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BioMarin Submits EU approval for Vosoritide

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BioMarin Submits EU approval for Vosoritide

July 23, 2020: BioMarin Pharmaceutical announced that the company submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for vosoritide, an investigational, once daily injection analog of C-type Natriuretic Peptide (CNP) for children with achondroplasia, the most common form of disproportionate short stature in humans.

Subject to completion of EMA’s validation check, BioMarin anticipates the start of the MAA review to commence in August 2020. 

The marketing application is based on the outcomes from the randomized, double-blind, placebo-controlled Phase 3 study evaluating the efficacy and safety of vosoritide, announced in December 2019, and further supported by the long-term safety and efficacy from the ongoing Phase 2 and Phase 3 extension studies, and extensive natural history data.

If approved, vosoritide would be the first medicine for the treatment of achondroplasia in Europe.

The company remains on track to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the third quarter of 2020. Vosoritide has Orphan Drug designation from the FDA and the EMA. 

“Years of scientific research have led to this important point in the development of the potentially first pharmacological treatment option for children with achondroplasia. 

We have worked alongside patient advocacy groups from around the world throughout the development, and we appreciate the implications of developing a treatment option for this community, recognizing that this potential new treatment would offer a choice for families who have a child with achondroplasia,” said Hank Fuchs, M.D., President Worldwide Research and Development at BioMarin. 

“Our goal is to provide a treatment option that addresses the underlying cause of the condition and over time demonstrate a reduction of complications that may result from achondroplasia. 

We respect the depth and breadth of views among the community about treatment options and have sought to be scientifically rigorous in providing a robust data set for regulators to evaluate the safety and efficacy of vosoritide. 

We remain grateful to the physicians and families who have participated in our studies that have helped increase the scientific understanding of this investigational treatment.”

“This is an important milestone bringing the achondroplasia community one step closer to a potential therapy,” said Klaus Mohnike, Professor of Paediatrics at Magdeburg University Hospital in Germany and investigator for the vosoritide clinical program. 

“Our scientific and medical knowledge around skeletal dysplasias and achondroplasia in particular continues to increase, which can help us treat the underlying cause of the condition and potentially make a meaningful impact on the lives of children with achondroplasia.”

“It is of critical importance that children with achondroplasia and their families have drug treatment options to advance the standard of care for this condition where currently none are available,” said Carmen Alonso Alvarez, Managing Director of Fundacion ALPE Foundation. 

“We look forward to expanding treatment options that can contribute to the improvement of the health and well-being of children with achondroplasia.”

Achondroplasia

Achondroplasia, the most common form of disproportionate short stature in humans, is characterized by slowing of endochondral ossification, which results in disproportionate short stature and disordered architecture in the long bones, spine, face and base of the skull. This condition is caused by a mutation in the fibroblast growth factor receptor 3 gene (FGFR3), a negative regulator of bone growth.

Beyond disproportionate short stature, people with achondroplasia can experience serious health complications, including foramen magnum compression, sleep apnea, bowed legs, mid-face hypoplasia, permanent sway of the lower back, spinal stenosis and recurrent ear infections.

Some of these complications can result in the need for invasive surgeries such as spinal cord decompression and straightening of bowed legs. In addition, studies show increased mortality at every age.

More than 80% of children with achondroplasia have parents of average stature and have the condition as the result of a spontaneous gene mutation. 

The worldwide incidence rate of achondroplasia is about one in 25,000 live births.  Vosoritide is being tested in children whose growth plates are still “open”, typically those under 18 years of age. 

This is approximately 25% of people with achondroplasia.  In the U.S., Europe, Latin America, the Middle East, and most of Asia Pacific, there are currently no licensed medicines for achondroplasia.

https://investors.biomarin.com/2020-07-23-BioMarin-Submits-Marketing-Authorization-Application-to-European-Medicines-Agency-for-Vosoritide-to-Treat-Children-with-Achondroplasia

Clinical Trial Protocol

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Clinical Trial Protocol

“A protocol for clinical trials is a document outlining how a clinical trial should be performed, including the objective(s), design, methodology, statistical considerations and structure of the study to ensure participants’ health and the validity of the data collected.

What is Clinical Trial Protocol?

If you are involved in clinical investigation, you may need to contribute to the preparation of a clinical trial protocol.

A clinical trial protocol is a document explaining how to perform a clinical trial, including the purpose(s), design, methodology, statistical criteria, and structure of the trial to ensure the health of the patients and the validity of the data collected.

The protocol too provides the background and rationale for conducting the study and the research questions that it addresses, as well as considerations on the ethical issues.

According to the International Conference on Harmonization of Technical Criteria for the Approval of Pharmaceuticals for Human Use ( ICH), the structure and content of clinical trial protocols are standardized and meet the guidelines for good clinical practice (GCP) (first published in 1995, last revised in 2016)

Why is the clinical trial protocol needed?

The protocol is a key quality control tool for all aspects of a clinical trial, being necessary for several reasons:

  • It ensures the health and safety of all study participants
  • It provides a specific study plan
  • It describes and manages the trial, and therefore it should be firmly followed by all the study investigators
  • It guarantees the reliability of data, allowing the combination and comparison of the data across all investigators and/or study sites
  • It notifies  the study administrators, which frequently are a contract research organization (CRO)
  • It is required to obtain ethical approval from the Research Ethics Committee or Institutional Review Board (IRB)

    Related:

Content Guidelines and Templates

It is not uncommon to apply a protocol without critical details, or even whole sections; however, it should be avoided entirely. Create a list of what needs to be included in a clinical research protocol with reference to the relevant ICH guidelines (ICH E6 [R2]) and FDA guidelines.

Templates may also be accessible online (e.g., the joint NIH / FDA protocol template); however, to ensure compliance each template should be carefully checked against current regulatory requirements.

