Drug Authorizations: JYNNEOS smallpox vaccine, RYBELSUS for Type 2 Diabetes, ERLEADA for Metastatic Prostate Cancer, OFEV for Interstitial Lung Disease

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JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Nonreplicating) suspension for subcutaneous injection

Bavarian Nordic A/S

INDICATION: Caccine indicated for prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high risk for smallpox or monkeypox infection.

ADDRESSING UNMET NEED: Only currently FDA-approved vaccine for the prevention of monkeypox disease

  • Routine vaccination of the American public was stopped in 1972; thus a large proportion of the U.S., as well as the global population has no immunity
  • Reflects U.S. government’s commitment to preparedness for intentional release of this highly contagious virus

MECHANISM OF ACTION: Live vaccine produced from the strain Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), an attenuated, non-replicating orthopoxvirus; elicits humoral and cellular immune responses to orthopoxviruses

EFFICACY:

  • Clinical study, n=400 healthy adults, 18 -42 years, never been vaccinated for smallpox
  • Endpoint: Noninferior immune responses with Jynneos vs.  ACAM2000, an FDA-approved vaccine smallpox prevention
  • Supportive data from non-human primates – Jynneos protected from exposure to viruses related to the smallpox virus.
  • Monkeypox effectiveness:  Antibody responses in smallpox clinical study participants and in non-human primates

SAFETY:

  • N>7,800 individuals receiving at least one dos
  • Commonly reported side effects: Pain, redness, swelling, itching, firmness at the injection site, muscle pain, headache and fatigue

REG PATHWAY: BLA

  • Priority Review and material threat medical countermeasure (MCM) priority review voucher
  • Vaccine also part of the Strategic National Stockpile (SNS), the nation’s largest supply of potentially life-saving pharmaceuticals and medical supplies for use in a public health emergency

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RYBELSUS (semaglutide) oral tablets 

Novo Nordisk

INDICATION: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

ADDRESSING UNMET NEED: First glucagon-like peptide (GLP-1) receptor protein treatment approved that does not need to be injected

MECHANISM OF ACTION: Acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1

EFFICACY:

  • Several clinical trials, placebo-controlled and compared to other GLP-1 injection treatments, stand-alone therapy and in combination with other diabetes treatments, paitents with Type 2 diabetes
  • In the placebo-controlled studies: Aignificant reduction in blood sugar (hemoglobin A1c);  after 26 weeks, 69%  – 77% on Rybelsus decreased their HbA1c to < 7%, vs.  31% on placebo

SAFETY:

  • Boxed warning:  Increased risk of thyroid c-cell tumors including medullary thyroid carcinoma (MTC)
  • Warnings: Pancreatitis,  Diabetic retinopathy, hypoglycemia, acute kidney injury and hypersensitivity reactions
  • Most common side effects: Nausea, diarrhea, vomiting, decreased appetite, indigestion and constipation

REG PATHWAY: NDA

  • Required  pediatric assessments: 52-week, randomized, double-blind, placebo-controlled parallel group study in pediatric patients ages 10-17
  • Postmarketing requirement: Medullary thyroid carcinoma registry-based case series of at least 15 years duration

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ERLEADA (apalutamide) tablets

Janssen

INDICATION FOR USE:  For treatment of Metastatic castration-sensitive prostate cancer (mCSPC)

EFFICACY & SAFEY:

  • Randomized, double-blind, placebo-controlled, multi-center clinical trial, n= 1,052 patients with mCSPC, Erleada vs . placebo
  • Major efficacy outcome: Overall Survival (OR) and radiographic progression-free survival (rPFS) . Statistically significant improvements in OS (hazrad ratio 0.67),  p=0.0053;  rPFS (hazard ratio 0.48), p<0.0001
  • Most common adverse reactions:  Fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture

REG PATHWAY: sBLA

  • Initially approved for non-metastatic prostate canacer
  • Used OCE’s Real-Time Oncology Review (RTOR) pilot program and accompanying Assessment Aid
  • Granted priority review

LABEL


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OFEV  (nintedanib) capsules

Boehringer Ingelheim

INDICATION: To slow the rate of decline in pulmonary function in patients with systemic sclerosisassociated interstitial lung disease (SSc-ILD).

