August 10, 2020: “The U.S. Food and Drug Administration today announced the following actions taken in its ongoing response effort to the COVID-19 pandemic:
As part of the FDA’s effort to protect consumers, the agency issued a warning letter to one firm for selling unapproved products with fraudulent COVID-19 claims.
The company, H-Lab Life, sells “Multi-Use Spray” products, with misleading claims that the products can mitigate, prevent, treat, diagnose, or cure COVID-19 in people.
There are currently no FDA-approved products to prevent or treat COVID-19.
FDA requested that H-Lab Life immediately cease selling these unapproved products. Consumers concerned about COVID-19 should consult with their health care provider.
FDA has taken additional action to help ensure that hand sanitizers produced under the agency’s temporary guidances do not contain unsafe levels of methanol.
FDA has updated its guidances to provide clarification that companies test each lot of the active ingredient (ethanol or isopropyl alcohol (IPA)) for methanol, if the ethanol or IPA is obtained from another source.
FDA has also included an additional denaturant formula in the temporary guidances.
Denaturing alcohol in hand sanitizers is critical to deter children from unintentional ingestion.
Consumer and health care personnel safety is a top priority for FDA, and an important part of FDA’s mission is to protect the public from harm, especially as we seek to facilitate an increase in the supply of hand sanitizer.
FDA issued an Emergency Use Authorization to George Washington University Public Health Laboratory for its GWU SARS-CoV-2 RT-PCR Test.
This molecular test is for use by health care providers for the qualitative detection of nucleic acid from SARS-CoV-2 in upper respiratory specimens (e.g., nasal, mid-turbinate, nasopharyngeal and oropharyngeal swabs) from individuals suspected of having contracted COVID-19.
Administration of this test is limited to the George Washington University Public Health Laboratory.
Testing updates:
To date, the FDA has currently authorized 208 tests under EUAs; these include 169 molecular tests, 37 antibody tests, and 2 antigen tests.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.
Aug 04, 2020: “In the study, published today in The Lancet Child and Adolescent Health the authors used mathematical modelling calibrated to the UK epidemic to explore the impact of combining test-trace-isolate (TTI) strategies with reopening schools and society from September 2020.
By assessing the impact of all school years going back in September accompanied by a relaxation of lockdown measures and the presence of different TTI strategies, researchers were able to quantify, for the first time, the amount of testing and tracing that would be needed to prevent a second wave of COVID-19 later this or early next year.
The results of the modelling suggest a second wave in the UK might be avoided with increased levels of testing (between 59% and 87% of symptomatic people tested during their active COVID-19 infection) and effective contact tracing and isolation.
Assuming 68% of contacts could be tracing and isolation.
Assuming 68% of contacts could be traced, as is suggested to be currently the case in the UK, the study estimates that 75% of those with symptomatic infection would need to be diagnosed and isolated if schools return full-time in September.
If only 40% of contacts could be traced, under a more pessimistic tracing scenario, this figure would need to be increase to 87%.
Lead author, Dr Jasmina Panovska-Griffiths (UCL Institute of Epidemiology & Health Care and The Queen’s College, Oxford University) said: “We need to scale up current TTI strategies to avoid COVID-19 resurgence later this year as we are planning to reopen schools in September.
“With UK schools reopening fully in September, prevention of a second wave will require a major scale-up of testing to test 75% of symptomatic infections – combined with tracing of 68% of their contacts, and isolation of symptomatic and diagnosed cases.”
Professor Chris Bonell, LSHTM, one of the senior authors on the study, commented: “We need all these measures to come together effectively in order to control the transmission of SARS-CoV-2 and prevent a large number of COVID-19 deaths later this year.”
Without such measures, the authors say the reopening of schools together with continual gradual relaxing of the lockdown measures are likely to induce a secondary wave that would peak in December 2020 if schools open full-time in September, alongside reopening of society and more people return to their workplaces.
The secondary wave would result in R rising above 1 could yield a secondary wave of infections 2-2.3 times the size of the original COVID-19 wave.
As with any modelling study, a number of assumptions were made using existing published data.
For example, recently published data was used to estimate how COVID-19 transmission and symptom probability changes with age as well as data used to quantify the number of contacts per day per person.
The authors also note that some of their assumptions about the implementation of TTI are likely to be optimistic in the UK context, so their findings should be interpreted as the minimal amount of testing that would need to be done.
While the authors explored two scenarios of the infectiousness among children and young adults under 20 years being either equal to or 50% lower than that of those older than 20 years old, these are approximations and the model can be rerun when more evidence becomes available.
Dr Panovska-Griffiths concluded: “Our findings suggest that reopening schools can form part of the next step of gradual relaxing of lockdown if combined with a high-coverage TTI strategy.
“If the strategy is effective enough, this would be a sufficient alternative to intermittent lockdown measures including further school closures while we await an effective vaccine against SARS-CoV-2.”
The international research team included scientists from UCL, LSHTM, Oxford University and the Institute of Disease Modeling (IDM), USA.
