Health Canada and FDA eSTAR Pilot
Introduction The Health Canada and U.S. Food and Drug Administration’s joint eSTAR pilot is now full, having reached its total of 9 participants. The joint pilot will test the use of a single eSTAR submitted to both the FDA and Health Canada. About eSTAR eSTAR is an interactive PDF form that guides applicants through the process of preparing a comprehensive medical device submission. The template contains the following features: automation (for example, form construction and autofill) content and structure that is: complementary to Center for Devices and Radiological Health (CDRH) internal review templates harmonized with the Non-In Vitro Diagnostic Device Market Authorization Table of Contentsdocument used by the International Medical Devices Regulators Forum (IMDRF) integration of multiple resources (for example, guidance’s and databases) guided construction for each submission section automatic verification eSTAR is free and available for voluntary use for all medical device submissions for 510(k)s and De Novo’s sent to CDRH. Important Note: The eSTAR is not currently for use with combination products. For more information on the use of eSTAR for premarket submissions, please visit the webpage Voluntary eSTAR Program. Joint pilot between Health Canada and the FDA The FDA and Health Canada are conducting a joint pilot. The pilot will test the use of a single eSTAR submitted to both the FDA and Health Canada. The feasibility of using eSTAR will be determined by the outcome of a pilot with 9 participants. Selected participants will use the non-In Vitro Diagnostic eSTAR, which follows the structure of the IMDRF Non-In Vitro Diagnostic Device Market Authorization Table of Contents (nIVD MA ToC). Health Canada is also launching our own pilot. For information on Health Canada only pilot, please refer to the Health Canada eSTAR pilot program page. Eligibility factors for the eSTAR pilot To be eligible to participate in this pilot: You must be ready to submit an eSTAR for the same medical device within 6 months of acceptance to both Health Canada and the FDA for: a new or significant change amendment Class III or IV submission to Health Canada and a 510(k), De Novo or pre-market approval (PMA) original, 180-day, real-time or panel track supplement to the FDA The medical device must not be an in-vitro diagnostic device, a combination product, CBER-led or an FDA dual 510(k)/CLIA waiver application. You must complete the eSTAR (a message at the top of the eSTAR will indicate this). For the joint eSTAR pilot, Health Canada will not be accepting regulatory enrolment process (REP) submissions. At this time, ONLY English eSTAR submissions are accepted. French eSTAR submissions will follow at a later time. How can you request participation in the eSTAR pilot To request participation in the pilot, send an email to both meddevices-instrumentsmed@hc-sc.gc.ca and eSubPilot@fda.hhs.gov with the subject line “Request for participation in eSTAR Pilot”. Include the following information in your email: a statement asking to take part in the pilot applicant name contact name and title device trade name(s) the FDA primary product code, Global Medical Device Nomenclature (GMDN) and Preferred Name Code (PNC) of your device a statement that the same medical device using the eSTAR will be submitted within 6 months of acceptance to both Health Canada and the FDA for Health Canada: specify if it is a new or significant change amendment for a Class III or IV submission for FDA: specify if it is a 510(k), De Novo or PMA submission (specify if the PMA submission is original, 180-day, real-time or a panel track supplement) The FDA and Health Canada intend to respond to your request for participation in the eSTAR pilot within 3 business days. Preparing a submission using eSTAR If you are accepted into the eSTAR pilot, the FDA will provide you with an information package that includes: the eSTAR to use in preparing your submission, with both Health Canada and FDA content enabled information regarding the submission process for each jurisdiction, such as: internet portal mail service Please note the following constraints regarding the size and count of attachments added to eSTAR. File size Try to keep the eSTAR under 1 GB in size (may take longer to process the submission if it’s larger than this). Make sure that attached images and videos are compressed in a Microsoft Windows-compatible format viewable in native Windows OS applications (for example, JPEG, MP4). Provide ultra-high-definition videos only if high resolution is necessary to support the review of the device. Take care when determining the proper resolution to display features of interest in images and videos. File count Combine attachments of similar content (for example, software requirements specifications) when possible so that only 1 attachment needs to be provided to each attachment type question in the eSTAR. Choose “Tools” then “Combine Files” in Adobe Acrobat Pro to combine attachments. Use bookmarks or a table of contents for combined documents, to make it easier to review. Submitting responses to requests for additional information For FDA Revise your original eSTAR and indicate in the “Application/Submission Type” section of the eSTAR that the Application Sub-Type is a response to a request for additional information. After you indicate the intent to provide a response to a request for additional information from the FDA, an additional section will appear near the end of the eSTAR. In this section, you can provide responses to requests for additional information. For Health Canada Responses to additional information requests are not within the scope of this pilot and should be submitted as per the instructions on the request. User fees for eSTAR pilot eSTAR submissions are subject to user fees. FDA user fees: MDUFA user fees Health Canada user fees: Fees for the examination of an application for a medical device licence Review timeline for eSTAR The review timelines will remain the same as they are for non-pilot submissions. Sources: https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-devices/application-information/guidance-documents/notice-industry-health-canada-fda-estar-pilot.html
