(Lange Medical Books) John Butterworth, David C. Mackey,
John Wasnick-Morgan and Mikhail's Clinical Anesthesiology, 5th
edition-McGraw-Hill Medical (2013)
1_pdfsam_miller_39_s_anaesthesia_8th_edition
Sunday 17 September 2017
Saturday 16 September 2017
Friday 15 September 2017
Leadership 4 ways for leaders to make a decision
Business leaders are faced with dozens of decisions that need to be made every day. As our organizations grow, the decisions generally become more frequent, more complicated, and have more serious ramifications. Sometimes it’s not about making the right decision, but just making a decision at all. The most successful entrepreneurs and business leaders in the world will tell you they have made many wrong decisions throughout the lifetime of their careers, but those failures always lead to valuable learning experiences, so above all, it’s important to find ways to make the tough decisions.
Business owners, executives and managers must master the ability to make good decisions quickly in order to keep the business moving forward. The best leaders, however, know when they need input from the team. Good leaders surround themselves with trusted advisors and subject matter experts, so that they can access a constant flow of data to make better decisions.
There are four basic decision-making styles that leaders can use:
Command: Command decision-making is where leaders make decisions without consulting their teams. This is an effective style, especially when things are moving quickly and the team is looking for immediate guidance. In a business setting, leaders use this style the most effectively on large financial decisions and in crisis situations.
Collaborative: Collaborative decision-making is just what it sounds like. Leaders gather their teams and request feedback and insight. The leader still makes the final call, but is armed with the proper data to make a more informed decision. This can also be referred to as evidence-based decision-making. With this style, and really in all business decisions, avoid surrounding yourself with people that always agree with you. You need people who are able to strongly argue the other side. Whether you use their advice or not, it will help clarify your decision.
Consensus: Consensus-based decision-making is done more like a democratic vote. Leaders gather their teams and everyone votes. Majority rules. This process can work well when the outcome of the decision affects the entire team, and generally won’t immediately affect the bottom line. In a quick-moving business environment, this is not the most efficient way to make a decision, but there are still some decisions that can be made this way. In a business, however, this type of decision-making can help mold the culture when the team is allowed to vote and have a voice. Just remember you generally can’t please everyone.
Convenience: When surrounded by trusted peers, sometimes the best decision a leader can make is to not be the one to make a certain decision. Complete delegation (convenience decision-making) has many benefits including measuring the decision-making abilities of your managers, empowering your team, and maintaining your own sanity! By handing over some decision-making responsibilities, leaders are also building a better management team and giving them the confidence they need as their responsibilities increase. And, convenience-based decision-making is a great way to avoid the decision trap of “we’ve always done it this way.” New decision makers take fresh approaches to solving problems.
How Good is Your Decision-Making?
Each decision presents its own challenges, and we all have different ways of approaching problems. So, how do you avoid making bad decisions – or leaving decisions to chance? You need a systematic approach to decision-making so that, no matter what type of decision you have to make, you can take decisions with confidence.
Tuesday 12 September 2017
Sandoz proposed biosimilar rituximab accepted for review by the FDA
- Rituximab is indicated to treat blood cancers and immunological diseases such as rheumatoid arthritis
- Sandoz believes the comprehensive data package submitted to the FDA for review confirms that our biosimilar rituximab matches the reference medicine in terms of safety, efficacy and quality
- The global leader in biosimilars, Sandoz has five biosimilars approved worldwide including biosimilar rituximab, which was approved in Europe* in June 2017
Holzkirchen, September 12, 2017 - Sandoz, a Novartis Division, and the pioneer and global leader in biosimilars, announced today that the US Food and Drug Administration (FDA) has accepted its Biologics License Application (BLA) under the 351 (k) pathway for a proposed biosimilar to the reference medicine, Rituxan®** (rituximab).
Rituxan®** is used to treat blood cancers including non-Hodgkin's lymphoma (follicular lymphoma and diffuse large B-cell lymphoma) and chronic lymphocytic leukemia, as well as immunological diseases such as rheumatoid arthritis.
