical trials or post-approval

datya visual 3 data visual 2 data visual 1


Strengthening the Clinical Trial Enterprise for Medical Devices: An FDA/CDRH Strategic Priority Update

  • Clinical trial data are required in premarket submissions for the highest risk devices :  To demonstrate reasonable assurance of safety and effectiveness,
  • FDA Objective :  Reducing the time and cost of regulatory and non-regulatory aspects of the U.S. clinical trial enterprise, while assuring the protection of human subjects and the generation of robust data.
  • New Guidances : benefits and risks for Investigational Device Exemptions (IDEs) decisions,adaptive designs
  • Early Feasibility Studies (EFS) program encouraged : Small clinical studies to gain early insights into an innovative technology during the development process before starting a larger clinical trial.


FDA’s Patient Preference Initiative: The Need for Evolving Tools and Policies

FDA launched  Patient Engagement Advisory Committee – see in  ‘What To Watch’.  Additional perspectives:draft guidance _ Pt Pref Info

  • Patient preference Initiative launched in 2013 : Captures patient-centered perspectives in its structured benefit-risk framework, for device evaluation and approvals
  •  Device product labeling could include description of patient preferences to make well-informed decisions.
  •  Better tools needed to accurately capture and characterize patient views on acceptable balances of benefits and risks
  • Draft Guidance will help device-makers assess patient valuations of benefit and risk related to relevant device types, illnesses, and conditions
  • Better understanding of patients’ experiences, needs, and views, will improve product development and enhance the safe and effective use


FDA approved

LONSURF ( trifluridine and tipiracil, Taiho Oncology, Princeton, NJ)

Description : Contains thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil. Tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation.

Indication: Treatment of metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

Efficacy: Single randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer, n= 800, LONSURF (N=534) plus best supportive care (BSC) vs placebo (N=266) plus BSC

  • Statistically significant improvement in overall survival (p,0.001) and progression-free survival (p<0.001) were demonstrated in patients

Safety: Anemia, Neutropenia, Thrombocytopenia, physical weakness, fatigue, decreased appetite, diarrhea, vomiting, abdominal pain and fever.

Patient-Focused Drug Development

Public Meeting on Patient-Focused Drug Development for Huntington’s and Parkinson’s Diseases

On September 22, 2015, FDA held a public meeting on Patient-Focused Drug Development for Huntington’s disease and Parkinson’s disease. To obtain:

  • Patients’ perspectives on the impact of Huntington’s disease and Parkinson’s disease on daily life
  • Patient views on treatment approaches.


Treatments for Crohn’s Disease

crohnsCrohn‘s disease is a chronic inflammatory condition that causes inflammation, or swelling, and irritation of any part of the digestive tract— also called the gastrointestinal tract (GIT). In some people with Crohn’s disease, only the last segment of the small intestine (ileum) is affected. In others, the disease is confined to the colon (part of the large intestine). The most common areas affected by Crohn’s disease are the last part of the small intestine and the colon. Signs and symptoms of Crohn’s disease can range from mild to severe. They usually develop gradually, but sometimes will come on suddenly, without warning. You may also have periods of time when you have no signs or symptoms (remission). More than a half million Americans have been diagnosed with Crohn‘s disease. Crohn’s disease–related inflammation is segmental and transmural, leading to various degrees of tissue damage. At disease onset, most patients have inflammatory lesions, which become predominantly strictures or penetrating lesions over time.

Ulcerative colitis is a chronic disease that affects about 620,000 Americans. It causes inflammation and ulcers in the inner lining of the large intestine and is one of two main forms of chronic inflammatory bowel disease. The inflammation can lead to abdominal discomfort, gastrointestinal bleeding, and diarrhea.

“Ulcerative colitis and Crohn‘s disease are debilitating diseases that impact the quality of life of those who have these conditions,” said Amy G. Egan, M.D., M.P.H., acting deputy director of the Office of Drug Evaluation III in the FDA‘s Center for Drug Evaluation and Research.

When the disease is active, signs and symptoms may include:

  •  Diarrhea
  • Abdominal pain and cramping
  • Blood in your stool
  • Reduced appetite and weight loss
  • Fever and fatigue
  • Mouth sores etc.

