Some Physicians Who Advise FDA Later Form Financial Relationships with Pharmaceutical Companies Interview with:

Stephanie L. Kuschel, B.A Indiana University School of Medicine Indianapolis, IN, 46202

Dr. Kuschel

Stephanie L. Kuschel, MD
Indiana University School of Medicine
Indianapolis, IN, 46202

Robert Dellavalle, MD, PhD, MSPH
Professor of Dermatology and Public Health
University of Colorado School of Medicine
Colorado School of Public Health
Chief, Dermatology Service
US Department of Veterans Affairs
Eastern Colorado Health Care System
Denver, CO 80220 What is the background for this study? What are the main findings? 

Response: Physicians can serve as external experts and voting members of FDA advisory committee panels, which help determine if a drug is acceptable for the US market. Considering that financial conflicts of interest (FCOI) have been shown to influence voting member habits, the FDA has regulations in place to minimize these FCOI. However, the FDA can grant waivers for some financially conflicted individuals if they meet certain requirements (like offering key insights that may out-weigh the risk of a possible FCOI). Additionally the FDA does not make stipulations regarding post-advisory role financial relationships. In fact, many former FDA committee advisors later engage in financial relationships with pharmaceutical companies. Some worry these post-hoc financial relationships could pose an ethical dilemma whereby future FDA advisory members are incentivized to alter their voting habits in expectation of future rewards. Others argue the situation may be more complex than expected.

For example, the author of one study, found that while there was evidence for a pro-industry voting bias among committee members with exclusive financial relationships to the sponsoring manufacturer (of the drug under review), this was not the case for members with nonexclusive financial ties to both the sponsor and its competitors 1. Furthermore, the author found that advisors with many corporate ties were (on average) actually more likely than their peers without any financial ties to vote against the sponsor. The author argued that these advisors were more likely to be experienced researchers, and their voting habits may reflect their experience evaluating medical research.

While this author and others have offered valuable insights into financial relationships of advisors during their advisory role, unfortunately little information is available regarding post-advisory role financial relationships and whether these relationship have any influence on the integrity of the voting process. The purpose of our study was to review Open Payment data on industry payments to former physician FDA dermatologic drug committee members.  Continue reading

Only 1 in 5 Cancer Drugs Receiving FDA Accelerated Approval Have Proven Benefits in Confirmatory Trials Interview with:

Bishal Gyawali  MD PhD Med Onc. Asst. Professor 

Dr. Gyawali

Bishal Gyawali  MD PhD

  • Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • Department of Oncology, Department of Public Health Sciences, and Division of Cancer Care and Epidemiology, Queen’s University, Kingston, Ontario, Canada What is the background for this study? What are the main findings?

Response: Accelerated approval pathway from the FDA allows cancer drugs to come to market sooner by showing improvement in surrogate measures such as change in tumor size. Surrogate measures do not reflect clinical benefit in terms of living longer or feeling better. So, when a drug receives accelerated approval, the drug is required to undergo a confirmatory trial to confirm that true clinical benefit from the drug actually exists.

Last year, a paper from the FDA argued that accelerated approval pathway is working effectively because 55% of such drugs confirmed clinical benefit. However, we saw that most of those drugs were actually improving only a surrogate measure even in confirmatory trials. So the confirmatory trials were not confirming clinical benefit but actually confirming benefit in a surrogate endpoint. We investigate that issue in our study using updated results from the confirmatory trials that were ongoing at the time of FDA review.

Our main finding is that only one-fifth of cancer drugs that received accelerated approval actually improved overall survival later in confirmatory trials. For, 20% of other drugs, the confirmatory trials tested the same surrogate endpoint as did the preapproval trial. For another 21%, the confirmatory trial showed benefit in a surrogate endpoint different from the one used in preapproval trial. Furthermore, when drugs fail to confirm clinical benefits in confirmatory trials, they still continue to remain on market.  Continue reading

NAYZILAM® (midazolam) Nasal Spray Approved To Treat Seizure Clusters Interview with:

Dr. Steven S. Chung, MDExecutive Director and Program ChairNeuroscience Institute and Director of the Epilepsy ProgramBanner – University Medical Center

Dr. Chung

Dr. Steven S. Chung, MD
Executive Director and Program Chair
Neuroscience Institute and Director of the Epilepsy Program
Banner – University Medical Center What is the background for this study? How is Nayzilam different from other treatments for epilepsy? Who/How is it administered? 

Response: NAYZILAM is the first medication and only FDA-approved nasal option for treating seizure clusters. NAYZILAM allows for administration by a non-healthcare professional to patients when a seizure cluster occurs, which could provide significant value to patients who currently have limited treatment options for SC.

The effectiveness of NAYZILAM was established in a randomized, double-blind, placebo-controlled trial (Study 1; NCT 01390220).

Study 1 was conducted in two phases: an open-label Test Dose Phase followed by a randomized, double-blind, placebo-controlled, Comparative Phase. In the Test Dose Phase, tolerability was assessed in 292 patients. Patients were excluded from participation in the Comparative Phase if they failed to meet pre-defined blood pressure, heart rate, sedation, electrocardiogram, and peripheral oxygen saturation criteria. In the Comparative Phase, 201 patients treated a single seizure cluster episode in an outpatient setting.

Numerical differences in favor of NAYZILAM were observed on each of the components of the treatment success responder definition; termination of seizure(s) within 10 minutes after initial dose of study drug (80.6 versus 70.1%) and the absence of seizure recurrence between 10 minutes and 6 hours after the initial dose of study drug (58.2 versus 37.3%).

Study 1 also evaluated the occurrence and time to next seizure after the initial blinded dose of study drug. A smaller proportion of NAYZILAM-treated patients experienced the next seizure within 24 hours after the initial blinded dose of study drug (37.3% versus 46.3%). NAYZILAM-treated patients experienced a statistically longer time-to-next-seizure than the placebo group.  

