Chapter 84 - The regulatory process from concept to market

The FDA's Regulatory Framework for Chimeric Antigen Receptor-TCell Therapies.

Section Editors: Marc Fisher MD Antoni Davalos MD The Food and Drug Administration (FDA) evaluates applications for new human drugs, biologics, and complex medical devices. Companies must obtain FDA approval to legally market these products. In August, the FDA gave Concentric Medical clearance to market its Merci Retriever system to “remove blood clots from the brain in patients experiencing an ischemic stroke.” Given that the FDA is charged with “protecting the public health by assuring the safety, efficacy, and security of… biological products and medical devices…, ” “advancing public health by helping to speed innovations that make medicines … more effective, safer, and more affordable,” and “helping the public get the accurate, science-based information they need to use medicines … to improve their health,”1 the FDA’s decision to approve the Merci Retriever system is of concern. The pathways to approval are reviewed by Felten et al in the accompanying article and are outlined in Figure 1. Figure 1. Potential pathways for device approval. The decision to approve the Merci Retriever was based on data from the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial; the approval was granted through the 510(k) process. The Merci Retriever system includes a flexible nickel titanium (nitinol) wire that obtains a helical shape once it is passed through the tip of the guidance catheter. In practice, the catheter/wire is passed distal to the thrombus, the catheter is removed, and the helical configuration assumed by the wire; the clot is then trapped in the helix and withdrawn from the vasculature (Figure 2). The 510(k) clearance means that the Merci Retriever was felt to be substantially equivalent to a predicate device. In this case, the predicate device was the Concentric Retriever, which itself received 510(k) clearance by the FDA in May 2001 for “use in …

The influence of patient advocates on FDA regulatory decision making has increased. Despite enhanced engagement with FDA, there remain challenges to achieving the regulatory goals of patients within FDA's regulatory framework. Gaps exist between patient advocates' knowledge of the agency's processes and FDA's need for rigorous, clinically meaningful patient experience data. This study examined the policy process in which patient experience data are collected by patient advocates and provided to FDA for regulatory decision making. Semistructured, narrative interviews were conducted with 14 professionals working in patient advocacy or at FDA. The purpose was to examine, in depth, participants' perceptions and experiences regarding this new regulatory process. Interviews were coded and examined for themes. The use of patient experience data by FDA is an evolving regulatory process. Participants identified a number of barriers and contributors to regulatory success. Well-organized and sophisticated patient advocacy groups with access to scientific and policy expertise are more likely to find success meeting FDA's patient experience data requirements. A conceptual model of this regulatory process was developed. Use of patient experience data by FDA has the potential to positively influence the regulation of medical products in the United States. Success within this new regulatory process will depend on clear guidance from FDA regarding the collection, analysis, and use of patient experience data. Patient advocacy groups must enhance internal capacity and expertise while engaging in substantive collaborations with FDA and other stakeholders in order to meaningfully contribute to the regulatory review of new therapeutics.

