Oncologic Drugs Advisory Committee Research Articles

Model-Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen.

Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefit-risk profile of the class PI3K inhibitors were scrutinized for use in hematological malignancies. Specifically, their unique toxicities may contribute to the high incidences in reported serious and high-grade treatment emergent adverse events (TEAEs), thereby reducing their overall tolerability and potentially limiting their successful use. These tolerability concerns may be contributed by or compounded by inadequate dose optimization. The recommended dosing regimen of copanlisib 60 mg administered on days 1, 8, and 15 of a 28-day cycle was selected as the maximal tolerated dose (MTD) during phase I. Thus, this analysis sought to justify the copanlisib dose regimen selection. Copanlisib exposure-efficacy relationships were considered from its large phase III trial, CHRONOS-3, whereas copanlisib safety was investigated by pooling data across its two large clinical trials to comprehensively assess its exposure-safety relationships. Results demonstrated a statistically significant positive linear exposure-efficacy relationship at the MTD. Exposure-safety analyses revealed a borderline significant linear relationship for grade ≥3 TEAEs and no significant exposure-safety relationships for other investigated safety end points. The model-based benefit/risk framework considered the established exposure-response models and defined clinical utility function which confirmed the appropriateness of the copanlisib dosing regimen across the range of its achieved exposures.

Melflufen: post-hoc subgroup analyses and the US FDA Oncologic Drugs Advisory Committee

In February, 2021, the US Food and Drug Administration (FDA) granted melphalan flufenamide (melflufen) accelerated approval for patients with relapsed or refractory multiple myeloma in the fifth or later line of treatment, for those with triple-class refractory disease (refractory to a proteasome inhibitor, immunomodulatory agent, and CD38-directed antibody). This approval was based on the single-arm HORIZON trial, 1 Richardson PG Oriol A Larocca A et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. 2021; 39: 757-767 Crossref PubMed Scopus (71) Google Scholar which showed an overall response rate to melflufen plus dexamethasone of 29% among 157 evaluable patients with relapsed or refractory multiple myeloma. The best responses reached were: one stringent complete response (1%), a very good partial response in 17 (11%) patients, and a partial response in 28 (18%) patients, with a median progression-free survival of 4·2 months (95% CI 3·4–4·9 months). 1 Richardson PG Oriol A Larocca A et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. 2021; 39: 757-767 Crossref PubMed Scopus (71) Google Scholar

Real-World Evidence (RWE) Studies Supported Hematologic Oncology United States Food and Drug Administration (US FDA) Approval: What Do They Look like?

