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  • How to Improve Transparency with Real World Data to Support Market Access?

    How to Improve Transparency with Real World Data to Support Market Access?

    The USFDA defines real-world data (RWD) as ‘the data relating to patient health status and/or the healthcare delivery that is routinely collected from a variety of sources’, and real-world evidence (RWE) as ‘the clinical evidence regarding the usage and potential risks/benefits of a medical product obtained from analysis of RWD.’[1] RWD includes data from electronic health records (EHRs), administrative and medical claim databases, pharmacy data; data from product, patient, and disease registries, patient-generated data (including in-home use settings, social media data, patient forums, etc), and data gathered from other sources that can inform on health status.[1]

    RWD has been extensively used for pharmacovigilance in the form of phase 4 post-marketing surveillance studies. Lately, it is being realised that RWE and RWD can play additional role in the drug approval cycle. For example, the approval of Avelumab for the treatment of metastatic Merkel cell carcinoma (MCC) in March 2017 utilised electronic health record (EHR) data as historical control data for efficacy. Likewise, the approval of Lutetium Lu 177 dotatate for the treatment of certain neuroendocrine tumors in 2018 by the USFDA made extensive use of safety and efficacy data from the ERASMUS study, which was an expanded access study.[2]

    RWD has also been used for market access and to make reimbursement decisions in several countries. For example, in France, RWD collected during temporary authorization for use of a drug can be used to assess the price and level of reimbursement through health technology assessment (HTA). In the UK, RWD collected during early access to medicine scheme can be used as dossier of market access. In fact, the UK NHS has performed cost-effectiveness studies based on RWE and established a scheme to collect RWD for pharmacovigilance purposes. RWD are also used for pay-for-performance schemes in the USA.[3]

    Despite the raising importance of RWD in improving market access, a constant critique of RWD is that, since RWD is collected from routine healthcare, there is no set objective for RWD collection, unlike randomized controlled trials (RCTs) which generally have an objective and hypothesis. In other words, since RWE studies are secondary analysis of existing data that are collected unplanned (i.e., without a specific objective), they are susceptible to bias; this is not that prominent an issue for pre-planned studies of prospectively collected data (such as RCTs). Thus, there are high chances that RWE studies are more susceptible to results-driven design modifications than RCTs, thus bringing a question about transparency of RWD and the resulting RWE.[4]

    Data transparency improves the ability of decision-makers to assess the quality and validity of an RWE study by giving a deeper understanding of why and how the research was conducted and whether the results reflect pre-established questions and methods. It also facilitates the replication of results and an understanding of why findings of apparently similar studies differ. In line with these concepts, attempts are being made to improve RWD transparency, with an intention to strengthen the confidence that different stakeholders have on RWD, thereby further boost its usage for different aspects, including enhancing market access of drugs.[4]

    One such method for improving data transparency is by promoting registries for RWE studies. Though existing registries register and ClinicalTrials.gov) collect many features that are required for improving data transparency, they focus on primary data, and are not specific for RWD.[4] In 2017, International society for Pharmacoeconomics and Outcomes Research (ISPOR) and International Society for Pharmacoepidemiology (ISPE) formed a joint task force to identify good practices for addressing the concerns and to enhance confidence in evidence derived from RWE studies. The ISPOR-ISPE Special Task force recommends the researchers should declare the hypothesis to be tested, post study protocols and analysis publicly; and during publication attestation of any conformation or deviation from the initial study protocol.[4] In lines with the same, the ISPOR RWE registry was formally launched in October 2021, and represents a fit-for-purpose platform for registering RWE study designs prior to data collection, with an intention to facilitate RWD transparency and to elevate the trust in the study results; the RWE registry can be accessed at https://osf.io/registries/rwe/discover.

    Another method to improve RWD transparency is the concept of tokenization of healthcare data, by which different sources of patient-level RWD (for example; claims, EHR, registries, molecular biomarkers, and laboratories) can be linked to provide a complete, non-duplicate, and comprehensive understanding of the patient’s health. By providing an option to cross-check same patient data from different sources, tokenization can help improve the confidence in RWD from different sources.[5]

    RWD play enormous role in research and development process, they also help in estimating the risks and benefits of any treatment in real world scenarios. Enhancing RWD with transparency can go a long way in increasing its usage for market access.

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    References

    1. Framework for FDA’s real-world evidence program. Dec 2018. Available from: https://www.fda.gov/media/120060/download
    2. Feinberg BA, Gajra A, Zettler ME, et al. Use of real-world evidence to support FDA approval of oncology drugs. Value Health. 2020 Oct;23(10):1358-1365. 
    3. Pulini AA, Caetano GM, Clautiaux H, et al. Impact of real-world data on market authorization, reimbursement decision & price negotiation. Ther Innov Regul Sci. 2021;55(1):228-238.
    4. Orsini LS, Berger M, Crown W, et al. Improving transparency to build trust in real-world secondary data studies for hypothesis testing-why, what, and how: recommendations and a road map from the real-world evidence transparency initiative. Value Health. 2020 Sep;23(9):1128-1136. 
    5. Dagenais S, Russo L, Madsen A, et al. Use of real-world evidence to drive drug development strategy and inform clinical trial design. Clin Pharmacol Ther. 2022;111(1):77-89.

