Endpoints In Drug Development Research Articles

A conceptual model for chronic hepatitis B and content validity of the Hepatitis B Quality of Life (HBQOL) instrument

BackgroundThere is increased emphasis on incorporating patient perspectives and patient-relevant endpoints in drug development. We developed a conceptual model of the impact of chronic hepatitis B (CHB) on patients’ lives and evaluated the content validity of the Hepatitis B Quality of Life (HBQOL) instrument, a patient-reported outcome tool for use in clinical studies, as a patient-relevant endpoint to measure health-related quality of life in patients with CHB.MethodsA literature review of qualitative studies of patient experience with CHB and concept elicitation telephone interviews with patients with CHB in the United Kingdom were used to develop a conceptual model of the experience and impact of living with CHB. The content validity of the HBQOL was evaluated using cognitive debriefing techniques.ResultsThe qualitative literature review (N = 43 publications) showed that patients with CHB experience emotional/psychological impacts. During concept elicitation interviews (N = 24), fatigue was the most commonly reported symptom, and most participants were worried/anxious about virus transmission and disease progression/death. A conceptual model of patients’ experiences with CHB was developed. The conceptual relevance and comprehensibility of the HBQOL were supported, though limitations, including the lack of a self-stigma item and recall period, were noted for future improvement.ConclusionsThe conceptual model shows that patients with CHB experience emotional/psychological impacts that affect their lifestyles, relationships, and work/schooling. The cognitive debriefing interviews support the content validity of the HBQOL as a conceptually relevant patient-reported outcome measure of health-related quality of life.

An end is in sight: a perspective on PCR as an endpoint for Chagas disease treatment trials

Novel therapies for chronic indeterminate Chagas disease (CICD) are needed, but trials are limited by the absence of tests to detect infection and early treatment efficacy. This perspective highlights the shortfalls and strengths of polymerase chain reaction (PCR) as a study endpoint for anti-parasitic drug development. Serologic reversion, the gold standard test of cure, may take decades to occur in adults and therefore is challenging as an endpoint for drug development. Use of PCR as a marker of infection and treatment response has notable limitations due to low parasitemia in CICD, fluctuations in circulating (versus tissue) parasite burden, strain differences, and assay performance. It is, however, rapidly responsive to therapy, and technological advances have improved detection of different strains and may allow for parasite quantification. Until we have more sensitive tests for parasitological clearance, PCR as a measure of treatment failure may be the best available efficacy endpoint to accelerate early development of much-needed novel therapies. Adequately designed clinical studies are needed to correlate PCR clearance with clinical outcomes and to identify novel biomarkers predictive of clinical outcomes in patients with CICD. Public-private partnerships and health authority engagement are paramount to identify feasible trial endpoints and deliver promising new drug candidates for Chagas disease.

Adaptive group-sequential design with population enrichment in phase 3 randomized controlled trials with two binary co-primary endpoints.

The use of co-primary endpoints in drug development allows investigators to capture an experimental intervention's multidimensional effect more comprehensively than a single primary endpoint. We propose the theoretical basis and development of an adaptive population enrichment design with co-primary endpoints, provide stage-wise boundary values for futility and efficacy, and discuss power under different efficacy configurations, subgroup prevalence, and analysis times using a pre-specified decision criterion. We considered a two-arm, two-stage, parallel group design where population enrichment occurs at the interim analysis by dropping any non-responsive subgroups. A test for efficacy is conducted only in the enriched population. Two binary endpoints are evaluated as co-primary endpoints. Our trial objective is to determine whether the experimental intervention is superior to the control intervention, with superiority required in both endpoints. We define the stopping boundary using alpha spending functions. Using a 0.025 significance level for each endpoint, we obtain the stage I threshold boundary values for futility and efficacy as -0.1040 and 2.2761, respectively, and the stage II boundary value for futility and efficacy is 2.2419. We show that in the presence of substantial heterogeneity of treatment effect, we gain more power to observe an effect in the subgroup where the benefits are greater. By allowing the dropping of non-responsive subgroups at an early stage, our design reduces the likelihood of obtaining false-negative results due to inclusion of the heterogeneous treatment effects of both subgroups, which would dilute the responsive subgroup's results.

Assessment of brain-derived neurotrophic factor and osteopontin in a healthy pediatric population.