Why Innovations Fail to Reach the Market: The Tragic Reality of Academic Research
Introduction Innovation is the lifeblood of progress and growth in any field, and academia is no exception. Universities and research institutions are constantly pushing the boundaries of what is possible and developing new technologies, theories, and methods. However, despite the abundance of innovation in academia, many of these ideas never see the light of day outside the lab. In this blog post, we will explore the reasons why this happens, and discuss the data that highlights the extent of this problem. High risk and expense of creating an marketable product: Clear understanding of clinical need, market potential, and technical risks is crucial for scientific and technical innovation in the medical device industry. This involves comprehensive technology and science management, clinical trials, thorough testing, and regulatory oversight. Defining technical feasibility without prior knowledge of functionality or early test data can result in high costs and long time to market, so the medical industry should aim to minimize these risks and reduce costs and time to market by addressing feasibility concerns early in development, ideally before significant investment. Investors and Funding One of the main reasons why innovations die in academia is a lack of funding and resources. Many universities and research institutions are underfunded, and researchers often have to rely on grants and other forms of external funding to support their work. However, these grants are often difficult to come by, and researchers may not have the resources they need to develop their ideas to the point where they can be commercialized. Additionally finding an investor might be challenging, investors may be cautious about advancements in technology. Medical professionals may have already invested in competing technologies. Investors may be unaware of the disruptive nature and safety, low cost, and non-invasive benefits of new technology. Some investors may also have reservations about the process of bringing medical technology to market. Gap between Academic Researchers and Businesses Many new products fail due to a lack of understanding of real user needs. Many prototypes never make it to market because they fail to consider clinical and patient requirements. It’s very important to work towards changing the culture of commercializing medical devices/technology among academic researchers and improving communication between students, clinicians, product engineers, and scientists as a solution to this issue. Another reason why innovations die in academia is a lack of understanding of the market. Many researchers are focused on advancing their field of study, and may not have the expertise or experience to understand how their ideas could be applied in the real world. This can make it difficult to find partners or investors who can help turn their ideas into viable products or services. The data also shows that the commercialization rate of academic research is quite low. According to a study by the National Science Board, only a small fraction of the research produced by universities and other research institutions is ever commercialized. The study found that only about 10% of all research conducted in the United States is eventually commercialized. Another data from a study by Elsevier, which analyzed the patent data of more than 400 universities and research institutions worldwide, found that only about 2% of all patents filed by these institutions are eventually commercialized. Knowledge of Regulatory affairs and FDA Obtaining FDA approval for a new medical device can be a lengthy and costly process. Many medical device companies believe the FDA needs to expedite the process to prevent foreign competitors from getting their innovations to market first. This can result in U.S. patients seeking cutting-edge treatments abroad that are not offered domestically. However, the FDA’s approval process is also criticized for various shortcomings that could put patients at risk from using defective devices. Under the Medical Device Amendments of 1976, the FDA classifies all medical devices as Class I, II, or III, with Class III representing the most potentially harmful devices such as implantables. A Pre-Market Approval (PMA) application for an innovative device requires a clinical trial or similar study. A PMA notification for a new device that is similar to one already on the market does not require detailed scientific information on effectiveness and safety. Considering the academics space, researchers and academicians lack the extensive knowledge of regulatory affairs thus get stuck in carving the regulatory approvals pathways for their innovative product. Clinical Trials The FDA mandates clinical trials before a new product can enter the market. These trials, also known as clinical studies, assess potential