IN THE MIDST OF A RANCOROUS ELECTION YEAR, BIPARTIsan accord in Congress is infrequent. A notable exception is the broad agreement on the US Food and Drug Administration (FDA) Safety and Innovation Act, approved by overwhelming majorities in the House of Representatives and the Senate, and signed into law by President Barack Obama in July 2012. Effective October 1, 2012, the legislation reauthorizes for 5 years the collection of user fees from industry for the reviews of prescription drugs and medical devices and establishes new user fee programs for generic drugs and “biosimilar” biological products. For years, the FDA has been a lightning rod for strong criticism from across the political and ideological spectrums, from members of Congress, industry officials, advocacy groups, the news media, and even its own employees. But the legislation was not a battlefield for settling these scores. The broad support reflects a wide recognition of the importance of the reviews of drugs, medical devices, and other products that represent the foundation of the nation’s regulatory system. Neither patient and consumer groups nor industry believe that the funding of product reviews through user fees is the best approach for the agency. The budget reality, however, is that if the FDA is to have sufficient resources to fulfill its public health and regulatory missions, it will require revenue from user fees indefinitely. Every 5 years, Congress reauthorizes the collection of user fees for drugs and medical devices, and considers additional provisions that might be included in the legislation. The FDA’s budget for fiscal year (FY) 2013, which started on October 1, 2012, is not yet known. Regardless of the final budget, fees from industry will represent a substantial and increasing share of all FDA spending. In FY 2012, Congress appropriated about $2.5 billion for the FDA. In FY 2013, the agency is expected to collect approximately an additional $1.7 billion in fees from industry, not just for the review of drugs and medical devices, but also for the regulation of food, tobacco, and additional products as authorized in other legislation (TABLE). If Congress were to appropriate the same amount for the FDA in FY 2013 as it did in FY 2012, then fees from industry would account for nearly 40% of the agency’s approximately $4.2 billion of spending. Congress first authorized the collection of prescription drug user fees in 1992 and has reauthorized the collection of these fees 4 times. During the last 2 decades, the number of scientific staff at the agency has increased, and the median approval times for drug applications have decreased markedly. Approval times for drugs the FDA views as priority have decreased from an average of 2 years to 1.1 years. Medical device user fees were first authorized in 2002 and have been reauthorized twice since then. Under the 2012 act, medical device user fees will increase and more companies will have to pay them, allowing the FDA to hire additional scientists and decrease review times. In 2011, approximately 4 of every 5 outpatient prescriptions in the United States were filled with generic drugs. The new user fees for generic drugs will provide the agency with the resources to eliminate a backlog of more than 2500 applications for drug approvals. The FDA will also be able to inspect foreign generic drug manufacturing facilities more often, so that they can be held to the same standards and inspection frequencies as domestic facilities. Other provisions of the act will broadly affect the FDA’s work in protecting the safety and quality of the drug supply chain, preventing drug shortages, encouraging the development of innovative antibiotics for serious or lifethreatening infections, and additional areas. The agency will gain authorities to register, regulate, and conduct riskbased inspections of foreign drug manufacturing facilities, where the majority of medications sold in the United States are produced. Authorities over foreign facilities that manufacture medical devices will be similarly strengthened. The FDA will have more authority to require companies to notify it about anticipated drug shortages and will gain the authority to mandate reporting of shortages of biological products. As an incentive for the development of innovative antibiotics, the FDA will be able to grant manufacturers of new qualified infectious disease products an additional 5 years of market exclusivity. By July 2014, the act also requires the FDA to issue longawaited guidance on Internet promotion of FDA-regulated medical products, including the use of social media. The Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act have improved the agency’s ability to meet the medical needs of children. The acts, which had been subject to reauthorization every 5 years, are made permanent.

Continual learning in medical devices: FDA's action plan and beyond

The latest response to consumers’ increased demand for accessible genetic health information is the US Food and Drug Administration (FDA)’s recent approval of 23andMe’s direct-to-consumer (DTC) genetic test for the three common BRCA1 and BRCA2 pathogenic variants found in the Ashkenazi Jewish population.1 23andMe and other DTC genetic testing companies officially report out ancestry, trait, and some health information, while also providing consumers with files of their raw genetic data. Up to 62% of consumers use third-party applications to interpret the raw data and health information not included in companies’ reports.2 Little data exists on the nature and prevalence of clinical follow up of third-party raw genetic data interpretation, nor on the psychosocial impact on the consumer and their families.3 This information is of timely importance as a recent study suggests that 40% of genetic variations within DTC raw data sent for clinical confirmation are false positives.4 This raises many questions about the impact of DTC genetic testing and third-party interpretation tools, including the appropriate use of healthcare resources, clinical utility, provider and patient understanding of limitations, and psychological impact on consumers. In this commentary, we present four case vignettes from cardiovascular genetics clinics to bring awareness to possible harms of DTC raw data interpretation. Future studies investigating the breadth and frequency of cases such as these are required to understand the scope of this harm.

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

The United States Food and Drug Administration's (FDA) regulatory approach for xenotransplantation products and xenografts encompasses regulatory considerations for biological products, medical devices, drugs, combination products, and genetically altered animals, depending on the product. This communication aims to clarify the regulatory approaches and considerations for animal-derived products, specifically xenotransplantation and xenograft products.

In the United States, drugs and medical devices are regulated by different divisions of the U.S. Food and Drug Administration (FDA). While defined similarly, drugs and medical devices differ in their modes of action. Both are products that are labeled, promoted, or used in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease. A device, however, does not achieve its intended purpose through a chemical action within or on the body or by being metabolized by the body. 1 Although both drugs and medical devices must comply with federal regulations regarding labeling, advertising, production, and postmarketing surveillance, there are differences in the FDA premarket review and approval processes. FDA clearance and prescription status of a device do not necessarily mean that safety and efficacy have been shown for the product or that clinical trials have been conducted. We conducted a literature review to (a) examine the historical legislation and approval processes for drugs, medical devices, and combination products and (b) discuss implications of the differences in FDA review processes for clinicians and payers. ■■ Methods

The aim of his research was getting acquainted with psycho-physiological functions of highly qualified judo competitors of various weight categories. 14 competitors, representatives of Poland in judo took part in the research. The age of the researched competitors ranged between 20-30 years (23,1±2,7), and period of training 6-20 years (12,8±4). Specially designed set of computer program Selftest («Dinamo» Kiev) was used in the research. In the result of the research different level of activity manifestation of psycho physiological functions of judokas depending on weight category was revealed.

