announced the U.S. Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) for DIFICID ® (fidaxomicin) for oral suspension, and a supplemental NDA (sNDA) for a new indication for use of DIFICID tablets and oral suspension for the treatment of Clostridium (also known as Clostridioides ) difficile infections (CDI) in children aged six months or older. Both applications have received a priority review classification by the FDA. The Prescription Drug User Fee Act (PDUFA), or target action date for both applications, is set for Jan. 24, 2020. The investigational pediatric indication for DIFICID was granted Orphan Drug Designation (ODD) in 2010.
“Evidence indicates the increasing incidence of C. difficile -associated diarrhea among hospitalized children 1,” said Dr. Nicholas Kartsonis, senior vice president, Clinical Research, infectious diseases and vaccines, Merck Research Laboratories. “The filings for the pediatric indication for the new investigational oral suspension formulation of DIFICID, as well as for DIFICID tablets, underscore Merck’s focus and dedication to developing infectious disease treatments for those with unmet needs.”
The sNDA is based primarily on results of the Phase 3 SUNSHINE study 2, which were presented as part of the Late Breaker Oral Abstracts on Emerging Infections at IDWeek 2018 in San Francisco, California.
About DIFICID (fidaxomicin)
DIFICID is a macrolide antibacterial medicine indicated in adults (18 years of age or older) for treatment of Clostridium difficile -associated diarrhea (CDAD). To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridiumdifficile. DIFICID is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in DIFICID. DIFICID should only be used for the treatment of C. difficile-associated diarrhea. DIFICID is not effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin.
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Merck & Co is working a major US hospital provider on a new software system that could help tackle the threat from healthcare-associated infections, the leading HAI: C. diff. infections.
The pharma company’s deal with Premier will see the partners develop and test the combination of a software-based platform and a coordinator to provide surveillance, consultation, support and education to patients with Clostridium difficile infection (C. diff).
Sam Bozzette, MD, chief scientist of Premier’s retrospective and interventional research division Premier Applied Sciences, said: “By increasing clinician and patient knowledge of this often prolonged, and sometimes deadly infection, and developing and testing a software-based application to help reduce the recurrence of C. diff. infection by improving follow-up and management, we believe there is a strong potential to make a real difference to address this critical public health problem.”
Sam Bozzette, MD, PhD, vice president and chief scientist of its retrospective and interventional research division, Premier Applied Sciences. An internationally-recognized researcher and physician executive, Dr. Bozzette provides strategic clinical, analytical and operational direction to further grow the Premier Applied Sciences research business and improve the overall quality, safety and cost-effectiveness of care. “Dr. Bozzette is a leader in medical and social sciences, and has more than 25 years of experience working with academic and non-profit healthcare providers to improve clinical decision-making practices, care delivery efficiency and effectiveness, and population health management,” said Leigh Anderson, chief information officer at Premier. “We are thrilled to have him on board to lead Premier’s data-driven research efforts to set new standards in care delivery through strategic partnerships with healthcare industry leaders across the U.S.”
Premier Applied Sciences, formerly known as Premier Research Services, combines data and analytics with objective clinical outcomes analyses, and partnerships with health systems, life sciences companies, academic institutions and professional societies to develop, teach, test and research care delivery practices and real-world interventions for healthcare improvement. It offers real-world research and analytics, retrospective research, healthcare education, clinical trial innovation and data licensing services.
The work expands Merck’s chronic disease work with Premier, which has seen them co-develop and test solutions that help promote wellness and prevention for specific groups of at-risk patients since 2016.
Raquel Tapia, associate VP, hospital/specialty marketing at Merck, said: “Combining the technical capabilities of Premier and the therapeutic area expertise of Merck has been instrumental in our ability to address these difficult healthcare challenges.
“By testing the solutions in real-world settings and learning from our growing knowledge base, we’re confident that our work together will help patients.”
The partners’ goal is to increase patient access to healthcare services, raise awareness of how to decrease patient risk of recurrence and help patients identify if they are having a recurrence.
The proposed C. diff software intervention will be tested within volunteer Premier member health systems. The firm current has an alliance of around 3,900 US hospitals and health systems and a further 150,000 or so healthcare providers and organizations.
C. diff infections cause serious and life-threatening diarrhea and have become one of the most common microbial cause of healthcare-associated infections in US hospitals. It’s thought that C. diff infections affect approximately half a million people and add $4.8 billion to US healthcare costs each year.
Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.
Recurrent Clostridium difficile Prevention
Wilcox MH1, Gerding DN1, Poxton IR1, Kelly C1, Nathan R1, Birch T1, Cornely OA1, Rahav G1, Bouza E1, Lee C1, Jenkin G1, Jensen W1, Kim YS1, Yoshida J1, Gabryelski L1, Pedley A1, Eves K1, Tipping R1, Guris D1, Kartsonis N1, Dorr MB1; MODIFY I and MODIFY II Investigators.
Background Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy.
Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively.
Methods – We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis.
The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population.
Results In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, -10.1 percentage points; 95% confidence interval [CI], -15.9 to -4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, -9.9 percentage points; 95% CI, -15.5 to -4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, -11.6 percentage points; 95% CI, -17.4 to -5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, -10.7 percentage points; 95% CI, -16.4 to -5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome.
The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively.
The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.
Conclusions Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo.
The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .). Also Resource:
Merck known as MSD outside the United States and Canada, on October 22, 2016 announced that the U.S. Food and Drug Administration (FDA) has approved ZINPLAVA (bezlotoxumab) Injection 25 mg/mL.
Merck anticipates making ZINPLAVA available in first quarter 2017.
ZINPLAVA is indicated to reduce recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence.
ZINPLAVA is not indicated for the treatment of CDI.
ZINPLAVA is not an antibacterial drug. ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI.
CDI is caused by bacteria that produce toxins, including toxin B. Symptoms of CDI include mild-to-severe diarrhea, abdominal pain and fever. The incidence of recurrent CDI is higher in certain patient populations, including people 65 years of age or older and those with compromised immune systems.
“For generations, Merck has been steadfast in its commitment to fighting infectious diseases – and that commitment continues today. ZINPLAVA is a human monoclonal antibody that binds to C. difficile toxin B and neutralizes its effects,” said Dr. Nicholas Kartsonis, vice president of clinical development, infectious diseases, Merck Research Laboratories.
Selected safety information about ZINPLAVA
Heart failure was reported more commonly in the two Phase 3 clinical trials in ZINPLAVA-treated patients compared to placebo-treated patients. These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of ZINPLAVA-treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period. Additionally, in patients with a history of CHF, there were more deaths in ZINPLAVA-treated patients [19.5% (23/118)] than in placebo-treated patients [12.5% (13/104)] during the 12-week study period. The causes of death varied, and included cardiac failure, infections, and respiratory failure. In patients with a history of CHF, ZINPLAVA (bezlotoxumab) should be reserved for use when the benefit outweighs the risk.
The most common adverse reactions occurring within 4 weeks of infusion with a frequency greater than placebo and reported in ≥4% of patients treated with ZINPLAVA and Standard of Care (SoC) antibacterial drug therapy vs placebo and SoC antibacterial drug therapy included nausea (7% vs 5%), pyrexia (5% vs 3%) and headache (4% vs 3%).
Serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of ZINPLAVA-treated patients and 33% of placebo-treated patients. Heart failure was reported as a serious adverse reaction in 2.3% of ZINPLAVA-treated patients and 1.0% of placebo-treated patients.
In ZINPLAVA-treated patients, 10% experienced one or more infusion specific adverse reactions compared to 8% of placebo-treated patients, on the day of or the day after, the infusion. Infusion specific adverse reactions reported in ≥0.5% of patients receiving ZINPLAVA and at a frequency greater than placebo were nausea (3%), fatigue (1%), pyrexia (1%), dizziness (1%), headache (2%), dyspnea (1%) and hypertension (1%). Of these patients, 78% experienced mild adverse reactions, and 20% of patients experienced moderate adverse reactions. These reactions resolved within 24 hours following onset.
As with all therapeutic proteins, there is a potential for immunogenicity following administration of ZINPLAVA. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bezlotoxumab in two Phase 3 studies with the incidence of antibodies in other studies or to other products may be misleading. Following treatment with ZINPLAVA in these two studies, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies.
Bezlotoxumab was developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb), and was licensed to Merck in 2009.
For 125 years, Merck has been a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships.
As Season II concludes, we wish to take this opportunity to sincerely thank each
and every guest for taking time out of their
busy schedule and joining us on Tuesday’s at
10:00a Pacific Time / 1:00p Eastern Time over the past seven months.
