Strategies for promoting recruitment to trials (STEPS project … and others!)

1. Strategies for promoting recruitment to trials (STEPS project … and others!) Marion Campbell

2. Background Conducting high quality trials is not easy!

3. Main challenges • Recruiting enough participants • Ensuring participants stay in the trial • Keeping clinicians/local centres motivated over the lifetime of the trial

4. The STEPS project • Strategies for Trials Enrolment and Participation Study • Commissioned by the NHS Methodology Panel (through funding from MRC and NHS HTA programme) • Aim - identify factors associated with good and poor recruitment to multicentre trials • Concentrating mainly on participation of collaborating researchers

5. Three components • Part A: Epidemiological review of cohort of trials that had been funded by MRC and HTA. • Part B: Case studies of trials that appeared to have interesting lessons for recruitment. • Part C: In-depth case study of one large multicentre trial to examine the feasibility of applying a business/management approach to the conduct of trial

6. Part A: Epidemiological review • MRC- and HTA-funded trials whose recruitment commenced from 1/1/94 and was due to be completed before 31/12/02 • At least two clinical centres • Individual randomisation • Reviewed data from applications and progress reports • 114 trials reviewed

7. Part A: key findings • Only 38 (31%) trials recruited ‘successfully’ (i.e. ≥ 100% of target within specified time) • 14 halted before end of recruitment period • 11 because of poor recruitment • 65 (57%) received an extension

8. Trial features and ‘success’ • Explored a series of pre-defined hypotheses about what might affect recruitment including: • Local recruitment coordinator • Run by trials unit • Multidisciplinary • Pilot phase • Dedicated trial manager • Calculated odds ratios (OR>1 if factor more common for ‘successful’ trials)

9. Factor Simple design >500k funding Trials unit Local recruitment co-ordinator Multidisciplinary OR (95% CI) 0.43 (0.08-2.25) 0.49 (0.19-1.26) 0.62 (0.26-1.50) 0.62 (0.14-0.84) 0.77 (0.21-2.82) Associations

10. Factor Pilot phase MRC funding Drug trial Interventions in trial only Consumer input Cancer trial Dedicated trial manager OR (95% CI) 1.09 (0.46-2.61) 1.09 (1.00-5.36) 1.47 (0.68-3.18) 1.66 (0.58-4.76) 2.10 (0.53-8.43) 2.77 (1.11-6.93) 3.80 (0.81-17.76) Associations (2)

11. Part A: limitations • Quality of reporting • Missing data, although drew on additional sources • ‘Exposure’ variables • Relatively crude and potentially misclassified • Interpretation difficult as many correlated • Other factors might have been more informative • Relatively small number of trials and some low exposures led to wide CIs • ‘Outcome’ variable • Recruitment used as surrogate for ‘success’ of trial

12. Part A: conclusions • Simple descriptive analyses do not give clear indications of factors that are likely to predispose to successful recruitment • Explanation of why some trials consistently recruit well and others do not appears complex • Look to more in-depth components of STEPS for additional insights

13. Part B: case studies • Funders identified four ‘exemplar’ trials • Semi-structured telephone interviews with 45 key players from these trials • Included those with different responsibilities and experiences (recruiting clinicians, central trial staff, PI etc)

14. Case studies • The Heart Protection Study (HPS) • Chemotherapy for Bowel Cancer (Fluorouracil, Oxaliplatin and Irinotecan (CPT11), Use and Sequencing (FOCUS) • Trial of Outcome for Child & Adolescent Anorexia Nervosa (TOuCAN) • Leukotriene receptor antagonists in primary care at steps two and three of the National Asthma Guidelines (ELEVATE)

15. Common factors in success (1) • Importance and timeliness of research question • Confidence that trial design scientifically sound • Treatment not available outside the trial • Respect for PIs • Getting foundations for trials well established • Helped if existing trials office or network of experienced trial collaborators, but not essential • Firmly grounded in clinical practice • Accommodation to needs of patients

16. Common factors in success (2) • Expertise fostered through training • Participating staff felt well-informed • Clinical collaborators protected from much workload associated with trial • e.g. dedicated research nurses • Responsibilities in the trial well delineated within efficient management system

17. Common factors in success (3) • Respondents identified themselves as part of a successful, hard-working and motivated team • Climate in which there was an important sense of collectivity, where central teams and collaborators were enthusiastic and keen to make their trials function well and to “deliver”. • These feelings bred greater success, confidence and ability to adapt to and overcome problems

