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Proceedings of a Workshop
Pages 1-114

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From page 1...
... Compared with standard chemotherapies, these new cancer therapies may demonstrate evidence of benefit at an earlier stage of development. However, there is a concern that the traditional processes for cancer drug development, evaluation, and regulatory approval could impede or delay the use of these promising cancer treatments in clinical practice.
From page 2...
... The workshop was held on December 12–13, 2016, at the National Academies of Sciences, Engineering, and Medicine in Washington, DC. This workshop convened cancer researchers, patient advocates, and representatives from industry, academia, and government to discuss challenges with traditional approaches to drug development, opportunities to improve the efficiency of drug development, and strategies to enhance the information available about cancer therapy throughout its life cycle in order to improve its use in clinical practice.3 Many workshop speakers discussed potential strategies for improving cancer drug development, including • patient-centered drug development that prioritizes patient needs and employs patient-reported outcomes; • biologically informed strategies in drug development, including the use of biomarkers to select patients most likely to respond to treatments and surrogate endpoints that are informed by a drug's mechanism of action; • more flexible, efficient, and continuous clinical trial designs that can evaluate multiple interventions in different patient populations, expand testing to larger numbers of patients when agents show initial promise, and conscientiously and efficiently manage limited patient availability and clinical trial resources; and • expanding clinical trial eligibility and leveraging the use of real world data to better understand how drugs perform in clinical practice.
From page 3...
... The workshop statement of task is in Appendix A and the workshop agenda is in Appendix B The webcast and speakers' presentations have been archived online.4 BACKGROUND ON DRUG DEVELOPMENT AND REGULATORY REVIEW A number of workshop speakers discussed the goals of oncology drug development, the traditional phased approach to drug development, the regulatory processes for review and evaluation of new cancer therapies, and the ethical standards for clinical research.
From page 4...
... (Joffe, Matrisian, Raju, Rockhold, Tendler) Establishing More Meaningful Endpoints in Drug Development •  nvest in the development, validation, and use of intermediate I endpoints and surrogate endpoints to measure tumor burden and patient response to new cancer therapies -- both quantitatively and q ­ ualitatively -- in order to identify effects earlier in drug develop ment and to improve the efficiency of clinical trials.
From page 5...
... •  evelop an explicit plan for biomarker analysis as part of oncology D clinical trial designs, including plans to ensure sufficient statistical power to determine treatment effects given expected biomarker prevalence both within and among patient populations. (Redman)
From page 6...
... Decision Making and Oversight of Clinical Trials •  ecognize that the decision-making processes in seamless trial R designs are more complex due to the altered benefit–risk analyses and the need for rapid continuation or expansion decisions. (Joffe)
From page 7...
... (Koehler, Sridhara) o  valuate eligibility criteria for clinical trials inform future trial e designs with expanded eligibility.
From page 8...
... •  llow patients with pediatric cancers to enroll in clinical trials of A novel cancer drugs. (Kline, Rothenberg)
From page 9...
... Safety, dosing, and short term side effects are also studied. Phase III Studies in larger and more varied patient populations, if efficacy is demonstrated in Phase II.
From page 10...
... . Staff from FDA's OHOP recently authored an article outlining an evolving drug development paradigm, indicating their willingness to consider alternatives to the traditional phased drug development process (Prowell et al., 2016; Theoret et al., 2015)
From page 11...
... Joffe added that a clinical trial should also have a favorable benefit-to-risk ratio for the individual patients participating in the research, as well as for future patients who stand to gain from the results of the research. Frank Rockhold, professor of biostatistics and bioinformatics at the Duke Clinical Research Institute, noted that the ethical imperatives for clinical research are defined in the Declaration of Helsinki,6 which states that the risks to participants in clinical trials must be continuously monitored, assessed, and documented by researchers.
From page 12...
... Failure can be due to a number of factors, Ratain said, such as not identifying the right dosage ­ 7 A DSMB is a "group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials.