treatments such as drugs, medical devices, or biologics (e.g. vaccines, gene therapy, blood products) on human volunteers to determine their safety and efficacy. Before human testing, the treatments undergo toxicity testing on laboratory animals. Clinical trials follow a protocol to answer specific research questions and can compare the new product to existing treatments or no treatment. Healthcare professionals closely monitor and evaluate trial participants in medical facilities or research centers. Clinical trials can cost approximately $12 million and require rigorous quality and effectiveness evaluations. To gain approval, innovators must demonstrate the clinical significance of their product through published research and trial results. Introducing a new medical device or drug is a complex and expensive process that requires thorough testing and clinical trials before receiving FDA approval. To prepare for commercialization, products must undergo stability tests, design and process validation, safety assessments, and regulatory clearance. By familiarizing themselves with FDA policies, procedures, and requirements through Pre-Sub FDA submission, scientists and innovators can streamline the approval process. Conlis Global Inc. aims to simplify this process by leveraging their extensive team’s expertise in regulatory affairs, clinical trials, and translational medicine, among others. Sources: https://koreascience.kr/article/JAKO201717447648339.pdf https://www.asianscientist.com/2011/05/features/7-reasons-academic-scientists-fail-commercialization/ https://link.springer.com/chapter/10.1007/978-3-030-78893-3_8
LiberDi receives FDA 510(k) for its digital dialysis clinic
Introduction January 2023, Israeli company liberDi received FDA 510(k) clearance for its Intelligent Dialysis Assistant (IDA). The company’s Intelligent Dialysis Assistant allows patients to undergo dialysis outside a clinic while being remotely supervised by a healthcare professional. Device comes with an IDA cartridge with a medical supervision portal, and IDA smartphone app. IDA gives a flexibility to patient to use the device at home. This allows patients to undergo peritoneal dialysis outside of a clinic while being remotely monitored by a medical professional via the device’s telemedicine capabilities. Peritoneal dialysis is one of the two methods of treating kidney failure and is typically performed at a dialysis center or in a hospital by trained healthcare professionals. The IDA device permits automatic single or multiple exchanges of dialysate solution for adults with renal failure. It comes with a single-use cartridge that interfaces with the Twin Bag Set (should that be the patient’s dialysis prescription) and the patient’s peritoneal catheter. The medical supervision portal is a physician-facing platform for healthcare professionals to oversee the patient’s dialysis treatment, and the IDA smartphone app allows patients to review their healthcare professional’s treatment recommendations. This system provides a cutting edge toolbox scaling up high-quality services to Health Care Professionals: existing and new dialysis organizations, as well as independent clinics and hospitals. Once registered on liberDi’s Digital Dialysis Clinic, Health Care Professionals can immediately provide personalized service through a secure cloud-based Digital Illness Management Portal Device Name Digital Dialysis Clinic – Intelligent Dialysis Assistant (IDA) & IDA Cartridge with Medical Supervision Portal and IDA Smartphone App Device Details: The liberDi portable PD system (PPDS™) is a portable automatic device for peritoneal dialysis (PD) exchange. It uses a small rechargeable battery-operated pump for injection/ejection mechanism to drain and fill the dialysate at a controlled rate, with automatic disinfection of the connectors which increases the safety of PD. The PPDS™ also enables monitoring the effluent stream speed, ultrafiltration and transmits the data to a PD centre to allow remote monitoring and detection of effluent characteristic changes that may indicate catheter malfunction or peritonitis. Indications for Use Intelligent Dialysis Assistant (IDA) is intended for automatic single exchange of dialysate solution exchanges in the treatment of adult renal failure patients undergoing peritoneal dialysis. All therapies using the Intelligent Dialysis Assistant (IDA) must be prescribed and performed under the responsibility of a physician who is familiar and well informed about peritoneal dialysis. The patient prescription may include single or multiple exchanges, depending on the patient’s need. The IDA Cartridge is a single-use, sterile cartridge exclusively for use with the IDA. It is intended to interface the IDA with the Twin Bag Set (patient dialysis prescription) and the patient’s peritoneal catheter. The Medical Supervision Portal is intended for use by healthcare professionals to remotely communicate new or modified treatment parameters with compatible dialysis instruments and transfer completed treatment data to a central database to aid in the review, analysis, and evaluation of patients’ historical treatment results. This Medical Supervision Portal is not intended to be a substitute for good clinical management practices, nor does its operation create decisions or treatment pathways. The IDA Smartphone App is a software medical application intended for patients to review their treatment parameters and review and approve their dialysis prescription provided by the healthcare professional through the Medical Supervision Portal. The user is not intended to take clinical action based on the application output without consultation of a qualified healthcare professional. Sources: https://www.accessdata.fda.gov/cdrh_docs/pdf22/K220935.pdf https://www.liberdi.com/ https://journals.sagepub.com/doi/10.1177/0896860820958956?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Facilitating Decentralised Clinical Trials in the EU