"The cost of treating cancer in the US is a major concern for many patients and their families as well as for the healthcare system[3]" said Mark Levick, MD PhD, Global Head of Development, Biopharmaceuticals. "With the FDA acceptance of our regulatory submission for proposed biosimilar rituximab, we plan to deliver patients a high-quality Sandoz biosimilar that, following approval, could help drive healthcare savings and increase competition, while freeing up resources for and supporting patient access in other areas of cancer care including innovative therapies."
The BLA consists of a comprehensive data package that includes analytical, preclinical and clinical data. Clinical studies included apharmacokinetic/
Sandoz is committed to increasing patient access to high-quality biosimilars. As the pioneer and global leader in biosimilars, Sandoz has five biosimilars marketed worldwide, as well as a leading global pipeline. We plan to launch a total of five major oncology and immunology biosimilars between 2017 and 2020. This includes biosimilar rituximab, which was approved by the European Commission for use in Europe in June 2017 (marketed as Rixathon®).
Sandoz is well positioned to continue leading the biosimilars industry based on its experience and capabilities in development, manufacturing and commercialization. As a division of Novartis, the first global healthcare company to establish a leading position in both innovative and off-patent medicines, Sandoz benefits strongly from this unique blend of experience and expertise in many different market environments.
Sandoz also continues to champion policy and legislation that enables patients and the healthcare system to benefit from biosimilars. This was demonstrated by the recent US Supreme Court unanimous positive decision related to the Notice of Commercial Marketing (NCM). The Supreme Court ruled that NCM can be provided before FDA approval, accelerating patient access to future US biosimilars by 180 days. The Court also provided additional clarity on how the "patent dance," the process by which biosimilar manufacturers may provide confidential and proprietary information to the manufacturer of the reference medicine in the patent exchange process, will function.
About Sandoz
Sandoz is a global leader in generic pharmaceuticals and biosimilars. As a division of the Novartis Group, our purpose is to discover new ways to improve and extend people's lives. We contribute to society's ability to support growing healthcare needs by pioneering novel approaches to help people around the world access high-quality medicine. Our portfolio of approximately 1000 molecules, covering all major therapeutic areas, accounted for 2016 sales of USD 10.1 billion. In 2016, our products reached well over 500 million patients and we aspire to reach one billion. Sandoz is headquartered in Holzkirchen, in Germany's Greater Munich area.
FDA approval brings first gene therapy to the United States
CAR T-cell therapy approved to treat certain children and young adults with B-cell acute lymphoblastic leukemia
This release was updated on Aug. 30, 2017 to correctly identify the FDA designations granted to Kymriah.
This release was updated on Aug. 30, 2017 to correctly identify the FDA designations granted to Kymriah.
The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.
The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).
“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”
Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.
Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.
ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.
“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”
The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.
Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.
The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.
Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.
To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.
The FDA granted Kymriah Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA's Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.
The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.
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.
Thursday 7 September 2017
What Impact Will the Shinal Case Have on Informed Consent in Clinical Research? By Darshan Kulkarni and Erin Grant
Introduction:
Informed consent recently made the headlines with Congress and the U.S. Food and Drug
Administration (FDA) expounding on circumstances where they will accept the alteration,
minimization or even outright elimination of informed consent in certain clinical research
trials. Some might argue that this continues the slide towards weakened protections
afforded to patients and clinical study participants. However, some courts have taken to
interpreting the requirements for informed consent rather strictly, especially as they apply
to the performer of the informed consent process.
Background:
According to the Code of Federal Regulations as applied by the Department of Health and
Human Services, an investigator may only involve a human being as a subject in research
if the investigator has obtained legally effective informed consent from the subject or the
subject's legally authorized representative. The Code of Federal Regulations, as applicable
to the FDA,echoes these expectations. However, FDA guidances further explaining these
practices4
allow not only the investigator, but also “other study staff” to “[conduct] the
informed consent interview [with] the subject.”
The FDA repeatedly states that the informed consent requirements in 21 C.F.R. § 50 do not
preempt any applicable federal, state or local laws that require additional information to be
disclosed for informed consent to be legally effective. Instead,“[w]here the regulations
differ, the regulations that offer the greater protection to human subjects should be
followed.”This approach ensures that clinical research subjects receive the maximum
protection offered under the law.
Who is an Investigator?