Biomarkers are routinely used for noninvasive identification or monitoring of disease processes in clinical practice, as well as surrogate end points for drug development. There is a significant lack of data regarding biomarkers in children. An understanding of biomarker levels in a healthy pediatric cohort is essential as more studies begin to apply noninvasive biomarkers to pediatric populations. Brain-derived neurotrophic factor (BDNF) functions in neuronal survival and plasticity and is associated with exercise capacity and inflammatory disease processes. Osteopontin (OPN) plays a regulatory role in inflammation and may be a clinically useful biomarker of cardiovascular disease processes, ventricular remodeling, and skeletal muscle regeneration. This study describes our initial experience with a cohort of healthy pediatric patients and seeks to provide normal values of BDNF and OPN with correlation to age, gender, and cardiovascular and fitness measures. Serum BDNF and plasma OPN were measured using enzyme-linked immunosorbent assay in 33 healthy pediatric subjects. Subjects underwent complete cardiac evaluation, including echocardiography, exercise stress testing, and health risk assessment. The 5th–95th percentile was 5.63–37.86 ng/ml for serum BDNF and 4.9–164.9 ng/ml for plasma OPN. Plasma OPN correlated with number of days of exercise per week (r = 0.46, p = 0.008). No other correlations were significant. This study provides the initial data on serum BDNF and plasma OPN in children and begins to explore the relationships of BDNF and OPN to cardiovascular health and fitness in the pediatric population.

Biomarkers and Surrogate Endpoints in Drug Development: A European Regulatory View.

To give a European regulatory overview of the requirements on and the use of biomarkers or surrogate endpoints in the development of drugs for ocular disease. Definitions, methods to validate new markers, and circumstances where surrogate endpoints can be appropriate are summarized. The key endpoints that have been used in registration studies so far are based on visual acuity, signs, and symptoms, or on surrogate endpoints. In some ocular conditions, established outcome measures such as those based on visual acuity or visual field are not feasible (as with slowly progressing diseases), or lack relevance (e.g., when central visual acuity may be preserved even though the patient is legally blind owing to a severely restricted visual field, or vice versa). There are several ocular conditions for which there is an unmet medical need. In some of these conditions, surrogate endpoints as well as new clinical endpoints are needed to help speed up patient access to new medicines. Interaction with European regulators through the pathway specific for the development of biomarkers or novel methods is encouraged.

The Role of Biomarkers and Surrogate End Points in Drug Development for Neonatal Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease in newborns, infants, and children. It is associated with significant morbidity and mortality, but has limited treatment options. Except for inhaled nitric oxide, which is approved for persistent pulmonary hypertension of the newborn (PPHN), no drug is approved for the treatment of newborns, infants, and children with PAH. The lack of developmentally appropriate pediatric efficacy end points and pediatric clinical trials contribute to this unmet medical need. The noninvasive biomarkers reported in the literature that can be used as potential surrogate end points to assess disease severity and treatment response in neonates, infants, and children with PAH are reviewed herein. In addition, the role of the US Food and Drug Administration in developing potential biomarkers as surrogate end points to facilitate drug development for the treatment of children with PPHN and PAH in children is reviewed herein.

Establishing Good Practices for Exposure-Response Analysis of Clinical Endpoints in Drug Development.

This tutorial aims at promoting good practices for exposure–response (E-R) analyses of clinical endpoints in drug development. The focus is on practical aspects of E-R analyses to assist modeling scientists with a process of performing such analyses in a consistent manner across individuals and projects and tailored to typical clinical drug development decisions. This includes general considerations for planning, conducting, and visualizing E-R analyses, and how these are linked to key questions.

Using endophenotypes to examine molecules related to candidate genes as novel therapeutics: The “endophenotype-associated surrogate endpoint (EASE)” concept

In this article, a new concept of an “endophenotype-associated surrogate endpoint (EASE)” is proposed. To examine effect of a novel therapeutic molecule on a target phenotype of a genotype associated with the molecule, state-dependent aspect of an endophenotype can be used as a surrogate endpoint. Desired characteristics for EASE are (1) a close relationship to the endophenotype associated with therapeutics, (2) longitudinal changes in illness severity, while the original “endophenotype” is primarily state independent, (3) a physical sign or laboratory measurement that occurs in association with a pathological process and has putative diagnostic and/or prognostic utility, and (4) serves as a substitute for a clinically meaningful endpoint. Advantages are expected for both surrogate endpoints in drug development and endophenotypes in uncovering pathogenesis. EASE are closer to molecules than clinically meaningful endpoints and can respond to administration of the molecule in a more direct manner. Therefore, a statistically significant effect is likely to be observed in clinical trials with smaller sample sizes and shorter durations. As with endophenotypes, reduced heterogeneity might be expected especially in heterogeneous syndromes such as psychiatric disorders. Potential interactions (e.g., elucidating biological mechanisms underlying novel treatments) can be further expected.