Introduction/Background: Although randomized controlled trials are considered the gold standard of evidence for safety and efficacy of a drug, they are subject to several limitations such as difficulty in recruiting patients with rare diseases or randomization of patients to studies with treatments that lack an established standard of care owing to efficacy or toxicity concerns. RWE can help overcome these challenges. RWE collects patient data from historical trials or retrospective observational studies and compares or contextualizes these data to experimental treatments by using proper statistical adjustments. The 21st Century Cures Act inspired the framework for the US FDA to use RWE to assess product effectiveness of approved drugs to support regulatory decision-making. Consequently, RWE is increasingly used in New Drug Applications (NDAs) and Biologics License Applications (BLAs) for hematologic malignancies, and findings suggest that submissions using RWE may receive faster approval. However, data are lacking on adoption of RWE for regulatory submissions and its use in regulatory decision-making. Here, we outline RWE utilization and limitations of regulatory submissions for hematologic malignancy therapeutics, which received accelerated or full approval in the US. Methods: Between 2017 and 2021, all NDA and BLA approvals from the Division of Hematological Malignancies were reviewed for hematology/oncology drugs or indications. The FDA Oncology Drug Advisory Committee (ODAC) briefing and/or multidisciplinary review documents were evaluated to identify the drug approvals using RWE. This assessment was performed by 4 independent reviewers who evaluated FDA comments regarding RWE. RWE sources, study methodology, drug indications, pivotal trial information, statistical analyses, and results were summarized. Results: A total of 74 hematologic malignancy approvals were identified, of which 7 (9.4%) provided RWE that supported regulatory approval. Detailed analyses of the FDA ODAC briefing and/or multidisciplinary review documents for these 7 drug compounds including comparison of trial and RWE data source, patient population, clinical endpoints and outcomes, comparison strategy, and FDA comments are shown in the Table. The FDA identified several key considerations for RWE use for drug applications based on single-arm studies. These included pivotal trials that demonstrated a high response or large treatment effect, an improved drug toxicity profile, or a novel drug mechanism of action. The most common RWE sources included retrospective observational studies from medical records, data from other clinical trials, commercial electronic health record databases, and literature reviews. The most common hematologic indications for RWE submissions were relapsed/refractory (R/R) large B-cell lymphoma and R/R multiple myeloma. The most common endpoints for RWE included presence of measurable residual disease, complete response rate, and duration of response. In contrast, the most common endpoints in pivotal trials included survival endpoints (eg, progression-free survival). The most common statistical methods used to adjust for baseline imbalances included propensity-score matching and inverse-probability of treatment weighting. The FDA identified several areas that may compromise the reliability of RWE: lack of early engagement and discussion of the study design with the FDA, absence of a prespecified statistical analysis plan or protocol, lack of transparency in data collection methods, dissimilar inclusion/exclusion criteria, dissimilar study endpoints, and an inconsistent method or frequency of outcome assessments. Comparator arms often missed baseline covariates, had selection bias, and used different outcome assessment criteria. Conclusion: Good data quality, comparable patient populations, consistent endpoints, prespecified protocols, and the establishment of statistical analysis plans before the start of a study may be the most important factors in the FDA's approval of RWE regulatory submissions. Although the use of RWE to define a direct comparator was limited by flaws in study design and statistical analyses, RWE can be used to establish historical outcomes for patients with currently available treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pooled Safety Analysis from Phase I-III Studies for Patients with Hematological Malignancies Treated with the PI3K Inhibitor Copanlisib

