FDA Approves Automated Insulin Delivery and Monitoring System for Use in Younger Pediatric Patients

 

The human pancreas naturally supplies a low, continuous rate of insulin, known as basal or background insulin. In patients with diabetes, the body’s ability to produce or respond to insulin is impaired. Because the pancreas does not make insulin in people with type 1 diabetes, patients must consistently monitor their glucose levels throughout the day and inject insulin with a syringe, pen or pump to avoid becoming hyperglycemic (high glucose levels). In addition, management of type 1 diabetes includes following a healthy eating plan and physical activity. Type 1 diabetes, also known as juvenile diabetes, is typically diagnosed in children and young adults.

 

The FDA has expanded the approval of the MiniMed 670G hybrid closed looped system, a diabetes management device that is intended to automatically monitor glucose (sugar) and provide appropriate basal insulin doses with little or no input from the user, to include individuals aged 7 to 13 with type 1 diabetes. The FDA originally approved this device in September 2017 for use in patients 14 years of age and older with type 1 diabetes.

 

The MiniMed 670G hybrid closed looped system works by measuring glucose levels in the body every five minutes and automatically adjusting insulin delivery by either administering or withholding insulin. The system includes: a sensor that attaches to the body to measure glucose levels under the skin; an insulin pump strapped to the body; and an infusion patch connected to the pump with a catheter that delivers insulin. While the device automatically adjusts insulin levels, users need to manually request insulin doses to counter carbohydrate consumption at mealtime.

 

The FDA evaluated data from a clinical trial of the MiniMed 670G hybrid closed looped system that included 105 individuals aged 7 to 11 years old. Study participants wore the device for approximately 3.5 months and participated in three phases of the study to evaluate both at-home use as well as remote use. The study found no serious adverse events associated with use of the MiniMed 670G and that the device is safe for use in people age 7 to 13 years with type 1 diabetes. Risks associated with use of the system may include hypoglycemia, hyperglycemia, as well as skin irritation or redness around the device’s infusion patch. As part of this approval, the FDA is requiring the product developer to conduct a post-market study to evaluate device performance in real-world settings in children between the ages of 7 and 13. This device is not approved for use in children 6 years of age or younger and in individuals who require less than eight units of insulin per day.

 

The expanded approval of MiniMed 670G hybrid closed looped system was granted to Medtronic.

 

Innovation at FDA

 

The following was taken from a posting on June 6, 2018 by FDA Voice, authored by Scott Gottlieb, M.D., and Anna Abram

 

Scientific advances in biotechnology, such as genome editing and synthetic biology, hold enormous potential to improve human and animal health, animal welfare, and food security. And researchers and companies based in the United States helped pioneer these technologies. To advance this progress, it’s key that the FDA adopt a regulatory approach to these technologies that’s as innovative and nimble as the opportunities that FDA is being tasked with evaluating. FDA is committed to helping ensure the safety of biotechnology products, while also facilitating innovation by applying a risk-based regulatory approach that provides developers with regulatory clarity and predictability and maintains public confidence in the regulatory system.

 

FDA is taking some new steps to approve products enabled by new techniques of biotechnology that have the potential to significantly enhance public health. For instance, new methods can be used to alter animals to minimize or prevent their ability to spread human disease. Genome editing in animals and plants also can be used to produce human drugs, devices, or biologics, including tissues or organs for xenotransplantation. Scientists are also exploring editing the genomes of animals with the goal of improving the health and welfare of food producing animals and public health, for example by reducing their susceptibility to diseases like novel influenzas and resistance to zoonotic or foreign animal diseases. Similar and equally beneficial applications of genome editing are currently being explored in food crops. These include the ability to develop disease-resistant plants and plants with increased resistance to environmental stress. Such advances can have many advantages to consumers, including better yields, more product variety, and healthier nutrient profiles.

 

FDA believes that it is uniquely committed and positioned – with the expertise, experience, credibility and trusted scientific framework – to advance innovation and support the development of products with immense potential for public benefit, since the breadth of FDA’s statutory authorities and regulatory framework allows it to comprehensively review the potential impacts of products on both human and animal health. For example, for genetically engineered animals, FDA evaluates not only the safety of food or drug products derived from that animal, but also the effect of the genetic alteration on the health of the animal. FDA has decades of experience successfully evaluating products of complex technologies, such as recombinant DNA-derived plant foods, medicines made with nanotechnology, and cellular and gene therapy products.