ADDRESSING UNMET NEED:

  • ~ 100,000 US individuals have scleroderma, and ~ half of scleroderma patients have interstitial lung disease associated SSc-ILD
  • Slows rate of decline in pulmonary function in SSc-ILD

MECHANISM OF ACTION: IUnhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs); blocks intracellular signaling which is crucial for proliferation, migration, transformation of fibroblasts related to IPF pathology

EFFICACY:

  • Randomized, double-blind, placebo-controlled trial, n=576 patients, 20-79 years with disease, treatment for 52 weeks – up to 100 weeks
  • Primary endpoint: .Forced vital capacity (FVC) – a measure of lung function, defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible
  • Less lung function decline with Ofev vs placebo

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SAFETY:

  • Most frequent serious adverse event: Pneumonia, diarrhea
  • Warnings: Moderate or severe hepatic impairment,  embryo-fetal toxicity

REG PATHWAY: sNDA

  • Originally approved in 2014 for idiopathic pulmonary fibrosis (IPF), which is another interstitial lung condition
  •  

    Received Priority Review designation, Orphan Drug designation

LABEL


Image credits: Bavarian Nordic, Novo Nordisk, Janssen, Boehringer Ingelheim

Vaping Illnesses

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Vaping Illnesses: Consumers can Help Protect Themselves by Avoiding Tetrahydrocannabinol (THC)-Containing Vaping Products

  • Consumers are likely aware of the recent reports of respiratory illnesses — including some resulting in deaths – following the use of vaping products
  • FDA remains deeply concerned about these incidents and is working closely with CDC, state and local public health partners to investigate
  • More information needed to better understand whether there’s relationship between specific products or substances and reported illnesses
  • CDC and the FDA encourage the public to submit detailed reports of any unexpected tobacco- or e-cigarette-related health or product issues to the FDA via the online Safety Reporting Portal.

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image credit: FDA

Biosimilars Basics

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New patient webpage o help increase awareness of and understanding of Biosimilars

  • Basic definitions: biological medications, biosimilar medications, and other terms to facilitate understanding the relationship between biosimilars and the original (reference) medications they are compared to
  • Increase awareness: FDA-approved biosimilar medications are safe and effective medications for treating many illnesses such as chronic skin and bowel diseases, arthritis, kidney conditions, and cancer
  • Provide details: How biosimilar medications can benefit patients

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2019 FDA Science Forum

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2019 FDA Science Forum

2019 FDA Science Forum entitled Transforming Health: Innovation in FDA Science  with topic areas

  1. Precision Health: For individuals and special populations
  2. Advanced Technology: 3D printing and nanomaterials
  3. Product Accessibility, Integrity, and Security: Theory, modeling, methodology
  4. Predictive Tools: In vitro/in vivo assays and computational modeling
  5. Advancing Digital Health and Artificial Intelligence: Artificial intelligence and evaluating digital health devices
  6. Outbreak! Prevention through cybersecurity, promoting medical product security, rapid response to infectious disease outbreaks
  7. Addiction: Neurobiology, opioids, cannabinoids, nicotine
  8. Empowering Consumers, Patients, and Other Stakeholders: Science of patient input.

