70 results found
Lythgoe M, 2023, Financial Toxicity from Newly Approved Second-/Third-Line Agents in Metastatic Urothelial Carcinoma, BJU International, ISSN: 1464-4096
Lythgoe M, 2023, Modernising the US FDA's Accelerated Approval pathway, The Lancet Oncology, Vol: 24, Pages: 203-205, ISSN: 1470-2045
On Dec 29, 2022, US President Joe Biden signed The Consolidated Appropriations Act into law. This wide-reaching Act contains notable reforms to the US Food and Drug Administration (FDA) statutory and regulatory frameworks. The legislation amends key regulatory frameworks, including changes to the FDA-expedited approval programme, Accelerated Approval. 1 This pathway has been substantial for drug development globally since its introduction in 1992, permitting early regulatory approval based on surrogate endpoints likely to predict clinical benefit for drugs treating serious or life-threatening conditions. 2 A further confirmatory study is typically required to validate true clinical benefit to permit conversion to standard approval, or in the case of a negative result, potentially medicine withdrawal. Recent scrutiny of the Accelerated Approval pathway, particularly after the approval of aducanumab for Alzheimer's disease, and the notable withdrawal of several cancer medicines (eg, bevacizumab in breast cancer), has led many to call for urgent reform of this pathway. 3 , 4 As Accelerated Approval is predominately used in oncology, with cancer drugs accounting for 85% of use over the past decade, reforms are highly relevant for new cancer drug development and approval. 2 We will therefore highlight key reforms, and potential opportunities and challenges these could present.
Lythgoe M, 2023, The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020, International Journal of Cancer, Pages: 1-11, ISSN: 0020-7136
Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2 = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.
Blagden SP, Yu L-M, Ellis S, et al., 2023, Additional consensus recommendations for conducting complex innovative trials of oncology agents: a post-pandemic perspective, British Journal of Cancer, Vol: 128, Pages: 474-477, ISSN: 0007-0920
In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.
Lythgoe M, 2023, The rise of immuno-oncology in China - a challenge to western dominance?, The Lancet Oncology, ISSN: 1470-2045
Khaki AR, Lythgoe MP, Prasad V, 2023, Adjuvant checkpoint inhibitor trials: Is disease-free survival an appropriate endpoint?, Journal of Cancer Policy, Vol: 35, Pages: 1-2, ISSN: 2213-5383
Chiang RS, Desai A, Glover MJ, et al., 2023, Racial diversity and reporting in United States Food and Drug Administration registration trials for thoracic malignancies from 2006-2020, Cancer Investigation, Vol: 41, Pages: 43-47, ISSN: 0735-7907
There is significant racial disparity in thoracic malignancies in terms of epidemiology and outcomes. We analyzed race reporting and racial diversity in the registration trials of drugs approved by the FDA for thoracic malignancies from 2006-2020. We found a significant under-representation of non-white participants in FDA drug registration trials in thoracic malignancies. Furthermore, though almost all trials report some race information, FDA guidelines are not universally followed. There is a disproportionate disease burden of lung cancer in under-represented race communities, and clinical trials should prioritize racial diversity and inclusion efforts.
Lythgoe M, 2022, No new ‘mabs’ in medicine – New nomenclature for monoclonal antibodies, British Journal of Pharmacology, Vol: 179, Pages: 5338-5339, ISSN: 0007-1188
Lythgoe MP, Mullish BH, Frampton A, et al., 2022, Polymorphic microbes: a new emerging hallmark of cancer, Trends in Microbiology, Vol: 30, Pages: 1131-1134, ISSN: 0966-842X
Recognition of the microbiome (and ‘polymorphic microbes’ within them) as a new emerging hallmark of cancer reflects a wide body of rapidly evolving research. Microbes may be directly carcinogenic, impact host immune responses to promote malignancy, and key effectors in determining anti-cancer therapy efficacy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.
