In December 2016, then-President Barack Obama signed the 21st Century Cures Act (Cures Act) into law. This key piece of bipartisan legislation increased funding for medical research and development and innovation, opioid addiction treatment and prevention, mental health, and developments in health information technology. The Act has the potential to have a significant effect on those involved in the US healthcare system, particularly for strategic evidence development and market access. In this article, we summarize the significant provisions of the Cures Act and highlight areas of impact for pharmaceutical and device manufacturers, payers, and patients.
Overview of the Cures Act
Significant provisions of the Cures Act include:
- Changes to regulatory evidentiary requirements: The Cures Act made several changes to regulatory pathways, with the goal of streamlining product approval. Now, new types of evidence (eg, real-world evidence [RWE] and surrogate endpoints) and adaptive trials (ie, clinical trials with prospectively planned modifications that are dependent on data obtained during the trial itself) can be included in product approval submissions.
- Updates to Food and Drug Administration Modernization Act (FDAMA) 114: There was further guidance around proactive manufacturer communications of healthcare economic information (HCEI) to relevant stakeholders, which clarified and expanded how manufacturers can approach information sharing.
- Establishment of new drug approval pathways: Two new pathways for drug approval were created: a regenerative medicine advanced therapy (RMAT) designation for cellular and gene therapy products; and a breakthrough designation for medical devices.
- Increases in patient focus: More attention will be placed onto the “patient experience” in drug development; manufacturers should consider the impact of a disease, condition, or therapy on patient lives as well as patient treatment preferences when developing products for regulatory approval.
- Improvements in interoperability and data management practices: The Cures Act hopes to enhance the interoperability of electronic health records (EHRs) and improve data management by increasing data sharing and collaboration between stakeholders throughout the care continuum.
Relevance to Manufacturers, Payers, and Patients
Pharmaceutical and Device Manufacturers
The Cures Act has the potential to significantly decrease the time and resources needed to develop, approve, and launch new products in the US market. The new provisions require the FDA to establish a framework to evaluate RWE in support of new doses, indications, or populations for currently approved drugs (Section 3022) and implement that framework within 2 years after the enactment date of the Cures Act. In addition, within 5 years of the enactment date, the FDA must issue draft guidance describing: 1) “the circumstances under which sponsors of drugs may rely” on RWE; and 2) acceptable standards and methodologies for collecting and analyzing RWE. On December 7, 2018, the FDA published the much-anticipated “Framework for FDA’s Real-World Evidence Program
” for drugs and biological products. Development of this framework motivates manufacturers to evaluate and expand their capabilities for capturing and analyzing these data.
As part of this, manufacturers need to consider how to best utilize RWE throughout a product’s entire life cycle, perhaps starting earlier in the drug development process than before. Beyond drug development and approval, RWE can help support outcomes-based contracting, reimbursement, and the communication of product value. For example, studies designed to demonstrate how a product will perform in larger, more diverse populations under routine practice conditions for a longer period of time than typically seen with randomized controlled trials (RCTs) yield valuable information that has historically not been widely available. RWE can also help advance knowledge and understanding of disease states, potentially opening new pathways for care innovation. While further FDA guidance is still outstanding for some aspects of the Cures Act (see Table 1), manufacturers should engage in early development conversations with the FDA to gain clarity on specific RWE, surrogate endpoints, and adaptive tools that may be leveraged to produce the most valuable outputs.
HCEI Sharing. In addition to the increased role of RWE in FDA decision making, Section 3037 of the Cures Act expanded and clarified the definition of HCEI that can be shared by manufacturers and addressed the particular audience for these communications. The Cures Act amended FDAMA 114 by expanding the audience to “a payor, formulary committee, or other similar entity with knowledge and expertise in the area of health care economic analysis, carrying out its responsibilities for the selection of drugs for coverage or reimbursement.” Final guidance released by the FDA in June 2018 further expanded the audience to include drug information centers, committees that perform health technology assessments, pharmacy benefit managers, and other multidisciplinary entities that make assessments and decisions related to formulary management, coverage, and reimbursement.
Furthermore, the definition of HCEI was broadened to include information that relates to an FDA-approved indication (rather than specifying that information must be “directly related,” as stated in FDAMA 114) and included “clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis that identifies, measures, or describes the economic consequences, which may be based on the separate or aggregated clinical consequences of the represented health outcomes, of the use of a drug.” This clarification provides a safe harbor for HCEI discussions between manufacturers and additional stakeholders, which may lead to more open and transparent discussions of product value. Legislative efforts are currently underway to reintroduce H.R. 2026 from last Congress, which amends Section 3037 to include pre-approval information exchange. Previous hearing testimony given on this, from the Energy and Commerce Committee, can be found here.