Introduction December 2022, The European Commission (EC), the Heads of Medicines Agencies (HMA) and the European Medicines Agency (EMA) have published recommendations that aim to facilitate the conduct of decentralised clinical trials (DCTs) while safeguarding the rights and well-being of participants as well as the robustness and reliability of the data collected. This is an outcome of their joint initiative to Accelerate Clinical Trials in the European Union (ACT EU). What are Decentralized clinical Trials: Decentralized Clinical Trials (DCTs), also known as “direct-to-participant” or “virtual” studies, involve the use of technology such as telemedicine, wearable devices, and virtual health care interfaces to collect data and communicate with patients remotely. This reduces the need for traditional research facilities and intermediaries. In fully decentralized trials, all aspects of the trial, including recruitment, medication administration, and data collection, are conducted remotely, with minimal in-person contact between the study team and patients. Many clinical trials for drug approval now incorporate decentralized elements, and DCTs often combine traditional trial design with decentralization of patient interactions. What are the advantages of DCT: DCTs can improve the logistics of conducting clinical trials by making it easier to recruit and retain participants. The use of remote monitoring and data collection in DCTs can remove barriers to participation, such as the cost of travel, difficulty in taking time off work, and mobility issues related to medical conditions. Additionally, DCTs may also increase participation from groups that are traditionally underrepresented in clinical trials, such as the elderly, low-income individuals, those living in remote areas, and ethnic minorities. This may also lead to faster recruitment and more representative results. Traditional clinical trials rely heavily on trained intermediaries, such as study coordinators, research assistants, and medical staff, to collect and compile data. In contrast, DCTs use partially or fully virtual methods for data collection. A partially virtual intermediary may still require some direct interaction with the patient, such as having the patient enter information about side effects into a research platform. A fully virtual data collection system would collect data automatically, for example, by transmitting data from a wearable device to the research platform, without any interaction from the patient or research intermediary. This can lead to the need for smaller investigative teams, lower costs for sponsors, and fewer inconveniences for patients, which can increase their willingness and ability to participate in the study, resulting in outcomes that better reflect the safety and efficacy behavior of the study drug in a “real-world” environment. Traditionally, clinical trials have been conducted at specific clinical trial sites, to which patients had to travel to. The aim of DCTs is to make it easier for patients to participate in clinical trials by reducing the need to travel to central trial sites. This approach has the potential to make clinical trials available to a wider demographic of participants and reduce drop-out rates. Challenges with conducting DCT trials: One of the main advantages of centralized studies over DCTs is that drug distribution and management is simpler. In centralized studies, drugs are shipped to a single location and managed centrally, whereas in DCTs, drugs must be shipped to multiple locations and potentially directly to patient homes. This requires proper storage facilities and measures to prevent unauthorized access, detect tampering, track temperature, and record drug administration. Additionally, local laws must be taken into consideration, which may vary by state. The complexity of decentralized drug shipping and management in DCTs can introduce greater complexity and risk to the trial, both for the participants and the integrity of the trial. One of the major challenges of DCTs is protecting patient privacy when using connected devices and transmitting data through connection services. DCTs require reliable cybersecurity systems to safeguard private patient data stored and transmitted. Traditional trials typically use locally managed data systems that are firewalled, but in DCTs, patients may interact with multiple health care providers using multiple electronic health record systems, creating challenges for central data amalgamation from multiple EHRs that may not communicate effectively with each other. Accelerate Clinical Trials in the European Union (ACT EU) initiative: ACT EU is a collaboration between the EC, HMA and EMA that seeks to transform how clinical trials are initiated, designed and run. The initiative was launched in January 2022 and aims to further develop the EU as a focal point for clinical research, to promote the development of high-quality, safe and effective medicines, and to better integrate clinical research in the European health system. ACT EU will strengthen the European environment for clinical trials, whilst maintaining the high level of protection of trial participants, data robustness