18. Part B: Limitations • Small number of trials • Interviews elicited perceptionsof reasons for success • Trials were selected as exemplars by HTA/MRC • Might have gained further insights if chosen trials which had achieved their target recruitment within the originally agreed timeframe • Even the exemplars needed extensions (perhaps partly because of over-optimistic projections in the initial funding application)

19. Part B: Conclusions • Interviewees saw themselves as members of successful teams • Management and teamwork play important roles in a successful trial. • The ways in which trials are organised and how teams operate are ripe for further research

20. Part C: Clinical trials as businesses • Businesses find customers and convince them to buy what is on offer • Clinical trials find doctors and patients and convince them to 'sign up'. • Clinical trials can be viewed as equivalent to quite large businesses • Some with £m+ revenues and recruitment targets of 1000s

21. Clinical trials – Business Perspective • Clinical trials require strategy, management, marketing and sales • Trials already undertake these activities, to some extent • A marketing specialist from the academic business sector was invited to work with the MRC CRASH trial (Placebo controlled trial of the effect of corticosteroid treatment on death and disability in patients with head injury)

22. Part C: Methods • Marketing specialist given access to all non-confidential trial related documents • Interviewed members of the central trial management team • Visited participating hospitals (in England) • Observed training sessions • Interviewed or facilitated group discussions with doctors (12), nurses (14) and ancillary staff (4)

23. Business approach • Management research emphasises that organisations need to be seen as systems with interacting activities • Performance of the system as a whole depends on: • the appropriateness of the activities, • the efficiency by which the activities are performed and • how the activities relate together to form a whole • This sequence of activities is known as a ‘value chain’ • Parallel with conduct of a clinical trial where a sequence of events require to be completed

24. Gaining Stakeholder Support Maintaining Scientific Standards Designing Installing Acquiring the Trial Finding and Developing Trial and Publishing and and Enrolling Valid Management Processing Disseminating Acquiring Participants Conclusions Processes Data Providing Value to Medical Knowledge Funding Practising Project Management Maintaining Financial Disciplines Value chain for a clinical trial

25. Value chain (2) • The extent to which a trial delivers its promise will be determined by the efficiency and effectiveness by which the 10 activities of the value chain are performed and the degree of integration between them • Construction of a value chain for a clinical trial will differ to some extent according to its specific requirements • Each activity in value chain presents distinct management challenge

26. A marketing and salesreference model for trials • A reference model was developed to define the capabilities required with: • 4 domains and • 12 components

27. IVc Ia Developing Facilitating 'Brand Values' Incorporation Into Routines IVb Providing Ib Gaining Frequent Positive Legitimacy / Reinforcement Prestige IVa Ensuring Positive Ic Signalling MAINTAINING BUILDING 'Moments of Worthiness ENGAGEMENT BRAND VALUES Truth' IV I III II IIa Providing IIIc Achieving Buy- Simple, PRODUCT AND MAKING THE In (in public) Complete MARKET SALE Processes PLANNING IIIb Delivering A Multi-Audience, IIb Devising Multi-Level Strategies For Message Overcoming Resistance IIIa Engaging Active Sponsors, Champions IIc Adopting An and Change Agents Explicit Marketing Plan

28. Interactive work • Developing the model for your trial

29. Part C: Key Insights • Without explicit brand values it is impossible to communicate a coherent and persuasive perception of a trial's promise – i.e. what the trial intends to deliver to medicine, doctors, patients. • A marketing plan should include definition of ‘target market segments’ (groups that need to 'buy in' to the trial) and the trial's unique selling points.

30. Part C: Levels of Commitment • Formal marketing plan identified five 'levels' of commitment by potential participants and defined strategies for each. • The Uninformed (Inform and persuade with targeted stories) • The Unconvinced (Address concerns point-by-point - get to yes") • The Laggards (Enrol, cajole, facilitate and target) • The Steady Performers (Reward, renew, upgrade and recognise) • The Stars (Honour, learn from, exploit and nourish)

31. Part C: Summary A successful trial requires BOTH: • good science AND • good management

32. STEPS: Lessons (2) • STEPS suggests that trialists should think about the different phases in the life of trials and put greater emphasis on processes of doing trials • Learn lessons from successful trial managers and support training • Funders may need to complement scientific expertise by skills in assessing capabilities for setting up and running trials, and agility in dealing with inevitable difficulties • Funders may also need to be more proactive in monitoring and responding

33. Summary • RCTs provide the best evidence of effectiveness of new interventions • They are difficult to deliver, but there are many pointers to good practice available • Trials require good science AND good management • The regulatory environment has changed dramatically (especially for trials with medicinal products) • Lots of time and energy have gone into preparing advice for researchers to help them navigate the new regulations • RCTs should continue to be the design of choice for evaluating new interventions