Introduction: As of 2021, four phosphatidylinositol 3-kinase (PI3K) inhibitors had received accelerated approval by the FDA for treatment of patients (pts) with indolent follicular lymphoma (FL) having received ≥2 systemic therapies. Recently, during confirmatory studies, three of the PI3K inhibitors have been voluntarily withdrawn over concerns for toxicities impacting overall survival and this issue was the focus of an Oncologic Drugs Advisory Committee (ODAC) meeting in April 2022. Copanlisib is the only PI3K inhibitor currently available for treatment of FL and is distinguished by being administered intravenously on an intermittent schedule. We report here a comprehensive pooled analysis of copanlisib safety with long-term follow-up from 10 completed Phase I-III studies in pts with hematologic malignancies. Methods: Pts with hematologic malignancies treated with copanlisib monotherapy in completed open-label Phase I or II studies and a randomized, placebo-controlled Phase III in combination with rituximab were included. Copanlisib 60 mg (i.v.) was administered intermittently on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. AEs were reported using MedDRA version 24.1 and assessed by duration of treatment in 6-month intervals or time of onset (worst grade or new AEs occurring ≤180 days [d], 181-360 d, 361-540 d, 541-720 d, or ≥721 d). Results: A total of 684 pts received copanlisib and were evaluable for safety (data cut-off Feb 2022). Median age was 64 years (range 22-93). A total of 51% of pts had a history of FL, 14% MZL, and 10% DLBCL. More than half (54%) were treated with copanlisib for less than 6 months, whereas 27% were treated for >12 months and 13% >2 yrs. The mean overall duration of treatment was 10.9 months (range 0.2-80 months). 24% of pts had at least one dose reduction and 73% had at least one dose interruption or delay (mean duration 3 days). Copanlisib-related treatment-emergent AEs (TEAEs) were reported in 92% of pts; 55% of pts had TEAEs of worst grade [g] 3, and 24% had TEAEs of worst g4. The most common reasons for discontinuation were progression (41%), AE not associated with clinical disease progression (29%) and withdrawal by subject (11%). The most common (≥10%) copanlisib-related TEAEs (% all-grade/g3/g4) were hyperglycemia (58/37/6), hypertension (42/33/0), diarrhea (23/4/0), neutrophil count decreased (20/7/7), neutropenia (19/8/7), nausea (17/0.3/0), white blood cell count decreased (13/5/0.6), fatigue (13/1/0), and anemia (11/3/0). Hyperglycemia and hypertension, both of which were infusion related and transient, had the highest incidence in the first 180 days of treatment. For diarrhea, pts treated for longer duration were more likely to have experienced diarrhea, but g3 events were constant per 6-month onset of event interval (2.2/2.5/3.2/0.8/3.3%). For AEs of interest, the incidence of colitis was low (0.9%; 6 pts: 2 g1, 3 g3 and 1 g4) as was the overall incidence of pneumonitis (6/2/0.6; one g5) with all the g4 events occurring <180 days. The occurrence of late onset AEs of increasing severity has been an issue with orally administered PI3K inhibitors. The greater exposure of pts to copanlisib with longer treatment notwithstanding, we examined the incidence and severity of AEs in pts treated ≤6 months, 6-12 months and >12 months, by overall duration of treatment and by interval of onset (Table) to ascertain the timing and severity of AEs. For hyperglycemia and hypertension, the overall incidence rate was similar for pts treated ≤6 months, 6-12 months and >12 months but was mostly accounted for higher rates day 1-180. Diarrhea was higher in pts treated >12 months, but mostly due to low grade events. There was a trend for a higher incidence of neutropenia and/or neutrophil count decrease depending on treatment duration, but infections remained low. A total of 50 (7%) pts died within 35 days of discontinuing copanlisib, with 18 (2.6%) due to progressive disease (PD) and 9 (1.3%) AEs related to PD, and 20 (2.9%) AEs not associated with clinical progression. Copanlisib-related g5 (death) TEAEs were reported in 10 pts (1.5%), with 8 events in pts treated <6 months; infection-related AEs reported in 5 pts. Conclusions: Based on this expanded safety dataset with long-term treatment of copanlisib, there is no evidence of late-onset toxicities or worsening of severity of TEAEs. No new or unexpected safety issues were identified. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rethinking the marketing strategy of anti-tumor drugs by single-arm trials supported

Single-arm trial refers to a clinical trial design that does not set up parallel control group, adopts open design, and does not involve randomization and blind method. These features, on the one hand, speed up the process of clinical trials, significantly shorten the time to market and meet the needs of patients with advanced malignancies, but also lead to the uncertainty of single-arm clinical trials themselves. Recently, the US Food and Drug Administration held a meeting of the oncologic drug advisory committee to discuss six tumor indications that have been accelerated approved, which once again triggered the discussion of single-arm trials. The basis of accelerated approval by single-arm trial is actually a compromise on the level of evidence-based medical evidence requirements after assessing the benefit risk. Therefore, the sponsor should strictly grasp the applicable conditions of single-arm trial in anti-tumor drugs and conduct single-arm trial scientifically. Post-marketing clinical trial should be implement as early as possible to ensure the benefit of patients. Based on the characteristics of single-arm trial, combined with two guidance relevant to single-arm trial issued by National Medical Products Administration recently, this article is supposed to propose and summarize the strategy of single-arm trial supporting the marketing of anti-tumor drugs.

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

Importing oncology trials from China: a bridge over troubled waters?

On Feb 10, 2022, the US Food and Drug Administration's Oncologic Drugs Advisory Committee will convene to discuss ORIENT-11, a clinical trial comparing chemotherapy plus sintilimab, an anti-PD-1 monoclonal antibody and member of the checkpoint inhibitor class, with chemotherapy alone as an initial treatment for metastatic non-small-cell lung cancer (NSCLC). 1 Roth LK Federal Register Vol. 86, No. 236. https://www.govinfo.gov/content/pkg/FR-2021-12-13/pdf/2021-26923.pdfDate: Dec 13, 2021 Date accessed: January 28, 2022 Google Scholar Done exclusively in China, the trial's design, patient population, and statistical analysis closely resembles landmark NSCLC trials that established checkpoint inhibitors as part of initial treatment regimens several years ago. 2 Yang Y Wang Z Fang J et al. Efficacy and safety of sintilimab plus pemetrexed and platinum as first-line treatment for locally advanced or metastatic nonsquamous NSCLC: a randomized, double-blind, phase 3 study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020; 15: 1636-1646 Google Scholar Rather than an isolated case, this application reflects an increasing number of oncology development programmes based solely or predominantly on clinical data from China, with at least 25 applications from China in drug development phases, planned to be submitted, or currently under review. 3 Beaver JA Pazdur R The wild west of checkpoint inhibitor development. N Engl J Med. 2021; (published online Dec 15.)https://doi.org/10.1056/NEJMp2116863 Google Scholar