Applicability Domain ANalysis (ADAN): a robust method for assessing the reliability of drug property predictions.

We report a novel method called ADAN (Applicability Domain ANalysis) for assessing the reliability of drug property predictions obtained by in silico methods. The assessment provided by ADAN is based on the comparison of the query compound with the training set, using six diverse similarity criteria. For every criterion, the query compound is considered out of range when the similarity value obtained is larger than the 95th percentile of the values obtained for the training set. The final outcome is a number in the range of 0-6 that expresses the number of unmet similarity criteria and allows classifying the query compound within seven reliability categories. Such categories can be further exploited to assign simpler reliability classes using a traffic light schema, to assign approximate confidence intervals or to mark the predictions as unreliable. The entire methodology has been validated simulating realistic conditions, where query compounds are structurally diverse from those in the training set. The validation exercise involved the construction of more than 1000 models. These models were built using a combination of training set, molecular descriptors, and modeling methods representative of the real predictive tasks performed in the eTOX project (a project whose objective is to predict in vivo toxicological end points in drug development). Validation results confirm the robustness of the proposed assessment methodology, which compares favorably with other classical methods based solely on the structural similarity of the compounds. ADAN characteristics make the method well-suited for estimate the quality of drug predictions obtained in extremely unfavorable conditions, like the prediction of drug toxicity end points.

Genetic Fuzzy System Predicting Contractile Reactivity Patterns of Small Arteries

Monitoring of physiological surrogate end points in drug development generates dynamic time-domain data reflecting the state of the biological system. Conventional data analysis often reduces the information in these data by extracting specific data points, thereby discarding potentially useful information. We developed a genetic fuzzy system (GFS) algorithm that is capable of learning all information in time-domain physiological data. Data on isometric force development of isolated small arteries were used as a framework for developing and optimizing a GFS. GFS performance was improved by several strategies. Results show that optimized fuzzy systems (OFSs) predict contractile reactivity of arteries accurately. In addition, OFSs identified significant differences that were undetectable using conventional analysis in the responses of arteries between groups. We concluded that OFSs may be used in clustering or classification tasks as aids in the objective identification or prediction of dynamic physiological behavior.

Measuring Soluble Biomarkers in Clinical Trials: Do Tiered Approaches to The Analysis and Validation of Assays Provide an Answer to The Fit-For-Purpose Challenge?

