Analysis of Clinical Trials in Children Registered in the Clinical Trials Registry of India S. Manikandan*, M. Jayanthi*, B. Gitanjali** and G. Sivagnanam* *Indira Gandhi Medical College & Research Institute, Pondicherry, India; ** WHO-SEARO, New Delhi 1

Introduction  World Health Organization (WHO) established International Clinical Trials Registry Platform (ICTRP) in 2005  20 items are listed as Trial Registration Data Set (TRDS) which is the minimum amount of information necessary for a given trial to be considered fully registered.  India launched ‘Clinical Trials Registry-India’ (CTRI) in July 2007 to enhance transparency and accountability of trial reporting from India.  The quality of information in the registry should be good in order to satisfy the three main stakeholders, i.e., health care professionals, policy makers and trial participants. 2

Introduction 1.Srivastava JS. Need for ethical oversight of clinical trials in India. Curr Sci. 2010;99: Moja LP et al. Compliance of clinical trial registries with the World Health Organization minimum data set: a survey. Trials. 2009;10:52.  Concerns about the conduct of clinical trials in India are growing. 1  Information provided in the trial registries is insufficient and not current; hence benefits of registries are undermined. 2  Paediatric trials are scarce due to difficulties involved in conducting them.  The need for ethical oversight of trials in India has been emphasized. 1  Hence the information in registries gains more significance with reference to trials in children.

Objectives  To critically analyze the information on paediatric clinical trials in Clinical Trials Registry – India (CTRI) in terms of: information - completeness, transparency, currency and compliance with WHO’s International Clinical Trial Registry Platform (ICTRP) data set, i.e., Trial Registration Data Set (TRDS).  To suggest measures to improve the quality of CTRI. 4

Methods  A cross-sectional study of paediatric clinical trials registered in CTRI.  Clinical trials in children < 18 years retrieved (as on 15 Aug 2010) by the keyword ‘children’ from CTRI website.  Two independent observers scored the response for each item, which was verified by a third person.  Method of scoring was defined a priori.  The completeness of reporting, appropriateness and degree of compliance of CTRI data with WHO- ICTRP items (WHO items) and CTRI-specific items were analyzed. 5

88 trials retrieved 7 adult studies 81 trials analyzed Results Completeness of Information  20 (25%) trials were completed; only 2 provided the results; 2 provided conclusions.  Fax number and affiliation of the Principal Investigator were not given in ~ 90% of trials.  Many participant countries have been left out.  Duration and frequency of drug administration was missing in 27% of trials. 6

7 Incomplete information - A few examples Name of Institute ? Reproduced from CTRI. Comments of authors are in red.

8 Incomplete information - a few examples ?? Placebo has same constituents as test drug Reproduced from CTRI. Comments of authors are in red.

Results Transparency of information  3 (4%) trials have not disclosed the sources of monetary & material support.  41 trials needed regulatory approval, but only 32 have obtained it.  Inconsistencies in the no. of sites, blinding etc. 9 Reproduced from CTRI. Comments of authors are in red.

10 CTRI No. Source undisclosed TypeName 2009/091/ Pharma Co.GSK 2009/091/ Research Foundation FABB, Italy 2010/091/ Pharma Co.Zydus, Roche Lack of transparency - examples Reproduced from CTRI. Comments of authors are in red.

Results Currency of information  31 (38%) trials were updated after registration whereas 7(9%) were not.  Remaining 43 (53%), the date of last update is prior to the date of registration. 11 Reproduced from CTRI. Comments of authors are in red.

Results Compliance with WHO items (n=20) in CTRI Compliance % No. of items Items 1006 Trial No; Registration date; Secondary Sponsor; Scientific Title; Health condition; Recruitment status Support source; Primary Sponsor; Study -Type; Countries; first enrollment date; sample size; outcome – Primary, secondary Public Title; Secondary Identifying No; Inclusion & Exclusion Criteria <603 Contact -public query; Scientific query; Intervention 12

Results Compliance with CTRI-specific items (n=13) Compliance % No. of items Items 1003 CTRI No. & Date; Contact details; No. of sites Site details; ethics committee approval; random sequence generation; blinding and masking; phase of trial; estimated duration of trial Regulatory approval <603 Principal investigator’s details; allocation concealment; summary 13

Results Unethical use of placebo in registered trials Health condition studied Reason to state use of placebo is unethical Bronchial asthmaStandard drug (bronchodilator) not used as comparator Bipolar depressionPlacebo for 8 weeks instead of standard therapy (antidepressants) Mild to moderate iron deficiency anemia Placebo (unfortified rice) for 7 months without iron therapy Rotaviral/ cryptosporidial gastroenteritis Only probiotic (test drug) / placebo used. Rehydration with ORS not given Active ulcerative colitisPlacebo for 10 weeks, when disease process is active Acute migrainePlacebo instead of an analgesic in acute migraine 14

Discussion 15  Though the quantum of compliance is satisfactory in CTRI, the quality is found wanting. Suggestions to improve CTRI  Regular reminder to the registrants to update results and information on completion of trial.  Errors in the date of update can be rectified through changes in the software.  Ethical issues like the inappropriate use of a placebo should be taken up with the principal investigators before registering the trial.  Summary of the clinical trials should be in English as well as vernacular – to help participants.  Separate link to be provided for children’s trials.

Conclusion  The information on children’s clinical trials in the CTRI is incomplete, not current, not regularly updated, and at times misleading.  The use of placebo is not justified in one third of the placebo-controlled trials in children.  The quality of information in CTRI may be improved by modifying the registry and making it user friendly and by providing assistance for registration. 16

17