From page 13...
... FIGURE 1  Drug discovery and development timeline. NOTE: FDA = Food and Drug Administration; IND = investigational new drug; Mfg.
From page 14...
... Often these interventions will be combinations of new agents, which are challenging to study, she noted. Ratain added that inefficient trial designs and misunderstandings of governmental regulations or corporate bureaucracy can delay the onset or lengthen the duration of clinical trials.
From page 15...
... , and we really do not know everything we need to know," she said. Several participants pointed out the inadequacy of commonly used endpoints to assess patient response in clinical trials, including the Response Evaluation Criteria in Solid Tumors (RECIST)
From page 16...
... . Weber said that unless a therapy has an unusually strong and immediate impact on tumors, large numbers of patients in clinical trials are needed in order for RECIST criteria to reliably predict improved outcomes.
From page 17...
... Harvey agreed, and noted that the maximum tolerated dose does not often apply when com 8 Maximum tolerated dose is "the highest dose of a drug or treatment that does not cause unacceptable side effects. The maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found." See https://www.cancer.gov/publications/dictionaries/­ancer c terms?
From page 18...
... She suggested that patients work with FDA in meaningful ways to ensure their needs are met by clinical trials for drug development, and added that an objective of the 21st Century Cures Act (see Box 2) is to incorporate patient perspectives into the regulatory process and address patients' unmet medical needs.
From page 19...
... •  odernizing trial design and evidence development by m requiring FDA to issue guidance addressing the use of novel clinical trial design in the development and review of drugs, and to evaluate and issue guidance on the use of evidence from sources other than clinical trials to support approval of a drug for a new indication. • ncreasing patient access to therapies and information i by allowing FDA to rely on a summary of clinical data to approve a supplemental application for a medication, for certain indications.
From page 20...
... . Lynn Matrisian, chief research officer of the Pancreatic Cancer Action Network, agreed, noting that "real-world evidence is something patients really care about." Koehler added that real-world evidence can facilitate patientcentered drug development by • focusing on broader populations and outcomes that are important to patients; • better informing and engaging patients through patient portals located in EHRs; • facilitating identification of patients who are eligible for trials, better ­ coordination of their health information, and enabling their partici pation in clinical trials; • accelerating broad access to new medications; and • promoting precision medicine in community care settings.
From page 21...
... He suggested it might be feasible to have patients agree that if they enter a hospital or other medical facility that uses EHRs, they automatically agree to share their EHR data for research purposes. "That may be needed for a pragmatic, clustered randomized clinical trial," he said.
From page 22...
... Patient Risk Joffe noted that there is increasing pressure to accelerate cancer drug development in order to provide patients who have life-threatening diseases with earlier access to promising new therapies. But he said an analysis of more than 100 Phase I cancer clinical trials found that faster approaches to escalating doses in studies was linked to increased toxicity rates, without improving efficacy (Koyfman et al., 2007)
From page 23...
... In addition to early testing aimed at determining dose and the patient population most likely to respond to a treatment, Kenneth Anderson, director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, suggested that researchers conduct more preclinical modeling studies with genetic analyses to guide later clinical trials. For example, such biologic explorations have informed drug development by assessing which patients with breast cancer are most likely to respond to an epidermal growth factor receptor (EGFR)
From page 24...
... For example, one EGFR inhibitor, gefitinib, was initially not shown to be effective in clinical trials for patients with lung cancer. Further research demonstrated that gefitinib did improve progression-free survival in patients whose tumors had specific EGFR mutations compared to standard chemotherapy (Maemondo et al., 2010)
From page 25...
... Finn noted that since palbociclib's approval, several other CDK inhibitors have progressed from the laboratory to Phase III studies, including ribociclib (Hortobagyi et al., 2016) .14 "The greatest advances in patient outcomes have come from integrating biology into clinical practice and critical use of preclinical models can guide that process.
From page 26...
