How FDA, Pfizer, and Flatiron Health did it

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Real world data played a role in FDA’s recent decision to expand the indications for Pfizer’s drug Ibrance (palbociclib) to include men.

On April 4, Ibrance joined the ranks of cancer drugs that were approved partly based on data extracted from electronic medical records and other data related to actual experience with the drug, as opposed to clinical studies. Approvals relying on such data have been occurring infrequently, and it appears that they haven’t been analyzed systematically.

To determine how Pfizer, its collaborator Flatiron Health, and FDA generated and processed RWD and how the agency approached the resulting real world evidence, The Cancer Letter posed a series of questions to FDA, Pfizer and Flatiron.

The answers appear here.

“While no precedent is being set, FDA continues to engage in discussions around generating and using real world evidence to support regulatory decision-making,” the agency said in response to questions from The Cancer Letter. “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.”

The just-approved sNDA allows Ibrance to be used in combination with an aromatase inhibitor or fulvestrant, and now includes men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer.

The drug was approved in 2015 for use in women.

Breast cancer in men is rare. This year 2,670 men would be expected to develop invasive breast cancer, and about 500 will die of metastatic disease.

The approval for use of Ibrance in men is based on data from electronic health records and post-marketing reports of the real world use of Ibrance in male patients sourced from three databases: IQVIA Insurance database, Flatiron Health Breast Cancer database and the Pfizer global safety database.

According to 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,” the agency said.

A more complete picture of Ibrance will emerge when these data are presented at an upcoming oncology meeting, the company said.

FDA recently created a framework for evaluating the use of real world evidence to support additional indications for already approved drugs as well as to satisfy drug post-marketing study requirements.

The framework lays out the fundamentals of the agency’s approach to developing guidances for using real world data in drug regulation. The report, published last December, as required by the 21st Century Cures Act, applies to drugs and biological products. It doesn’t apply to medical devices.

In addition to staking out a swath of the burgeoning field of real world evidence, the agency has recruited Amy Abernethy, an expert in generating and applying real world evidence, to the job of principal deputy commissioner, making her the second-highest ranking official at FDA (The Cancer Letter, Jan. 4).

Abernethy is the former chief medical officer, chief scientific officer and senior vice president of oncology at Flatiron Health.

“I think that the major takeaways [from the FDA framework] are consistent with what we were expecting before, which is that there’s a move towards trying to understand how to use real world evidence,” Abernethy said to The Cancer Letter recently. “And that move is asking, ‘How do we make sure that the data quality and the analytic quality is adequate to address the kinds of questions that are going to be brought before the agency?’ Really focusing on quality is going to be critical.”

Today, RWE is being used for modifying indications, varying doses, adding populations, or including information on safety and effectiveness. To gain in importance, RWE has to be used with the same rigor as clinical trial data, with a clear prospective statistical plan and a prospective definition of success, agency officials say.

Also, databases are far from being able to replace randomized clinical trials, because RCTs have the capacity to measure impact of factors that aren’t known to researchers and therefore cannot be incorporated into RWE models.

Pfizer’s Ibrance is now approved for adult patients with HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women or in men; or with fulvestrant in patients with disease progression following endocrine therapy.

With the latest approval, Ibrance becomes the first and only CDK 4/6 inhibitor indicated in combination with an aromatase inhibitor for the first-line treatment of men with HR+, HER2- metastatic breast cancer in the U.S.

The prescribing information for Ibrance can be found here.

Matthew Bin Han Ong contributed to this story.

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Spanning part of September and October, it is a time to celebrate and recognize Hispanics or Latinos or Latinx persons* for their contributions. This nationwide observation begins on Sept. 15 when several countries in Latin America celebrate independence—Costa Rica, El Salvador, Guatemala, Honduras, and Nicaragua. Mexico celebrates independence on Sept. 16 and Chile on Sept. 18. Towards the end of Hispanic Heritage Month, Oct. 12 is also recognized as Día de la Raza.1 Persons of Hispanic ancestry have walked the Americas since 1492.
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