On December 6, 2018, Commissioner Scott Gottlieb introduced the FDA’s extremely anticipated new strategic framework for assessing the potential use of real-world proof (RWE) in reference to the company’s drug and biologic evaluation program. The Framework follows a collection of steerage paperwork, demonstration tasks and different initiatives that FDA has already undertaken to discover and facilitate using real-world knowledge (RWD) and RWE within the context of post-market surveillance actions, medical trials and medical system regulatory determination making.
The Framework outlines key motion gadgets for FDA’s additional evaluation of using RWE and RWD and improvement of relevant requirements that might be of curiosity to producers, RWD corporations and well being care suppliers concerned about harnessing RWD and RWE to reinforce affected person security and remedy, and different stakeholders.
As FDA Commissioner Scott Gottlieb famous, RWD and RWE is a “top strategic priority” for the company. FDA issued the Framework in response to the 21st Century Cures Act (Cures Act), which added part 505F (21 USC § 355g) to the Federal Meals, Drug, and Beauty Act (FDCA), requiring FDA to determine a program to guage the potential use of proof from medical expertise to assist (1) help the approval of a brand new indication for a drug already accepted beneath part 505(c) (21 USC § 355(c)) of the FDCA or (2) help or fulfill drug post-approval research necessities. FDA introduced it is going to additionally apply the Framework to organic merchandise licensed beneath the Public Well being Service Act.
The Framework shouldn’t be FDA’s first foray into the difficulty of RWD and RWE. Key prior initiatives and steerage paperwork embrace:
The Framework, nevertheless, is significant in its institution of a extra definitive roadmap for FDA’s improvement of requirements for using RWD and RWE. Particularly, the Framework outlines numerous areas during which FDA will consider using RWD and RWE; FDA’s plan for evaluating how RWD could be included into research designs and the regulatory issues for such use of RWD; and FDA’s plan for creating steerage in quite a lot of key areas, together with on knowledge requirements and extra sources of RWD to assist handle present gaps within the seize of key info.
FDA plans to make use of the Framework to guage each the potential use of RWE to help labeling modifications, corresponding to including or modifying a sign, and to fulfill post-marketing necessities. FDA said it intends to proceed to interact with inner and exterior stakeholders to adapt or develop requirements and implementation methods, together with via future public conferences and different boards.
Overview of Framework
The Framework identifies RWD and RWE as follows:
Actual World Knowledge (RWD): knowledge referring to affected person well being standing or supply of well being care routinely collected from quite a lot of sources, reminiscent of registries, collections of digital well being data (EHRs), and administrative and medical claims databases.
Actual World Evidence (RWE): medical proof concerning the utilization and potential advantages or dangers of a medical product derived from evaluation of RWD by means of, e.g., randomized trials (giant easy trials, pragmatic medical trials) and observational research (retrospective or potential).
Evidence That Will Be Thought-about RWE
FDA distinguishes RWE from conventional medical knowledge. Evidence from conventional medical trials won’t be thought-about RWE. The company usually considers conventional medical trials to be research supported by a analysis infrastructure largely separated from routine medical apply, designed to regulate variability (e.g., by means of restrictive eligibility standards) and to maximise knowledge high quality (e.g., by way of randomization and double-blinding).
FDA notes, nevertheless, that RWD might come up from hybrid design trials (e.g., the place sure trial knowledge is collected from RWD sources, resembling EHRs or claims knowledge, whereas different trial knowledge is collected from study-specific interventions) or pragmatic design trials (i.e., trials that embrace parts that extra intently resemble routine medical apply).
Key FDA Motion Merchandise: As a part of the Framework, FDA will consider the strengths and limitations of pragmatic approaches to review design that use RWD, together with the: (1) kinds of interventions and therapeutic areas that could be well-suited to routine medical care settings, (2) high quality of knowledge that may be captured in these settings, (three) variety of sufferers that may be accessed (notably when outcomes are uncommon) and (four) variations inherent in medical apply.
