May 28, 2020: “Novartis announced today that Mayzent data from the Phase III EXPAND trial were published in the European Journal of Neurology after the 6th EAN, held virtually due to COVID-19.
These data, which included separate post hoc analyses from the Phase III EXPAND trial, continue to build on existing clinical evidence that Mayzent has a significant impact on reducing the risk of disease progression, including physical disability and cognitive decline for patients with SPMS.
“We are pleased to highlight data demonstrating that Mayzent helps slow disability progression and declining cognitive function,” said Norman Putzki, M.D., Global Head of Development Neuroscience. “For people living with MS, it’s essential to get ahead of disease progression and treat early so that they can maintain as much independence as possible in the future. We are dedicated to reimagining MS treatment and bringing hope to people with progressive diseases like MS.” https://www.novartis.com/news/media-releases/novartis-data-highlight-benefit-early-treatment-initiation-patients-secondary-progressive-multiple-sclerosis-spms
May 27, 2020: “The Janssen Pharmaceutical Companies of Johnson & Johnson announced that the U.S. FDA has granted approval for a new pediatric formulation of SIRTURO® (bedaquiline).
SIRTURO® is now indicated for use as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary multidrug-resistant tuberculosis (MDR‑TB).
In the U.S., the medicine should be reserved for use when an effective treatment regimen cannot otherwise be provided.
This indication received accelerated approval based on time to sputum culture conversion.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
SIRTURO® should not be used for the treatment of latent TB infection, extra-pulmonary or drug-sensitive TB, or for the treatment of infections caused by non-tuberculous mycobacteria.
The safety and efficacy of SIRTURO® in the treatment of HIV-infected patients with MDR-TB have not been established, as clinical data are limited.
Today’s decision marks the first regulatory approval for the pediatric formulation of SIRTURO® and is a key component of Johnson & Johnson’s global pediatric research and development (R&D) program for the medicine.
The new 20 mg tablet can be administered with water for patients who are able to swallow the intact tablet and taken with food.
For patients who have difficulty swallowing intact tablets, the tablet can be dispersed in water and administered. To aid with administration, the dispersed mixture in water can be further mixed with a beverage or soft food.
Alternatively, the tablet can be crushed and mixed with soft food immediately prior to use and administered.
“The first-ever approval of a pediatric formulation of bedaquiline is a significant advancement for children with multidrug-resistant tuberculosis,” said Martin Fitchet, M.D., Global Head, Global Public Health, Johnson & Johnson.
“TB is already an often-overlooked area in global health, and children with the disease are especially vulnerable.
Modernizing pediatric treatment is a critical step toward reducing the suffering of these young patients and ending TB once and for all.”
When SIRTURO® first received accelerated approval from the U.S. FDA for use in eligible adult patients in 2012, it was the first novel TB medicine in more than 40 years.
In 2019, the FDA granted approval for SIRTURO® 100 mg tablets as part of combination therapy in adolescent patients (12 to less than 18 years of age and weighing at least 30 kilograms (66 pounds)) with pulmonary MDR-TB, when an effective treatment regimen cannot otherwise be provided.
Further research is ongoing in children aged two to four, and in infants younger than two years old.
TB is the world’s deadliest infectious disease, claiming approximately 1.5 million lives in 2018 alone – more than HIV and malaria combined.
While TB most often affects adults in their most productive years, in 2018, an estimated 1.1 million children became ill with TB worldwide and more than 200,000 died.
According to the World Health Organization, however, these are likely underestimates of the true burden of the disease in children.
These grim statistics underscore the urgent need for effective pediatric TB treatments.
“In the last 10 years, we have seen great advances in innovation for tuberculosis, especially for the hardest to treat forms,” said Ruxandra Draghia-Akli, M.D., Ph.D., Global Head, Global Public Health R&D, Janssen Research & Development, LLC.
“Johnson & Johnson is proud to be driving this research and development for patients of all ages. This latest accomplishment for our bedaquiline pediatric program will provide a new tool to address MDR-TB in vulnerable populations.”
Today’s FDA approval is supported by evidence from a single-arm, open-label, Phase 2 study that enrolled pediatric patients aged 5 to less than 12 years of age with confirmed or probable pulmonary MDR-TB infection who were treated at half the adult dose with the SIRTURO® 20mg tablet for 24 weeks in combination with a background regimen for the treatment of MDR-TB.
The application for the pediatric formulation obtained priority review from the FDA.
INDICATIONS AND USAGE
SIRTURO® (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB).
Reserve SIRTURO® for use when an effective treatment regimen cannot otherwise be provided.
This indication is approved under accelerated approval based on time to sputum culture conversion.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Limitations of Use
Do not use SIRTURO® for the treatment of:
Latent infection due to Mycobacterium tuberculosis
Drug-sensitive tuberculosis
Extra-pulmonary tuberculosis
Infections caused by non-tuberculous mycobacteria
The safety and efficacy of SIRTURO® in the treatment of HIV-infected patients with MDR-TB have not been established as clinical data are limited.
IMPORTANT SAFETY INFORMATION
WARNINGS: INCREASED MORTALITY AND QT PROLONGATIONINCREASED MORTALITY An increased risk of death was seen in the SIRTURO® treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial in adults. Only use SIRTURO® in patients 5 years of age and older when an effective treatment regimen cannot otherwise be provided.QT PROLONGATION QT prolongation can occur with SIRTURO®. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO® if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops.
Warnings and Precautions
Increased Mortality: An increased risk of death was seen in the SIRTURO® treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial in adults (based on the 120 week visit window).
One death occurred during the 24 weeks of administration of SIRTURO®.
The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, or severity of disease could be observed.
Only use SIRTURO® in patients 5 years of age and older when an effective treatment regimen cannot otherwise be provided.
QT Prolongation: SIRTURO® prolongs the QT interval. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO®.
Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected.
SIRTURO® has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
The following may increase the risk for QT prolongation when patients are receiving SIRTURO®: use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine; a history of Torsade de Pointes; a history of congenital long QT syndrome; a history of or ongoing hypothyroidism; a history of or ongoing bradyarrhythmias; a history of uncompensated heart failure; serum calcium, magnesium, or potassium levels below the lower limits of normal.
If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.
Discontinue SIRTURO® and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG).
If syncope occurs, obtain an ECG to detect QT prolongation.
Risk of Development of Resistance to Bedaquiline: A potential for development of resistance to bedaquiline in Mycobacterium tuberculosis exists. Bedaquiline must only be used in an appropriate combination regimen for the treatment of pulmonary MDR-TB to reduce the risk of development of resistance to bedaquiline.
Hepatotoxicity: In clinical trials, more hepatic-related adverse reactions were reported in adults with the use of SIRTURO® plus other drugs to treat tuberculosis compared to other drugs used to treat tuberculosis without the addition of SIRTURO®.
Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO®, especially in patients with impaired hepatic function. Hepatic-related adverse reactions have also been reported in pediatric patients 5 years of age and older.
Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed.
Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs. Discontinue SIRTURO® if:
aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
aminotransferase elevations are greater than eight times the upper limit of normal
aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two weeks
Drug Interactions
CYP3A4 Inducers/Inhibitors:Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4.
Avoid co-administration of strong CYP3A4 inducers such as rifamycins (ie, rifampin, rifapentine, and rifabutin) or moderate CYP3A4 inducers such as efavirenz, during treatment with SIRTURO®.
Co-administration of SIRTURO® with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions.
Therefore, avoid the use of strong CYP3A4 inhibitors used for more than 14 consecutive days while on SIRTURO®, unless the benefit of treatment with the drug combination outweighs the risk.
Appropriate clinical monitoring for SIRTURO®-related adverse reactions is recommended.
Use in Specific Populations
Pregnancy Risk Summary: Available data from published literature of SIRTURO® use in pregnant women are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
There are risks associated with active tuberculosis during pregnancy. Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oral administration of bedaquiline to pregnant rats and rabbits during organogenesis at exposures up to 6 times the clinical dose based on AUC comparisons.