and transparency that EU/EEA citizens expect. The recommendations include an overview of national provisions for specific decentralised clinical trial elements to be used in clinical trials. They were put together by the European medicines regulatory network with experts from regulatory bodies responsible for the authorisation of clinical trials, members of ethic committees, good clinical practice inspectors, methodology experts and representatives of patient organisations. Drafting of the paper was coordinated by the clinical trials coordination group (CTCG). These recommendations under ACT EU are a first and important step towards clarifying the use of decentralised clinical trials in the EU/EEA by the European medicines regulatory network. They are expected to evolve as knowledge increases and experience is gained. In particular, the overview of national provisions will be updated on a continuous basis. Additional Initiative by other agencies: DCTs initiatives have been supported by other agencies. The first entirely web-based trial, under an Investigational New Drug application, was carried out by Pfizer in 2011 in the REMOTE (Research on Electronic Monitoring of Overactive Bladder Treatment Experience) trial. During REMOTE, no in-person site visits occurred at all and the study investigators used internet recruitment, online questionnaires, electronic diaries, and home delivery of the investigational drug. The Clinical Trials Transformation Initiative (CTTI), was cofounded by the Food and Drug Administration (FDA) and Duke University in 2007 to identify and promote quality and efficacy of clinical trials and has recently issued
Total Product Life Cycle Advisory Program (TAP) TAP Pilot
Introduction The Soft Launch phase of the Total Product Life Cycle Advisory Program (TAP) TAP Pilot will begin on January 1, 2023. During the TAP Pilot Soft Launch phase, the FDA intends to enroll up to 15 devices in the Office of Health Technology 2 (OHT2): Office of Cardiovascular Devices. The FDA’s Center for Devices and Radiological Health (CDRH) has launched the voluntary Total Product Life Cycle (TPLC) Advisory Program (TAP) Pilot. TAP is intended to help ensure that U.S. patients have access to high-quality, safe, effective, and innovative medical devices first in the world for years to come by promoting early, frequent, and strategic communications between the FDA and medical device sponsors. Goals of the TAP Pilot The TAP Pilot is intended to demonstrate the feasibility and benefits of process improvements to the FDA’s early interactions with participants and stakeholders that support the vision for TAP. Through the TAP Pilot, the FDA will provide the following types of strategic engagement for innovative devices of public health importance: Improving participants’ experiences with the FDA by providing for more timely premarket interactions; Enhancing the experience of all participants throughout the device development and review process, including FDA staff; Facilitating improved strategic decision-making during device development, including earlier identification, assessment, and mitigation of device development risk; Facilitating regular, solutions-focused engagement between FDA review teams, participants, and other stakeholders, such as patients, providers, and payers, beginning early in device development; and Collaborating to better align expectations regarding evidence generation, improve submission quality, and improve the efficiency of the premarket review process. The long-term vision for TAP is to help spur more rapid development and more rapid and widespread patient access to safe, effective, high-quality medical devices of public health importance. A mature TAP is also intended to help ensure the sustained success of the Breakthrough Devices Program. FY 2023 Enrollment Criteria For the TAP Pilot Soft Launch in FY 2023, the FDA intends to enroll up to 15 devices in the Office of Cardiovascular Devices (OHT2) using the following enrollment criteria: Devices will be those with a granted Breakthrough Device designation; Potential participants will not have submitted a Pre-Submission about the device after being granted a Breakthrough Device designation; Devices will be early in their device development process (e.g., have not yet initiated a pivotal study for the device) at time of enrollment; and Each potential participant will have a maximum of one device enrolled in the TAP Pilot per fiscal year. FY 2023 Enrollment Process Beginning January 1, 2023, the FDA is seeking requests for enrollment in the TAP Pilot Soft Launch for FY 2023. To have a device considered for enrollment, sponsors should submit an amendment to the Q-submission under which their device was granted Breakthrough designation, with the following information: A subject heading clearly indicating “TAP Pilot Request for Enrollment”; Name and address of the device sponsor; and The Q-Submission number under which the device proposed for enrollment in the TAP Pilot was granted Breakthrough Device designation. Following receipt of a request for enrollment in the TAP Pilot, the FDA intends to consider the request using the enrollment criteria outlined above until the TAP Pilot has reached capacity for the fiscal year. Eligible TAP Pilot participants will be enrolled on a first-come, first-served basis. Within 30 days of receipt, the FDA intends to notify the potential participant in writing whether or not the device has been enrolled into the TAP Pilot. If a participant’s device is enrolled into the TAP Pilot, the FDA will contact the participant