FDA Briefing Document Pulmonary-Allergy Drugs Advisory Committee Meeting August 31, 2020 sNDA 209482: fluticasone furoate/umeclidinium/vilanterol fixed dose combination to reduce all-cause mortality in patients with chronic obstructive pulmonary disease NDA209482/S-0008 PADAC Clinical and Statistical Briefing Document Fluticasone furoate/umeclidinium/vilanterol fixed dose combination for all-cause mortality DISCLAIMER STATEMENT The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought the supplemental New Drug Application (sNDA) 209482, for fluticasone furoate/umeclidinium/vilanterol, as an inhaled fixed dose combination, for the reduction in all-cause mortality in patients with COPD, to this Advisory Committee in order to gain the Committee’s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2 NDA209482/S-0008 PADAC Clinical and Statistical Briefing Document Fluticasone furoate/umeclidinium/vilanterol fixed dose combination for all-cause mortality Table of Contents Page Division Memorandum 4 Draft Points to Consider 20 Clinical Statistical Briefing Document 22 Reference List 134 3 NDA209482/S-0008 PADAC Clinical and Statistical Briefing Document Fluticasone furoate/umeclidinium/vilanterol fixed dose combination for all-cause mortality DIVISION MEMORANDUM Date: August 4, 2020 From: Banu A. Karimi-Shah, MD, Deputy Director Sally Seymour, MD, Director Division of Pulmonology, Allergy, and Critical Care (DPACC), Office of Immunology and Inflammation (OII), Office of New Drugs (OND), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA) To: Members, Pulmonary-Allergy Drugs Advisory Committee (PADAC) Subject: Overview of the FDA background materials for the supplemental New Drug Application (sNDA) 209482/S-008, TRELEGY ELLIPTA (fluticasone furoate [FF], umeclidinium [UMEC], vilanterol [VI] inhalation powder), at a dose of 100/62.5/25 mcg (once-daily), to evaluate the proposed claim of decreased all-cause mortality (ACM) in patients with chronic obstructive pulmonary disease (COPD) Thank you for your participation in the Pulmonary-Allergy Drugs Advisory Committee (PADAC) meeting to be held on August 31, 2020. As members of the PADAC you provide important expert scientific advice and recommendations to the US Food and Drug Administration (the Agency) on the regulatory decision-making process related to the approval of a drug or biologic product for marketing in the United States, as well as the evaluation of important claims to be added to approved product labeling. The upcoming meeting is to discuss a supplemental New Drug Application (sNDA) from GlaxoSmithKline Pharmaceuticals (GSK, or the Applicant), in which the Applicant has submitted data to evaluate the proposed claim that treatment with TRELEGY ELLIPTA reduces all-cause mortality (ACM) in patients with COPD. This is an important topic for discussion and an area of unmet medical need, as there are no approved therapies which have been shown to reduce ACM in patients with COPD. Introduction TRELEGY ELLIPTA (Trelegy) is a fixed-dose triple combination inhalation powder containing fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI). Trelegy includes three therapeutic modalities to treat COPD: an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA), and a long-acting beta-agonist (LABA), respectively. Trelegy is approved for the maintenance treatment of patients with COPD. The Clinical Studies section (Section 14) of the US package insert (USPI) describes the efficacy of Trelegy with respect to lung function, acute exacerbations of COPD (AECOPD), and health-related quality of life (i.e., St. George’s Respiratory Questionnaire, SGRQ). This memorandum summarizes data submitted by GSK to evaluate the proposed claim that treatment with Trelegy reduces all-cause mortality (ACM) in patients with COPD. To support this claim, the Applicant has submitted analyses of the results of a randomized, double-blind, partial factorial, active control trial (InforMing the PAthway of COPD Treatment: IMPACT) of Trelegy (FF/UMEC/VI). Subjects were randomized to FF/UMEC/VI, FF/VI, or UMEC/VI, respectively. Specifically, the Applicant cites the results for FF/UMEC/VI versus UMEC/VI 4 NDA209482/S-0008 PADAC Clinical and Statistical Briefing Document Fluticasone furoate/umeclidinium/vilanterol fixed dose combination