Clinical Considerations: Disease-associated Maternal and/or Embryo/Fetal Risk Active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death.
Lactation Risk Summary: There is no information regarding the presence of bedaquiline in human milk. Minimal data are available on the effects of the drug on the breastfed infant.
No data are available on the effects of the drug on milk production. Bedaquiline is concentrated in the milk of rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SIRTURO® and any potential adverse effects on the breastfed infant from SIRTURO® or from the underlying maternal condition.
Pediatric Use:The safety, effectiveness and dosage of SIRTURO® in pediatric patients less than 5 years of age and/or weighing less than 15 kg have not been established.
Renal Impairment: SIRTURO® has mainly been studied in adult patients with normal renal function.
Renal excretion of unchanged bedaquiline is not substantial (less than or equal to 0.001%).
No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis, SIRTURO® should be used with caution.
Monitor adult and pediatric patients for adverse reactions of SIRTURO® when administered to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis.
Adverse Reactions
Adult: Adverse reactions that occurred more frequently than placebo during treatment with SIRTURO® included: nausea (38% vs 32%), arthralgia (33% vs 22%), headache (28% vs 12%), hemoptysis (18% vs 11%), chest pain (11% vs 7%), anorexia (9% vs 4%), transaminases increased (9% vs 1%), rash (8% vs 4%), and blood amylase increased (3% vs 1%).
Pediatric:
The safety assessment of bedaquiline is based on the Week 24 analysis from 30 pediatric patients in an ongoing, single-arm, open-label, multi-cohort trial, (Study 4).
Pediatric Patients (12 years to less than 18 years of age)
The first cohort was designed to enroll patients 12 years to less than 18 years of age (fifteen patients 14 years to less than 18 years of age were enrolled) with confirmed or probable pulmonary MDR-TB infection who received SIRTURO® (400 mg once daily for the first 2 weeks and 200 mg 3 times/week for the following 22 weeks) in combination with a background regimen.
The most common adverse reactions were arthralgia in 6/15 (40%) patients, nausea in 2/15 (13%) patients, and abdominal pain in 2/15 (13%) patients. Among the 15 patients, no deaths occurred during treatment with SIRTURO®.
Observed laboratory abnormalities were comparable to those in adults.
Pediatric Patients (5 years to less than 12 years of age)
The second cohort was designed to enroll patients 5 years to less than 12 years of age (fifteen patients aged 5 years to less than 11 years of age were enrolled) with confirmed or probable pulmonary MDR-TB infection who received SIRTURO® (200 mg once daily for the first 2 weeks and 100 mg 3 times/week for the following 22 weeks) in combination with a background regimen.
The most common adverse reactions were related to elevations in liver enzymes (5/15, 33%), and led to discontinuation of SIRTURO® in three patients.
Elevations in liver enzymes were reversible upon discontinuation of SIRTURO® and some of the background regimen drugs.
May 27, 2020: “AbbVie announced that it will present new safety and efficacy results for RINVOQ™ (upadacitinib) in adult patients with moderate to severe active rheumatoid arthritis, primary data of RINVOQ for investigational use in psoriatic arthritis, as well as additional data on HUMIRA® (adalimumab) in psoriatic arthritis at the European E-Congress of Rheumatology (EULAR) 2020, June 3-6.
A total of 25 abstracts will be presented across multiple rheumatic conditions, including rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis.
“As a leader in immunology for over two decades, AbbVie is dedicated to developing innovative therapies for patients living with debilitating, chronic immune-mediated conditions,” said Marek Honczarenko MD, PhD, vice president, global immunology development, AbbVie.
“The new research from across our portfolio presented at EULAR underscores our commitment to improving the standard of care and highlights the potential for our therapies to make a meaningful difference in patients living with rheumatic diseases.”
AbbVie will for the first time present data from the SELECT-CHOICE clinical trial.
It is the sixth study in the SELECT rheumatoid arthritis clinical trial program, evaluating efficacy and safety of RINVOQ compared to abatacept in patients with moderate to severe active rheumatoid arthritis and prior inadequate response or intolerance to biologic DMARDs.
In addition, new long-term efficacy and safety data of up to 72 weeks from the SELECT-COMPARE study and up to 84 weeks from the SELECT-MONOTHERAPY study, along with three additional analyses evaluating the safety profile of RINVOQ, will be presented.
In addition to sharing new data from the robust Phase 3 SELECT rheumatoid arthritis clinical trial program, AbbVie will present investigational data evaluating RINVOQ in adult patients with active psoriatic arthritis from the SELECT-PsA 1 study in a late-breaker presentation andprimary data from the SELECT-PsA 2 study.
In SELECT-PsA 1, RINVOQ was compared to placebo and adalimumab in patients with an inadequate response to non-biologic DMARDs. In SELECT-PsA 2, RINVOQ was compared to placebo in patients with an inadequate response to biologic DMARDs.
RINVOQ is being investigated for the treatment of psoriatic arthritis and its efficacy and safety have not been established.
AbbVie Data at EULAR
RINVOQ Abstracts Rheumatoid Arthritis
Efficacy and Safety of Upadacitinib Versus Abatacept in Patients with Active Rheumatoid Arthritis and Prior Inadequate Response or Intolerance to Biologic Disease-Modifying Anti-Rheumatic Drugs (SELECT-CHOICE): A Double-Blind, Randomized Controlled Phase 3 Trial; SAT0151; Poster View Session; Saturday, June 6, 2020; 10:30 a.m. – 12:00 p.m. CEST
Upadacitinib as Monotherapy in Patients with Rheumatoid Arthritis and Prior Inadequate Response to Methotrexate: Results at 84 Weeks from the SELECT-MONOTHERAPY Study; THU0213; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
Long-Term Safety and Effectiveness of Upadacitinib or Adalimumab in Patients with Rheumatoid Arthritis: Results at 72 weeks from the SELECT-COMPARE Study; THU0201; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
Upadacitinib Monotherapy in Methotrexate-Naïve Patients with Rheumatoid Arthritis: Results at 72 weeks from SELECT-EARLY; THU0217; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
Radiographic Outcomes in Patients with Rheumatoid Arthritis Receiving Upadacitinib as Monotherapy or in Combination with Methotrexate: Results at 2 years from the SELECT-COMPARE and SELECT-EARLY Studies; THU0211; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
Characterization of Serious Infections with Upadacitinib in Patients with Rheumatoid Arthritis; FRI0141; Poster View Session; Friday, June 5, 2020; 11:50 a.m. – 1:30 p.m. CEST
Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-Naïve Patients with Early Active Rheumatoid Arthritis Receiving Treatment within 3 months of Diagnosis: A Post-Hoc Analysis of the SELECT-EARLY Study; SAT0145; Poster View Session; Saturday, June 6, 2020; 10:30 a.m. – 12:00 p.m. CEST
Efficacy and Safety of Upadacitinib in Patients from China, Brazil and South Korea with Rheumatoid Arthritis who have had Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs; SAT0160; Poster View Session; Saturday, June 6, 2020; 10:30 a.m. – 12:00 p.m. CEST
Proteomics Analysis Comparing the Mode of Action of Upadacitinib and Adalimumab Head to Head in Rheumatoid Arthritis Identifies Novel, Discrete Early Immune Pathway Modulation in the SELECT-COMPARE Phase 3 Study; FRI0026; Poster Tour Session; Friday, June 5, 2020; 11:50 a.m. – 1:30 p.m. CEST
Sustainability of Response to Upadacitinib as Monotherapy or in Combination Among Patients with Rheumatoid Arthritis and Prior Inadequate Response to Conventional Synthetic DMARDs; THU0207; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
Incidence and Risk Factors for Herpes Zoster in Rheumatoid Arthritis Patients Receiving Upadacitinib; THU0218; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
Safety Profile of Upadacitinib Up to 3 Years of Exposure in Patients with Rheumatoid Arthritis; THU0197; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
Sustainability of Response Between Upadacitinib and Adalimumab Among Patients with Rheumatoid Arthritis and Prior Inadequate Response to Methotrexate; FRI0131; Poster View Session; Friday, June 5, 2020; 11:50 a.m. – 1:30 p.m. CEST