People with severe Crohn’s disease may also experience:

  • Inflammation of skin, eyes and joints
  • Inflammation of the liver or bile ducts
  • Delayed growth or sexual development, in childrenAnti-inflammatory drugs are often the first step in the treatment of inflammatory bowel disease. These include:  Azathioprine and mercaptopurineThese are the most widely used immunosuppressants for treatment of inflammatory bowel disease. Short term, they also can be associated with inflammation of the liver or pancreas and bone marrow suppression. Long term, although rarely, they are associated with certain infections and cancers including lymphoma and skin cancer. They may also cause nausea and vomiting.Methotrexate This drug, which is used to treat cancer, psoriasis and rheumatoid arthritis, is sometimes used for people with Crohn’s disease who don’t respond well to other medications.


  • Infliximab, adalimumab and certolizumab pegol These drugs, called TNF inhibitors or “biologics,” work by neutralizing an immune system protein known as tumor necrosis factor (TNF). They are used for adults and children with moderate to severe Crohn’s disease to reduce signs and symptoms. They also may induce remission. Researchers continue to study these drugs to compare their benefits.
  • Corticosteroids A newer type of corticosteroid, budesonide works faster than do traditional steroids and appears to produce fewer side effects. However, it is only effective for Crohn’s disease that’s in certain parts of the bowel.
  • Oral 5-aminosalicylatesThese drugs have a number of side effects, including nausea, diarrhea, vomiting, heartburn and headache. These drugs have been widely used in the past but now are generally considered of limited benefit.
  • Treatment for Crohn’s disease usually involves drug therapy or, in certain cases, surgery. There is currently no cure for the disease, and there is no one treatment that works for everyone. By reducing the inflammation that triggers your signs and symptoms, it improves long-term prognosis by limiting complications. In the best cases, this may lead not only to symptom relief but also to long-term remission.

Vedolizumab (Entyvio ): It is approved to treat those conditions when one or more standard therapies have not resulted in an adequate response. The recommended dosage of vedolizumab in adults with ulcerative colitis or Crohn’s disease is 300 mg administered by intravenous infusion over 30 min at zero, two and six weeks and then every eight weeks thereafter.

Similar pharmacokinetics were observed in ulcerative colitis and Crohn’s disease patients administered 300 mg vedolizumab as a 30 minute intravenous infusion on Weeks 0 and 2, followed by 300 mg vedolizumab every eight weeks starting from Week 6. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day, the serum half-life was approximately 25 days at 300 mg dosage, and the distribution volume was approximately 5 L.

The safety and effectiveness of vedolizumab for Crohn‘s disease were established in three clinical trials involving approximately 1,500 patients who had not responded adequately to corticosteroids, immunomodulators, or tumor necrosis factor blocker medications. Results showed that a greater percentage of participants treated with Entyvio compared to a placebo achieved clinical response, achieved clinical remission, and achieved corticosteroid-free clinical remission.

Under Investigation:

 Mongersen, an Oral SMAD7 Antisense Oligonucleotid; is a formulation containing a 21-base single-strand phosphorothioate oligonucleotide that hybridizes to the human SMAD7 messenger RNA (mRNA) and facilitates RNase H–mediated RNA degradation through a classic antisense mechanism. Mongersen is a modified-release tablet, designed to deliver the active substance primarily into the lumen of the terminal ileum and right colon.

Pharmacokinetic analysis of plasma before and after treatment suggested that mongersen was not systemically available. Drug acts locally, no systemic exposure. Therefore, it has better define the efficacy and safety for treating adults with active Crohn’s disease. The researchers found that 55 and 65% of patients in the 40mg and 160mg mongersen groups, respectively, reached the primary end point, compared with 10% of patients in the placebo group.

New CDRH Learnings, Small Business Conference, New CDRH Advisory Committee, CDER Workshop

CDRH Learn

CDRH Learn

  • Innovative multimedia catalog of medical device laws, regulations, and policies
  •  80 educational modules.


