Ari Gnanasakthy - Publications(1) Doward LC, Gnanasakthy A, Baker MG. Patient reported outcomes: looking beyond the    lab...
researchers in identifying further information that will need to be developed to support the      clinical development pro...
(11) Reed SD, Friedman JY, Velazquez EJ, Gnanasakthy A, Califf RM, Schulman KA.     Multinational economic evaluation of v...
(DC-median method) for each diagnosis in each country. Additional modifications were      explored through adjustment of t...
model of disease progression to estimate Long-term differences in cognitive functioning      between patients receiving ri...
completed at a dose <80 mg/kg/day. The average number of seizures per month in the      39 patients who completed the stud...
than 50% reduction in seizure frequency (compared to placebo) was observed in 60     patients. Sedation and weight gain we...
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  1. 1. Ari Gnanasakthy - Publications(1) Doward LC, Gnanasakthy A, Baker MG. Patient reported outcomes: looking beyond the label claim. Health and Quality of Life Outcomes 2010;8. Abstract: The use of patient reported outcome scales in clinical trials conducted by the pharmaceutical industry has become more widespread in recent years. The use of such outcomes is particularly common for products developed to treat chronic, disabling conditions where the intention is not to cure but to ameliorate symptoms, facilitate functioning or, ultimately, to improve quality of life. In such cases, patient reported evidence is increasingly viewed as an essential complement to traditional clinical evidence for establishing a products competitive advantage in the marketplace. In a commercial setting, the value of patient reported outcomes is viewed largely in terms of their potential for securing a labelling claim in the USA or inclusion in the summary of product characteristics in Europe. Although, the publication of the recent US Food and Drug Administration guidance makes it difficult for companies to make claims in the USA beyond symptom improvements, the value of these outcomes goes beyond satisfying requirements for a label claim. The European regulatory authorities, payers both in the US and Europe, clinicians and patients all play a part in determining both the availability and the pricing of medicinal products and all have an interest in patient-reported data that go beyond just symptoms. The purpose of the current paper is to highlight the potential added value of patient reported outcome data currently collected and held by the industry for these groups(2) Mordin M, Lewis S, Gnanasakthy A, Demuro-Mercon C, Copley-Merriman K, Fehnel S. Patient-Reported Outcomes in Product Development Guidance. Value in Health 2010;13(3):A17-A18.(3) Gnanasakthy A, DeMuro C, Mordin M, Copley-Merriman K, Mauskopf J. The Role of the Patient Voice in Health Technology Assessment. Value in Health 2010;13(3):A19.(4) Mordin M, Clark M, Siersma C, Copley-Merriman K, Gnanasakthy A. Impact of the Fda Draft Guidance on Patient Reported Outcomes (Pro) Label Claims for Approved Drug Products in the Us: Has It Made A Difference? Value in Health 2009;12(3):A29.(5) Gnanasakthy A. Controlling measurement error of patient-reported-outcomes during the implementation stage of clinical trials. Value in Health 2008;11(3):A178.(6) Revicki DA, Gnanasakthy A, Weinfurt K. Documenting the rationale and psychometric characteristics of patient reported outcomes for labeling and promotional claims: the PRO Evidence Dossier. Quality of Life Research 2007;16(4):717-23. Abstract: The Food and Drug Administration (FDA) and European Medicines Agency (EMEA) are willing to consider including information on patient reported outcomes (PROs) in product labeling and advertising. Pharmaceutical industry researchers must provide sufficient evidence supporting PRO benefit before an approval may be granted. This report describes the purpose and content of a PRO Evidence Dossier, which consists of important information supporting PRO claims. The dossier should be completed by pharmaceutical industry or other researchers to document the planning of the PRO assessment strategy, psychometric evidence, desired target labeling statements, and the clinical trial evidence of PRO benefits. The systematic reporting and documentation of information on the rationale for including PROs, rationale for the selection of specific PRO instruments, evidence on the psychometric qualities of the PRO measures, and guidelines for interpreting PRO findings will facilitate achieving a PRO labeling or promotional claim. Combining all the relevant information into a single document will facilitate the review and evaluation process for clinical and regulatory reviewers. The PRO Evidence Dossier may also be helpful to industry and academic
