By Dominic Galante, M.D., Precision for Value
Randomized clinical trials (RCTs) of prescription drugs and other medical products have been considered the gold standard of evidence to support decision making by clinicians and policymakers. However, it is increasingly recognized that most RCTs are unable to generate information about a product’s real-world effectiveness. Measures such as long-term outcomes, comparisons among multiple treatment options, and utilization are not well captured in trials. Furthermore, benefit-risk balance and value for money are best learned in cost-effectiveness or cost-benefit analyses.
After almost three years of public meetings, debate, and building consensus, the 21st Century Cures Act became law on Dec. 13, 2016. The bipartisan legislation allocates a total of $6.3 billion to advance biomedical innovation by funding basic science research at the National Institutes of Health ($4.8 billion) and streamlining regulatory processes at the U.S. Food and Drug Administration ($500 million).
This article will:
- Describe key provisions of the Cures Act pertinent to biopharmaceutical and medical technology product development, regulation, and approval
- Define real-world evidence (RWE) and discuss its use
- Offer examples of ways pharma is currently using RWE
- Suggest considerations for incorporation of patient experience data within study designs and value frameworks
- Propose next steps for life sciences companies
Provisions Of The Cures Act
The Cures Act includes provisions intended to modernize the drug development and approval process, creating avenues for innovation and regulatory flexibility. Such provisions aim to streamline clinical trials using new drug development tools and frameworks and require the FDA to evaluate the use of RWE during the approval process, ensuring that patient experience is reflected in assessments of benefit/risk. Similarly, the FDA is required to evaluate the use of RWE to support the approval of a new indication for a previously approved drug and to help support or satisfy post-approval study requirements. The act stipulates that the FDA create a framework in partnership with industry stakeholders for its RWE program within two years, and within five years create guidance describing “the circumstances under which sponsors of drugs may rely” on RWE, defining acceptable standards and methodologies for collecting and analyzing RWE.
Definition And Uses Of RWE
RWE can be defined as information about a drug that is collected outside of clinical trials. It is not a new concept, but is receiving more attention because the Cures Act seeks to accelerate the FDA drug and medical device approval processes by shifting to RWE. In some instances, the act will shift some of the evidentiary requirements from clinical trials to the post-market setting, or “real world.”
In the United States, a number of organizations focus on health technology assessment and comprehensively review evidence. Evidence summaries typically include information from efficacy trials (both pre- and post-approval) as well as RWE from observational studies. For example, the Institute for Clinical and Economic Review independently evaluates the clinical effectiveness and comparative value of healthcare interventions. Similarly, the Agency for Healthcare Research and Quality funds large-scale systematic reviews of evidence through its Evidence-Based Practice Centers. These reviews are used extensively by payers, but they do not focus specifically on RWE.
Regulatory agencies, including the FDA, are increasingly requesting real-world post-approval studies. Despite this recent focus, these studies have been around for a long time, utilized both pre- and post-approval in the product life cycle.
More recently, industry has been leveraging existing healthcare data sources (e.g., electronic health records) for research purposes, primarily in an attempt to increase efficiency (e.g., lowering per-patient costs). A hybrid study design combining prospective data collection and linkage to medical records or other healthcare data sources is increasingly common.
Demonstration of the value of expensive medicines and other interventions for treating common conditions often requires new study models necessitating large-scale studies and follow-up of 10 years or more. For joint replacements, for example, payers and other stakeholders want to know how long the new joint will function. For some cardiovascular diseases, stakeholders are interested in knowing whether a medication’s use will be able to alter the course of disease.
Flexible approaches to clinical trials, such as adaptive trial design, which allows modifications to clinical trial protocol as outcomes observations are made, increase the potential that certain safety signals, or risks posed to populations not studied, may not be as evident during clinical trials prior to approval. However, flexible approaches often allow for quicker patient access to treatments and real-world data (RWD) collection. Advocates for expediting the approval process suggest that making the product available to patients allows for observational studies that remove artificial controls included in randomized controlled trials. In these circumstances, RWE could help improve understanding of the health impacts of drugs. Regulatory flexibility allowing for drug approvals based on limited information often calls for greater surveillance programs post-launch—a trade-off that the Cures Act aims to address by creating an avenue to leverage RWE in post-marketing studies.
How Life Sciences Companies Are Leveraging RWE
Life sciences companies are capitalizing on the use of RWE to demonstrate the safety of their products and expand opportunities for precision medicine. Below are two such examples.
