Pharmaceutical Medicine

, Volume 25, Issue 1, pp 7–15 | Cite as

Tackling the Challenges of Clinical Trials in Palliative Care

  • David C. Currow
  • Meera R. Agar
  • Amy P. Abernethy
Review Article


There is an ethical imperative to provide the best quality of care for all people, including people at the end of life. In order to provide such care, each intervention used in clinical practice must be tested objectively for net clinical benefit (response and toxicity). For pharmacological and non-pharmacological interventions, the gold standard of evidence remains a phase III randomized, controlled study. In palliative care, there is a gradually emerging evidence base for clinical practice derived from rigorously designed and conducted interventional studies. Such studies can effectively recruit, even in this clinical setting, to completion.

There are design and implantation challenges in all controlled clinical trials. Some issues are highly likely in palliative care and will influence trial design and analysis including expected attrition unrelated to the intervention, wide variation in the diagnosis and timing of referral to individual palliative care services and responsible reporting of serious adverse events. Factors that are not unique to palliative care but are often magnified in such studies include concerns by referrers and participants about randomization and blinding, how and when to measure endpoints that are clinically relevant, how to minimize the burden of data collection, ensuring studies are adequately powered and how best to deal with primary outcomes that are subjective. Many studies in the palliative care population have successfully overcome these challenges by thoughtful study design. Factors associated with successful (palliative care) study completion include (i) a shared vision about what the research is designed to achieve; (ii) governance structures independent of the researchers; (iii) ways of defining standard practice for the control arm using best available evidence and consensus; (iv) face-to-face meetings especially for protocol development; (v) adequate funding given estimates that four to six palliative care patients will be screened for every person who completes the study; (vi) collaboration with a wide range of experts in clinical trials and other clinical disciplines of importance to the study question; (vii) adequate timelines given recruitment difficulties; (viii) adequate feasibility planning; (ix) standard operating procedures; (x) web-based data management in multi-site research; and (xi) site visits as a two-way learning and quality process, especially for services that are new to controlled clinical trials. Systematically, analyses need to include the characteristics of the sub-population(s) who will most predictably benefit from an intervention.

Improving the quality of care for people at the end of life with rigorously designed, adequately powered studies that can inform clinical practice and policy directly, is an important health research agenda. Such studies are feasible and can help to inform practice improvement.


