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FDA Regulatory and Compliance Monthly Recap — December 2018

FDA lays out strategic framework to leverage real-world evidence in decision-making

Acting on what’s been called a key strategic priority, the FDA outlined a framework to leverage real-world evidence to improve regulatory decisions. The framework will apply to drug and biologic review programs and will leverage input from patients and the medical community to inform and shape decisions across the FDA’s drug and biologic development efforts. 

The FDA published a strategic framework to evaluate the potential use of real-world evidence (RWE) to support the approval of a new indication for approved drugs, support or satisfy post-approval study requirements, and support applications for biological products licensed under the Public Health Service Act. The framework, which was developed pursuant to the Cures Act, outlines the FDA’s plans to implement a multifaceted RWE program. 

The Cures Act established section 505F of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which defines RWE as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than traditional clinical trials.” The FDA distinguishes between real-world data (RWD), which relate to patient health data and the delivery of healthcare collected from a variety of sources, and RWE, which is clinical evidence about the potential benefits or risk of a medical product generated by analyzing RWD. 

Under the RWE program, the FDA will not consider evidence from traditional trials as RWE. Hybrid or pragmatic trial designs and observational studies, however, may provide RWE. This may include clinical trials integrated into the healthcare system with pragmatic elements to use RWD to provide evidence of the potential benefits or risks of a treatment. The RWE program will also explore the possible use of observational studies in generating evidence of the efficacy of a drug product, supported by recent efforts to leverage more rigorous design and statistical methods to provide valid results using RWD.

The framework establishes criteria for exploring the potential of RWD/RWE to support regulatory decisions such as changes to labeling about drug product effectiveness, which may include adding or modifying an indication, a change in dose or route of administration, the addition of a new population, or the addition of comparative effectiveness or safety information. Per the framework, three key aspects will be assessed to evaluate individual supplemental applications and generally guide the RWE program:

  • The fitness of the RWD for use in regulatory decisions: The suitability of the data for the specific regulatory question as well as the clinical methodology and reliability and relevance of the underlying data. Reliability relates to the data accrual and data quality control, though the specific elements to consider will likely vary by RWD type and the type of research for which the data are being used. The FDA notes that while data from other countries may be valuable, their suitability for regulatory decision-making by the FDA may be limited due to differences in healthcare systems.
  • Whether the trial design used to generate the RWE may provide sufficient scientific evidence to support regulatory decision-making: The strengths and limitations of study designs using RWD, including the types of interventions and therapeutic areas that may be well-suited to routine care settings, the quality of data captured in those settings, and variations in clinical practices. The RWE program will create guidance on considerations for designing trials with pragmatic design elements, and generate evidence to support regulatory decision-making. The FDA is considering pragmatic approaches for various stages of a clinical trial, from recruitment and enrollment to assessing outcomes.
  • Whether the study adheres to regulatory requirements: Adherence to regulatory requirements such as informed consent, requirements for oversight and monitoring, and guidance on the use of electronic data. As part of its RWE program, the FDA will explore how its regulatory requirements are applied to health data generated from trials integrated in healthcare systems and observational studies. The FDA will also issue guidance on regulatory considerations for different study designs using RWD and explore data standards related to the use of RWD/RWE. 

The program will include demonstration projects, stakeholder engagement, the use of internal processes to promote shared learning and feed input from senior leadership in the evaluation of RWE, and the development of guidance documents to help sponsors interested in using RWE.

FDA updates guidance on data integrity, compliance with CGMP

The updated guidance is part of what the FDA commissioner called a multilayered approach to ensure data associated with drug manufacturing are compliant, consistent and accurate. The guidance is designed to promote efforts to ensure data integrity by providing recommendations to help manufacturers address data integrity lapses and ensure ongoing awareness of data integrity.  

The FDA issued an updated Q&A guidance document on data integrity and compliance with current good manufacturing practices (CGMP), reflecting revised recommendations in response to public comments on best practices. The guidance document discusses the role of data integrity in CGMP for drugs, which allows for flexible and risk-based strategies to address data integrity. It provides input to help drugmakers implement “meaningful and effective” strategies to manage data integrity risks, taking into consideration the design, operation, and monitoring of systems and controls.