... In traditional drug development, academic laboratories complete basic cancer biology research that can suggest new pathways and mechanisms of action for how cancer grows and spreads, Anderson explained. Industry then discovers new agents that act on these pathways and develops these agents further with preclinical testing before working with academia to conduct clinical trials.
From page 27...
... For example, preclinical findings suggest that there is synergy in combining a proteasome inhibitor with protein kinase B inhibitors -- also known as Akt inhibitors -- in multiple myeloma, prostate cancers, and other cancers. "The correlative science can inform going forward clinically, not only in one disease, but more broadly," he said.
From page 28...
... Iniparib failed in Phase III clinical trials (Mateo et al., 2013) , and PET imaging later showed that the molecule does not inhibit PARP at clinically relevant doses at the tumor site while olaparib, which has FDA approval for the treatment of ovarian cancer, is able to do so (Michel et al., 2017)
From page 29...
... . New Endpoints Several workshop participants discussed the need to develop new endpoints to assess therapeutic responses more quickly, compared with current endpoints used in cancer clinical trials, such as progression-free and overall survival.
From page 30...
... She suggested designing studies with endpoints that reflect both efficacy and futility, which is the inability of a clinical trial to show statistically significant changes in outcomes between treatment and control arms. She stressed evaluating futility separately from efficacy because there are different statistical standards and methodologies to demonstrate that a trial is unable to differentiate any effect versus a trial definitively showing no effect of the treatment.
From page 31...
... Several participants discussed how process modeling can help researchers predict the optimal drug development pathway for a therapy, as well as dosage modeling to determine optimal dosing for a therapy or combinations of therapies. In addition, DSMBs and FDA can use benefit–risk modeling to better ascertain the potential benefits and risks of an investigational new drug when making decisions about whether clinical trials should proceed, and whether it should receive FDA approval for use in clinical practice.
From page 32...
... "Our conventional dose escalation approaches are unlikely to adequately solve the problem," he said, and added that investigating interactions between or among drugs in combination therapies is expensive, so investigators need to know in advance whether interactions are expected and design their clinical trials accordingly. "With drug combinations, we will need larger designs and we have no alternative but to pay the price when those drug interactions are clinically important," he said.
From page 33...
... Another dosage modeling approach is the surface design method, which is widely used to optimize multiple variables in industrial or chemical processes, but is not often used in clinical trials, Piantadosi said. Surface design relies on systematically generating responses as control variables are changed, and fitting the responses on a flexible surface to determine optimum dosing.
From page 34...
... and cyclophosphamide (CY) dose combinations to produce the highest vaccine response in breast cancer.
From page 35...
... He said that the benefit of conducting these analyses is that it provides the rationale for FDA decision making, and added that this type of benefit–risk modeling could also inform earlier development decisions and trial designs, as well as at later stages when more data have been collected. Development and Use of Biomarkers in Cancer Clinical Trials Redman stressed that clinical trials for cancer drug development need to include an explicit plan for biomarker analysis.
From page 36...
... NOTE: Afa = afatinib; Ale = alectinib; ALK+ = anaplastic lymphoma kinase-positive; Bev = bevacizumab; Cer = ceritinib; Cet = cetuximab; Cri = crizotinib; EGFR = epidermal growth factor receptor; Erl = erlotinib; Gef = gefitinib; Nec = necitumumab; Niv = nivolumab; NSq = nonsquamous; ORR = overall response rate; OS = overall survival; Osi = osimertinib; PD-L = programmed death-ligand; Pemb = pembrolizumab; PFS = progression-free survival; Ram = ramucirumab; Sq = squamous. SOURCES: Raju presentation, December 13, 2016; Raju et al., 2016b.
From page 37...
... She described three clinical trial designs that include biomarker analysis as a main objective (see Figure 5)
From page 38...
... Because of this, Redman said that it can be difficult to establish appropriate thresholds for biomarker-based patient selection in clinical trials. Another challenge with biomarker-determined subgroup analyses of clinical trial data is that the smaller size of each subgroup decreases the statistical reliability of the data, Redman noted.