The study was supported by National Institute for Health Research (NIHR) Applied Health Research and Care North Thames at Bart’s Health NHS Trust (NIHR ARC North Thames) and from Bill and Melinda Gates through the Global Good Fund.”
Aug 06, 2020: “GlaxoSmithKline announced the US FDA has approved BLENREP (belantamab mafodotin-blmf) as a monotherapy treatment for adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor and an immunomodulatory agent.
This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
BLENREP is the first anti-BCMA (B-cell maturation antigen) therapy approved anywhere in the world.
Dr Hal Barron, Chief Scientific Officer and President R&D, GSK, said: “As the second most common form of blood cancer in the US, multiple myeloma is an incurable and devastating disease. BLENREP is the first approved anti-BCMA therapy and has the potential to transform the treatment of patients with relapsed or refractory myeloma who have limited treatment options today.’’
BLENREP is GSK’s fifth major medicine approval in 2020 across areas of significant unmet medical need such as cancer, HIV and chronic kidney disease. This approval marks the second FDA approval for GSK’s oncology portfolio in four months.
BLENREP employs a multi-faceted mechanism of action and is directed toward BCMA, a cell-surface protein that plays an important role in the survival of plasma cells and is expressed on multiple myeloma cells.
The approval of BLENREP was based on six-month primary results from the pivotal DREAMM-2 study, which enrolled patients with relapsed or refractory multiple myeloma who had actively progressing disease that had worsened despite current standard of care.
Dr Sagar Lonial, MD, Chief Medical Officer, Winship Cancer Institute of Emory University in Atlanta, Georgia, Chair of Emory Department of Hematology and Medical Oncology and Principal Investigator for DREAMM-2, said: “While treatable, refractory multiple myeloma is a significant clinical challenge with poor outcomes for patients whose disease has become resistant to the current standard of care.
Due to the limited options currently available, these patients are often retreated with drugs from the same classes after they relapse, which is why the approval of BLENREP, the first anti-BCMA therapy, is significant for both patients and physicians alike.”
In the DREAMM-2 study, treatment with single-agent BLENREP 2.5 mg/kg every three weeks demonstrated a clinically meaningful overall response rate (ORR) of 31% (97.5% CI; 21-43) in patients who had received a median of seven prior lines of treatment (n=97). The median duration of response (DoR) had not been reached at the six-month analysis, but 73% of responders had a DoR equal to or greater than six months.
The most commonly reported adverse events (≥20%) were keratopathy, decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue. Keratopathy is characterised as changes in the corneal epithelium as seen on eye examination, which can manifest with or without symptoms.
Ocular adverse reactions occurred in 77% of the 218 patients in the pooled safety population and included keratopathy (76%), changes in visual acuity (55%), blurred vision (27%) and dry eye (19%).
Corneal adverse events were monitored with eye exams prior to each dose, allowing for dose reductions or interruptions as appropriate. Patients also used preservative-free eye drops. Keratopathy leading to treatment discontinuation affected 2.1% of patients in the 2.5 mg/kg cohort.
BLENREP is available through participation in the BLENREP Risk Evaluation and Mitigation Strategy (REMS), which was developed to ensure appropriate use of the medicine.
The programme requires education for all physicians prescribing BLENREP and their patients regarding the ocular risks associated with treatment as well as monitoring.
Paul Giusti, President and CEO of the Multiple Myeloma Research Foundation (MMRF), said: “The approval of BLENREP is an important advancement for patients with relapsed or refractory multiple myeloma, as it brings a much-needed new treatment to patients who face limited options due to their progressing disease. We are grateful for GSK’s continued commitment to myeloma patients and their families.”
In 2017, BLENREP was granted Breakthrough Therapy designation by the FDA, which is intended to facilitate the development of investigational medicines that have shown clinical promise for conditions where there is significant unmet need.
Multiple myeloma Multiple myeloma is the second most common blood cancer in the US and is generally considered treatable, but not curable.
In the US, more than 32,000 people are estimated to be diagnosed with multiple myeloma this year and nearly 13,000 people will die from the disease. Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.
B-cell maturation antigen (BCMA) The normal function of BCMA is to promote plasma cell survival by transduction of signals from two known ligands, BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand). This pathway has been shown to be important for myeloma cell growth and survival.
BCMA expression is limited to B cells at later stages of development. BCMA is expressed at varying levels in myeloma patients and BCMA membrane expression is universally detected in myeloma cell lines.iii
BLENREP (belantamab mafodotin-blmf) BLENREP is an antibody drug conjugate comprising a humanised anti-B cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent auristatin F via non-cleavable linker.
The drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa.”
Aug 06, 2020: “Novartis announced that the European Commission EC has approved Xolair® (omalizumab) as an add-on therapy with intranasal corticosteroids (INC) for the treatment of adults (18 years and above) with severe chronic rhinosinusitis with nasal polyps (CRSwNP) for whom therapy with INC does not provide adequate disease control.
Phase III studies have shown that Xolair reduces nasal polyp size (defined by Nasal Polyp Score; NPS) and improves symptoms and quality of life in patients with CRSwNP.