 

Moreover, because of the wide spectrum of products that FDA regulates, and the in-depth scientific and policy engagement that the agency has with innovators and counterpart regulatory agencies around the world, FDA can help facilitate the progression of research and development. For example, FDA is focused on the timely transition of technologies from animal research models to products intended for use in humans. As knowledge of genome editing applications increases over different product areas, FDA expect to build on those even greater synergies and increase its understanding to help with assessments of risks to human and animal health.

 

FDA will continue to apply a risk-based framework grounded in sound science to evaluate products of plant and animal biotechnology, and our framework will continue to evolve as science advances and experience with these technologies grows. FDA is looking forward to working with stakeholders to help understand current scientific information and describe challenges and gaps in regulatory science that are important for regulatory decision-making. FDA is also going to take new steps to help developers understand their responsibility to ensure product safety and we’ll identify ways to help reduce unnecessary regulatory burden and undue barriers to bring potential beneficial products to commercialization while ensuring their safety.

 

Protecting and promoting public health is FDA’s mission at the same time FDA wants to support innovation and sustaining public confidence. To help advance these goals, in early May, FDA formed a new Biotech Working Group. This Working Group is comprised of representatives from multiple FDA centers and offices. In the coming months, FDA will release an Action Plan that lays out the steps it intends to take to ensure that FDA will have a flexible regulatory framework for evaluating the safety of products that also supports plant and animal biotechnology innovation.

 

Our actions will focus on three key areas:

 

First, advancing and protecting public and animal health by promoting innovation through an efficient and predictable science- and risk-based regulatory framework; second, strengthening public outreach and communication through strong, effective and transparent engagement with stakeholders; and third, increasing engagement with domestic and international partners through coordinated and collaborative actions to support regulatory alignment and efficiency.

 

FDA is taking concrete and proactive steps to help ensure the safety of plant and animal biotechnology products, while promoting innovation and enhancing public and market confidence in FDA’s regulation of these products at home and abroad. FDA recognizes the tremendous opportunities offered by this new technology and is committed to developing a framework that allows these innovations to safely advance and fulfill the potential envisioned by those who are pioneering these approaches, as well as inspire public confidence in these methods. Clearly, the advance of these technologies holds significant public health promise and unlocking their full potential and competitiveness depends on the trust FDA builds now and in the years to come.

 

FDA Approves First Artificial Iris

 

Patients with iris defects may experience severe vision problems, as well as dissatisfaction with the appearance of their eye. Congenital aniridia is a rare genetic disorder in which the iris is completely or partially absent. This disorder affects approximately 1 in 50,000 to 100,000 people in the U.S. The iris controls the amount of light entering the eye, and those with aniridia have sensitivity to light and other severe vision problems.

 

The FDA has approved the CustomFlex Artificial Iris, the first stand-alone prosthetic iris in the United States. The CustomFlex Artificial Iris is a surgically implanted device to treat adults and children with aniridia or other damage to the eye. According to the FDA, this first artificial iris provides a novel method to treat iris defects that reduces sensitivity to bright light and glare, and also improves the cosmetic appearance of the eye. In addition to congenital aniridia, the CustomFlex Artificial Iris is indicated to treat iris defects due to other reasons or conditions, such as albinism, traumatic injury or surgical removal due to melanoma

 

The CustomFlex Artificial Iris is made of thin, foldable medical-grade silicone and is custom-sized and colored for each individual patient. A surgeon makes a small incision, inserts the device under the incision, unfolds it and smooths out the edges using surgical instruments. The prosthetic iris is held in place by the anatomical structures of the eye or, if needed, by sutures.

 

The safety and effectiveness of the CustomFlex Artificial Iris was demonstrated primarily in a non-randomized clinical trial of 389 adult and pediatric patients with aniridia or other iris defects. The study measured patients’ self-reported decrease in severe sensitivity to light and glare post-procedure, health-related quality of life, and satisfaction with the cosmetic improvement or appearance of the prosthesis. More than 70% of patients reported significant decreases in light sensitivity and glare as well as an improvement in health-related quality of life following the procedure. In addition, 94% of patients were satisfied with the artificial iris’ appearance.

