Real World Evidence in Regulatory Submissions - Story of IBRANCE for male breast cancer

In April 2019, FDA approved Pfizer's IBRANCE for male breast cancer. The approval is for the label extension for an already produce based on the real-world data (RWD). The IBRANCE approval in male breast cancer patients is considered as the first case that an FDA approval is mainly based on the RWD and has been used as an example in many lectures discussing the real-world evidence (RDE). Here is what is said in the press release about IBRANCE's approval for male breast cancer. 

“Men with breast cancer have limited treatment options, making access to medicines such as IBRANCE critically important,” said Bret Miller, founder of the Male Breast Cancer Coalition. “We applaud the use of real-world data, a new approach to drug review, to make IBRANCE available to certain men with metastatic breast cancer and help address an unmet need for these patients.”

Real-world data is playing an increasingly important role in expanding the use of already approved innovative medicines. Due to the rarity of breast cancer in males, fewer clinical trials are conducted that include men resulting in fewer approved treatment options. In the U.S. in 2019, it is estimated that there will be 2,670 new cases of invasive breast cancer and about 500 deaths from metastatic breast cancer in males. 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.

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. Based on limited data from postmarketing reports and electronic health records, the safety profile for men treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.

In the original approval of IBRANCE for breast cancer, a randomized, controlled clinical trial was conducted, however, the male breast cancer patients were excluded from the study. In order to obtain the label extension to the male breast cancer patients, the RWE from electronic health records (EHR) for the off-label use of IBRANCE in male breast cancer patients was used. According to the FDA's review documents:

Male patients with breast cancer were ineligible in studies that provided the data to demonstrate the clinical benefit to support prior approvals of palbociclib (IBRANCE®). According to the current clinical practice standards, in the absence of safety and efficacy data from adequate and well-controlled studies, male patients with breast cancer are treated similarly to women with breast cancer. In this submission, the applicant 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 palbociclib 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.

In a recorded webinar "Applying Real-World Evidence to Regulatory and Drug Development Challenges", Dr. Rebecca Miksad from Flatiron Health (the CRO who did the RWD analyses for Pfizer) summarized five key learnings from IBRANCE example for RWE in regulatory submissions: 

 

Pre-specification of study protocol & analysis plans 

“Without having reviewed and consented to a protocol and SAP, FDA cannot be certain that the protocol and SAP were pre-specified and unchanged during the data selection and analyses” 

- ODAC Briefing Document 

Appropriate Cohort selection for the research question 

Real-world patient cohorts need to be representative of population of interest 

Appropriate cohort selection criteria is context- and disease-dependent 

It is important to understand the feasibility of capturing each clinically meaningful variable 

A documented and traceable selection processes is needed (e.g., detailed cohort diagram) 

Missingness impacts ability of RWD to align with typical trial inclusion/exclusion (I/E) criterion 

Agreement is an additional layer of quality needs to be assessed for abstracted data 

Suitability of real-world endpoints 

Data quality suitability for the use case is critical for drawing confident conclusions from real-world endpoints 

depending on context, data quality considerations for real-world endpoints include: 

Can the endpoint be benchmarked to a reference or gold standard? 

How reproducible is the variable’s performance? 

Traceability back to source data 

Fit for purpose analytical methodologies 

Good analysis cannot fix low quality data; but bad analysis wastes high quality data 

Potential RWD quality issues need to be considered as part of the analysis plan. For example, 

Address potential bias in the data due to data quality issues (selection/ascertainment/confounding/immortal time) 

Assess the impact of missing data (sensitivity analysis) 

The cancerletter.com published an article including the responses from the regulatory agency (FDA), the sponsor (Pfizer), and the CRO (Flatiron Health) "How real-world evidence was used to support approval of Ibrance for male breast cancer". Some of the responses are copied here:

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.

 

The Cancer Letter:

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.

Using RWE/RWD to support regulatory submission is a trend. Statisticians are meeting the challenges in developing the methods of integrating the RWD into the clinical trials and into the regulatory submissions. We are seeing the popular terms 'historical control', 'external control', 'synthetic control arms', 'digital twin', 'propensity score', 'Bayesian dynamic borrowing', 'causal inferences'... We hope to see that the regulatory agencies will be more receptive to the RWE in supporting regulatory approvals.