  1. 1.
    WHO. Health statistics and health information systems [online]. Available from URL: [Accessed 2010 Jun 29]Google Scholar
  2. 2.
    Clark D. Palliative care history: a ritual process? Eur J Cancer Care 2000; 7 (2): 50–4Google Scholar
  3. 3.
    Clark D. From margins to centre: a review of the history of palliative care in cancer. Lancet Oncol 2007; 8 (5): 430–8PubMedCrossRefGoogle Scholar
  4. 4.
    Doyle D. Palliative medicine: the first 18 years of a new subspeciality of general medicine. J R Coll Physicians Edinb 2005; 35: 199–205Google Scholar
  5. 5.
    Lunney JR, Lynn J, Foley DJ, et al. Patterns of functional decline at the end of life. JAMA 2003; 289: 2387–92PubMedCrossRefGoogle Scholar
  6. 6.
    Gill TM, Gahbauer EA, Han L, et al. Trajectories of disability in the last year of life. N Engl J Med 2010; 362 (13): 1173–80PubMedCrossRefGoogle Scholar
  7. 7.
    Solano J, Gomes B, Higginson I. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage 2006; 31: 58–69PubMedCrossRefGoogle Scholar
  8. 8.
    Currow DC. Why don’t we do more rigorous clinical research so that we can stop experimenting on patients? J Pall Med 2010; 13 (6): 636–7CrossRefGoogle Scholar
  9. 9.
    Currow DC, To THM, Abernethy AP. Prescribing at times of clinical transition in chronic or progressive diseases. Int J Gerontology 2009; 3 (1): 1–8CrossRefGoogle Scholar
  10. 10.
    Masso M, Dodds S, Fildes D, et al. Ethical research in palliative care: a guide through the Human Research Ethics Committee process. Canberra (ACT), Commonwealth of Australia Department of Health and Ageing, 2004Google Scholar
  11. 11.
    White C, Gilshenan K, Hardy J. A survey of the views of palliative care healthcare professionals towards referring cancer patients to participate in randomized controlled trials in palliative care. Support Care Cancer 2008 Dec; 16 (12): 1397–405PubMedCrossRefGoogle Scholar
  12. 12.
    White C, Hardy J. What do palliative care patients and their relatives think about research in palliative care? A systematic review. Support Care Cancer 2010; 18 (8) 905–11PubMedCrossRefGoogle Scholar
  13. 13.
    Steinhauser KE, Christakis NA, Clipp EC, et al. Factors considered important at the end of life by patients, family, physicians, and other care providers. JAMA 2000 Nov 15; 284 (19): 2476–82PubMedCrossRefGoogle Scholar
  14. 14.
    Duke S, Bennett H. A narrative review of the published ethical debates in palliative care research and an assessment of their adequacy to inform research governance. Palliat Med 2010; 24 (2): 111–26PubMedCrossRefGoogle Scholar
  15. 15.
    Carter R. Cicely Saunders: founder of the Hospice Movement. Selected letters 1959–1999 [book review]. J R Soc Med 2003 Mar; 96 (3): 149–51CrossRefGoogle Scholar
  16. 16.
    Tieman J, Sladek R, Currow DC. Changes in the quantity and level of evidence of palliative and hospice care literature: the last century. J Clin Oncol 2008; 26 (35): 5679–83PubMedCrossRefGoogle Scholar
  17. 17.
    McWhinney IR, Bass MJ, Donner A. Evaluation of a palliative care service: problems and pitfalls. Br Med J 1994 Nov 19; 309 (6965): 1340–2CrossRefGoogle Scholar
  18. 18.
    Aoun SM, Kristjanson LJ. Challenging the framework for evidence in palliative care research. Palliat Med 2005 Sep; 19 (6): 461–5PubMedCrossRefGoogle Scholar
  19. 19.
    National Health andMedical Research Council. National statement on ethical conduct in human research [online]. Available from URL: [Accessed 2010 Jun 29]Google Scholar
  20. 20.
    ICH. International Conference on Harmonisation/WHO good clinical practice standards [online]. Available from URL: [Accessed 2010 Jun 29]Google Scholar
  21. 21.
    LeBlanc TW, Wheeler JL, Abernethy AP. Research in end-of-life settings: an ethical inquiry. J Pain Palliat Care Pharmacother 2010; 24 (3): 244–50PubMedCrossRefGoogle Scholar
  22. 22.
    Clark K, Currow DC, Agar M, et al. A pilot phase II randomized, cross-over, double-blinded, controlled efficacy study of octreotide versus hyoscine hydrobromide for control of noisy breathing at the end-of-life. J Pain Palliat Care Pharmacother 2008; 22 (2): 131–8PubMedCrossRefGoogle Scholar
  23. 23.
