1. SYDNEY MEDICAL SCHOOL Experiences in Clinical Trials: The Good, the Bad and the Ugly Janette Vardy Concord Cancer Centre

2. Background Medical Oncology -Sydney Cancer Centre -Busy clinical commitments -Research meetings: chemotherapy trials, basic science, PhD (Clin Epi) and Clinical Fellowship Prof Ian Tannock Princess Margaret Hospital – Toronto -Clinical Epidemiology – U of Toronto -Mentoring -Strong research culture, infrastructure, biostatisticians, data managers, trials staff -Protected research time -Projects: Cognitive function & fatigue in cancer patients: CRC, Breast Cancer Dexamethasone –for delayed emetic control Acetaminophen/paracetamol – with strong opioids 2

3. Research vs Clinical? Sydney or Toronto? QOL Research or my QOL? 3

4. Sydney or Toronto? Cancer Institute NSW Clinical Research Fellowship -2 X 3 years “My primary career objective is to be a successful clinician researcher, enabling me to combine clinical research in psycho-social oncology and survivorship with a practice in clinical medical oncology. …… The major focus of this research programme will be cognitive function and fatigue, and its underlying mechanisms …. I plan subsequently to extend the research programme to address other needs and concerns of cancer survivors, particularly targeting the psychosocial issues that many survivors face after treatment. Within 5 years I expect to establish a comprehensive clinical research and clinical practice specialising in survivorship issues..” 4

5. Back to Sydney 5 January 2007: Welcome Home! Cancer Institute NSW – wage (70/30%) and $100K p.a. for research NHMRC Grant – CRC Cognitive Study Reality: Shared desk, no computer, most of dept on holiday Hospital –bureaucracy: -Having to deal with finance dept/HR/admin -Employing staff – 6 months to employ an RA from grant -Invited speaker at AACR/ASCO –TESL leave refused – pro-rata -days

6. The Good Dr. Haryana Dhillon – Behavioural scientist Research co-ordinator running CRC-cognitive study  Research partners Established and co-lead Survivorship Research Group - SuRG >$10m in grants 6.4 FTE “ The Team” - Critical to success Post grad and grad students: 5 PhD, 1 Masters Psychology and Medical Student Electives, RMO projects Writing up largest comprehensive cognitive study in cancer patients Collaborators : neuropsychology, oncology, imaging, animal models Local, National, International Mentors: Ian Tannock, Martin Tattersall, Stephen Clarke MPRU  CeMPeD Psycho-Oncology Co-operative Group (PoCOG) and tumour site specific groups 6 Importance of the Team and Collaboration:

7. The Bad Research Culture: Lack of research infra-structure Lack of protected research time for others Lack of appreciation for investigator initiated studies and psycho-oncology Lack of support for each others studies Lack of support for junior staff Give it 2-3 years: Can I change things, and if not can I live with it? Attempted to improve research culture and build research capacity Organised a research retreat –medical oncologists Regular research meetings for fellows – supportive environment Became a Clinical Academic – employed through university More academic freedom, financial disincentives/no TESL 7 Many times – ready to go back to North America

8. The Bad Funding: time writing grants instead of doing studies NHMRC: inexperienced / “too junior”, not enough grants  $2.5m CHALLENGE – Physical activity in Colon Cancer patients 21 sites across Australia Collaboration with NCIC Difficult / uncertain career as researcher: Year to year funding – affect on staff and pressure on researcher Your own job and others are reliant on you getting grants Dec 2012 – for first time had project grants for most of our studies and were able to keep on all our staff, but no guaranteed funding for wages for Haryana or myself 8

9. The Bad Recruitment to clinical studies remains a major issue Psycho-oncology / supportive care studies –not seen as essential as chemotherapy treatment trials or treatment affecting survival Often difficult to get access to patients: Lack of sponsorship  low budget – lack of reimbursement for centres Doctors – act as “gatekeepers” - what’s in it for me? Lot of time/money wasted opening sites that then don’t recruit patients 9 Recruitment:

10. The Really Ugly “A randomized double-blind placebo controlled cross-over trial of the impact on quality of life of continuing dexamethasone beyond 24 hours following adjuvant chemotherapy for breast cancer” Dual endpoints: Patient preference for one cycle over other Change in QOL D1 – D8 –comparing 2 cycles In house funding – 2 hospitals Detailed protocol n= 100 (50/group) Experienced Trials nurse Start up meetings Regular progress meetings Reviewed 1 st cycle data Analyse data for abstract preparation 10

11. The Really Ugly Review data – missing Cycle 2 Day 8 data: Patient Preference, QOL data Nurse – hadn’t collected data Review source documents: Poor record keeping Duplication of study numbers Blood tubes – incorrectly labelled Missing test results and questionnaires Major International Study – same nurse was involved in – Monitor expressed concerns re data inaccuracies – data not to be used. PMH – Put on Hold Every Study in Breast Cancer Review and Formal Audit 11 Dex Study

12. Gets even uglier…. Outcomes: Audits of all studies –problems were isolated to studies she was involved in Nurse was dismissed - multiple problems across a number of her studies Despite weekly meetings, supervision and verbal reassurances from experienced nurse about data and study progress  PI (supervisor) ultimately responsible for oversight of the study Importance of checking source data Extremely stressful for all concerned Me – lost 3 years of work Dexamethasone Study: In end, only used data from other hospital  repeated the study 5 years later – finished and published. -in meantime aprepitant became mainstream so study less topical 12

13. Would I do it again? Still have a passion for research in psycho-oncology/supportive care/survivorship issues but envious of research cultures and facilities at large North American facilities Now we have infrastructure and grants for our studies, it has got easier SuRG – well trained team  increased grants  expanded our research programme Funding opportunities in Australia, particularly for cancer, have improved Research culture is growing Increased focus on QOL/psycho-oncology studies & better quality trials in this area 13

14. For other researchers Early researchers –make use of concept and protocol workshops Get support from co-operative trials groups Find a mentor Build and retain a strong committed team Mentoring and training for your staff  do good quality trials to obtain high quality evidence using same rigour as applied to drug trials  apply the evidence to clinical practice 14