What’s the Latest on Acrylamide?

Regulatory initiatives for natural latex allergy: US perspectives

Pharmaceutical regulation of genetically modified organisms (GMOs) is one of the critical issues for developing viral vector-based medicines. In this perspective, we introduce the recent improvement of regulatory operations in GMOs like viral vector-based products in Japan by comparing those in the United States and the European Union. The recent advancements in genetic modification and editing techniques have accelerated the development of advanced-therapy medicinal products using genetically modified viral vectors and cells.1 Despite the increase in use of GMOs/living modified organisms (LMOs) in medicine, the potential risk of GMOs/LMOs on the environment is a concern. To address internationally the environmental issues related to biological diversity, including the usage of GMOs/LMOs, 196 nations as of 2021 have concluded or signed the Convention on Biological Diversity (CBD), which is the first global agreement to cover all aspects of biological diversity. The Cartagena Protocol based on CBD aims to ensure the safe handling, transport, and use of GMOs/LMOs, produced by modern biotechnology, which may have an impact on biological diversity. The Cartagena Protocol was entered into force on September 11, 2003. The Cartagena Protocol requires the parties to consider the necessity of the standard of handling of GMOs/LMOs and, if necessary, to establish the standard. The EU countries had already established domestic laws based on Directive 2001/18/EC that addressed the handling of GMOs/LMOs for medical use before the establishment of the Cartagena Protocol. Therefore, the EU countries did not have to take any additional actions to regulate the handling of GMOs/LMOs for pharmaceuticals. In 2003, the Japanese government established the Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms,2 known as the Cartagena Act, for the handling of the GMOs/LMOs. This Act is similar to Directive 2001/18/EC and the domestic laws established in the EU countries. In contrast to the European Union and Japan, the United States is one of the few countries that have not signed the CBD and the Cartagena Protocol. The United States enacted one specific environmental law named the National Environmental Policy Act of 1969 (NEPA) that regulates all kinds of environmental assessments. For initiating clinical trials, developers should submit appropriate clinical trial-related applications (investigational new drug (IND) application in the United States, clinical trial application (CTA) in the European Union, and clinical trial notification (CTN) in Japan) to each regulatory agency. In the European Union and Japan, approval of the usage of the GMOs/LMOs in the clinical trials is also mandatory before starting clinical trials (Figure 1). The objective of the EU domestic laws is to protect humans and the environment when carrying out deliberate release of GMOs/LMOs into the environment. Thus, developers (academia and/or industry) planning clinical trials in the EU countries should submit an environmental risk assessment (ERA) of each GMO to each country where the clinical trial will be conducted. In Japan, the Cartagena Act has two types of GMO/LMO regulations, the deliberate release, with GMO/LMO-specific rules for usage (Type-1 Use Regulation (T-1R)) and containment use for closed production sites and laboratories (Type-2 Use Regulation (T-2R)). Clinical trials are within the scope of T-1R, therefore developers planning to conduct clinical trials in Japan should submit an ERA and the T-1R application for GMOs/LMOs. In the United States, the submission of an ERA is not required for IND applications. However, when GMOs/LMOs may affect the quality of the environment, the US Food and Drug Administration (FDA) will request an ERA during the review process of the IND (the Title 21 of the Code of Federal Regulations (CFR) 25.21 and 25.31). In both the European Union and the United States, applicants should submit an ERA result of GMOs/LMOs when applying for marketing authorization, and the FDA or European Medicines Agency (EMA) reviews the appropriateness of the usage of drugs in clinical practice based on the ERA result (Figure 1). In Japan, the resubmission of an ERA is not mandatory when applying for marketing authorization. If developers obtain new data that indicates the environmental risk is lower than expected, resubmission is acceptable at any time to relax the T-1R. Some clinical researchers in Japan recently commented that the Cartagena Act delays the development of medicines containing GMOs/LMOs when compared to that of the medicines regulated by the similar laws in the European Union and the United States.3 But the regulatory framework of Japan is not significantly different from that of at least the European Union (Figure 1). The Pharmaceuticals and Medical Devices Agency (PMDA) is the Japanese regulatory agency responsible for a scientific review of new drug applications and Cartagena Act-related applications. The PMDA believed that such opinions came from the differences between the scheme of the Cartagena Act implementation and the procedure of actual development of drugs, and a lack of information on the Cartagena Act applications among academia. To solve these problems, since 2019, the Ministry of Health, Labor, and Welfare and the PMDA have started to improve the implementation of the Cartagena Act to ensure faster development of drugs (Table 1). The first improvement made in 2019 was the establishment of the PMDA official consultations to address specific measures of the Cartagena Act. The consultations for the Cartagena Act were the first established at the PMDA for the environmental law, and the developers can officially discuss the Cartagena Act-related matters with the PMDA since the establishment. It takes < 3 months to complete the official consultations and for official minutes to be published. The applicant can then submit the T-1R application as soon as the issues pointed out in the consultations are resolved. The administrative processing time after the submission is officially < 6 months, and the median actual administrative processing time and total processing time in 2021 were ~ 2.7 months and < 5 months, respectively. Section 42 of the German Drug law indicates that the evaluation period of CTA for trials dealing with GMOs/LMOs is 90 days after receiving the application conforming to the regulations. Thus, the actual administrative processing time before starting clinical trials is similar between Japan and the European Union. Since 2021, the parallel application of CTN and T-1R is acceptable. Now, developers should receive the approval of the T-1R application before at least the first patient enrollment of the clinical trial in Japan. In the European Union, several countries, such as France, accept the parallel application of CTA and ERA, but some countries, such as Poland, demand the approval of usage of the GMOs in the clinical trials before submitting a CTA.4 The PMDA has published a considerable number of instructions, such as the specific descriptions of ERA for adeno-associated virus (AAV) vectors,5 to provide information about the Cartagena Act to future applicants. The specific ERA for AAV vectors includes the general information and prior knowledge about AAVs and the general principles of risk assessment for AAV vectors. The European Commission has also published specific ERA for AAV in June 2022.6 These instructions and specific descriptions will significantly reduce the burden on applicants and regulators in Japan. Because the ERA submission is not mandatory when applying for marketing authorization, the regulation of the development of gene therapy products in Japan is not more time-consuming than that in the European Union and the United States. No funding was received for this work. The authors declared no competing interests for this work.

