We posed the same 10 questions to FDA, Pfizer and Flatiron Health.
Here is what came back:
The Cancer Letter: Was this the first approval based at least in part on real world evidence in oncology?
FDA: Ibrance (palbociclib) was initially approved in 2015. It is a kinase inhibitor, now approved in combination with an aromatase inhibitor as the first hormonal-based therapy in women who have gone through menopause and in men, or with fulvestrant in patients whose disease progressed following hormonal therapy.
Pfizer provided the results of an analysis of real world data (RWD) from electronic health records (EHRs) as additional supportive data to characterize the use of Ibrance in combination with endocrine therapy (aromatase inhibitor or fulvestrant) in male patients with breast cancer based on observed tumor responses in this rare subset of patients with breast cancer.
Leveraging RWD to improve regulatory decisions is a key strategic priority for the FDA. This data may be derived from a variety of sources, such as electronic health records, medical claims, product and disease registries, laboratory test results and even cutting-edge technology paired with mobile devices.
These types of data are being used to develop real world evidence (RWE) that can better inform regulatory decisions.
Because they include data covering the experience of physicians and patients with the actual use of new treatments in practice, and not just in research studies, the collective evaluation of these data sources has the potential to inform clinical decision-making by patients and providers, develop new hypotheses for further testing of new products to drive continued innovation and inform us about the performance of medical products.
FDA has previously accepted RWD to support drug product approvals, primarily in the setting of oncology and rare diseases.
RWD has been used to determine prognosis or natural history of disease in order to help inform regulatory decision-making, for example, data on historical response rates drawn from expanded access, practice settings, or chart reviews.
Chris Boshoff, chief development officer, oncology, Pfizer Global Product Development: Defer to FDA.
Ken Carson, senior medical director, Flatiron Health: Defer to FDA.
What were the RWE endpoints being used here?
FDA: The RWE endpoints used were real world tumor response and safety data. Real world tumor response was taken from the electronic health record as part of routine clinical care and information about each response event was retrospectively collected.
Therefore, this response included several factors, such as physical exam, symptom improvement, and pathology reports, which were used to supplement descriptions of radiology findings in the overall clinicians’ assessment of response.
Additional data on use and durations of prescriptions were also provided.
Pfizer: The expanded indication in breast cancer is based on limited data from post-marketing reports and electronic health records sourced from three databases: IQVIA Insurance database, Flatiron Health Breast Cancer database and the Pfizer global safety database.
Based on these limited data, the safety profile for men treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.
A detailed analysis of the use of IBRANCE in men with HR+, HER2- advanced or metastatic breast cancer will be presented at an upcoming medical meeting.
Flatiron: For this dataset, Pfizer engaged Flatiron to explore baseline characteristics, treatment patterns and clinical outcomes from patient-level, de-identified data for a group of male patients with metastatic breast cancer.
As with any project in which a partner is considering the inclusion of RWE as part of a regulatory submission, we consider it critical to ensure the data is “fit-for-purpose,” that is, ensuring that the dataset is fit for the intended use and can provide adequate scientific evidence.
Why was this application the right setting to use RWE?
FDA: Breast cancer is rare in males, with only 2,670 cases of male breast cancer estimated in 2019—less than 1% of all cases of breast cancer.
Due to the rarity of male breast cancer, there is limited evidence available to guide treatment decisions and it is not feasible to conduct prospective clinical studies.
FDA has previously extrapolated efficacy and safety by granting indications in breast cancer to male patients, even if no male breast cancer patients were enrolled in the supporting trial.
However, in certain cases when there is the potential of differential efficacy or safety results between men and women with breast cancer, such as when a drug is combined with endocrine therapy and results in or relies upon manipulation of the hormonal axis, further evidence may be necessary to support a labeling indication for male patients.
This need for additional evidence, combined with the rarity of male breast cancer, made this the right setting to use RWD.
Pfizer: Real world data are playing an increasingly important role in expanding the use of already-approved innovative medicines.