Xolair is the first treatment for CRSwNP specifically targeting and blocking immunoglobulin E (IgE), a key driver in the inflammatory pathway of this disease.
“People with chronic rhinosinusitis with nasal polyps can experience significant quality of life impairment as a result of their symptoms.
The symptoms include long-term nasal congestion and blockage, sleep disruption and loss of smell and taste,” said Lars Ingemann, Academic Director, EUFOREA.
“The EUFOREA* patient advisory board welcomes today’s approval, which will provide an additional treatment option to patients with severe chronic rhinosinusitis with nasal polyps.”
Xolair® (omalizumab) Xolair is the only approved anti-immunoglobulin E (IgE) antibody treatment specifically designed to target and block IgE.
By reducing free IgE, down-regulating high-affinity IgE receptors and limiting mast cell degranulation, Xolair minimizes the release of mediators throughout the allergic inflammatory cascade.
An injectable prescription medicine, Xolair is approved for the treatment of moderate-to-severe or severe persistent allergic asthma in more than 100 countries, including the US since 2003 and the EU since 2005.
Xolair is approved for the treatment of chronic spontaneous urticaria in over 90 countries including the EU and for chronic idiopathic urticaria (CIU), as it is known in the US and Canada.
Xolair has over 1.3 million patient years of exposure. In addition, a liquid formulation of Xolair in pre-filled syringes has been approved in the EU and in more than 20 countries outside of the EU, including Canada, the US and Australia.
The self-administration indication for Xolair in pre-filled syringes was also approved in the EU in 2018, and has since been approved in several other countries, including Australia, Taiwan, Argentina and Brazil.
For chronic rhinosinusitis with nasal polyps (CRSwNP), Xolair is indicated in the EU as an add-on therapy with intranasal corticosteroids (INC) for the treatment of adults (18 years and above) with severe CRSwNP for whom therapy with INC does not provide adequate disease control.
Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) Chronic rhinosinusitis with nasal polyps (CRSwNP) impacts up to 4% of people worldwide. It is a potentially debilitating condition in adults that is characterized by inflammation of the nose and paranasal sinuses with the presence of benign inflammatory polyps (nasal polyps) on the lining of the nasal sinuses or nasal cavity, which can block normal airflow.
It is possible to have a single polyp or several, and the size of the polyps can vary from microscopic to several centimeters.”
July 28, 2020: The U.S. Food and Drug Administration announced the following actions taken in its ongoing response effort to the COVID-19 pandemic:
Today, FDA posted the audio and transcript versions of Episode 6 in its new podcast series, FDA Insight, which features Dr. Peter Marks, Director of the FDA Center for Biologics Evaluation and Research (CBER), in part 2 of a discussion on COVID-19 vaccines.
The podcast is hosted by Dr. Anand Shah, FDA’s Deputy Commissioner for Medical and Scientific Affairs. Part 1 of this discussion, posted July 21, is accessible also in audio and transcript versions as Episode 5.
FDA issued emergency use authorizations (EUAs) today for two molecular diagnostic tests for the qualitative detection of SARS-CoV-2 to:
Eli Lilly and Company, for its Lilly SARS-CoV-2 Assay, and
Sandia National Laboratories, for its SNL-NM 2019 nCoV Real-Time RT-PCR Diagnostic Assay.
Testing updates:
To date, the FDA has currently authorized 193 tests under EUAs; these include 158 molecular tests, 33 antibody tests, and 2 antigen tests.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.
The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
“An adaptive clinical trial is a clinical trial evaluating a medical procedure or treatment by monitoring patient results (and possibly other steps, such as side effects) on a specified schedule and changing the trial protocol parameters in compliance with those findings.
The adaptation process, as specified in the trial protocol, usually continues during the trial. Changes can include dosage, sample size, trial drug, patient selection criteria, and a combination of “cocktails.”
Table of Contents
What are Adaptive Design Clinical Trials?
An adaptive design is defined as a design that allows modifications to the trial and/or statistical procedures of the trial after its initiation without undermining its validity and integrity.
The purpose is to make clinical trials more flexible, efficient and fast. Due to the level of flexibility involved, these trial designs are also termed as “flexible designs.
Adaptive clinical trial designs have been widely used in medical device production, and the lessons gained are now being applied to drug development.
Adaptive designs can make clinical trials more flexible by the use of results that accumulate in the trial to adjust the direction of the trial according to pre-specified guidelines.
These trials are often more effective, comprehensive and ethical than traditional fixed design trials , as they also allow better use of resources such as time and money and may involve fewer people. Adaptive designs can be implemented in all stages of clinical study, from early dose initiation to confirmatory testing.
Adaptive design will reduce the number of patients in a trial, as well as the total number of trials. This could also yield the outcomes of more insightful trials.
The added flexibility provided by adaptive design could also improve acceptability of stakeholders.
Also, these trials are especially useful in clinical safety and efficacy studies which are closely monitored. Adaptive design can also be very useful in early-stage research and exploratory studies as well as in subsequent post-marketing tests.