    Bach JR. Palliative care becomes ‘uninformed euthanasia’ when patients are not offered non-invasive life preserving options. J Palliat Care 2007 Autumn; 23 (3): 181–4PubMedGoogle Scholar
  24. 24.
    Keeley PW. Improving the evidence base in palliative medicine: a moral imperative. J Med Ethics 2008; 34 (10): 757–60PubMedCrossRefGoogle Scholar
  25. 25.
    Pavis H, Wilcock A. Prescribing of drugs for use outside their licence in palliative care: survey of specialists in the United Kingdom. BMJ 2001 Sep 1; 323 (7311): 484–5PubMedCrossRefGoogle Scholar
  26. 26.
    Bredin M. Multicentre randomised controlled trial of nursing intervention for breathlessness in patients with lung cancer. Br Med J 1999; 31 (7188): 901–4CrossRefGoogle Scholar
  27. 27.
    Abernethy AP, McDonald CF, Frith PA, et al. Effect of palliative oxygen versus medical (room) air in relieving breathlessness in patients with refractory dyspnea: a double-blind randomized controlled trial (NCT00327873). Lancet 2010; 376 (9743): 784–93PubMedCrossRefGoogle Scholar
  28. 28.
    Corner J. Is there a research paradigm for palliative care? Palliat Med 1996; 10 (3): 201–8PubMedGoogle Scholar
  29. 29.
    Rinck GC, van den Bos GA, Kleijnen J, et al. Methodologic issues in effectiveness research on palliative cancer care: a systematic review. J Clin Oncol 1997; 15 (4): 1697–707PubMedGoogle Scholar
  30. 30.
    Currow DC, Wheeler J, Glare P, et al. A framework for generalizability in palliative care. J Pain Symptom Manage 2009; 37: 373–86PubMedCrossRefGoogle Scholar
  31. 31.
    Palmer J. Analysis of missing data in palliative care studies. J Pain Symptom Manage 2004; 286: 612–8CrossRefGoogle Scholar
  32. 32.
    Fielding S. Methods for handing missing data in palliative care. Palliat Med 2006; 20: 791–8PubMedCrossRefGoogle Scholar
  33. 33.
    Currow DC, Shelby-James TM, Agar M, et al. Planning phase III multi-site clinical trials in palliative care: the role of consecutive cohort audits to identify potential participant populations. Support Care Cancer 2010; 18 (12) 1571–9PubMedCrossRefGoogle Scholar
  34. 34.
    Abernethy AP, Clark K, Currow DC. How should we conduct and interpret phase III clinical trials in palliative care? J Pain Symptom Manage 2010; 39 (1):E6–8CrossRefGoogle Scholar
  35. 35.
    Hardy J, Shelby-James T, Currow DC. Research in palliative care: is death always an adverse event? Intern Med J 2010 Jan; 40 (1): 89–90PubMedCrossRefGoogle Scholar
  36. 36.
    Abernethy AP, Currow DC, Wurzelmann J, et al. Enhancing enrollment in palliative care trials: key insights from a randomized, placebo-controlled study. J Support Oncol 2010; 8 (3): 139–44PubMedGoogle Scholar
  37. 37.
    Rowett D, Ravenscroft PJ, Hardy J, et al. Using national health policies to improve access to palliative care medications in the community. J Pain Symptom Manage 2009; 37 (3): 395–402PubMedCrossRefGoogle Scholar
  38. 38.
    CONSORT. The CONSORT Statement [online]. Available from URL: [Accessed 2010 Oct 7]Google Scholar
  39. 39.
    Whalen GF, Kutner J, Byock I, et al. Implementing palliative care studies. J Pain Symptom Manage 2007; 34 (1 Suppl.): S40–S8PubMedCrossRefGoogle Scholar
  40. 40.
    McCaffrey N, Eckermann S, Currow DC. Measuring impacts of value to patients is crucial when evaluating palliative care. J Pain Symptom Manage 2009; 37 (6): 7–9CrossRefGoogle Scholar
  41. 41.
    Currow DC, Agar M, Tieman J, et al. Multisite research allows adequately powered palliative care trials: web-based data management makes it achievable today. Pall Med 2008; 22 (1): 91–2CrossRefGoogle Scholar
  42. 42.
    Nikles J, Mitchell G, Walters J, et al. Prioritising drugs for single patient (n-of-1) trials in palliative care. Palliat Med 2009; 23 (7): 623–34PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • David C. Currow
    • 1
  • Meera R. Agar
    • 1
    • 2
  • Amy P. Abernethy
    • 1
    • 3
  1. 1.Discipline, Palliative and Supportive ServicesFlinders UniversityDaw ParkAustralia
  2. 2.Department of Palliative CareBraeside HospitalPrairiewoodAustralia
  3. 3.Division of Medical Oncology, Department of MedicineDuke University Medical CentreDurhamUSA

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