Clinical review considerations of class I PI3K inhibitors in hematolymphatic malignancies by Center for Drug Evaluation.

Several phosphoinositide 3-kinase (PI3K) inhibitors are currently approved to treat hematolymphatic malignant diseases worldwide, and many drugs that have the same target are in the clinical research stage. In March 2022, duvelisib became the first PI3K inhibitor approved in China indicated for the treatment of hematolymphatic malignant diseases. Meanwhile, linperlisib and copanlisib have almost completed the technical review of the clinical specialty. The Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) found that class I PI3K inhibitors can cause various degrees of immune-related adverse events, which are associated with action mechanisms, affecting the benefit-risk assessment of the drugs. On April 21, 2021, the United States Food and Drug Administration (FDA) convened the Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the safety of PI3K inhibitors indicated for hematolymphatic malignancies and their related risk of death. The hematological tumor group of CDE of the China NMPA summarized and combined the data on PI3K inhibitors listed or under technical review for marketing authorization applications and found that such products may have unique efficacy and safety characteristics in Chinese patients with malignant lymphoma.

Biosimilar epoetin for cancer and chemotherapy-induced anaemia in the US

Biosimilars are biological drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety and efficacy. Biosimilar epoetin received US Food and Drug Administration (FDA) approval in 2018 [1]. The manufacturer received an FDA non-approval letter in 2017, despite receiving a favourable review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) and an FDA non-approval letter in 2015 for an earlier formulation.

The Oncologic Drugs Advisory Committee Votes of April 2021—Implications for the Fate of Accelerated Approval

The Oncologic Drugs Advisory Committee Votes of April 2021—Implications for the Fate of Accelerated Approval

Drug Transporter ABCB1 SNP Predicts Outcome in Patients with Acute Myeloid Leukemia Treated with Gemtuzumab Ozagamicin: A Report from Children's Oncology Group AAML0531 Trial