The 21st Century Cures Act, enacted in 2016, was created to help accelerate medical product development, allowing new innovations and advances to become available to patients who need them faster and more efficiently.
This law places additional focus on the use of real world data to support regulatory decision-making.
Further, the rarity of male breast cancer can make it difficult to recruit a significant number of patients for a formal clinical trial.
The expanded indication in breast cancer is based on limited data from post-marketing reports and electronic health records, and we’re pleased to have played a role in this innovative approach that now provides a much-needed option for men living with HR+, HER2- MBC.
Flatiron: Given the potentially challenging and time-consuming process (source) of accruing patients as part of a prospective clinical trial in rare cohorts such as males with metastatic breast cancer, using RWE to pursue an indication in this population held the potential to provide an avenue to support regulatory approval.
However, as with any decision impacting patient care and treatment, the “fit for purpose” of RWE must always be considered.
To what extent was RWE used—as primary evidence or as confirmatory evidence?
FDA: Certain treatments for metastatic breast cancer are gender-neutral in their indication, but some therapies have been approved only for women, although they are often prescribed for male patients.
The safety and efficacy of Ibrance had been previously demonstrated in women and therefore was only supported by RWD in order to extend the indication to men.
The initial studies of Ibrance in breast cancer did not enroll male patients and thus this supportive RWD information was helpful to further assess the ability to extend the indication to this rare subgroup of patients.
Pfizer: The expanded indication in breast cancer is based on limited data from post-marketing reports and electronic health records sourced from three databases: IQVIA Insurance database, Flatiron Health Breast Cancer database and the Pfizer global safety database.
Based on these limited data, the safety profile for men treated with Ibrance is consistent with the safety profile in women treated with Ibrance.
Defer to FDA for additional information.
Flatiron: The dataset provided by Flatiron, along with other data sources, was used as primary evidence within Pfizer’s supplemental NDA submission.
Which conventional endpoints were the RWE endpoints being tied to? What gives you comfort that these are equivalent metrics?
FDA: Real world tumor response is related to objective response rate, but these are not considered equivalent metrics.
RWD provides insight into how providers administer the drug, and while there are limitations to real world tumor response, this endpoint provides an estimate of drug response and benefit.
Pfizer: Based on limited data from post-marketing reports and electronic health records, the safety profile for men treated with Ibrance is consistent with the safety profile in women treated with Ibrance.
The efficacy and safety of Ibrance in women with HR+, HER2- metastatic breast cancer is supported by robust clinical trial data from three randomized pivotal trials across the PALOMA program that consistently demonstrated a meaningful PFS benefit.
Today in the U.S., Ibrance is the most prescribed FDA-approved oral combination treatment for HR+, HER2- MBC. Ibrance currently is approved in more than 90 countries and has been prescribed to more than 200,000 patients globally.
A detailed analysis of the use of Ibrance in men with HR+, HER2- advanced or metastatic breast cancer will be presented at an upcoming medical meeting
Flatiron: There are important distinctions between assessing endpoints in the real world versus a clinical trial setting (which is what we take to be implied by “conventional”).
Endpoints collected through randomized clinical oncology trials such a tumor response, progression, and treatment-related toxicity are collected intentionally, with pre-specified methods at fixed time intervals.
Endpoints in real world data are collected within the patients’ medical records and later incorporated into a study dataset.
For this project, we did not compare endpoints to a clinical trial or “conventional” endpoints.
However, we have previously performed exercises which have demonstrated clinically appropriate correlations between endpoints such as real world progression and real world overall survival and their conventional counterpoints.
What was the FDA’s role in deciding which RWE endpoints were to be used?
FDA: Multiple conversations between the FDA and the company allowed for determination of appropriate endpoints and the amount of data needed prior to the submission.
As with all of our reviews, during this review cycle, information was requested of the company and exchanged back to FDA clarifying individual data elements and narratives.