Incidence and Risk of Venous Thromboembolic Events Among Patients With Rheumatoid Arthritis Enrolled in the Upadacitinib SELECT Clinical Trial Program; THU0195; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
Impact of Baseline Demographics and Disease Activity on Outcomes in Patients with Rheumatoid Arthritis Receiving Upadacitinib; FRI0140; Poster View Session; Friday, June 5, 2020; 11:50 a.m. – 1:30 p.m. CEST
Upadacitinib Treatment and the Routine Assessment of Patient Index Data 3 (RAPID3) Among Patients with Rheumatoid Arthritis; THU0192; Poster View Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST
The Impact of Upadacitinib Versus Methotrexate or Adalimumab on Individual and Composite Disease Measures in Patients with Rheumatoid Arthritis; FRI0138; Poster View Session; Friday, June 5, 2020; 11:50 a.m. – 1:30 p.m. CEST
Psoriatic Arthritis and Axial Spondyloarthritis
Efficacy and Safety of Upadacitinib Versus Placebo and Adalimumab in Patients with Active Psoriatic Arthritis and Inadequate Response to Non-Biologic Disease-Modifying Anti-Rheumatic Drugs (SELECT-PsA-1): a Double-Blind, Randomized Controlled Phase 3 Trial; LB-0001; Oral Abstract Presentation; Wednesday, June 3, 2020; 4:20 p.m. – 4:30 p.m. CEST
Efficacy and Safety of Upadacitinib in Patients with Active Psoriatic Arthritis and Inadequate Response to Biologic Disease-Modifying Anti-Rheumatic Drugs (SELECT-PsA-2): a Double-Blind, Randomized Controlled Phase 3 Trial; OP0223; Oral Abstract Presentation; Friday, June 5, 2020; 10:15 a.m. – 10:25 a.m. CEST
Improvements in Global Functioning and Health-related Quality of Life and Their Association with Disease Activity and Functional Improvement in Patients with Active Ankylosing Spondylitis Treated with Upadacitinib: Results from the SELECT-AXIS 1 Trial; THU0375; Poster Tour Session; Thursday, June 4, 2020; 11:50 a.m. – 1:30 p.m. CEST”
Before understanding the difference between central lab and local lab, let’s understand about “why lab tests are conducted”
In Clinical trials, several lab tests need to be performed for each patient as per the protocol. These tests are needed to evaluate the following things:
Inclusion/Exclusion criteria or eligibility check
Safety checks
Study drug dose determination
Sponsor or Pharmaceutical companies have two options-Central labs and Local labs to perform these tests.
What is the central lab in clinical research:
Central labs are the sponsor assigned well-equipped laboratories.
Samples are collected from different sites (hospitals) and they are sent to one lab (sponsor assigned) for testing purpose. Sites may be situated in different countries but the samples need to be sent to one special laboratory (which is called central lab).
What is the local lab in clinical research:
Local labs are the regular lab facilities that are available in the hospital or nearby location. Each site (hospital) will have their lab.
Sample of the patients on a particular site will be analysed in lab affiliated to that particular hospital.
Now the question comes, why there are two different kinds of labs
In the central lab, all the samples are processed by using the same analytical methods so that unintentional differences in laboratory results and reference ranges can be avoided.
For example, you can observe much difference in haemoglobin lab results if performed by different methods. Even different labs may use different ranges for haemoglobin.
Central Laboratories are equipped with better facilities which are not possible to provide at each hospital-associated lab (local lab).
For example, the central laboratory uses sophisticated software to record, track and transmit the lab results after analyzing the samples.
Central labs can conduct many different kinds of protocol-specific tests because they are maintained mainly for clinical trial-related work.
In general, Pharmacokinetic parameters such as the concentration of drug in blood from different time points, metabolites concentration, genetic mutations and another biomarker test on the tissue sample etc are performed in the central lab.
There are also issues with central labs and local labs need to be used in these cases. Let us discuss one by one:
lab test at Central lab is times consuming process as all sites sample has to reach one lab and it may take 4-7 days or more.
Sample stability may be compromised if any issue in transportation.
In the case of the adverse event, immediate lab tests are needed which can be done in the local lab only. Central labs are not feasible.
Dosing of study drugs: Lab tests need to be performed in a short period. In the case of oncology studies, drug dosing and adjustment of dose generally depend on blood biochemistry and Blood cells counts and these tests can be done easily in the local lab facility without wasting time.
In the case of local labs, Clinical research coordinator (CRC) has to share the reference range manuals to clinical research associate(CRA) and clinical research associate enters the reference ranges in the clinical database (eDC). (The document containing all the reference rages to be used in the local lab for a particular study is called local lab manual.)*
In the case of the central lab, manual data entries of reference ranges are not needed.
Local lab-results are manually entered in clinical databases (eDC) by the clinical research coordinator.
Form 1572, section 4 mentions about local lab facility. No need to mention about the central lab here.
Key Note: Based on protocol, requirements and availabilities, sponsor decides about the use of local labs and central labs.
May 27, 2020: “Novartis announced that new ofatumumab data from the Phase III ASCLEPIOS trials and the Phase II APLIOS trial were presented virtually at the 6th Congress of the European Academy of Neurology (EAN).
The data continue to demonstrate ofatumumab (OMB157) as a potential novel treatment option for patients with RMS. The safety profile was comparable to teriflunomide.
Ofatumumab is a targeted B-cell therapy that, if approved, addresses a clinical unmet need as the first B-cell therapy that can be self-administered at home through an autoinjector pen.
In addition to being presented virtually, the data were also published in the European Journal of Neurology, Volume 27, Supplement 1, May 2020.
A post hoc analysis from the Phase III ASCLEPIOS I and II trials (n=1882) assessed the odds of patients achieving NEDA-3 with ofatumumab versus teriflunomide within the first (Month 0–12) and second year (Month 12–24) of treatment.
NEDA-3 is a comprehensive composite measure commonly used to assess treatment outcomes in patients with RMS.
It is defined as an absence of three measures of disease activity: relapses; disease progression, measured as 6-month confirmed disability worsening (CDW), and gadolinium enhancing (Gd+) T1 lesions.
The study results showed that compared with teriflunomide, a greater proportion of patients treated with ofatumumab achieved NEDA-3 in year 1 (47.0% vs 24.5%; P<.001) and in year 2 (87.8% vs 48.2%; P<.001).
“Achieving no evidence of disease activity is widely recognized as an important treatment goal for multiple sclerosis therapies,” said Professor Ludwig Kappos, University Hospital Basel.
“These data suggest that halting new disease activity is possible by targeted B-cell therapy in RMS.”
A separate analysis from the APLIOS trial (n=284) showed ofatumumab treatment led to rapid and sustained depletion of both CD20+ B- and T-cells in patients with RMS.
Ofatumumab depleted different B- and T-cell subsets including memory B-cells and naïve B-cells, as well as a subset of T-cells that are known to exhibit an activated phenotype. However, CD3+ T-cells that do not express the CD20 receptor, were largely unaffected.
“These results are encouraging and support our belief that, if approved, ofatumumab could have the potential to significantly improve the lives of people with RMS,” said Krishnan Ramanathan, Neuroscience Global Program Head at Novartis.
“These data are a testament to our commitment to reimagining medicine and advancing innovative treatments that help people with this serious and progressive disease.”
Regulatory action for ofatumumab in the US is expected in June 2020. Novartis is committed to bringing ofatumumab to patients around the world, and additional regulatory filings are currently under way.
Ofatumumab (OMB157) is a fully human anti-CD20 monoclonal antibody (mAb) in development for RMS that is self-adminstered by a once-monthly injection, delivered subcutaneously.