Background: Gemtuzumab Ozogamicin (GO), is first ever approved immunotherapy for relapsed AML patients. GO is a humanized anti-CD33 antibody linked with the toxin calicheamicin gamma. Calicheamicin induces DNA damage and cell death once the linked CD33 antibody facilitates its uptake. Previous studies have shown that the drug efflux transporter PgP1, which is encoded by gene ABCB1, influences the cellular accumulation of calicheamicin. PgP1 activity in leukemic cells is also inversely correlated with GO response in patients with AML. Although GO was withdrawn from market due to lack of benefit and increase in early mortality observed in SWOG-S0106 study subsequent multiple randomized studies have shown benefit of GO with significant improvement observed in patients with favorable cytogenetic risk features. In light of these results and recent favorable voting by FDA oncology drug advisory committee based on results of ALFA-0701 trail demonstrating a favorable risk:benefit profile for GO there is increased enthusiasm among AML investigators. Given the potential comeback of GO, it is very timely to focus efforts on identifying genetic biomarkers that can improve our ability to develop personalized treatment with GO. In this study evaluate whether single nucleotide polymorphisms (SNPs) in ABCB1 gene are predictive of GO response in patients with AML.Method: Genomic DNA samples from 942 patients enrolled in the COG trial AAML0531 who gave consent for the study were genotyped for 12 SNPs in the ABCB1 gene . Since AAML0531 was designed to test the benefit of GO in a randomized manner, we analyzed the effect of ABCB1 genotypes on outcomes and risk of relapse (RR) between patients treated with or without addition of GO (GO vs. No-GO respectively).Results: The ABCB1 SNP C3435T (rs1045642) was significantly associated with outcome when analyzed by GO vs. No-GO arm. Presence of C3435T change has been previously associated with lower PgP1 expression. For AML patients in the GO arm, presence of variant allele (CT and TT genotype) was significantly associated with lower risk of relapse (RR) from the end of course 1 (GO vs. No-GO arm: RR: 30 ± 6%, n = 259 vs. 46 ± 7%, n= 235; P < 0.0001) and better 5-year event free survival (EFS) from study than for those in the No-GO arm (GO vs. No-GO arm: 55 ± 6%, n = 340 vs. 45 ± 5%, n= 337; P= 0.006). However, patients with the CC genotype showed no differences in RR (GO and No-GO arms: 45 ± 10%, n = 97 vs. 40 ± 11%, n= 91; P= 0.514) and EFS (GO and No-GO arms: 44 ± 9%, n = 128 vs. 50 ± 9%, n= 132; P= 0.425) between the GO and No-GO arms (Fig 1). Further the rs1045642 genotype was significantly associated with EFS (CC vs. CT/TT: 44 ± 9% vs. 55 ± 6%; P=0.022) and RR (CC vs. CT/TT 45 ± 10% vs. 30 ± 6%, P=0.007) for patients in the GO arm but for those in the No-GO arm no difference in outcome between the genotypes was observed (RR: P=0.278; EFS P=0.466).Conclusion: Our results show that for the nonsynonymous SNP rs1045642 (C>T) in an drug efflux transporter ABCB1, the presence of T allele is associated with better response in patients treated with GO based as compared to standard arm. Since ABCB1 is involved in efflux of calicheamicin the presence of a low expression T allele might result in higher intracellular accumulation of calicheamicin and thus better response in patients treated with GO. [Display omitted] DisclosuresLoken:Hematologics Inc: Employment, Equity Ownership. Walter:ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding.

Mixed View of "Dangling" Accelerated Approvals.

A changing treatment landscape prompted members of the FDA's Oncologic Drugs Advisory Committee to recommend withdrawing accelerated approvals for two PD-1 inhibitors. The same panel, however, voted to maintain four other accelerated approvals after confirmatory trials showed signs, albeit not statistically significant, of clinical benefit.

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

Research advances and new challenges in overcoming triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification. TNBC includes a collection of multiple distinct disease entities based upon genomic, transcriptomic and phenotypic characterization. Despite improved clinical outcomes with the development of novel therapeutics, TNBC still yields the worst prognosis among all clinical subtypes of breast cancer. We will systematically review evidence of the genomic evolution of TNBC, as well as potential mechanisms of disease progression and treatment resistance, defined in part by advances in next-generation DNA sequencing technology (including single cell sequencing), providing a new perspective on treatment strategies, and promise to reveal new potential therapeutic targets. Moreover, we review novel therapies aimed at homologous recombination deficiency, PI3 kinase/AKT/PTEN pathway activation, androgen receptor blockade, immune checkpoint inhibition, as well as antibody-drug conjugates engaging novel cell surface targets, including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC. Despite major advances in treatment for TNBC, including FDA approval of 2 PARP inhibitors for metastatic TNBC, the crossing of the superiority boundary in a phase 3, placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer, the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC, and the FDA approval of the first antibody drug conjugate for TNBC, significant challenges remain. For example, despite the dawn of immunotherapy in metastatic TNBC, durable responses are limited to a small subset of patients, definitive biomarkers for patient selection are lacking, and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 checkpoint antibody high risk early-stage TNBC in the neoadjuvant setting. Also, despite early positive randomized phase 2 studies of AKT inhibition in metastatic TNBC, a recent phase 3 registration trial failed to validate earlier phase 2 data. Finally, we note that level one evidence for clinical efficacy of androgen receptor blockade in TNBC is still lacking. To meet these and other challenges, we will catalogue the ongoing exponential increase in interest in basic, translational, and clinical research to develop new treatment paradigms for TNBC.

