Clinical Studies Abroad: What Can We Learn?

Published: June 18, 2005  |  Source: themiamiproject.org
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Recently there has been news from various countries of the effects of transplanting olfactory ensheathing cells (OECs) into people with spinal cord injury (SCI). Of note to the scientific community are anecdotal reports that people who have undergone these procedures have had improvements in sensory and Motor function within the first days after the procedures. While there is interest within the scientific community, these anecdotal reports are leading to more questions than scientific answers.

Several studies in animals support the idea that OEC transplants may increase function, thus leading some doctors in other countries to offer such treatments. Because these experimental surgical procedures are both invasive and permanent, many scientists feel that transplanting these cells in humans is premature. There are numerous questions about the effectiveness of the procedures and concerns about potential adverse effects. The Miami Project has been asked its opinion of these procedures. While more information is required before safety and efficacy can be ascertained, The Miami Project has taken the position that there may be an opportunity to advance scientific knowledge from these clinical experiences if more comprehensive information can be obtained. The following explains this position in relation to one of these experimental procedures.

Experimental Transplant
One experimental transplant that has gained the attention of people with SCI, the media, and scientists is that of Dr. Hongyun Huang in Beijing, China. In February 2004, representatives from The Miami Project had attended the Clinical Trials Workshop sponsored by the International Campaign for Cures of spinal cord Paralysis (ICCP) where Dr. Huang was among several clinicians who presented their experiences with experimental treatments in humans with SCI. Following this meeting, The Miami Project decided to initiate open communication with Dr. Huang to more completely understand his transplant procedure using olfactory bulb-derived fetal cells as a means to promote recovery of function following SCI. Miami Project scientists and other researchers have been experimenting with OECs as a potential cell therapy in experimental models of SCI, however, limited data were available concerning the clinical use of these cells.

Afirst step in this information-gathering effort was to invite Dr. Huang to The Miami Project to present a lecture summarizing his clinical experiences. Dr. Huang presented a lecture, entitled Transplantation of Olfactory Ensheathing Glia in Patients with Spinal Cord Injury, where scientists and clinicians had the opportunity to listen to his presentation and ask specific questions regarding procedures and outcome measures. Although this presentation provided new information including the suggestion that some patients experience Functional benefit, many important scientific questions were left unanswered and led to various concerns. One concern was the lack of appropriate outcome measures that would adequately assess any long-term benefits. Another was the lack of follow-up information that would help determine the incidence of adverse effects of the procedure.

Direct Observations
Large numbers of individuals have undergone these procedures in Beijing. In an effort to obtain better scientific data, The Miami Project faculty decided it would be important to obtain first-hand information concerning the procedures and the clinical effects. To this end, two scientists/clinicians within The Miami Project traveled to Beijing and, over a ten-day period, had the opportunity to observe twelve patients, evaluating six of them for neurological function before and after surgery. It is important to note that several patients demonstrated a modest degree of improvement in motor and sensory function. Interestingly, this improvement in neurological status occurred immediately after the surgical procedure. In addition to these positive findings, some adverse effects were also observed. For example, wound breakdowns were noted in two patients, one of whom had a reduction in leg function after surgery. Meningitis occurred in another, however, the Chinese doctors did not record these complications in the patients’ medical records.

The Miami Project’s representatives had the opportunity to observe what they describe as a relatively simple surgical procedure of cell injections into the spinal cord of four different patients. While they did have the opportunity to witness the surgical procedures and examine some patients, they were not permitted access to the laboratory where the cells for transplantation were prepared. Therefore, little information is currently available concerning the cellular content of these human fetal olfactory bulb cultures. One cell preparation, however, that was not transplanted into a patient was provided to The Miami Project for analysis. This analysis has been initiated and is ongoing. At this time, apart from descriptions from Dr. Huang, researchers can only guess at the important aspects of the preparation such as: What method of cell processing was used? Does the transplant tissue actually contain OECs? In what stage of development are the cells?

Unanswered Questions
Even after having the opportunity to directly observe patients and the procedure, there are still many important questions that need to be answered that are critical for scientific understanding. A major limitation of Dr. Huang’s work is the lack of long-term assessment of neurological function. It appears that patients who undergo the surgery do not have a set schedule to return for follow-up assessments. Apparently, the only data collected is obtained immediately following the surgery, therefore, it is unclear if the benefits experienced in the short-term are maintained over time. Without consistent follow-up data in all patients, few conclusions regarding the long-term benefits and safety of this surgical procedure can be made.

Additionally, when considering invasive surgical procedures in people with SCI, it is of utmost importance to understand the potential complications and risks of the procedure. The detection of adverse effects requires careful and consistent documentation. Presently, it does not appear that data related to adverse effects are being systematically collected and documented by the Chinese group. Therefore, if adverse effects such as Neuropathic Pain or tumor formation are occurring in this group of patients, these effects may not be detected and reported.

While questions remain about the benefits and potential risks of this procedure, the observation that some functional improvements occur soon after the surgery is intriguing. The reason for these early improvements is unknown. One explanation for rapid neurological improvements in some patients may be a trophic or nourishing effect. The transplanted tissue may be secreting growth factors that enhance nerve signal conduction in the synapses or along the axons. To better understand if a trophic effect is responsible for the functional improvements, researchers will need to conduct studies on the cells used for transplantation to determine if they actually release neurotrophic (nerve nourishing) factors. If this can be confirmed, it would provide a clearer rationale for their use.

What Have We Learned?
Because accurate and conclusive information concerning the surgical protocol, methods of cell processing, and the long-term safety and efficacy of this procedure is lacking, The Miami Project’s faculty do not endorse this procedure and at this time would not advise individuals to undergo this surgical transplantation strategy. While some people with SCI will view current experimental procedures abroad as their only hope, by participating they may be putting themselves at risk as well as potentially disqualifying themselves from participating in future more promising and well-designed clinical trials.

Presently, Dr. Huang’s work would not meet the standards for clinical trials set by the FDA or European regulatory agencies. His work should therefore be viewed as a series of clinical treatments rather than a clinical trial. This is a very important distinction since a clinical trial would allow for definitive conclusions while a treatment series cannot. To properly assess this treatment, a more rigorous clinical trial is required; one that includes specific outcome measures and comparisons to a control group. It would also include accurate documentation of whether adverse effects occur over the long-term.

While there may be disagreement among clinicians and researchers as to when and which promising pre-clinical strategies should be advanced to clinical trials, it is important to emphasize that scientists all over the world are coming together to develop valid clinical trial guidelines for treatments targeting SCI. ICCP supported and funded the international Clinical Trials Workshop on SCI in Vancouver that brought a varied team of researchers and clinicians together to discuss progress in clinical trials and the complexities involved in effective clinical trial design. A report of this meeting was peer-reviewed and published by J Steeves, J Fawcett, and M Tuszynski in 2004 (Spinal Cord 42: 591-597). As a result of this meeting, an international advisory panel was created to develop more detailed guidelines on how to conduct future SCI clinical trials in the most accurate and effective manner.

It is hoped that further information coming from individual clinical studies as well as continued research into this important and exciting field will stimulate well-controlled multi-center trials utilizing the appropriate safety and outcome measures. Well-designed FDA-approved clinical trials will minimize the chances of a procedure being harmful to the patient and will maximize the opportunity to document long-lasting improvements in the future. Only through a strategy such as this can evidence-based medicine be advanced, and the safest and most effective treatments be advanced to the clinic and applied.