As shown in preclinical studies, ofatumumab is thought to work by binding to a distinct epitope on the CD20 molecule inducing potent B-cell lysis and depletion.
The selective mechanism of action and subcutaneous administration of ofatumumab allows precise delivery to the lymph nodes, where B-cell depletion in MS is needed, and may preserve the B-cells in the spleen, as shown in preclinical studies.
Once-monthly dosing of ofatumumab also allows fast repletion of B-cells and offers more flexibility.
Ofatumumab was originated by Genmab and licensed to GlaxoSmithKline; Novartis obtained rights for ofatumumab from GlaxoSmithKline in all indications, including RMS, in December 2015.
ASCLEPIOS I and II studies The ASCLEPIOS I and II studies are twin, identical design, flexible duration (up to 30 months), double-blind, randomized, multi-centre Phase III studies evaluating the safety and efficacy of ofatumumab 20 mg monthly subcutaneous injections versus teriflunomide 14 mg oral tablets taken once daily in adults with RMS.
The ASCLEPIOS I and II studies enrolled 1882 patients with MS, between the ages of 18 and 55 years, with an Expanded Disability Status Scale (EDSS) score between 0 and 5.5.
The studies were conducted in over 350 sites in 37 countries. Ofatumumab demonstrated a significant reduction in annualized relapse rate (ARR) by 50.5% (0.11 vs 0.22) and 58.5% (0.10 vs 0.25) compared with teriflunomide (P<.001 in both studies) in ASCLEPIOS I and II respectively (primary endpoint). Ofatumumab showed significant reduction of both Gd+T1 lesions and new or enlarging T2 lesions.
It significantly reduced the mean number of both Gd+ T1 lesions (97.5% and 93.8% relative reduction in ASCLEPIOS I and II, respectively, both P<.001) and new or enlarging T2 lesions (82.0% and 84.5% relative reduction in ASCLEPIOS I and II, respectively, (both P<.001).
Ofatumumab also showed a relative risk reduction of 34.4% (P=.002) in 3-month CDW and 32.5% (P=.012) in 6-month CDW compared with teriflunomide in pre-specified meta-analysis, as defined in ASCLEPIOS.
Ofatumumab demonstrated that it lowered neurofilament light levels in serum at the first assessment at Month 3 compared with teriflunomide.
There was no difference in the slope of brain volume change from baseline between treatments. In a measure of 6-month confirmed disability improvement events, a favourable trend was seen but this did not reach significance.
The frequency of serious infections and malignancies was similar across both treatment groups, and overall, ofatumumab had a similar safety profile to teriflunomide.
Injection-related reactions, injection-site reactions and upper respiratory tract infection were the most commonly observed adverse events across both treatment groups, occurring in ≥10% of patients.
A separate post hoc analysis demonstrated ofatumumab may halt new disease activity in RMS patients.
It showed the odds of achieving NEDA-3 (no relapses, no MRI lesions, and no disability worsening combined) with ofatumumab versus teriflunomide were >3-fold higher at Month (M) 0–12 (47.0% vs 24.5% of patients; P<.001) and >8-fold higher at M12–24 (87.8% vs 48.2% of patients; P<.001).
Overall ofatumumab, a fully human antibody targeting CD20+ B-cells, delivered superior efficacy and demonstrated a safety and tolerability profile with infection rates similar to teriflunomide2.
APLIOS study The APLIOS study is a 12-week, open-label, Phase II bioequivalence study to determine the onset of B-cell depletion with ofatumumab subcutaneous monthly injections and the bioequivalence of subcutaneous administration of ofatumumab via a pre-filled syringe—as used in ASCLEPIOS I and II—and an autoinjector pen in patients with RMS.
Patients were randomized according to injection device and site including the abdomen and the thigh. B-cell depletion was measured nine times over 12 weeks and Gd+ lesion counts were assessed at baseline and at Weeks 4, 8 and 12.
Regardless of injection device or site, ofatumumab 20 mg subcutaneous monthly injections resulted in rapid, close to complete and sustained B-cell depletion.
The proportion of patients with B-cell concentrations of <10 cells/μL was >65% after the first injection by Day 7, 94% by Week 4 and sustained >95% at all following injections.
Ofatumumab treatment reduced the mean number of Gd+ lesions from baseline (1.5) to 0.8, 0.3 and 0.1 by Weeks 4, 8 and 12, respectively.
May 27, 2020: “Novartis announced a new exploratory subgroup analysis of the Phase III MONALEESA-3 and MONALEESA-7 trials, to be presented during the ASCO20 Virtual Scientific Program, reinforcing the overall survival (OS) benefit of Kisqali® (ribociclib).
In this subgroup analysis, Kisqali plus endocrine therapy increased OS compared to endocrine therapy alone among women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer with visceral metastases, consistent with the benefit seen in the overall study populations.
“The analysis, looking across two Phase III trials, supports the use of Kisqali in the first-line setting regardless of menopausal status or metastatic location,” said Denise Yardley, MD, Principal Investigator, Sarah Cannon Research Institute.
“Patients with visceral metastases generally face worse prognosis and a higher risk for treatment resistance, so the consistent overall survival results with Kisqali combination therapy for these patients is compelling.”
In the MONALEESA trials, where Kisqali was studied in premenopausal women in combination with NSAI plus goserelin (MONALEESA-7) and in postmenopausal women in combination with fulvestrant (MONALEESA-3), approximately 60% of the participants had visceral metastases (excluding visceral crisis), reflective of real-world clinical practice.
In these patients, Kisqali in combination with endocrine therapy showed a 30% reduction in the risk of death in MONALEESA-7 [median OS of not evaluable (NE) vs. 39.9 months with NSAI plus goserelin; HR= 0.698 (95% CI: 0.462-1.054)] and a 20% reduction in the risk of death in MONALEESA-3 [median OS of 41.0 vs. 39.4 months with fulvestrant; HR=0.804 (95% CI: 0.596-1.083)].
In patients with liver metastases, Kisqali combination therapy showed a 47% reduction in the risk of death in MONALEESA-7 [median OS of NE vs. 33.6 months with NSAI plus goserelin; HR=0.531 (95% CI: 0.321-0.877)] and a 37% reduction in the risk of death in MONALEESA-3 [median OS of 36.1 vs. 24.1 months with fulvestrant; HR=0.629 (95%CI: 0.421-0.942)]. The adverse events were consistent with the overall populations.
“Superior overall survival with Kisqali is proven in two phase III trials, and this subgroup analysis shows that Kisqali could make a difference in survival even among patients with the most aggressive forms of advanced breast cancer,” said Susanne Schaffert, PhD, President, Novartis Oncology.
“Patients are the inspiration behind everything we do, and we will continue to pursue bold treatment advancements that help reimagine the future for people with cancer in hopes that they can live longer, and better.”
Additional Kisqali data presented during the ASCO20 Virtual Scientific Program include:
An oral presentation on the largest pooled biomarker dataset of any CDK4/6 inhibitor in advanced breast cancer to date across a targeted panel of approximately 550 genes related to cancer and signaling pathways.
The analysis identifies key potential gene alterations and their associations with response or resistance to Kisqali across all three MONALEESA trials.
Updated results from complement-1, a Phase IIIb single-arm trial of 3,246 patients in first-line setting evaluating Kisqali plus letrozole in an expanded and diverse population closely resembling real-world clinical practice.
Results were consistent with those observed in the MONALEESA trials, including the median time to progression 27.1 months (95% CI: 25.7-NE) and overall response rate 43.6% (95% CI: 41.5-45.8%).
The most common AEs were neutropenia, nausea and fatigue. Treatment-related AEs led to discontinuation in 12.9% of patients.
A retrospective study using real-world data assessing the economic burden of neutropenia, the most common adverse event following the administration of CDK4/6 inhibitors.