Sample Protocol Templates and Resources:

Protocol development assistance covering a wide-range of therapeutic areas is available. For cancer research protocol templates and additional guidance, please see Cancer Center Investigational Trials Resource Forms.

https://hub.ucsf.edu/protocol-development

Clinical trial Protocol Includes:

The ICH website lists the full list of the topics to be included in the protocol. Note that site specific information may be included in a separate agreement, and some of the information mentioned below may be included in other related protocol documents, such as a brochure for an investigator.

Depending on the anticipated study design, various specific guidelines were created, most of them providing a full list of items to be covered. You can access a standardized treatment template from the US National Cancer Institute’s Cancer Therapy Assessment System as an example here.

  1.  Title page (general information)
    Including protocol title; protocol identification number; date; potential amendments (more information about amendments in a following section); name and contact details of the sponsor, monitor, medical expert, investigator, and other institutions involved.
  2. Background information
    Includes name and description of the investigational product(s); a summary of results from non-clinical and other clinical studies; known and possible risks and benefits; definition of route of administration and dosage; statement ensuring compliance with protocol, GCP and regulatory requirements; description of the population; references to relevant literature.
  3. Objectives/purpose
    A detailed description of the objectives and the purpose of the trial.
  4. Study design
    Including information about the primary and secondary endpoints, description of the nature of the experiment, description of bias minimization steps (including randomization and blinding), description of the medication and dosage schedule, estimated length of subject participation, description of discontinuation requirements, accountability procedures, etc.
  5. Selection and exclusion of subjects
    Explanation of inclusion, exclusion, and withdrawal criteria, as well as withdrawal procedures.
  6.  Treatment of subjects
    Information about treatment (product name, dose, dosing schedule, route, treatment period, follow-up), other permitted or not permitted medications/treatments, procedures for monitoring compliance.
  7.  Assessment of efficacy
    Specification of efficacy parameters, as well as methods and timing for their assessment, recording, and analysis.
  8.  Assessment of safety
    Specification of safety parameters; methods and timing for assessment, recording, and analysis of safety parameters; reporting and follow-up after adverse events.
  9.  Statistics
    Description of the statistical methods to be used; sample size; termination criteria; accounting procedures for incomplete, unused, and spurious data; reporting procedures for any deviations; selection of subjects to be included in the analyses.
  10.  Direct access to source data/documents
    The sponsor will ensure that the protocol (or other written agreement) specifies that the investigator(s)/institution(s) must provide for trial-related monitoring, audits, IRB analysis and regulatory inspection(s), including direct access to the source data and records.
  11. Quality control and assurance
    Definition of the quality assurance and quality management processes implemented for ensuring data quality (including any training session, investigator supervision, instruction manuals, use of independent internal or external audit procedures, etc.).
  12.  Ethics
    Definition of ethical issues relating to the court, describing the legal code enforcement. For example, you will clarify how you handle specific ethical issues appropriately and satisfy the appropriate regulatory criteria for the trial in an emergency situation (such as when the participant ‘s prior consent is not possible).You can read the EU document about ethical considerations for trials on medicinal products conducted with the paediatric population in this link.
  13. Data handling and record-keeping
    This section ensures that the electronic data processing system(s) complies with the criteria for completeness, precision, reliability, and consistent intended performance defined by the sponsor. It should state that an independent data-monitoring committee has been set up to evaluate the trial ‘s progress.
  14. Financing and insurance
    Details about the trial financing and the clinical trial participant’s insurance that is compulsory in many countries.
  15.  Publication policy
    Description of clinical data publishing policies ( e.g. papers, abstracts, posters, oral reports, and review articles published by peer-reviewed medical journals or delivered at scientific meetings and congresses), pledging adherence to GCP and related guidelines. (Note: topics 13-15 should be included in the protocol if not addressed in a separate agreement.)
  16.  Project timetable/flowchart
    Timeline description, including the planed start and end of the trial.
  17.   References
  18.   Supplements/appendices

Clinical trial Protocol: A team effort

  • Protocols for clinical trials are not typically written by a single person. Instead, they are published by a multi-disciplinary team that also involves a medical expert, a statistician, a pharmacokinetics researcher, the supervisor of clinical testing, the project manager, and a scientific writer who incorporates all the contributions in a final article, among others.

The medical expert plays a leading role in research preparation, relating to sections such as study design, priorities and endpoints, selection criteria, and evaluation procedures. The medical professional also offers guidance on the use of parallel treatments or the guidelines for preventing dose escalation studies. The role of the medical expert is not normally outsourced.

The statistician conducts estimates for the sample size and research power (key to detect clinically relevant discrepancies between treatment groups) and contributes to the targets and endpoints being set. The statistician is responsible for carrying out all statistical procedures and ensuring the study’s possible variability is minimised. The role of the statistician can be outsourced to a temporary statistician or biostatistics consultant.

  • The pharmacokinetic specialist assists in determining targets and endpoints, as well as in dosing protocols, defining the drug ‘s critical pharmacokinetic specifications.

    This specialist also participates in the development of statistical methods for the assessment of pharmacokinetic data and in the determination of dosing frequencies from single to multiple ascending dose studies.

    One can outsource the role of the pharmacokinetic expert.
  • The Clinical Research coordinator contributes to clinical research management and logistics, including laboratory health and storage of samples.

    In addition, the planner is also responsible for assessing the effectiveness of the various assessments, planning their timetable and definition. The position of coordinator of clinical research is not usually outsourced.
  • Apart from managing data processing, the project manager is responsible for creating comprehensive timelines for the protocol and the research set-up specifications.

    The project manager will also need to describe the requirements of the sponsor. The project manager job can be outsourced.
  • Other people contributing to the clinical trial protocol include regulatory affairs specialists (that guarantee the adoption of all regulatory guidances, communicate with health authorities, and submit the Investigational Medicinal Product Dossier); laboratory staff (that handles samples and performs laboratory procedures); and the medical affairs/pharmacovigilance experts that manage the reporting of adverse events. Some of these roles can be outsourced.

The medical writer compiles the clinical trial protocol using feedback from the rest of the team, ensuring accuracy of the details in the entire text. They may outsource the role of the medical writer.

The SPIRIT Statement

In order to improve the content and quality of protocols, an international group of experts developed the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement.