BioanalysisVol. 6, No. 5 Mini Focus Issue: Tiered approach to bioanalysis - CommentaryMeasuring soluble biomarkers in clinical trials: do tiered approaches to the analysis and validation of assays provide an answer to the fit-for-purpose challenge?Richard Hucker, Carl Watson, Ian James, Scott Vincent & David MuirheadRichard Hucker* Author for correspondenceA4P Consulting Limited, Innovation House, Discovery Park, Sandwich, Kent, CT13 9NJ, UK. Search for more papers by this authorEmail the corresponding author at richard.hucker@a4pbio.com, Carl WatsonA4P Consulting Limited, Innovation House, Discovery Park, Sandwich, Kent, CT13 9NJ, UKSearch for more papers by this author, Ian JamesA4P Consulting Limited, Innovation House, Discovery Park, Sandwich, Kent, CT13 9NJ, UKSearch for more papers by this author, Scott VincentA4P Consulting Limited, Innovation House, Discovery Park, Sandwich, Kent, CT13 9NJ, UKSearch for more papers by this author & David MuirheadA4P Consulting Limited, Innovation House, Discovery Park, Sandwich, Kent, CT13 9NJ, UKSearch for more papers by this authorPublished Online:12 Mar 2014https://doi.org/10.4155/bio.14.11AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleKeywords: biomarkersclinicalfit-for-purposetiered approachvalidationReferences1 Boulton M, Dally J. Biomarkers in oncology drug development. Regulatory Rapporteur7(4), (2010).Google Scholar2 Katz R. Biomarkers and surrogate markers: an FDA perspective. NeuroRx1,189–195 (2004).Crossref, Medline, Google Scholar3 Lesko L, Atkinson A. Use of biomarkers and surrogate end points in drug development and regulatory decision making. Ann. Rev. Pharmacol. Toxicol.41,347–366 (2001).Crossref, Medline, CAS, Google Scholar4 Paul SM, Mytelka DS, Dunwiddie CT et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov.9,203–214 (2010).Crossref, Medline, CAS, Google Scholar5 BoothB. When do you need a validated assay? Bioanalysis3(24),2729–2730 (2011).Link, CAS, Google Scholar6 Lee JW, Devanarayan V, Barrett YC et al. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm. Res.23(2),312–328 (2006).Crossref, Medline, CAS, Google Scholar7 FDA Guidance for industry: bioanalytical method validation draft guidance September 2013.Google Scholar8 Timmerman P, Herling C, Stoellner D et al. European Bioanalysis Forum recommendations on method establishment and bioanalysis of biomarkers in support of drug development. Bioanalysis4(15),1883–1894 (2012).Link, CAS, Google Scholar9 EMA GCP Inspectors Working Group. Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples. EMA/INS/GCP/532137/2010 28 February 2012.Google Scholar10 Timmerman P, Anders L, Kall M, Gordon B, Laakso S, Freisleben A, Hucker R. Best practices in a tiered approach to metabolite quantification: views and recommendations of the European Bioanalysis Forum. Bioanalysis2(7),1185–1194 (2010).Link, Google Scholar11 Watson CJ et al. Fit for purpose biomarker validation. Presented at: 8th Annual Biomarkers Conference. Manchester, UK, 19–20 February 2013.Google ScholarFiguresReferencesRelatedDetailsCited ByEnsuring quality and compliance in outsourcing of bioanalysis of clinical biomarkersTianke Wang & Arkady I Gusev16 March 2017 | Bioanalysis, Vol. 9, No. 7Surrogate matrix: opportunities and challenges for tissue sample analysisStacy Ho & Hong Gao23 September 2015 | Bioanalysis, Vol. 7, No. 18Scientific or regulated validation: a tiered approach? Meeting report from a joint EBF/DVDMDG workshopPhilip Timmerman, Steve Lowes, Stuart McDougall, Irina Colligon, Joy Miksic, Swapan Chowdhury, Steve White, Anne-Françoise Aubry, Rand Jenkins & Christopher Kemper13 August 2015 | Bioanalysis, Vol. 7, No. 14Tiered approach to metabolite quantification: regional practices reviewed by Japan Bioanalysis Forum discussion groupMakoto Niwa, Takahide Uchimura, Nozomu Koseki, Masahiro Satsukawa, Yoshitaka Hashimoto, Tsuyoshi Mayumi, Yutaka Yasuda & Hiroyuki Yokoi12 May 2015 | Bioanalysis, Vol. 7, No. 8 Vol. 6, No. 5 Follow us on social media for the latest updates Metrics Downloaded 274 times History Published online 12 March 2014 Published in print March 2014 Information© Future Science LtdKeywordsbiomarkersclinicalfit-for-purposetiered approachvalidationFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

New challenges in endpoints for drug development in advanced melanoma.

During the past 3 decades, the field of clinical research for the treatment of advanced melanoma lacked significant advances. Available drugs had low antitumor activity and no proven benefit in overall survival. Recently, new drugs developed based on an in-depth understanding of the biology of this disease have shown significant benefit, with ipilimumab and vemurafenib having recently shown a positive impact in overall survival in patients with metastatic melanoma leading to approval in this indication by the U.S. Food and Drug Administration. This rapid introduction of new active agents is likely to challenge current notions on how to develop future agents for the treatment of melanoma. The strong evidence of benefit for initial agents that modulate immune regulatory checkpoints or target driver oncogenes has spurred great interest in developing other similarly acting agents. However, this will pose problems in the choice of endpoints for the future definitive clinical trials, and the hurdles for achieving these endpoints will be higher given the similar activity for comparator agents or the availability of competing agents for salvage therapy. This new reality will likely require tailoring registrational clinical trial endpoints to the patient benefits shown in early clinical testing. In this perspective article, we illustrate the challenges in the choice of endpoints for registrational trials in metastatic melanoma and that, with an improved understanding of the agent being developed, the design of the registrational programs can be informed by earlier mechanistic studies to define the assumptions for definitive clinical testing.