  2. 2. researchers in identifying further information that will need to be developed to support the clinical development program and the PRO endpoints (7) Lamotte M, Annemans L, Gnanasakthy A, Khan Z. A health-economic evaluation of the real life long-term consequences of an angiotensin II receptor blocker (ARB) in the management of post-MI patients. Case study on valsartan in Canada. European Heart Journal 2005;26:612-3. (8) Wonder M, Backhouse M, Gnanasakthy A. At what cost? A review of drug acquisition cost issues in modelled economic evaluations. Value in Health 2005;8(3):384. (9) Reed SD, Anstrom KJ, Bakhai A, Briggs AH, Califf RM, Cohen DJ, Drummond MF, Glick HA, Gnanasakthy A, Hlatky MA, OBrien BJ, Torti FM, Tsiatis AA, Willan AR, Mark DB, Schulman KA. Conducting economic evaluations alongside multinational clinical trials: Toward a research consensus. American Heart Journal 2005;149(3):434-43. Abstract: Demand for economic evaluations in rnultinational clinical trials is increasing, but there is little consensus about how such studies should be conducted and reported. At a workshop in Durham, North Carolina, we sought to identify areas of agreement about how the primary findings of economic evaluations in multinational clinical trials should be generated and presented. In this paper, we propose a framework for classifying multinational economic evaluations according to (a) the sources of an analysts estimates of resource use and clinical effectiveness and (b) the analysts method of estimating costs. We review existing studies in the cardiology literature in the context of the proposed framework. We then describe important methodological and practical considerations in conducting multinational economic evaluations and summarize the advantages and disadvantages of each approach. Finally, we describe opportunities for future research. Delineation of the various approaches to multinational economic evaluation may assist researchers, peer reviewers, journal editors, and decision makers in evaluating the strengths and limitations of particular studies(10) Yost KJ, Sorensen MV, Hahn EA, Glendenning GA, Gnanasakthy A, Cella D. Using multiple anchor- and distribution-based estimates to evaluate clinically meaningful change on the functional assessment of Cancer Therapy-Biologic Response Modifiers (FACT-BRM) instrument. Value in Health 2005;8(2):117-27. Abstract: Objective: The interpretation of health-related quality of life (HRQL) data from clinical trials can be enhanced by understanding the degree of change in HRQL scores that is considered meaningful. Our objectives were to combine distribution-based and two anchor-based approaches to identify minimally important differences (MIDs) for the 27-item Trial Outcome Index (TOI), the seven-item Social Well-Being (SWB) subscale, and the six-item Emotional Well-being (EWB) subscale from the Functional Assessment of Cancer Therapy-Biological Response Modifiers (FACT-BRM) instrument. Methods: Distribution-based MIDs were based on the standard error of measurement. Anchor-based approaches utilized patient-reported global rating of change (GRC) and change in physician-reported performance status rating (PSR). Correlations and weighted kappa statistics were used to assess association and agreement between the two anchors. FACT-BRM changes were evaluated for three time periods: baseline to month 1, month 2 to month 3, and month 5 to month 6. Results: Association between GRC and change in PSR was poor. Correlation between the anchors and HRQL change scores was largest at month 1 and decreased through month 6. Combining results from all approaches, the MIDs identified were 5-8 points for the TOI, 2 points for the SWB subscale, and 2-3 points for the EWB subscale. Conclusions: We combined patient-reported estimates, physician-reported estimates, and distribution-based estimates to derive MIDs for HRQL outcomes from the FACT-BRM. These results will enable interpretation of treatment group effects in a clinical trial setting, and they can be used to estimate sample size or power when designing future studies 2