Regulatory Education for Industry (REdI) Conference

Redi Conf

CDRH Patient Engagement & New Advisory Committee

new AC

  • New CDRH advisory committee focused on patient engagement –  complex issues relating to medical devices, the regulation of devices, and their use by patients
  • To consider patient perspectives in CDRH regulatory decision-making


Coalition Against Major Diseases (CAMD)  Workshop :  Alzheimer’s and Parkinson’s diseases

major diseases workshop

  • Understand accomplishments of CAMD scientific projects
  • Application of tools to drug development
  • Sharing information/data on tools


FDA Brief, Week of September 14, 2015

MIND1U.S. FDA Accepts First Digital Medicine New Drug Application for Otsuka and Proteus Digital Health

  • The first Digital Medicine, a drug/device product, combines Otsuka’s ABILIFY® (aripiprazole) for serious mental illness, embedded with the Proteus® ingestible sensor in a single tablet to digitally record ingestion and, with patient consent, share information with their healthcare professionals and caregivers
  • Otsuka and Proteus are pursuing a regulatory filing for a drug-device combination across multiple divisions of the FDA to support the unique system
  • First opportunity to demonstrate the potential of Digital Medicines to provide an objective measure of medication adherence and physiologic response

This is the first time an FDA-approved medication (ABILIFY) has been combined and submitted for approval with a sensor within the medication tablet (the Proteus ingestible sensor) to measure actual medication-taking patterns and physiologic response. This objective information is communicated to the patient – and with the consent of the patient – to the patient’s physician and/or caregiver. Digital Medicines may enable improved patient medication adherence and better informed physician decision-making to tailor treatment to the patient’s needs.

Digital Health inclDigital healthudes mobile medical Apps (MMAs), Health IT , wearable devices. FDA’s evolving regulations at this site:


Quick Recap Federal Food, Drug, and Cosmetic Act (FD&C Act): Drug, Not a Drug, or More?



– Is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease

– Is intended to affect the structure or any function of the body of man or other animals

Medical Device:

– Is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease

– Is intended to affect the structure or any function of the body of man or other animals

– Does not achieve its primary intended purposes through chemical action within or on the body of man or other animals

– Is not dependent upon being metabolized for the achievement of any of its primary intended purposes

Cosmetic is intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body. . . for cleansing, beautifying, promoting attractiveness, or altering the appearance.

Dietary supplement (as defined in the Dietary Supplement Health and Education Act (DSHEA) of 1994) is a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet.

Biological product, as defined in section 351(i) of the Public Health Service Act, is a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

Combination Product:

  • Two or more regulated products (drug/device, biologic/device, drug/biologic, drug/device/biologic) impregnated with a drug or biologic.
  • Two or more separate products packaged together in a single package
  • Packaged separately but both are required to achieve the intended use, indication, or effect
  • Packaged separately that is for use only with another individually specified investigational drug, device, or biological product


FDA approved

Vraylar  (Cariprazine, Forest Laboratories LLC of Jersey City, NJ)


  •  Treatment of schizophrenia
  • Acute treatment of manic or mixed episodes associated with bipolar I disorder

Mechanism of Action:

Could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors.


Schizphrenia : Three 6-week, randomized, double-blind, placebo-controlled trials

  • Primary endpoint: Positive and Negative Syndrome Scale (PANSS)
  • Secondary endpoint  : Clinical Global Impressions-Severity (CGI-S)
  • All studies  showed superiority to placebo on the PANSS total score and the CGI-S.

Bipolar Disorder : Three, 3-week placebo-controlled trials

  • Primary endpoint : Young Mania Rating Scale (YMRS)
  • Secondary endpoint : CGI-S:
  • All studies showeed superiority to placebo in  YMRS total score and the CGI-S.


Warnings and Precautions: Increased Mortality in Elderly Patients, Stroke, in Elderly Patients, Neuroleptic Malignant Syndrome, Tardive Dyskinesia.

Other events :

Schizophrenia :  Extrapyramidal symptoms, such as tremor, slurred speech, and involuntary muscle movements.

Bipolar disorder : Extrapyramidal symptoms, the urge to move (akathisia), indigestion (dyspepsia), vomiting, drowsiness (somnolence) and restlessness.

The sponsor is requited to conduct a Pediatric program.

SureFire Precision System (Sure Fire Medical, Westminster, CO)


Reg Pathway : 510K

Use : System for delivering drugs directly into tumors. It’s designed to focus chemotherapy within the tumor itself, avoiding unnecessary damage to healthy tissue around the tumor. So far it’s only intended for attacking liver cancer.