Biomarkers and Proteomics in Corneal Cell Biology

AbstractPurpose Developing a basis for personalized medicine requires instrumentation that has a high throughput and appropriate senstivity. To discover proteomic biomarkers of ocular surface diseases using quantitative mass spectrometry for discovery of molecular representatives within the tear film that can be used for clinical application and pharmacological development. Additionally, proteomics carried out by mass spectrometry provides a ready tool for use with quantitative biomarkers.Methods Tear samples can be collected by several means, our lab usually uses type I Schirmer’s test from patients and has been used successfully with patients with dry eye, pterygium or on anti‐glaucoma medications as well as age‐matched healthy unmedicated controls. Tear proteins are analyzed using iTRAQ (Isobaric tags for relative and absolute quantification) based quantitative proteomics or SELDI mass spectrometry. ELISA is used for confirmation of proteomic findings.Results In dry eye patients, over 200 tear proteins have been identified. Potential biomarkers include up‐regulated proteins, alpha‐enolase, alpha‐1‐acid glycoprotein 1, S100 A8, S100 A9, S100 A4 and S100. In chronic glaucoma patients, 128 tear proteins were identified with 99% confidence. We found 5 proteins whose iTRAQ ratios showed significant changes (p < 0.05) when comparing non‐medicated control group and medicated group. Levels of 4 tear proteins (S100 A8, S100 A9, mammaglobin B and 14‐3‐3 z/d protein) were elevated.Conclusion Proteomic biomarkers provide new insights into the disease process as with the inflammatory S100 proteins found here and they are measurable end points for drug development, diagnosis and response to treatment. A biomarker panel for dry eye has been developed for patient use.

What do patients rank as more important in quality-of-life (QL) and patient-reported outcome (PRO) evaluation: Symptoms (Sx) or summative assessments? Results of a 3,860-patient survey in lung, breast, and prostate cancers with implications for drug development.

9093 Background: Patient (pt) involvement in establishing content validity (CV) is critical for QL and PRO instrument development. Instruments usually contain both multidimensional summative items and single Sx items. As endpoints in drug development, the FDA has emphasized Sx assessment in PRO guidance and has questioned the CV of many instruments as not having sufficient pt input. This survey was conducted to 1) provide in depth CV in several major cancers, and 2) provide an opportunity to assess whether pts agree with the FDA in prioritizing Sx over summative items in PRO/QL evaluation. Methods: Lung, breast, or prostate cancer pts registered with the web-based NexCura resource were surveyed. Pts ranked 20 to 21 issues, including general, physical, functional, psychosocial and summative items, on a 5-point scale. 3,860 pts completed the anonymous web survey. Multiple demographic factors were also assessed to allow subgroup analysis. Results: The Table shows the 5 highest ranked items as rated in the si...

Using Surrogate Biomarkers to Predict Clinical Benefit in Men with Castration-Resistant Prostate Cancer: An Update and Review of the Literature

Recurrent prostate cancer has a complex molecular etiology and a prolonged disease course. Although initially responsive to androgen ablation, many men eventually become castration resistant, develop skeletal metastases, and are palliatively treated with docetaxel-based chemotherapy, radiation therapy, bisphosphonates, and best supportive care. Given the modest success rates of the current standard of care, clinical trial enrollment is encouraged. Castration-resistant prostate cancer (CRPC) is a heterogeneous disease, both in clinical manifestations and outcomes, requiring an individualized approach to both patient care and trial design. Herein, we review surrogate markers of disease progression and treatment efficacy in advanced prostate cancer in light of recently published guidelines that have redefined eligibility, response criteria, and suitable endpoints in prostate cancer drug development. The guidelines have refined outcome measures to potentially better capture clinical benefit and the ability of novel targeted molecular and biologic agents to impact favorably on this disease. We consider prostate-specific antigen changes, circulating tumor cells, bone scan alterations, markers of bone metabolism (urinary N-telopeptide and bone-specific alkaline phosphatase), pain improvements, and progression-free survival. To illustrate the role and challenges of these potential biomarkers and endpoints in drug development, we discuss a class of novel molecularly targeted agents, the src kinase inhibitors. Given that there are currently no validated surrogate markers of overall survival for assessing early clinical benefit from systemic therapy in metastatic CRPC, incorporation of relevant biomarkers into all phases of clinical development is essential to accelerate drug development in this field.

The Value, Qualification, and Regulatory Use of Surrogate End Points in Drug Development

The acceptance and use of either surrogate end points (SEPs) or efficient clinical end points are associated with greater and more rapid availability of new medicines as compared with disease situations for which clinical end points are inefficient or no surrogates exist. This review of the history of the development, qualification, and acceptance of key SEPs shows that both successes and failures had three key characteristics: (i) apparent biologic plausibility, (ii) prognostic value for the outcome of the disease, and (iii) an association between changes in the SEP and changes in outcome with therapeutic intervention--the three factors recommended for SEPs in the International Conference on Harmonisation's "Statistical Principles for Clinical Trials." We recommend that only prognostic value be an absolute prerequisite for surrogacy, because therapeutic interventions may not exist a priori, and biological plausibility can be subjective. Ideally, all three of these factors would be traded off against one another in a consistent and transparent risk-management process.