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  • An Overview of Registry Studies and Considerations for Regulators

    An Overview of Registry Studies and Considerations for Regulators

    A patient registry has been defined as “an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition or exposure, and that serves a predetermined scientific, clinical or policy purpose.”(1) Patient registries provide an infrastructure for the standardized recording of data from routine clinical practice on individual patients classified by a characteristic or an event. These may include the diagnosis of a disease (disease registry), the occurrence of a condition (e.g., pregnancy registry), a birth defect (e.g., birth defect registry), a molecular or genomic or any other patient characteristics, or an encounter with particular healthcare service.(2, 3)

    Studies based on registries (registry studies) aim to investigate a research question using the infrastructure of new or existing registries for patient recruitment and data collection. The objectives of these studies may include epidemiological data collection, trend analysis, efficacy, safety, long term and short term outcomes of different treatment options, and patient-reported outcomes such as quality of life and patient satisfaction.(3) A registry study may implement primary data collection and/or secondary use of data collected in a patient registry for a different purpose from the given study. When ‘patient’ and ‘registry’ are used in combination (i.e., patient registry), they highlight the focus of the dataset on health information.(4)More importantly, such registry studies offer different stakeholders in the pharmaceutical industry (including prescribers, healthcare providers, regulators, payers, government, and also the patients) an additional layer of evidence beyond clinical trials, surrounding the efficacy and safety of drugs and medical devices. (1)

    Patient registries are particularly useful for generalizing the findings of clinical trials to populations not included in those trials. Additionally, they can also help evaluate the impact of physician decision-making and actions on care delivery. Registries are also increasingly being utilized for observational comparative effectiveness studies as they have proven to be cost-effective while providing useful information in comparison with the alternative methods.(2) Registry data have great potential to enhance the efficiency of clinical trials, making them less expensive, and speeding up the availability of new treatments to patients. Depending on the capabilities and characteristics (e.g., interoperability, connectivity, flexibility, sustainability), a registry can be used either as a) an observational data source for the generation of clinical evidence and hypotheses or b) an important reusable element of the clinical trial infrastructure for prospective randomized studies.(5) Information collected in clinical observational registries, such as demographics, medical history, diagnosis, and outcomes data, often overlap with clinical trial data. Therefore, integration of clinical trials within registries may offer opportunities to 1) Avoid data collection duplicity, 2) More efficient identification and recruitment of patients, 3) Faster database lock, 4) Faster critical decision-making, and 5) Reduction of clinical trial costs.(5)

    Considering the extent of impact that registry studies can have on the usage of drugs and medical devices, factors surrounding patient privacy, confidentiality, ethics, and other regulatory issues gain extreme significance. Regulatory oversight is essential to ensure that the outcomes of registry audits are done appropriately, avoiding misguiding claims of efficacy and/ or safety. Thus it becomes crucial for regulators to assess whether the historical evidence generated from registry studies demonstrates the reliability, robustness, and relevance to support regulatory decision-making. Additionally, the assessment of an existing registry can also be done to see if it contains the elements for a randomized clinical trial, as it can potentially provide high-quality evidence for regulatory decision-making.(5)

    On the other hand, while designing a new registry, there are a few general guidelines that need to be considered along with specific ones for a particular regulatory authority. The new registry must have the lowest possible barriers for inclusion, thus maximizing the inclusion of those having the disease/condition to be studied. Different treatment modalities, including drugs, biologics, devices, and combination products, should be considered. Identification of data elements should be performed on the basis of their clinical relevance while maintaining recognized standards and nomenclature. Data collection processes must be systematic, reproducible, reliable, and in accordance with informatics standards. The new registry design should be valid across multiple stakeholder analyses. Finally, a provision should be made to incorporate patient-reported information within the registry.(5)

    Appropriately and ethically conducted registry studies can therefore immensely contribute to medical evidence, and prudent regulatory oversight is essential to ensure that the quality of evidence coming from the registry studies is not compromised.