Clinical Evaluation : , Clinical study on primary liver cancer, Surefire technology enabled increased uptake of particles by an average of 68 percent, and up to 90 percent, compared to use of conventional end-hole catheters.

Source: Surefire Medical…

FDA News, Week of September 7, 2015

FDA Voice

FDA Taking Genomic Testing to the Next Level


  • Based on President Obama’s Precision Medicine Initiative (PMI)
  • New regulatory strategies for Next Generation Sequencing (NGS)  based clinical test – analyzing and interpreting a  unique genetic makeup and alterations that may impact health
  • December 2014 : Preliminary Discussion paper
  • November 12th ; Public Workshop – Analytical performance evaluation standards
  • November 13th : Public Workshop –  Current challenges in clinical validation of NGS tests

OpenFDA Makes Medical Device-Related Data Easier to Access and Use


  • Releasing information on medical devices for easy access to researchers, scientists, and developers
  •  6,000 device classification records
  • 24,000 registrations of device companies and establishments
  • >100,000 devices
  • 30,000 PMAs and supplements
  • 141,000 510(k)s and  de novo requests
  • 9,500 device recalls
  • 4.2 million adverse event reports
  • Safeguards: Protect personal identity and confidential commercial information
  • Active in GitHub and StackExchange, encourage external parties to participate

SUMMARY  : FDA initiatives to  spur innovation, advance scientific research, engage public and foster collaboration

FDA approved

XURIDEN® (uridine triacetate, Wellstat Therapeutics Corporation, Gaithersburg, MD)

Rare disease treatment for hereditary orotic aciduria , a rare metabolic disorder, reported in approximately 20 patients worldwide. Patients cannot synthesize adequate amounts of uridine and consequently can suffer from hematologic abnormalities, failure to thrive, a range of developmental delays, and episodes of crystalluria leading to obstructive uropathy

Reg Pathway : Orphan designation, priority review, granted rare pediatric disease priority review voucher

Indication : treatment of hereditary orotic aciduria

Efficacy :

Open-label study in 4 patients (3 to 19 years), 6 weeks.

  • Primary endpoint was stability of hematological paramters (eg neutrophil count, percent neutrophils, white blood cell count, mean corpuscular volume)
  • Patients 1 and 3 met pre-specified criteria
  • Patient 2 pre-specified criteria remained stable
  • Patient 4 did not meet the pre-specified endpoint
  • In 6-mo extension treatment, hematologic parameters for patients normalized or remained stable
  • Growth improved or remained stable

Safety : No adverse reactions

SUMMARY  Congratulations to Wellstat Therapeutics for pursuing and succeeding in drug development in an ultra rare potentially life-threatening, genetic disorder

New Tuberculosis Treatment

TB Treatment

Tuberculosis (TB) caused from infection of Mycobacterium tuberculosis continues as a global epidemic. Third of the world population is at risk of developing active TB. Each year, 9 million patients are newly diagnosed with active TB and 2 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive. The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings).

Limitations associated with the currently available TB treatment are:

1) Duration and complexity of treatment result in nonadherence to treatment. This leads to suboptimal response (failure and relapse), the emergence of resistance, and continuous spread of the disease.

2) Adverse events in response to anti-TB drugs are common and contribute to the problem of nonadherence. The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings).

3) Multidrug-resistant (MDR) -TB is defined as TB caused by M. tuberculosis strains that are resistant to, at least, the two most powerful first-line anti-TB drugs, isoniazid and rifampicin; extensively drug-resistant (XDR)-TB refers to a form of disease caused by strains of M. tuberculosis that are resistant to isoniazid and rifampicin, in addition to any fluoroquinolone, and to at least one of the three following injectable drugs: capreomycin, kanamycin or amikacin. Resistant TB occurs in the presence of partially suppressive drug concentrations that enable replication of bacteria, the formation of mutants, and overgrowth of wild-type strains by mutants (selective pressure). Mathematical models show that the MDR and XDR-TB epidemics have the potential to further expand, thus threatening all gains in TB control over recent decades.