Continue reading

How Much of Your Sunscreen is Absorbed? Interview with:

David Strauss, MD, PhDDirector, Division of Applied Regulatory ScienceU.S. Food and Drug AdministrationCenter for Drug Evaluation and Research

Dr. Strauss

David Strauss, MD, PhD
Director, Division of Applied Regulatory Science
U.S. Food and Drug Administration
Center for Drug Evaluation and Research What is the background for this study? What are the main findings?

Response: It is unknown whether most active ingredients in sunscreens are absorbed. FDA has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies.

This randomized clinical trial demonstrated systemic exposure of 4 commonly used sunscreen active ingredients on application of sunscreen products under maximal use conditions consistent with current sunscreen labeling.

All 4 sunscreen active ingredients tested resulted in exposures exceeding 0.5 ng/mL.  Continue reading

Cancer Drug Trials: Does Changing the Endpoint from Overall Survival Hasten the Approval Process? Interview with:

Emerson Chen, MDChief Fellow, Hematology-Oncology, PGY-6Oregon Health & Science University

Dr. Chen

Emerson Chen, MD
Chief Fellow, Hematology-Oncology, PGY-6
Oregon Health & Science University What is the background for this study? What are the main findings?

Response: Many cancer drugs are approved annually giving the appearance of innovation; however, some drugs may have been approved because of a lower bar. Use of lesser endpoints like response rate (how tumor shrinks) and progression-free survival (how tumor has delayed growth) have been proposed to speed trials when compared against traditional endpoints like overall survival (how long patients might live).

Using published trials that led to cancer drug approval from 2006 to 2017, we estimated how long it would take to get each of these three endpoints across all cancer drugs and indications to see how much time we could save by using these weaker but faster endpoints.

We see that many trials using overall survival used less time than anticipated, and many trials using response rate or progression-free survival actually took quite a bit of time.  In part that is due to researchers needing to document the duration of the response. But, whatever the reason, the time to get each of the three endpoints is actually more similar than different, and we estimate that our current use of  these faster endpoints are saving us only 11 months compared to using only overall survival.

Continue reading

Suncreens: FDA Proposed Regulations Would Update Testing and Labeling Requirements Interview with:

Anna Benevente

Anna Benevente

Anna Benevente
Director of product, labeling, and ingredient review at Registrar Corp (, an FDA consulting firm that helps companies comply with FDA regulations.
She has been assisting companies with U.S. FDA regulations since 2009.
She and her team have researched thousands of products to determine whether they meet FDA requirements for compliance.

In February 2019, the U.S. Food and Drug Administration (FDA) published a proposed rule to put into effect a final monograph for over-the-counter (OTC) sunscreen drug products.  If finalized, the rule will update conditions under which OTC sunscreen products may be marketed in the United States.  Given the effect this rule could have on the pharmaceutical and cosmetic industries, sat down with Anna Benevente, Director of Product, Labeling, and Ingredient Review at FDA consulting firm Registrar Corp, to dig deeper into the article they recently published on the rule.  What is the background for this announcement?

Response:  FDA issues monographs for specific types of over-the-counter (OTC) drug products, which establish conditions under which a drug may be marketed without FDA approval of a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA). The conditions that are established by the monograph include the active ingredients that have been deemed generally recognized as safe and effective (GRASE) and statements that must appear on the labeling in the form of a Drug Facts panel. Sunscreens have never had an effective final monograph.  Instead, they have been largely regulated under enforcement discretion since 2001, when FDA issued a stay on a final monograph for OTC sunscreen drug products.

The Sunscreen Innovation Act (SIA) of 2014 calls for FDA to establish a final monograph for OTC sunscreen by November 26, 2019. If finalized, the rule proposed in February would lift the stay on the final monograph and amend certain regulations for OTC sunscreen drug products.  What is enforcement discretion?

Response: FDA rulemaking can take a considerable amount of time.  During this process, FDA may issue guidance or an enforcement policy that specifies stipulations under which the Agency permits the marketing of certain products in the absence of codified regulations.  While these documents are not legally-binding, they often outline provisions where FDA states that the Agency does not intend to take regulatory action.  These provisions are often incorporated into an FDA rule, as we are seeing in the case of this new rule for sunscreen.  Would you explain what GRASE ingredients are?

Response: When FDA establishes a monograph for an OTC drug product, the Agency reviews scientific data on ingredients used for that product and classifies them into three categories:

Category I: The ingredient is generally recognized as safe and effective for its intended use.

Category II: The ingredient is not generally recognized as safe and effective for its intended use.  This ingredient may be not safe as a whole, may be not be safe for the specific intended use, or may not be effective for the specific intended use relative to its health risk.

Category III: There is insufficient scientific data to determine whether the ingredient is safe and effective for its intended use.

While a monograph is still in the rulemaking stage, FDA permits the marketing of products formulated with active ingredients that are deemed Category I or Category III. At this time, industry may submit data to support a Category I designation for a Category III ingredient. When the final monograph is published, FDA no longer uses the terms “Category I”, “Category II”, and “Category III.”  Those ingredients that were deemed Category I become “monograph conditions,” while Category II and III ingredients become “nonmonograph conditions” and may not be marketed after the compliance date identified in the final rule.

Q: What are the main products that would require a label change?

Response:The statement of identity for all sunscreen products would be required to list the sunscreen active ingredients in alphabetical order followed by “Sunscreen” and the product’s dosage form (e.g. “Titanium Dioxide, Zinc Oxide Sunscreen Lotion”).  Additionally, the rule proposes formatting changes to sunscreen labels that would make SPF, broad spectrum, and water resistance statements more prominent.

The rule would require all products over 15 SPF to satisfy broad spectrum testing requirements and the associated labeling requirements for broad spectrum products.  Products under 15 SPF that do not satisfy broad spectrum requirements would be required to include “*See Skin Cancer/Skin Aging Alert” next to the SPF value as a reference to the warning required under 21 CFR 201.327(d)(2).