  3. 3. (11) Reed SD, Friedman JY, Velazquez EJ, Gnanasakthy A, Califf RM, Schulman KA. Multinational economic evaluation of valsartan in patients with chronic heart failure: Results from the Valsartan Heart Failure Trial (Val-HeFT). American Heart Journal 2004;148(1):122-8. Abstract: Background The Valsartan Heart Failure Trial (Val-HeFT) compared valsartan versus placebo in 5010 patients taking prescribed background therapy for New York Heart Association class II to IV heart failure. Valsartan reduced the risk of heart failure hospitalization and improved clinical signs and symptoms of heart failure. We sought to compare resource use, costs, and health outcomes among patients taking prescribed therapy for heart failure and randomly assigned to receive valsartan or placebo. Methods Measures of resource use were based on data collected during the trial. Unit cost estimates were collected from individual countries and converted to 1999 US dollars. Total costs were estimated for hospitalizations, inpatient and outpatient physician services, ambulance transportation, deaths outside the hospital, and outpatient cardiovascular medications. Results Mean follow-up was 23 months. Mean costs for heart failure hospitalizations were $423 lower among patients receiving valsartan (95% CI, -706 to -146). Mean total costs were $9008 for patients receiving valsartan and $8464 for patients receiving placebo, a net incremental cost of $545 (95% CI, -149 to 1148), including the cost of valsartan. There was an overall reduction in total costs of $929 (95% CI, -3243 to 1533) among patients not receiving an ACE inhibitor at baseline but a slight increase in costs of $334 (95% CI, -497 to 1199) among those receiving an ACE inhibitor without a p-blocker and a $1246 increase (95% CI, 54 to 2230) in patients receiving both an ACE inhibitor and a beta-blocker at baseline. Conclusions Valsartan provided clinical benefits at a mean incremental cost of $285 per year during the trial. In patients not taking ACE inhibitors, valsartan was economically attractive, increasing survival while reducing or marginally increasing overall costs(12) Smith DG, Gnanasakthy A, Ouednau K. Cost-effectiveness of blood pressure and urinary albumin control in diabetics with an angiotensin II receptor antagonist and a calcium channel blocker: Pharmacoeconomic analysis of the Marval trial-the case of Germany. Value in Health 2003;6(6):681.(13) Delea TE, Jacobson TA, Edelsberg JS, Gnanasakthy A, Oster G. Fluvastatin for the prevention of cardiac events following successful first percutaneous coronary intervention: analysis of cost-effectiveness based on the lescol intervention prevention study (LIPS). European Heart Journal 2003;24:246.(14) Friedman JY, Curtis L, Gnanasakthy A, Whellan D, Schulman KA. Investigator and site characteristics of the navigator trial. Value in Health 2003;6(3):335-6.(15) Reed SD, Friedman JY, Velazquez EJ, Gnanasakthy A, Califf RM, Schulman KA. Cost-effectiveness of valsartan in patients not receiving angiotensin-converting enzyme inhibitors at baseline. European Heart Journal 2002;23:137.(16) Reed SD, Friedman JY, Gnanasakthy A, Schulman KA. Comparison of hospital costing methods in an economic evaluation of a multinational clinical trial. International Journal of Technology Assessment in Health Care 2003;19(2):396-406. Abstract: Objectives: To develop and evaluate strategies for estimating hospitalization costs in multinational clinical trials. Methods: Hospital cost estimates for eleven diagnoses were collected from twelve countries participating in a trial of therapies for congestive heart failure. Estimates were combined with U.S.-based diagnosis-related group weights to compute country-specific unit cost estimates for all reasons for hospitalization. Variations of hospital costing methods were developed. The unit cost method assigns a country-specific unit cost estimate to each hospitalization. The other methods adjust for length of stay using a daily cost (DC) estimate for each diagnosis, based on either the mean length of stay (DC-mean method) or the median length of stay 3