From page 39...
... Rothenberg framed the question of when to begin diagnostic test development as: "Do we know enough [about the biomarker test] to pull the trigger and modify the clinical trial design?
From page 40...
... Finn noted that the PALOMA-1/TRIO-18 clinical trial changed patient enrollment criteria midway into the study to specifically select only ER-positive and HER2-negative patients who had biomarkers for amplification of cyclin D1, loss of p16, or both (Finn et al., 2015)
From page 41...
... Innovative Clinical Trial Designs Many participants discussed innovations in clinical trial designs for cancer drug development. These include adaptive protocols that are amended based on new findings, seamless protocols that more easily transition between the different phases of drug testing, master protocols that enable the testing of multiple drugs and/or biomarkers in multiple diseases simultaneously, and clinical trials with common control arms.
From page 42...
... One category -- sequential designs -- involves analyzing and reviewing the data at periodic prespecified time points in a study and deciding whether to continue the trial based on the results. At these points, investigators can also decide to amend the study to increase the sample size or to narrow the clinical trial to a subset of patients.
From page 43...
... Clinical Trial Designs Several workshop participants described opportunities to create a more seamless drug development paradigm. Theoret illustrated a seamless drug
From page 44...
... . He noted that FDA is receptive to considering opportunities to use seamless drug development designs in appropriate circumstances, and noted that he and other FDA colleagues had recently authored a perspective with a conclusion that a "desire to provide earlier access to highly effective drugs should encourage further use of seamless expansion-cohort trials, particularly as drugs with unprecedented levels of efficacy advance into clinical trials" (Prowell et al., 2016)
From page 45...
... seamless oncology drug development paradigms. SOURCES: Theoret presentation, December 13, 2016; Reprinted from Clinical Cancer Research, © 2015, 21(20)
From page 46...
... assess if greater efficacy is achieved with doses greater than the minimal effective dose (see Box 4 for more information on the challenges of dosing in seamless clinical trials)
From page 47...
... Harvey found that since 2011, there have been 28 new Food and Drug Administration (FDA) approvals of oral cancer drugs, 11 of which were accelerated approvals.
From page 48...
... These doses should be optimally defined by these populations' clinical variables. In addition, Harvey pointed out that chronic administration of cancer drugs is often approached by giv ing standard doses initially, but subsequently many patients need dose reductions after 1–2 months in order to tolerate the drug over longer periods of time.
From page 49...
... Gideon Blumenthal, lead medical officer in thoracic, head, and neck cancers at FDA's Office of Hematology and Oncology Products (OHOP) , concurred, noting that he has seen this done within master protocols that are still accruing patients despite multiple FDA approvals.
From page 50...
... For example, investigators may use a master protocol to test one treatment on multiple types of cancer, or to test multiple treatments on a single type of cancer, or even to test multiple types of treatments on multiple types of cancer. Many master protocols are seamless clinical trials with adaptive design features to enable investigators to set up evolving treatment arms of a single trial protocol.
From page 51...
... National Clinical Trials Network, the Foundation for the National Institutes of Health (FNIH) , a number of patient advocacy organizations, and a number of phar maceutical companies.
From page 52...
... •  perational efficiency -- The single master protocol can be O amended as needed as drugs enter and exit the study. •  onsistency -- Every drug entered into the trial will be tested in C an identical manner.
From page 53...
... -Biomarker Sub-studies Non-NGS-Matched Sub-studies Biomarker 1 Positive …Biomarker n Positive Not Biomarker 1-n Sub-study 1 …Sub-study n Non-Match Biomarker-driven Biomarker-driven Sub-study Stage 1: Targeted Therapy Targeted Therapy R Investigational Investigational Therapy 1 Therapy n Non-match Standard of Investigational Care Therapy Stage 2: R R Investigational Standard of Investigational Standard of Therapy 1 Care Therapy n Care Design: Primary Endpoint: Sample Size: Biomarker Non-match Unchanged Phase II ->III Phase II: Response Phase II: 40 Phase III: OS Phase III: 150-200 Lung-MAP trial schematic, December 2015. NOTE: NGS = next-generation sequencing; OS = overall survival.