Continue reading

Medical Research Metaanalyses Can Contain Corrupted Data Interview with:

Craig Alexander Garmendia, PhDOffice of Bioresearch Monitoring Operations, Office of Regulatory AffairUS Food and Drug AdministrationMiami, Florida

Dr. Garmendia

Craig Alexander Garmendia, PhD
Office of Bioresearch Monitoring Operations
Office of Regulatory Affairs
US Food and Drug Administration
Miami, Florida What is the background for this study? What are the main findings? 

Response: Clinical trials under the U.S. Food and Drug Administration’s (FDA) purview have been shown to suffer from falsified data. While the FDA warns researchers when falsified data are discovered, these data still make their way into medical literature.

In this novel study, Dr. Garmendia and colleagues conducted a systematic review to examine the effects of publications containing falsified data on meta-analyses using sensitivity analyses. Almost half of all meta-analyses had conclusions altered by publications containing falsified data, while nearly one-third of all analyses had considerable changes in outcomes. Continue reading

FDA Warns of Increased Risk of Aortic Rupture with Fluoroquinolones in Some Patients

Dissection of the descending part of the aorta (3), which starts from the left subclavian artery and extends to the abdominal aorta (4). The ascending aorta (1) and aortic arch (2) are not involved in this image Wikipedia image

Dissection of the descending part of the aorta (3), which starts from the left subclavian artery and extends to the abdominal aorta (4). The ascending aorta (1) and aortic arch (2) are not involved in this image
Wikipedia image

“[12-20-2018] A U.S. Food and Drug Administration (FDA) review found that fluoroquinolone antibiotics can increase the occurrence of rare but serious events of ruptures or tears in the main artery of the body, called the aorta.  These tears, called aortic dissections, or ruptures of an aortic aneurysm can lead to dangerous bleeding or even death.  They can occur with fluoroquinolones for systemic use given by mouth or through an injection.”

Please read the full FDA warning HERE

Computer Simulation Study Favors Tomosynthesis over Digital Mammography Interview with:

Aldo Badano, Ph.D. Deputy Director, Division of Imaging, Diagnostics, and Software Reliability Office of Science and Engineering Laboratories Center for Devices and Radiological Health Silver Spring, MD 20993

Aldo Badano, Ph.D.
Deputy Director, Division of Imaging, Diagnostics, and Software Reliability
Office of Science and Engineering Laboratories
Center for Devices and Radiological Health Silver Spring, MD 20993 What is the background for this study? What are the main findings? 

Response: Expensive and lengthy clinical trials can delay regulatory evaluation of innovative technologies, affecting patient access to high-quality medical products. Although computational modeling is increasingly being used in product development, it is rarely at the center of regulatory applications.

Within this context, the VICTRE project attempted to replicate a previously conducted imaging clinical trial using only computational models. The VICTRE trial involved no human subjects and no clinicians. All trial steps were conducted in silico. The fundamental question the article addresses is whether in silico imaging trials are at a mature development stage to play a significant role in the regulatory evaluation of new medical imaging systems. The VICTRE trial consisted of in silico imaging of 2986 virtual patients comparing digital mammography (DM) and digital breast tomosynthesis (DBT) systems.

The improved lesion detection performance favoring DBT for all breast sizes and lesion types was consistent with results from a comparative trial using human patients and radiologists.  Continue reading

FDA Approves Dupixent: Only Self-Administered Biologic for Moderate-to-Severe Asthma Interview with:
RegeneronNeil Graham,  M.B.B.S., M.D., M.P.H
VP of Immunology & Inflammation
Regeneron What is the background for this announcement? 

Response: Patients with moderate-to-severe asthma often have uncontrolled, persistent symptoms despite standard-of-care therapy that may make them suitable for treatment with a biologic therapy. They live with coughing, wheezing and difficulty breathing, and are at risk of severe asthma attacks that may require emergency room visits or hospitalizations. [i],[ii] Oral corticosteroids can provide relief for severe, short-term symptoms. However, their chronic use is limited to the most severe patients due to the potential for serious side effects. [iii],[iv]

A particular type of inflammation contributes to the cause of uncontrolled symptoms in multiple inflammatory diseases such as asthma and atopic dermatitis.[v] Dupixent is a medicine that inhibits the overactive signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13), two key proteins that contribute to this type of inflammation. This inhibits cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide, and IgE; however, the mechanism of action of Dupixent in asthma has not been definitively established. Continue reading

FDA Fast Tracks Development of PaxVax Vaccine for Chikungunya Interview with:

Lisa Danzig, MD Chief Medical Office PaxVax

Dr. Danzig

Lisa Danzig, MD
Chief Medical Office
PaxVax Would you briefly explain what is meant by Chikungunya infection?  Whom does it primarily affect?  How is it transmitted and what the  complications?

Response: Chikungunya is caused by the chikungunya virus (CHIKV), an arthropod-borne virus (arbovirus) spread by infected mosquitos.

Infection with chikungunya virus results in severe, often debilitating joint pain in infected patients, known as arthralgia. Symptoms can include intense discomfort in joints, such as the wrists, fingers, ankles, and feet, in the knees and in the hips or shoulders. Those affected can also frequently suffer from headaches, fever, and severe muscle pain, rashes on the torso and limbs and swelling in one or more cervical lymph nodes. Individuals who are at a higher risk for contracting chikungunya include infants, elderly and those with chronic conditions.

The virus is a small, spherical, enveloped, positive-strand RNA virus. The virus is transmitted by the Aedes aegypti and Aedes albopictus mosquito, which originated in Africa, first spreading to Asia and recently expanding to the western hemisphere.  Outbreaks are rapid and widespread.  In February 2005 a major outbreak of chikungunya occurred in the islands of the Indian Ocean after which over 1.9 million cases have been reported in India, Indonesia, Maldives, Myanmar and Thailand.