Disagreements Between FDA and its Oncologic Drugs Advisory Committee (ODAC).

Cases of discordance between the US Food and Drug Administration (FDA) and its advisory committees are uncommon. Due to the importance of oncology therapies, we sought to identify and discuss instances of disagreement between the regulatory decision made by FDA, and the recommendation made by its Oncologic Drugs Advisory Committee (ODAC) via committee vote. Public databases (Oncologic Drugs Advisory Committee Meeting Materials, Drugs@FDA) as well as publicly available documents from ODAC meetings were reviewed to discern cases of disagreement between the two bodies. This review of public data yielded six (6) instances in which FDA's ultimate regulatory decision went against the recommendation of the ODAC. The six cases are briefly discussed and key drivers for or against an approval decision are outlined. In cases where FDA's decision was less conservative than that of the ODAC, the value of therapies with novel mechanisms of action which provide new options for patients, as well as regulatory precedent were observed as key drivers for regulatory decision-making. In cases where FDA took a more conservative approach than the ODAC, the importance of appropriate clinical trial design, clinically relevant trial endpoints, and the integrity of the data collected were stressed as driving the ultimate regulatory decision.

End of an era of administering erythropoiesis stimulating agents among Veterans Administration cancer patients with chemotherapy-induced anemia.

Erythropoisis stimulating agent (ESA) use was addressed in Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) meetings between 2004 and 2008. FDA safety-focused regulatory actions occurred in 2007 and 2008. In 2007, black box warnings advised of early death and venous thromboembolism (VTE) risks with ESAs in oncology. In 2010, a Risk Evaluation Strategies (REMS) was initiated, with cancer patient consent that mortality and VTE risks were noted with ESAs. We report warnings and REMS impacts on ESA utilization among Veterans Administration (VA) cancer patients with chemotherapy-induced anemia (CIA). Data were from Veterans Affairs database (2003–2012). Epoetin and darbepoetin use were primary outcomes. Segmented linear regression was used to estimate changes in ESA use levels and trends, clinical appropriateness, and adverse events (VTEs) among chemotherapy-treated cancer patients. To estimate changes in level of drug prescription rate after policy actions, model-specific indicator variables as covariates based on specific actions were included. ESA use fell by 95% and 90% from 2005, for epoetin and darbepoetin, from 22% and 11%, respectively, to 1% and 1%, respectively, among cancer patients with CIA, respectively (p<0.01). Following REMS in 2010, mean hematocrit levels at ESA initiation decreased from 30% to 21% (p<0.01). Black box warnings preceded decreased ESA use among VA cancer patients with CIA. REMS was followed by reduced hematocrit levels at ESA initiation. Our findings contrast with privately- insured and Medicaid insured cancer patient data on chemotherapy-induced anemia where ESA use decreased to 3% to 7% by 2010–2012. By 2012, the era of ESA administration to VA to cancer patients had ended but the warnings remain relevant and significant. In 2019, oncology/hematology national guidelines (ASCO/ASH) recommend that cancer patients with chemotherapy-induced anemia should receive ESAs or red blood cell transfusions after risk-benefit evaluation.

ES10.05 Brazilian Health Regulatory Agency - Agência Nacional de Vigilância Sanitária

