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FDA Takes Steps to Limit Lead in Juice to Further Reduce Exposure to Toxic Elements in Foods

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FDA Takes Steps to Limit Lead in Juice to Further Reduce Exposure to Toxic Elements in Foods

April 27, 2022: “The U.S. FDA issued draft action levels for lead in single-strength (ready to drink) apple juice and other single-strength juices and juice blends.

This action is intended to reduce the potential for negative health effects from dietary exposure to lead, and supports the agency’s Closer to Zero action plan that sets forth the FDA’s science-based approach to reducing exposure to toxic elements in foods. 

“Exposure of our most vulnerable populations, especially children, to elevated levels of toxic elements from foods is unacceptable,” said FDA Commissioner Robert M. Califf, M.D.

“This action to limit lead in juice represents an important step forward in advancing FDA’s Closer to Zero action plan, which we are confident will have a lasting public health impact on current and future generations.”

Today’s draft guidance outlines action levels, which are recommended limits of lead in juice that can be achieved by industry and progressively lowered as appropriate. 

In particular, Action Levels for Lead in Juice: Draft Guidance for Industry, provides draft action levels of 10 parts per billion (ppb) for lead in single-strength apple juice and of 20 ppb for lead in all other single-strength juice types, including juice blends that contain apple juice. 

As part of its commitment in the Closer to Zero action plan to consider the biological effects from exposure to harmful elements in food, the draft action levels for lead in juice were guided by the FDA’s interim reference level (IRL) for lead, a measure of the contribution of lead in food to blood lead levels.

The FDA estimates that establishing a 10 ppb action level could result in as much as a 46% reduction in exposure to lead from apple juice in children.

For all other fruit and vegetable juices, establishment of an action level of 20 ppb is estimated to result in a reduction of 19% in exposure to lead from all other juices in children.

The FDA issued a lower draft action level for apple juice because it is the most commonly consumed juice that young children drink.

“As we outlined in the Closer to Zero action plan, the agency is increasing targeted compliance activities as part of our efforts to monitor levels of these elements in foods through the FDA’s Total Diet Study, Toxic Elements in Food and Foodware program and sampling assignments,” said Susan Mayne, Ph.D., director of the FDA’s Center for Food Safety and Applied Nutrition.

“In addition, our work in this important area of food safety will progress with advancements in science.

For example, action levels may be progressively lowered over time, as appropriate, to make continual improvements in reducing the levels of lead, arsenic, cadmium and mercury in foods eaten by babies and young children.”  

The FDA is accepting comments on the draft guidance. A manufacturer may choose to implement the recommendations in a draft guidance before the guidance becomes final. The FDA will work with manufacturers of these products to encourage the adoption of best practices to lower levels of lead in juice.

The FDA routinely monitors levels of toxic elements in food and considers on a case-by-case basis whether a food that contains a contaminant is adulterated under the Federal Food, Drug, and Cosmetic Act and subject to enforcement action.

Because lead is in the environment as a naturally occurring element and from consumer and industrial products and processes, it is not possible to remove it entirely from the food supply. However, the action levels recommended in the draft guidance document will help limit consumer exposure.

The FDA recommends that for good nutrition, parents follow the Dietary Guidelines for Americans, which recommends limits on juice intake for children.

Decreasing juice consumption would also reduce potential exposure to lead from juice.

The Dietary Guidelines recommends that children should get at least half of their fruit needs each day from whole fruit rather than juice and that children under 12 months of age should not consume juice. 

Issuing the draft guidance for lead in juice is part of the FDA’s broader efforts to reduce exposure to lead, arsenic, mercury and cadmium from foods and to advance the goals laid out in the Closer to Zero action plan, initiated in April 2021.

As it enters the second year of the Closer to Zero action plan, the FDA is working to identify reference levels for arsenic, cadmium and mercury, and to issue draft guidance to industry on action levels for lead in foods commonly eaten by babies and young children.

We’re also continuing to work towards issuing final guidance on an action level for inorganic arsenic in apple juice.”

https://www.fda.gov/news-events/press-announcements/fda-takes-steps-limit-lead-juice-further-reduce-exposure-toxic-elements-foods

Ultomiris approved in the US for adults with generalised myasthenia gravis

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Ultomiris approved in the US for adults with generalised myasthenia gravis

April 28, 2022: “Ultomiris (ravulizumab-cwvz) has been approved in the US for the treatment of adult patients with generalised myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive, which represents 80% of people living with the disease.  

The approval by the Food and Drug Administration (FDA) was based on positive results from the CHAMPION-MG Phase III trial, in which Ultomiris was superior to placebo in the primary endpoint of change from baseline in the Myasthenia Gravis-Activities of Daily Living Profile (MG-ADL) total score at Week 26, a patient-reported scale that assesses patients’ abilities to perform daily activities.

This FDA action marks the first and only approval for a long-acting C5 complement inhibitor for the treatment of gMG.

gMG is a rare, debilitating, chronic, autoimmune neuromuscular disease that leads to a loss of muscle function and severe weakness.

The diagnosed prevalence of gMG in the US is estimated at approximately 90,000.

