This document lists publications by Ari Gnanasakthy related to patient-reported outcomes in clinical trials and health economics evaluations. It includes 22 publications ranging from 2005 to 2010 related to establishing minimally important differences in patient-reported outcomes, developing guidance for collecting patient-reported data, evaluating the cost-effectiveness of drugs like valsartan and rivastigmine, and methods for conducting economic evaluations alongside multinational clinical trials. The publications indicate Gnanasakthy has extensive experience in analyzing patient-reported outcomes and health economics data from clinical trials.

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 product's 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. 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, O'Brien 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
analyst's estimates of resource use and clinical effectiveness and (b) the analyst's
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
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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
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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
Alzheimer's 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 Alzheimer's 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
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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 Alzheimer's disease - Treatment with rivastigmine.
Pharmacoeconomics 2000;17(4):351-60.
Abstract: Objective: To estimate savings in the cost of caring for patients with Alzheimer's
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
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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
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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.
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