LEARN


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News & Views: Patient-Focused drug development, Benefit-Risk for weight loss devices, Humanitarian Device Exemption, Warning for umbilical cord blood products, Special 510(k) program, Warning to JUUL, Safer Technologies Program


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Patient-Focused Drug Development (PFDD) Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making

Series of four methodological guidance documents to collect and submit patient experience data and other relevant patients and caregivers information

  1. Collecting Comprehensive and Representative Input
  2. Methods to Identify What is Important to Patients
  3. Selecting, Developing or Modifying Fit-for-Purpose Clinical Outcome Assessments
  4. Incorporating Clinical Outcome Assessments into Endpoints for Regulatory Decision M​aking​

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Capture.JPGConsideration of Benefit-Risk Approaches for Weight-Loss Devices

Proposal for assessing tolerability of risk in light of varying degrees of effectiveness for devices intended for weight loss

Benefits: 

  • Weight loss: Amount of weight loss, proportion of patients experiencing weight loss, durability of weight loss
  • Changes in comorbidities: Clinically significant reduction in HbA1c18, hypertension, and/or hyperlipidemia

Risks: 

  • Adverse events: Severity, types, numbers, rates, duration 
  • Long-term effects of the device permanent implantation, anatomic changes, restriction of future treatment options, reversibility limitations
  • Clinical treatments/procedures related to the device: Expected concomitant medications or therapies, rate of early device removal, risks related to placement/removal procedures

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Humanitarian Device Exemption (HDE) and Humanitarian Use Devices (HUDs)

Devices intended to benefit US patients in the treatment or diagnosis of diseases or conditions that affect or are manifested in not more than 8,000 individuals per year

  • Will not expose patients to an unreasonable or significant risk of illness or
    injury, and probable benefit to health outweighs the risk
  • Would not be available to a person with the disease or condition in question
    without the HDE; No comparable device

Scope of guidance:

  • FDA Review Actions
  • Assessing Probable Benefit and Risk
  • Post-Approval Requirements
  • Special Considerations for Devices Marketed Under an HDE
  • Appendices to support the HDE Program: Filing Checklist, Probable Benefit-Risk Assessment Summaries

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Capture.JPGUnapproved Stem cell therapy – Warning to Stemell for selling unapproved umbilical cord blood and umbilical cord products that may put patients at risk

Warning to Stemell, Inc. (Stemell), CA, for products derived from umbilical cord blood and umbilical cord: StemL UCB-Plus and StemL UCT-Plus

  • Significant deviations from current good tissue practice (CGTP) and current good manufacturing practice (CGMP) requirements
  • Deficient donor eligibility practices and environmental monitoring
  • Creating potential significant safety concerns that put patients at risk

False claim that stem cell products don’t fall under the regulatory provisions for drugs and biological products

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Special 510(k) Program

Facilitate submission, review, clearance of change to manufacturer’s own legally marketed predicate device (“existing device”) authorized through 510(K) or De Novo

  • Performance data are unnecessary
  • If performance data are necessary, well-established methods are available
  • All performance data necessary to support SE can be reviewed in a summary or risk analysis format

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Warning to JUUL Labs for marketing unauthorized modified risk tobacco products, including in outreach to youth

For marketing unauthorized modified risk tobacco products

  • Engaging in labeling, advertising, and/or other activities directed to consumers
  • Presentation given to youth at a school.

Requesting more information, about several issues raised in a recent Congressional hearing regarding JUUL’s outreach and marketing practices

  • Targeted at students, tribes, health insurers and employers

Part of series of FDA actions for providing strong oversight of e-cigarettes and other electronic nicotine delivery systems (ENDS) 

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Safer Technologies Program (STeP) for Medical Devices

To spur innovation towards safer medical devices and was modeled after the Breakthrough Devices Program

  • For PMA, De Novo and 510(K) pathways; Devices and device-led combination products
  • Should be reasonably expected to significantly improve the benefit-risk profile
  • reduction in the occurrence of a known serious adverse event
  • reduction in the occurrence of a known device failure mode
  • reduction in the occurrence of a known use-related hazard or use error
  • improvement in the safety of another device or intervention.