From page 54...
... Biomarker discovery and validation is also incorporated into the master protocol. "This pushes the modern trial design envelope from a patient perspective," Matrisian said.
From page 55...
... Study designed for pancreatic cancer patients. NOTE: CR = complete response; DDR = DNA damage response; Gem/abx = gemcitabine and abraxane; HA = hyaluronan; MATCH = National Cancer Institute-Molecular Analysis for Therapy Choice; PD = progressive disease; PDA = pancreatic ductal adenocarcinoma; Plat.Tx = platinum-based treatment; PR = partial response; SD = stable disease; TAPUR = Targeted Agent Profiling Utilization Registry Study.
From page 56...
... expansion cohort master protocol, in which pembrolizumab was tested in patients with different types of solid tumors (see Figure 7)
From page 57...
... FIGURE 7  The KEYNOTE-001 dose expansion cohorts in solid tumors, melanoma, and non-small cell lung cancer. NOTE: IPI = ipilimumab; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; Q2W = once every 2 weeks; Q3W = once every 3 weeks.
From page 58...
... But there are tremendous advantages to adaptive designs and they add to the seamlessness of drug development," Woodcock said. Theoret discussed several advantages of expanding cohorts under a master protocol clinical trial.
From page 59...
... In this type of trial design, consideration for independent oversight should be considered early on," said Theoret. Clinical Trials with Common Control Arms Sridhara pointed out that comparing various interventions using the same patient group as the control arm can save time and resources.
From page 60...
... The results from this Phase I study led the researchers to acquire Breakthrough Therapy designation from FDA and they proceeded directly from their Phase I study to a randomized Phase III study in multiple tumor types (Robert et al., 2015)
From page 61...
... This combination was tested in a Phase I study and found to have robust activity that was confirmed with a subsequent Phase III study in a larger group of patients with multiple myeloma (Richardson et al., 2014)
From page 62...
... Rockhold noted that an independent DSMB needs to assess the data and provide oversight in a continuous trial design, in order to adequately address ethical concerns and protect patients and make sound scientific decisions. He cited a paper written by FDA staff that found that independent DSMBs provide important quality control in seamless clinical trials (Prowell et al., 2016)
From page 63...
... Rockhold also suggested there be more clarity on the communication pathways in seamless trial designs. "If an independent [DSMB]
From page 64...
... , there is always the same list of seven names that come up and I think some of them desperately want to retire. So it is a challenge and as designs become more complex and involved, the greater the challenge." Piantadosi added that there is also a paucity of trained clinical trial statisticians, due to a large migration of statisticians into the bioinformatics field.
From page 65...
... We need to recognize that when we bring a drug to market, we never have full certainty," noted Rothenberg. He emphasized that "we need to know enough to be able to accurately characterize the benefit–risk relationship for the patients" and pointed out that the established process of postmarketing surveillance leads to regular label updates, usually based on experience of the drug when used in children, in individuals who have liver or kidney dysfunction, or in other rare patient populations.
From page 66...
... Blumenthal ­ noted that there has been a long track record of accelerated and sometimes even full approval of cancer drugs based on response rate and duration of response in single-arm trials. He noted that FDA is often blamed for not approving a drug without a randomized clinical trial, but he argued that the agency often takes an activist role in ensuring flexibility and will even, on occasion, directly and proactively ask sponsors if randomization is necessary.
From page 67...
... Koehler defined real-world data as health care data that are not collected through randomized controlled clinical trials and used for decision-making purposes (Annemans et al., 2007; Garrison et al.,
From page 68...