Informed consent laws and regulations apply to investigators and subinvestigators. The
regulations define an investigator as “an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the drug is administered or dispensed
to a subject). In the event an investigation is conducted by a team of individuals, the
investigator is the responsible leader of the team. Subinvestigators include other members
of the team that perform certain significant functions. Clinical research is almost always
conducted by a team of individuals, typically led by the principal investigator listed on FDA
Form 1572 as the “responsible leader of the team.” The FDA clarifies, however, that the
principal investigator need not be a medical doctor and that a “physician can be a
subinvestigator to perform those study functions requiring the appropriate level of medical
expertise.” This suggests a great deal of flexibility in federal regulations and their
interpretation as to who may be considered a principal investigator or a subinvestigator, and
it also means that an individual who is not a physician may be delegated the primary
responsibility to obtain a subject’s informed consent.
In recognition of the time constraints investigators might face, FDA guidance allows “other
study staff” to conduct the informed consent interview.Practically speaking, this typically
involves the study nurse or coordinator. Still, the regulations seem relatively clear that they
expect the principal investigator to obtain legally effective informed consent.
The Shinal Case :Although federal guidance is relatively flexible as to how the clinical research informed
consent process is to be performed, a recent court case may signal a change to a stricter
model. On June 20, 2017, a divided 4-3 Pennsylvania court, speaking on a seemingly
unrelated issue, interpreted the law to support the plain meaning of the regulations
themselves and not the interpretation of these regulations as seen in the FDA guidance. (It
is not clear whether the court was even aware of FDA’s guidance or if it deemed clinical
research relevant.) The case, Shinal v. Toms, involved a woman undergoing surgery to treat
brain cancer.The treating physician’s assistant obtained a signed informed consent form
from Mrs. Shinal prior to surgery. Unfortunately, during surgery, Mrs. Shinal suffered
permanent injury from complications and sued the physician, alleging his failure to explain
the risks of and alternatives to her surgery.
Until the Shinal case, physicians interpreted the duty to obtain informed consent as one that
could be delegated to a qualified staff member. This delegation could include the entire of
informed consent process, including talking with the patient, discussing the procedure in
question, and then obtaining the patient’s informed consent. However, the Shinal Court
found that effective informed consent stems from the contractual nature of the physician
patient relationship and consequently requires a “meeting of the minds” between the
parties, which could only occur by a physical interaction between the doctor and patient. In support of its holding, the Court quoted Kelly v. Methodist Hospital, noting that the
physician’s unique relationship with the patient, as well as the physician’s education and
training, mean that “the physician is in the best position to know the patient’s medical
history and to evaluate and explain the risks of a particular operation in light of the
particular medical history.”Further, the physician has a duty to disclose these risks to the
patient.Consequently, the Court held that, in the state of Pennsylvania, the duty to
provide informed consent belonged to the physician alone and was non-delegable, because
“obtaining informed consent results directly from the duty of disclosure, which lies solely
with the physician.
Implications for Informed Consent in Clinical Research
Although the Shinal case applied to medical practice, its reverberations can already be felt
in clinical trials, where some might argue that informed consent requirements are, if
anything, more stringent than for medical care. A prima facie interpretation of the Court’s
opinion suggests that informed consent by the physician is non-delegable. While this
reading is not any more burdensome than a strict reading of the regulations, which prima
facie require that only the principal investigator can perform the informed consent
interview, it does place an unexpected burden on clinical research facilities. Although it is
unclear whether the Court intended to apply this opinion to clinical research, there is little to
suggest that courts would not uniformly apply the same informed consent standards used in
the medical practice to clinical research.
If this interpretation of the law applies, the Court’s holding in Shinal will likely have a
significant implication on the speed of clinical research in the face of an already timeconsuming
informed consent process. The Court’s interpretation of this law suggests that
investigators will likely need to personally engage with each potential study participant to
discuss the procedure, possible alternatives, and to make all necessary disclosures.
Investigators are notoriously busy and typically delegate much of the process of obtaining
informed consent to qualified study personnel. However, they should, at minimum, ask the
person if he or she has any questions about the study and determine whether the person is
giving proper informed consent. This flexibility allows greater efficiency and smoother
process flow even as the investigators workflow grows more demanding. In fact, in some
cases, the study nurse might be more knowledgeable about certain study details than the
principal investigator. In addition, consent by the study nurse minimizes the chance of
undue influence that is inherent in the patient/physician relationship.
