Nikola Stepanov – Research Ethics

Nikola Stepanov

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Why the reporting of clinical trial outcomes is an important social issue by  Nikola Stepanov. This article forms part of a Doctor of Philosophy Thesis.

Introduction

The recent development of an international campaign calling for reporting of all clinical trials results has highlighted global concerns about the lack of transparency and access to clinical trial data and outcome reporting.

The ‘AllTrials’ 1 campaign began in January 2013 as a collaborative initiative of Bad Science,2 British Medical Journal (‘BMJ’),3 Centre for Evidence-based Medicine,4 Cochrane Collaboration,5 James Lind Initiative,6 PLOS 7 and Sense About Science.8 It is being led in the United States by the Dartmouth’s Geisel School of Medicine 9 and the Dartmouth Institute for Health Policy & Clinical Practice (United States of America).10 The campaign’s aims include that all results from past and present clinical trials be published. To date a petition begun by the campaign has secured almost 60,000 signatures with support from more than four hundred institutions, organisation and professional bodies including the Royal College of Paediatrics and Child Health (U.K.), Medical Journal of Australia, and the International Alliance of Patients’ Organizations. 11

Other successful campaigns with similar aims including the online campaign by Dr. David Healy, an internationally respected psychiatrist, psychopharmacologist, scientist, and author, 12 demonstrate that there is a shared global consensus among multi-disciplinary professionals, institutions, communities and other individuals that deficiencies in accessing and reporting clinical trial outcomes are emerging as very significant social problems.

What are Clinical Trials?

As distinguished from medical care which wholly focuses on outcomes for the patient,13 the primary aim of clinical trials involving human participants is to test novel and potential treatments for their safety and efficacy in humans, with the purpose of contributing to knowledge about the diagnosis, management or treatment of a disease or condition.14

In choosing to take part in clinical trials participants may be motivated by a desire to benefit others by contributing to new knowledge. They may also be motivated by a desire to receive some personal benefit for themselves, although the extent and type of personal benefit that can be anticipated is contentious and subject to much debate.15

However, irrespective of participant motivations, clinical trials are not primarily designed to clinically benefit them. Moreover, due to the nature of experimentation in clinical trials, involvement may mean being exposed to significant research-related risk and harms in the form of side-effects and toxicities.16 The purpose of clinical trials is to help persons in the future by publishing empirical data about which treatments are effective, and which are harmful. The data can also be used to develop future clinical trials.17 The ethical justification for clinical trials is that any potential burden or harm to participants will not be in vain, but will contribute to new knowledge about treating or managing some medical condition,18 and that the ratio of risks to benefits is as low as possible. This is particularly the case for clinical trials that involve more than a minimal risk to participants; non-therapeutic early-phase studies; and trials involving vulnerable populations such as children, participants from minority populations, and participants from developing nations or poorer socio-economic areas.19

The success of campaigns like AllTrials and Dr Healy’s among others indicates that there are widely-held concerns about deficiencies in accessing and publishing outcomes and data, including accessing information about the occurrences of any side-effects of agents being tested.20 There is evidence that these concerns are well-founded.21 A meta-analysis of all clinical trials conducted in the United States and Canada, registered with ClinicalTrials.gov after December 31, 1999 and updated as having been completed by June 8, 2007 showed that the results of fewer than half of all clinical trials were published, with positive results being twice as likely to be published.22 More recently Jones et al. conducted a cross-sectional analysis of clinical trials registered with ClinicalTrials.gov, that contained more than 500 participants, and that were completed prior to 2009.23 They found that of 585 registered trials, 171 or 29% remained unpublished. The unpublished studies involved an estimated 299 763 study participants.24 Industry funded studies (150) were also more likely to be unpublished than those that were not funded by industry. 25 Deficiencies in reporting results have been explained as being due to publishing bias; a lack of positive results; and transparency conflicts between public interest and safety, and commercial interests and intellectual/commercial property rights.26 Non-industry funded studies are also more likely to be published than industry sponsored studies.27 Publishing bias is also evident, for example in paediatric clinical trials. In a cross-sectional survey Hartling et al. noted that of 166 paediatric randomised controlled trials (RCT) undertaken in the United States and presented at professional meetings, results from 83% were never submitted for publishing.28 Any knowledge deficit that leads to uncertainty in gauging the efficacy and safety of new and existing treatments, and the ability to accurately predict risk and harms, is significant. This is particularly the case where the knowledge exists but is purposefully withheld from the public or is unreported for other reasons (including publication bias).29

Are Deficiencies in Reporting Clinical Trial Outcomes a Significant Social Problem?