Chikungunya spread has been identified in 45 countries in the Americas alone with more than 1.7 million suspected cases reported to the Pan American Health Organization since 2015, increasing the incidence of the disease and risk to U.S. travelers. In 2016 there were approximately 60,000 cases of chikungunya across India. Beyond the Indian subcontinent, the Caribbean, Central America and South America, inhabitants and travelers visiting sub-Saharan Africa and Southeast Asia are also at risk.

Continue reading

FDA Grants Fast Track Designation to Nintedanib for Scleroderma with Lung Disease Interview with:

Dr. Thomas Leonard, Ph.D. Executive director, Clinical Development and Medical Affairs, Specialty Care Boehringer Ingelheim Pharmaceuticals, Inc.

Dr. Thomas Leonard

Dr. Thomas Leonard, Ph.D.
Executive director, Clinical Development and Medical Affairs, Specialty Care
Boehringer Ingelheim What is the background for this announcement? Would you briefly explain what is meant by systemic sclerosis? What are the disease symptoms and manifestations?

Response: The FDA recently granted Fast Track designation to nintedanib for the treatment of systemic sclerosis with interstitial lung disease (SSc-ILD) – paving the way for Boehringer Ingelheim to take an important step in advancing this potential therapy for those affected by this disease. The designation was based on Boehringer Ingelheim’s Investigational New Drug application (IND) and the anticipated efficacy and safety data from SENSCIS™ (Safety and Efficacy of Nintedanib in Systemic SClerosIS), a double-blind, randomized, placebo-controlled global Phase III trial which is fully enrolled and includes more than 520 patients from 32 countries.

The FDA’s Fast Track designation facilitates the development of new therapies that treat serious conditions and fulfill an unmet medical need in an effort to get treatments to those in need sooner, like those living with systemic sclerosis.

Systemic sclerosis, also known as scleroderma, is a rare disease characterized by thickening and scarring of connective tissue of multiple organs in the body, typically affecting women between ages 25 and 55. Most people with the disease will develop some degree of lung scarring, or interstitial lung disease (ILD), which is the leading cause of death among people with systemic sclerosis.

Nintedanib, currently marketed as Ofev®, is approved for treatment of a rare lung disease called idiopathic pulmonary fibrosis, or IPF, and has been shown to slow disease progression as measured by annual rate of decline in lung function. Because SSc-ILD and IPF share similarities in how the underlying lung scarring, or fibrosis, forms in people with the disease, Boehringer Ingelheim is evaluating the impact of nintedanib on SSc-ILD.

Continue reading

LUXTURNA Proves Effectiveness of Single Gene Therapy To Cure Rare Cause of Blindness Interview with:

Dr. Stephen M. Rose, PhD Chief Research Officer Foundation Fighting Blindness

Foundation Fighting Blindness

Dr. Stephen Rose PhD
Chief Research Officer
Foundation Fighting Blindness (FFB)

Dr. Rose comments on the announcement of the FDA approval of voretigene neparvovec (LUXTURNA™) gene therapy for inherited blindness due to mutations in the RPE65 gene.

What is the background for this announcement? What were the main findings from the study?

Response: While it has been 30 years since the RPE65 gene was identified as causing Leber’s Congenital Amaurosis, this shows that it is possible to have an effective gene therapy for an inherited disease. As the first gene therapy for the eye or for an inherited disease, LUXTURNA is a historic milestone in the search for cures for all inherited retinal diseases (IRDs). As a one-time gene therapy, LUXTURNA will not only be life-changing for patients with vision loss due to mutations in the RPE65 gene, it also provides critical momentum for gene therapies – for the eye and other diseases – now in the clinic.  Continue reading

Sex and Ethnicity Data Missing From Many FDA Medical Device Approval Reports Interview with:

Sanket Dhruva, MD, MHS, FACC Cardiology, VA Connecticut Healthcare System Robert Wood Johnson Foundation Clinical Scholar Yale University

Dr. Dhruva

Sanket Dhruva, MD, MHS, FACC
Cardiology, VA Connecticut Healthcare System
Robert Wood Johnson Foundation Clinical Scholar
Yale University What is the background for this study? What are the main findings?

Response: In 2012, Congress passed the Food & Drug Administration (FDA) Safety and Innovation Act, with the goal of increasing enrollment and availability of data in important patient groups such as the elderly, women, and racial and ethnic minorities. In 2014, as mandated by the legislation, the FDA released an Action Plan to address these issues. This Action Plan included the goal of increasing the transparency by posting demographic information of pivotal (or key) clinical trials used to support approval decisions.

We examined how often these data were available in 2015 for all studies used to support approval of all original high-risk medical devices approved in the calendar year following the FDA Action Plan. Examples of these medical devices include stents, bone grafts, heart valves, and spinal cord stimulators. We wanted to understand if age, sex, and race and ethnicity data were available and if the results of clinical studies supporting these medical devices were analyzed to assess if there were differences in safety and effectiveness by these important demographic factors.

Our main findings are that FDA Summaries publicly reported age for 65% of study populations, sex for 66%, and race and/or ethnicity for 51%. Analyses to assess if demographic factors may have impacted device safety and effectiveness were only conducted by age for 9%, by sex for 17%, and by race for 4% of clinical studies.

Continue reading

FDA Reports on Patient Satisfaction With LASIX Procedure Interview with:

Malvina Eydelman, M.D. Division Director; Division of Ophthalmic and Ear, Nose and Throat Devices Office of Device Evaluation Center for Devices and Radiological Health FDA.

Dr. Malvina Eydelman

Malvina Eydelman, M.D.
Division Director; Division of Ophthalmic and Ear, Nose and Throat Devices
Office of Device Evaluation
Center for Devices and Radiological Health
FDA. What is the background for this study?

Response: In October 2009, the FDA, the National Eye Institute (NEI), and the Department of Defense (DoD) launched the LASIK Quality of Life Collaboration Project (LQOLCP) to help better understand the potential risk of severe problems that can result from LASIK. The project aimed to develop a tool to determine the percent of patients who develop difficulties performing their usual activities following LASIK, and to identify predictors for those patients.