for all-cause mortality (ICS/LAMA/LABA vs. LAMA/LABA) to support their assertion that Trelegy reduces ACM. Based on this comparison, the benefit in ACM proposed by the Applicant is attributed to the addition of FF (the ICS). Based on the Agency’s analyses, there are several statistical and clinical uncertainties in the interpretation of the ACM data, and whether these data provide substantial evidence to support the proposed claim that Trelegy reduces ACM in patients with COPD. We have convened this meeting of the Pulmonary-Allergy Drugs Advisory Committee (PADAC) to draw on the expertise of the panel members, so that we may better address these uncertainties in our regulatory decision-making process. Major discussion points for the advisory committee members include: 1) the statistical persuasiveness of the ACM results in IMPACT, as a single trial, 2) the timeframe of efficacy observed in the IMPACT trial, 3) the evidence across the IMPACT, SUMMIT, and TORCH trials to support the efficacy of fluticasone on ACM, 4) the potential effect of ICS removal on IMPACT results, and 5) the generalizability of these results to the care of patients with COPD in clinical practice. We ask that the committee members consider each of these issues to determine whether the results of IMPACT support the addition of the proposed labeling claim to Section 14 (Clinical Studies) of the USPI. This Division Memorandum will provide a high-level overview of the regulatory history, IMPACT trial design, ACM results, and the statistical and clinical issues with the data that warrant the committee’s consideration with regard to each of these discussion points. A more detailed discussion is provided in the Agency’s Clinical and Statistical Briefing Document. Regulatory History Trelegy was initially approved in 2017 for the long-term, once-daily maintenance treatment of patients with COPD, including chronic bronchitis and/or emphysema, who are on a fixed-dose combination of fluticasone furoate and vilanterol for airflow obstruction and reducing exacerbations in whom additional treatment of airflow obstruction is desired, or for patients who are already receiving umeclidinium and a fixed-dose combination of fluticasone furoate and vilanterol. The IMPACT trial was a large, 1-year, partial factorial trial, specifically designed to demonstrate the contribution of FF and UMEC to the triple combination in reducing acute exacerbations of COPD (AECOPD). Based on the results of the IMPACT trial, the indication for Trelegy was amended to: the long-term, once-daily, maintenance treatment of airflow obstruction in patients with COPD and also to reduce exacerbations of COPD in patients with a history of exacerbations. To comply with updated labeling practices, and harmonize indications across COPD products, the Division initiated labeling changes to generalize the indication statement for Trelegy in 2019, to its current language: for the maintenance treatment of COPD. Many of the statistical and clinical issues to be discussed before the committee were raised with the Applicant through regulatory interactions. The original statistical review of the IMPACT trial recommended control of the probability of Type I error for secondary endpoints, referencing mortality, at the 0.01 level. Prior to submission of the ACM supplement under discussion (i.e., the pre-sNDA meeting), the Agency raised this issue again, noting the lack of multiplicity control, since ACM analyses were not part of the statistical hierarchy, and ACM was designated as an 5 NDA209482/S-0008 PADAC Clinical and Statistical Briefing Document Fluticasone furoate/umeclidinium/vilanterol fixed dose combination for all-cause mortality “other” endpoint. The Agency noted that this lack of control for multiple endpoints would need to be considered carefully in the setting of a single trial without replicate evidence from another COPD trial to confirm the finding. The Applicant noted plans to include supportive data for ICS efficacy on ACM from two previous trials (SUMMIT and TORCH), as it was the Applicant’s assertion that the ACM benefit for Trelegy relied primarily on the efficacy contribution of the ICS as well. From a clinical perspective, preliminary review of the IMPACT results had revealed that there may be an unexpected early