Since informed consent is a time-consuming process, reserving the responsibility to just the
principal investigators — who probably have the least amount of time — raises other issues
about the adequacy of consent. It adds one more burden to physicians who already feel
overburdened by clinical research duties and are not always available when it is convenient
for the patient.
Issues with the Shinal Ruling
The court found for the plaintiff because the physician relied on a subordinate to obtain
informed consent from the patient, which the court held was a duty non-delegable by the
physician. This raises several issues:
First, it is not clear whether the explanation was inadequate because the physician
possessed a duty inherent in his or her role to obtain informed consent, or whether the
informed consent process must simply be performed by the professional in the best position
to do so. In medical practice, it is reasonable to expect that the physician is the individual
best-placed to discuss the clinical implications of a potential procedure. The physician will
know the patient’s health condition better than the other individuals participating in the
procedure, will have the most experience and training in performing the patient’s procedure,
and will best understand the risks and alternatives.
However, informed consent in clinical studies requires a broader discussion that might need
the involvement of additional team members. For example, clinical trial subjects must be
informed of the possibility of compensation in the event of injury caused by the trial.Although the physician might be the best individual to obtain a subject’s informed consent
with respect to medical procedures, other team members might need to participate in the
informed consent process to ensure the patient is adequately informed in all aspects of the
clinical study. If the study involves a technical procedure, an expert in that procedure might
be better qualified to explain it to the subject. Similarly, the investigator might not be the
best person to explain the logistics or financial ramifications of the study. In some cases, a
subinvestigator might be more expert in the specifics of the medicine than the principal
investigator, who might be more knowledgeable in the mechanics of clinical research.
Ultimately, the Shinal court found that the reason the physician is in the best position to
obtain informed consent is the “education, training and expertise” upon which the patient relies.Requiring the physician to serve as the sole touchpoint for informed consent in
clinical studies might not accomplish that objective.
Exacerbating this issue is the time span for informed consent. In medical practice, the
informed consent process begins when the patient meets with his or her physician for the
first time to discuss treatment. However, the time span is much longer in clinical trials and
does not always involve human interaction. Many human subjects protection experts assert
that the informed consent process starts with the first advertisement the potential subject
sees and continues through the end of a clinical study. Considering the extended time span
of informed consent in the clinical trial setting and the additional procedures and issues that
might arise not involving the original investigator, it is impractical to expect the investigator
to manage all aspects of the informed consent process from beginning to end. Accordingly,
additional team members will become involved as different aspects of the trial process call
for their unique expertise.
Causing further confusion is the difference in professional designations between medical
practice and clinical trials. While the Shinal Court refers to the “physician,” the term
“physician” is not synonymous with the term “principal investigator.” This might cause
confusion as to who obtains the subject’s informed consent. As mentioned above, the
principal investigator in a study might not even be a physician, so under a strict reading of
Shinal suggesting that only a physician performing the procedure can obtain informed
consent, the Shinal case might not apply. However, in the scenario where the
subinvestigator is a physician, then that physician might have the duty to the patient. Under
a looser reading of Shinal, where the person obtaining informed consent must be the
individual in the best position to do so, this duty might fall ultimately on the principal
investigator or on other team members, depending on their areas of expertise.
Causing further confusion is the difference in professional designations between medical
practice and clinical trials. While the Shinal Court refers to the “physician,” the term
“physician” is not synonymous with the term “principal investigator.” This might cause
confusion as to who obtains the subject’s informed consent. As mentioned above, the
principal investigator in a study might not even be a physician, so under a strict reading of
Shinal suggesting that only a physician performing the procedure can obtain informed
consent, the Shinal case might not apply. However, in the scenario where the
subinvestigator is a physician, then that physician might have the duty to the patient. Under
a looser reading of Shinal, where the person obtaining informed consent must be the
individual in the best position to do so, this duty might fall ultimately on the principal
investigator or on other team members, depending on their areas of expertise.