Lythgoe M, Krell J, Bower M, et al., 2022, From the European Medicines Agency to Project Orbis: new activities and challenges to facilitate UK Oncology Drug Approval following Brexit, The Lancet Oncology, ISSN: 1213-9432
The departure of the UK from the European Union (EU) and affiliated European regulatory bodies on the 31st December 2020, including the European Medicines Agency, (EMA), has resulted in the Medicines and Healthcare products Regulatory Agency (MHRA) becoming an independent national regulator. This has required a fundamental transformation of the UK drug regulatory landscape, creating both opportunities and challenges for future oncology drug development. New UK pharmaceutical policy has sought to establish the UK as an attractive market for drug development and regulatory review, by offering expedited review pathways coupled to strong collaborative relations with other leading international medicines regulators, outside of Europe. Oncology is a key global therapy area for both drug development and regulatory approval, and the UK government has been keen to demonstrate regulatory innovation and international collaboration in the approval of new cancer medicines. In this review, we examine the new UK regulatory frameworks, policies, and global collaborations affecting new oncology drug approvals following departure from the EU. We explore some of the challenges which may lie ahead as the UK forges ahead with new and independent regulatory review and approval processes for the next generation of cancer medicines.
Rizwan N, Khaki AR, Desai A, et al., 2022, 427 Approval timings and review speed of immune checkpoint inhibitors (ICIs) in cancer therapy between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) from 2010-2022, SITC 37th Annual Meeting (SITC 2022) Abstracts, Publisher: BMJ Publishing Group Ltd
Lythgoe M, Mullish B, Frampton A, et al., 2022, 627 Oral administration of MRx0518 in treatment-naïve cancer patients is associated with compositional taxonomic and metabolomic changes indicative of anti-tumorigenic efficacy, SITC 37th Annual Meeting (SITC 2022) Abstracts, Publisher: BMJ Publishing Group Ltd
Jenei K, Lythgoe MP, Prasad V, 2022, General payments from Biogen to U.S. physicians between 2015 and 2020., J Am Geriatr Soc, Vol: 70, Pages: 3035-3038
Jenei K, Lythgoe MP, Prasad V, 2022, CostPlus and implications for generic imatinib, The Lancet Regional Health - Americas, Vol: 13
Lythgoe MP, Prasad V, 2022, Repositioning canakinumab for non-small cell lung cancer-important lessons for drug repurposing in oncology, British Journal of Cancer, Vol: 127, Pages: 785-787, ISSN: 0007-0920
Canakinumab is an anti-interleukin-1β monoclonal antibody approved for use in a range of immune-related disorders. During the clinical investigation (CANTOS trial) for prevention of cardiovascular complications, therapy was linked to a reduction in both the occurrence and mortality of lung cancer. This unexpected observation fuelled the rapid initiation of four large clinical trials to evaluate potential anticancer efficacy (in combination with chemotherapy and/or immunotherapy), before fully validating these observations in a dedicated study. The first two trials (CANOPY-1 and 2) have now been reported and have both have failed to meet their primary efficacy endpoints. In this article, we explore the scientific and clinical rationale behind the development of canakinumab in oncology, the repurposing approach utilised and implications this may have for the wider drug repurposing field in the development of new cancer medicines.
Mirón-Barroso S, Correia JS, Frampton AE, et al., 2022, Polymeric carriers for delivery of RNA cancer therapeutics, Non-Coding RNA, Vol: 8, Pages: 58-58, ISSN: 2311-553X
As research uncovers the underpinnings of cancer biology, new targeted therapies have been developed. Many of these therapies are small molecules, such as kinase inhibitors, that target specific proteins; however, only 1% of the genome encodes for proteins and only a subset of these proteins has ‘druggable’ active binding sites. In recent decades, RNA therapeutics have gained popularity due to their ability to affect targets that small molecules cannot. Additionally, they can be manufactured more rapidly and cost-effectively than small molecules or recombinant proteins. RNA therapeutics can be synthesised chemically and altered quickly, which can enable a more personalised approach to cancer treatment. Even though a wide range of RNA therapeutics are being developed for various indications in the oncology setting, none has reached the clinic to date. One of the main reasons for this is attributed to the lack of safe and effective delivery systems for this type of therapeutic. This review focuses on current strategies to overcome these challenges and enable the clinical utility of these novel therapeutic agents in the cancer clinic.