How clinical trials are conducted is an important global social issue and any lack of transparency in reporting clinical trials outcomes is a social problem. Barber (1980) defines a ‘social problem’ as being ‘some social condition that a sizable group comes to define as both bad and unnecessary and improvable or removable’. 30

Most people will experience one or more medical conditions during the course of their lives. Where possible, medical practitioners make decisions about which treatment/s to offer patients based on the best available evidence. Often this means that medical practitioners are reliant on published findings of clinical trial outcomes to assist in their deliberations about what treatment options are suitable for each particular patient. During deliberations medical practitioners must also take into consideration any other illnesses and conditions the patient may have; any other medical interventions they patient may already be receiving such as medicines; and how any new treatments might affect the patient in terms of side-effects and interactions with existing medications.31 Any failure in transparency about clinical trial outcomes, particularly regarding results such as potential or actual side-effects or drug interactions, will inevitably influence decision-making by medical practitioners. This may lead them to make decisions based on insufficient evidence, or evidence of a poor quality. Treating clinicians also rely on published data from clinical trials to make decisions about whether to recommend clinical research involvement to their patients. Finally, clinical and human research ethics review committees and funding bodies also rely on published evidence of outcomes when they consider the ethical and scientific merit of future studies.32

Conclusion

The assertion that any lack of transparency in reporting outcomes of clinical trials is an important social problem is not a radical position. Moreover, it is not an unreasonable position in view of the fact that the primary justification for conducting clinical trials is that the outcomes will contribute to new knowledge.

Internationally it is recognised that the lack of transparency about clinical trials outcomes impacts not only on research participants, but also on decision-making by medical practitioners as they try to ascertain the best treatments for their patients.

Foot Notes

1AllTrials. (2013). “All Trials Registered: All Results Reported”. Retrieved November 4, 2013., 2013, from http://www.alltrials.net/blog/

2 http://www.badscience.net/
3 http://www.bmj.com/
4 http://www.cebm.net/
5 http://www.cochrane.org/
6 http://www.lindalliance.org/
7 http://www.plos.org/
8 http://www.senseaboutscience.org/
9 http://geiselmed.dartmouth.edu/
10 http://tdi.dartmouth.edu/; AllTrials. n 1 (2013).
11A llTrials. n 1 (2013).
12 http://davidhealy.org/

13 Kerridge, I., M. Lowe and C. Stewart (2013). Ethics and law for the health professions. Leichhardt, The Federation Press, Stepanov, N. and M. K. Smith (2013). “Double standards in special medical research : questioning the discrepancy between requirements for medical research involving incompetent adults and medical research involving children.” Journal of Law and Medicine 21: 47-52.

14 Miller, F. G. and S. Joffe (2008). “Benefit in phase 1 oncology trials: therapeutic misconception or reasonable treatment option?” Clinical Trials (London, England) 5(6): 617-623, Kottow, M. (2009). “Clinical and research ethics as moral strangers.” Archivum Immunologiae et Therapiae Experimentalis 57(3): 157-164, Stepanov, N. (2013). Understanding the Existence and Implications of Therapeutic Misconceptions in First-in–human and Early Phase Research Involving Children. Unpublished Thesis, Centre for Health & Society, and the Melbourne Medical School. The University of Melbourne. Merritt, M. (2005). “Moral Conflict in Clinical Trials.” Ethics: 306-330. Ott, A. (2007). “One Goal? One Consensus? One More Trip to the Drawing Board: A Review of Global Bioethics: The Collapse of Consensus.” Journal of Law, Medicine and Ethics: 748-750.