  4. 4. (DC-median method) for each diagnosis in each country. Additional modifications were explored through adjustment of the distribution of daily costs incurred during a hospital stay. Results: The mean cost for all hospitalizations was $10,242 (SID, 10,042) using the unit cost method, $10,242 (SD, 12,760) using the standard DC-mean method, and $13,967 (SD, 18,762) using the standard DC-median method. In comparisons of costs for all 5,486 hospitalizations incurred by a subset of 2,352 patients in the trial, the unit cost method provided 92% power to detect a $1,000 cost difference. The standard DC-mean method provided 76% power, and the standard DC-median method provided 44% power. Conclusions: Hospital costing methods that adjust for differences in length of stay require a significantly larger sample to attain comparable statistical power as methods that assign unadjusted unit cost estimates to hospitalization events(17) Fiedman JY, Curtis L, Gnanasakthy A, Schulman KA. Physician characteristics of the navigator trial predict average length of stay (ALOS) in acute coronary syndrome (ACS). Value in Health 2002;5(6):478.(18) Reed SD, Friedman JY, Velazquez EJ, Gnanasakthy A, Califf RM, Schulman KA. Valsartan is cost-effective in heart failure patients not receiving ACE inhibitors. Circulation 2002;106(16):4.(19) Friedman J, Weinfurt K, Curtis L, Gnanasakthy A, Schulman K. Development of a method to increase power in economic analyses of multinational trials. Circulation 2002;106(16):167.(20) Hahn EA, Gnanasakthy A, Glendenning GA, Sorensen MV, Odom L, Cella D. Using patient- and clinician-rated anchors to evaluate change on the functional assessment of cancer Therapy-Biologic Response Modifiers. Clinical Therapeutics 2002;24:13.(21) Backhouse ME, Gnanasakthy A, Schulman KA, Akehurst R, Glick H. The development of standard economic datasets for use in the economic evaluation of medicines. Drug Information Journal 2000;34(4):1273-91. Abstract: Regulatory imperatives and competitive forces have led pharmaceutical companies to focus on extending the scope of their randomized controlled trials (RCTs) to collect data to address economic as well as safety and efficacy questions. To guide researchers, a significant literature exists on various methodological aspects of conducting economic evaluations within an RCT framework. Little has been published however, about data handling issues surrounding the management of the economic data collection effort. Thus, the objective of this paper is to present an overview of a project conducted in order to tackle various aspects of the economic data management process with a view to improving the efficiency of study conduct. The project outputs include case report forms (CRF), guidelines for CRF completion, and templates for producing statistical analysis plans and study protocols. Directions for further research are highlighted(22) Hauber AB, Gnanasakthy A, Mauskopf JA. Savings in the cost of caring for patients with Alzheimers disease in Canada: An analysis of treatment with rivastigmine. Clinical Therapeutics 2000;22(4):439-51. Abstract: Objective: To estimate per-patient potential cost savings using rivastigmine in the treatment of Alzheimers disease (AD) in Canada. Background: In recent years, new members of a class of pharmaceuticals known as cholinesterase inhibitors have been introduced for the treatment of patients with AD. Two recent studies conducted in the United Kingdom acid the United States estimated potential cost savings from the new cholinesterase inhibitor rivastigmine. The present study combined the disease-progression model used in those 2 studies with Canadian costs to estimate per-patient potential savings resulting from the treatment of AD in Canada. Methods: Efficacy data from 2 pivotal, phase III clinical trials of rivastigmine were used in a hazard 4
  5. 5. model of disease progression to estimate Long-term differences in cognitive functioning between patients receiving rivastigmine and patients receiving no treatment. We used the Mini-Mental State Examination (MMSE) score as our measure of disease progression. We also used Canadian costs of AD care, estimated as a function of MMSE score, to estimate cost savings experienced by treated patients compared with patients receiving no treatment. All costs and cost savings are presented in 1997 Canadian dollars. We used a societal perspective in this analysis. Results: Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively. For patients with the mild stage of AD, estimated average daily cost savings (excluding the cost of rivastigmine) ranged from Can $0.45 per