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RSS Merseyside Meeting, 26 February 2016: Pharmaceutical Statistics Sarah J. Nolan Department of Biostatistics University of Liverpool,

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Presentation on theme: "RSS Merseyside Meeting, 26 February 2016: Pharmaceutical Statistics Sarah J. Nolan Department of Biostatistics University of Liverpool,"— Presentation transcript:

1 RSS Merseyside Meeting, 26 February 2016: Pharmaceutical Statistics Sarah J. Nolan (sjn16@liv.ac.uk) Department of Biostatistics University of Liverpool, United Kingdom Young Statisticians’ Section of the Royal Statistical Society Data Sharing : A young statistician’s perspective

2 All views are my own and do not represent the University of Liverpool, our project funder or other young statisticians! To start… …with a disclaimer RSS Merseyside meeting: 26 February 2016 Pharmaceutical Statistics: Data Sharing

3 Context October 2011: 3 year research project for Cochrane Epilepsy Group funded by National Institute of Health Research (NIHR): “Clinical and cost effectiveness of interventions for epilepsy in the NHS” o Individual Participant Data (IPD) Meta-analysis and Network Meta Analysis of anti-epileptic drugs used in monotherapy RSS Merseyside meeting: 26 February 2016 Pharmaceutical Statistics: Data Sharing

4 Network Meta-Analysis Ten Antiepileptic Drugs Carbamazepine (CBZ) Phenobarbitone (PB) Oxcarbazepine (OXC) Phenytoin (PHT) Valproate (VPA) Lamotrigine (LTG) Gabapentin (GBP) Topiramate (TPM) Levetiracatam (LEV) Zonisamide (ZNS) RSS Merseyside meeting: 26 February 2016 Pharmaceutical Statistics: Data Sharing

5 Network Meta-Analysis Ten Antiepileptic Drugs Carbamazepine (CBZ) Phenobarbitone (PB) Oxcarbazepine (OXC) Phenytoin (PHT) Valproate (VPA) Lamotrigine (LTG) Gabapentin (GBP) Topiramate (TPM) Levetiracatam (LEV) Zonisamide (ZNS) 45 pairwise comparisons (direct and indirect) RSS Merseyside meeting: 26 February 2016 Pharmaceutical Statistics: Data Sharing

6 IPD Meta-analyses in Epilepsy Primary outcome: Time to withdrawal of randomised treatment RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

7 IPD Meta-analyses in Epilepsy Primary outcome: Time to withdrawal of randomised treatment RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

8 IPD Meta-analyses in Epilepsy Primary outcome: Time to withdrawal of randomised treatment RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing Withdrawal event: Lack of efficacy Withdrawal event: Adverse effects Loss to follow up: Censored Completed study without withdrawing: Censored

9 IPD Meta-analyses in Epilepsy Secondary outcome: Time to first seizure after randomisation, time to remission of seizures RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing Number of seizures per week Date of seizure 1 Date of seizure 2

10 IPD Meta-analyses in Epilepsy Treatment-covariate interactions RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing Age? Seizure type? Number of seizures? MRI or EEG results?

11 IPD Meta-analyses in Epilepsy Primary outcome: Time to withdrawal of randomised treatment – COMPLEX Secondary outcome: Time to first seizure after randomisation, time to remission of seizures – LACK OF UNIFORMITY Treatment-covariate interactions Level of detail not available in publications (Nolan 2013) Individual participant data approach needed! RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

12 Meta-Analysis: IPD approach RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

13 Meta-Analysis: IPD approach RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

14 Meta-Analysis: IPD approach RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

15 Network Meta-Analysis RSS Merseyside meeting: 26 February 2016 Pharmaceutical Statistics: Data Sharing Update of a network meta-analysis published in 2007 Individual participant data provided from 18 trials Plus two SANAD trials conducted out of the CTRC in Liverpool (Marson 2007a, Marson 2007b)

16 29 studies of interest 1985-2005 (n=5881) – 12 Academic studies (n=1383) – 13 Pharmaceutical studies (n=3320) – 4 Government studies (n=1178) Data provided from 18 studies (n=4697, 80%) – 2 Academic studies (n=286, 21%) – 13 Pharmaceutical studies (n=3320, 100%) – 3 Government studies (n=1091, 93%) 20 years of data requesting Pharmaceutical Statistics: Data SharingRSS Merseyside meeting: 26 February 2016