Use of Real-world Data for New Drug Applications and Line Extensions

While computer-related failures are known to play a significant role in deaths and injuries involving medical devices reported to the U.S. Food and Drug Administration (FDA),1 there is no similar reporting system that meaningfully captures security-related failures in medical devices.Medical device software must satisfy system properties, including safety, security, reliability, resilience, and robustness, among others. This column focuses on the challenges to satisfying a security property for medical devices: post-market surveillance, integrity and availability, and regulation and standards.Medical devices depend on software for patient care ranging from radiation therapy planning to pharmaceutical compounding to automated diagnosis of disease with mobile medical apps. Meanwhile, the medical community has observed an uptick in reported security vulnerabilities in medical device software—raising doubts of cybersecurity preparedness. It should come as little surprise that security risks in medical devices "could lead to patient harm" as recently explained by the chief scientist at the FDA Center for Devices and Radiological Health.2 Device manufacturers and healthcare providers ought to more carefully and deliberately consider security hazards during the phases from design to use of medical devices.Between years 2006 and 2011, 5,294 recalls and approximately 1.2 million adverse events of medical devices were reported to the FDA's Manufacturer and User Facility Device Experience (MAUDE) database.1 Almost 23% of these recalls were due to computer-related failures, of which approximately 94% presented medium to high risk of severe health consequences (such as serious injury or death) to patients.1 For security incidents on medical devices, no systematic national reporting system exists.3 Yet, individual hospitals know of hundreds of security incidents on medical devices.2For instance, the FDA MAUDE does not capture adverse events such as lack of or impaired availability of function when malware infects a medical device's operating system. FDA's own disclaimer explains that the MAUDE database is qualitative rather than quantitative. MAUDE is incomplete with underreporting and reporting bias.Imagine the reaction of a clinician using a high-risk pregnancy monitor that begins to perform more slowly because of a Conficker infection. Would the clinician report a malware infection? Likely not. Admitting to playing a role in accidentally infecting a medical device-would likely lead to consequences ranging from disciplinary action to loss of reputation. Thus, the actual incidence of security failures leading to healthcare delivery failures may be significantly greater than the available statistics suggest. To have a better understanding of medical device security, the bad-news diode must be shorted. Reporting must be incentivized rather than penalized.If you watch television crime dramas, you may be duped into thinking that hacking of medical devices is the number-one risk for public health today. You would be wrong. The most pressing risks are much less sexy: the unavailability of patient care and the lack of health data integrity. Here, we highlight a few examples that illustrate the consequences of unavailability and lack of integrity.Interventional radiology suites and cardiac catheterization labs contain a number of computer systems to perform time-sensitive cardiac procedures, such as angioplasty, to open blocked arteries for improved outcomes in patients suffering acute heart attacks or strokes.According to The Wall Street Journal,2 a Department of Veterans Affairs (VA) catheterization laboratory in New Jersey was temporarily closed in January 2010. Malware had infected the computer systems. The consequence? Patients do not receive the safe and effective care they deserve when malware causes unavailability of care. The VA has experienced hundreds of malware infections in medical devices such as X-ray machines and lab equipment made by well-known, reputable companies.Conficker was detected on 104 devices at the James A. Haley Veterans Hospital in Tampa.2 The affected devices included an X-ray machine, mammography, and a gamma camera for nuclear medicine studies. Conficker is a relatively old piece of malware with well-known mitigation strategies. Why does old