Professor James F. Howard, Jr, MD, Department of Neurology at The University of North Carolina School of Medicine and lead primary investigator in the CHAMPION-MG trial said: “Despite recent advances, managing gMG is complex.

Earlier intervention can preserve function and quality of life. This approval offers patients, including those with milder symptoms, a long-acting C5 inhibitor with early onset and reliable efficacy.”

Samantha Masterson, Chief Executive Officer, Myasthenia Gravis Foundation of America (MGFA), said: “gMG takes a physical and emotional toll on those living with the disease. We are grateful for continued innovation and research into new treatment and dosing options to meet the needs of more patients and reduce the treatment burden.

With the approval of Ultomiris, we’re excited that MG patients now have another option to consider as part of their personalised treatment strategies that may offer more convenience and improve muscle weakness.”

Marc Dunoyer, Chief Executive Officer, Alexion, said: “Since bringing forward thefirst complement inhibitor, we’ve continued to listen to the community and focused innovation on the needs of gMG patients.

We’re proud to deliver on this commitment with today’s approval. Ultomiris, the only long-acting C5 inhibitor, will benefit a broader range of patients, including those with milder symptoms.

As presented at the 2022 American Academy of Neurology Annual Meeting, Ultomiris has demonstrated clinical benefit through 60 weeks, with treatment every eight weeks, compared to Soliris every two weeks.”   

In the trial, the safety profile of Ultomiris was comparable to placebo and consistent with that observed in Phase III trials of Ultomiris in paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS).  

The most common adverse reactions in patients receiving Ultomiris were upper respiratory tract infection and diarrhoea.

Results from the CHAMPION-MG trial were recently published online in NEJM Evidence and presented at the 2022 American Academy of Neurology Annual Meeting in April.

Regulatory submissions for Ultomiris for the treatment of gMG are currently under review with multiple health authorities, including in the European Union (EU) and Japan.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/ultomiris-approved-in-the-us-for-adults-with-generalised-myasthenia-gravis.html

Enhertu granted Breakthrough Therapy Designation in US HER2-low metastatic breast cancer

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Enhertu granted Breakthrough Therapy Designation in US HER2-low metastatic breast cancer

April 27, 2022: “AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) has been granted Breakthrough Therapy Designation in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.

Patients with hormone receptor (HR) positive breast cancer should additionally have received or be ineligible for endocrine therapy.

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

The Food and Drug Administration’s (FDA) BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need.

The new medicine needs to have shown encouraging preliminary clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

Up to half of all patients with breast cancer have tumours with a HER2 immunohistochemistry (IHC) score of 1+, or 2+ in combination with a negative in-situ hybridisation (ISH) test, a level of HER2 expression not currently eligible for HER2-targeted therapy.1-4 Low HER2 expression occurs in both HR-positive and HR-negative disease.5

HER2 testing is routinely used to determine appropriate treatment options for patients with metastatic breast cancer.

Targeting the lower range of expression in the HER2 spectrum may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.

Currently chemotherapy remains the only treatment option for patients with HR-positive tumours following progression on endocrine (hormone) therapy.

Few targeted options are available for those who are HR-negative.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: “Today’s news is a significant validation of the potential we see for the historic DESTINY-Breast04 trial to enable a paradigm shift in how breast cancer is classified by targeting the full spectrum of HER2 expression. 

Enhertu continues to show transformative potential, and this milestone represents an important advance for patients with HER2-low metastatic breast cancer who are in urgent need of new treatment options and better outcomes.”

Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: “Historically, only patients with HER2-positive metastatic breast cancer were shown to benefit from HER2-directed therapy.

DESTINY-Breast04, in which Enhertu showed a clinically meaningful survival benefit in patients with HER2-low metastatic breast cancer, is the first trial to demonstrate that selecting patients for treatment based on low expression of HER2 has the potential to change the diagnostic and treatment paradigms for these patients.

This Breakthrough Therapy Designation acknowledges the potential of Enhertu to fulfil an unmet medical need and we look forward to working closely with the FDA to bring the first HER2-directed therapyto patients with metastatic breast cancer whose tumours have lower levels of HER2 expression.”

The FDA granted the BTD based on data from the pivotal DESTINY-Breast04 Phase III trial which reported positive high-level results in February 2022.

In the trial, Enhertu demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) in patients with HER2-low unresectable and/or metastatic breast cancer in all randomised patients with HR-positive and HR-negative disease versus physician’s choice of chemotherapy, which is the current standard of care.

The safety profile of Enhertu was consistent with previous clinical trials with no new safety concerns identified. The data will be presented at an upcoming medical meeting.

This is the third BTD for Enhertu in breast cancer. Enhertu previously received BTD’s for the treatment of second-line HER2-positive metastatic breast cancer in 2021 and later-line HER2-positive metastatic breast cancer in 2017.

Two additional BTD’s for Enhertu were granted in 2020 for HER2-mutant metastatic non-small cell lung cancer (NSCLC) and HER2-positive metastatic gastric cancer.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/enhertu-granted-btd-her2-low-breast-cancer.html

FDA Approves First COVID-19 Treatment for Young Children

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FDA Approves First COVID-19 Treatment for Young Children

April 25, 2022: “The U.S. FDA expanded the approval of the COVID-19 treatment Veklury (remdesivir) to include pediatric patients 28 days of age and older weighing at least 3 kilograms (about 7 pounds) with positive results of direct SARS-CoV-2 viral testing, who are:

  • Hospitalized, or
  • Not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. 

