Clinical Researcher—August 2021 (Volume 35, Issue 6)

SITES & SPONSORS

Lucia Zaccardi

 

In a multilateral paradigm shift, sponsors, payers, regulators, physicians, and patients are increasingly recognizing the value of real-world late-phase (RWLP) trials. The increasing use of real-world data (RWD) and real-world evidence (RWE) to support clinical development has been informed by recent regulatory guidance and accelerated by the global COVID-19 pandemic. Stakeholders across the spectrum are demanding evidence of the benefits of treatment interventions. According to “The State of the Biopharmaceutical Industry 2021,” a survey by GlobalData, RWE ranks fourth among the top trends in the industry.{1} Verified Market Research estimates that the global RWE market will reach $1.9 billion by 2026.{2}

Data from RWLP studies are invaluable in bridging the gap from drug efficacy to effectiveness and from development to commercialization. As pricing and market access pressures mount and the cost of drug development rises, the use of RWE in research and development has become a strategic focus for sponsors and regulators alike. Increasingly, RWE is being used to support regulatory filings and augment traditional randomized controlled trials.

Understanding the Need for Real-World Data and Evidence

Drugs are typically approved on the basis of pivotal Phase III trials involving strict inclusion criteria and clinical endpoints that have been agreed upon between the sponsor and the relevant regulatory agency(ies). Regulatory approval is not synonymous with market adoption and reimbursement. Sponsors are increasingly tasked with demonstrating that a drug is meaningful to patients, prescribers, and payers.

RWD—unstructured data relating to patient health status and/or healthcare delivery that are routinely collected from a variety of sources, including wearables, disease registries, and electronic medical records—form a critical bridge from clinical effectiveness to commercial viability. RWE is the clinical evidence about the usage and potential benefits and risks of a medical product derived from the analysis of RWD. It provides:

• The evidence physicians need to prescribe a drug with confidence.
• The information patients need to adhere to a drug.
• The value story payers need to authorize and pay for a drug.

RWLP trials seek to collect data in less-controlled, more real-world settings. One of the key objectives of these trials is to ensure that once a drug is on the market, it is safe and effective for a broader patient population within the approved indication. RWLP trials may be designed to collect additional efficacy data or to perform surveillance. Given that these trials are often of long duration, they may be costly. As regulators increasingly require RWLP trials, sponsors are seeking ways to conduct these studies in a more efficient, cost-effective manner. This can be accomplished by using integrative technologies and decentralized trial strategies that break down traditional evidence-generation silos.

Regulatory authorities are encouraging the use of RWLP trials and are becoming more supportive of using RWD and RWE in both the pre-approval and post-marketing phases of development. Both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have released guidance on the use of RWD in pre-market decision-making. In 2019, the FDA released draft guidance on the use of RWE in regulatory submissions.{3} An EMA reflection paper, “Regulatory Science to 2025,” promotes the use of high-quality RWD in decision making as one of the EMA’s key strategic goals.{4}

Defining the Scope of RWLP Studies

RWLP studies can be categorized broadly as interventional and non-interventional studies. Interventional studies are generally requested by regulatory agencies to generate supporting data for full market authorization. These studies involve an investigational product (IP) or conditionally approved drug.

Non-interventional studies, which may or may not be conducted with a marketed drug, are used to build or broaden the value story. If a marketed drug is used, it is purchased from the pharmacy or taken during a physician consultation, not supplied by the sponsor. Non-interventional studies generate RWD to support commercial viability.

Table 1: Types of Real-World and Late-Phase Studies

Interventional Studies	Non-Interventional Studies
Late Phase IV studies	Registries
Expanded access or compassionate use programs	Natural history studies
Extended access programs or open-label extensions	Post-authorization safety and efficacy studies
Competitive marketing claims studies	Medical chart review studies
Pragmatic trials under standard of care	Health economics and outcomes research

The regulatory framework for non-interventional studies differs from traditional studies. In the U.S., non-interventional studies do not need to follow Good Clinical Practice guidelines, and data formatting guidelines typically do not apply. In the Europoean Union, these studies need to conform to country regulations, and while submission to ethics committees is required, submission to competent authorities is not.

What non-interventional studies have in common with studies in earlier phases is the need to deliver high-quality data but at reduced site cycle time. That said, conducting real-world and late-phase studies is quite different from conducting clinical trials to support regulatory approval. As such, sponsors need to think differently about the process, costing, and strategies. Implementing a decentralized trial strategy—whether it is a completely virtual trial or a hybrid, decentralized study—and applying remote monitoring enables sponsors to bring these trials to patients in the real world.

Value of Real-World Evidence Outside the Clinical Trial

Outside the controlled clinical trial environment, patients may interact differently with the therapy under investigation. Potential applications for RWE include:

• Supporting regulatory submissions and/or label expansion
• Performing comparative effectiveness research
• Augmenting study design by using RWD as a synthetic control arm
• Understanding subpopulations and heterogeneity of treatment responses
• Informing the design of value-based contracts

The ability to build evidence during and after a clinical trial—whether through natural history studies, patient registries, RWLP data, or health economics and outcomes research, enables sponsors to show differentiated outcomes. This is essential for demonstrating value and ensuring that the product is accessible and affordable to the patients who need it most.