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    References

    1. R. E. Gliklich and N.A. Dreyer, “Registries for Evaluating Patient Registries: A User’s Guide,” Agency for Healthcare Research and Quality, publication No. 07-EHC001 (AHRQ, Rockville, MD, 2007).
    2. Gliklich R. Clinical Trials vs. Registries. April 2009. Available at: https://www.appliedclinicaltrialsonline.com/view/clinical-trials-vs-registries
    3. European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. April 2022. Available at: https://www.encepp.eu/standards_and_guidances/methodologicalGuide4_3.shtml
    4. European Medicines Agency. Guideline on registry-based studies. (EMA/502388/2020) September 2020. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-registry-based-studies_en.pdf
    5. Clinical Trials Transformation Initiative (CTTI). CTTI Recommendations: Registry Trials. Available at: https://ctti-clinicaltrials.org/wp-content/uploads/2021/06/CTTI_Registry_Trials_Recs.pdf

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  • The Real World Evidence Registry by ISPOR: an Initiative to Enhance Transparency

    The Real World Evidence Registry by ISPOR: an Initiative to Enhance Transparency

    The world today is observing an exponential growth in the volume and variety of the real-world data (RWD). Thanks to the technological advancements and the rise in the use of integrated electronic medical records (EMRs), RWD is ever more accessible and applicable in the regulatory domain as well as outcomes research. The evidence from randomized controlled trials (RCTs) is still undoubtedly the gold standard for assessing treatment efficacy; however, the interest and potential for adapting RWD into real-world evidence (RWE) is on the rise. This can prove extremely beneficial to make informed healthcare decisions. (1)

    RWE has several advantages over RCT findings, particularly in research to aid decision making for healthcare delivery. These advantages include the availability of well-timed data at reasonable cost, large sample sizes enabling analyses of subgroups and less common effects, and the overall better representation of the real-world practices and behaviours. (1) Nonetheless, RWE has several concerns questioning its credibility, including data quality, biases – thanks to lack of randomization, and possibly false results owing to data mining. Some other major challenges, as highlighted by the USFDA, include inconsistency in sources and formats, different nature of source data captured by different regions, differences in terminology and exchange, different methods used to build datasets for aggregation, and differences in overall data quality. (2) These are the challenges that have haltered the progress of RWE in healthcare despite its significant data capabilities. (1) In the same context, USFDA has acknowledged the need for standardizing RWD for healthcare decision making. As a result, a draft guidance has been recently released for the industry, outlining USFDA’s requirements from the sponsors for submission of drug and biological product study data by RWD sources. (2)

    Acknowledging similar concerns over RWD quality, the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), in collaboration with the International Society for Pharmacoepidemiology, the Duke-Margolis Center for Health Policy, and the National Pharmaceutical Council, has recently launched the Real-World Evidence Transparency Initiative with the purpose to promote health economics and outcomes research (HEOR) excellence to improve global healthcare decision making. Additionally, it will help instituting a culture of transparency for analysis and reporting of hypotheses to evaluate RWE studies on treatment effects. (3)

    In order to further improve transparency and credibility, the Real-World Evidence Transparency Initiative, on October 26th 2021, launched the Real-World Evidence Registry. (4, 5) The registry will offer a fit-for-purpose platform to the researchers to prospectively register their study designs before starting data collection. (4) The registry will implement open, centralized workflows that will enhance collaboration and facilitate the transparency needed to promote the trust in the study results. (4, 5)

    The RWE registry is a streamlined registration website, especially for RWE studies conducting the hypothesis evaluation of treatment effects (HETE studies) using secondary data. This searchable platform will provide a place for pre-registration of studies that may not need registration for regulatory purposes, but benefit from the accuracy of transparent study methods and also provide a reference (such as a URL or doi) to share with the involved stakeholders, such as peer reviewers, assessors, or other decision makers. (4)

    With the growing adaptation of RWE studies alongside RCTs, the launch of the registry could not have happened at a more opportune time. We hope that researchers optimize this resource and this move helps improving the transparency and credibility of RWD and thus, RWE studies. At Marksman Healthcare, we are well equipped to provide services in this domain, including RWE study protocol development, study/protocol registration in the RWE registry, RWD analysis, and RWE publication support, among others.

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    References

    1. Real World Evidence. ISPOR Strategic Initiatives. Available at: https://www.ispor.org/strategic-initiatives/real-world-evidence
    2. FDA drafts data standards guidance for RWD. October 2021. Available at: https://www.raps.org/news-and-articles/news-articles/2021/10/fda-drafts-data-standards-guidance-for-rwd
    3. Real-World Evidence Transparency Initiative. ISPOR Strategic Initiatives. Available at: https://www.ispor.org/strategic-initiatives/real-world-evidence/real-world-evidence-transparency-initiative?utm_medium=press_release&utm_source=public&utm_campaign=general_ispor&utm_content=press_release_oct26&utm_term=rwe_registry
    4. Real-World Evidence Registry. Available at: https://www.ispor.org/strategic-initiatives/real-world-evidence/real-world-evidence-registry
    5. New Real-World Evidence Registry Launches. October 26 2021. Available at: https://www.newswise.com/articles/new-real-world-evidence-registry-launches

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