Is there consensus in the definition of endpoints in metastatic breast cancer?.

Abstract Abstract #3102 Objective: Progression-free survival (PFS) is defined as the time between treatment initiation and tumor progression or death from any cause, with censoring of patients who are lost to follow-up. Time to tumor progression (TTP) is theoretically different from PFS in that the event of interest is only disease progression. Both PFS and TTP have been considered as appropriate endpoints in drug development, but the extent to which investigators agree on their definition is unknown. We therefore assessed the recent literature regarding the consistence of the definition of PFS and TTP when used as primary endpoints in advanced breast cancer.
 Methods: We searched PubMed using the medical subject headings “breast neoplasms” and “drug therapy”, limiting the search to phase III trials on systemic antineoplastic therapies published between January 1, 2000, and December 31, 2007 in one of ten leading medical journals in the field (Annals of Oncology, Breast Cancer Research and Treatment, British Journal of Cancer, Cancer, European Journal of Cancer, Journal of Clinical Oncology, Journal of the National Cancer Institute, Lancet Oncology, The Lancet and The New England Journal of Medicine). We excluded randomized phase II trials, factorial trials, studies on high-dose chemotherapy, papers reporting combined analyses of two or more separate trials, and companion studies on correlative biology or prognostic factors.
 Results: The search yielded 59 trials enrolling a total of 23,371 evaluable patients in 122 treatment arms. PFS was the primary endpoint in 14 cases, and TTP in 21 when all treatment lines and modalities were considered (response rate was used in 20 cases, and overall survival in only one). For first-line chemotherapy trials (N=24), PFS and TTP were used as primary endpoints in 5 and 7 cases, respectively. In 5 of the 21 trials using TTP as the primary endpoint, no definition of this endpoint was reported in the article. Analysis of the other 16 cases showed that progressive disease was always considered an event in TTP analysis. However, in 13 of these cases, death (either from breast cancer or from any cause) was also counted as an event. The definition of PFS was reported in the article in 13 of the 14 trials using this primary endpoint. In all cases, the events of interest in Kaplan-Meier analyses included both progressive disease and death. In some cases, both terms (PFS and TTP) were even used to denote the same endpoint in the same paper.
 Conclusion: Our review suggests that investigators are frequently using PFS and TTP interchangeably in metastatic breast cancer. Such use of terms may lead to confusion when results of different trials are evaluated in perspective, and standardization of the definitions seems therefore in order. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3102.

Functional neuroimaging endpoints in drug development

Functional neuroimaging endpoints in drug development

Overview of biomarkers and surrogate endpoints in drug development.

There are numerous factors that recommend the use of biomarkers in drug development including the ability to provide a rational basis for selection of lead compounds, as an aid in determining or refining mechanism of action or pathophysiology, and the ability to work towards qualification and use of a biomarker as a surrogate endpoint. Examples of biomarkers come from many different means of clinical and laboratory measurement. Total cholesterol is an example of a clinically useful biomarker that was successfully qualified for use as a surrogate endpoint. Biomarkers require validation in most circumstances. Validation of biomarker assays is a necessary component to delivery of high-quality research data necessary for effective use of biomarkers. Qualification is necessary for use of a biomarker as a surrogate endpoint. Putative biomarkers are typically identified because of a relationship to known or hypothetical steps in a pathophysiologic cascade. Biomarker discovery can also be effected by expression profiling experiment using a variety of array technologies and related methods. For example, expression profiling experiments enabled the discovery of adipocyte related complement protein of 30 kD (Acrp30 or adiponectin) as a biomarker for in vivo activation of peroxisome proliferator-activated receptors (PPAR) γ activity.

Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies.

In the future, biomarkers will play an increasingly important role in all phases of drug development, including regulatory review. However, only a few of these biomarkers will become established well enough to serve in regulatory decision making as surrogate endpoints, thereby substituting for traditional clinical endpoints. Even generally accepted surrogate endpoints are unlikely to capture all the therapeutic benefits and potential adverse effects a drug will have in a diverse patient population. Accordingly, combinations of biomarkers probably will be needed to provide a more complete characterization of the spectrum of pharmacologic response. In the future, pharmacogenomic approaches, including those based on differential expression of gene arrays, will provide panels of relevant biomarkers that can be expected to transform the drug development process.