Using adaptive design in an exploratory setting would allow assessment of a broad range of doses, regimens, populations, and so on, with the ability to discontinue evaluation of suboptimal choices. This approach has the ethical advantage of exposing smaller amount subjects to suboptimal procedures, in addition to increased flexibility.
What are the Types of Adaptive Design Trials?
Based on adaptations employed, commonly considered adaptive design methods in clinical trials include
an adaptive randomization design,
a group sequential design,
a sample size re-estimation design,
a drop-the-loser design,
an adaptive dose finding design,
a biomarker-adaptive design,
an adaptive treatment-switching design,
a hypothesis-adaptive design,
an adaptive seamless phase II/III trial design and
a multiple adaptive design.
Another way to classify adaptive design clinical trials is by categorizing them according to different rules, usually four by number.
The allocation rule defines how the participants in a trial will be assigned to different arms and involves sensitive randomization and covariate adaptive allocation.
Sampling rule defines how many subjects will be sampled at the next stage and consists of sample size re-estimation design (both blinded and unblinded) and drop-the-loser design.
Stop rule defines when to stop the trial and consists of group sequential design and adaptive treatment-switching design.
Decision rule includes changes not covered by the other three categories and consists of hypothesis-adaptive design and changes to the primary endpoint or statistical method or population design of patients.
Sometimes, a fifth rule is added consisting of multiple adaptations, also comprising adaptive seamless phase II/III trial designs.
Adaptive vs. Non-Adaptive Clinical Trial Design
What is adaptive design, and how can it be used effectively?
In November 2019, FDA released its final guidance on “Adaptive Designs for Drug and Biologic Clinical Trials” to help address this issue. This document provides guidance to sponsors and applicants submitting investigational new drug applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or supplemental applications on the appropriate use of adaptive designs for clinical trials to provide evidence of the effectiveness and safety of a drug or biologic.
The Guidance for 2019 describes an adaptive design as “a design for clinical trials that allows for prospectively designed changes to one or more elements of the design based on the accumulation of subject data in that trial. Non-adaptive trial designs do not include such opportunities for modification.
Adaptive and Non-Adaptive Clinical Trial Examples
In early stage dose escalation studies, a common illustration of the adaptive design is present. Such research often employ prospectively designed interim analyzes by a Pharmacokinetic and Safety Data evaluation committee, which then takes decisions on how to proceed. For these situations, the protocol should describe the committee membership simply and prospectively, and the conditions for stopping dosing, repeating the previous dose or continuing at a higher dose.
For a non-adaptive clinical design trial, critical research parameters are formulated using the assumptions and the best estimates. This includes issues such as population mean and incidence rate, variability, size and location of the dose-response effect, and rates of discontinuation. This will work well if estimates and assumptions are accurate, but if they are not, problems will arise.
Non-adaptive designs for the analysis also contain elements to reduce the risks associated with uncertainty.
For example, if the analysis is intended to determine the dose-response, multiple randomized fixed-size groups might be included in the procedure to ensure a appropriate dose is taken. Such design decisions are based on the basis that suboptimal doses are likely to be used for various types of treatment.
But what if you didn’t have to compromise effectiveness in order to make sure the optimal dose is taken? Unlike conventional study designs, an adaptive design may select Phase 2 doses using a model-based approach.
The model could then be modified when intermediate data became available and used to make improvements to the design of the study to minimize the number of participants receiving suboptimal doses and to concentrate on doses with the potential for efficacy.
Adaptive design can also provide futility requirements that are useful in situations where the drug may not be effective. Insead sof waiting for the study to complete, an adaptive design could use interim data to determine whether further subject enrollment will result in a failed study. Another example of where adaptive design could be helpful is the selection of an acceptable sample size for research.
In a conventional trial, there is a threat of underpowering a study if estimates of variance and treatment effect are excessively enthusiastic; similarly, if these parameter estimates are too conventional, then you can end up with an excessively large study population.
When a study is underpowered then the evidence for the analysis would not be adequately accurate from a statistical point of view to draw valid conclusions. If the study population is too big then substantial amounts of time and money would be needed. The sample size can be adjusted using an adaptive approach based on the accumulation of data from the study in such a way as to avoid such unexpected effects.
In short, the core benefit of adaptive design is the ability to include prospectively developed opportunities for modifying research design elements and hypotheses based on interim data analyses. These improvements in the protocol need to be prepared prospectively and any intermediate analyzes for statistical bias need to be monitored.
Adaptive Design versus Conventional Trials
In conventional or classical clinical trials, one proceeds to accept/reject the null hypothesis in a well-defined population.
No modification in the design of trials or statistical procedures or population of patients is permitted after a trial has started without recording protocol changes and the approval of the Committee on Institutional / Independent Ethics, although pre-specified modifications are permitted in adaptive designs based on the interim review.
In classical trials, not more than two or three study arms are undertaken at a given time, while in adaptive design clinical trials, several treatment arms can be tested at the same time [Table].