Comparing Safety of Alternative Treatments for Diabetes
Astra Zeneca leveraged RWE to evaluate cardiovascular risk associated with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors versus sulfonylureas for diabetes treatment in 200,000 patients. For the study, the company created comparator groups on the basis of presence or absence of codes for CVD in claims data as well as similar demographic, clinical, and other risk factors from patient health records. It then calculated hazard ratios (probability of death ratios) for each group. This analysis showed no increased risk of heart failure from use of DPP-4 inhibitors compared with sulfonylureas.
Accelerating Clinical Research
In 2016, Celgene Corporation announced a collaboration with M2gen and the Oncology Research Information Exchange Network (ORIEN), an alliance of leading cancer centers throughout the United States. The collaboration will generate massive amounts of genetic and clinical data on patients in an effort to identify eligible patients to participate in biomarker-driven clinical trials. Patients will have access to therapies most suited to the unique molecular features of their disease.
Comprehensive Incorporation Of Patient Experience
Existing value frameworks typically give less than full consideration to ways that drugs and medical technologies create value for patients, caregivers, and the general public. The passage of the Cures Act presents pharmaceutical manufacturers with opportunities to integrate (into pre- and post-approval studies) tools for more robust investigation of patients’ experiences with therapies. Collection and reporting of this data will further accelerate development of more comprehensive value frameworks. Frameworks impact drug reimbursement models; optimally, they will include value drivers that take into account:
- Clinical utility and health outcomes associated with the product
- Impact on nonmedical benefits for the patient or caregiver, the patient experience, and patient economics, such as out-of-pocket costs
- Effect on revenues and costs for a provider, payer, or provider-sponsored plan
- Impact on the healthcare system, employers, and the public
Next Steps For Life Sciences Companies
Many provisions aimed at expediting drug development require the FDA to issue further guidance; however, the biopharma industry can take some steps now to benefit from regulatory changes.
Step 1: Invest in the study and application of collaborative drug development tools.
Expansion of the Center for Drug Evaluation and Research’s Drug Development Tool Qualification Programs supports the commitment of the CDER and the FDA to explore novel approaches to drug development. While awaiting official guidance on this topic, the industry can move forward with submitting letters of intent to evaluate tools. Biopharma companies should consider engaging in proactive conversations with the FDA early in development to understand which innovative tools might apply to their programs and potentially expedite development, getting treatments to patients faster.
Step 2: Expand capabilities required to access, collect, and analyze RWD.
RWD, including data from claims, EHRs, surveys, registries, and laboratory tests— even social media, apps, and wearable devices—can present an opportunity to link disparate data sources to provide a better understanding of the patient experience and what happens during an episode of care. A 2017 RWE benchmarking study found that many biopharma companies are starting to invest in RWE capabilities and exploring a number of use cases.
Step 3: Explore public-private partnerships.
Many RWE use cases extend beyond drug development and approval. RWE can help demonstrate improvements in patient outcomes across large populations and support market access. Many public-private partnerships, such as the Reagan-Udall Foundation, are playing a larger role in improving access to data and incorporating RWD into drug applications for new indications. RWD can have certain biases; as such, advances in health information technology, standards, and methodologies need to continue for it to be widely accepted to support regulatory approvals. Best practices on how to incorporate RWE into research and development will continue to emerge from public-private partnerships; other examples of multiple stakeholders working together to advance RWE use and interpretation are likely to develop as well.
RWE is neither a panacea nor a replacement for RCTs, which for the foreseeable future are likely to remain the gold standard for demonstrating safety and efficacy. However, RWD can have a broad number of applications. As the use of RWE expands, it is anticipated that an acceleration in the improvement of the methodologies and regulatory science associated with its use will occur, building confidence in its utility.
The Cures Act presents an opportunity for biopharma companies and the FDA to discuss what the RWE framework could look like. Early and regular dialogue can help companies understand how to benefit from Cures-driven regulatory process changes, building capabilities to access, integrate, and analyze real-world and patient-experience data. As the volume, variety, and, indeed, the velocity of RWD continue to grow, the need for newer information management and analytics technologies is likely to become even more apparent.
About The Author:
Dominic Galante, M.D., is chief medical officer of quality and population health solutions at Precision for Value. He is a leading authority in managed care, pharmaceutical markets, clinical quality management, healthcare provider performance-based delivery and reimbursement models, healthcare system migrations, community health alliances, organizational change, communications, and medical marketing.