patient per day at 6 months to Call $6.44 per patient per day after 2 years of treatment. For all patients, these estimated average daily cost savings ranged from a low of Can $0.71 per patient per day after 6 months of treatment to a high of Can $4.93 per patient per day after 2 years. Conclusion: On average, treatment with rivastigmine yields savings in the direct cost of caring for AD patients that exceed the cost of the drug after 2 years of treatment(23) Hauber AB, Gnanasakthy A, Snyder EH, Bala MV, Richter A, Mauskopf JA. Potential savings in the cost of caring for Alzheimers disease - Treatment with rivastigmine. Pharmacoeconomics 2000;17(4):351-60. Abstract: Objective: To estimate savings in the cost of caring for patients with Alzheimers disease (AD) during 6 months, 1 year and 2 years of treatment with rivastigmine. An intermediate objective was to estimate the relationship between disease progression and institutionalisation. Design and setting: We assessed the relationship between Mini-Mental State Examination (MMSE) score and institutionalisation using a piecewise Cox proportional hazard model. To estimate cost savings from treatments lasting 6 months, 1 year and 2 years, estimates of the probability of institutionalisation were integrated with data from two 6-month phase III clinical trials of rivastigmine and a hazard model of disease progression. Main outcome measures and results: Our data suggest that savings in the overall cost of caring for patients with mild and moderate AD can be as high as $US4839 per patient after 2 years of treatment. Furthermore, the probability of institutionalisation increases steadily as MMSE score falls. Among our study individuals, age, race, level of education and marital status were significant predictors of institutionalisation, whereas gender had little effect. Conclusions: Using rivastigmine to treat AD results in a delay in disease progression for patients who begin treatment during the mild or moderate stages of the disease. By delaying the probability that a patient will be institutionalised, the cost of caring for AD patients can be significantly reduced(24) Kopelman P, Maclaughlin B, Norris L, Gnanasakthy A, Wilson K. Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Safety Study to Assess the Effect of Single Doses of Vigabatrin on Blood-Glucose Levels in Insulin-Treated Diabetic Subjects. Epilepsia 1995;36:S107-S108.(25) Dallabernardina B, Fontane E, Vigevano F, Fusco L, Torelli D, Galeone D, Buti D, Cianchetti C, Gnanasakthy A, Iudice A. Efficacy and Tolerability of Vigabatrin in Children with Refractory Partial Seizures - A Single-Blind Dose-Increasing Study. Epilepsia 1995;36(7):687-91. Abstract: The efficacy and tolerability of vigabatrin (VGB) in children with refractory partial epilepsy were assessed in a single-blind, add-on, fixed-sequence, placebo-controlled trial. After 1-month observation, the patients entered a 7-month treatment period that involved administration of placebo for 1 month followed by VGB at the initial dosage of 40 mg/kg/day, to be increased to 60 and 80 mg/kg/day at 2-month intervals if seizures persisted. Of the 46 children enrolled in the study, 7 dropped out prematurely due to lack of efficacy of the drug (n = 6) or increased seizure frequency (n = 1). In 11 patients who either became seizure-free (n = 3) or improved markedly (n = 8), treatment was 5
  6. 6. completed at a dose <80 mg/kg/day. The average number of seizures per month in the 39 patients who completed the study decreased from 97 during placebo to 21, 12, and 9 after 2, 4, and 6 months of VGB treatments respectively (p < 0.0001 at each time). Response to VGB remained statistically significant when dropouts were included in the evaluation. The number of patients who had >50% reduction in Seizure frequency after 2, 4, and 6 months was 28, 33, and 35, respectively. Eight patients became seizure-free during the last 2 months of VGB treatment (3 at 40, 3 at 60, and 2 at 80 mg/kg/day, as compared with none during placebo treatment). Serum levels of associated antiepileptic drugs (AEDs) showed no significant changes, except for serum phenytoin (Pi-IT) concentration, which significantly (p < 0.01) decreased after VGB treatment. Increased appetite and sedation were observed in 17 and 11% of cases, respectively. VGB is effective in the management of refractory partial epilepsy in children, and in some patients a