Likewise, FDA posits that non-interventional observational research (both retrospective or potential) might generate RWE. In accordance with the company, observational research sometimes share sure traits, similar to using outcomes when there’s much less diagnostic variability and the place the shortage of blinding is much less more likely to affect outcomes (e.g., myocardial infarction or stroke). The place blinding is infeasible, FDA will search to determine conditions when researchers can probably management bias through the use of outcomes which might be much less more likely to be influenced by information of remedy task, corresponding to clinically goal outcomes (e.g., stroke or tumor measurement).
FDA notes that as a result of observational research rely on remedy task by a doctor slightly than at random, they pose a problem for establishing causal inference, and up to date efforts to duplicate randomized trial outcomes with observational research have proven divergence in outcomes.
Key Motion Merchandise: FDA intends to focus on quite a lot of areas that would have an effect on the power to attract a dependable causal inference, together with: (1) traits knowledge enhance the prospect of a legitimate outcome; (2) traits of research design and evaluation that enhance the prospect of a legitimate outcome (e.g., whether or not an lively comparator can enhance the prospect of a legitimate end result and whether or not there’s a position for non-inferiority designs); and (three) the sensitivity analyses and statistical diagnostics that must be pre-specified to generate RWE for effectiveness.
Use of RWD and RWE to Help Effectiveness Determinations
FDA notes it has an extended historical past of utilizing RWE to watch and consider the post-market security of drug merchandise. The company’s personal main supply for pharmacoepidemiologic queries and research (i.e., analyzing the utilization and results of medicine in giant numbers of individuals) has been medical claims and pharmacy allotting knowledge collected via the Sentinel System. The company’s use of RWE to help effectiveness determinations, nevertheless, has been rather more restricted. So far, FDA has accepted RWE to help drug product approvals in restricted situations which might be primarily in oncology and uncommon illnesses.
Key Motion Merchandise: To facilitate using RWD and RWE in selections relating to product effectiveness, FDA introduced a three-part strategy to evaluating whether or not RWD can generate RWE to help regulatory selections relating to the effectiveness of a drug or biologic product. Particularly, FDA will think about:
Whether or not the RWD are match to be used;
Whether or not the trial or research design used to generate RWE can present sufficient scientific proof to reply or assist reply the regulatory query; and
Whether or not the research conduct meets FDA regulatory necessities (e.g., for research monitoring and knowledge assortment).
FDA intends to construct out this strategy by way of stakeholder engagement, using inner processes that interact senior company management, demonstration tasks, and extra steerage paperwork to help sponsors serious about utilizing RWE in help of their work.
Making use of comparable standards as in its RWE for Medical Units steerage, FDA said that the power of RWE relies upon on the reliability and relevance of the underlying knowledge. The reliability evaluation considers the validity and integrity of the info (i.e., knowledge assurance and knowledge high quality management), whereas the relevance evaluation considers whether or not the info are match for the aim and whether or not the info seize is related. Beneath the Framework, FDA additionally intends to guage whether or not its present steerage paperwork associated to using digital knowledge in medical investigations are related to totally different research designs utilizing RWD to generate RWD for drug product effectiveness.
Health of Knowledge and Gaps in RWD Sources
A key element of FDA’s capacity to make use of RWD and RWE in regulatory determination making is making certain that the RWD and RWE is appropriate for the proposed use. As famous above, FDA’s RWE experience has, thus far, been developed largely from working with claims—relatively than EHR—knowledge.
With respect to claims knowledge, FDA notes that it has a great understanding of the strengths and limitations of such knowledge. For EHR knowledge, which tends to incorporate rather more strong medical info, vital challenges come up from the truth that key info is usually captured as unstructured knowledge (e.g., in doctor notes) that can’t be readily harnessed to be used—a problem that’s exacerbated insofar as huge quantities of EHR knowledge is important for a specific objective. FDA’s recognition of the challenges that EHR knowledge presents is clear in steerage paperwork it has beforehand issued, together with its Use of Digital Well being Document Knowledge in Medical Investigations steerage. Moreover, FDA notes that EHR knowledge typically fails to uniformly code or embrace laboratory check outcomes and should not absolutely seize affected person outcomes and the development of signs and circumstances.