Features
Conventional trial
Adaptive design
Design
More rigid
Flexible
Treatment arms
Maximum two or three
Many simultaneously
Hypothesis
Test the hypothesis under consideration
Fit data into a hypothesis
Modifications
Not allowed without protocol amendments
Pre-specified allowed
Phases
Phases I–II are well defined
Can be seamless phase 2/3 design
Statistical analysis
Use routine frequentists methods
Use complicated Bayesian approach
Organization
Much simple
Complicated, requiring simulations
Interim analysis
Not a routine
Done routinely and frequently
Role of IDMC
More once trial/phase is over
Proactive role throughout the trial
Regulatory view
Well endorsed
Still speculative
Comparison between conventional trial and adaptive design trial
Adaptive Design Clinical Trials for Drugs and Biologics Guidance for Industry
This document offers guidance to sponsors and candidates submitting study new product applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or additional applications on the correct use of adaptive designs for clinical trials to provide proof of drug or biological effectiveness and protection.
Such guidance describe the principles required for the design, conduct and reporting of the outcomes of an appropriate clinical trial. The guideline also advises sponsors on the types of details to send to allow FDA review of adaptive design clinical trials, including adaptive Bayesian and complex trials that rely on computer simulations for their design.”
July 27, 2020: Sandoz, the Novartis generics and biosimilars division, is pleased to announce plans for a joint investment, together with the Austrian federal government, to strengthen the long-term future of integrated antibiotics manufacturing in Europe.
Sandoz CEO Richard Saynor said: “This plan is a great example of government and the private sector working closely together to protect the long-term interests of patients in Europe and beyond.
Antibiotics are the backbone of modern medicine and our Kundl facility in Austria is the hub and center of the last remaining integrated production chain for antibiotics in the western world. This joint investment will help to keep it that way.”
Sandoz intends to invest more than EUR 150 million over the next five years to strengthen the long-term competitiveness of its integrated antibiotic manufacturing operations at Kundl, developing and introducing innovative manufacturing technology for both active pharmaceutical ingredients (APIs) and finished dosage forms (FDFs).
Under the joint plan, which is subject to formal approvals by both parties, the Austrian federal government would contribute or coordinate public funding totalling approximately EUR 50 million towards the total investment, as part of its efforts to increase European-based production of essential medicines.
Sandoz and the Austrian government anticipate a formal closing of the agreement before the end of the year.
The government funding would primarily support new process technology to produce API for penicillin products at Kundl. Sandoz would commit to related penicillin API production in Europe for the next 10 years, despite fierce global price competition, particularly from China.
Steffen Lang, Global Head of Novartis Technical Operations (NTO), said: “Novartis is committed to sustain a resilient and competitive supply chain for the essential medicines Sandoz markets.
I am proud that NTO is leveraging its market-leading manufacturing expertise to enable Sandoz to further strengthen supply of these vital medicines, and we can build upon the high manufacturing and quality standards at the Kundl site and further deepen its vertical integration.”
July 27, 2020: The U.S. Food and Drug Administration today announced the following actions taken in its ongoing response effort to the COVID-19 pandemic:
On July 24, the FDA reissued the LabCorp COVID-19 RT-PCR Test emergency use authorization (EUA) to include two new indications for use: testing for people who do not have COVID-19 symptoms or who have no reason to suspect COVID-19 infection, and to allow pooled sample testing.
Specifically, the FDA reissued the LabCorp COVID-19 RT-PCR Test EUA to expand use of the test to anyone after the company provided scientific data showing the test’s ability to detect SARS-CoV-2 in a general, asymptomatic population.
Additionally, the reissuance also includes authorization for LabCorp to test pooled samples containing up to five individual swab specimens collected under observation.
In general, sample pooling allows for fewer tests to be conducted overall, conserving resources and potentially allowing more tests to be evaluated more quickly.
The FDA continues to warn consumers and health care professionals not to use certain alcohol-based hand sanitizers due to the dangerous presence of methanol.
The agency issued a warning earlier this month about an increasing number of adverse events, including blindness, cardiac effects, effects on the central nervous system, and hospitalizations and death, primarily reported to poison control centers and state departments of health.
The agency continues to see these figures rise.
The agency has also taken additional action to help prevent certain hand sanitizers from entering the United States by placing them on an import alert.
The FDA is proactively working with manufacturers to recall products and is encouraging retailers to remove products from store shelves and online marketplaces.
A warning letter has also been issued to Eskbiochem S.A. de C.V. regarding the distribution of products labeled as manufactured at its facilities with undeclared methanol, misleading claims — including incorrectly stating that FDA approved these products — and improper manufacturing practices.
On July 24, the agency approved an abbreviated new drug application, or generic, for heparin sodium. The FDA continues to work to help patients suffering from COVID-19 by reviewing and approving generic medicines, such as anti-coagulants, used in the prevention and treatment of blood clotting.
On July 24, FDA issued emergency use authorizations (EUAs) to two companies for serology-based tests for the qualitative detection and differentiation of IgG and IgM antibodies to SARS-CoV-2.
The tests are intended for use as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection. The companies that were each issued an EUA are:
Xiamen Biotime Biotechnology Co., Ltd., for its BIOTIME SARS-CoV-2 IgG/IgM Rapid Qualitative Test, and
Access Bio, Inc., for its CareStart COVID-19 IgM/IgG.