Additionally, as stated above, the Shinal Court found that effective informed consent stems
from the personal, interactive nature of the physician-patient relationship, noting that
“[w]ithout direct dialogue and a two-way exchange between the physician and patient, the
physician cannot be confident that the patient comprehends the risks, benefits, likelihood of
success, and alternatives [to treatment].”If this ruling were to be fully applied, it could
invalidate all consent obtained without a physical physician-patient interaction. While the
relationship is justifiably special, there is nothing in the contractual aspect of that
relationship that requires physical interaction. The success of telemedicine even argues
against the need for physical interaction in the medical part of the relationship.
Additionally, if the principal investigator is in the process of explaining the study to a
potential participant, it is unlikely that the court would prohibit the study nurse from
interjecting a clarification or providing supplemental information. Or, if the principal
investigator and the study participant cannot converse fluently in the same language, it is
doubtful that the court would disallow the use of an interpreter.
Conclusion
The Shinal case, like many, raises more questions than it answers, especially when applied
to clinical research, which does not constitute traditional medical care due to its
investigative nature.Physicians conducting clinical research in Pennsylvania should obtain advice from their legal
counsel, should probably be involved in the consent process if they are the principal
investigator, and, in consideration of the potential demands placed on researchers regarding
adequate informed consent, should certainly strive to obtain informed consent using either
their physician researchers or their experts best positioned to obtain effective informed
consent.
With the issues discussed above, the mere existence of the ruling invites plaintiff attorneys
to argue it in other cases, even outside Pennsylvania
Author
Darshan Kulkarni, Pharm.D, MS, Esq., is Principal Attorney at The Kulkarni Law Firm. He is
also a Visiting Professor at the University of the Sciences and is Vice Chair of the Life
Sciences Interest Group of the American Bar Association. Contact him at 1.215.948.8183
Tuesday 5 September 2017
Novartis landmark Phase III trial shows fingolimod significantly reduces relapses in children and adolescents with MS
Novartis landmark Phase III trial shows fingolimod significantly reduces relapses in children and adolescents with MS
- Phase III PARADIGMS study in pediatric MS met its primary endpoint, showing a significant reduction in relapses occur with fingolimod versus interferon beta-1a
- There is a significant unmet need for safe and effective MS treatments for children and adolescents, for whom there are no specifically approved disease-modifying therapies
- Children and adolescents living with MS face physical and cognitive disability that severely limits their ability to go about daily activities, such as going to school
- PARADIGMS is a first of its kind study in pediatric MS. Other current treatments have not been evaluated in head to head trials specifically designed for children and adolescents
Basel, September 05, 2017 - Novartis today announced positive topline results from the Phase III PARADIGMS study, investigating the safety and efficacy of oral once-daily fingolimod in children and adolescents (ages 10 to 17) with multiple sclerosis (MS). Data show that oral fingolimod resulted in a significant and clinically meaningful reduction in the number of relapses (annualized relapse rate) in this patient population over a period of up to two years, compared to interferon beta-1a intramuscular injections. The safety profile of fingolimod was consistent with that seen in other clinical trials, with overall more adverse events reported in the interferon group. The PARADIGMS study is the first ever randomized, controlled Phase III study of a disease-modifying therapy (DMT) in pediatric MS.
"Living with MS is a tremendous challenge at any age. However, its appearance in children and adolescents, when these young individuals should be developing and focusing on their future, can be devastating," said Vas Narasimhan, Global Head of Drug Development and Chief Medical Officer, Novartis. "With no specifically approved treatment options based on a thorough study such as PARADIGMS, the risk of long-term disease progression in these patients is much greater. The outcome of this study is very exciting news for the MS patient community, all of whom benefit from potential advances in high-quality, evidence-based care such as this. I would like to thank the young people with MS and their families, physicians and nurses who participated and made this landmark study possible."
Results of the Phase III PARADIGMS study will be presented at the 7th Joint ECTRIMS-ACTRIMS meeting, taking place October 25 - 28, 2017, in Paris, France.
Commonly diagnosed during adolescence, pediatric MS is associated with relapses that are more frequent and often more severe than those seen in adults with MS. Relapses negatively affect mobility, balance and cognitive function, and patients with pediatric MS are more likely to accumulate physical disability at an earlier age than those diagnosed as adults. There is currently no treatment indicated for children and adolescents living with MS, based on randomized, controlled, clinical study data.