At the time we developed our project, there was a limited amount of valid scientific data on certain patient-reported outcomes (PROs) related to LASIK. A PRO is a report of a condition experienced and reported by the patient, not the health care provider.

Most LASIK studies used tools, such as questionnaires, to assess visual symptoms, but only after the surgery. The Patient-Reported Outcomes with LASIK (PROWL) studies in the LQOLCP assessed visual symptoms both before and after their LASIK surgery to identify changes over time. The studies also measured the impact symptoms directly had on performing usual activities, which had not previously been done.

Continue reading

Smoking Warnings in Pictures Worth a Thousand Words? Interview with:

Marissa G. Hall, MSPH Doctoral Candidate, Department of Health Behavior Gillings School of Global Public Health University of North Carolina at Chapel Hill

Marissa Hall

Marissa G. Hall, MSPH
Doctoral Candidate, Department of Health Behavior
Gillings School of Global Public Health
University of North Carolina at Chapel Hill What is the background for this study? What are the main findings?

Response: The US Food and Drug Administration (FDA) requires pictorial warnings on cigarette packs, but implementation was stalled by a 2012 lawsuit by the tobacco industry. The US Court of Appeals for the DC Circuit ruled against pictorial warnings, saying that FDA had “not provided a shred of evidence” that the pictorial warnings reduce smoking. To address this critique, our randomized trial examined the impact on smoking behavior of adding pictorial warnings to the front and back of cigarette packs. We found that smokers with pictorial warnings on their packs were more likely to attempt to quit and to successfully quit than those whose packs had text-only warnings.

Continue reading

Incomplete Follow Up Rates Exceed 10% in Oral Antithrombotic Trials

Victor Serebruany, MD, PhD HeartDrug Research, Towson, Maryland Department of Neurology Johns Hopkins University Baltimore, Maryland

Dr. Victor Serebruany Interview with:
Victor Serebruany, MD, PhD
HeartDrug Research, Towson, Maryland
Department of Neurology Johns Hopkins University Baltimore, Maryland

Medical Research: What is the background for this study? What are the main findings?

Dr. Serebruany: Missing data are common challenges to the validity of trial results, yet it is unclear how to characterize the extent of missing data.  We compared the published lost-to-follow-up rates to incomplete follow-up rates determined from subject records submitted to the FDA for major oral antithrombotic trials.  The 21 trials having both sets of rates included 270,089 patients followed for a median duration of 20 months.  The mean published lost-to-follow-up rates is 0.4% (median 0.3%, range 0.005% to 2%), consistently much lower than the FDA incomplete follow-up rates: mean 12% (median 13%, range 2% to 23%).  There is no correlation between the publication and FDA-calculated  rates (R 0.07, p = 0.76).   The FDA rates exceed greatly the endpoint rate differences: mean 1.3% (median 1,0%, range 0.2% to 3.0%).

Medical Research: What should clinicians and patients take away from your report?

Dr. Serebruany: That the FDA incomplete follow-up rates greatly exceed the endpoint rate differences raises questions of whether the endpoint differences may be due to differential follow-up rather than drug effect.  That they greatly exceed the measures routinely reported for trials, i.e., lost-to-follow-up rates, suggests that current trial reporting is inadequate.  Completeness of follow-up and other indicators of trial data quality should be considered when interpreting trial results.

Continue reading

FDA Proposes Restricting Sunlamps To Adults: Tanning = Skin Damage

Dr. Jennifer A. Stein MD PhD Associate Professor Department of Ronald O. Perelman Department of Dermatology NYU Langone Medical Center

Dr. Jennifer Stein Interview with:
Dr. Jennifer Stein MD
Associate Professor

Department of Ronald O. Perelman
Department of Dermatology
NYU Langone Medical Center

Medical Research: What is the background for this FDA decision? What is the issue surrounding tanning beds?

Dr. Stein:  This is an important proposal from the FDA because it restricts minors from tanning and requires adults to sign an acknowledgement stating they have been informed about the risks of tanning.

There is clear evidence that indoor tanning significantly increases a person’s risk for skin cancer, including melanoma, a potentially deadly form of skin cancer.

It is important to protect young people from the dangers of tanning beds, especially because many patients report that they started indoor tanning as teens. There are 1.6 million minors using tanning beds every year.

MedicalResearch: What is the problem with tanning?  Isn’t a tan better than a sunburn?

Dr. Stein: Tanning beds deliver intense amounts of UVA. We know that UVA penetrates deep into the skin and causes mutations that lead to skin cancers, including melanoma. Tanning is a sign that skin cells have been damaged by UV light.

Continue reading

FDA Study Compares Anaphylactic Risk of IV Iron Products

Cunlin Wang, MD, PhD Division of Epidemiology I, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research US Food and Drug Administration

Dr. Wang Interview with:
Cunlin Wang, MD, PhD
Division of Epidemiology I,
Office of Surveillance and Epidemiology,
Center for Drug Evaluation and Research
US Food and Drug Administration

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Wang:  IV Iron has been known for its risk of anaphylactic reaction, but there has been little research on the comparative safety of individual IV Iron products from a large population-based study. This study included 688,183 new users of IV iron not on dialysis from the U.S. Medicare program over a ten-year span (January 2003 to December 2013). The main findings of the study are:  the risk for anaphylaxis at first exposure was higher for iron dextran than non-dextran IV iron products combined (iron sucrose, gluconate and ferumoxytol).  When individual IV Iron products were compared, the data suggested that iron dextran has the highest risk of anaphylaxis and Iron sucrose has the lowest risk, estimated both at the first time exposure and after cumulative exposures.  The low and high molecular weight dextran products could not be individually identified during most of study period. However,  from January 2006 through March 2008, during which the use of two dextran products could be distinguished, there was very low use of high molecular weight dextran (Dexferrum@). This suggested that the study results likely represent the risk of the low molecular weight dextran (Infed@).