... that is intended to complement clinical trials by providing more generalizable knowledge. "Big data more clearly complete the picture of what is happening to patients in the real world in routine clinical practice," she said.
From page 69...
... In contrast, an explanatory trial determines how well a drug works and how safe the drug is when it is evaluated under ideal conditions in a clinical trial setting (Roland and Torgerson, 1998)
From page 70...
... NOTE: In order to assess whether a study design matches its intended purpose, these nine domains can be evaluated on a 5-point scale, with 1 = very explanatory (clinical trial–like conditions) to 5 = very pragmatic (usual care conditions)
From page 71...
... Because trastuzumab had been shown to cause heart damage, patients with less than optimal ejection fraction were excluded from clinical trials. Consequently, it was not truly known how patients with the lower ejection fraction would fare with this combination drug.
From page 72...
... Koehler suggested that pragmatic trials could play a larger role in answering regulatory questions, such as formulating drug labels. She emphasized that "the most useful source of knowledge will come from randomization in the context of clinical practice .
From page 73...
... for women with metastatic breast cancer receiving the drug letrozole. Koehler emphasized that although evidence on the safety and efficacy of a drug is gathered as it goes through preapproval clinical trials, the evidence generated is from a much smaller and more homogeneous patient population than in the real-world setting once the drug enters the market.
From page 74...
... "We cannot really use progressionfree survival or tumor response rate because RECIST criteria are used by specialists and that is not going to be available in every community hospital," she said. Although it is possible to follow patients over time, she added that in general, the formal recordkeeping and follow-up observed in traditional clinical trials are not possible with pragmatic trials because the records of patients are not often carried over when they switch from one provider to another.
From page 75...
... He described the efforts of the South Texas Accelerated Research Therapeutics (START) , which uses a high-quality and innovative information technology infrastructure to ensure accurate and rapid clinical trials of novel anticancer agents (START, 2017)
From page 76...
... He added that EHR companies do not use a common standard for reporting oncology or other disease data, so CMS set its own data standards for the Oncology Care Model for the field to use. Rockhold added that unless an agency such as CMS requires it, standardization of real-world clinical data is unlikely to occur.
From page 77...
... Ison pointed out that one of the goals of clinical trials is to facilitate the ability to generalize study findings and apply them to all patients with the disease. "To that end, eligibility criteria are a key component of the design of a clinical trial," she said.
From page 78...
... Patients with current non-threatening malignancies, such as non melanoma skin cancer, should also be included in clinical trials. In addition, the working groups recommended using liberal criteria for creatinine clearance when excluding patients because of suboptimal kidney function, especially if the agent being tested is not thought to be excreted 21 See https://am.asco.org/daily-news/eligibility-criteria-project-seeks-benefit-patients (accessed May 18, 2017)
From page 79...
... No changes were recommended for the current criteria for liver or cardiac functioning of eligible patients, although investigators were encouraged to include geriatric patients in clinical trials, as well as to include specific cohorts of these patients in their studies. The working group is publishing their recommendations and plans to promote standardized and inclusive eligibility criteria that can be adopted by protocols, and to encourage sponsors to follow the recommendations.
From page 80...
... . This study is a non-­ randomized clinical trial that is evaluating FDA-approved cancer drugs in the treatment of patients with advanced cancer whose tumors have a genomic variant that is known to be a drug target or to predict sensitivity to a drug.
From page 81...
... Collaboration Several speakers stated that the new drug development paradigm requires greater collaboration among companies and other stakeholders, and provided several examples of how companies are sharing their data, and in some cases, participating in the same clinical trials. Sigal stressed that due to the growing complexity of cancer diagnostics and treatments, there also is a growing need for collaboration in the testing of these agents.
From page 82...
... The NCI was a catalyst, but the Cooperative Groups of the NCI Clinical Trials Network, patient groups, and the companies all collaborated for this trial. "Collaboration among all sectors is very important and it is a way to get us there faster.
From page 83...