The SPIRIT Statement provides guidance in the form of the checklist of recommended items to include in a clinical trial protocol and related documents.

The use of this guideline to write the study protocol optimizes the quality of the reporting and facilitates the peer review process. SPIRIT has created an electronic tool (SPIRIT Electronic Protocol Tool & Resource, SEPTRE) to help researchers to produce high-quality clinical trial protocols using SPIRIT guidance.”

Protocol deviations, violations and/or amendments

“Protocol deviations are characterized as unintended or unintentional changes to the protocol or non-compliance with the research protocol that do not increase the risk or decrease the benefit or have no significant impact on the rights, protection or welfare of the subject and/or the integrity of the data. Deviations in the protocol arise from the behavior of the subject or research staff.

Examples of the protocol deviations include a rescheduled study visit or failure to collect an ancillary self-report questionnaire. An example of protocol deviation is measuring vital signs prior to obtaining informed consent. 

Protocol deviations should be distinguished from protocol violations involving unintended or unintentional protocol adjustments, or non-compliance with the protocol approved by the IRB, without prior sponsor and approval by the IRB. In general, violations increase the risk or decrease the benefit, affect the rights, health or welfare of the subject or the quality of the data.

Examples of protocol violations include the use of an insufficient informed consent, the enrollment of the subjects not meeting the inclusion and/or exclusion criteria, the use of forbidden medication, etc.

Protocol modifications that potentially impact the development of the study, the potential patient’s benefit, or may affect patient’s safety (including changes to the study objectives, study design, patient population, eligibility criteria, sample sizes, study procedures, or significant administrative aspects) require a formal amendment to the protocol.

Examples of the protocol changes that must be reported include any enhancement in drug dosage or duration of drug exposure, any important increase in the number of subjects to be enrolled, new test procedures, or the inclusion of a new investigator in multi-centric studies.

As an example, the Substantial Amendment Notification Form in the EU can be found here.

Alternatively minor corrections and/or clarifications that do not affect the way the study is conducted are considered administrative changes and should be documented in the memorandum.”

References:
https://www.kolabtree.com/blog/how-to-write-a-clinical-trial-protocol/
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf
https://osp.od.nih.gov/wp-content/uploads/2014/01/Protocol_Template_05Feb2016_508.pdf

https://hub.ucsf.edu/protocol-development

https://www.nuventra.com/resources/blog/best-practices-clinical-study-protocol-writing/

Coronavirus (COVID-19) Update: Daily Roundup July 23, 2020

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Coronavirus (COVID-19) Update: Daily Roundup July 23, 2020

July 23, 2020: “The U.S. Food and Drug Administration announced the following actions taken in its ongoing response effort to the COVID-19 pandemic:

  • Today, the FDA updated the Testing Supply Substitution Strategies slide show. This presentation includes validated supply alternatives that labs can use to continue performing testing when there is a supply issue with some components of a molecular test. Download the 1.5MB PowerPoint slide show file and click Slide Show > From Beginning.
  • This week, FDA and the Federal Trade Commission issued a joint warning letter to 21st Century LaserMed Pain & Regenerative Medicine Institute (d/b/a Create Wellness Clinics) for offering unapproved, unlicensed, uncleared and unauthorized products for the mitigation, prevention, treatment, diagnosis or cure of COVID-19.

    There are currently no FDA-approved products to prevent or treat COVID-19. Consumers concerned about COVID-19 should consult with their health care provider.
  • Testing updates:
    • To date, the FDA has currently authorized 187 tests under EUAs; these include 154 molecular tests, 31 antibody tests, and 2 antigen tests.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.

The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-july-23-2020

Novartis announces Phase III study of Jakavi® in chronic graft-versus-host disease

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Novartis announces Phase III study of Jakavi® in chronic graft-versus-host disease
July 23, 2020: “Novartis announced that the Phase III REACH3 study evaluating Jakavi® (ruxolitinib) in patients with steroid-refractory or steroid-dependent chronic graft-versus-host disease (GvHD) met its primary endpoint of superior overall response rate (ORR) at Week 24 versus best available therapy (BAT).

The study also met key secondary endpoints, significantly improving failure-free survival and patient-reported symptoms assessed by a validated chronic GvHD-specific score.

These topline results build on positive data from the previously reported REACH2 trial, which demonstrated that Jakavi improved outcomes across a range of efficacy measures in patients with steroid-refractory or steroid-dependent acute GvHD.

Related News: Novartis announces data showing Jakavi® (ruxolitinib) more effective than best available therapy in acute graft-versus-host disease

Novartis announces plan to initiate clinical study of Jakavi® in severe COVID-19 patients and establish international compassionate use program

“These positive topline results of the pivotal Phase III trial in chronic GvHD show that treatment with Jakavi results in superior overall response and failure-free survival compared to alternative treatment options and will help to inform treatment decisions among patients refractory to steroids following bone marrow transplantation,” said David Feltquate, Head Hematology Development Unit, Novartis.

“We look forward to sharing further details of the data, which complement the previous findings for Jakavi in the acute form of the disease, and plan to initiate regulatory filings for steroid-refractory GvHD in Europe and other ex-US countries.”

REACH3 (NCT03112603) is a Phase III, randomized, open-label, global multicenter study to evaluate Jakavi compared to BAT in patients with steroid-refractory or steroid-dependent chronic GvHD following allogeneic stem cell transplant.

Data from this study are expected to be presented at an upcoming major medical congress.

Jakavi® (ruxolitinib)
Jakavi® (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. Jakavi is approved by the European Commission for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea and for the treatment of disease- related splenomegaly or symptoms in adult patients with primary myelofibrosis (MF) (also known as chronic idiopathic MF), post-polycythemia vera MF or post-essential thrombocythemia MF.