This action makes Veklury the first approved COVID-19 treatment for children less than 12 years of age.

As a result of today’s approval action, the agency also revoked the emergency use authorization for Veklury that previously covered this pediatric population. 

Before now, Veklury was only approved to treat certain adults and pediatric patients (12 years of age and older who weigh at least 40 kilograms, which is about 88 pounds) with COVID-19. 

“As COVID-19 can cause severe illness in children, some of whom do not currently have a vaccination option, there continues to be a need for safe and effective COVID-19 treatment options for this population,” said Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research.

“Today’s approval of the first COVID-19 therapeutic for this population demonstrates the agency’s commitment to that need.”

Veklury is not a substitute for vaccination in individuals for whom COVID-19 vaccination and booster doses are recommended.

The FDA has approved two vaccines, and three vaccines are available for emergency use, to prevent COVID-19 and the serious clinical outcomes associated with COVID-19, including hospitalization and death.

The FDA urges the public to get vaccinated and receive a booster when eligible. Learn more about FDA-approved and authorized COVID-19 vaccines.

Given the similar course of COVID-19 disease in adults and pediatric patients, today’s approval of Veklury in certain pediatric patients is supported by efficacy results from phase 3 clinical trials in adults.

Information on the trials in adults can be found in the FDA-approved drug labeling for Veklury.

This approval is also supported by a phase 2/3, single-arm, open-label clinical study of 53 pediatric patients at least 28 days of age and weighing at least 3 kilograms (about 7 pounds) with confirmed SARS-CoV-2 infection and mild, moderate or severe COVID-19.

Patients in this pediatric phase 2/3 trial received Veklury for up to 10 days. The safety and pharmacokinetic results from the phase 2/3 study in pediatric subjects were similar to those in adults.

The only approved dosage form is Veklury for injection.  

Possible side effects of using Veklury include increased levels of liver enzymes, which may be a sign of liver injury; and allergic reactions, which may include changes in blood pressure and heart rate, low blood oxygen level, fever, shortness of breath, wheezing, swelling (e.g., lips, around eyes, under the skin), rash, nausea, sweating or shivering.

The FDA granted approval to Gilead Sciences Inc.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-approves-first-covid-19-treatment-young-children

Sanofi’s Rezurock patient-reported outcomes correlated with clinical response in chronic graft-versus-host disease

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Sanofi’s Rezurock patient-reported outcomes correlated with clinical response in chronic graft-versus-host disease

April 21, 2022: “Results from a pooled analysis of Rezurock® (belumosudil) for the treatment of chronic graft-versus-host disease (cGVHD) show certain organ clinical responses correlated with clinically meaningful changes in patient-reported outcomes (PROs).

Kadmon, a Sanofi Company, will present the results at the 2022 American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR) Tandem Meetings in Salt Lake City, Utah.

Jonathan Ieyoub
Head of Sanofi US Rezurock Medical
“These Rezurock data reinforce the importance of patient-reported outcome measures by showing their correlation to clinical response. 

Knowing the impact that chronic graft-versus-host disease has on patients, the results add support for use of patient-reported outcomes to assess responses in clinical care.”

The pooled analysis of the ROCKstar (KD025-213) and KD025-208 studies demonstrates a very strong, but not universal, correlation between organ clinical response measures and clinically meaningful changes in PROs in patients treated with Rezurock.

In particular, the clinically meaningful changes in PROs were reported in the skin, mouth, eye, upper GI, lung (clinical lung scale score), and overall measures.

These data support use of PROs for response assessment in cGVHD clinical trials and patient care to help capture the patient’s perspective on cGVHD disease activity.

About the Pooled Analysis

The pooled analysis of clinical and PRO data included 170 (91.3%) patients enrolled in two Rezurock studies (n=132, KD025-213; n=54, KD025-208) who had baseline PROs, at least one follow-up PRO, and at least one response assessment.

The median age was 54.5 years, 98 (58%) were men, the median number of prior treatments was 3, 70% had severe cGVHD, and the median duration of follow-up at the time of data cut-off was 15 months (range, 0.6-44 months).

Organ responses, defined as complete responses (CR) and partial responses (PR), were 35% (48/135) in skin, 68% (84/124) in joints, 57% (56/99) in mouth, 41% (52/128) in eyes, 73% (19/26) in upper GI, 87% (13/15) in lower GI, 23% (14/61) in lungs, and 77% (130/170) overall.

For all organs except for joints, oesophagus, and lower GI there was at least one PRO that was statistically correlated at p<0.05 with National Institutes of Health (NIH) organ response. NIH clinical lung response, but not the lung response based on FEV1% change, was associated with the lung PRO.