 

The study found low rates of adverse events associated with the device or the surgical procedure. In the study, complications associated with the use of the CustomFlex Artificial Iris device included: device movement or dislocation, strands of device fiber in the eye, increased intraocular pressure, inflammation of the iris (iritis), adhesion of the iris to the cornea or lens (synechiae) and the need for secondary surgery to reposition, remove or replace the device. Complications associated with the surgical procedure included: increased intraocular pressure, blood leakage in the eye, swelling of the center of the retina (cystoid macular edema), secondary surgery, corneal swelling, iritis, and retinal detachment.

 

The CustomFlex Artificial Iris is contraindicated, or should not be used, in eyes with any of the following conditions: uncontrolled or severe chronic inflammation (uveitis), abnormally small eye size (microphthalmus), untreated retinal detachment, untreated chronic glaucoma, cataract caused by rubella virus, abnormal blood vessels on the iris (rubeosis), certain kinds of damaged blood vessels in the retina, and intraocular infections. It is also contraindicated for patients who are pregnant.

 

The CustomFlex Artificial Iris was approved through a premarket approval application (PMA), which is the most stringent type of device marketing application and generally required for high-risk devices. A PMA approval is primarily based on a determination by the FDA that the PMA contains sufficient valid scientific evidence that provides reasonable assurance that the device is safe and effective for its intended uses. CustomFlex Artificial Iris was granted Breakthrough Device designation, meaning the FDA provided intensive interaction and guidance to the company on efficient device development, to expedite evidence generation and the agency’s review of the device. To qualify for such designation, a device must provide for more effective treatment or diagnosis of a life-threatening or irreversibly debilitating disease or condition, and meet one of the following criteria: the device must represent a breakthrough technology; there must be no approved or cleared alternatives; the device must offer significant advantages over existing approved or cleared alternatives; or the availability of the device is in the best interest of patients.

 

The FDA granted approval of the CustomFlex Artificial Iris to Clinical Research Consultants, Inc.

 

FDA Approves a New Treatment for PKU

 

Phenylketonuria (PKU) is rare and serious genetic disease that affects about 1 in 10,000 to 15,000 people in the United States. Patients with PKU are born with an inability to break down phenylalanine (Phe), an amino acid present in protein-containing foods and high-intensity sweeteners used in a variety of foods and beverages. If untreated, PKU can cause chronic intellectual, neurodevelopmental and psychiatric disabilities. Lifelong restriction of phenylalanine intake through the diet is needed to prevent buildup of Phe in the body, which can cause long-term damage to the central nervous system.

 

The FDA has approved Palynziq (pegvaliase-pqpz) for adults with PKU. Palynziq is a novel enzyme therapy for adult PKU patients who have uncontrolled blood Phe concentrations on current treatment. The safety and efficacy of Palynziq were studied in two clinical trials in adult patients with PKU with blood phenylalanine concentrations greater than 600 ?mol/L on existing management. Most PKU patients in the Palynziq trials were on an unrestricted diet prior to and during the trials. The first trial was a randomized, open-label trial in patients treated with increasing doses of Palynziq administered as a subcutaneous injection up to a target dose of either 20 mg once daily or 40 mg once daily. The second trial was an 8-week, placebo-controlled, randomized withdrawal trial in patients who were previously treated with Palynziq. Patients treated with Palynziq achieved statistically significant reductions in blood phenylalanine concentrations from their pre-treatment baseline blood Phe concentrations.

 

The most common adverse events reported in the Palynziq trials included injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough and diarrhea. Hypersensitivity reactions occurred in most patients, likely due to formation of antibodies to the product. The most serious adverse reaction in the Palynziq trials was anaphylaxis, which occurred most frequently during upward titration of the dose within the first year of treatment. Because of this serious risk, the labeling for Palynziq includes a Boxed Warning and the product is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Palynziq REMS Program. Notable requirements of the Palynziq REMS Program include the following:

 

1. Prescribers must be certified by enrolling in the REMS program and completing training

2. Prescribers must prescribe auto-injectable epinephrine with Palynziq

3. Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive Palynziq

4. Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with Palynziq

5. Patients must have auto-injectable epinephrine available at all times while taking Palynziq

 

The FDA granted approval of Palynziq to BioMarin Pharmaceutical Inc.

 

FDA Expands Approval of Gilenya to Treat Multiple Sclerosis in Pediatric Patients

 

Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. It is among the most common causes of neurological disability in young adults and occurs more frequently in women than men. For most people with MS, episodes of worsening function and appearance of new symptoms, called relapses or flare-ups, are initially followed by recovery periods (remissions). Over time, recovery may be incomplete, leading to progressive decline in function and increased disability. Most people with MS experience their first symptoms, like vision problems or muscle weakness, between the ages of 20 to 40. Two to five percent of people with MS have symptom onset before age 18 and estimates suggest that 8,000 to 10,000 children and adolescents in the U.S. have MS.