Jakavi is approved in over 100 countries for patients with MF, including EU countries, Switzerland, Canada, Japan and in more than 85 countries for patients with PV, including EU countries, Switzerland, Japan and Canada. The exact indication for Jakavi varies by country. Additional worldwide regulatory filings are underway in MF and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Ruxolitinib is marketed in the United States by Incyte Corporation as Jakafi® for patients with PV who have had an inadequate response to or are intolerant of hydroxyurea, for patients with intermediate or high-risk MF, and steroid-refractory acute GvHD in adult and pediatric patients 12 years and older.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in MF is 15 mg given orally twice daily for patients with a platelet count between 100,000 cubic millimeters (mm) and 200,000 mm, and 20 mg twice daily for patients with a platelet count of >200,000 mm. Doses may be titrated based on safety and efficacy.

There is limited information to recommend a starting dose for MF and PV patients with platelet counts between 50,000/mm and <100,000/mm. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously.

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation. The safety and efficacy profile of Jakavi has not yet been established outside of its approved indications.”

https://www.novartis.com/news/media-releases/novartis-announces-phase-iii-study-jakavi-chronic-graft-versus-host-disease-met-primary-and-key-secondary-endpoints

FDA Ok’s Expanded BOTOX® Label for the Treatment of Pediatric Patients with Spasticity

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FDA Ok’s Expanded BOTOX® Label for the Treatment of Pediatric Patients with Spasticity
 July 9, 2020:  “Allergan, an AbbVie company announced that the U.S.FDA approved a supplemental Biologics License Application (sBLA) that supports expanded use of BOTOX® for the treatment of spasticity in pediatric patients 2 years of age and older, including those with lower limb spasticity caused by cerebral palsy.

This label expansion is based on Allergan and another manufacturer selectively waiving orphan exclusivity marketing rights each company held for the use of their respective neurotoxins in the treatment of pediatric patients with spasticity caused by cerebral palsy.

BOTOX® was first approved in June 2019 for the treatment of pediatric patients with upper limb spasticity and in October 2019 for the treatment of pediatric patients with lower limb spasticity, excluding spasticity caused by cerebral palsy.

BOTOX® has not been shown to improve upper extremity functional abilities, or range of motion at a joint affected by a fixed contracture.

Spasticity is a debilitating neurological condition involving muscle stiffness that can result in tight muscles in the upper and lower limbs.

The severity can range from mild to severe, often interfering with normal muscular movement and function. This can result in delayed or impaired motor development, as well as difficulty with posture and positioning.

Common causes of spasticity in children include cerebral palsy, traumatic brain injury, multiple sclerosis, spinal cord injury, and stroke.

“Cerebral palsy is the most common cause of pediatric spasticity, which can have a profound impact on a child’s development and quality of life.

With its established safety and efficacy profile, we are pleased that BOTOX® can now more broadly support physicians treating pediatric spasticity,” said Mitchell F. Brin, M.D., Senior Vice President, Chief Scientific Officer, BOTOX® & Neurotoxins, AbbVie. 

“Building upon our 30 years of research and development efforts with BOTOX®, our commitment to neurotoxin innovation continues, and it is particularly rewarding to bring forth new treatments to advance care for pediatric patients.”

The safety and efficacy of BOTOX® as treatment for lower limb spasticity for pediatric patients is supported by a Phase 3 study with more than 300 patients two to 17 years of age with lower limb spasticity because of cerebral palsy. These trials included a 12-week, double-blind study and a one-year open-label extension study.

Allergan is committed to providing resources and services, such as the BOTOX® Savings Program, to help ensure BOTOX® is accessible and affordable to patients.

BOTOX®

BOTOX® is one of the most widely researched medications in the world, with a proven history as a therapeutic agent. 

First approved by the FDA in 1989 for two rare eye muscle disorders – blepharospasm and strabismus in adults, BOTOX® was the world’s first approved botulinum toxin type A treatment.

BOTOX® is FDA-approved for 11 therapeutic indications, including Chronic Migraine, overactive bladder, leakage of urine (incontinence) due to overactive bladder caused by a neurologic condition, cervical dystonia, spasticity, and severe underarm sweating (axillary hyperhidrosis).

Backed by strong science and continuous innovation, BOTOX® proudly embraces its past while boldly looking to the future.

BOTOX® (onabotulinumtoxinA) Important Information

Indications
BOTOX® is a prescription medicine that is injected into muscles and used:

  • To treat overactive bladder symptoms such as a strong need to urinate with leaking or wetting accidents, a strong need to urinate right away, and urinating often in adults 18 years and older when another type of medicine (anticholinergic) does not work well enough or cannot be taken
  • To treat leakage of urine (incontinence) in adults 18 years and older with overactive bladder caused by a neurologic disease who still have leakage or cannot tolerate the side effects after trying an anticholinergic medication
  • To prevent headaches in adults with chronic migraine who have 15 or more days each month with headache lasting 4 or more hours each day in people 18 years or older
  • To treat increased muscle stiffness in people 2 years of age and older with spasticity
  • To treat the abnormal head position and
    neck pain that happens with cervical dystonia (CD) in people 16 years and older
  • To treat certain types of eye muscle problems (strabismus) or abnormal spasm of the eyelids (blepharospasm) in people 12 years and older

BOTOX® is also injected into the skin to treat the symptoms of severe underarm sweating (severe primary axillary hyperhidrosis) when medicines used on the skin (topical) do not work well enough in people 18 years and older.

It is not known whether BOTOX® is safe or effective to prevent headaches in patients with migraine who have 14 or fewer headache days each month (episodic migraine).

BOTOX® has not been shown to help people perform task-specific functions with their upper limbs or increase movement in joints that are permanently fixed in position by stiff muscles. 

It is not known whether BOTOX® is safe or effective for severe sweating anywhere other than your armpits. 

IMPORTANT SAFETY INFORMATION

BOTOX® may cause serious side effects that can be life threatening. Get medical help right away if you have any of these problems any time (hours to weeks) after injection of BOTOX®:

  • Problems swallowing, speaking, or breathing, due to weakening of associated muscles, can be severe and result in loss of life.