Correlation of NIH organ response (CR+PR) with clinically meaningful patient-reported outcomes (PROs)
OrganResponse measureClinically meaningful changePatient-reported outcomeClinically meaningful changeOR, 95% CI, for improvement in PRO predicting NIH responsep-value
SkinNIH Skin score 0-31 ptLSS skin scale 0-10011 pts2.16 (1.12-4.16)0.021
 Sclerotic skin 0-102 ptsLSS skin scale 0-10011 pts1.66 (0.91-3.01)0.098
 Sclerotic skin 0-102 ptsSkin tightening 0-102 pts2.50 (1.28-4.87)0.007
JointP-ROM 4-252 ptsLSS single item joints 0-41 pt1.49 (0.84-2.66)0.175
 NIH joint score 0-31 ptLSS single item joints 0-41 pt1.26 (0.73-2.20)0.408
MouthOral mucositis rating scale2 ptsLSS mouth scale 0-10013 pts6.36 (2.94-13.74)<0.0001
 Oral mucositis rating scale2 ptsMouth sensitivity 0-102 pts4.53 (2.25-9.09)<0.0001
GINIH esophagus score 0-31 ptLSS nutrition scale 0-1007 pts1.32 (0.53-3.29)0.546
 NIH upper GI score 0-31 ptLSS nutrition scale 0-1007 pts4.44 (1.74-11.35)0.002
 NIH lower GI score 0-31 ptLSS nutrition scale 0-1007 pts0.91 (0.27-3.05)0.878
EyeNIH eye score 0-31 ptLSS eye scale 0-10015 pts3.39 (1.98-5.82)<0.0001
 NIH eye score 0-31 ptWorst eye compliant 0-102 pts2.35 (1.33-4.15)0.003
LungFEV1%10%LSS lung scale 0-1008 pts0.90 (0.43-1.87)0.779
 NIH lung score 0-31 ptLSS lung scale 0-1008 pts2.81 (1.70-4.65)<0.0001
OverallNIH responder CR+PR vs. nonresponder LSS summary scale 0-1007 pts1.89 (1.17-3.06)0.010
 NIH responder CR+PR vs. nonresponder Overall cGVHD 0-102 pts2.37 (1.48-3.77)<0.001
 Overall severity 0-102 ptsLSS summary scale 0-1007 pts1.84 (1.08-3.11)0.024
 Overall severity 0-102 ptsOverall cGVHD 0-102 pts3.46 (2.17-5.52)<0.0001
Pt, point; LSS, Lee symptom scale; GI, gastrointestinal; P-ROM, photographic range of motion

About cGVHD

cGVHD is a complication that can occur following allogeneic stem cell transplantation, resulting in significant morbidity and mortality. In cGVHD, transplanted immune cells (graft) attack the patient’s cells (host), leading to inflammation and fibrosis in multiple tissues, including skin, mouth, eye, joints, liver, lung, oesophagus and gastrointestinal tract.

Approximately 14,000 patients in the United States are living with cGVHD.

About Rezurock® (belumosudil)

Rezurock® (belumosudil) is the first and only approved therapy inhibiting Rho-associated coiled-coil kinase 2 (ROCK2).

Rezurock is approved in the United States for the treatment of adult and pediatric patients 12 years and older with cGVHD after failure of at least two prior lines of systemic therapy.”

https://www.sanofi.com/en/media-room/press-releases/2022/2022-04-21-07-00-00-2426054

FDA Considers New Approach to Improve Safe Disposal of Prescription Opioid Analgesics

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FDA Considers New Approach to Improve Safe Disposal of Prescription Opioid Analgesics

April 20, 2022: “U.S. FDA announced it is seeking public comment on a potential change that would require opioid analgesics used in outpatient settings to be dispensed with prepaid mail-back envelopes and that pharmacists provide patient education on safe disposal of opioids.

This potential modification to the existing Opioid Analgesic Risk Evaluation and Mitigation Strategy would provide a convenient, additional disposal option for patients beyond those already available such as flushing, commercially available in-home disposal products, collection kiosks and takeback events.

“The FDA is committed to addressing the opioid crisis on all fronts, including exploring new approaches that have the potential to decrease unnecessary exposure to opioids and prevent new cases of addiction.

Prescribing opioids for durations and doses that do not properly match the clinical needs of the patient not only increases the chances for misuse, abuse and overdose, but it also increases the likelihood of unnecessary exposure to unused medications,” said FDA Commissioner Robert M. Califf, M.D.

“As we explore ways to further address this issue more broadly, the mail-back envelope requirement under consideration for these unused medications would complement current disposal programs and provide meaningful and attainable steps to improve the safe use and disposal.”

Patients commonly report having unused opioid analgesics following surgical procedures, thereby creating unfortunate opportunities for nonmedical use, accidental exposure, overdose and potentially increasing new cases of opioid addiction.

Since many Americans gain access to opioids for the first time through friends or relatives who have unused opioids, requiring a mail-back envelope be provided with each prescription could reduce the amount of unused opioid analgesics in patients’ homes.

Data show educating patients about disposal options may increase the disposal rate of unused opioids and that providing a disposal option along with education could further increase that rate.

Mail-back envelopes have several favorable characteristics. They do not require patients to mix medications with water, chemicals or other substances nor use other common at-home disposal techniques.

Opioid analgesics sent back to Drug Enforcement Administration-registered facilities in mail-back envelopes do not enter the water supply and landfills (instead, they are incinerated).