C. diff. Spores and More Global Broadcasting Network will be taking a break and will return to live broadcasting on January 17th, 2017 with the Centers for Disease Control and Prevention (CDC) leading the way with our guest Dr. Katherine Fleming-Dutra, Medical Officer, CDC’s Office of Antibiotic Stewardship.
A Prescription for Over-Prescribing: The Key to Fighting
Dr. Fleming-Dutra is a medical epidemiologist with the Office of Antibiotic Stewardship in the Division of Healthcare Quality Promotion at the Centers Disease Control and Prevention (CDC).
Dr. Fleming-Dutra is a pediatrician and pediatric emergency medicine physician and has focused on infectious diseases epidemiology and antibiotic stewardship in the outpatient setting in her career at CDC.
Join Dr. Fleming-Dutra as she discusses a recent study published by the Journal of the American Medical Association, was released showing that at least 30 percent of all prescriptions written in doctors’ offices and emergency rooms are completely unnecessary. So how do we use these alarming results to transform the culture of over-prescribing Dr. Katherine Fleming-Dutra, M.D., will:
Give a detailed explanation of the study results, and provide an in-depth review of specific findings;
Highlight what CDC is doing to promote antibiotic stewardship across healthcare settings, and
Identify what clinicians, other health care professionals, and patients can do to improve antibiotic prescribing, therefore fighting antibiotic resistance.
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Hard Facts: Deaths and illnesses are much higher than reports have shown. Nearly half a million Americans suffered from Clostridium difficile (C. diff.) infections in a single year according to a study released today, February 25, 2015, by the Centers for Disease Control and Prevention (CDC).
• More than 100,000 of these infections developed among residents of U.S. nursing homes.
Approximately 29,000 patients died within 30 days of the initial diagnosis of a C. diff. infection. Of these 29,000 – 15,000 deaths were estimated to be directly related to a C. diff. infection. Therefore; C. diff. is an important cause of infectious disease death in the U.S.
Previous studies indicate that C. diff. has become the most common microbial cause of Healthcare-Associated Infections found in U.S. hospitals driving up costs to $4.8 billion each year in excess health care costs in acute care facilities alone. Approximately
two-thirds of C. diff. infections were found to be associated with an inpatient stay in a health care facility, only 24% of the total cases occurred in patients while they were hospitalized. The study also revealed that almost as many cases occurred in nursing homes as in hospitals and the remainder of individuals acquired the
Healthcare-Associated infection, C. diff., recently discharged from a health care facility.
This new study finds that 1 out of every 5 patients with the Healthcare-Associated Infection (HAI), C. diff., experience a recurrence of the infection and 1 out of every 9 patients over the age of 65 diagnosed with a HAI – C. diff. infection died within 30 days of being diagnosed. Older Americans are quite vulnerable to this life-threatening diarrhea infection. The CDC study also found that women and Caucasian individuals are at an increased risk of acquiring a C. diff. infection. The CDC Director, Dr. Tom Frieden, MD, MPH said, “C. difficile infections cause immense suffering and death for thousands of Americans each year.” “These infections can be prevented by improving antibiotic prescribing and by improving infection control in the health care system. CDC hopes to ramp up prevention of this deadly infection by supporting State Antibiotic Resistance Prevention Programs in all 50 states.”
“This does not include the number of C. diff. infections taking place and being treated in other countries.” “The C Diff Foundation supports hundreds of communities by sharing the Foundation’s mission and raising C. diff. awareness to healthcare professionals, individuals, patients, families, and communities working towards a shared goal ~ witnessing a reduction of newly diagnosed C. diff. cases by 2020 .” ” The C Diff Foundation volunteer Advocates are greatly appreciated and continue to create positive changes by sharing their time aiding in the success of our mission “Raising C. diff. awareness ” worldwide.
“C. diff. Spores and More “ spotlights world renowned topic experts, research scientists, healthcare professionals, organization representatives, C. diff. survivors, board members, and their volunteers who are all creating positive changes in the
C. diff. community and more.
Through their interviews, the C Diff Foundation mission will connect, educate, and empower listeners worldwide.
Questions received through the show page portal will be reviewed and addressed by the show’s Medical Correspondent, Dr. Fred Zar, MD, FACP, Dr. Fred Zar is a Professor of Clinical Medicine, Vice Head for Education in the Department of Medicine, and Program Director of the Internal Medicine Residency at the University of Illinois at Chicago. Over the last two decades he has been a pioneer in the study of the treatment of Clostridium difficile disease and the need to stratify patients by disease severity.
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