The guidance comes amid increasing observations of CGMP violations related to data integrity, which have led to several regulatory actions, ranging from warning letters to import alerts and consent decrees. When drugmakers are examining how to meet regulatory requirements, the guidance recommends they take into consideration:

  • Whether controls are in place to ensure data are complete.
  • Whether activities are documented at the time of performance and attributable to a specific person.
  • Whether the ability to make changes to records is restricted to authorized individuals;
  • Whether records are reviewed for accuracy, completeness and compliance, and records are kept of changes to data.
  • Whether data are maintained securely.

Per the guidance, data integrity means having “complete, consistent and accurate data” that are “attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA).” Data integrity should be considered throughout the data life cycle, from creation to processing, transition and disposition. Data should be maintained throughout a record’s retention period, alongside associated metadata, which provide contextual information required to understand data. The link between data and metadata should be preserved in a securable and traceable manner, the guidance notes. In addition, an audit trail should be maintained, which provides a “secure, computer-generated, time-stamped electronic record” of data creation, modification or deletion. Audit trails should be reviewed by personnel responsible for record review under CGMP. 

The guidance notes that all data become a CGMP record when generated to meet a CGMP requirement. Drugmakers must document or save the data at the time of performance to establish a record in compliance with CGMP requirements. For batch records, the guidance makes clear that data created for a CGMP record need to be reviewed by the quality unit and maintained. Even in instances in which test results are legitimately invalidated, a full batch record needs to be provided to the quality unit with the original, invalidated data.  

Per the guidance, the FDA expects processes to ensure data cannot be modified without a record of modification. The guidance also notes that personnel should be trained to prevent and detect data integrity issues. In order to address data integrity issues, the guidance recommends that drugmakers investigate the scope and root causes of the issue, carry out a scientifically valid risk assessment of its potential impacts, and implement a management strategy, complete with a global corrective action plan, to address the root cause.

FDA outlines plans for new Safety and Performance Based Pathway for 510(k)-eligible devices

The FDA is making changes to its 510(k) clearance pathway in an effort to modernize device development and keep pace with emerging technologies. The new proposed pathway would allow companies to show a novel device meets performance-based criteria established or recognized by the agency, while ensuring devices are compared with more recent predicates. 

The director of the Center for Devices and Radiological Health (CDRH), Jeff Shuren, joined FDA Commissioner Scott Gottlieb to outline proposed changes to modernize the 510(k) clearance pathway for medical devices. The goal, they said, is to ensure that new devices entering the market through the 510(k) pathway – which accounted for 82 percent of devices cleared or approved in 2017 – meet modern safety and performance criteria. As part of the agency’s efforts to advance the Medical Device Safety Action Plan, the proposal is meant to build on the risk-based approach to regulation adopted by the CDRH while allowing technological advances to more efficiently make it to market. The FDA recognizes, however, that support from Congress may be needed to realize some of the proposals. 

The plan centers on ensuring assessments of safety and effectiveness are based on newer predicates, and on retiring outdated predicates when safer or more effective technology is available. Under the 510(k) pathway, device makers rely on comparative testing against predicate devices. However, Shuren and Gottlieb said older predicates may not reflect the modern technology of newer devices or the most up-to-date understanding of benefits and risks. According to FDA data, almost 20 percent of the current 510(k)s are cleared based on predicates more than a decade old. Given that, the FDA is implementing efforts to ensure newer predicates are the basis of comparative analyses. 

To begin, the FDA is considering publishing a list of cleared devices for which the demonstration of substantial equivalence was based on older predicates. The CDRH is considering starting with a list based on predicates more than 10 years old. The agency will seek public feedback before publishing a list to determine whether other criteria should be used as a basis of reference and to ascertain whether other actions could be useful in promoting the use of newer predicates. Ultimately, the FDA believes that using a market-based approach to encourage the use of newer predicates will not only provide consumers with a choice between newer and older devices, but also bolster competition to adopt more modern safety and performance features and help ensure devices reflect newer standards. 

The FDA is also planning to finalize guidance in the new year establishing an alternative 510(k) pathway to permit makers of certain well-understood device types to leverage objective safety and performance criteria to demonstrate substantial equivalence. The agency is planning to extend the pathway across the 510(k) program and establish it as the primary pathway for devices eligible for 510(k) review. The new pathway – to be renamed the Safety and Performance Based Pathway – will require a device maker to demonstrate a novel device meets performance-based criteria established or recognized by the FDA, and that it also reflects current technological values. Shuren and Gottlieb also said they anticipate more devices will use the De Novo pathway. The FDA issued a proposed rule to elucidate procedures and requirements for such submissions.