Continue reading

New Immunotherapy May Extend Lives Of Some Lung Cancer Patients Interview with:
Dickran Kazandjian, MD
Office of Hematology and Oncology Products
Center for Drug Evaluation and Research
US Food and Drug Administration
Silver Spring, Maryland

Medical Research: What is the background for this study? What are the main findings?

Dr. Kazandjian: Nivolumab is the first approved immunotherapy, for the treatment of metastatic squamous non–small-cell lung cancer (NSCLC) after platinum-based chemotherapy.  FDA initiated an expedited review after obtaining the data monitoring committee report of a planned interim analysis of a second-line squamous NSCLC trial demonstrating a large overall survival benefit (CheckMate 017).

Nivolumab efficacy in metastatic Squamous (SQ) NSCLC has been previously reported in two studies.  CheckMate 063 was a single-arm trial in 117 patients with metastatic SQ NSCLC who had progressed after previous treatment with 2 systemic regimens including platinum-based doublet chemotherapy (Rizvi et al)  CheckMate 017 was a randomized study of nivolumab compared to docetaxel in 272 patients with metastatic SQ NSCLC who had progressed after prior platinum-based doublet chemotherapy (Brahmer et al).  The median survival of patients randomized to nivolumab was 9.2 months vs 6.0 months for docetaxel (hazard ratio, 0.59; 95%CI, 0.44-0.79; P < .001) a 41% improvement in the risk of death. Approval was supported by the single-arm study which demonstrated an objective response rate of 15% and at the time of analysis, 10 of the 17 responding patients (59%) had response  durations of 6 months or longer. The FDA approved nivolumab on March 4, 2015, saving 6 months by not waiting for formal preparation of data by the sponsor and 2.5 months by expediting review.

Continue reading

“Breakthrough” FDA Labeling of New Drugs Can Lead To Unwarranted Expectations

Dr. Tamar Krishnamurti PhD Department of Engineering & Public Policy Carnegie Mellon University Pittsburgh, PA Interview with:
Dr. Tamar Krishnamurti PhD
Department of Engineering & Public Policy
Carnegie Mellon University
Pittsburgh, PA 15213 

Medical Research: What is the background for this study? What are the main findings?

Dr. Krishnamurti: In 2012, the Food and Drug Administration Safety and Innovation Act became law. As part of this law, FDA can assign drugs the “breakthrough” designation. Breakthrough drugs are drugs that are intended to treat a serious or life threatening condition and have shown preliminary evidence of a substantial improvement over existing therapies on at least one one clinically significant endpoint. These clinical endpoints can be surrogate outcomes and don’t have to be a direct outcome of the disease. All FDA press releases announcing approval of breakthrough-designated drugs use the term “breakthrough” and about half use the term “promising” when describing the drugs. Our study randomly assigned participants to read 1 of 5 short descriptions of a recently approved drug. These vignettes differed by the term assigned to the drug (e.g. “breakthrough” or “promising”) or by whether the basis for the designation was clearly and succinctly explained in the description. We found that using the terms “breakthrough” and “promising” to describe these drugs resulted in people having unwarranted confidence about the effectiveness of breakthrough drugs, which could prevent them from making a fully informed decision about whether to take the drug or not. The influence of these terms on peoples’ judgments was mitigated by explaining the regulatory meaning of the drug’s approval (which is required in the drug’s professional label, but not in public discourse about the drug).

Continue reading

Some Adverse Events Not Reported in Regulated Time Frame To FDA

Dr. Pinar Karaca-Mandic Ph.D Associate Professor, Health Policy & Management School of Public Health Division of Health Policy & Management Minneapolis MN University of Interview with:
Dr. Pinar Karaca-Mandic Ph.D
Associate Professor, Health Policy & Management
School of Public Health
Division of Health Policy & Management Minneapolis MN
University of Minnesota

Medical Research: What is the background for this study? What are the main findings?

Dr. Karaca-Mandic: Drug safety has received a lot of attention recently, and FDA’s post-marketing drug surveillance program (FAERS) offers and important opportunity to monitor drug safety and update drug warnings. There has been an increasing trend in reports to FAERS of serious adverse drug events and earlier studies suggested that these trends were primarily driven by increased manufacturer reports of serious and unexpected adverse events. While these studies highlighted the overall increase in adverse event rates, manufacturer timeliness in reporting and compliance with the 15 calendar day regulation for expedited reports was unknown, though some recent media coverage has offered anecdotal examples of delay. My co-authors and I were interested in studying not only the reporting of these events, by manufacturers to FDA, but also their timely reporting as required by the Federal regulation. Delays in reporting can have important public health consequences because the FDA uses this information to update drug warnings.

We found that about 10% of serious and unexpected adverse events that are subject to the 15-day regulation were not reported by 15 days. We also found that events that involved a patient death were more likely to be delayed. For example, we found that after adjusting for other characteristics of the report and the patient, about 12% of events that involved patient death, and 9% of those that did not involve patient death were delayed beyond 15 days.

Continue reading

Co-ingestion of Benzodiazepines and Opioids Contributes to Overdose and Death Interview with:
Christopher M. Jones, Pharm D., M.P.H
Senior advisor, Office of Public Health Strategy and Analysis
Office of the Commissioner, Food and Drug Administration

Medical Research: What is the background for this study?

Dr. Jones: Opioid analgesics and benzodiazepines are the two most common drug classes involved in prescription drug overdose deaths. In 2010, 75% of prescription drug overdose deaths involved opioid analgesics and 29% involved benzodiazepines. Opioid analgesics and benzodiazepines are also the most common drugs associated with emergency department visits due to nonmedical use of prescription drugs.

Combined opioid and benzodiazepine use has been suggested as a risk factor for overdose death.

Opioids and benzodiazepines have complex drug interactions and in combination can result in synergistic respiratory depression, but the exact mechanisms by which benzodiazepines worsen opioid-related respiratory depression are not fully understood.