Advantages

  • Interactive and timely communications with the FDA, review team support, senior management engagement
  • Prioritized review
  • May reduce the total time to develop a device and achieve marketing authorization, while still meeting the agency’s gold standard for safety and effectiveness

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News & Views: New health warnings on cigarette packages, Investigation of respiratory illnesses with e-cigarette use, Duodenoscopes with enhanced safety, Uncertainty in device benefit-risk determinations, Benefit-Risk determinations in De Novo classifications, Drugs for male breast cancer, Expediting access to drugs

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New required health warnings with color images for cigarette packages and advertisements to promote greater public understanding of negative health consequences of smoking

Science-based approach to develop and evaluate the new proposed cigarette health warnings

  • Focus on serious health risks – such as bladder cancer, diabetes, erectile dysfunction and conditions that can cause blindness

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CaptureFederal and CDC collaboration to investigate respiratory illnesses reported after use of e-cigarette products

FDA and CDC collaborating to investigate incidents of severe respiratory disease associated with use of e-cigarette products

  • Updating the number of potential cases of respiratory illnesses after use of e-cigarette products
  • Sharing more details about CDC and FDA work
  • Providing public and health partners across the country with information to help mitigate risk of additional incidents

More information needed to better understand relationship between specific products and reported illnesses

  • THC and cannabinoids use reported in many cases
  • e-cigarette products should not be used by youth, young adults, pregnant women, and adults who do not currently use tobacco products

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Capture.JPGTransition to Duodenoscopes with Innovative Designs to Enhance Safety

  • Duodenoscopes used in more than 500,000 endoscopic retrograde cholangiopancreatography (ERCP) procedures each year
  • Have complex designs with reusable hard-to-clean components
  • Failure to correctly reprocess duodenoscope could result in patient-to-patient disease transmission
  • Recommendation to use duodenoscopes with innovative device designs that make reprocessing easier, more effective, or unnecessary. (e.g. Fujifilm Corporation, Duodenoscope model ED-580XT, Pentax Medical, Duodenoscope model ED34-i10T)

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Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions

In premarket decision-making for devices, there exists some uncertainty around benefits and risks – type, magnitude, duration, frequency, other aspects

Appropriate uncertainty in a benefit-risk determination would depend on totality of information covering several factors

  • Extent of probable benefits of the device – magnitude, probability, duration, frequency
  • Extent of probable risks of the device- severity, type, number, rates, probability,  duration
  • Extent of uncertainty of benefit-risk profile of  precedent devices
  • Patients’ perspective on appropriate uncertainty
  • Extent of the public health need
  • Feasibility of generating extensive premarket clinical evidence
  • Ability to reduce or resolve remaining uncertainty postmarket
  • Effectiveness of mitigations, such as labeling, and other tools
  • Type of decision being made (e.g., HDE vs PMA)
  • Probable benefits of earlier patient access to the device

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Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications

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Male Breast Cancer: Developing Drugs for Treatment

Breast cancer is rare in males (<0.1%),  diagnosed at an older age, with more advanced stage of disease, and more likely to have lymph node involvement 

  • Eligibility criteria for clinical trials of breast cancer drugs should allow for inclusion of both males and females
  • May be possible to extrapolate findings to male patients where no difference in efficacy or safety between males and females is anticipated

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Delivering Promising New Medicines Without Sacrificing Safety and Efficacy

Congress has established five programs to expedite patient access to drugs that treat serious or life-threatening conditions while maintaining FDA’s gold standard of safety and efficacy

To assist drug development

  • Fast Track designation:  Drug is intended to treat a serious disease and that laboratory, animal model, or human data show promise
  • Breakthrough Therapy designation:  Preliminary clinical evidence indicates that  drug may demonstrate substantial improvement over available therapy
  • Regenerative Medicine Advanced Therapy designation (RMAT): Preliminary clinical evidence indicates regenerative medicine therapy has potential to address unmet medical needs for such condition

To expedite FDA review timelines: 

  • Priority Review designation FDA aims to take action on a marketing application within six months, compared to 10 months under standard review. Only granted if  data submitted in the marketing application appear to show a significant improvement in safety or effectiveness for a serious condition

Different route for expediting:

  • Accelerated Approval: Approval of a drug that demonstrates an effect on a “surrogate endpoint” that is reasonably likely to predict clinical benefit

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