 

The FDA has approved Gilenya (fingolimod) to treat relapsing MS in children and adolescents age 10 years and older. This is the first FDA approval of a drug to treat MS in pediatric patients. Gilenya was first approved by the FDA in 2010 to treat adults with relapsing MS.

 

The clinical trial evaluating the effectiveness of Gilenya in treating pediatric patients with MS included 214 evaluated patients aged 10 to 17 and compared Gilenya to another MS drug, interferon beta-1a. In the study, 86% of patients receiving Gilenya remained relapse-free after 24 months of treatment, compared to 46% of those receiving interferon beta-1a. The side effects of Gilenya in pediatric trial participants were similar to those seen in adults. The most common side effects were headache, liver enzyme elevation, diarrhea, cough, flu, sinusitis, back pain, abdominal pain and pain in extremities.

 

Gilenya must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Serious risks include slowing of the heart rate, especially after the first dose. Gilenya may increase the risk of serious infections. Patients should be monitored for infection during treatment and for two months after discontinuation of treatment. A rare brain infection that usually leads to death or severe disability, called progressive multifocal leukoencephalopathy (PML) has been reported in patients being treated with Gilenya. PML cases usually occur in patients with weakened immune systems. Gilenya can cause vision problems. Gilenya may increase the risk for swelling and narrowing of the blood vessels in the brain (posterior reversible encephalopathy syndrome). Other serious risks include respiratory problems, liver injury, increased blood pressure and skin cancer. Gilenya can cause harm to a developing fetus; women of child-bearing age should be advised of the potential risk to the fetus and to use effective contraception.

 

The FDA granted Priority Review and Breakthrough Therapy designation to Novartis for this indication.

 

FDA Approves New Uses For Two Drugs Administered Together For The Treatment of BRAF-Positive Anaplastic Thyroid Cancer

 

Clearly, pharmaceutical companies must be viewed in part as chemical companies with multipurposed products.

 

Thyroid cancer is a disease in which cancer cells form in the tissues of the thyroid gland. Anaplastic thyroid cancer is a rare, aggressive type of thyroid cancer. The National Institutes of Health estimates there will be 53,990 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018. Anaplastic thyroid cancer accounts for about 1-2% of all thyroid cancers.

 

The FDA has approved Tafinlar (dabrafenib) and Mekinist (trametinib), administered together, for the treatment of anaplastic thyroid cancer (ATC) that cannot be removed by surgery or has spread to other parts of the body (metastatic), and has a type of abnormal gene, BRAF V600E (BRAF V600E mutation-positive). This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat. According to the FDA, this approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients.

 

Both Tafinlar and Mekinist are also approved for use, alone or in combination, to treat BRAF V600 mutation-positive metastatic melanoma. Additionally, Tafinlar and Mekinist are approved for use, in combination, to treat BRAF V600E mutation-positive, metastatic non-small cell lung cancer. The efficacy of Tafinlar and Mekinist in treating ATC was shown in an open-label clinical trial of patients with rare cancers with the BRAF V600E mutation. Data from trials in BRAF V600E mutation-positive, metastatic melanoma or lung cancer and results in other BRAF V600E mutation-positive rare cancers provided confidence in the results seen in patients with ATC. The trial measured the percent of patients with a complete or partial reduction in tumor size (overall response rate). Of 23 evaluable patients, 57% experienced a partial response and 4% experienced a complete response; in nine (64%) of the 14 patients with responses, there were no significant tumor growths for six months or longer.

 

The side effects of Tafinlar and Mekinist in patients with ATC are consistent with those seen in other cancers when the two drugs are used together. Common side effects include fever (pyrexia), rash, chills, headache, joint pain (arthralgia), cough, fatigue, nausea, vomiting, diarrhea, myalgia (muscle pain), dry skin, decreased appetite, edema, hemorrhage, high blood pressure (hypertension) and difficulty breathing (dyspnea). Severe side effects of Tafinlar include the development of new cancers, growth of tumors in patients with BRAF wild-type tumors, serious bleeding problems, heart problems, severe eye problems, fever that may be severe, serious skin reactions, high blood sugar or worsening diabetes, and serious anemia. Severe side effects of Mekinist include the development of new cancers; serious bleeding problems; inflammation of intestines and perforation of the intestines; blood clots in the arms, legs or lungs; heart problems; severe eye problems; lung or breathing problems; fever that may be severe; serious skin reactions; and high blood sugar or worsening diabetes. Both Tafinlar and Mekinist can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

 

The FDA granted Priority Review and Breakthrough Therapy designation for this indication. Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases, was also granted for this indication.