RWE can aid in regulatory decision-making, spur faster approvals, and reduce the need for further studies by providing supporting data that cannot be found elsewhere. Importantly, RWE can be used to inform decisions about which study designs and clinical endpoints are most meaningful for patients, caregivers, physicians, and payers. It can also shed light on the existing patient population size and demographics, which, in turn, helps sponsors better define inclusion and exclusion criteria and reduce trial failure rates through improved protocol design and site selection strategy. Still, while RWLP trials are a practical data source to support pre- and post-approval research, they do not replace proof-of-concept or pivotal studies.

Key Considerations for RWLP Trials

There is no one-size-fits-all approach to designing and conducting RWLP trials, but there are some key considerations to keep in mind. Planning for real-world studies should begin as early as Phase I. Well-designed real-world studies can shorten timelines, lower costs, optimize the impact of research investments, and, most importantly, get therapies to patients more quickly.

When developing the protocol, even if there is no IP, sponsors should be mindful of the need to keep the study procedures as closely aligned to the standard of care as possible. If a late-phase trial includes any procedures that are not performed in routine clinical practice, it will fall under the interventional regulatory framework, even if it is designed as an observational study. If biomarkers are used in a therapeutic area where the treatment pathway is well defined, they may not be reimbursed by the healthcare system if they are not considered to be standard of care.

Managing the protocol so it is simple for both the patient and the site increases the likelihood of success. Leveraging secondary data that already exist in the healthcare ecosystem can reduce the number of data entry points required on the case report form, limiting duplicative efforts and allowing investigators to focus on capturing new information. These secondary data may come from electronic health records, administrative claims, or other real-world sources.

The ultimate goal of RWLP trials is to decrease patient and site burden and costs while increasing value and participation.

Trends in RWLP Trials

Over the next five years, we expect a rapid increase in RWLP trials in the U.S., particularly in the therapeutic areas of oncology, central nervous system diseases, and cardiology. The Asia-Pacific market will be the fastest-growing one for RWD. As sponsors adopt decentralized strategies for RWLP studies, we will see increased cost efficiency in commercialization and improved access.

For many sponsors, lack of research-grade data is an obstacle to using RWE in research and development, emphasizing the need for strategic partnerships. According to Deloitte’s 2020 RWE benchmarking study, more than 80% of companies surveyed are developing partnerships to access new sources of RWD.{5} Companies are also investing in data and analytics platforms that provide more meaningful access to RWD and internal capabilities that enable them to design, conduct, and analyze RWE studies.

Conclusion

Market approval is just the beginning. We are entering a new era of healthcare where demonstration of value through RWD will increasingly determine market access. Sponsors, regulatory authorities, physicians, patients, and payers want to know how a product performs in the real world.

RWLP studies can answer critical questions about the long-term effects of a drug or its impact on different types of patients excluded from the clinical trials used to support market approval. Working with a contract research organization experienced in these post-marketing trials leads to optimal, cost-effective management of RWLP studies and more substantial regulatory submission packages. By accessing, analyzing, and interpreting the right data in late-phase studies, sponsors can fill the knowledge gap between clinical trials and clinical practice, bringing revolutionary therapies to the patients who can benefit from them.

References

1. GlobalData. 2021. Telemedicine expected to be a leading industry trend in 2021, with some telemedicine apps having reported whopping 8,270% increase in downloads in 2020, says GlobalData. https://www.globaldata.com/telemedicine-expected-leading-industry-trend-2021-telemedicine-apps-reported-whopping-8270-increase-downloads-2020-says-globaldata/
2. Verified Market Research. 2021. Real World Evidence Solutions Market Size and Forecast. https://www.verifiedmarketresearch.com/product/real-world-evidence-solutions-market/
3. U.S. Food and Drug Administration. 2019. Submitting documents using real-world data and real-world evidence to FDA for drugs and biologics: Guidance for industry. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submitting-documents-using-real-world-data-and-real-world-evidence-fda-drugs-and-biologics-guidance
4. European Medicines Agency. EMA regulatory science to 2025: Strategic reflection. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/ema-regulatory-science-2025-strategic-reflection_en.pdf
5. Deloitte. 2020. RWE focus is shifting to R&D, early investments begin to pay off. https://www2.deloitte.com/us/en/insights/industry/health-care/real-world-evidence-study.html

Lucia Zaccardi serves as Executive Director, Real-World Late-Phase at Premier Research. She has more than 20 years of international experience in the industry and currently provides strategic planning, coordination, medical knowledge, and expertise to Premier Research’s sponsors. Her therapeutic expertise includes gastroenterology; osteoporosis; cardiovascular disease; and hepatocellular carcinoma, breast, leukemia, lung, and liver cancers.