Widespread co-use of benzodiazepines and opioids has been documented in both chronic pain and addiction treatment settings. Studies suggest that among patients who receive long-term opioids for chronic non-cancer pain, 40% or more also use benzodiazepines. Among patients who abuse opioids, benzodiazepine abuse also is prevalent, and co-users report using benzodiazepines to enhance opioid intoxication.

This study builds on the prior literature by analyzing trends on how the combined use of opioids and benzodiazepines in the U.S. contributes to the serious adverse outcomes of nonmedical use–related ED visits and drug overdose deaths. A better understanding of the consequences of co-use of these medications will help identify at-risk populations, inform prevention efforts, and improve the risk–benefit balance of these medications.

Medical Research: What are the main findings?

Dr. Jones: From 2004 to 2011, the rate of nonmedical use–related Emergency Department visits involving both opioid analgesics and benzodiazepines increased from 11.0 to 34.2 per 100,000 population. During the same period, drug overdose deaths involving both drugs increased from 0.6 to 1.7 per 100,000. Statistically significant increases in Emergency Department visits occurred among males and females, non-Hispanic whites, non-Hispanic blacks, and Hispanics, and all age groups except 12–17-year-olds. For overdose deaths, statistically significant increases were seen in males and female, all three race/ethnicity groups, and all age groups except 12–17-year-olds. Benzodiazepine involvement in opioid analgesic overdose deaths increased each year, increasing from 18% of opioid analgesic overdose deaths in 2004 to 31% in 2011.

Continue reading

Heroin Addiction Most Often Preceded by Opioid Abuse Interview with:
Christopher M. Jones, Pharm D., M.P.H.

Senior advisor, Office of Public Health Strategy and Analysis
Office of the Commissioner, Food and Drug Administration

Medical Research: What is the background for this study?

Dr. Jones:  Heroin use and overdose deaths have increased significantly in the United States in recent years. Most heroin users have a history of nonmedical use of prescription opioid pain relievers as well, and an increase in the rate of heroin overdose deaths has occurred concurrently with an epidemic of prescription opioid overdoses.

Although it has been postulated that efforts to curb opioid prescribing, resulting in restricted prescription opioid access, have fueled heroin use and overdose, a recent analysis of 2010–2012 drug overdose deaths in 28 states found that decreases in prescription opioid death rates within a state were not associated with increases in heroin death rates; in fact, increases in heroin overdose death rates were associated with increases in prescription opioid overdose death rates.

In addition, a study examining trends in opioid pain reliever overdose hospitalizations and heroin overdose hospitalizations between 1993 and 2009 found that increases in opioid pain reliever hospitalizations predicted an increase in heroin overdose hospitalizations in subsequent years. Thus, the changing patterns of heroin use and overdose deaths are most likely the result of multiple, and possibly interacting, factors. Moreover, there is a lack of research examining recent trends in the prevalence of other substance use among persons using heroin, especially among the high-risk population of heroin users who meet diagnostic criteria for heroin abuse or dependence.

We wanted to better understand how heroin use is changing and identify the demographic and substance using groups that are at greatest risk for use. Knowing this information can help prevention efforts.

HHS Secretary Sylvia M. Burwell has made addressing opioid abuse, dependence, and overdose a priority and work is underway within HHS on this important issue. The evidence-based initiative focuses on three promising areas: informing opioid prescribing practices, increasing the use of naloxone – a drug that reverses symptoms of a drug overdose, and using medication-assisted treatment to slowly move people out of opioid addiction.

The Obama Administration is also committed to tackling the prescription drug and heroin epidemic, proposing significant investments to intensify efforts to reduce opioid misuse and abuse.

Medical Research: What are the main findings?

Dr. Jones:  Heroin use has increased significantly across most demographic groups. There were significant increases in heroin use among demographic groups that have had historically lower rates of heroin use, including women, the privately insured, and people with higher incomes. In fact, the gap between men and women, low and high incomes, and people with Medicaid and private insurance have narrowed in the past decade.

Heroin use is occurring in the context of broader poly-substance use, including marijuana, alcohol, cocaine, and prescription drugs. The use of heroin with other substances increases the risk of overdose. Nearly all (96%) people who reported heroin use also reported using at least one other drug in the past year. More than half (61%) used at least three other drugs.

Among heroin users in 2011-2013:

  • 45% had past-year prescription opioid painkiller abuse or dependence
  • 36% had past-year alcohol abuse or dependence
  • 25% had past-year cocaine abuse or dependence
  • 24% had past-year marijuana abuse or dependence

As heroin abuse and dependence have increased, so have heroin-related overdose deaths. From 2002 through 2013, the rate of heroin-related overdose deaths nearly quadrupled.

The strongest risk factor for heroin abuse or dependence was opioid pain reliever abuse or dependence followed by cocaine abuse or dependence.

Medical Research: What should clinicians and patients take away from your report?

Dr. Jones:  Clinicians can follow best practices for responsible painkiller prescribing to reduce opioid painkiller addiction, the strongest risk factor for heroin addiction. This entails

  • 1) using state prescription drug monitoring programs and asking patients about past or current drug and alcohol use prior to considering opioid treatment;
  • 2) prescribing the lowest effective dose of an opioid and only the quantity needed for each patient; and
  • 3) linking patients with substance use disorders to effective substance abuse treatment services, including the use of medication assisted treatment for people with opioid use disorders.

Patients and others can learn more about the risks of using heroin and other drugs and become trained in how to recognize and respond to an opioid overdose. For people who are struggling with substance abuse problems, they can call 1-800-662 HELP for assistance.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: More research is needed to evaluate the impact of interventions designed to reduce prescription opioid and heroin abuse. We also need to conduct additional research to further understand the risk and protective factors for heroin initiation and heroin addiction.