In addition to outlining the proposed changes, Shuren and Gottlieb discussed a performance report on the 510(k) program, which showed that the average quantity of information provided in 510(k) submissions has more than doubled, from 475 pages in 2009 to 1,185 pages in 2017, but the average total time for decision-making has decreased. The pair also discussed the agency’s active surveillance efforts and committed to ensuring the FDA is consistently among the first global regulators to identify and act upon medical device safety signals. As part of that effort, the agency is exploring changes to establish more streamlined processes to implement special controls to address medical device safety concerns and to more efficiently up-classify a device type in response to safety issues. 

Proposed rule establishes procedures, criteria for De Novo classification

The proposed rule establishes a pathway for reviewing low- to moderate-risk medical devices and outlines the requirements for De Novo requests. The FDA expects the proposed rule, if finalized, to increase the efficiency of medical device classification – a goal set forth under MDUFA IV. 

The FDA published a proposed rule to establish procedures and requirements for the De Novo classification process, including expectations for the format and content of requests and the criteria for accepting, granting, declining or withdrawing requests. The De Novo process applies to low- to moderate-risk devices for which general or special controls provide a reasonable assurance of safety and efficacy, but for which no existing predicate exists to establish substantial equivalence. Special controls may include performance standards or testing, postmarket surveillance, dissemination of guidelines, and patient registries. 

The proposed rule would allow sponsors to submit a De Novo request after submitting a 510(k) application and receiving a not substantially equivalent (NSE) determination or without submitting a 510(k) if there is no legally marketed device available to test substantial equivalence. Per the rule, De Novo requests should be submitted to the center that has the lead in regulating the device. A request should include a cover page designating it as a “De Novo Request” as well as a table of contents. Requests should also include: 

  • Administrative information: Contact information and the establishment registration number of requester, if applicable.
  • Regulatory history: A statement describing whether there have been prior submissions to the FDA for the device, including any feedback or deficiencies related to those submissions.
  • Name and indications: Any generic, proprietary or trade names for the device, as well as indications for use and information about whether the device would be prescription or over the counter.
  • Device description: A complete description of the device, including narrative description of the device in pictorial representations, device specifications and engineering drawings. The FDA is also requesting that each functional component, properties relevant to the device’s intended use and operational principles be described. The description should also include FDA-assigned reference numbers for legally marketed devices intended to be used with the device, as well as a description of known or reasonably known alternative procedures to address the intended use of the device.
  • Classification summary information: For devices that have not previously been the subject of a premarket notification, the FDA is asking for information to help establish that a De Novo classification is appropriate, including a description of the searches used to determine that no legally marketed device of the same type exists, and a list of potentially similar devices. For devices that have been the subject of a premarket notification, the FDA wants the requester to include pertinent 510(k) numbers and a summary of the search performed to ensure no legally marketed device of the same type exists since an NSE determination was made. The request should also include a recommended class I or II classification, with a description of the general or special controls that provide assurance of safety and effectiveness.
  • Benefits and risks: A summary of known or reasonably known risks and mitigations to each, based on the best available information at the time of submission. Summaries or proposed mitigations should make clear whether it is a general control or special control, with details of each control. The request should also summarize each study used to support the request, including nonclinical laboratory studies and clinical investigations involving humans. The request should also include a discussion demonstrating that the data constitute valid scientific evidence. The rule makes clear that the benefit and risk section must explicitly demonstrate that the probable benefits from the device, when subject to general or special controls, outweigh probable risks.
  • Performance data: Requests should include a reference to published standards – including voluntary standards already recognized by the FDA and those not yet recognized but cited in the De Novo request – relevant to the safety or effectiveness of the device. A technical section should be provided detailing the data from each nonclinical laboratory study or clinical investigation, including a discussion of clinical protocols, subject selection and exclusion criteria, and safety and effectiveness data. 

Upon receiving a De Novo request, the FDA will start a substantive review and may request additional information, grant the request or deny it. A request may be denied if the device is ineligible or if the sponsor hasn’t provided enough information to support a De Novo classification. The rule establishes a timeline of 120 days after receiving a request to review and grant or decline a request. To date, the FDA has authorized 235 devices under the De Novo process.