    You are at the highest risk if these problems are pre-existing before injection. Swallowing problems may last for several months
  • Spread of toxin effects. The effect of botulinum toxin may affect areas away from the injection site and cause serious symptoms including: loss of strength and all-over muscle weakness, double vision, blurred vision and drooping eyelids, hoarseness or change or loss of voice, trouble saying words clearly, loss of bladder control, trouble breathing, and trouble swallowing

There has not been a confirmed serious case of spread of toxin effect away from the injection site when BOTOX® has been used at the recommended dose to treat chronic migraine, severe underarm sweating, blepharospasm, or strabismus.

BOTOX® may cause loss of strength or general muscle weakness, vision problems, or dizziness within hours to weeks of taking BOTOX®. If this happens, do not drive a car, operate machinery, or do other dangerous activities.

Do not receive BOTOX® if you: are allergic to any of the ingredients in BOTOX® (see Medication Guide for ingredients); had an allergic reaction to any other botulinum toxin product such as Myobloc® (rimabotulinumtoxinB), Dysport® (abobotulinumtoxinA), or Xeomin® (incobotulinumtoxinA); have a skin infection at the planned injection site.”

https://news.abbvie.com/news/press-releases/fda-approves-expanded-botox-onabotulinumtoxina-label-for-treatment-pediatric-patients-with-spasticity.htm

7 Steps to learn SAS quickly

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7 Steps to learn SAS quickly

Students often find SAS as a lucrative career opportunity. Good programming skills are needed to pass through the interview process.

Proper planning, right guidance and hard work can make you a skilled programmer in a few months.

On LifeProNow request,  Nanigopal Panigrahi agreed to share his knowledge. He is quite a skilled programmer and associated with one of the MNC. He has summarised the whole journey to SAS into 7 steps:

SAS (Statistical Analysis System) is a software suite developed by SAS Institute and we can access, manage, analyze and present the data by applying SAS programming techniques

Download and install SAS software/ Access the SAS studio online and learn the interface.

Practice is very important while learning any coding language, so we need to practice a lot along with the theory part. One should have a basic understanding of different windows on SAS and their use. It is one of

Learn the basic SAS programming

Once we understand how to work in SAS software, we need to learn basic SAS coding like:

How to write as SAS statements, Steps in SAS programming, SAS naming convention, data types in SAS etc.

How to create SAS dataset/ Import /Export

Next important thing is we should know how to import different datafile and create SAS dataset from that. Frequently used data files are Excel, CSV file, txt file etc. We should also learn how to export our output to different file format. It is also important to learn the concept of SAS libraries to access sas Dataset from different source.

Learn SAS functions:

SAS function are very important wile while writing programs. We should learn some of the common SAS functions from Character functions, Numeric functions and Date functions to ease our coding.

PROC SQL

We should learn basic proc sql like SQL clauses, how to select observation and column while printing a table, how to create tables in proc sql. SQL joins to merge datasets.

SAS Macro

SAS macro is very important, In the beginning we should learn different ways to create macro variables, different ways to create macro program, Macro debugging techniques etc

SAS procedures

We should learn some basic SAS procedures like proc print, proc contents, proc sort, proc freq, proc means, proc report etc.

He has created one tube channel DataCoder where he will be posting videos on SAS programming from basics. You can subscribe to the channel and watch all the upcoming videos.

https://youtu.be/8nQdOZX6RHw

NICE backing for Astella’s Xospata for acute myeloid leukaemia

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NICE backing for Astella’s Xospata for acute myeloid leukaemia

July 16, 2020: “NICE has recommended the use of Astellas’ Xospata (gilteritinib) for adults with relapsed or refractory FLT3 mutation-positive acute myeloid leukaemia (AML).

The backing, as outlined in a Final Appraisal Determination, is contingent on a commercial agreement being offered by the company and does not include its use as a maintenance therapy after haematopoietic stem cell transplant.

Related News: Data fron XOSPATA® in FLT3 Mutation-Positive Relapsed/Refractory Acute Myeloid Leukemia at the 2019 American Society of Hematology Annual Meeting

AML is a rare and aggressive cancer of the blood and bone marrow that, if untreated, can be fatal within a few months.

Around 3,100 people in the UK are diagnosed with AML each year, of which one-third will test positive for the FLT3 gene mutation, which can result in higher relapse rates and lower rates of survival than other forms of the disease.

The prognosis of patients with AML has remained poor despite advances in chemotherapy and little progress has been made that improves the long-term outcome for these patients.

NICE’s recommendation of NHS funding for Xospata is based on data from the Phase III ADMIRAL trial, which showed that relapsed or refractory FLT3 mutation-positive AML patients who received the drug experienced significantly longer overall survival than those who received salvage chemotherapy.

Median overall survival for patients who received Xospata was 9.3 months, compared to 5.6 months for patients who received salvage chemotherapy, while rates of one-year survival were 37% and 17%, respectively.

“This marks a pivotal moment as, for the first time, adults in the UK with this specific form of AML have a much-needed option at the point when current treatment no longer works or they relapse,” said Jackie Williams, general manager for Astellas in the UK.

“We are proud to bring such an important treatment option that could significantly extend the lives of these patients.”

https://www.nice.org.uk/guidance/GID-TA10460/documents/129

AZ’s Farxiga-Tracked heart failure following acute myocardial infarction

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AZ’s Farxiga-Tracked heart failure following acute myocardial infarction

July 16, 2020: “AstraZeneca has been granted Fast Track Designation in the US for the development of Farxiga (dapagliflozin) to reduce the risk of hospitalisation for heart failure (hHF) or cardiovascular (CV) death in adults following an acute myocardial infarction (MI) or heart attack.

The designation is based on the Phase III DAPA-MI trial that will explore the efficacy and safety of Farxiga in this patient population.

Related News: Farxiga approved in the US for the treatment of heart failure in patients with heart failure with a reduced ejection fraction

Farxiga reduced the incidence of heart failure worsening or cardiovascular death in a sub-analysis from landmark Phase III DAPA-HF trial

Acute MI is a serious condition and a known cause of heart failure (HF). Approximately seven million heart attacks occur globally each year.1

The Food and Drug Administration’s (FDA) Fast Track programme is designed to accelerate the development and review of new medicines for the treatment of serious conditions where there is an unmet treatment need.