to schedule an initial meeting to provide an overview of the TAP Pilot processes, expectations, and engagement opportunities. If, after review of a request for enrollment, a device is not enrolled in the TAP Pilot, the FDA will identify the reason(s) for that decision. If the maximum number of devices has been enrolled for the fiscal year in which a request is received, the FDA intends to notify the sponsor submitting the request that enrollment in the TAP Pilot has reached capacity for the current fiscal year. The FDA also intends to provide enrollment updates, including a notification that we have reached capacity for a given fiscal year. Performance Metrics To achieve the TAP Pilot objectives, the FDA has committed to implement and track the following quantitative performance metrics, beginning in FY 2024: CDRH will engage in a teleconference with the participant on requested topic(s) pertaining to the TAP device within 14 days of the request for 90% of requests for interaction. CDRH will provide written feedback on requested biocompatibility and sterility topics(s) pertaining to the TAP device within 21 days of the request for 90% of such requests for written feedback. CDRH will provide written feedback on requested topic(s) pertaining to the TAP device other than biocompatibility and sterility within 40 days of the request for 90% of requests for written feedback. For informational purposes, the FDA will conduct an assessment of the TAP Pilot using an independent third party (or parties). This assessment will include a participant survey and quantitative and qualitative success metrics, starting in FY 2024, that include but are not limited to: the extent to which the FDA is successful at meeting the quantitative goals described above; participant satisfaction with the timeliness, frequency, quality, and efficiency of interactions with and written feedback from the FDA; participant satisfaction with the timeliness, frequency, quality, and efficiency of voluntary interactions with non-FDA stakeholders facilitated by the FDA (if utilized); and an overall assessment of the outcomes of the Pilot and opportunities for improvement. Sources: https://www.fda.gov/medical-devices/how-study-and-market-your-device/total-product-life-cycle-advisory-program-tap#TAP%20Pilot%20Enrollment%20Process https://www.federalregister.gov/documents/2022/10/12/2022-21835/medical-devices-voluntary-total-product-life-cycle-advisory-program-pilot
U.S. Food and Drug Administration approved Leqembi (lecanemab-irmb) via the Accelerated Approval pathway for the treatment of Alzheimer’s disease.
Introduction January 6th 2023, the U.S. Food and Drug Administration approved Leqembi (lecanemab-irmb) via the Accelerated Approval pathway for the treatment of Alzheimer’s disease. Leqembi is the second of a new category of medications approved for Alzheimer’s disease that target the fundamental pathophysiology of the disease. These medications represent an important advancement in the ongoing fight to effectively treat Alzheimer’s disease. The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. The approval of Leqembi was granted to Eisai R&D Management Co., Ltd. Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research said “Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones. This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.” What is Alzheimer’s disease: It is an irreversible, progressive brain disorder affecting more than 6.5 million Americans that slowly destroys memory and thinking skills and, eventually, the ability to carry out simple tasks. While the specific causes of Alzheimer’s are not fully known, it is characterized by changes in the brain—including amyloid beta plaques and neurofibrillary, or tau, tangles—that result in loss of neurons and their connections. These changes affect a person’s ability to remember and think. Who is affected by Alzheimer’s disease? Age is the best-known risk factor for Alzheimer’s disease with symptoms usually appearing after age 60. Older African American and Hispanic/Latino adults are more likely to have Alzheimer’s disease than older white adults. You may also be at higher risk of developing Alzheimer’s disease if you: Are a woman. Have ever had a moderate or severe head injury. Have heart disease, stroke, high blood pressure, diabetes, or obesity. Have an immediate family member with Alzheimer’s disease. Engage in few physical, mental, or social activities. Treatment: Lecanemab-irmb is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta, and is expressed in a Chinese hamster ovary cell line. Lecanemab-irmb has an approximate molecular weight of 150 kDa. LEQEMBI (lecanemab-irmb) injection is a preservative-free, sterile, clear to opalescent and colorless to pale yellow solution for intravenous use by infusion after dilution. LEQEMBI is supplied in single-dose vials available in concentrations of 500 mg/5 mL (100 mg/mL) or 200 mg/2 mL (100 mg/mL). Leqembi was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and a drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. The results of a Phase 3 randomized, controlled clinical trial to confirm the drug’s clinical benefit have recently been reported and the agency anticipates receiving the data soon. Clinical Trials: Researchers evaluated Leqembi’s efficacy in a double-blind, placebo-controlled, parallel-group, dose-finding study of 856 patients with Alzheimer’s disease. Treatment was initiated in patients with mild cognitive impairment or mild dementia stage of disease and confirmed presence of amyloid beta pathology. Patients receiving the treatment had significant dose- and time-dependent reduction of amyloid beta plaque, with patients receiving the approved dose of lecanemab, 10 milligram/kilogram every two weeks, having a statistically significant reduction in brain amyloid plaque from baseline to Week 79 compared to the placebo arm, which had no reduction of amyloid beta plaque. These results support the accelerated approval of Leqembi, which is based on the observed reduction of amyloid beta plaque, a marker of Alzheimer’s disease. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology. Warning and precautions: Amyloid-related imaging abnormalities (ARIA): The prescribing information for Leqembi includes a warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur. ARIA most commonly presents as temporary swelling in areas of the brain that usually resolves over time and may be accompanied by small spots of bleeding in or on the surface of the brain, though some people may have symptoms such as headache, confusion, dizziness, vision changes, nausea and seizure. Another warning for Leqembi is for a risk of infusion-related reactions, with symptoms such as flu-like symptoms, nausea, vomiting and changes in blood pressure. The most common side effects of Leqembi were infusion-related reactions, headache and ARIA. As specified in the prescribing information, Leqembi is indicated for the treatment of Alzheimer’s disease. The labeling states that treatment with Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was studied in clinical trials. The labeling also states that there are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. Infusion-Related Reactions: Infusion-related reactions were observed in 20% (32/161) of patients treated with LEQEMBI compared to 3% (8/245) of patients on placebo; and the majority (88%, 28/32) occurred with the first infusion. Infusion-related reactions were mild (56%) or moderate (44%) in severity. Infusion-related reactions resulted in discontinuations in 2% (4/161) of patients treated with LEQEMBI. Symptoms of infusion-related reactions include fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation. After the first infusion, 38% of patients treated with LEQEMBI had transient decreased lymphocyte counts to less than 0.9 x109 /L compared to 2% in patients on placebo, and 22% of patients treated with LEQEMBI had transient increased neutrophil counts to greater 7.9 x109 /L compared to 1% of patients on placebo. In the event of an infusion-related reaction, the infusion rate may be reduced, or the infusion may be
European Medicines Agency (EMA) approved first therapy to treat transplant patients with post-transplant lymphoproliferative disease.
The European Medicines Agency (EMA) has recommended a marketing authorisation in the European Union (EU) for Ebvallo (Tabelecleucel) for the treatment of adult and paediatric patients who experience a serious complication following solid organ transplantation (SOT) or bone marrow transplantation (hematopoietic cell transplant – HCT) called Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD). Ebvallo will be available as a dispersion for injection containing 2.8 × 107 – 7.3 × 107 viable T cells/mL. The active substance of Ebvallo is tabelecleucel, an allogeneic, EBV-specific T-cell immunotherapy which targets and eliminates EBV-infected cells in a human leukocyte antigen (HLA)-restricted manner. This medicine was designated an “orphan medicine”. This means that it was developed for use against a rare, life-threatening or chronically debilitating condition or, for economic reasons, it would be unlikely to have been developed without incentives. About 30 million people living in the European Union (EU) suffer from a rare disease. The European Medicines Agency (EMA) plays a central role in facilitating the development and authorisation of medicines for rare diseases, which are termed ‘orphan medicines’ in the medical world. EBV+ PTLD is one of the most important malignancies after transplantation. It is a result of the immunosuppression caused by the medication required to reduce the possibility of rejection of the transplanted organ or cells and the most common form of this condition is associated with the Epstein-Barr virus. Ebvallo is indicated in patients after a transplant and who have received at least one prior therapy when the symptoms of the disease come back after treatment (relapsed) or when the treatment does not work (refractory). A significant unmet need exists for patients who fail first-line therapies as they have only weeks to a few months’ survival after treatment failure, and other treatment options are limited. The aim of new treatments is to achieve the disappearance of all signs of cancer after treatment (complete remission) and prolong overall-survival, thereby reducing transplantation-related mortality of patients with EBV+ PTLD. Tabelecleucel, the active substance of Ebvallo, targets and eliminates infected cells. It is an advanced therapy medicinal product made of cells of the immune system called T-cells that have been taken from a donor (allogeneic). The T-cells are first mixed with another type of white blood cells in the immune system (B-cells) from the same donor that have been infected with the Epstein-Barr virus so that the T-cells learn to recognise infected B-cells. The T-cells are then grown to increase their numbers. When the medicine is given to the patient, the T-cells are expected to attack and kill the patient’s own infected B-cells, thereby helping to control cancers associated with the virus. At the time of