The nondescript mail-back envelopes provided would be postage paid, offering patients a free disposal option.

Additionally, there are long-standing regulations and policies in place to ensure that mail-back envelopes are fit for that purpose and can safely and securely transport unused medicines from the patient’s home to the location where they will be destroyed.

The change under consideration underscores the agency’s efforts to address the dynamic facets of the opioid crisis and supports the HHS Overdose Prevention Strategy, which focuses on four priority areas — primary prevention, harm reduction, evidence-based treatment and recovery support.

The FDA is accepting public comments from interested parties, including patients, patient advocates, health care professionals, academics, researchers, the pharmaceutical industry and other government entities until June 21, 2022; however, comments are welcome at any time.”

https://www.fda.gov/news-events/press-announcements/fda-considers-new-approach-improve-safe-disposal-prescription-opioid-analgesics-decrease-unnecessary

FDA Warns of Risks Associated with Non-Invasive Prenatal Screening Tests

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FDA Warns of Risks Associated with Non-Invasive Prenatal Screening Tests

April 19, 2022: “The U.S. FDA is warning the public of the risk of false results, inappropriate use and inappropriate interpretation of results with non-invasive prenatal screening (NIPS) tests, also called cell-free DNA tests or non-invasive prenatal tests (NIPT).

These tests look for signs of genetic abnormalities in a fetus by testing a sample of blood from the pregnant person.

Given the increased use of these tests and rece0nt media reports, the FDA is providing this information to educate patients and health care providers and to help reduce the inappropriate use of NIPS tests.

“While genetic non-invasive prenatal screening tests are widely used today, these tests have not been reviewed by the FDA and may be making claims about their performance and use that are not based on sound science,” said Jeff Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health.

“Without proper understanding of how these tests should be used, people may make inappropriate health care decisions regarding their pregnancy.

We strongly urge patients to discuss the benefits and risks of these tests with a genetic counselor or other health care provider prior to making decisions based on the results of these tests.”

NIPS tests can provide information about the possibility a child will be born with a serious health condition.

However, NIPS tests are screening tests – not diagnostic tests.

They only provide information about the risk that a fetus may have a genetic abnormality, and additional testing may be needed to confirm whether or not a fetus is affected.

Genetic abnormalities may be caused by a missing chromosome or an extra copy of a chromosome, known as an aneuploidy, a small piece missing from a chromosome called a microdeletion, or an extra piece of chromosome called a duplication.

These genetic abnormalities can cause serious health conditions.

Conditions caused by a missing chromosome or an extra copy of a chromosome are more common and may be easier to detect, such as Down syndrome, which can cause physical and intellectual challenges.

A missing or extra piece of a chromosome may result in rarer conditions, such as DiGeorge syndrome, which can cause heart defects, feeding difficulties, immune system problems and learning difficulties.

All NIPS tests on the market today are offered as laboratory developed tests (LDTs). Most LDTs, including NIPS tests, are offered without review by the FDA.

While LDTs are medical devices under the Federal Food, Drug, and Cosmetic Act, the FDA has had a general policy of enforcement discretion for most LDTs since the Medical Device Amendments were enacted in 1976.

That means that FDA does not generally enforce applicable regulatory requirements for most LDTs.

FDA is continuing to work with Congress on legislation to establish a modern regulatory framework for all tests, including LDTs. 

Many laboratories offering these tests advertise their tests as “reliable” and “highly accurate,” offering “peace of mind” for patients.

The FDA is concerned that these claims may not be supported with sound scientific evidence. While these laboratories claim their tests are highly accurate, there are limitations due to the rarity of some of the conditions included in the screening.

For example, when screening for a very rare condition, a positive screening result may be more likely to be a false positive than a true positive, and the fetus may not actually be affected.

In other cases, a positive screening result may accurately detect a chromosomal abnormality, but that abnormality is present in the placenta and not in the fetus, which may be healthy. 

Patients and health care providers should be aware of the risks and limitations of using these genetic prenatal screening tests and that they should not be used alone to diagnose chromosomal (genetic) abnormalities.

However, the FDA is aware of reports that patients and health care providers have made critical health care decisions based on results from these screening tests without additional confirmatory testing.

Pregnant people have ended pregnancies based on the results of genetic prenatal screening alone, without understanding the limitations of the screening tests and that the fetus may not have the genetic abnormality identified by the screening test.   

The FDA recommends that patients and health care providers discuss the benefits and risks of all prenatal genetic testing, including NIPS tests, with a genetic counselor or other health care provider before considering such testing or making any decisions about their pregnancy.

Please see the safety communication linked below for a full list of recommendations for patients and health care providers.

The FDA will continue to closely monitor safety issues around the use of NIPS tests and is committed to protecting public health.”

https://www.fda.gov/news-events/press-announcements/fda-warns-risks-associated-non-invasive-prenatal-screening-tests

US FDA accepts New Drug Application for daprodustat

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US FDA accepts New Drug Application for daprodustat

April 19, 2022: “GlaxoSmithKline plc announced that the USFDA accepted the NDA for daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), for the potential treatment of patients with anaemia of chronic kidney disease (CKD).

Daprodustat was developed based upon the unique Nobel Prize-winning science that demonstrated how cells sense and adapt to oxygen availability.