Fingolimod is not currently approved for the treatment of pediatric MS. Novartis plans to complete a thorough analysis of these important data to speak to health authorities to agree on next steps for submission.
About the Phase III PARADIGMS study
The Phase III PARADIGMS study (NCT01892722) is a flexible duration (up to two years), double-blind, randomized, multi-center Phase III study to evaluate the safety and efficacy of oral fingolimod compared to interferon beta-1a in children and adolescents with a confirmed diagnosis of multiple sclerosis (MS), followed by a five-year open label extension phase. The study enrolled 215 children and adolescents with MS, between the ages of 10 and 17 years with an Expanded Disability Status Scale (EDSS) score between 0 and 5.5. Patients were randomized to receive once-daily oral fingolimod (0.5 mg or 0.25 mg, dependent on patients' body weight) or intramuscular interferon beta-1a once weekly.
The primary endpoint of the study was the frequency of relapses in patients treated up to 24 months (annualized relapse rate). Secondary endpoints include the number of new or newly enlarged T2 lesions, Gadolinium enhancing T1 lesions, safety and the pharmacokinetic properties of fingolimod, all measured throughout the treatment period.
The Phase III PARADIGMS study was conducted in 87 sites over 25 countries, and was designed in partnership with the US Food and Drug Administration, European Medicines Agency and the International Pediatric Multiple Sclerosis Study Group.
About Multiple Sclerosis
Multiple sclerosis (MS) is a chronic disorder of the central nervous system (CNS) that disrupts the normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss. In adults, there are three types of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). In children, RRMS accounts for nearly all cases (approximately 98 percent).
The evolution of MS results in an increasing loss of both physical and cognitive (e.g. memory) function. This has a substantial negative impact on the lives of the approximately 2.3 million people worldwide affected by MS, of which between three and five percent are estimated to be children.
About Gilenya (fingolimod) in adults
Gilenya (fingolimod) is an oral disease-modifying therapy (DMT) that is highly efficacious at controlling disease activity in relapsing multiple sclerosis (RMS). Gilenya has a reversible lymphocyte redistribution effect targeting both focal and diffuse central nervous system (CNS) damage caused by MS. Long-term clinical trial and real-world evidence and experience has shown Gilenya treatment to be convenient for individuals to incorporate into everyday life, leading to high treatment satisfaction, long-term persistence, and ultimately, improved long-term outcomes for people with RMS.
Gilenya impacts four key measures of RMS disease activity: relapses, MRI lesions, brain shrinkage (brain volume loss) and disability progression. Its effectiveness on all of these measures has been consistently shown in multiple controlled clinical studies and in the real-world setting. Studies have shown its safety and high efficacy to be sustained over the long term, demonstrating that switching to Gilenya treatment as early in the disease course as possible can be beneficial in helping to preserve individuals' function.
Gilenya is approved in the US for the first-line treatment of relapsing forms of MS in adults and in the EU for adult patients with highly-active relapsing-remitting MS (RRMS) defined as either high disease activity despite treatment with at least one DMT, or rapidly-evolving severe RRMS
Gilenya has been used to treat more than 213,000 patients in both clinical trials and the post-marketing setting, with approximately 453,000 years of patient experience.
About Novartis in Multiple Sclerosis
Alongside Gilenya (fingolimod, an S1P modulator), Novartis' multiple sclerosis (MS) portfolio includes Extavia® (interferon beta-1b for subcutaneous injection) which is approved in the US for the treatment of relapsing forms of MS. In Europe, Extavia is approved to treat people with relapsing-remitting MS, secondary progressive MS (SPMS) with active disease and people who have had a single clinical event suggestive of MS.
Investigational compounds include BAF312 (siponimod), under investigation in MS, and OMB157 (ofatumumab), a fully human monoclonal antibody under investigation in relapsing MS. OMB157 targets CD20, and is currently being investigated in two Phase III pivotal studies.
In the US, the Sandoz Division of Novartis markets Glatopa® (glatiramer acetate injection) 20mg/mL, the first generic version of Teva's Copaxone®* 20mg.
*Copaxone® is a registered trademark of Teva Pharmaceutical Industries Ltd.
Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," "exciting," "underway," "upcoming," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational and approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 119,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com
Monday 4 September 2017
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