Neutropenia was reported in 38 patients (25%) in the palbociclib group and 25 patients (17%) in the Kisqali group.
Similar rates of neutropenia were observed for grades 1/2 and 4, however, a numerical difference was observed for grade 3: palbociclib 35% vs. Kisqali 26%.
Kisqali is approved for use in more than 75 countries around the world, including the United States and European Union member states.
Kisqali has shown a statistically significant overall survival benefit in two Phase III trials with two distinct patient populations.
Kisqali® (ribociclib) Kisqali is the CDK4/6 inhibitor with the largest body of first-line clinical trial evidence demonstrating consistent and sustained efficacy compared to endocrine therapy alone.
Overall survival results from MONALEESA-7 and MONALEESA-3 were presented at ASCO 2019 and ESMO 2019 respectively, demonstrating Kisqali plus endocrine therapy significantly extends life in pre/perimenopausal or postmenopausal women with HR+/HER2- advanced breast cancer.
Overall survival follow-up is ongoing for the Phase III MONALEESA-2 trial.
Kisqali was initially approved by the US Food and Drug Administration (FDA) in March 2017 and by the European Commission (EC) in August 2017, as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor based on findings from the pivotal MONALEESA-2 trial.
Kisqali in combination with an aromatase inhibitor was approved for the treatment of pre-, peri- or postmenopausal women as initial endocrine-based therapy, and also indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women by the FDA in July 2018 and by the EC in December 2018.
Regulatory filings are underway with other health authorities worldwide.
Novartis is continuing to reimagine cancer by investigating Kisqali in early breast cancer.
The NATALEE study is a Phase III clinical trial of Kisqali with endocrine therapy in the adjuvant treatment of HR+/HER2- early breast cancer being conducted in collaboration with Translational Research In Oncology (TRIO).
Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.”
May 26, 2020: “Merck, known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics LP, a closely held biotechnology company, announced that the companies have entered into a collaboration agreement to develop EIDD-2801, an orally available antiviral candidate currently in early clinical development for the treatment of patients with COVID-19.
“In addition to our efforts to develop potential vaccines to SARS-CoV-2, we have also been evaluating our own anti-viral assets and those from external sources for their potential to treat individuals with COVID-19,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.
“Clinical evaluation of EIDD-2801 in COVID-19 patients is just beginning, now that phase 1 studies have demonstrated that the compound is well-tolerated. Since preclinical studies demonstrate that EIDD-2801 has potent antiviral properties against multiple coronavirus strains including SARS-CoV-2, we are eager to advance the next phase of clinical studies as rapidly and responsibly as possible.”
Under terms of the agreement, Merck, through a subsidiary, will gain exclusive worldwide rights to develop and commercialize EIDD-2801 and related molecules.
Ridgeback Bio will receive an undisclosed upfront payment, specified milestones and a share of the net proceeds of EIDD-2801 and related molecules, if approved.
Merck will be responsible for clinical development, regulatory filings and manufacturing.
The transaction is subject to the expiration or earlier termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act, and other customary closing conditions.
“Since the start of the COVID-19 pandemic we have worked closely with our network of esteemed collaborators to advance EIDD-2801 into the clinic,” says Wendy Holman, chief executive officer, Ridgeback Biotherapeutics.
“This agreement with Merck, a leader in infectious disease therapeutics, positions us to harness the full potential of EIDD-2801 and, if approved, deliver it to the patients that need it globally.”
Merck and Ridgeback are committed to ensure that any medicines we develop for SARS-CoV-2 will be accessible and affordable globally.
EIDD-2801 is an investigational, orally-bioavailable form of a potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2, the causative agent of COVID-19.
In animal studies of two distinct coronaviruses (SARS-CoV-1 and MERS), EIDD-2801 has been shown to improve pulmonary function, decrease body-weight loss and reduce the amount of virus in the lung. EIDD-2801 was invented at Drug Innovations at Emory (DRIVE), LLC, a not-for-profit biotechnology company wholly owned by Emory University.”
May 26, 2020: “Merck, known as MSD outside the United States and Canada, and IAVI, a nonprofit scientific research organization dedicated to addressing urgent, unmet global health challenges announced a new collaboration to develop an investigational vaccine against SARS-CoV-2 to be used for the prevention of COVID-19.
This vaccine candidate will use the recombinant vesicular stomatitis virus (rVSV) technology that is the basis for Merck’s Ebola Zaire virus vaccine, ERVEBO® (Ebola Zaire Vaccine, Live), which was the first rVSV vaccine approved for use in humans.
Merck has also signed an agreement with the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Assistant Secretary for Preparedness and Response within an agency of the United States Department of Health and Human Services, to provide initial funding support for this effort.
Under the agreement IAVI and Merck will work together to advance the development and global clinical evaluation of a SARS-CoV-2 vaccine candidate designed and engineered by IAVI scientists.
The vaccine candidate is in preclinical development, and clinical studies are planned to start later in 2020.
Merck will lead regulatory filings globally. Both organizations will work together to develop the vaccine and make it accessible and affordable globally, if approved.
“COVID-19 is an enormous scientific, medical, and global health challenge. Merck is collaborating with organizations around the globe to develop anti-infectives and vaccines that aim to alleviate suffering caused by SARS-CoV-2 infection,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.
“Merck and IAVI are eager to combine our respective strengths to accelerate the development of an rVSV vaccine candidate, with the goal of blunting the trajectory of the COVID-19 pandemic.”
“We believe an rVSV-based vaccine strategy represents a promising approach to combating the novel coronavirus pandemic and look forward to implementing an accelerated development program, together with Merck, to evaluate the potential of our vaccine candidate against SARS-CoV-2.
The collaboration between Merck and IAVI represents an innovative partnership model and approach to utilize our joint capabilities in complementary and synergistic ways to address this difficult global health challenge,” said Dr Mark Feinberg, IAVI President and CEO.
“A safe, effective vaccine will help prevent future outbreaks of SARS-CoV-2,” said BARDA Acting Director Gary Disbrow, Ph.D.
“We are encouraged by the willingness of our private sector counterparts to come together as force multipliers to expedite vaccine development and to help save lives.”
Merck is a global leader in infectious diseases and vaccines, with a decades-long history of researching, developing, manufacturing and distributing vaccines for children, adolescents and adults.
In response to the COVID-19 pandemic, Merck is focused on protecting the safety of its employees and their families, ensuring that our supply of medicines and vaccines reaches our patients and customers, contributing our scientific expertise to the development of antiviral and vaccine approaches, and supporting health care providers and our communities.
IAVI’s rVSV vaccine preclinical development, including work on the SARS-CoV-2 vaccine candidate, is being done by scientists at IAVI’s Design and Development Laboratory (DDL) in Brooklyn, New York.
This program is part of a long-standing effort to develop rVSV vaccines for HIV as well as other emerging infectious diseases such as Lassa fever, Marburg, and Ebola Sudan disease, under the leadership of Dr Swati Gupta, head of Emerging Infectious Diseases and Scientific Strategy, IAVI.
rVSV Vaccine Platform
The recombinant vesicular stomatitis virus (rVSV) vaccine platform uses an attenuated strain of vesicular stomatitis virus, a common animal virus that has been modified to express proteins that stimulate an immune response.
IAVI and Merck will leverage experience gained with this platform during the development of Merck’s rVSV-based vaccine for Ebola Zaire.”
May 26, 2020: “Sanofi announced that it has agreed to sell 11.8 million shares of Regeneron common stock through a registered offering at a price of $515.00 per share.
As previously announced, Regeneron will repurchase 9.8 million shares or $5 billion in common stock from Sanofi at the offering price less the underwriting discount.
Sanofi expects to use the net proceeds of the offering and the repurchase to further execute on its strategy to drive innovation and growth.
In connection with the offering, the underwriters have been granted an option to purchase up to 1.2 million additional Regeneron shares at the price payable by the underwriters in the offering, exercisable within the next 30 days.