In addition to Fast Track Designation, the FDA recently granted a Special Protocol Assessment (SPA) agreement to the DAPA-MI trial.

The SPA is a rarely granted, advanced declaration by the FDA that a Phase III trial’s design is acceptable for a future marketing application.

The DAPA-MI trial integrates routine care and registries with the requirements of a rigorous placebo-controlled, randomised clinical trial, thus aiming for an approvable label indication.

Registries are used by physicians to store patient health data collected over time, often during regular recurrent visits. In DAPA-MI, patients and their treating physicians participating in registries can join the trial and integrate it within their routine clinical practice.

Unlike conventional studies where patients often need to travel to a trial centre that may be far from home, this pragmatic, innovative approach delivers rigorous safety and efficacy data, while reducing patient burden and streamlining trial delivery.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The Phase III DAPA-MI trial is the first indication-seeking registry-based randomised controlled trial which will provide quicker access to data and reduce recruitment time and cost, while minimising patient and investigator burden.

Today’s FDA decision acknowledged the importance of this trial, which will provide valuable insights into Farxiga’s potential in patients who had a heart attack and went on to develop heart failure and also into how we can improve clinical trial design in the future.”

The DAPA-MI trial is conducted in collaboration with Uppsala Clinical Research Center (UCR) and Myocardial Ischaemia National Audit Project (MINAP) in the UK. I

t will explore the benefit of Farxiga in patients without type-2 diabetes (T2D) following an acute MI. It is expected to begin recruiting in the fourth quarter of 2020.

In May 2020, Farxiga was approved in the US to reduce the risk of CV death and hHF in adults with HF (NYHA class II-IV) with reduced ejection fraction (HFrEF) with and without T2D. 

Farxiga is also indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. Additionally, Farxiga is being evaluated for patients with chronic kidney disease (CKD) in the Phase III DAPA-CKD trial, which was stopped early after a Data Monitoring Committee determination of overwhelming efficacy.

Myocardial Infarction

Acute MI, also known as a heart attack, is a common, serious condition and cause of HF.

The strongest predictor of in-hospital mortality following an acute coronary event is HF.

Many patients who experience acute MI will develop HF, and these patients have a higher mortality risk than patients already presenting with HF at admission.

The standard of care for patients with acute MI has improved considerably over the years, butthe prognosis has not shown a dramatic change indicating that novel approaches are needed to reduce CV risk.

DAPA-MI

DAPA-MI (DAPAgliflozin effects in patients without diabetes with Myocardial Infarction) is an international, multi-centre, double-blinded registry-based randomised controlled trial designed to assess the efficacy and safety of Farxiga 10mg, compared to placebo, given once daily to reduce the risk of hHF and CV disease in adults without T2D following an acute MI.

DAPA-MI integrates traditional, pragmatic, and innovative study design elements with the goal of minimizing patient and investigator burden while producing real-world evidence of efficacy that adds to the existing body of evidence generated by Farxiga randomised controlled trials.

The trial will recruit around 6,400 patients from approximately 50 sites in Sweden and 50 sites in the UK. Prospective data collection is done through two national CV disease quality registries.

Farxiga

Farxiga (dapagliflozin) is a first-in-class, oral once-daily sodium-glucose co-transporter-2 (SGLT2) inhibitor indicated in adults for the treatment of insufficiently controlled T2D as both monotherapy and as part of combination therapy as an adjunct to diet and exercise to improve glycaemic control, with the additional benefits of weight loss and blood-pressure reduction.

In the DECLARE CV outcomes trial in adults with T2D, Farxiga reduced the risk of the composite endpoint of hHF or CV death versus placebo, when added to standard of care.

Farxiga is also being tested for patients with HF in the DELIVER (HF with preserved ejection fraction, HFpEF) and DETERMINE function and symptom (HFrEF and HFpEF) trials. 

Farxiga has a robust programme of clinical trials that includes more than 35 completed and ongoing Phase IIb/III trials in more than 35,000 patients, as well as more than 2.5 million patient-years’ experience.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/farxiga-granted-fast-track-designation-in-the-us-for-heart-failure-following-acute-myocardial-infarction-leveraging-an-innovative-registry-based-trial-design.html

Centralized Monitoring in Clinical Trial

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Centralized Monitoring in Clinical Trial

“The FDA definition of centralized monitoring states that it: “Consists of a remote evaluation performed by sponsor personnel or representatives (e.g., clinical monitors, data management personnel, or statisticians) at a location other than the sites where the clinical investigation is being conducted.”

Centralized Monitoring is also known as risk-based monitoring or remote monitoring.

Centralized Monitoring

Monitoring is defined as the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, The Principles of GCP, and the Medicines for Human Use (Clinical Trails) Regulations – where applicable.

Centralized Monitoring is one of the critical components of modern Risk-based Quality Management (RBQM) strategies in clinical research.

Centralized monitoring has been acknowledged as the most appropriate and cost-effective approach for  achieving higher data quality levels and enhanced patient safety oversight by key European and American regulatory agencies; FDA, EMA, and MHRA.

The key benefits of centralized monitoring:

  • Helps in early identification and mitigation of data quality risk/issue(s) which may compromise validity of study results.
  • Supports in better monitoring of patient safety and helps in enhancing subject protection.
  • Increases effectiveness of CRAs and helps utilization of their time very efficiently and objectively during on-site monitoring.
  • Keeps track of sites’ performances to help plan on-site monitoring visits.
  • Optimizes on-site monitoring visits, thereby reducing related costs.
  • Creates overall efficiencies in clinical trial operations.

Effective process restructuring and cross-functional alignment of resources must be in place to initiate productive unified control activities, and the necessary technologies must be in place.