• Testing updates:
To date, the FDA has currently authorized 191 tests under EUAs; these include 156 molecular tests, 33 antibody tests, and 2 antigen tests.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.
July 24,EMA’s human medicines committee (CHMP) recommended eleven medicines for approval at its July 2020 meeting, including a medicine for use in countries outside the European Union.
The CHMP adopted a positive opinion for Dapivirine Vaginal Ring (dapivirine) used to reduce the risk of infection with the human immunodeficiency virus type 1 (HIV-1), in combination with safer sex practices when oral pre-exposure prophylaxis is not used, cannot be used or is not available.
Placed in the vagina, the ring slowly releases the antiretroviral medicine dapivirine over a period of 28 days.
This is the eleventh medicine recommended by EMA under EU Medicines for all (EU-M4All), a mechanism that allows the CHMP to assess and give opinions on medicines that are intended for use in countries outside the EU under Article 58 of Regulation (EC) No 726/2004. For more information, see the press release in the grid below.
The Committee recommended granting a conditional marketing authorisation for Blenrep* (belantamab mafodotin), a new antibody-drug conjugate for adult patients with relapsed and refractory multiple myeloma who no longer respond to treatment with an immunomodulatory agent, a proteasome inhibitor and a CD-38 monoclonal antibody. Blenrep benefited from the support of the PRIME scheme, EMA’s platform for early and enhanced dialogue with developers of promising new medicines that address unmet medical needs. For more information, see the press release in the grid below.
The CHMP recommended granting a marketing authorisation for Adakveo* (crizanlizumab), for the prevention of recurrent vaso-occlusive crises (when blood vessels are blocked by abnormal red blood cells, restricting the flow of blood to an organ) in patients with sickle cell disease.
The CHMP adopted a positive opinion for Arikayce liposomal* (amikacin), for the treatment of non-tuberculous mycobacterial lung infections caused by Mycobacterium avium Complex in adults with limited treatment options who do not have cystic fibrosis.
The Committee recommended granting a conditional marketing authorisation for Ayvakyt* (avapritinib), for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours harbouring the platelet-derived growth factor receptor alpha D842V mutation.
The Committee adopted a positive opinion for Calquence* (acalabrutinib) for the treatment of chronic lymphocytic leukaemia, a type of cancer affecting white blood cell called lymphocytes.
Jyseleca (filgotinib) received a positive opinion for the treatment of rheumatoid arthritis.
The CHMP recommended granting a marketing authorisation for Zynrelef (bupivacaine / meloxicam) for the treatment of post-operative pain.
The biosimilar medicine Equidacent (bevacizumab) received a positive opinion for the treatment of carcinoma of the colon or rectum, breast cancer, non-small cell lung cancer, renal cell cancer, epithelial ovarian, fallopian tube or primary peritoneal cancer, and carcinoma of the cervix.
The CHMP recommended granting marketing authorisations for two generic medicines: Arsenic trioxide medac (arsenic trioxide), for the treatment of acute promyelocytic leukaemia (blood cancer) and Fampridine Accord (fampridine), intended to improve walking of adult patients suffering from multiple sclerosis with walking disability.
Negative recommendations on new medicines
The CHMP adopted negative opinions recommending the refusal of marketing authorisations for Elzonris (tagraxofusp) and Gamifant (emapalumab).
Elzonris was expected to be used for the treatment of blastic plasmacytoid dendritic cell neoplasm, a rare and aggressive type of acute myeloid leukaemia (blood cancer).
Gamifant was expected to be used to treat primary haemophagocytic lymphohistiocytosis (a genetic disease characterised by an overactive immune system) in children under 18 years of age.
For more information on these negative opinions, see the question-and-answer documents in the grid below.
Nine recommendations on extensions of therapeutic indication
The Committee recommended extensions of indication for Crysvita, HyQvia, Imbruvica, Imfinzi, Kalydeco, Latuda, NovoThirteen, Prezista and Shingrix.
Change to non-prescription status
The CHMP recommended a change in classification status from prescription to non-prescription for Fortacin (lidocaine / prilocaine), a medicine to treat men with primary (lifelong) premature ejaculation. For more information, see the summary of opinion document in the grid below.
Outcome of review on medicines tested by Panexcell Clinical Laboratories
The Committee recommended the suspension of the marketing authorisations of generic medicines tested by Panexcell Clinical Laboratories Priv. Ltd at its site in Mumbai, India.
July 26, 2020: “The government has revealed a package of new measures falling under its new Obesity Strategy that are designed to improve health, ease the related burden on the NHS, and strengthen the public’s resilience to COVID-19.
Almost two thirds (63%) of adults in England are overweight or living with obesity, one in three children leave primary school overweight or obese, and obesity-related illnesses cost the NHS some £6 billion a year, highlighting the urgent need for effective action.
The urgency is further fuelled by recent data showing that obesity has an affect on COVID-19 survival, with those severely obese at twice the risk of dying from the virus.