Lythgoe MP, Sullivan R, 2022, Project Orbis: the UK experience after 1 year., Lancet Oncol, Vol: 23, Pages: 978-981
Lythgoe M, Desai A, Gyawali B, et al., 2022, Cancer therapy approval timings, review speed and publication of pivotal registration trials in the US and Europe from 2010-2019, Jama Network Open, Vol: 5, ISSN: 2574-3805
Importance: Ensuring patients have access to safe and efficacious medicines in a timely manner is an essential goal for regulatory agencies, which has particular significance in oncology due to the significant unmet need for new therapies. The two largest regulatory agencies, the FDA and EMA have pivotal global roles, and their recommendations and approvals are frequently followed by other national regulators.Objective: To compare market authorization dates for new oncology therapies approved in the US and Europe over the past decade and to examine and contrast the regulatory activities of the FDA and EMA in the approval of new cancer medicines.Design, Setting and Participants: A review of the FDA and EMA regulatory databases to identify new oncology therapies approved in both the US and Europe from 2010 to 2019, and characterization of the timings of regulatory activities. Main Outcome Measures: Regulatory approval date, review time, submission of market authorization application, accelerated approval or conditional marketing authorisation status and proportion of approvals prior to peer-reviewed publication of pivotal trial results. Results: In total, 89 new concomitant oncology therapies were approved in the US and Europe from 2010 to 2019. The FDA approved 85 (95%) oncology therapies before European authorization and 4 (5%) therapies after. The median delay in market authorization for new oncology therapies in Europe was 241 days compared to the US. The median review time was 200 days and 426 days for the FDA and EMA, respectively. 60 (67%) new licensing applications were submitted to the FDA first, compared to 25 (28%) to the EMA. 35 (39%) oncology therapies were approved by the FDA prior to pivotal study publication, whereas only 8 (9%) by the EMA.Conclusion and Relevance: In this study we demonstrate that new oncology therapies are approved earlier in the US than Europe. The FDA receives licensing applications sooner and has shorter review times. However, mor
Lythgoe MP, Sullivan R, 2022, Approved anti-PD-1 monoclonal antibodies in China: A bridge too far for US approval, EUROPEAN JOURNAL OF CANCER, Vol: 169, Pages: 103-105, ISSN: 0959-8049
Benjamin DJ, Prasad V, Lythgoe MP, 2022, FDA decisions on new oncological drugs, The Lancet Oncology, Vol: 23, Pages: 585-586, ISSN: 1470-2045
Talukder R, Makrakis D, Diamantopoulos LN, et al., 2022, Response and Outcomes to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer Based on Prior Intravesical Bacillus Calmette-Guerin, CLINICAL GENITOURINARY CANCER, Vol: 20, Pages: 165-175, ISSN: 1558-7673
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Jenei K, Prasad V, Lythgoe MP, 2022, High US drug prices have global implications., BMJ, Vol: 376
Benjamin DJ, Xu A, Lythgoe MP, et al., 2022, Cancer drug approvals that displaced existing standard-of-care therapies, 2016-2021, Jama Network Open, Vol: 5, Pages: 1-9, ISSN: 2574-3805
Importance Although several cancer drugs receive US Food and Drug Administration (FDA) approval each month, it is unclear how many of these cancer drugs transform the treatment landscape significantly by tumor group. Specifically, it remains unclear how many of these newly approved cancer drugs displace the existing standard-of-care therapies for their indication vs being added to existing therapies.Objective To examine how many cancer drugs displace the standard-of-care therapies vs being added to existing therapy or filling breaks in systemic treatments in the metastatic setting, adjuvant setting, or maintenance setting.Design, Setting, and Participants Retrospective cross-sectional study using landmark trials leading to FDA approval of cancer drugs between May 1, 2016, and May 31, 2021. The study evaluated all FDA approvals for cancer drugs between May 1, 2016, and May 31, 2021, using the FDA Oncology (Cancer)/Hematologic Malignancies Approval Notifications website. All clinical trials leading to FDA approval of cancer drugs during this period were examined.Main Outcomes and Measures A drug was determined to have displaced the prior standard-of-care therapy by evaluating the comparator arm (or lack thereof) in the clinical trial leading to the drug’s approval and also by reviewing National Comprehensive Cancer Network Guidelines. Cancer drug approvals were categorized as first-line displacing if a drug was approved for use in the first-line setting and displaced the prior standard-of-care drug for an indication, first-line drug alternatives/new if a drug was approved for use in the first-line setting but did not displace the standard of care at the time of approval or was a new drug that was first of its class for an approved indication, add on if a drug was approved in combination with a previously approved therapy for a disease or if a drug was approved for use in the adjuvant or maintenance settings, and later line if a drug was approved for use in t