Image Source: Cyntegrity.com

Centralized Monitoring Implementation

The key steps involved in centralized monitoring implementation are as follows:

• Determining and identifying key risks and their thresholds

• Design of an extensive monitoring plan and relevant documentation

• Continuous monitoring of risks or problems using the right technology

• Corrective planning of actions to manage / mitigate identified risks / issues

There needs to be a well-thought-out, comprehensive monitoring plan in place for efficient and effective centralized implementation of monitoring. One that explains in detail what aspects of data monitoring with centralized monitoring would be achieved.

  • The strategy will detail the site contact procedure and timings, or on-site inspection visits based on established critical issues. The specific risk factors, thresholds, and success measures should be defined up front in the plan and monitored and recorded during the process.
  • The regulators require a systematic approach in order to identify and justify the key risk indicators.
  •  frequency and extent of centralized monitoring activities
  • provides a elegant template to report findings
  • lists the team members involved and their roles and responsibilities
  • Communication and co-ordination between the centralized monitoring team and the different stake-holders for issue escalation & resolution and any specific training requirements for a centralized monitoring team.
  • The monitoring plan should have provision in order to make amendments based on new risks recognized related to data, procedures, sites or overall operations.

Role of a Central Monitor

It is important to ensure that we have the right skills and qualified people in place to drive the process, as it is a newer approach.

The central monitors would spend a significant amount of time remotely tracking the data and reviewing reports, recognizing the risk / problems.

They should have previous monitoring experience, and good knowledge of data management activities.

Also have should have strong communication, teamwork, analytical skills and use critical thinking to recognize patterns and outliers, especially those risks associated with data quality or patient health.

Technology Requirements

Since centralized control involves remote data processing, robust and cutting-edge technology can only be used.

Considering that data is collected in separate, distinct ways, the right technology must be in place that can combine the various data sources and manage large volumes of data.

The technology should be user-friendly and capable of recognizing trends, patterns and outliers, as well as assessing the output of data at the level of study or program, site or region.

From the perspective of reporting and visualization, the technology requires the ability to review and evaluate the data, and provide graphical and visual representations that can easily identify risks or problems.

As the industry is moving towards newer monitoring approaches, the market has seen the advent of the number of collaborative, analytic clinical tools in order to support remote tracking of risks or issues related to the clinical trial operations or data quality.

On the other hand, whichever system is used, the technology should have undergone a strong system validation process to ensure compliance with regulatory requirements, that the technology consistently meets its specification, and is consequently suitable for its intended purpose.

Many organizations create and standardize their centralized monitoring process. Assessing its integration with main current processes such as data collection, washing, and monitoring.

Centralized control is an efficient method with the required program, procedure and qualified personnel to ensure the plan is implemented properly, resulting in effective patient treatment and accurate research outcomes, while also reducing the expense of clinical trials.

Monitoring metrics related to efficiency, safety, timelines and budget using a centralized monitoring approach can help explain the advantages and opportunities of centralized monitoring and offer industry more insight in improving processes, tools, and technology to ensure better performance.”

http://www.appliedclinicaltrialsonline.com/centralized-monitoring-smart-reliable-approach

http://www.appliedclinicaltrialsonline.com/basics-clinical-trial-centralized-monitoring

https://www.imarcresearch.com/hs-fs/hub/149400/file-18013506-pdf/docs/onsite_monitoring2.pdf

https://www.clinicalleader.com/doc/centralized-monitoring-a-smarter-cost-efficient-approach-to-clinical-quality-0001

Novartis launches first-of-its-kind not-for-profit portfolio of medicines for symptomatic treatment of COVID-19

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Novartis launches first-of-its-kind not-for-profit portfolio of medicines for symptomatic treatment of COVID-19
July 16, 2020: “Novartis announced a new initiative to help patients in low-income and lower-middle-income countries access affordable medicines to treat the major symptoms of COVID-19 – a critical need in the absence of a vaccine or curative treatment.

Inflammation and respiratory problems linked to COVID-19 can cause severe medical complications and can lead to death in some people, putting immense strain on fragile healthcare systems.

The Novartis COVID-19 portfolio includes 15 medicines from its Sandoz division for gastro-intestinal illness, acute respiratory symptoms, pneumonia as well as septic shock.

The medicines were chosen based on clinical relevance and availability to ensure demand can be met globally.

The medicines will be made available to governments, Non-Governmental Organizations (NGOs) and other institutional customers in up to 79 eligible countries at zero-profit to support financially-strained healthcare systems.

Countries will have the flexibility to select the medicines in the portfolio that meet their healthcare needs.

Eligible countries must be included on the World Bank’s list of LICs & LMICs.

“Access to medicine can be a challenge for patients in low- and lower-middle-income countries and the situation has worsened during COVID-19.

With our COVID-19 portfolio, we wish to help address the additional healthcare demands of the pandemic in the countries we are targeting,” said Dr Lutz Hegemann, Chief Operating Officer for Global Health at Novartis.

“This initiative builds on our earlier global commitment to keep prices stable for a basket of essential drugs used to treating COVID-19 patients,” said Sandoz CEO Richard Saynor.

“The COVID-19 Response Portfolio for low-income and lower-middle-income countries is designed to support governments in treating COVID-19 symptoms before they lead to complications in patients.”

The following medicines are included in the Novartis COVID-19 Response Portfolio:
Amoxicillin, Ceftriaxone, Clarithromycin, Colchicine, Dexamethasone, Dobutamine, Fluconazole, Heparin, Levofloxacin, Loperamide, Pantoprazole, Prednisone, Prednisolone, Salbutamol, Vancomycin.

The portfolio will be offered in addition to the Novartis Access portfolio (on- and off-patent medicines against key non-communicable diseases) via the local Novartis or Sandoz affiliate.

This global pandemic has placed extreme pressure on healthcare systems in low- and lower-income countries.

The pandemic response portfolio complements the previously launched Novartis COVID-19 Response Fund to support healthcare workers and communities in over 50 projects around the world.

The COVID-19 medicines portfolio is Novartis latest contribution to the global effort to combat the pandemic and support the stability of global healthcare systems.

The company has committed to donating USD 40 million to support communities around the world impacted by the pandemic.