designation, post-transplant lymphoproliferative disorder affected approximately 1.6 in 10,000 people in the European Union (EU). This was equivalent to a total of around 82,000 people and is below the ceiling for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP). Before this approval no satisfactory method was authorised in the European Union for the treatment of post-transplant lymphoproliferative disorder. Patients with the condition were treated with medicines authorised for non-Hodgkin’s lymphoma. EMA’s recommendation is based on the results of an ongoing multicentre, phase 3, single-arm, open-label clinical trial. The study investigated the efficacy and safety of tabelecleucel in 43 patients with relapsed/refractory EBV+ PTLD who had received at least one prior therapy. Approximately half of the treated subjects achieved partial or complete remission. A significant number of patients enrolled in the study responded to the treatment with a durable response of six months or more without disease signs or symptoms after treatment. The most common side effects are fever, diarrhoea, tiredness, feeling sick, low levels of red blood cells, decreased appetite and low blood sodium levels. In its overall assessment of the available data, the Committee for Advanced Therapies (CAT), EMA’s expert committee for cell and gene-based medicines, found that the benefits of Ebvallo outweighed the risks in patients with EBV+ PTLD. The CHMP, EMA’s human medicines committee, agreed with the CAT’s assessment and positive opinion, and recommended approval of this medicine under exceptional circumstances. A marketing authorisation under exceptional circumstances allows patients’ access to medicines that cannot be approved using a standard authorisation route as comprehensive data cannot be obtained under normal conditions of use. Sometimes this is due to the small number of patients with the disease. In other cases, the collection of complete information on the efficacy and safety of the medicine is not possible or would be unethical. The medicines concerned are subject to specific post-authorisation obligations and monitoring. The CHMP requested the applicant to submit data to further characterise the long-term efficacy and safety of patients enrolled in the clinical trials, and to conduct a post-authorisation observational safety study in patients treated with the medicine in Europe. The opinion adopted by the CHMP is an intermediary step on Ebvallo’s path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on the EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of this medicine in the context of the national health system of that country. Sources: https://www.ema.europa.eu/en/news/first-therapy-treat-transplant-patients-post-transplant-lymphoproliferative-disease https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/16/1627-public-summary-opinion-orphan-designation-allogeneic-epstein-barr-virus-specific-cytotoxic-t_en.pdf https://www.ema.europa.eu/en/human-regulatory/overview/orphan-designation-overview
Cellular and Gene Therapy approved by FDA
June 2022 FDA approved BREYANZI (lisocabtagene maraleucel) for treatment of adult patients with large B-cell lymphoma (LBCL). Large B-cell lymphoma (LBCL) is the most common type of non-Hodgkin lymphoma (NHL). Indication: For treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have: Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or Relapsed or refractory disease after two or more lines of systemic therapy. Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma Description: BREYANZI (lisocabtagene maraleucel) is a CD19-directed genetically modified autologous T cell immunotherapy administered as a defined composition of CAR-positive viable T cells (consisting of CD8 and CD4 components). The CAR is comprised of the FMC63 monoclonal antibody-derived single-chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. In addition, BREYANZI includes a nonfunctional truncated epidermal growth factor receptor (EGFRt) that is co-expressed on the cell surface with the CD19-specific CAR. BREYANZI is a T cell product. BREYANZI is prepared from the patient’s T cells, which are obtained via a standard leukapheresis procedure. The purified CD8-positive and CD4-positive T cells are separately activated and transduced with the replication-incompetent lentiviral vector containing the anti-CD19 CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved as separate CD8 and CD4 component vials that together constitute a single dose of BREYANZI. The product must pass a sterility test before release for shipping as a frozen suspension in patient-specific vials. The product is thawed prior to administration The BREYANZI formulation contains 75% (v/v) Cryostor® CS10 [containing 7.5% dimethylsulfoxide (v/v)], 24% (v/v) Multiple Electrolytes for Injection, Type 1, 1% (v/v) of 25% albumin (human). How it Works: BREYANZI is a CD19-directed genetically modified autologous cell immunotherapy administered as a defined composition to reduce variability in CD8-positive and CD4-positive T cell dose. The CAR is comprised of an FMC63 monoclonal antibody-derived single chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. CD3 zeta signaling is critical for initiating activation and antitumor activity, while 4-1BB (CD137) signaling enhances the expansion and persistence of BREYANZI. CAR binding to CD19 expressed on the cell surface of tumor and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells. Sources: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel https://www.fda.gov/media/145711/download