17 20 years of data requesting 2012-2013: 39 new studies identified (n=8242) – 22 Academic studies (n=1653) – 16 Pharmaceutical studies (n=5996) – 1 Government study (n=593) 31 Dec 2015: 15 datasets provided (n=5316, 64%) – 7 Academic studies (n=799, 48%) – 8 Pharmaceutical studies (n=4517, 75%) – 0 Government study (n=0, 0%) Total: 35 studies, 10013 participants (71% of IPD) RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

18 20 years of data requesting From time of initial data requests (39 studies): Median time to receiving data (n=15) – Academic studies: 343 days (range 154 to 861) – Pharmaceutical studies: 363 days (range 280 to 725) Median time to negative response (n=11): – 287 days (range 0 to 784) – Data lost, data not recorded, ethics restrictions, costs prohibitive due to age of trial, country specific restrictions Median time to closing unanswered request (n=13) – 972 days (range 640 to 1448) RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

19 20 years of data requesting From time of initial data requests (39 studies): Median time to receiving data (n=15) – Academic studies: 343 days (range 154 to 861) – Pharmaceutical studies: 363 days (range 280 to 725) Median time to negative response (n=11): – 287 days (range 0 to 784) – Data lost, data not recorded, ethics restrictions, costs prohibitive due to age of trial, country specific restrictions Median time to closing unanswered request (n=13) – 972 days (range 640 to 1448) RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

20 Network meta-analysis timeline RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

21 Network meta-analysis timeline RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

22 Clinical Study Data Request.com (previously ‘GSK Share’) June 2013: Enquiry submitted (3 studies) June 2014: Data provided (1 study) Length of request: 364 days 2013-2014: Three enquiries unsuccessful Length of requests: 17 – 245 days Negative response better than unanswered request! RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

23 The age of data transparency RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

24 The age of data transparency RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing June 2013: 7% of data requested – Over half of requests unanswered December 2015: 64% data requested – Around a quarter of requests unanswered – All pharmaceutical requests answered – Other pharmaceutical companies that provided data directly are now part of CSDR – High quality data, little ‘cleaning’ required.

25 The age of data transparency RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing Systematic review of 780 IPD meta-analyses published from 1987 to August 2015 Only a quarter were provided with 100% of IPD Only half were provided with >80% of IPD Barriers to doing IPD analyses (Kovalchik 2012) Time and resources involved Too difficult to access data Will data sharing initiatives improve this?

26 Problem: Remote data access environments Total: 35 studies, 10013 participants (71% of IPD) Analysis dataset created for each of 35 studies – 1 dataset inside the remote SAS Environment – 34 datasets outside of the remote SAS Environment I can’t download the 1 dataset I can’t upload some of the 34 datasets – Data sharing agreements prevent this I can never have a full analysis dataset – One stage network meta-analysis is impossible – Two stage analysis is the only option (less flexible) RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing

27 Reflections RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing IPD meta-analyses are complex and time consuming Compared to ‘traditional’ data requesting: Data sharing platforms increase the time and resources required Result in higher quality data, reduce in the time spent data cleaning Knock on effect outside of the platforms Potentially restricts analytic methods Implications for future IPD meta-analyses?

28 References RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing  Nolan SJ, Sutton L, Marson A, Tudur Smith C. Consistency of outcome and statistical reporting of time-to-event data: the impact on Cochrane Reviews and meta-analyses in epilepsy. Proceedings of the 21st Cochrane Colloquium; 2013 September 19-23; Quebec City. Quebec City: The Cochrane Collaboration, 2013:114-5.  Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, et al.; Sanad Study Group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. The Lancet 2007;369(9566):1000-15.  Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, et al.; Sanad Study Group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. The Lancet 2007;369(9566):1016-26.  Kovalchik SA. Survey finds that most meta-analysts do not attempt to collect individual patient data. J Clin Epidemiol 2012;65(12):1296-9.

29 Acknowledgements RSS Merseyside meeting: 26 February 2016Pharmaceutical Statistics: Data Sharing o Dr Catrin Tudur Smith o Professor Anthony Marson o Cochrane Epilepsy Group All trial investigators and pharmaceutical companies who have responded to our data requests

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