Experiences in Clinical Trials: The Good, the Bad and the Ugly

1. 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 (ClinEpi) 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

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

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..”

5. Back to Sydney 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 Importance of the Team and Collaboration: Dr. Haryana Dhillon – Behavioural scientist Research co-ordinatorrunning 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

7. The Bad Many times – ready to go back to North America 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

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

9. The Bad Recruitment: 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

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 1st cycle data Analyse data for abstract preparation

11. The Really Ugly Dex Study 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

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

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

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