If the option is fully exercised, the offering and repurchase will together result in gross proceeds to Sanofi of $11.7 billion and the sale of Sanofi’s entire holding in Regeneron, excluding 400,000 Regeneron shares that Sanofi is retaining.
The public offering is occurring simultaneously in the United States and internationally through underwriters led by BofA Securities and Goldman Sachs, together with Barclays, BNP Paribas, Citigroup, J.P. Morgan, Morgan Stanley as joint book-running managers.
The shares offered to the public are being offered pursuant to an existing effective shelf registration statement (including a base prospectus) that has been filed by Regeneron with the U.S. Securities and Exchange Commission (the “SEC”).
Before you invest, you should read the prospectus in that registration statement and other documents Regeneron has filed with the SEC, including the preliminary prospectus supplement dated May 26, 2020, for more complete information about Regeneron and this offering.”
May 27, 2020: “Roche announced positive topline results from the phase III Archway study, evaluating Port Delivery System with ranibizumab (PDS) in people living with neovascular or “wet” age-related macular degeneration (nAMD).
PDS is a permanent refillable eye implant, approximately the size of a grain of rice, which continuously delivers a customised formulation of ranibizumab over a period of months.
The Archway trial met its primary endpoint, demonstrating that patients with PDS who received refills every six months achieved visual acuity outcomes equivalent to those receiving monthly ranibizumab 0.5 mg injections.
In Archway, PDS was generally well-tolerated with a favourable benefit-risk profile.
Neovascular AMD is a leading cause of blindness in people aged 60 and older globally.
The current standard of care for nAMD requires patients to visit their ophthalmologist as often as monthly for eye injections of anti-vascular endothelial growth factor (VEGF) therapy to help maintain vision gains and/or prevent vision loss.
This high treatment burden with anti-VEGF therapy can lead to under-treatment of nAMD and, potentially, less than optimal vision outcomes.
“For people around the world receiving frequent eye injections for neovascular AMD, this continuous delivery system could greatly reduce their treatment burden,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development.
“We look forward to presenting detailed Archway results at future medical meetings and discussing these data with regulatory authorities, with the aim of bringing this new treatment option to patients as soon as possible.”
In addition to Archway, the Portal study is investigating the long-term safety and tolerability of PDS for the treatment of nAMD.
Furthermore, PDS is also being studied in the Pagoda trial for the treatment of diabetic macular edema (DME), a vision-threatening complication of diabetes.
Full results from the Archway study will be presented at an upcoming medical meeting and submitted to health authorities around the world, including the US Food and Drug Administration and European Medicines Agency, for consideration of regulatory approval for the treatment of nAMD.
Archway study Archway (NCT03677934) is a randomised, multicentre, open-label phase III study evaluating the efficacy and safety of Port Delivery System with ranibizumab (PDS), refilled every six months at fixed intervals, compared to monthly intravitreal injections of ranibizumab 0.5 mg, in 418 people living with neovascular age-related macular degeneration.
The primary endpoint of the study is the change in best-corrected visual acuity (BCVA) score (the best distance vision a person can achieve – including with correction such as glasses – when reading letters on an eye chart) from baseline at the average of week 36 and week 40.
Secondary endpoints include: safety; overall change in BCVA from baseline; and change from baseline in center point thickness over time.
Neovascular age-related macular degeneration Age-related macular degeneration (AMD) is a condition that affects the part of the eye that provides sharp, central vision needed for activities like reading.
Neovascular or “wet” AMD (nAMD) is an advanced form of the disease that can cause rapid and severe vision loss. It develops when new and abnormal blood vessels grow uncontrolled under the macula, causing swelling, bleeding and/or fibrosis.
Worldwide, around 17 million people are living with nAMD – the leading cause of vision loss in people over the age of 60 – and the disease will affect even more people around the world as the global population ages.
Port Delivery System with ranibizumab Port Delivery System with ranibizumab (PDS) is a permanent refillable eye implant, approximately the size of a grain of rice, which is designed to continuously release a customised formulation of ranibizumab into the eye over time.
Ranibizumab is a vascular endothelial growth factor (VEGF) inhibitor designed to bind to and inhibit VEGF-A, a protein that plays a critical role in the formation of new blood vessels and the leakiness of the vessels.
PDS contains a customised formulation of ranibizumab not approved by regulatory authorities.
It is different from the ranibizumab intravitreal injection, a medicine marketed as Lucentis®* (ranibizumab injection) which is approved to treat neovascular age-related macular degeneration (nAMD) and other retinal diseases.
By maintaining therapeutic drug concentration levels of ranibizumab with two refills per year, PDS may offer greater outcomes certainty in terms of vision gains and maintaining those gains for people living with nAMD.
Additionally, by decreasing the need for frequent injections and physician visits, PDS may reduce the burden of treatment associated with standard anti-VEGF treatments.
“A clinical study report (CSR) on a clinical trial is a document, typically very long, providing much detail about the methods and results of a trial.
A CSR is a scientific document addressing efficacy and safety, not a sales or marketing tool; its content is similar to that of a peer-reviewed academic paper.
The clinical and statistical description, presentations, and analyses are integrated into single report, incorporating tables and figures into main text of the report or at the end of the text, with appendices containing such information as the protocol, sample case report forms, investigator-related information, information related to the test drugs/investigational products including active control/comparators, technical statistical documentation, related publications, patient data listings, and the technical statistical details such as derivations, computations, analyses, and computer output.
While this guideline is specifically intended for effectiveness and safety research, the basic concepts and framework outlined can be applicable to other types of research, such as clinical pharmacology.
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The report will provide a straightforward description of how the study’s vital design features were chosen and adequate detail about the study’s strategy, procedures, and behavior so there is no confusion about how the research was performed.
The report and its appendices should also include ample individual patient data, including demographic and longitudinal data, and analytical method information, to allow the vital analyzes to be repeated if the authorities wish to.
It is also particularly important that all analyses, tables, and figures carry, in text or as part of the table, clear identification of the set of patients from which they were generated.
The individual study’s full integrated report will provide the most thorough review of specific adverse effects or laboratory anomalies, but these should generally be re-examined as part of an overall safety examination of all available evidence for any use.
The report will explain demographic and other potentially predictive characteristics of the study population and present data for demographic (e.g., age, sex , race, weight) and other (e.g., renal or hepatic function) subgroups where the research is broad enough to permit this, in order to identify possible variations in effectiveness or health.
The provisions of this guideline should be used in conjunction with other ICH guidelines.
1. TITLE PAGE
The title page should contain the following information:
Study title.
Name of test drug/investigational product.
Indication studied.
If not apparent from the title, a brief (one to two sentences) description giving design (parallel, cross-over, blinding, randomized) comparison (placebo, active, dose/response), duration, dose, and patient population.
Name of the sponsor.
Protocol identification (code or number).
The development phase of the study.
Study initiation date (the first patient enrolled or any other verifiable definition).
Date of early study termination, if any. Study completion date (the last patient completed).
Name and affiliation of principal or coordinating investigator(s) or sponsor’s responsible medical officer.
Name of company/sponsor signatory (the person responsible for the study report within the company/sponsor).
The name, telephone number, and fax no. of the company/sponsor contact persons for questions arising during the review of the study report should be indicated on this page or in the letter of application.
A statement indicating whether the study was performed in the compliance with good clinical practice (GCP), including the archiving of essential documents.
Report Date (identify any earlier reports from the same study by title and date)
2. SYNOPSIS:
A brief synopsis (usually limited to three pages) that summarizes the study should be provided (see Annex I of the guideline for an example of the synopsis format used in Europe).
The synopsis should include numerical data in order to illustrate results, not just text or p-values.
3. TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL STUDY REPORT
The table of contents should include:
The page number or other section locating content, including summary tables, statistics, and graphs.
A list and the locations given for the appendices, tabulations, and forms for any case study.