... Consequently, ASCO, FDA, and the American Association for Cancer Research convened a workshop to address this issue, at which an industry workgroup volunteered to develop a blueprint proposal of potential solutions using non-small cell lung cancer as the first test case (FDA, 2017a)
From page 84...
... Driven by projections of market demand and a desire to share their expertise, Pfizer and Merck KGaA collaborated to develop the PD-L1 inhibitor avelumab, said Rothenberg. Sigal added that FDA is also concerned about this redundancy because there are not enough patients to test all of the inhibitors, and suggested a master protocol in which multiple treatments from multiple companies could be tested simultaneously.
From page 85...
... and Expanded Access Program, and the Cancer Moonshot. A number of workshop participants also considered other potential policy strategies, such as some of the recommendations made by the Blue Ribbon Panel of the Cancer Moonshot.
From page 86...
... Expanded Access Steven Lemery, lead medical officer in the Division of Oncology P ­ roducts 2 at FDA's OHOP, provided a summary of FDA's Expanded Access Program. This program enables patients to receive investigational agents if they have a serious or immediately life-threatening disease or condition and meet all of the following conditions26: • There is no comparable or satisfactory alternative therapy.
From page 87...
... Lemery noted that often it is not feasible to enroll patients with rare cancer mutations into a clinical trial because they do not live in a location where the trial is offered, "so expanded access might be a good way to obtain information about the use of your drug in these rare populations. You could maybe get data on patients who do not meet eligibility criteria, but can give you some real-world experience.
From page 88...
... The federal task force delineated several policy goals, including the following: • Support greater access to new research, data, and computational capabilities. • Improve patient access to clinical trials and standard of care.
From page 89...
... The task force also recommended bringing new therapies to patients faster by modernizing eligibility criteria for clinical trials, and developing trials for patients with specific genetic defects rather than tissue-specific types of cancer, such as the ­ CI-MATCH trial, and using real-world evidence. N The Working Groups of the Blue Ribbon Panel made several recommendations focused on research that also have policy implications in drug development (Cancer Moonshot Blue Ribbon Panel, 2016)
From page 90...
... This partner ship will fund precompetitive cancer research and share broadly all data generated for further research, with initial focus areas that include identifying and validating biomarkers for treatment response and resistance to cancer therapies, clinical trial platforms for combination therapies, and predictive modeling approaches and therapies for rare cancers. • Applied Proteogenomics Organizational Learning Outcomes, which is a partnership between DOE, the NCI, and the Depart
From page 91...
... The Blue Ribbon Panel also identified several current policy barriers to drug development that were not covered in its scope, but will need to be addressed in order to advance its recommendations (Cancer Moonshot Blue Ribbon Panel, 2016) : • coverage of the costs of routine care and clinical trials for patients with cancer • uniform patient consent forms and patient access to data • use of a central IRB, data sharing among federal agencies, and adequate clinical trial site evaluation processes • improved delivery of cancer care in communities through reducing economic burden of clinical trial enrollment on patients and prac titioners, sharing EHR data, and releasing best practices for state vaccine registries • incentives for development of pediatric cancer drugs, especially molecularly targeted therapies • data-sharing mechanisms, including standardization and harmoni zation of data, licensing, and sharing among the private sector EXAMPLES OF INNOVATIONS IN CANCER DRUG DEVELOPMENT A number of workshop speakers discussed examples of drug development pathways and clinical trial designs reflective of the move toward a new drug development paradigm for oncology.
From page 92...
... . Then Pfizer opened two Phase III trials simultaneously: One to test crizotinib as a second-line treatment for lung cancer patients versus single-agent chemotherapy (Shaw et al., 2013)
From page 93...
... In August 2011, FDA approved crizotinib for the treatment of patients with locally advanced or metastatic non-small cell lung cancer that is ALKpositive, about 6 years after it was first tested in patients (FDA, 2011)
From page 94...