The World Health Organization developed the directly observed therapy short course (DOTS) strategy to optimize response and adherence to TB treatment. However, DOTS is labor-intensive and expensive. It causes a high burden on public health programs, especially in developing countries with limited human resources. The rapid development of new anti-TB drugs has been hampered by several obstacles. First of all, the TB drug market is associated with insufficient profit opportunity or investment return to instigate pharmaceutical industries to develop new drugs.

New Drug:

TMC207 is a first-in-class diarylquinolone compound with a novel mechanism of action and potent activity against drug-sensitive and drug-resistant TB.

TMC207 has bactericidal and sterilizing activity against M. tuberculosis and other mycobacterial species but little activity against other bacteria. An EBA study in treatment-naive patients with pulmonary TB showed delayed, modest activity of the drug after 7 days, and a Phase II efficacy study conducted in patients with MDR-TB taking TMC207 plus an individualized background regimen showed impressive results after 2 months of treatment, with the results of a longer TMC207-based treatment course to follow. The drug appears to be safe and well tolerated, and development plans with the goal of an MDR-TB indication are well underway. the management of the over 500,000 cases of MDR-TB and XDR-TB would greatly benefit from availability of a new drug like TMC207, which is potent, well tolerated and structurally and mechanistically unrelated to current first-line TB drugs. Fortunately, given the product development partnership between Industry and the TB Alliance, both strategies (using TMC207 in shorter first-line regimens or using it in second line regimens for drug-resistant M. tuberculosis infections) are being pursued.

The maximum plasma concentration (Cmax) is reached after 5 h (Tmax). Average steady-state plasma concentration of 0.6 μg/ml form 8 weeks of treatment (400 mg daily dose for 2 weeks, followed by 200 mg three times a week for 6 weeks). It has an exceedingly long terminal half-life of 173 hr. It is metabolized by oxidative metabolism via cytochrome P450 isoenzyme CYP3A4. The majority of adverse events are of mild or moderate intensity. Nausea is significantly more frequently reported by patients treated with TMC207 in the MDR-TB trial. Diarrhea, arthralgia, dizziness, hyperuricemia and eye disorders are more frequent, but not of statistical significance. TMC207 produces increases in the QT interval, but no pathologically prolonged QT or corrected-QT values are observed. The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis.

FDA News, Week of Aug 24 and Aug 31, 2015

Kicking off the PDUFA VI Reauthorization Process

FDA Voice

Highlights of progress:

  • FDA continues to meet or exceed review goals.
  • High rates of approvals for novel products during first submission – including rare diseases ( 17 orphan drug approvals in 2014).
  • Improved and increased communication between FDA and sponsors
  • implementation of a structured risk-benefit framework for reviews
  • Patient-Focused Drug Development program has been successful in systematically obtaining patient perspectives on certain diseases and related treatments.

Ideas for further enhancements:

  • Involve patient perspective in drug development processes;
  • Expand FDA’s Sentinel System for active surveillance of safety issues
  • Enhancing regulatory science initiatives, including the use of patient-reported outcomes and biomarkers.

SUMMARY : Tracking and Optimization of FDA Drug review will be critical components for the PDUFA VI re0authorizaiton


FDA approved

Promacta (Eltrombopag) : Extension of use in yound children with rare blood disorder  ( GlaxoSmithKline, Research Triangle Park, NC).

Designation: Orphan, Priority Review

Indication :  Treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy

Description : Eltrombopag olamine, a small molecule thrombopoietin (TPO) receptor agonist, interacts with the transmembrane domain of the TPO receptor (also known as cMpl) leading to increased platelet production

Efficacy : Patients ages one to 17 years with chronic ITP

  • Two double-blind, placebo-controlled trials, n=159
  • More pediatric patients treated with PROMACTA (75%) compared with placebo (21%) had imporved platetelt counts (Prespecified)
  • Fewer treated patients required rescue treatment

Safety :

  • Liver Enzyme elevation : An elevation of ALT greater than or equal to 3x upper limit of normal occurred in 5% of patients in the eltrombopag group, and of those 2% had increases in ALT greater than or equal to 5x upper limit of normal.
  • No deaths or thromboembolic events

Varubi  (rolapitant) for nausea and vomiting from chemotherapy ( Tesaro Inc., Waltham, MA)

Designation : Standard

Indication: In combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy

Description: Substance P/neurokinin-1 (NK-1) receptor antagonist. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by certain cancer chemotherapies, particularly in the delayed phase.