Vital Signs: Demographic and Substance Use Trends Among Heroin Users — United States, 2002–2013


July 10, 2015 / 64(26);719-725

Christopher M. Jones, Pharm D., M.P.H. (2015). Heroin Addiction Most Often Preceded by Opioid Abuse 

High-Dose Flu Vaccine Prevented More Influenza Infections In Elderly Than Standard Dose

Dr Richard Forshee PhD Food and Drug Administration, Silver Spring, MD Interview with:
Dr Richard Forshee PhD

Associate Director for Research in the Office of Biostatistics and Epidemiology Center for Biologics Evaluation and Research
U.S. Food and Drug Administration

Silver Spring, MD
On behalf of the study authors

Medical Research: What is the background for this study? What are the main findings?

Dr. Forshee: Influenza continues to be a major public health concern causing illness, hospitalization, and death. The elderly are at highest risk for seasonal influenza complications, including hospitalization and death. As people grow older their ability to raise a strong protective immune response can weaken.  The availability of a vaccine that uses a higher dose to induce a stronger immune response could reduce the serious impact of influenza in this age group.  The purpose of this study was to determine whether a high-dose inactivated influenza vaccine was more effective for prevention of probable influenza infections and influenza-related hospital admissions, compared to standard-dose inactivated influenza recipients.

In December 2009, the U.S. Food and Drug Administration (FDA) licensed Fluzone High Dose, an injectable inactivated trivalent seasonal influenza vaccine for people ages 65 years and older. This high-dose vaccine contains four times more hemagglutinin—the active ingredient in influenza vaccines that cause the human body to produce antibodies against the influenza viruses—than the standard-dose vaccine. The FDA approved the high-dose vaccine using the accelerated approval regulatory pathway, which allows the agency to approve products for serious or life-threatening diseases based on reasonable evidence of a product’s effectiveness.  This pathway reduces the time it takes for needed medical products to become available to the public.  Studies conducted prior to licensure showed an enhanced immune response to the high-dose vaccine compared with the standard-dose vaccine in individuals 65 years of age and older indicating that the high-dose vaccine was reasonably likely to be more effective in preventing influenza disease.

As part of the accelerated approval process, the manufacturer, Sanofi Pasteur, was required to conduct a randomized clinical study post-licensure to confirm that the high-dose vaccine decreased seasonal influenza disease after vaccination relative to standard dose vaccine. This confirmatory study demonstrated that the high–dose vaccine prevented 24% more cases of laboratory-confirmed influenza illness compared to standard-dose vaccines in people 65 years of age and older. However, the study was not large enough to determine efficacy of the vaccine against severe disease.

A team of scientists from FDA, the Centers for Disease Control and Prevention, Centers for Medicare and Medicaid Services, and Acumen LLC ( an independent research organization) studied the relative effectiveness of the high-dose influenza vaccine in the U.S. population ages 65 years and older.  The observational study, which covered the 2012-2013 influenza season, found a significant reduction both in influenza-associated illness and in influenza-related hospitalizations among individuals who received the high-dose vaccine, compared to those receiving the standard dose.

Additional background about this study: “Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis” is available at:

A commentary on the study titled “Novel observational study designs with new influenza vaccines” is available at: Continue reading

Raw Milk Link To Higher Risk of Foodborne Illnesses Interview with:
Benjamin Davis BA
CLF-Lerner Fellow at the Johns Hopkins Center for a Livable Future.

Medical Research: What is the background for this study? What are the main findings?

Response: The Food and Drug Administration banned the inter-state sale of raw (i.e. unpasteurized) milk in 1987. Currently 30 states still allow raw milk sales on local farms or in stores. We were requested by the Maryland General Assembly’s Health and Government Operations Committee to conduct a review of the health benefits and risks of raw versus pasteurized milk in response to proposed legislation that would legalize raw milk in the state. After reviewing over 80 scientific articles we concluded that raw milk carries a substantially higher risk of foodborne illness when compared to pasteurized milk. However drinking raw milk may reduce allergies among children in rural settings. Continue reading

FDA Study on Diabetes Medication Use In US Shows Marked Increase in Number of Prescriptions

Christian Hampp PhD Senior Staff Fellow/Epidemiologist at FDA Division of Epidemiology-I, Office of Pharmacovigilance and Epidemiology, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Interview with:
Christian Hampp PhD
Senior Staff Fellow/Epidemiologist at FDA
Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD What are the main findings of the study?

Dr. Hampp: Our study described U.S. market trends for antidiabetic drugs, focusing on newly approved drugs, concomitant use of antidiabetic drugs, and effects of safety concerns and restrictions on thiazolidinedione use.

We found that since 2003, the number of adult antidiabetic drug users increased by approximately 43% to 18.8 million in 2012.  During 2012, 154.5 million prescriptions for antidiabetic drugs were filled in outpatient retail pharmacies.  Since 2003, metformin use increased by 97% to 60.4 million prescriptions dispensed in 2012.  Among antidiabetic drugs newly approved for marketing between 2003 and 2012, the dipeptidyl-peptidase-4 (DPP-4) inhibitor sitagliptin had the largest share with 10.5 million prescriptions in 2012.

Possibly triggered by safety concerns, the use of pioglitazone declined in 2012 to approximately 52% of its peak in 2008, when 14.2 million prescriptions were dispensed in outpatient retail pharmacies and the use of rosiglitazone use decreased to fewer than 13,000 prescriptions dispensed in retail or mail-order pharmacies in 2012.

Continue reading

FDA Drug Approvals Have Variable Clinical Trial Evidence Record Interview with:
Nicholas S. Downing, AB
Yale University School of Medicine
New Haven, Connecticut What are the main findings of the study?

Answer: In our systematic review of all new drugs approved by the FDA over an 8 year period, we found that there was real variability in the quality and quantity of clinical trial evidence used as the basis of the agency’s approval decisions. Some drugs were studied in multiple randomized, double-blinded, controlled clinical trials that provide very helpful information for patients and physicians. However, other drugs were studied in clinical trials that did not produce as much information about their safety and effectiveness.
Continue reading