A letter in the British Medical Journal this week goes to the heart of the problems facing clinical medical research (authors Antonuccio and Healy). It discusses the critical status of raw data
, the rights of study participants, and proposes a new credo for researchers. Patients who take part in clinical trials expose themselves to risk in the interest of all of us. They have a right to know that the information derived from their assumption of risk will not be misused, suppressed or distorted. The problem of cheating in commercial clinical trials will not be solved by any clinical trials register. Another letter by Geisler reinforces the point. Neither letter discusses the fact that raw data may not be accessible
to "authors" either
- a further layer of complexity. Both letters are in response to an excellent paper by Lenzer and Brownlee ( Lenzer, Jeanne; Shannon Brownlee (2008-03-08). "An untold story?". BMJ 336 (7643): 532-534 - PDF here
). The adoption of such a credo will go a far way towards solving many of the problems of falsified clinical research.
Both letters are reproduced below:Letter 1: The researcher’s credo
Antonuccio, David O; David Healy (2008-03-22). "The researcher's credo". BMJ 336 (7645): 629.
Lenzer and Brownlee hit the nail on the head regarding the important issue of data access. We owe all human subjects who volunteer for behavioural and medical research more than they have been getting. For years, the top scientific journals have required that all clinical trials be publicly registered before data collection begins, in order to be eligible for publication. This was an important step designed to reduce publication bias, but it did not go far enough. The recent FDA Amendments Act mandating public access to data summaries is another step in the right direction, but, as Lenzer and Brownlee say, this too may not go far enough. Several examples from the psychopharmacology literature have shown that nothing short of total public access to raw human subject data on efficacy and safety will be enough to ensure that data are independently and thoroughly evaluated.[2,3] Issues of distorted or selective publication continue to corrupt our ostensible scientific database.[4,5]We urge all institutional review boards to require that, in exchange for the privilege of doing human subject research, researchers make their raw data (not just summaries of the data) accessible (without identifying information) within a reasonable period of time via the internet or in some other suitable fashion.
We believe scientists owe this unfettered access to all participants who have ever volunteered for a scientific study with the hope, belief, and promise that their sacrifices would help science advance. We offer the following brief universal commitment to human subjects that can be used by any institutional review board in the world:"I agree, in exchange for the privilege of doing research with human subjects, to not only register the trial in a publicly accessible clinical trials database, but also to make summaries of the primary results and the actual raw data internet accessible (without identifying information) within 1 year of collecting data on the last human subject, or within 2 years after the start of the study, whichever is sooner. This is my commitment to all human subjects who volunteer with the hope, expectation and promise that their efforts and sacrifices will result in independently verifiable contributions to science. I recognize that failure to follow through on this commitment may jeopardize approval for any future research protocols in which I may participate."
David O Antonuccio, Professor of psychiatry and behavioral sciences, University of Nevada School of Medicine
David Healy, Professor, North Wales Department of Psychological Medicine, Cardiff UniversityReferences
Letter 2: Excessively closed science hurts
- Lenzer J, Brownlee S. Antidepressants. An untold story? BMJ 2008;336:532.
- Antonuccio DO, Danton WO, McClanahan TM. Psychology in the prescription era: building a firewall between marketing and science. Am Psychol 2003;58:1028-43.
- Healy D. Let them eat Prozac: the unhealthy relationship between the pharmaceutical industry and depression. New York: New York University Press, 2004.
- Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008;5:260-8.
- Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252-60.
Geisler, Fred H. (2008-03-22). "Excessively closed science hurts". BMJ 336 (7645): 629-a.
I would like to add to Lenzer and Brownlee’s reporting of my comments on how excessively closed science can hurt physicians and patients.
Statistician Michael Bracken led the NASCIS 2 and 3 studies of high dose steroids in acute spinal cord injury. The National Institute of Neurological Disorders and Stroke conducted a public campaign in advance of the scientific publication of NASCIS 2 on 17 May 1990. The institute sent a fax on 13 April 1990 to some 19 000 emergency room physicians and hospitals, after a press release had resulted in coverage by the New York Times and the Chicago Tribune on 31 March 1990, by Science News on 7 April 1990, by Newsweek on 9 April 1990.
This led to widespread use of steroids, off label. No application for regulatory approval for this indication was completed, and no agency ever approved it. Surgeons report that methylprednisolone is administered from fear of litigation, not belief in efficacy. Bracken reinforced this fear by testifying against physicians; he was deposed on 9 June 1998 in Civil Action File No 96A-7768-6, Superior Court of Fulton County, GA.
We have criticised NASCIS science.4 The later guidelines for the management of acute cervical spine and spinal cord injuries from the American Association of Neurological Surgeons and the Congress of Neurological Surgeons (AANS/CNS) rated the NASCIS publications as evidence class III, citing flaws in study design, data presentation, interpretation, and analysis. They listed steroid treatment only as an "option."
The lack of demonstrated benefit must be weighed against documented risks. The CRASH trial showed a 3% greater mortality when corticosteroids were given to a multitrauma group with head injury. If this increased death rate held in SCI, then 5000 extra patients may have died in the US since 1990.
Yet it’s difficult to stop the momentum—especially when primary data are unavailable for independent review.
Fred H. Geisler, Director, Illinois Neuro-Spine CenterReferences
- Lenzer J, Brownlee S. Antidepressants. An untold story? BMJ 2008;336:532. (8 March.)[Free Full Text]
- Bracken MB, Shepard MJ, Collins WF Jr, Holford TR, Baskin DS, Eisenberg HM, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the second national acute spinal cord injury study. N Engl J Med 1990;322:1405-11.
- Eck JC, Nachtigall D, Humphreys SC, Hodges SD. Questionnaire survey of spine surgeons on the use of methylprednisolone for acute spinal cord injury. Spine 2006;31:E250-253.
- Coleman WP, Benzel E, Cahill DW, Ducker T, Geisler F, Green B, et al. A Critical appraisal of the reporting of the NASCIS II and III studies of MPSS in acute spinal cord injury. J Spinal Disord 2000;13:185-99.
- Hadley MN, Walters BC. Pharmacological therapy after acute cervical spinal cord injury. In: Guidelines for the management of acute cervical spine and spinal cord injuries. Neurosurgery 2002;50:S63-S72.
- Edwards P, Arango M, Balica L, Cottingham R, El-Sayed H, Farrell B. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet 2005;365:1957-9.
Labels: Raw_data, Research Participant Rights