The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of 1 February 2023.

The daprodustat NDA is based on positive results from the ASCEND phase III clinical trial programme, which included five pivotal trials assessing the efficacy and safety of daprodustat for the treatment of anaemia across the spectrum of CKD.

Results from the key cardiovascular outcomes trials were published in the New England Journal of Medicine in November 2021 and included non-dialysis (ASCEND-ND) and dialysis (ASCEND-D) CKD patients.

These trials demonstrated that daprodustat improved and/or maintained haemoglobin (Hb) within the target level (10-11.5 g/dL) without increased major adverse cardiovascular events (MACE) in the intention-to-treat (ITT) populations in each pivotal study, when compared to the standard of care, an erythropoietin stimulating agent (ESA), across both non-dialysis and dialysis patient settings.

Daprodustat is currently approved in Japan as Duvroq for patients with renal anaemia.

In March 2022, the European Medicines Agency (EMA) validated the marketing authorisation application (MAA) for daprodustat, which is currently under review. Additional regulatory filings are anticipated to continue throughout 2022.

About the ASCEND phase III clinical trial programme
The ASCEND programme includes five phase III trials to assess the efficacy and safety profile of daprodustat for treating anaemia of CKD across the disease pathway.

The programme enrolled over 8,000 patients treated for up to 4.26 years. Results from all five trials were presented at the American Society of Nephrology’s Kidney Week 2021.

Results from the two pivotal cardiovascular outcomes trials, ASCEND-ND and ASCEND-D, which investigated patients not on dialysis and on dialysis, respectively, were also published in the New England Journal of Medicine:

  • ASCEND-ND (Anaemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-Non-Dialysis) enrolled 3,872 non-dialysis dependent patients with anaemia of CKD who were either switched from the standard of care (ESA) or not currently receiving ESA therapy to receive daprodustat or ESA control (darbepoetin alfa).

    Iron management protocols were instituted across both arms of the trial.

    The trial met its primary efficacy and safety endpoints. Results showed that daprodustat improved and/or maintained Hb within the target level (10-11.5 g/dL) for these patients, and the primary safety analysis of the ITT population showed that daprodustat achieved non-inferiority of MACE compared to ESA control.
  • ASCEND-D (Anaemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-Dialysis) enrolled 2,964 dialysis patients with anaemia of CKD who were switched to receive daprodustat or ESA control from a standard of care ESA therapy.

    A uniform iron management protocol was instituted across both arms of the trial. The trial met its primary efficacy and safety endpoints.

    Results showed daprodustat improved or maintained Hb within target levels (10-11.5 g/dL) for these patients, and the primary safety analysis of the ITT population showed that daprodustat achieved non-inferiority of MACE compared to ESA control.

About anaemia of chronic kidney disease
CKD, characterised by progressive loss of kidney function, is an increasing global public health burden. 

Risk factors for CKD include hypertension, diabetes, obesity and primary renal disorders.

Furthermore, CKD is an independent risk factor for cardiovascular disease.

Anaemia is an important and frequent complication of CKD. However, it is often poorly diagnosed and undertreated in patients with early-stage CKD, such as those not on dialysis.

Over 700 million patients suffer from CKD worldwide, and an estimated 1-in-7 of these patients have anaemia.

When left untreated or undertreated, anaemia of CKD is associated with poor clinical outcomes and leads to a substantial burden on patients and healthcare systems.

About daprodustat
Daprodustat, a HIF-PHI, belongs to a novel class of oral medicines indicated for the potential treatment of anaemia of CKD in adult patients not on dialysis and on dialysis.

Inhibition of oxygen-sensing prolyl hydroxylase enzymes stabilises hypoxia-inducible factors, which can lead to transcription of erythropoietin and other genes involved in the correction of anaemia, similar to the physiological effects that occur in the human body at high altitude.

Daprodustat has been developed to provide a convenient oral treatment option for patients with anaemia of CKD.”

https://www.gsk.com/en-gb/media/press-releases/us-food-and-drug-administration-accepts-new-drug-application-for-daprodustat/

Shionogi and NEC Enter into Strategic Research Collaboration for Novel Hepatitis B Therapeutic Vaccine

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Shionogi and NEC Enter into Strategic Research Collaboration for Novel Hepatitis B Therapeutic Vaccine

April 18, 2022: “Shionogi & Co., Ltd. and NEC Corporation announced the execution of a strategic research collaboration agreement for the development of a novel hepatitis B therapeutic vaccine.

NEC OncoImmunity (Head Office: Oslo, Norway, CEO: Richard Stratford Ph.D.), an NEC subsidiary that specializes in artificial intelligence-driven biotechnology, is also participating in this research collaboration.

Hepatitis B is a potentially life-threatening liver disease caused by the hepatitis B virus (HBV). Chronic infection with HBV results in a high risk of death from cirrhosis and liver cancer.

About 300 million people are living with chronic hepatitis B infection worldwide, and hepatitis B resulted in an estimated 820,000 deaths in 2019.

Although the widespread use of hepatitis B vaccines in infants has considerably reduced the incidence of new chronic HBV infections under the age of 5, the number of new infections by other routes continues to increase.

