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Patient-Reported Outcomes Considered During FDA Clinical Reviews


Patient feedback is quickly becoming a vital component of the FDA’s regulatory decision-making process for drug applications.

Disease symptoms, symptomatic adverse events, and physical function top the list of patient-reported outcomes (PROs) from cancer clinical trials of interest to the FDA during application reviews for both new products and new indications for existing medications.1 During the recent 61st American Society of Hematology Annual Meeting & Exposition in Orlando, Florida, for benign and malignant hematology indications, data were presented on just how often the FDA considers PROs during clinical review, when PROs are included in product labels, and what the PROs referenced.

Investigators from the FDA and the Center for Biologics Evaluation and Research (CBER) gathered PRO data for approvals between 2017 and 2018 from the Center for Drug Evaluation and Research in the Office of Hematology and Oncology Products and CBER, as well as determined the frequency with which those data were included on clinical study reports (CSRs)2, final FDA review, and drug labels. The FDA handed down 64 approvals during the study period (31 new molecular entity [NME]3 and 33 supplemental applications).

The investigators determined that PRO data were included on 30% (3/10) of the CSRs for benign hematology NMEs and biologics license applications (BLAs) and 47% (7/15) of CSRs for malignancy applications. However, the FDA subsequently included that data in its clinical review for 9 submissions (3, benign; 6 malignant), and labels for Hemlibra (emicizumab; Chugai) and Rituxan Hycela (rituximab/hyaluronidase human; Genentech/Biogen) ultimately incorporated the data. Hemlibra4 treats hemophilia A, and Rituxan Hycela5 treats relapsed or refractory follicular lymphoma (FL), previously untreated FL, nonprogressing FL, previously untreated diffuse large B-cell lymphoma, and previously untreated and treated chronic lymphocytic leukemia (CLL).

PRO data were also included on 38% (3/8) of the CSRs for supplemental benign hematology indications and 65% (13/20) for malignant indications. The FDA went on to include that data in its clinical review for 15 submissions (3, benign; 12, malignant), and labels for Feraheme (ferumoxytol; AMAG) and Imbruvica (ibrutinib; Pharmacyclics/Janssen Biotech) include the data. Feraheme6 treats iron deficiency anemia, and Imbruvica treats mantle cell lymphoma, CLL, CLL/small lymphocytic leukemia with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma and chronic graft versus host disease.

Overall, more labels for benign indications (33% [1/3], NMEs and BLAs; 33% [1/3], supplemental) included PROs data than did those for malignant indications (16% [1/6] and 8% [1/12], respectively), and these data covered disease symptoms and physical function.8

The FDA is currently developing guidelines for the use of PROs in cancer clinical trials.


  1. Patient-centered initiatives at the FDA: a conversation with Vishal Bhatnagar, MD, Bellinda King-Kallimanis, PhD, Janice Kim, PharmD, and Paul G. Kluetz, MD. The ASCO Post. ascopost.com/issues/september-25-2019/patient-centered-initiatives-at-the-fda/. Published September 25, 2019. Accessed December 12, 2019.
  2. Navigating the four types of clinical study reports. MMS Holdings website. mmsholdings.com/navigating-the-four-types-of-clinical-study-reports/. Accessed December 12, 2019.
  3. Chemicool Dictionary. Definition of molecular entity. chemicool.com/definition/molecular_entity.html. Accessed December 12, 2019.
  4. Hemlibra (emicizumab-kxwh) injection, for subcutaneous use [package insert]. South San Francisco, CA: Genentech, Inc; 2018.
  5. Rituxan Hycela (rituximab and hyaluronidase human) injection, for subcutaneous use [package insert]. South San Francisco, CA: Genetech, Inc; 2017.
  6. Feraheme (ferumoxytol injection). [package insert]. Waltham, MA: AMAG Pharmaceuticals; 2018.
  7. Imbruvia (ibrutinib) capsules, for oral use; Imbruvica (ibrutinib) tablets, for oral use [package insert]. Sunnyvale, CA, and Horsham, PA: Pharmacyclics and Janssen; 2019.
  8. Kim J, Kanapuru B, Roydhouse JK, et al. 2017-2018 hematology drug approvals at the Food and Drug Administration (FDA): communication of patient-reported outcomes (PRO) information in FDA clinical reviews and prescribing information. Presented at: 61st American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 3450. ash.confex.com/ash/2019/webprogram/Paper125798.html. Accessed December 6, 2019.

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