Pfizer: Defer to FDA.
Flatiron: Defer to FDA.
How were the RWE data sources selected? How were these databases harmonized in terms of data collection standards?
FDA: While there are multiple potential RWE data sources, through discussions with the company, appropriate sources, endpoints, and the amount of information that would be required for a full review were selected.
FDA is currently in the process of developing set data standards for regulatory use and will continue to expand its work in this area.
Pfizer: A detailed analysis of the use of Ibrance in men with HR+, HER2- advanced or metastatic breast cancer will be presented at an upcoming medical meeting.
Flatiron: Defer to Pfizer.
What’s the take-away message here? What can oncology learn about what it takes to generate regulatory-grade RWE?
FDA: We were able to use the extensive substantial evidence of safety and effectiveness that Ibrance had previously demonstrated in women and supporting RWD in order to extend the indication to men.
The FDA recognizes the importance of RWD/RWE and is committed to realizing the full potential of these tools in advancing the development of treatments for patients.
In December 2018, the FDA published a Framework for the RWE program to apply across our programs. We are committed to leveraging information gathered from the medical community and patients to help inform our regulatory decisions regarding drug and biologic development efforts.
Pfizer: We appreciate that our partnership with the FDA has allowed us to take a significant step forward in the use of real world data to bring medicines to patients who are most in need.
Real world data are playing an increasingly important role in expanding the use of already approved, innovative medicines.
The 21st Century Cures Act, enacted in 2016, was created to help accelerate medical product development, allowing new innovations and advances to become available to patients who need them faster and more efficiently. This law places additional focus on the use of real world data to support regulatory decision making.
A detailed analysis of the use of Ibrance in men with HR+, HER2- advanced or metastatic breast cancer will be presented at an upcoming medical meeting.
Flatiron: RWD can serve as a strong evidence source, enabling us to learn from patients who are being treated in the real world and reinvest those learnings back into research to help future patients.
The FDA’s acceptance of RWE as part of this submission is consistent with implementing the draft framework that the agency outlined in December 2018, and is another critical datapoint in the FDA’s evolving position regarding RWE.
Flatiron continues to be optimistic about the possibility of RWE in the appropriate circumstances to support regulatory decision-making, and appreciates the FDA’s leadership and collaboration in these efforts.
Is there a precedent being set here, and if so what is it?
FDA: While no precedent is being set, FDA continues to engage in discussions around generating and using RWE to support regulatory decision-making.
Specifically, FDA’s RWE Program will evaluate the potential use of RWE to support changes to labeling about drug product effectiveness, including adding or modifying an indication, such as a change in dose, dose regimen, or route of administration; adding a new population; or adding comparative effectiveness or safety information.
Pfizer: Defer to FDA.
Flatiron: Defer to FDA.
Is there anything you’d like to add?
FDA: The RWE Program will involve the establishment of demonstration projects, engagement with stakeholders, the use of internal processes that bring senior leadership input into the evaluation of RWE and promote shared learning and consistency in applying the framework, and the development of guidance documents to assist sponsors interested in using RWE to support their work.
As part of its RWE Program, FDA will also evaluate the potential role of observational studies in contributing to evidence of drug product effectiveness. Efforts to replicate the results of randomized controlled trials using more rigorously designed observational studies may provide insight into the opportunities and limitations of using these designs in regulatory decisions.
FDA is committed to advancing the use of RWE and looks forward to working with companies to further advance the field. As the reliability RWE data improves and the data collection science evolves, we hope to be able to use RWE as primary evidence supporting an approval.
Pfizer: This approval represents a significant step forward in the use of real world data, particularly for underserved populations.
With this approval, Ibrance is the first and only CDK 4/6 inhibitor in the U.S. indicated in combination with an aromatase inhibitor for the first-line treatment of men living with HR+, HER2- metastatic breast cancer, further reinforcing Pfizer’s deep commitment to putting patients first and meeting unmet treatment needs with our innovative medicines.