Patient Voice. The increased focus on the importance of the patient voice in drug development also has important implications for manufacturers. The paradigm is shifting—patient-specific understanding regarding burden of disease, symptom management, satisfaction with treatment, how a patient feels and functions, risk vs benefit of efficacy and safety, adherence, compliance, patient-perceived value and importance, and patient economics (ie, out-of-pocket costs) will likely have an increasing role in clinical development programs thanks to the Cures Act. Historically, many clinical trials have utilized primary endpoints that have regulatory and statistical significance but may not translate well to patient benefit from their unique perspective. Therefore, input is needed to identify additional endpoints that are clinically meaningful to patients and positively impact their lives. For example, a 75% reduction in the Psoriasis Area and Severity Index (PASI 75) is currently the standard primary endpoint for RCTs that evaluate psoriasis agents, but some patients achieving PASI 75 may not feel a substantial overall difference in symptoms such as itching, flaking, and scaling. Patient input would also be very valuable early on, particularly in the creation of new disease assessment tools, as current tools may not include symptoms that are the most significant and meaningful to patients. Performing qualitative and quantitative research to gain a better understanding of patients’ perspectives on disease burden, symptoms, and preferences early in the clinical development program can help inform the design of clinical and RWE studies and tools to produce valuable data for all stakeholders.
Timing of Information Exchange. The legislative changes outlined in the Cures Act have implications for the way payers make their coverage decisions and the evidence that manufacturers develop during and alongside clinical trials. The possibility of faster drug development and approval means that payers will need information prior to product approval in order to be prepared to make appropriate coverage decisions at launch for new, and sometimes high-priced, therapies. Additional funding for innovative treatments in cell and gene therapy, as well as regenerative medicine, will likely bring forth novel treatments / treatment approaches for diseases that payers may be unfamiliar with, and where exists a paucity of evidence by which to make coverage decisions. Based on the aforementioned scenario, there is a need for early bi-directional information sharing prior to approval of new molecular entities and line extensions; results from a 2018 Academy of Managed Care Pharmacy workshop showed that payers would ideally like information 12 to 18 months prior to drug approval for appropriate fiscal planning.
Real-World Evidence. Payers are familiar and comfortable with utilizing data from RCTs for the evaluation of drugs for formulary placement and coverage decisions. However, with the anticipated submission of RWE by manufacturers, payers will need to incorporate this new data source into the evaluation of products at launch and thereafter. The need for transparency in the data provided by manufacturers as well as selection bias and information gaps typically present in RWE are some of the challenges payers have highlighted. Manufacturers should discuss the types of RWE that will be most useful (eg, pragmatic trials, retrospective claims analyses, etc) and impactful for formulary decision making and build RWE into their plans early in product development. To facilitate this, the payer voice needs to be heard earlier in clinical and RWE development planning.
Value-Based Contracts. As reimbursement models become more value-based, the addition of RWE to a product’s evidence package is likely to become significantly more important to payers making coverage decisions. Value-based contracts (VBCs) link payment to real-world product performance. As such, RWE will play an important role in assessing risk, identifying appropriate contract terms, and managing existing contracts. With RWE, payers will gain insight into how a product will perform in various patient populations under routine clinical practice conditions rather than under the highly standardized conditions of RCTs. Depending on the data available, use of RWE may help address key challenges in establishing VBCs. For example, an appropriate measure of value attributable to therapy that can be identified, measured, and tracked should be chosen as a link to payment. Robust and validated systems will be needed to capture and analyze the outcomes data for individual patients in order to support payment agreements.
The Patient-Focused Drug Development (PFDD) section of the Cures Act places an emphasis on the need for patient engagement in drug development and is composed of provisions designed to define and standardize the use of patient experience data in regulatory programs. Patient experience data are defined as “data collected by any person (including patients, family members, and caregivers of patients, patient advocacy organizations, disease research foundations, researchers, and drug manufacturers) that are intended to provide information about patients’ experiences with a disease or condition.” Historically, regulatory standards for patient experience data have centered on the use of patient-reported outcome (PRO) endpoint data in pivotal clinical trials. The content outlined in the FDA’s plan for PFDD suggests that the new guidance will address different methods to gather patient experience data (eg, patient stakeholder input, advisory boards, etc) that may be used across the cycle of drug development.
The topics for the several PFDD guidances outlined in the FDA’s plan describe patient experience data as they relate to burden of illness, burden of treatment, meaningful clinical outcomes assessments, and patient-acceptable benefit-risk ratios. The FDA plan targets the development of numerous guidance documents within the next 5 years to provide clarity on how to develop, collect, and communicate patient experience data (Table 1). The issuance of this PFDD plan suggests drug development will involve the systematic inclusion of patients’ perspectives and experiences across the drug development cycle as an integral part of the approval and development process, thus making it essential for manufacturers to include the patient perspective within clinical development.