4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
A list should be included of the abbreviations and lists and meanings of specific or unusual words or units of measurement used in the study. Abbreviated words should be written out and the abbreviation indicated in parentheses should appear in the text at first appearance.
5. ETHICS
5.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
It should be confirmed that an IEC or IRB has been reviewing the study and any amendments. A list of all consulted IECs or IRBs should be given in Appendix 16.1.3 and the name of the committee chair should be provided if requested by the regulatory authority
5.2 Ethical Conduct of the Study
It should be confirmed that the study was conducted in accordance with ethical principles that have their origins in the Declaration of Helsinki.
5.3 Patient Information and Consent
How and when informed consent in relation to patient enrollment (e.g. at allocation, prescreening) has been obtained should be described.
Appendix 16.1.3 will include descriptive written information for the patient (if any) and a description of the patient consent form used.
6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
The study’s administrative structure (e.g., principal investigator, organizing investigator, steering committee, administration, control and assessment committees, agencies, statisticians, central laboratory facilities, contract research organization (C.R.O.), clinical trial supply management) should be briefly defined in the report’s collection.
A list of the investigators with their affiliations, their role in the study and their qualifications (curiculum vitae or equivalent) should be provided in Appendix 16.1.4.
A similar list should also be set out in Appendix 16.1.4 for other individuals whose presence adversely influenced the conduct of the research.
The listing should include:
A. Investigators.
B. Any other person carrying out observations of primary or other major efficacy variables
C. The author s of the report, including the responsible biostatistician(s). Where regulatory authorities include the signatures of the principal or coordinating inspectors, these should be included in Appendix 16.1.5 (see a sample form in Annex II). Where these are not needed, a signature should be given in Appendix 16.1.5 for the responsible medical officer of the sponsor.
7. INTRODUCTION
The introduction will include a brief statement (maximum: one page) placing the study in the context of the development of the test drug / research product, relating to that development the essential features of the study ( e.g. rationale and goals, target population, treatment, length, primary endpoints).
It is necessary to identify or describe any guidelines that have been followed in the development of the protocol or any other agreements / meetings between the sponsor / company and regulatory authorities relevant for the particular study.
8. STUDY OBJECTIVES:
A statement describing the overall purpose(s) of the study should be provided.
9. INVESTIGATIONAL PLAN
9.1 Overall Study Design and Plan: Description
The research ‘s overall study plan and design (configuration) (e.g., parallel, cross-over) should be briefly but clearly defined, using charts and diagrams as appropriate.
If a somewhat similar protocol has been used in other 7 studies, it may be helpful to mention this and explain any major variations.
Appendix 16.1.1 will contain the actual protocol and any modifications as well as a sample case report form (only single pages; i.e., it is not appropriate to include similar pages from the forms for various assessments or visits) as Appendix 16.1.2. If any of the information in this section comes from sources other than protocol, it is important to classify those.
9.2 Discussion of Study Design, Including the Choice of Control Groups:
As required the basic control selected and the study design used should be addressed. Following are examples of concept problems that would attract discussion.
Usually, known control (comparison) classes are placebo concurrent control, no concurrent control of treatment, active concurrent control of treatment, concurrent control of the dose comparison, and historical control.
9.3 “Selection of Study Population
9.3.1 Inclusion Criteria
9.3.2 Exclusion Criteria
9.3.3 Removal of Patients From Therapy or Assessment
9.4 Treatments
9.4.1 Treatments Administered
9.4.2 Identity of Investigational Products(s)
9.4.3 Method of Assigning Patients to Treatment Groups
9.4.4 Selection of Doses in the Study
9.4.5 Selection and Timing of Dose for Each Patient
9.4.6 Blinding
9.4.7 Prior and Concomitant Therapy
9.4.8 Treatment Compliance
9.5 Efficacy and Safety Variables
9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart
9.5.2 Appropriateness of Measurements
9.5.3 Primary Efficacy Variable(s)
9.5.4 Drug Concentration Measurements
9.6 Data Quality Assurance
9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size
9.7.2 Statistical and Analytical Plans
9.7.2 Determination of Sample Size
9.8 Changes inthe Conduct of the Study or Planned Analyses“
10. STUDY PATIENTS
10.1 Disposition of Patients
A list of all patients discontinued from the study after enrollment should also be given in Appendix 16.2.1, broken down by center and treatment category, giving a patient name, particular reason for discontinuation, medication (drug and dosage), total dose (if applicable), and period of care prior to discontinuation.
10.2 Protocol Deviations
In Appendix 16.2.2, individual patients with these protocol deviations should be listed, broken down by the center for multicenter studies
11. EFFICACY EVALUATION
11.1 Data Sets Analyzed
A tabular listing of all patients, visits and findings should be made, apart from the efficacy review given in Appendix 16.2.3 (see for example Annex VI). The reasons for exclusion are also to be evaluated over time for the entire patient population (see for example Annex VII).
11.2 Demographic and Other Baseline Characteristics
The critical variables will depend on the specific nature of the disease and on the protocolbut will usually include:
Demographic variables: – Age – Sex – Race
Disease factors:
Specific (if not uniform) entry requirements, length, stage and severity of disease, and other specific use or established prognostic importance clinical classifications and subgroupings.
Baseline values for vital clinical tests that were performed during the study or identified as essential markers of prognosis or therapy response.
Concomitant disease upon initiation of the trial, such as kidney disease , diabetes, heart failure.
Prior illness relevant.
Related previous diagnosis in the study for the illness treated. Concomitant treatment continued, even though the dosage was changed during the study, including oral contraceptive treatment and hormone replacement therapy; therapy stopped at the start of the research period (or changed during the research).
Other factors that may affect response to therapy (e.g., weight, renin status, antibody levels, metabolic status).
Other possibly relevant variables (e.g., smoking, alcohol intake, special diets) and, for the women, menstrual status and date of last menstrual period, if pertinent for the study.
In addition to tables and graphs including group data for these baseline variables, specific individual patient demographic and baseline data, including laboratory values, and all concurrent drugs for all randomized individual patients (broken down by care and multicenter research center) should be provided in Appendix 16.2.4 of the by-patient tabular lists.
11.3. Measurements of Treatment Compliance
11.4 Efficacy Results and Tabulations of Individual Patient Data
11.4.1 Analysis of Efficacy
11.4.2 Statistical/Analytical Issues
The statistical analysis used should be described for the clinical and statistical reviewers in the text of the report, with detailed documentation of statistical methods (see Annex IX) presented in Appendix 16.1.9.
11.4.2.1 “Adjustments for the Covariates
11.4.2.2 Handling of the Dropouts or Missing Data
11.4.2.3 Interim Analyses and Data Monitoring
11.4.2.4 Multicenter Studies
11.4.2.5 Multiple Comparisons/Multiplicity
11.4.2.6 Use of an “Efficacy Subset” of the Patients
11.4.2.7 Active-Control Studies Intended to Show Equivalence
11.4.2.8 Examination of the Subgroups
11.4.3 Tabulation of the Individual Response Data
11.4.4 Drug Dose, Drug Concentration, and Relationships to the Response
11.4.5 Drug-Drug and Drug-Disease Interactions
11.4.6 By-Patient Displays
11.4.7 Efficacy Conclusions“
12. SAFETY EVALUATION
The ICH Guideline entitled “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting” defines serious adverse events as follows:
“A significant adverse event (experience) or reaction is any medical incident that at any dose: results in death, is life-threatening, needs hospitalization or prolongation of current hospitalization, results in permanent or severe disability/incapacity or is a congenital anomaly/birth defect.”
In the following sections, three kinds of analysis and display are called for:
1. Summarized data, often using tables and graphical presentations presented in the main body of the report;
2. Listings of individual patient data; and
3. Narrative statements of events of particular interest.
12.1 “Extent of Exposure(Duration, Dose, Drug concentration)
12.2 Adverse Events
12.2.1 Brief Summary of Adverse Events
12.2.2 Display of Adverse Events
12.2.3 Analysis of Adverse Events
12.2.4 Listing of Adverse Events by Patient“
All adverse effects for each patient should be mentioned in Appendix 16.2.7, including the same case on multiple occasions, giving both preferred term and original term used by the investigator. The list should be by investigator and category of care, which should include:
Patient identifier.