malware persist on medical devices?We observe that one of the cultural challenges to improved cybersecurity and t herefore safety and effectiveness is a lifecycle mismatch. For instance, operating system software with production lifecycles measured in months does not match well with a medical device having production lifecycles measured in years or decades. The equivalent of a transformer for impedance matching does not yet exist for safely connecting these different production cultures.Risks of depending on unsupported software has parallels to depending on a device where parts are no longer manufactured or repaired. Medical devices still rely on the original versions of Windows XP (circa 2001). In October 2012, the Beth Israel Deaconess Medical Center in Boston reported to the NIST Information Security and Privacy Advisory Board that the hospital depends on 664 Windows-based medical devices primarily because of supply chain issues. Of the 664 computers, 600 devices run the original version of Windows XP. There are no Service Pack 1 (SP1) machines, but there are 15 SP2 machines and 1 SP3 machine. One MRI machine still runs Windows 95. Security support for SP1, SP2, and SP3 ended on October 10, 2006, July 13, 2010, and April 14, 2014, respectively. In many cases, a medical device manufacturer does not provide an effective way for hospitals to upgrade to supported versions of operating systems. Today, healthcare providers are told to maintain a secure system from insecure devices.4A medical device infected with malware can stray from its expected behavior. For instance, malware can cause a device to slow down and miss critical interrupts. When this happened on a high-risk pregnancy monitor, healthcare professionals could no longer trust the integrity of the sensor readings and depended on backup methods.5Antivirus software can help mitigate certain cybersecurity risks, but they also introduce their own risks. On April 21, 2010, a third of the hospitals in Rhode Island were forced to "postpone elective surgeries and stop treating patients without traumas in emergency rooms" because an automated antivirus software update had accidentally misclassified a critical Windows DLL as malicious. The problem with antivirus software is that by definition, antivirus software is a postmarket afterthought to make up for design flaws in the device. Antivirus software does not remove the need to incorporate security into the early design of medical devices.According to the FDA mission statement, the agency holds responsibility for protecting public health by assuring the safety, efficacy, and security of medical devices. In June of this year, the FDA issued draft guidance on cybersecurity6 and gave examples of what FDA reviewers would expect to see during premarket review. The draft guidance intentionally does not prescribe any particular approach or technology but instead recommends that manufacturers consider cybersecurity starting at the concept phase of the medical device.The FDA recommends that manufacturers provide:Standards bodies are taking actions to improve medical device cybersecurity. For instance, the Association for the Advancement of Medical Instrumentation (AAMI) recently formed a working group on medical device security that includes engineers from manufacturing and regulators. AAMI has already released standards specific to network-related cybersecurity risks (ANSI/AAMI/IEC-80001). International harmonization of cybersecurity guidance is likely on the horizon, given that phrases such as "security patches" appear in proposals from the International Medical Device Regulators Forum.Modern healthcare delivery depends on medical device software to help patients lead more normal and healthy lives. Medical device security problems are real, but the focus on hacking goes only skin deep. Consequences of diminished integrity and availability caused by untargeted malware include the inability to deliver timely and effective patient care. By addressing security and privacy risks at the concept phase, medical devices can remain safe and effective despite the cybersecurity threats endemic to computing. Security of medical devices is more than just a potential problem on the horizon.This work was supported in part by NFS CNS-1331652 and HHS 90TR0003/01. Any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect the views of NSF or HHS.