15 It is not within the scope of this article to suitably address the debates about clinical trial benefits, however for further clarity please see: King, N. (2000). “Defining and describing benefit appropriately in clinical trials.” Ibid. 28(4): 332-343, Lewens, T. (2006). “Distinguishing treatment from research: a functional appraoch.” Journal of Medical Ethics 32: 424-429, Kimmelman, J. (2012). Gene Transfer and the Ethics of First-in-Human Research: Lost in Translation. Cambridge, Cambridge University Press.

16 Furman, W., C. Pratt and G. Rivera (1989). “Mortality in pediatric phase I clinical trials.” Journal of National Cancer Institute 81(15): 1193-1194, Kim, A., E. Fox, K. Warren, S. Blaney, S. Berg, P. Adamson, M. Libucha, E. Byrley, F. Balis and B. Widemann (2011). “Characteristics and Outcomes of pediatric patietns Enrolled in Phase I Oncology Trials.” The Oncologist 17: 5982-5990, Mosse, Y., E. Lipsitz and E. e. a. Fox (2012). “Pediatric Phase I Trial and Pharmocokinetic Study of MLN8237, an Investigational Oral Selective Small-Molecule Inhibitor of auroa Kinase A: A Children’s Oncology Group Phase I Consortium Study.” Clinical Cancer Research 18: 6058-6064. Common toxicities may include serum sickness, neurotoxicity, mucositis/stomatitis, myleosuppression, persistent nausea or diarrhoea, pathologic changes consistent with organ involvement, failure or damage.

15 Lewens, n 17 (2006); Stepanov & Smith, n 15 (2013).

18 Stepanov & Smith, n 15 (2013).

19 Stepanov, n 12 (2013).

20 Sismondo, S. and M. Doucet (2010). “Publication Ethics and the Ghost Managment of Medical Publications “ Bioethics 24(6): 273-283, Schroeder, D. and E. Gefenas (2011). “Realizing Benefit Sharing: The Case of Post-study Obligations.” Ibid.: no-no.

21 Stepanov, n 12 (2013).

22 Excluding phase I trials: see Ross, J., G. Mulvey, E. Hines, S. Nissen and H. Krumholz (2009). “Trial Publication after registration in Clincal Trials.Gov: A Cross-sectional Analysis.” PLoS Medicine Sep 8(6:e 1000144), Bourgeois, F., S. Murthy and K. Mandl (2010). “Outcome reporting among drug trials registered in Clincal Trials.gov.” Annals Of Internal Medicine 3(153(3)): 158-166. IHR (2010). Heatlh Technology Assessment Program. NHS, NHS.

23 Ross, J., G. Mulvey, E. Hines, S. Nissen and H. Krumholz (2009). “Trial Publication after registration in Clincal Trials.Gov: A Cross-sectional Analysis.” PLoS Medicine Sep 8(6:e 1000144).
24 Ross, n 23 (2013).
25 Ross, n 23, (2013).

26 Stepanov, n 12 (2013). Although outside the remit of this paper, the lack of published data is in itself an ethical issue given the primary justification for conducting research is that it will contribute to generalisable knowledge usually

27 Ross, n 22, (2009).

28 Hartling, L., W. Craig, K. Russell, K. Stevens and T. Klassen (2004). “ Factors Influencing the Publication of Randomised Controlled Trials in Child Health Research.” Archives of Paediatric and Adolescent Medicine 983-987.

29 Stepanov, n 12 (2013).

30 Barber, B. (1980). Informed consent in medical therapy and research. New Brunswick, NJ, Rutgers University Press p2.

31 See also: Leah Cowan and Ancel-la Santos. “Access to Trial Data”. Retrieved November 9, 2013 from http://davidhealy.org/health-action-international-access-to-trial-data/?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+DrDavidHealy+%28Dr.+David+Healy%29.

32 Stepanov, n 12 (2013).

33 Personal communiqué, Dr David Healy, November 11, 2013.

References

Barber, B. (1980). Informed consent in medical therapy and research. New Brunswick, NJ, Rutgers University Press

Bourgeois, F., S. Murthy and K. Mandl (2010). “Outcome reporting among drug trials registered in Clincal Trials.gov.” Annals Of Internal Medicine 3(153(3)): 158-166.

Furman, W., C. Pratt and G. Rivera (1989). “Mortality in pediatric phase I clinical trials.” Journal of National Cancer Institute 81(15): 1193-1194.