Brazil, the largest country in South America, has become the second largest pharmaceutical market in the emerging world. The Brazilian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria – ANVISA) was created in 1999 with the primary goal to protect and promote public health surveillance over products and services in Brazil. Its hallmarks are administrative independence, financial autonomy, and the stability of its directors. Within the federal public regulatory structure, the agency is linked to the Ministry of Health [1]. Despite major advances in the regulatory process in Brazil, it is important to highlight that a major delay in cancer drugs approval over the last decade has had a negative impact on patient access to novel medications in Brazil. According to Barrios et al., [2] well-established and adequately functional drug approval legislation is indispensable to guarantee a country’s population health. Any malfunctions or delay in such a crucial process have serious consequences. As an example, the drug Crizotinib (Xalcori®Pfizer, NY, USA), which had its approval denied by ANVISA in June 2014 may be seen as a landmark. Assuming different premises, Barrios et al. [2] calculated 1.367 years of life lost over 34 months due to lack of access to Crizotinib between August 2011 (FDA approval) to June 2014 (refusal by ANVISA). Of note, Crizotinib was not approved in Brazil until Feb 2016, what may have added additional 804 years of life lost to final numbers due to this delay. Other example of unexplained delay in drug approval in lenalidomide. The gap between the drug approval in the US and Brazil was 12 years. Regarding drugs that do require a companion diagnostic, the situation may become more complicated since, unlike the US Food and Drug Administration, no clear mechanism is in place with ANVISA for the simultaneous linking of most companion diagnostic tests with their respective targeted therapeutic drug [3]. In trying to understand the reasons behind this delayed drug approval process, methodological, cultural, political and ideologic reasons may account. At odds with other regulatory agencies such the FDA that allow conditioned approval based on non randomized data for drugs addressing unmet medical needs. For many years ANVISA authorities mandated randomized phase 3 data for a definitive approval, since no conditioned approval was allowed. In this context, having a specific oncology area or committee, such as the FDA Oncology Drug Advisory Committee [4], may be crucial. Fast track approval, breakthrough designation, companion diagnostics, different surrogate endpoints, integration of real world evidence (RWE) into the regulatory process are very specific topics from the oncology field and do require to be analyzed under the perspective of cancer specialists. From a political, cultural and ideologic perspective, although it is notorious that Brazil has invested substantially in expanding access to health care for all of its citizens, the country has, essentially, two clear distinct and dissimilar health systems [3]. The public system allows drugs to become commercially available through processes that are different from those in place in the private health-care system. Although difficult to measure those disparities and difficulties to reimburse expensive drugs in the public system, may have influenced the delayed process during the last decade. Over the last decade, delays at ANVISA’s approval process have been considered the only reason for the inequitable access to oncology care between the USA and Brazil. Yet, this may be a biased conclusion and a more comprehensive analysis in needed. By analyzing a basket of twenty-three oncology products approved by ANVISA after 2002 Bustamante et al. [5] identified that on average there was a difference of 8.6 months (449 X 186 days). However, on average, a delay in the manufacturers’ submission for regulatory approval of 1.1 years (393 days between Brazil and the USA) was also identified. More recently, a trend toward improvements in the drug approval process has been identified (ex. Osimertinib and Durvalumab). Osimertinib was firstly approved by ANVISA in 2017 as a second line treatment in patients who did not respond well to the initial drug. With the new determination, in 2018 ANVISA approved its use as a first therapy to treat locally advanced non-small cell lung cancer. Durvalumab was approved by ANVISA in 2017. Nevertheless, there is clear room for a continuous improvement. Increase in the number of ANVISA technicians, continuous training and collaboration with academic institutions and other regulatory agencies elsewhere are mandatory. Close scientific collaboration and open and transparent dialogue between ANVISA and pharmaceutical companies are required. In sum, if we are to have a continuous improvement in the oncology drug approval process, all the stakeholders (ANVISA, drug manufactures, patient advocacy, players at the private and public health systems) must act together.

Editorial introductions

Editorial introductions

Financial Conflicts of Interest at FDA Drug Advisory Committee Meetings.

The U.S. Food and Drug Administration's drug advisory committees provide expert assessments of the safety and efficacy of new therapies considered for approval. A committee hears from a variety of speakers, from six groups, including voting members of the committee, FDA staff members, employees of the pharmaceutical company seeking approval of a therapy, patient and consumer representatives, expert speakers invited by the company, and public participants. The committees convene at the request of the FDA when the risks and harms of novel products are not immediately clear, and their final decisions carry significant weight, as most therapies that receive advisory committee approval are subsequently approved by the FDA. In recent years, across a series of diverse publications, the financial conflicts of interest of each category of participants in the meetings have been investigated. Here, we summarize these findings and their ethical implications, focusing on the FDA Oncologic Drugs Advisory Committee, and we suggest ways to move toward more transparent and impartial advisory committee meetings.

Editorial introductions

Editorial introductions