Living with excess weight puts people at greater risk of serious illness or death from COVID-19, with risk growing substantially as BMI increases, the government stressed, noting that nearly 8% of critically ill patients with COVID-19 in intensive care units have been morbidly obese, compared with 2.9% of the general population.
In response, ministers have set out new measures to help people lose weight, get active and adopt a healthier lifestyle, alongside a new campaign led by Public Health England, Better Health, which will call on people to embrace a healthier lifestyle with support from a range of tools and apps providing advice on how to do so.
The new measures include:
Banning unhealthy food adverts – new laws will ban the advertising of food high in fat, sugar or salt (HFSS) on television and online before 9pm when children are most likely to see them.
The government will also hold a new short consultation on whether the ban on online adverts for HFSS, should apply at all times of day.
The move follows analysis published by Cancer Research UK showing that 47.6% of all food adverts shown over the month on ITV1, Channel 4, Channel 5 and Sky1 were for products high in fat, sugar and salt, rising to nearly 60% during the 6.00 to 9.00pm slot – during which children’s viewing peaks.
Evidence shows that exposure to HFSS advertising can affect what and when children eat, both in the short term and the longer term by shaping children’s preferences at a young age.
Ending BOGOF promotions – new legislation will restrict the promotion of foods high in fat, sugar, such as ‘buy one get one free’ offers. There will also be a ban on these items being placed in prominent locations in stores, such as at checkouts and entrances and online.
A survey from 2018 shows that around 43% of all food and drink products located in prominent areas were for sugary foods and drinks, compared to just 1% for healthy items. Shops will be encouraged to promote healthier choices and offer more discounts on food like fruit and vegetables.
Calorie labelling – new laws will require large restaurants, cafes and takeaways with more than 250 employees to add calorie labels to the food they sell. Research shows eating out is becoming more common, particularly among families, with 75% of people visiting a restaurant, fast food eatery or getting a takeaway in the past week, compared to 69% in 2010.
However, information on calorie content is often lacking, and research suggests people consume around 200 more calories a day if they eat out compared to food prepared at home.
Alcohol calorie labelling – the government will launch by the end of the year new consultation on plans to provide calorie labelling on alcohol.
It is estimated that alcohol consumption accounts for nearly 10% of the calorie intake of those who drink, but research shows that the majority of the public (80%) is unaware of the calorie content of common drinks.
Expanding NHS services – weight management services are to be expanded to increase support for those needing to lose weight. This will include more self-care apps and online tools for people with obesity-related conditions and accelerating the NHS Diabetes Prevention Programme.
Also, from 2021, doctors will be offered incentives to ensure people living with obesity is given support for weight loss and primary care staff will also have the opportunity to become ‘healthy weight coaches’ though training delivered by Public Health England.
Front of pack nutritional labelling – another consultation will be launched to gather views and evidence on the current ‘traffic light’ labelling system to increase understanding on how it is used by consumers and industry, compared to international examples.
Research shows that those who look at front of pack nutritional labelling have healthier shopping baskets.
“These plans are ambitious and rightly so. Tackling obesity will help prevent serious illness and save lives,” said Dr Alison Tedstone, chief nutritionist at PHE.
“The main reason we put on weight is because of what we eat and drink, but being more active is important too. Making healthier choices easier and fairer for everyone, and ensuring the right support is there for those who need it, is critical in tackling obesity.”
“We know obesity increases the risk of serious illness and death from coronavirus – so it’s vital we take action on obesity to protect the NHS and improve our nation’s health,” added health secretary Matt Hancock.
“Helping people to improve their health and wellbeing are welcome and will ultimately reduce the burden on NHS services in any circumstances. That is especially true during the pandemic when the measures have the potential to help reduce the severity of the virus,” said Dr Layla McCay, director at the NHS Confederation.
“However, we recognise that benefits will mostly be long term and the Government will need to continue to support services and their staff during what is expected to be a challenging period. It will be particularly important to recognise any additional workload on primary care.
July 24, 2020: “Swedish Orphan Biovitrum AB announced that the Committee for Medicinal Products for Human use (CHMP) has adopted a negative opinion recommending a refusal of the marketing authorisation for emapalumab for the treatment of primary haemophagocytic lymphohistiocytosis (HLH) in children under 18 years of age in Europe.
Given the significant unmet medical need that emapalumab addresses in patients with primary HLH with no approved treatments in Europe, Sobi will be requesting a re-examination by the CHMP with an expected opinion by end of year 2020.
Primary HLH is a rare syndrome that typically presents in infancy but can also be seen in adults and is associated with high morbidity and mortality. In spite of some treatment advances, there continues to be a very high unmet medical need in particular in patients that have failed conventional therapy as there are no approved treatment options outside the US.
In the US, emapalumab is the first therapy approved by the US Food & Drug Administration (FDA) for primary HLH. Over 100 patients have been treated in the US and the benefit/risk profile continues to be favourable.
“Emapalumab has demonstrated a positive benefit/risk profile in primary HLH in a post-approval real life setting in the US since the FDA approval in 2018. The product has been able to make a substantial difference for a very vulnerable group of patients in the US.