 

The FDA granted this approval to Novartis Pharmaceuticals Corporation.

Digital Health Guidance From FDA

 

The FDA has recognized that it can help encourage digital health innovation by making its policies and processes more efficient and modernizing its regulatory tools. As part of the FDA’s Digital Health Innovation Action Plan issued in 2017, the agency committed to developing a new regulatory framework for reviewing software as a medical device and issuing a suite of guidances to provide transparency and clarity to product developers about the agency’s regulatory process.

 

On April 26, 2018, the FDA published an important progress update on the software precertification pilot program, the FDA’s proposed voluntary pathway for pre-certifying companies to enable a more streamlined review of their software as a medical device. The FDA is releasing a working model for its vision of the pilot, which outlines the most critical components of the pilot, like the precertification of companies, the premarket review process and postmarket surveillance. The agency is asking for public comment on the working model in order to obtain the critical feedback necessary to continue developing the program.

 

In addition to the pilot progress update, the FDA is releasing a draft guidance that addresses an important provision of the 21st Century Cures Act. The draft guidance offers additional clarity about where the FDA sees its role in digital health, and importantly, where the agency will not be involved. Since medical products may contain several functions, some of which are subject to the FDA’s regulatory oversight as medical devices, while others, in isolation, are not, the draft guidance, entitled, “Multiple Function Device Products: Policy and Considerations,“ explains the FDA’s proposed regulatory approach and policy for all multiple function device products. This guidance clarifies when and how the agency intends to look at the impact of non-regulated functions on the safety and effectiveness of device functions that are subject to FDA review. For example, consider a hospital monitor that detects and transmits vital patient signal information like heart rhythms into a patient’s electronic health record. In this case, the FDA would only review the heart monitor function, unless the transmission function impacts the safety or effectiveness of the monitor function or adversely affects the monitor capability. In that case, the developer only needs to show that they’ve addressed any potential for an adverse impact between the two different functions – the one the FDA oversees, and the one it does not. This example and others provided in the guidance demonstrate that by providing greater transparency and clarity on how the agency intends to approach these multiple function products, the FDA hopes to further encourage innovation in this important field.

 

Next Generation Sequencing-Based Tests (NGS)

 

Next generation sequencing (NGS) works by looking at a person’s DNA to detect genomic variations that may determine whether a person has or is at risk of developing a genetic disease and, in certain cases, may help to inform treatment decisions. Unlike traditional diagnostics that typically detect chemical changes associated with a single disease or condition, NGS can look at millions of DNA changes in a single test to help determine the cause of a person’s disease or condition. Availability of these types of tests plays an important role in the advancement of the field of precision medicine.

 

The FDA has finalized two guidances to drive the efficient development of NGS technology. The guidances provide recommendations for designing, developing, and validating tests that use NGS, and will play an important role in the continued advancement of individualized, genetic-based medicine. The first guidance, “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics,“ describes an approach where test developers may rely on clinical evidence from FDA-recognized public databases to support clinical claims for their tests and help provide assurance of the accurate clinical evaluation of genomic test results. The guidance describes how product developers can use these databases to support the clinical validation of NGS tests that they are developing. These public databases may include resources like ClinGen, which is maintained by the National Institutes of Health (NIH). Using FDA-recognized databases will provide test developers with an efficient path for marketing clearance or approval of a new test.

 

The second guidance, “Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases,“ provides recommendations for designing, developing, and validating NGS-based tests used to diagnose individuals with suspected genetic diseases. It describes what the FDA would look for in premarket submissions to determine a test’s analytical validity, including how well the test detects the presence or absence of a particular genomic change. According to FDA, since information about genetic variants is generally stored in a manner that is not publicly accessible, the release of the FDA’s final guidance should help to provide an even more efficient path to market by encouraging data sharing, as well as the accumulation in public databases of evidence supporting the clinical validity of genomic tests.