positive dose-response relationship appears to occur over the assessed dosing range(26) Dubrey SW, Gnanasakthy A, Stein WK, Song JG, Hardman T, Hynd J, Noble MIM. Enoximone in Chronic Stable Angina - A Double-Blind Placebo-Controlled Cross-Over Trial. Journal of Cardiovascular Pharmacology 1994;23(4):532-8. Abstract: Enoximone, a phosphodiesterase inhibitor (PDEI), has both positive inotropic and vasodilatory properties. We examined the effect of a single oral dose of enoximone as compared with placebo on myocardial ischaemia and global left ventricular (LV) function using both exercise ECG and Doppler measurements of aortic blood flow, respectively. Twenty patients (16 men, 4 women) with a mean age of 59 years and stable angina were studied. Total exercise duration was significantly longer after enoximone as compared with placebo treatment, with a mean difference of 22.8 s (p = 0.003). Times (mean +/- SD) to onset of angina and development of significant ST-segment decrease were similar after placebo (454 +/- 101 and 352 +/- 155 s, respectively) or enoximone (500 +/- 155 and 413 +/- 192 s, respectively), although both showed trends in favour of enoximone. As compared with placebo, significantly higher heart rate (HR) was measured for enoximone both at rest (75 +/- 18 vs. 90 +/- 22 beats/min, p < 0.01) and on recovery from exercise (81 +/- 18 vs. 89 +/- 19 beats/min, p < 0.05). Enoximone had no significant effect on systolic or diastolic blood pressure (SBP, DBP) or rate-pressure product (RPP) generated at rest or during exercise. Changes in both acceleration and velocity of aortic blood flow during exercise were similar after administration of enoximone or placebo. We showed that a single oral dose of enoximone is well tolerated in patients with ischaemic heart disease, improving both exercise capacity and favourably influencing ST-segment changes with no increase in adverse events or significant haemodynamic disturbances(27) Loeb C, Iudice A, Perucca E, Gnanasakthy A, Angeleri F, Scarpino O, Avanzini G, Binelli D, Baruzzi A, Procaccianti G, Bergamasco B, Bianco C, Canger R, Mai R, Diperri R, Pisani F, Cocito L, Manfredi M, Faedda MT, Mutani R, Gianelli M, Tartara A, Tassinari CA, Michelucci R, Zappoli R et al. Single-Blind, Placebo-Controlled Multicenter Trial of Vigabatrin in the Treatment of Epilepsy. Italian Journal of Neurological Sciences 1992;13(9):741-7. Abstract: A single-blind, placebo-controlled multicenter trial of vigabatrin was carried out in 101 epileptic patients (mostly with partial seizures) refractory to conventional therapy. The study design included four consecutive periods: (i) an observation phase (run-in), (ii) a placebo period, (iii) fixed-dosage add-on vigabatrin (2 g/day) and (iv) dose titration (up to a maximum of 4 g/day) to optimize clinical response. Each period lasted 8 weeks, except for the titration phase, which could be extended to 16 weeks. 90 patients completed the trial. Eleven dropped out, one patient developing absence status and 4 cases showing an increased seizure frequency. In the patients completing the trial, the median number of seizures/month decreased from 16 (inter-quartile range 8-34) during placebo to 5 (2-10) during the last 8 weeks on vigabatrin (p<0.0001). Both partial and generalized tonic clonic (mostly secondary) seizures were significantly reduced. A greater 6
  7. 7. than 50% reduction in seizure frequency (compared to placebo) was observed in 60 patients. Sedation and weight gain were the most frequently reported adverse events(28) Morant SV, Gnanasakthy A. A New Approach to the Mathematical Formulation of Lactation Curves. Animal Production 1989;49:151-62.(29) Webster AJF, Saville C, Church BM, Gnanasakthy A, Moss R. Some Effects of Different Rearing Systems on Health, Cleanliness and Injury in Calves. British Veterinary Journal 1985;141(5):472-83.(30) Webster AJF, Saville C, Church BM, Gnanasakthy A, Moss R. The Effect of Different Rearing Systems on the Development of Calf Behavior. British Veterinary Journal 1985;141(3):249-64.(31) Maughan GL, Cooke DA, Gnanasakthy A. The Effects of Soil-Applied Granular Pesticides on the Establishment and Yield of Sugar-Beet in Commercial Fields. Crop Protection 1984;3(4):439-50.(32) Agha M, Gnanasakthy A. A Cluster-Analysis of the Effects of Storage Mites As Allergens in Relation to Certain Occupations and Living-Conditions. Clinical Allergy 1981;11(5):499-504. 7