Lythgoe MP, Prasad V, 2022, The last word to new FDA draft guidance for cancer clinical trial eligibility criteria for patients with incurable cancer, Journal of Cancer Policy, Vol: 31, Pages: 100322-100322, ISSN: 2213-5383
Benjamin DJ, Lythgoe M, Raymakers AJN, et al., 2022, Cost effectiveness of newly approved second/third-line agents in metastatic urothelial carcinoma (mUC)., Journal of Clinical Oncology, Vol: 40, Pages: 574-574, ISSN: 0732-183X
<jats:p> 574 </jats:p><jats:p> Background: Over the past years, the treatment landscape of platinum-refractory mUC has drastically changed with the advent of immunotherapy. More recently, several new agents including enfortumab, erdafitinib, and sacituzumab have received F.D.A. approval for the treatment of platinum-refractory mUC. It is unclear if these newly approved therapies may be cost prohibitive for patients and/or hospitals/clinics compared to the recommended NCCN category 1 second-line agent, pembrolizumab. Methods: Using acquisition costs from our home institution’s cancer center pharmacy department, we calculated the total cost of treatment for each agent. We used phase II clinical trial data to determine the median duration of treatment for each therapy. For weight-based therapies, we used 70 kg as the weight for an average human adult. Results: The three newly approved therapies for mUC have total acquisition costs in descending order as follows: enfortumab vedotin ($153,697.50), edafitinib ($131,642.62), and sacituzumab govitecan ($63,198.07). Enfortumab and sacituzumab likely have higher total costs given both therapies require infusion center use for administration, and are associated with infusion center administration fees. In comparison, pembrolizumab (standard of care per NCCN guidelines) has a total acquisition cost of $51,343.60. Conclusions: Based off median duration of treatment, pembrolizumab has the lowest total acquisition cost compared to the three newly approved therapies for mUC. Further statistical analysis of this data set is ongoing. In particular, analysis will include out-of-pocket costs for patients as well as quality-adjusted life years (QALY).[Table: see text] </jats:p>
Glover M, Hui G, Chiang R, et al., 2022, Disparity of race reporting in US Food and Drug Administration drug approvals for urinary system cancers from 2006 to 2021, BJU International, Vol: 129, Pages: 168-170, ISSN: 1464-4096
Lythgoe MP, Jenei K, Prasad V, 2022, Regulatory decisions diverge over aducanumab for Alzheimer’s disease, BMJ, Vol: 376, Pages: 1-2, ISSN: 1759-2151
Lythgoe MP, Sullivan R, 2022, Could the UK's fixed-fee subscription improve access to antimicrobials and other essential medicines in low-income and middle-income countries?, The Lancet Microbe
Haslam A, Lythgoe MP, Greenstreet Akman E, et al., 2021, Characteristics of Cost-effectiveness Studies for Oncology Drugs Approved in the United States From 2015-2020., JAMA Netw Open, Vol: 4
IMPORTANCE: Increasingly, cost-effectiveness analyses are being done to determine the value of rapidly increasing oncology drugs; however, this assumes that these analyses are unbiased. OBJECTIVE: To analyze the characteristics of cost-effectiveness studies and to determine characteristics associated with whether an oncology drug is found to be cost-effective. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study included 254 cost-effectiveness analyses for 116 oncology drugs that were approved by the US Food and Drug Administration from 2015 to 2020. EXPOSURES: Each drug was analyzed for the incremental cost-effectiveness ratio per quality-adjusted life year, the funding of the study, the authors' conflict of interest, the threshold of willingness-to-pay, from what country's perspective the analysis was done, and whether a National Institute for Health and Care Excellence cost-effectiveness analysis had been done. MAIN OUTCOMES AND MEASURES: The main outcome was the odds of a study concluding that a drug was cost-effective. RESULTS: There were 116 drug approvals with 254 studies and country perspectives. Of the country perspectives, 132 (52%) were from the US. Forty-seven of 78 drugs with cost-effective studies had been shown to improve overall survival, whereas 15 of 38 of drugs without a cost-effectiveness study had been shown to improve overall survival. Having a study funded by a pharmaceutical company was associated with higher odds of a study concluding that a drug was cost-effective than studies without funding (odds ratio, 41.36; 95% CI, 11.86-262.23). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, pharmaceutical funding was associated with greater odds that an oncology drug would be found to be cost-effective. These findings suggest that simply disclosing potential conflict of interest is inadequate. We encourage cost-effectiveness analyses by independent groups.
Lythgoe MP, Olivier T, Prasad V, 2021, The iceberg plot, improving the visualisation of therapy response in oncology in the era of sequence-directed therapy, EUROPEAN JOURNAL OF CANCER, Vol: 159, Pages: 56-59, ISSN: 0959-8049
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