Hartling, L., W. Craig, K. Russell, K. Stevens and T. Klassen (2004). “ Factors Influencing the Publication of Randomised Controlled Trials in Child Health Research.” Archives of Paediatric and Adolescent Medicine 983-987.

Kerridge, I., M. Lowe and C. Stewart (2013). Ethics and law for the health professions. Leichhardt, The Federation Press.

Kim, A., E. Fox, K. Warren, S. Blaney, S. Berg, P. Adamson, M. Libucha, E. Byrley, F. Balis and B. Widemann (2011). “Characteristics and Outcomes of pediatric patietns Enrolled in Phase I Oncology Trials.” The Oncologist 17: 5982-5990.

Kimmelman, J. (2012). Gene Transfer and the Ethics of First-in-Human Research: Lost in Translation. Cambridge, Cambridge University Press.

King, N. (2000). “Defining and describing benefit appropriately in clinical trials.” Journal of Law, Medicine and Ethics 28(4): 332-343.

Kottow, M. (2009). “Clinical and research ethics as moral strangers.” Archivum Immunologiae et Therapiae Experimentalis 57(3): 157-164.

Lewens, T. (2006). “Distinguishing treatment from research: a functional appraoch.” Journal of Medical Ethics 32: 424-429.

Merritt, M. (2005). “Moral Conflict in Clinical Trials.” Ethics: 306-330.

Miller, F. G. and S. Joffe (2008). “Benefit in phase 1 oncology trials: therapeutic misconception or reasonable treatment option?” Clinical Trials (London, England) 5(6): 617-623.

Mosse, Y., E. Lipsitz and E. e. a. Fox (2012). “Pediatric Phase I Trial and Pharmocokinetic Study of MLN8237, an Investigational Oral Selective Small-Molecule Inhibitor of auroa Kinase A: A Children’s Oncology Group Phase I Consortium Study.” Clinical Cancer Research 18: 6058-6064.

Ott, A. (2007). “One Goal? One Consensus? One More Trip to the Drawing Board: A Review of Global Bioethics: The Collapse of Consensus.” Journal of Law, Medicine and Ethics: 748-750.

Ross, J., G. Mulvey, E. Hines, S. Nissen and H. Krumholz (2009). “Trial Publication after registration in Clincal Trials.Gov: A Cross-sectional Analysis.” PLoS Medicine Sep 8(6:e 1000144).

Schroeder, D. and E. Gefenas (2011). “Realizing Benefit Sharing: The Case of Post-study Obligations.” Bioethics: no-no.

Sismondo, S. and M. Doucet (2010). “Publication Ethics and the Ghost Managment of Medical Publications “ Bioethics 24(6): 273-283.

Stepanov, N. (2013). Understanding the Existence and Implications of Therapeutic Misconceptions in First-in–human and Early Phase Research Involving Children. Unpublished Thesis, Centre for Health & Society, and the Melbourne Medical School. The University of Melbourne.

Stepanov, N. and M. K. Smith (2013). “Double standards in special medical research : questioning the discrepancy between requirements for medical research involving incompetent adults and medical research involving children.” Journal of Law and Medicine 21: 47-52.

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Check out Nikola Stepanov’s other article in Live Encounters LINK
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Nikola Stepanov is a doctoral scholar in philosophy and law (Rights of Children) with the Melbourne Medical School & School of Population and Global Health, The University of Melbourne, and recipient of an Australian Postgraduate Award. Nikola also works part-time as a lecturer in Medical Ethics and Law with the School of Medicine, the University of Queensland.

Broadly, her research interests include children’s ethics, metaphysics, philosophy of law, and moral philosophy. More specific research interests include: ethics and law of first-in-human and early phase clinical research involving children (including gene transfers); perinatal and neonatal clinical ethics; paediatric clinical ethics; and adolescent health ethics and law including consent, contraception, abortion, and competence.

Nikola enjoys working as part of a small but committed international paediatric ethics community, and together with Nigerian Bioethicist Sam Ujewe, will be spending the summer in Cyprus as an invited visiting scholar of the University of Central Lancashire’s (UCLan) Centre for Professional Ethics and UCLan Faculty of Law-Cyprus.

Email: n.stepanov@uq.edu.au

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