 

Issuance of these final guidances is based on extensive feedback from the public and stakeholders who are developing NGS-based technologies, and the guidances serve as a continuation of the FDA’s work creating regulatory efficiencies in the development and review of NGS tests. In 2017, the FDA took several actions to streamline the development and review of a variety of genetic-based tests – authorizing a third-party option for conducting reviews NGS tumor profiling tests and making clearance recommendations to FDA, as well as outlining standardized development criteria for carrier screening tests to allow for their marketing without prior agency review. FDA also established such criteria for genetic health risk tests and proposed to allow their marketing after a one-time agency review. As NGS technologies continue to evolve, the FDA remains dedicated to adapting our regulatory review capabilities and leveraging our authorities to the fullest extent in order to make innovative and accurate testing technologies available to patients as efficiently as possible.

 

The Voice of the Patient

 

The following is based on a press release from Dr. Scott Gottlieb, FDA Commissioner.

 

Benefit-risk assessment is at the heart of what FDA does to ensure that Americans have access to medical products that are safe, effective and meet their needs. But FDA is also deeply aware that serious chronic illnesses aren’t monolithic. Patient perception of the benefits and risks of different treatment options can vary based on the stage of the disease, the age of onset, alternative therapies available to treat the disease (if any) and whether a novel therapy improves a patient’s ability to function normally, slows the rate of disease progression or impacts other aspects of a patient’s quality of life.

 

A 45-year-old father of two who is diagnosed with aggressive prostate cancer may have very different goals than an 80-year-old man diagnosed with the same disease. To address these realities, FDA will continue to work in close partnership with patients to incorporate their experience into FDA’s benefit-risk assessments. First-hand knowledge of living with a serious illness – communicated in science-based terms that patients value and understand – is integral to facilitating the successful development of safe and effective products that can deliver meaningful benefits in each disease, or disease state.

 

Today there are many more tools to measure these patient benefits – including wearable devices, medical apps and even machine-learning programs. These tools can bring a better understanding of how patients experience their illness, including how it affects their day-to-day feeling or functioning and how a given treatment may impact the course of that illness. Tools for capturing the patient experience may be quantitative or qualitative, but they are transforming nearly every aspect of medical product development. Patients can teach all of us about the benefits that matter most to them and the risks that they are most concerned about. Patients are, rightly so, becoming the driving force of the medical research enterprise.

 

Structured and Transparent Benefit-Risk Assessments

 

FDA’s ongoing work to enhance their benefit-risk assessment and communication in the human drug review process began in 2013 as part of the Prescription Drug User Fee Act (PDUFA) V. The priority to enhance benefit-risk assessment has continued with new efforts begun in 2017, as part of PDUFA VI and further expanded under 21st Century Cures. Implementing these key pieces of legislation is improving clarity and consistency in communicating the reasoning behind the FDA’s drug regulatory decisions. It’s also helping integrate the patient’s perspective into drug development and regulatory decision-making.

FDA has issued an update to their implementation plan, titled “Benefit-Risk Assessment in Drug Regulatory Decision-Making.“ This document provides an overview of the steps the FDA has taken since 2013 to enhance benefit-risk assessment in human drug review, which included implementation of the FDA’s Benefit-Risk Framework into our drug regulatory review processes and documentation. This document also provides a roadmap for enhancing the Benefit-Risk Framework, working toward a goal of providing guidance by June 2020 that articulates the FDA’s decision-making context and framework for benefit-risk assessment. This forthcoming guidance will also outline how patient experience data and related information can be used to inform benefit-risk assessment.

 

In order for a drug or biologic product to be approved, the FDA conducts a comprehensive analysis of all available data to determine if the drug is effective and that its expected benefits outweigh its potential risks. This assessment is fundamental to our regulatory process. The goal of the FDA’s Benefit-Risk Framework is to improve the clarity and consistency in communicating the reasoning behind drug regulatory decisions, and ensure that the FDA reviewers’ detailed assessments can be readily understood in the broader context of patient care and public health. The structured framework also helps drug sponsors and other external stakeholders better understand the factors that contribute to the FDA’s decision-making process when evaluating new drugs, including drugs under development. A standard Benefit-Risk Framework will also better ensure that the patient community can continue to engage effectively with the agency, and help FDA improve how it evaluates benefits and risks from the patient’s perspective. The Benefit-Risk Framework has been applied in FDA reviews of novel drugs and biologics over the past few years, and FDA is now using it more broadly.