  • Three multicenter, randomized, double-blind, parallel group, controlled clinical studies, n=2800
  • Compare VARUBI regimen (VARUBI, granisetron and dexamethasone) vs Control (placebo, granisetron and dexamethasone)
  • Greater reduction in vomiting and use of rescue medicarion with varubi regimen


  • Contraindication : Varubi inhibits the CYP2D6 enzyme, Contraindicated with the use of thioridazine (metabolized bt CYP2D6); combination can cause abnormal heart rhythm that can be serious.
  • Other : Low white blood cell count (neutropenia), hiccups, decreased appetite, dizziness

Drug Advocacy, Device Public Workshop, FDA Monthly Track



To provide a focal point for advocacy, to enhance two-way communication and collaboration with healthcare professionals, patients, patient groups, and others on CDER issues concerning drug development, drug review, and drug safety.


PUBLIC WORKSHOP : In Vitro Diagnostic Testing for Direct Oral Anticaogulants

The Food and Drug Administration (FDA) is announcing a public workshop entitled “In Vitro Diagnostic Testing for Direct Oral Anticoagulants”. The objective of the workshop is to discuss analytical performance requirements for the diagnostic assessment of direct oral anticoagulants (DOACs), and the clinical circumstances under which patients receiving these agents would require testing. Specifically, this workshop aims to 1) evaluate the impact of DOACs on traditional coagulation testing results; 2) identify clinical circumstances where testing of DOACs anticoagulant activity or concentration would be relevant; 3) discuss clinically meaningful interpretation of coagulation testing results for patients on DOACs; and 4) review the regulatory requirements for granting clearance for in vitro diagnostic devices intended for coagulation testing in patients treated with DOACs.


FDA MONTHLY TRACK: Agency-wide Program PerformanceFDA Track

FDA Track 2


Cystic Fibrosis: current treatments and newly (July 2015) approved therapy


Cystic fibrosis (CF) is known to cause your lungs to produce extra-thick, sticky mucus. This mucus builds up and clogs the airways and becomes a source of inflammation and infection that can lead to lung damage. As the white blood cells fight the infection caught in the mucus, they leave behind remains called extracellular DNA. The buildup of these remains makes the mucus in lungs affected by CF even thicker than before, leaving the lungs even more vulnerable to irreversible structural changes, progressive decline in function, and eventually respiratory failure. Disease severity for CF is based on lung capacity measured by spirometry pulmonary function tests such as forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC). Normal pulmonary disease is defined as FEV1 percentage of greater than 90% predicted, 70-89% predicted for mildly impaired, 40-69% predicted for moderately impaired, and an FEV1 percentage of less than 40% predicted is defined as severely impaired. Despite several supportive therapies; the median age of death is still 27 years. CF affects about 30,000 people in the United States and about 70,000 people globally.

CF is a serious genetic condition. It caused by reduced quantity and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein due to mutations in the CFTR gene in CF patients. The CFTR protein is an epithelial chloride channel that aids in regulating salt and water absorption and secretion and pH balance in multiple organs, including the lungs, pancreas and other gastrointestinal organs, and sweat glands. Decreased CFTR chloride transport results in multisystem pathology, beginning at birth.  Salt loss may contribute to symptoms early in life and is the traditional diagnostic test for CF. Despite several supportive therapies; the median age of death is still 27 years.


For Infections:

  • Antibiotics (ciprofloxacin and tobramycin)

To open airways in the lungs or keep them open:

  • Bronchodilators (albuterol or salmeterol), which are used to make breathing easier. They may also make it easier to cough up mucus.
  • Anticholinergics (Atrovent)

To control the amount and thickness of mucus:

  • Pulmozyme is a purified solution for inhalation of recombinant human deoxyribonuclease (rhDNase) which reduces lung sputum viscosity and improves secretion clearance. Pulmozyme is recommended for the chronic treatment of moderate to severe CF pulmonary disease. The recommended dosage for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended jet nebulizer/compressor system or eRapid Nebulizer System. Most patients gain optimal benefit from regular daily use of Pulmozyme. In studies in which Pulmozyme was given in an intermittent regimen, improvement in pulmonary function was lost on cessation of therapy. Patients should therefore be advised to take their medication every day without a break.
  • Saltwater solution (hypertonic saline). This is sometimes used to help clear mucus from the lungs. It is low-cost, and it may help reduce inflammation in the airways.