In addition, Novartis has been active in two key cross-industry research initiatives, the COVID-19 Therapeutics Accelerator, coordinated by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard, as well as a COVID-19 directed partnership organized by the Innovative Medicines Initiative (IMI).

Novartis continues to provide hydroxychloroquine for ongoing investigator-initiated trials (IITs) and upon government requests, as appropriate.

The company is also separately supporting COVID-19 related clinical investigations of several Novartis medicines. To su

pport access, the Novartis generics and biosimilars division Sandoz became the first company to commit to keeping stable prices for a basket of essential medicines that may help in the treatment of COVID-19 and entered into a partnership with US-based Civica Rx to support stable supply of essential generic hospital medicines.  

Furthermore, AveXis, Novartis gene therapy unit, entered into a manufacturing agreement with Massachusetts Eye and Ear and Massachusetts General Hospital to produce its novel genetic COVID-19 vaccine candidate called AAVCOVID.”

https://www.novartis.com/news/media-releases/novartis-launches-first-its-kind-not-profit-portfolio-medicines-symptomatic-treatment-covid-19

Coronavirus (COVID-19) Update: Daily Roundup July 15, 2020

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Coronavirus (COVID-19) Update: Daily Roundup July 15, 2020
July 15, 2020: “The U.S. Food and Drug Administration announced the following actions taken in its ongoing response effort to the COVID-19 pandemic:
  • Today, the Food and Drug Administration (FDA) updated its Frequently Asked Questions on Testing for SARS-CoV-2. The revised FAQs now include a list of laboratories that have been removed from the list of laboratories that had notified FDA that they had developed and validated diagnostic tests as set forth in Section IV.

    A of the Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised) — titled “Laboratories Certified under CLIA that Meet the CLIA Regulatory Requirements to Perform High Complexity Testing Using Their Validated Diagnostic Tests Prior to EUA Submission.”

    Any laboratory on this list has been removed from the notification list because FDA has determined that there are significant problems with its test that cannot be, or have not been, addressed in a timely manner and should no longer be used.
  • Testing updates:
    • To date, the FDA has currently authorized 179 tests under EUAs; these include 148 molecular tests, 29 antibody tests, and 2 antigen tests.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.

The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-july-15-2020

What is “Expanded access”?

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What is “Expanded access”?

“Expanded access, also referred to as “compassionate use,” is a potential pathway for the patients with an immediately life-threatening disorder or severe illness or disease to obtain access to an investigational medical product (drug, biological or medical device) for treatment outside of clinical trials where there are no equivalent or appropriate alternative therapy choices.

Introduction:

Expanded access may be suitable when all the following apply:

  • People with serious illness or disability, or whose lives are instantly endangered by their disease or condition.
  • No equivalent or adequate alternative treatment is available for diagnosing, tracking or treating a disease or disorder.
  • It is not possible to register patients to a clinical trial.
  • Possible benefits to patients outweigh future medical costs.
  • Providing the investigational medical product will not interfere with investigational trials that might support a medical product’s development or marketing approval for the treatment indication.

FDA has not yet licensed or cleared investigational drugs, biologics or medical devices and FDA has not considered such products safe and effective for their particular use.

In addition, the investigational medicinal drug may or may not be effective in treating the disease, and use of the medication may cause unintended severe side effects.

What are the roles and responsibilities?

Exploring alternative approved care options, available and clinical trials or determining if expanded access could be another choice.

  1. Licensed Physician
    Agrees to supervise the patient’s treatment and works with a company (industry), files paperwork with FDA and Institutional Review Board (IRB), and is responsible for the patient care and reporting.

  2. Company (Industry)
    Willing to provide the investigational medical substance and working with the FDA and the licensed physician of the patient to provide the details needed for the extended access request or to submit the requests to the FDA.

  3. Institutional Review Board (IRB)
    Ensures that appropriate steps are taken to protect the rights and safety of the participating persons as participants in a research study.

The IRB reviews the extended access application for expanded access, including the informed consent to help ensure the patient knows the nature of the planned treatment’s investigational medical product.

How should we post our expanded access policy?

  • The 21st Century Cures Act requires that a company developing investigational drugs (including biologics) shall make its policy regarding evaluating and responding to requests for the expanded access public and readily available.
  • Posting this information on the Reagan-Udall Foundation’s Expanded Access NavigatorExternal Link Disclaimer, including links to a company’s own web page describing its policy for the investigational drug, can be used in order to satisfy this requirement.
  • If a company develops multiple investigational drugs, it will carry out specific expanded access policies for each of its investigational drugs and post them individually by name as outlined above.
  • Companies developing investigational drugs should keep in mind that, among other provisions of the FDA’s investigational new drug (IND) regulations, a sponsor of an investigational drug product or an individual acting on behalf of a sponsor may not reflect, in a promotional sense, that an investigative drug is safe or successful for the purposes for which it is being investigated.
  • For more information, see FDA regulations relating to INDs as 21 CFR 312. 

What are the reporting requirements for industry sponsors of expanded access?

Reporting requirements differ depending on the type of investigational medical product and expanded access request.

Drugs and Biologics:

  • As with any IND, sponsors are responsible for sending IND compliance reports (as required by 21 CFR 312.32) and annual reports (as required by 21 CFR 312.33  if the IND or procedure persists for 1 year or more) to FDA (see 21 CFR 312.305(c) in both cases of extended access.

  • For individual patient expanded access, the regulations (21 CFR 312.310(c)(2)  specify that after treatment the sponsor must have provide to FDA a written summary of the results of the expanded access use, including adverse effects.

Medical devices:

  • Sponsors must provide follow-up reports on the outcomes of extended access usage, including any harmful user consequences, for application-widened access requests. Documents should be sent within 5 days for individual patient emergency cases, as set out in 21 CFR 812.150. (a)

    Additionally, IDEs used for care will meet the reporting criteria set out in 21 CFR 812.36.”

https://www.fda.gov/news-events/expanded-access/expanded-access-information-industry

https://www.fda.gov/news-events/public-health-focus/expanded-access

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