 

Incorporating Patient Voice into Benefit-Risk Assessments

 

The Benefit-Risk Framework recognizes that when FDA reviewers conduct a benefit-risk assessment, they consider not only the submitted evidence related to the benefit and risk and effects reported in clinical studies, but also, importantly, the “clinical context“ of the disease. This context encompasses two major considerations: 1) an analysis of the disease condition, including the severity of the condition; and 2) the degree of unmet medical need. As part of this work, the FDA recognizes a need to learn about the clinical context more comprehensively and directly from the perspective of the patients who live with the disease and their caregivers. After conducting patient-focused drug development meetings in over 20 disease areas, the FDA has concluded that patient input can: 1) inform the clinical context and provide insights to frame the assessment of benefits and risk; and 2) provide a direct source of evidence regarding the benefits and risks, if methodologically-sound data collection tools could be developed and used within clinical studies of an investigational therapy. The FDA is now developing guidance to enable more widespread development of such patient experience data to inform regulatory decision-making, as part of our implementation of PDUFA VI and 21st Century Cures. Other efforts to more systematically incorporate patients’ experiences and perspectives include:

 

1. Hosting patient-focused drug development public meetings to advance a more systematic way of gathering patients’ perspectives on their conditions and available treatments;

2. Encouraging patient stakeholders and others to conduct their own externally-led, patient-focused drug development meetings;

3. Providing patients, caregivers, advocates and others with more channels to provide meaningful input into drug development and regulatory decision-making, and to more easily access information provided by others; and

4. Launching pilot programs – and advancing policies, in collaboration with the medical community – that help foster the design of clinical trials that place less burden on patients.

 

The benefit-risk implementation plan issued today is part of the FDA’s ongoing commitment to advancing its mission of protecting and promoting public health. It marks another important step forward in increasing transparency of FDA decisions as well as streamlining the process by which FDA obtains input from the patient and stakeholder communities. In the battle against disease, engaged and informed patients are our best allies and one of the greatest resources.

FDA Expands Approval of Blincyto for Treatment of B-Cell Precursor ALL in Patients Who Have a Certain Risk Factor for Relapse

 

B-cell precursor ALL is a rapidly progressing type of cancer in which the bone marrow makes too many B-cell lymphocytes, an immature type of white blood cell. The National Cancer Institute estimates that approximately 5,960 people in the United States will be diagnosed with ALL this year and approximately 1,470 will die from the disease.

 

The FDA has granted accelerated approval to Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse. According to FDA, this is the first FDA-approved treatment for patients with MRD-positive ALL, and because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer.

 

Blincyto works by attaching to CD19 protein on the leukemia cells and CD3 protein found on certain immune system cells. Bringing the immune cell close to the leukemia cell allows the immune cells to attack the leukemia cells better. The FDA first approved Blincyto under accelerated approval in December 2014 for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive B-cell precursor ALL. Full approval for this indication was granted in July 2017, and at that time, the indication was also expanded to include patients with Philadelphia chromosome-positive ALL.

 

The efficacy of Blincyto in MRD-positive ALL was shown in a single-arm clinical trial that included 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of Blincyto treatment, in addition to the length of time that the patients remained alive and in remission (hematological relapse-free survival). Overall, undetectable MRD was achieved by 70 patients. Over half of the patients remained alive and in remission for at least 22.3 months.

 

The side effects of Blincyto when used to treat MRD-positive B-cell precursor ALL are consistent with those seen in other uses of the drug. Common side effects include infections (bacterial and pathogen unspecified), fever (pyrexia), headache, infusion related reactions, low levels of certain blood cells (neutropenia, anemia), febrile neutropenia (neutropenia and fever) and low levels of platelets in the blood (thrombocytopenia). Blincyto carries a boxed warning alerting patients and health care professionals that some clinical trial participants had problems with low blood pressure and difficulty breathing (cytokine release syndrome) at the start of the first treatment, experienced a short period of difficulty with thinking (encephalopathy) or other side effects in the nervous system. Serious risks of Blincyto include infections, effects on the ability to drive and use machines, inflammation in the pancreas (pancreatitis), and preparation and administration errors – instructions for preparation and administration should closely be followed. There is a risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative; therefore, the drug prepared with preservative free saline should be used for patients weighing less than 22 kilograms.

 

This new indication for Blincyto was approved under the accelerated approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study in randomized controlled trials is required to verify that achieving undetectable MRD with Blincyto improves survival or disease-free survival in patients with ALL.

 

The FDA granted this application Priority Review and it received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

 

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