Table 1. Summary of Guidance and Timeline for Issuing PFDD Guidance Documents
||Focus on methods and approaches to “collect meaningful patient input throughout the drug development process, and methodological considerations for data collection, reporting, management, and analysis.”
||December 18, 2017
||Draft guidance released in June 2018
||Planned: Q1 2020
||Aims to delineate methodological approaches to “collecting comprehensive and representative patient and caregiver input on burden of disease and current therapy.”
||October 15–16, 2018
||Planned: Q2 2019
||Planned: Q1 2021
||Focus on approaches to identifying a “holistic set of impacts that are important to patients” with a specific disease.
||Planned: Q4 2019
||Planned: Q2 2020
||Planned: Q4 2021
||Designed to define standards for the selection, design, and development of clinical outcome assessments and will “as appropriate, revise or supplement the 2009 Guidance to Industry on Patient-Reported Outcome Measures (2009).”
||Planned: Q2 2019
||Planned: Q2 2020
||Planned: Q2 2021
||Provide stakeholders with information required to “develop and submit proposed draft guidance relating to patient experience data for consideration by FDA” on patient experience-related topics (eg, “planning and conduct of clinical trials to be more patient focused, enhancing patients’ ability to enroll and continue to sustain participation in clinical studies, and the quality of their experiences as participants in such studies”).
||Planned: Q2 2018
||Planned: Q4 2019
||Outline how the FDA intends to respond to patient experience submissions, and time frames for response to submissions made for the drug development qualification program for COAs and PROs.
||Planned: Q4 2019
||Planned: Q4 2020
||The final guidance is expected to define how the FDA intends to use “relevant patient experience data and related information, including with respect to the structured benefit-risk assessment framework” to “inform regulatory decision-making.”
||Planned: Q4 2019
||Planned: Q4 2020
||Planned: Q4 2021
Key: COA – clinical outcome assessment; FDA – Food and Drug Administration; PRO – patient-reported outcome.
Patient-centered outcomes and their use in discerning the value of treatment have been explored in several emerging value-based frameworks, which attempt to evaluate drugs to aid in payer, patient, and physician decisions regarding treatment. In frameworks such as that developed by the American Society of Clinical Oncology, patient experience data may provide higher value to drugs that show meaningful improvements in domains such as symptom palliation or treatment-free intervals. Similarly, the Institute for Clinical and Economic Review (ICER) is a nonprofit organization that seeks “to try to provide a fair and objective analysis of evidence as the starting point for bringing all stakeholders—patients, doctors, drug makers, insurers, and others—together to seek better ways to help patients gain sustainable access to high-value care.” Patients are an essential element of ICER’s mission to help provide an independent source of analysis of evidence on effectiveness and value to improve the quality of care that patients receive.
The Cures Act seats healthcare innovation at the head of the US national agenda. As previously mentioned, this key piece of legislation will have a vast number of implications for manufacturers, as it significantly impacts clinical research and drug development. Future health economic analyses may uncover the true effect of the Cures Act as RWE is incorporated into regulatory decision making. Despite the assistance from administrative hurdles that the Cures Act provides, manufacturers will have a responsibility to collaborate with regulatory entities to advance drug development. It would be prudent for manufacturers to develop a sound strategy to maximize and leverage these new legal and regulatory considerations, to ensure product success. To keep abreast of how the FDA is progressing with implementing the Cures Act initiatives, check here to monitor updates on specific deliverables tied to each initiative.
The article should be referenced as follows:
Dobie C, Kang I, Ruban C, Duhig A. 21st Century Cures Act: Impact on US stakeholders. HTA Quarterly. Spring 2019. May 16, 2019.
- 21st Century Cures Act. H.R. 34, 114th Congress. 2016. https://www.gpo.gov/fdsys/pkg/BILLS-114hr34enr/pdf/BILLS-114hr34enr.pdf.
- Chalasani M, Vaidya P, Mullin T. Enhancing the incorporation of the patient’s voice in drug development and evaluation. Res Involv Engag. 2018;4:10. doi:10.1186/s40900-018-0093-3.
- Goble JA. The potential effect of the 21st Century Cures Act on drug development. J Manag Care Spec Pharm. 2018;24(7):677-681.
- ICER. Patient Participation Guide. April 2018. https://icer-review.org/patient-participation-guide/.
- Jackson J, Onwudiwe N, Khachatourian KW, Saha S. Best practices to implementing proactive communications between manufacturers and payers. Presented at: AMCP Managed Care & Specialty Pharmacy Annual Meeting 2018; April 23-26, 2018; Boston, MA.
- Schnipper LE, Davidson NE, Wollins DS, et al. Updating the American Society of Clinical Oncology Value Framework: revisions and reflections in response to comments received. J Clin Oncol. 2016;34(24):2925-2934.
- US FDA. 21st Century Cures Act. https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/significantamendmentstothefdcact/21stcenturycuresact/default.htm.
- US FDA. Drug and Device Manufacturer Communications with Payors, Formulary Committees, and Similar Entities—Questions and Answers. Guidance for Industry and Review Staff. Final Guidance. June 2018. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537347.pdf.
- US FDA. Plan for Issuance of Patient-Focused Drug Development Guidance. May 2017. https://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm563618.pdf.