Age, race, sex, weight (height, if any).
Location of the case report forms, if provided. The adverse event (preferred term, reported term).
Action taken (none, dose reduced, treatment stopped, specific treatment instituted, and so forth). Outcome (e.g., CIOMS format).
Causality assessment (e.g., related/not related).
How this was determined should be described in the table or elsewhere.
Date of onset or date of clinic visit at which the event was discovered.
Timing of onset of the adverse event in relation to the last dose of the test drug/investigational product (when applicable).
Study treatment at the time of event or the most recent study treatment taken. Test drug/investigational product dose in absolute amount, mg/kg or mg/m2, at time of event.
Drug concentration (if known).
Duration of test drug/investigational product treatment.
Concomitant treatment during study
Any abbreviations and codes should be clearly explained at the beginning of the listing or, preferably, on each page.
12.3. Incidents, Other Serious Adverse Events, and Other Notable Incidents in Adverse Events, Other Moderate Adverse Events, and Other Critical Adverse Effects warrant special consideration.
12.3.1 For the following incidents, the summary of Deaths, Other Serious Adverse Incidents and Other Important Adverse Events Listings, containing the same details as called for in section 12.2.4, should be given. Listings, containing the same information as called for in the section 12.2.4, should be provided for the following events.
12.3.2 Death accounts, other serious adverse events, and several other significant adverse events Please provide the following information: Patient Identifier. Patient age and sex; general health condition, if applicable. Test drug / research product administered; dosage of medication, if this differed among patients; and length of time given.
12.3.3 Analysis and Discussion of the Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
12.5. Vital Signs, Physical Findings, and Other Observations Related to Safety
12.6 Safety Conclusions
13. DISCUSSION AND OVERALL CONCLUSIONS
The study’s effectiveness and safety findings and the risk-benefit relationship should be summarized and addressed briefly, referring as needed to the tables , figures and sections above. The presentation does not necessarily replicate performance explanations or add new outcomes.
14. TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT
Figures should be used in order to visually summarize the important results, or to clarify results that are not easily understood from tables.
Significant demographic, efficiency, and safety data should be provided in the text of the report in summary figures or tables.
Moreover, if these are obtrusive due to size or number they should be listed here, cross-referenced to the document, along with supporting, or supplementary, statistics, charts, or lists.
The following information may be presented in this section of the core clinical study report:
14.1 “Demographic Data Summary figures and tables.
14.2 Efficacy Data Summary figures and tables
14.3 Safety Data Summary figures and tables
14.3.1 Displays of the Adverse Events
14.3.2 Listings of the Deaths, Other Serious and Significant Adverse Events
14.3.3 Narratives of the Deaths, Other Serious and Certain Other Significant Adverse Events
14.3.4 Abnormal Laboratory Value Listing (each patient)“
15. REFERENCE LIST
A list of articles from the literature pertinent to the evaluation of the study should be provided.
Copies of important publications (Appendices 16.1.11 and 16.1.12) will be included in an Appendix. In accordance with the internationally agreed standards of the 1979 Vancouver Declaration on “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” or the system used in “Chemical Abstracts,” references should be given.”
16. APPENDICES
This section should be prefaced by the full list of all Appendices available for the study report.
Where allowed by the regulatory authority, some of the following Appendices do not need to be submitted with the report but should only be submitted on request.
Therefore, the applicant should clearly indicate those Appendices submitted along with the study.
To have Appendices available on request they will be completed by the time the application is submitted.
16.1 Study Information
16.1.1 Protocol and protocol amendments.
16.1.2 Sample case report form (unique pages only).
16.1.3 List of IEC’s or IRB’s (plus committee chair name if needed by regulatory authority) and representative written information for forms of consent for patients and sample consent.
16.1.4 List and summary of investigators and other significant participants in the research, including brief (one page) curriculum vitae or equivalent summaries of training and experience relevant to clinical study results.
16.1.5 Signatures of responsible medical officer of principal or coordinating investigator(s) or sponsor, depending on the provision of the regulatory authority.
16.1.6 List of patients taking study drug(s)/research product(s) from different batches where more than one lot has been used.
16.1.7 Scheme and codes for randomisation (assigned to patient recognition and treatment).
16.1.8 Certificates of inspection (if available).
16.1.9 Documentation of the processes used.
16.1.10 Documentation of methods for inter-laboratory standardization and procedures for quality assurance where used.
16.1.11. The Study-based publications.
16.1.12 Significant publications which are listed in the study.
16.2 Listings of patient info.
16.2.1 Patients Discontinued.
16.2.2 Deviations from protocol.
16.2.3 Patients exempt from consideration of the effectiveness.
16.2.4 Human demographics.
16.2.5 Data on compliance and/or concentration of drugs (if available).
16.2.6 Data on individual efficacy response.
16.2.7 Adverse case lists (every patient).
16.2.8 Listing by patient of individual laboratory measurements, if necessary by regulatory authorities.
16.3. Formulas for a Case Report (CRF)
16.3.1 CRFs for deaths, other significant adverse effects and adverse event withdrawals.
May 25, 2020: “Sanofi announced its intent to sell its equity investment in Regeneron through a registered public offering and related share repurchase by Regeneron.
The registered offering and share repurchase will have no impact on the ongoing collaboration between Sanofi and Regeneron.
A preliminary prospectus supplement relating to the offering of Regeneron’s shares will be filed with the U.S. Securities and Exchange Commission.
Sanofi currently holds approximately 23.2 million shares of Regeneron’s common stock, representing approximately 20.6% ownership.
Regeneron has agreed to repurchase $5 billion of its stock from Sanofi conditional on completion of the proposed public offering.
If the offering and repurchase are completed and the underwriters fully exercise their option to purchase additional shares, Sanofi will continue to own approximately 400,000 shares of Regeneron’s common stock, which Sanofi is retaining in support of the ongoing collaboration with Regeneron.
“Sanofi and Regeneron’s collaboration has been one of the most productive in the industry, creating significant value for both companies but more importantly, resulting in five important medicines for patients.
Sanofi remains committed to continuing our collaboration with Regeneron which remains an integral part of our overall strategy, and this decision was fully aligned with Regeneron, said Paul Hudson, Chief Executive Officer, Sanofi.
“The decision to divest our holdings is consistent with our efforts to enhance value creation for our shareholders. We believe the proceeds from this transaction will help further our ability to execute on our strategy to drive innovation and growth.”
Following completion of the proposed public offering and share repurchase, Sanofi will discontinue accounting for its ownership in Regeneron’s common shares under the equity method.
After a restatement of Sanofi previously reported non-GAAP indicator (Business Net Income) and change of its definition to exclude the effect of equity method accounting for Regeneron investment, Sanofi business EPS is expected to grow by approximately +5% in 2020 at constant exchange rate compared to 2019 restated business EPS of €5.64, which is in line with Sanofi’s 2020 business EPS growth guidance.
The Companies have had a successful and long-standing clinical and commercial collaboration dating back to 2003 that has resulted in five approved treatments to date with additional candidates currently in clinical development. Sanofi originally purchased a shareholding in Regeneron in 2004.
Sanofi’s decision to sell its Regeneron common shares was made in consultation with Regeneron and the contemplated structure will allow both companies to achieve their mutual objectives.
The transaction has been approved by Sanofi and Regeneron’s Boards of Directors.
The public offering will occur simultaneously in the United States and internationally through underwriters led by BofA Securities and Goldman Sachs as joint book-running managers.
The shares offered to the public are being offered pursuant to an existing effective shelf registration statement (including a base prospectus) that has been filed by Regeneron with the U.S. Securities and Exchange Commission (the “SEC”).”