We are proud of having made a significant contribution with our product in the primary HLH indication and we are gratified by the recent academic validation of our work via publication in the New England Journal of Medicine.
During the last years our team has gained a lot of experience in this rather complex disease area. We will do our utmost to share these insights and address the open questions by CHMP during the re-examination with a view to secure access for primary HLH in children to this treatment in Europe”, says Guido Oelkers, CEO and President of Sobi.
HLH is a rare disease but with a large unmet medical need globally. The most important markets based on number of patients for both primary and secondary HLH are China followed by the US, Europe and Japan. In addition to HLH, Sobi will initiate clinical studies with emapalumab for potential indications such as pre-emptive treatment of patients with risk factors of HSCT acute graft failure which will further expand the patient population and market potential for emapalumab. Sobi’s earlier communicated estimated peak sales target for emapalumab beyond USD 500 million remains unchanged regardless of an approval in Europe.
Professor Franco Locatelli, Principal Investigator in the EU says “In my role as Principal Investigator of the NI-0501-04/05 studies in Europe I was significantly surprised about the EMA decision not to approve emapalumab for children with primary HLH who failed or are intolerant to front-line therapy.
I had the privilege to observe that this monoclonal antibody, targeting the main cytokine involved in the disease pathophysiology, was well tolerated and effective in a large proportion of the patients, representing a model of precision medicine.
While US children have since almost 2 years the possibility to be treated with this novel, safe, highly effective and targeted therapy, the EMA decision paves the way for migratory health flows towards non-European Centers that can grant this treatment.”
Professor Michael Jordan, Principal Investigator in the US confirms “The NI-0501-04/05 studies have demonstrated that emapalumab has clear therapeutic activity in primary HLH and have validated interferon gamma as a key target in these patients.
These studies have also demonstrated that this unique and targeted approach to therapy has a very favorable safety profile. I am grateful for the opportunity to help lead these trials which were conducted with the greatest rigor and transparency, far exceeding that of any trial to date in this very challenging patient population.
The worldwide team of collaborators, including physicians at many centers in the US and Europe, as well as individuals at Sobi, should be proud of this ground-breaking achievement. I believe that emapalumab will benefit patients around the world with HLH, especially as we continue to learn how to best apply this unique drug in patients with HLH.”
Recently, the results from the pivotal study evaluating the efficacy and safety of emapalumab in patients with primary HLH were published in one of the highest-ranking medical journals, New England Journal of Medicine.
Emapalumab Emapalumab is a monoclonal antibody that binds to and neutralises interferon gamma (IFNγ). In the US, emapalumab is indicated for paediatric (newborn and older) and adult primary haemophagocytic lymphohistiocytosis (HLH) patients with refractory, recurrent or progressive disease, or intolerance to conventional HLH therapy.
Emapalumab is the first and only medicine approved in the US for primary HLH, a rare syndrome of hyperinflammation that usually occurs within the first year of life and can rapidly become fatal unless diagnosed and treated. The FDA approval is based on data from the phase 2/3 studies (NCT01818492 and NCT02069899).
July 24, 2020: AstraZeneca’s BreztriAerosphere (budesonide/glycopyrrolate/formoterol fumarate) has been approved in the US for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).
The approval by the US Food and Drug Administration (FDA) was based on positive results from the Phase III ETHOS trial in which Breztri Aerosphere, a triple-combination therapy, showed a statistically significant reduction in the rate of moderate or severe exacerbations compared with dual-combination therapies Bevespi Aerosphere (glycopyrrolate/formoterol fumarate) and PT009 (budesonide/formoterol fumarate).
The approval was also supported by efficacy and safety data from the Phase III KRONOS trial.
Dr. Fernando J. Martinez, Chief of Division of Pulmonary and Critical Care Medicine at Weill Cornell Medicine and New York-Presbyterian Weill Cornell Medical Center, New York, US and Investigator in the ETHOS trial, said: “Preventing exacerbations is central to the management of chronic obstructive pulmonary disease.
Even a single exacerbation can have a negative impact on a patient’s lung function and quality of life, and it can increase the risk of death. BreztriAerosphere has demonstrated significant benefits in reducing exacerbations in patients suffering from COPD.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “Breztri Aerosphere has demonstrated a strong clinical profile compared with dual-combination therapies and offers a meaningful new treatment option for patients.
Chronic obstructive pulmonary disease is a debilitating progressive condition and the fourth leading cause of death in the US. We look forward to discussing all-cause mortality data from the Breztri Aerosphere ETHOS trial with health authorities.”
Results from the Phase III ETHOS trial were published in The New England Journal of Medicine in June 2020 and results from the Phase III KRONOS trial were published in The Lancet Respiratory Medicine in September 2018.
In both trials, the safety and tolerability of Breztri Aerosphere were consistent with the profiles of the dual comparators.
Breztri Aerosphere is not indicated for the relief of acute bronchospasm or for the treatment of asthma in the US or other countries. Breztri Aerosphere is approved in Japan and China for patients with COPD and under regulatory review in the EU.