... This led Merck-Serono to test it in a Phase I study that had multiple cohorts of likely responders, with the assumption that the cohorts showing the most response would be expanded. Currently, there is an expansive international clinical trial program exploring the use of PD-L1 inhibition with avelumab to treat multiple types of cancer, such as solid tumors, gastric cancer, Merkel cell carcinoma,29 and non-small cell lung cancer (Pfizer, 2015)
From page 95...
... Initial striking responses in melanoma patients led to the expansion of that cohort, including patients who had previously not responded to ipilimumab, another cancer immunotherapy, as well as lung cancer patients. Additional patients were added after an analysis of the melanoma patients in the Phase I study found that those who had progressed on i ­pilimumab might respond to pembrolizumab.
From page 96...
... Rubin noted several challenges with adaptive trial design that were encountered in the development of pembrolizumab. It created operational burden due to rapid accrual in multiple cohorts and increased manufacturing demands.
From page 97...
... . Three randomized Phase III trials have now demonstrated that the combination of a BRAF inhibitor (vemurafenib or dabrafenib)
From page 98...
... . Furthermore, a Phase I study in patients with treatment-naïve lung cancer also showed high response rates of 77 percent, leading investigators to conduct a Phase III trial that randomized patients to receive osimertinib or two other EGFR inhibitors.
From page 99...
... In addition, doses tested in clinical trials showed significant toxicity, including arrhythmias and hyperglycemia. The short half-life of the drug required patients to receive more treatments to maintain concentration of the drug in a patient's system and increased the likelihood of toxicities.
From page 100...
... AURA = trial of AZD9291; AZ = AstraZeneca; CE-IVD = Conformité Européene in Vitro Diagnostic; ctDNA = circulating tumor DNA; EGFR = epidermal growth factor receptor; EU = European Union; FDA = Food and Drug Administration; PMA = premarket approval; PMDA = Pharmaceutical and Medical Devices Agency in Japan. SOURCES: Jänne presentation, December 12, 2016; Yver, A., Osimertinib (AZD9291)
From page 101...
... To that end, there needs to be a focus on clinically meaningful outcomes and endpoints in clinical trials, including patient-reported outcomes. Another recurrent topic of discussion at the workshop was that biomarker or diagnostic test development tends to lag behind therapeutic
From page 102...
... The basic understanding of the pharmacology of the drug should include whether it is the right chemical entity, the optimal formulation, dosing, pharmacodynamics, and pharmacokinetics. Schilsky referred to Brown's notion that data gathered to support drug approvals or labeling should be fit for purpose.
From page 103...
... . "It all comes down to clearly articulating the question we want to answer and the best approach to answering that question among an entire range of clinical trial designs and data sources available to us." He added that the Cancer Moonshot offers many opportunities for improving drug development.
From page 104...
... 2010. Globalization of clinical trials.
From page 105...
... 2014. Twenty years post-NIH Revitalization Act: Renewing the case for enhancing minority participation in cancer clinical trials.
From page 106...
... 2006. Guidance for clinical trial sponsors: Establishment and operation of clinical trial data monitoring committees.
From page 107...
... 2017. Biomarkers Consortium -- Vol-PACT: Advanced metrics and modeling with volumetric CT for precision analysis of clinical trial results.
From page 108...
... 2010. A national cancer clinical trials system for the 21st century: Reinvigorating the NCI cooperative group program.
From page 109...
... 2006. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: A meta-analysis.
From page 110...
... Clinical Trials.
From page 111...
... 2014. Lung-MAP launches: First precision medicine trial from National Clinical Trials Network.
From page 112...
... 2015. Rociletinib in EGFR-mutated non–small-cell lung cancer.
From page 113...
... 2017. A Bayesian adaptive design for estimating the maximum tolerated dose curve using drug combinations in cancer Phase I clinical trials.
From page 114...
... 2009. Elucidation of relationship between tumor size and survival in non-small-cell lung cancer patients can aid early decision making in clinical drug development.


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