To reduce inflammation:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen)
  • Membrane stabilizers (such as cromolyn)
  • Corticosteroids (such as fluticasone or prednisone)

With digestive enzymes:

  • Enzyme replacement therapy (such as Creon or Pancreaze)

With cystic fibrosis transmembrane conductance regulator (CFTR) potentiators:

  • Ivacaftor (CFTR), a potentiator, is used for treatment of CF in patients age 2 years and older who have the G551D mutation in the CFTR gene.

2-5 years, <14 kg: 50 mg granules PO q12hr before or after eating fat-containing food

2-5 years, ≥14 kg: 75 mg granules PO q12hr before or after eating fat-containing food

6-17 years: 150 mg PO q12hr before or after eating fat-containing food

 Dose needs to be reduced to 150 mg PO twice-a-week when co-administrating with strong or moderate CYP3A inhibitors. Co-administration with a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s Wort is not recommended.

 This compound offers a novel approach to the treatment of CF, as it is the only marketed drug that targets the underlying cause of this lethal condition, instead of the downstream disease processes that occur as a result of lacking or defective CFTR. Available clinical trial data indicate that compared with placebo, ivacaftor has superior efficacy for improving respiratory function, and it has been shown to lower the risk of pulmonary exacerbations. The adverse-effect profile of ivacaftor does not differ substantially from placebo, but patients will need to be monitored for hepatic function and potential drug interactions during treatment.

 Newly approved therapy

If the patient is homozygous for the F508del mutation in the CFTR gene, needs a CFTR corrector with Ivacaftor (Lumacaftor/Ivacaftor (Orkambi), approved by FDA in July 2015. Lumacaftor corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR proteins. The combination is indicated for cystic fibrosis in patients aged 12 yr or older who are homozygous for the F508del mutation in the CFTR gene: ≥12 yr: 1 tablet (Lumacaftor/Ivacaftor: 200 mg/125 mg) PO q12hr with fat containing food. Study data show that lumacaftor in combination with ivacaftor provides benefit for patients with cystic fibrosis homozygous for the F508del CFTR mutation The most common side effects of Orkambi include shortness of breath, upper respiratory tract infection, nausea, diarrhea, and rash. Women who took Orkambi also had increased menstrual abnormalities such as increased bleeding.

Wearable, Noninvasive Devices for Parkinsons Disease

Device Sponsor Summary
Fall Detection SystemsD1 Phillips, GreatCall, etc. • Detect a fall

• Connect to Certified Response Agent

mPower AppD2 Sage Bionetworks, Unv. of Rochester, MJFRF • Track symptoms using memory game, finger tapping, speaking, walking

• Collect data from wearable device

Non-Invasive Galvanic Vestibular StimulatorD3 Unv. of Gothenburg, Sweden, collaboration with NASA • Target loss of motor control, tremors, stiffness

• Electrically stimulates vestibular system to improve balance

• Tested in both medicated and un-medicated patients; greater effect in un-medicated patients

BalanceWear® BW300D4 Motion Therapeutics, Inc., CA • Balance-Based Proprioceptive Neuromuscular Strategic Weighting Full Torso Device

• Flexible weights placed in garment based on Body Chart Weight Locator

• Improve the balance and stability

Mobile App


Roche •  Continuous measurement of disease fluctuation

•  Objective measures and realtime monitoring of Tx response by HCP

STIMbandD6 Johns Hopkins Unv. •3D printed device with electrodes, fits over a patient’s head

•Apply electrical stimulation to ease symptoms

Personal Kinetigraph (FDA cleared)D8 Global Kinetics Corporation • Collects data on movement

• Reminds patient to register levodopa ingestion

• Info sent to Physician; MAY lead to treatment decisions

CalibraceD10 AbiliLife • Increases postural stability by realigning shoulder and spine

• Functional, breathable, light; may prevent falls