Interferon (IFN) and nucleotide analog therapy are currently used in the treatment of hepatitis B. However, treatment with IFN has a high frequency of side effects, and nucleotide analog therapy has a high recurrence rate if treatment is interrupted, so it is necessary to take drugs for a lifetime.

Therefore, the unmet medical need for safe and highly effective drugs that can finally achieve a complete cure for hepatitis B is high.

Isao Teshirogi, President & CEO, Shionogi said:

“Shionogi has been engaged in the research and development of infectious diseases for over 60 years.

As a leading infectious disease company, we are taking on the challenge of protecting people from the threat of infectious diseases and realizing total care.

One company, and even the entire pharmaceutical industry on its own, can only go so far in dealing with a global pandemic like COVID-19.

We will further enhance our contribution to global health by integrating NEC’s AI technologies while leveraging our strengths.”

Nobuhiro Endo, Chairman of the Board, NEC Corporation said:

“NEC is committed to our vision of ‘Orchestrating a brighter world,’ and we are delighted to collaborate with Shionogi to realize this vision through the development ofnovel treatments for patients. 

The innovative AI technologies of the NEC Group have the potential to overcome several challenges in what is usually a long and labor-intensive drug discovery process .

Through this new partnership with Shionogi, a recognized leader in the field of infectious disease, we aim to maximize the contribution of our AI to accelerate the pace of drug discovery, and thereby to contribute to society.”

By fusing Shionogi’s drug discovery capability, focused on the infectious disease field, with NEC’s expertise in artificial intelligence (AI), the companies will accelerate the progress toward a new therapeutic vaccine.

Going forward, the companies will continue to actively expand such joint research into other infectious diseases where unmet medical needs remain.”

https://www.shionogi.com/global/en/news/2022/04/e-220418.html

Enhertu granted Priority Review in US for patients with previously treated HER2-mutant metastatic NSCLC

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Enhertu granted Priority Review in US for patients with previously treated HER2-mutant metastatic NSCLC

April 19, 2022: “AstraZeneca and Daiichi Sankyo have received notification of acceptance of the supplemental Biologics License Applicationof Enhertu (trastuzumab deruxtecan) for the treatment of adult patients in the US with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have a HER2(ERBB2) mutation and who have received a prior systemic therapy.

The application has also been granted Priority Review.

Enhertu is a HER2–directed antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

FDA grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance.

The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for their regulatory decision, is during the third quarter of 2022.

The Priority Review follows Breakthrough Therapy Designation granted by the FDA for Enhertu in this cancer type in May 2020.

Lung cancer is the second most common form of cancer globally, with more than two million new cases diagnosed in 2020.

For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.

There are currently no HER2-directed therapies approved specifically for the treatment of HER2–mutant NSCLC, which occurs in approximately 2-4% of patients with non-squamous NSCLC.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “The DESTINY-Lung01 trial confirmed the HER2 mutation as an actionable biomarker in non-small cell lung cancer.

If approved, Enhertu has the potential to become a new standard treatment in this patient population, offering a much-needed option for patients with HER2-mutant metastatic non-small cell lung cancer who currently have no targeted treatment options.”

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: “The results of DESTINY-Lung01 showed that Enhertu is the first HER2-directed therapy to demonstrate a strong and robust tumour response in more than half of patients with previously treated HER2-mutant metastatic non-small cell lung cancer.

Seeking approval in the US for a third tumour type in three years further demonstrates the significant potential of Enhertu in treating multiple HER2-targetable cancers.”

The sBLA is based on data from the registrational DESTINY-Lung01 Phase II trial published in The New England Journal of Medicine, and is supported by the Phase I trial (DS8201-A-J101) published in Cancer Discovery.

Primary results from previously-treated patients with HER2-mutations (cohort 2) of DESTINY-Lung01 demonstrated a confirmed objective response rate (ORR) of 54.9% (95% confidence interval [CI]: 44.2-65.4) in patients treated with Enhertu (6.4mg/kg) as assessed by independent central review (ICR).

One (1.1%) complete response (CR) and 49 (53.8%) partial responses (PR) were observed.

A confirmed disease control rate (DCR) of 92.3% was seen with a reduction in tumour size observed in most patients. After a median follow-up of 13.1 months, the median duration of response (DoR) for Enhertu was 9.3 months.

The median progression-free survival (PFS) was 8.2 months and the median overall survival (OS) was 17.8 months.

The safety profile of the most common adverse events with Enhertu in DESTINY-Lung01 was consistent with previous clinical trials with no new safety concerns identified.

Enhertu is being further assessed in a comprehensive clinical development programme evaluating efficacy and safety across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers.”

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/enhertu-granted-priority-review-for-her2m-nsclc.html

FDA Takes New Steps Regarding Evaluating Public Health Importance of Additional Food Allergens

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FDA Takes New Steps Regarding Evaluating Public Health Importance of Additional Food Allergens

April 18, 2022: “The U.S. FDA issued a draft guidance that, when finalized, will outline the agency’s approach to evaluating the public health importance of food allergens that are not one of the major nine food allergens identified by law in the U.S (non-listed food allergens). 

