Tag Archives: Stem Cells

Using Observational Data to Complement RCT Results – Examples Based on Multiple Sclerosis

A common scenario in modern research arises when a long-term treatment has been evaluated in RCTs, but with only limited follow-up. Not surprisingly patients do not want to continue to take medicines in the long-term that have been shown to be inferior in the shorter-term. Such was the case with the first generation of multiple sclerosis (MS) drugs, and so I found myself chairing the scientific advisory committee for a long-term observational study based on the MS Risk Sharing scheme. ‘Risk sharing’ because the tax payer and pharmaceutical companies shared the risk that the medicines would appear more or less successful in the longer-term than had been estimated in the RCTs (all of which were of 2-3 years duration). This study is now closed and the resulting paper has been submitted for publication.

In the meantime, new treatments have been developed for the treatment of MS. One class of treatments involves autologous bone marrow cell transplantation.[1] This treatment, unlike drugs used in the MS Risk Sharing scheme, is suitable only for patients with rapidly progressing disease, because it is an aggressive treatment with a mortality of about 2%, and a long-term cancer risk of about 1%. As with the first generation drugs, benefits in the short-term (about two years) had been well-established, but long-term effects were unknown. So a long-term study was conducted. In the case of the MS Risk Sharing scheme, progression on treatment was compared to a control population recruited in British Columbia before use of drugs became widespread. Patients recruited to this Canadian study therefore constituted a natural history control cohort for patients in the Risk Sharing scheme. In contrast, long-term follow-up was uncontrolled in the autologous bone marrow cell transplant study. Nevertheless, the authors rely on the large observed effect size to conclude that bone marrow cell therapy was effective over a mean of six years follow-up. The biological mechanism is a little unclear, but the agreement with short-term RCT outcomes (clinical progression and surrogate markers on MRI), along with the large apparent benefit, suggests that this treatment is worth its costs, in terms of money and side-effects, in people with aggressive disease.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Muraro PA, Pasquini M, Atkins HL, et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017; 74(4): 459-69.
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A Device for Failing Hearts

Back in 2005 I was approached by Sally Davies, then languishing as deputy director general of Research and Development, and asked to evaluate the utility of a trial of left ventricular assist devices (LVADs) for heart failure. We elicited a Bayesian prior from a chapter of surgeons from the American Society of Heart Surgeons. This prior was the basis for a value of information study,[1] which suggested that expensive LVAD technology might be a bridge too far for the hard-pressed NHS. Anyway, the world moves on and the New England Journal of Medicine has recently carried out a trial comparing two different LVADs, one more sophisticated (type 3) than the original version we studied (type 2).[2] The latest version had less problems with clotting up of the device, but survival free of a serious stroke at six months was similar, at over 80% in both groups – quite high considering how sick these patients were. The article has some extremely good diagrams explaining the devices. These devices are sometimes used to rest the heart, for example in a case of inflammation of the heart muscle. Most often they are used when the heart muscle packs up permanently, say as a result of heart attacks. In that case LVADs can be used to keep a person alive until a match can be found for a heart transplant, so called ‘bridge to transplant’, or as a permanent solution. However, I think the devices are themselves a bridge to a more subtle regenerative medicine approach based on stem cells.

— Richard Lilford, CLAHRC WM Director

References:

  1. Girling AJ, Freeman G, Gordon JP, Poole-Wilson P, Scott DA, Lilford RJ. Modeling payback from research into the efficacy of left-ventricular assist devices as destination therapy. Int J Technol Assess Health Care. 2007; 23(2): 269-77.
  2. Mehrea MR, Naka Y, Uriel N, et al. A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure. New Engl J Med. 2017; 376: 440-50.

Stem Cells for Stroke – Still a Long Way Off

The Lancet recently reported the results of stem cell therapy given six months or more after a hemiplegic stroke in eleven subjects.[1] A small degree of functional improvement was noted but in the absence of contemporaneous controls no firm cause and effect conclusion is possible – no dramatic effect here, such that such controls are not needed. An interesting question concerns the design of a proper trial – should the controls undergo a sham procedure? I am opposed to sham surgery trials involving more than minimal risk of harm for reasons spelled out elsewhere.[2] In the meantime, acute embolectomy is a highly effective treatment and the NHS needs to urgently reconfigure services to accommodate this new technology, as argued previously.[3] [4]

— Richard Lilford, CLAHRC WM Director

References:

  1. Borlongan CV. Age of PISCES: stem-cell clinical trials in stroke. Lancet. 2016; 388: 736-8.
  2. Wolf BR & Buckwalter JA. Randomized Surgical Trials and “Sham” Surgery: Relevance to Modern Orthopaedics and Minimally Invasive Surgery. Iowa Orthop J. 2006; 26: 107-11.
  3. Lilford RJ. Meta-analysis of emergency embolectomy for acute thrombotic stroke. NIHR CLAHRC West Midlands News Blog. September 2, 2016.
  4. Lilford RJ. First the heart, now the brain. NIHR CLAHRC West Midlands News Blog. April 10, 2015.