One other limitation of claims and EHR knowledge is the lack to successfully seize knowledge relating to affected person expertise. Thus, using registries and EHR methods with patient-targeted knowledge assortment platforms, and digital well being instruments together with wearables and cellular medial apps, shall be essential mechanisms for the company to think about in filling present gaps in important RWD. Certainly, the MyStudies software, developed to help knowledgeable consent in addition to safe knowledge assortment from sufferers at a number of research websites or knowledge companions, represents an effort by the company to facilitate investigators’ capability to gather real-time affected person expertise knowledge to help FDA-regulated research.
FDA’s Commitments beneath the Framework
FDA famous it’s actively creating RWD knowledge requirements (guidelines relating to how a specific sort of knowledge ought to be outlined, formatted or exchanged between pc methods) for regulatory use.
FDA additionally outlined quite a lot of commitments and plans for the Framework associated to review designs utilizing RWD to help effectiveness and associated regulatory issues. Particularly, FDA indicated it intends to:
Consider the potential position of observational research in contributing to proof of drug product effectiveness;
Develop steerage on issues for designing medical trials that embrace pragmatic design parts and that generate proof of effectiveness for regulatory selections. FDA will discover pragmatic approaches to every stage of a medical trial, together with recruiting and enrollment of sufferers, methods for facilitating interventions and approaches to assessing outcomes;
Think about steerage on using RWD to generate exterior management (e.g., historic management) arms;
Concern steerage about observational research designs utilizing RWD, together with whether or not and the way these research may present RWE to help product effectiveness in regulatory choice making. FDA may also think about reporting necessities for such research, analogous to ClinicalTrials.gov reporting necessities for medical trials, used to help effectiveness determinations as a way to promote transparency;
Think about whether or not present steerage paperwork that handle using digital knowledge in medical investigations adequately handle considerations related to totally different research designs utilizing RWD to generate RWE or whether or not further steerage is required;
Look at how FDA’s regulatory necessities are utilized to knowledge from randomized medical trials which are built-in into the well being care system and observational research when they’re meant to generate RWE for regulatory choice making;
Think about whether or not its present steerage adequately addresses inspection-related considerations related to totally different sources of RWD used to generate RWE relating to the security and effectiveness of drug merchandise, e.g., consent and privateness; and
Finalize the Use of Digital Data and Digital Signatures in Medical Investigations Beneath 21 CFR half 11 – Questions and Solutions steerage and think about its applicability to totally different research designs. FDA will even challenge further steerage as wanted on regulatory issues raised by totally different research designs utilizing RWD to generate RWE.
The Framework reveals various priorities for FDA because it continues to guage the right position and use of RWD and RWE. Whereas the Framework is expressly restricted to the drug and biologic evaluate packages, the issues described within the Framework could also be reflective of areas of focus for the company’s regulatory technique extra broadly, together with with respect to medical system regulation. In that regard, stakeholders might want to think about the next areas of focus by FDA:
The event and use of digital well being instruments and different platforms to reinforce the gathering of patient-reported outcomes;
Fixing for challenges referring to EHR knowledge, together with the power to effectively and successfully summary unstructured knowledge and normalize giant quantities of EHR knowledge collected from totally different methods and a number of entities; and
Correctly documenting the implementation of FDA requirements that might be developed underneath the Framework to reveal compliance throughout FDA’s assessment of submitted RWD or RWE, together with by means of insurance policies and procedures and strong documentation of knowledge requirements, knowledge management and different knowledge administration mechanisms.
The power to leverage RWD and RWE for discrete elements of medical trials and different regulatory makes use of (corresponding to speculation era, trial feasibility assessments, and as a part of hybrid medical trials). The position of RWE to help advertising claims is especially related in mild of the Medical Product Communications That Are Constant With the FDA-Required Labeling – Questions and Solutions steerage. Whereas the Framework and proposed future motion gadgets handle numerous points, the Framework leaves open questions relating to using RWE to help advertising claims.