Currently, the major food allergens are milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat and soybeans, though more than 160 foods are known to cause food allergic reactions.

Sesame becomes the ninth major food allergen, effective Jan. 1, 2023. 

“The nine major food allergens don’t currently represent all foods nationwide that people are allergic to or that cause food hypersensitivities,” said Susan Mayne, Ph.D., Director, Center for Food Safety and Applied Nutrition.

This draft guidance is part of the FDA’s efforts to evaluate emerging evidence about other non-listed food allergens that can cause serious reactions in a consistent and transparent manner, which can inform potential future actions to better help protect the health of consumers.” 

Food allergies and other types of food hypersensitivities affect millions of people in the U.S. and occur when the body’s immune system reacts to certain proteins in food.

Food allergic reactions vary in severity from mild symptoms, involving localized hives and lip swelling, to severe, life-threatening symptoms, called anaphylaxis, which may involve fatal respiratory problems and shock.

Reactions to some non-listed food allergens have relatively low prevalence rates, with some as low as single cases.

The draft guidance focuses on immunoglobulin E antibody (IgE)-mediated food allergies, which are capable of triggering anaphylaxis and are considered the most severe and immediately life-threatening food allergies.

Food allergic reactions caused by the nine major food allergens are all IgE-mediated. The draft guidance describes the approach the FDA generally intends to take when evaluating the public health importance of a non-listed food allergen.

It includes a discussion of the evidence that establishes the food as a cause of IgE-mediated food allergy and key scientific factors, such as prevalence, severity and allergenic potency, that the FDA intends to consider in its evaluations.

The draft guidance also provides the FDA’s recommendations for identifying and evaluating the relevant body of evidence to determine the public health importance of a non-listed food allergen.

In August 2004, the Food Allergen Labeling and Consumer Protection Act (FALCPA) was signed into law.

At that time, eight major food allergens were responsible for 90 percent of IgE-mediated food allergies and were the most common causes of severe food reactions in the U.S. On April 23, 2021, the Food Allergy Safety, Treatment, Education, and Research (FASTER) Act was signed into law, declaring sesame as the 9th major food allergen recognized by the U.S., effective Jan. 1, 2023.

To ensure comments about “Evaluating the Public Health Importance of Food Allergens Other Than the Major Food Allergens Listed in the Federal Food, Drug, and Cosmetic Act” are considered before the FDA begins work on the final guidance, comments at www.regulations.gov should be submitted using Docket ID: FDA-2021-N-0553 within 120 days of publication of the draft guidance in the Federal Register.”

https://www.fda.gov/news-events/press-announcements/fda-takes-new-steps-regarding-evaluating-public-health-importance-additional-food-allergens

FDA Authorizes First COVID-19 Diagnostic Test Using Breath Samples

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FDA Authorizes First COVID-19 Diagnostic Test Using Breath Samples

April 14, 2022: “Tthe U.S. FDA issued an emergency use authorization for the first COVID-19 diagnostic test that detects chemical compounds in breath samples associated with a SARS-CoV-2 infection.

The test can be performed in environments where the patient specimen is both collected and analyzed, such as doctor’s offices, hospitals and mobile testing sites, using an instrument about the size of a piece of carry-on luggage.

The test is performed by a qualified, trained operator under the supervision of a health care provider licensed or authorized by state law to prescribe tests and can provide results in less than three minutes.

“Today’s authorization is yet another example of the rapid innovation occurring with diagnostic tests for COVID-19,” said Jeff Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health.

“The FDA continues to support the development of novel COVID-19 tests with the goal of advancing technologies that can help address the current pandemic and better position the U.S. for the next public health emergency.” 

The performance of the InspectIR COVID-19 Breathalyzer was validated in a large study of 2,409 individuals, including those with and without symptoms.

In the study, the test was shown to have 91.2% sensitivity (the percent of positive samples the test correctly identified) and 99.3% specificity (the percent of negative samples the test correctly identified).

The study also showed that, in a population with only 4.2% of individuals who are positive for the virus, the test had a negative predictive value of 99.6%, meaning that people who receive a negative test result are likely truly negative in areas of low disease prevalence.

The test performed with similar sensitivity in a follow-up clinical study focused on the omicron variant.

The InspectIR COVID-19 Breathalyzer uses a technique called gas chromatography gas mass-spectrometry (GC-MS) to separate and identify chemical mixtures and rapidly detect five Volatile Organic Compounds (VOCs) associated with SARS-CoV-2 infection in exhaled breath.

When the InspectIR COVID-19 Breathalyzer detects the presence of VOC markers of SARS-CoV-2, a presumptive (unconfirmed) positive test result is returned and should be confirmed with a molecular test.

Negative results should be considered in the context of a patient’s recent exposures, history and the presence of clinical signs and symptoms consistent with COVID-19, as they do not rule out SARS-CoV-2 infection and should not be used as the sole basis for treatment or patient management decisions, including infection control decisions. 

InspectIR expects to be able to produce approximately 100 instruments per week, which can each be used to evaluate approximately 160 samples per day.

At this level of production, testing capacity using the InspectIR COVID-19 Breathalyzer is expected to increase by approximately 64,000 samples per month.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-covid-19-diagnostic-test-using-breath-samples

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