Preclinical And Clinical Testing Of New Therapies

Published: April 1, 2004
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Researchers have identified a wide variety of potential therapies for spinal cord injury. To efficiently evaluate these therapies, however, investigators need to carry out well-designed preclinical and clinical trials that will reveal the benefits and drawbacks of each strategy.

Preclinical Testing

Each of the factors contributing to secondary damage presents opportunities for therapeutic intervention. Among these are neuroprotective drugs that might be combined with or even replace methylprednisolone. These drugs include antioxidants, calcium blockers, and drugs that control excitotoxicity. Drugs that enhance Axon signaling, such as 4-aminopyridine, form another category of potential therapies. Drugs designed to promote Regeneration by capitalizing on newfound knowledge about guidance molecules, trophic factors, and growth-inhibiting substances make up a third class. Other kinds of interventions, such as transplantation, Peripheral nerve grafts, Hypothermia (cooling), and combinations of therapies also show promise in regrowing spinal cord tracts and promoting recovery of function.

While all of these potential therapies appear promising, not all are at the same stage of development. Some neuroprotective drugs, including certain antioxidants and antiexcitotoxic drugs, are already being tested in humans for other purposes. Recently discovered molecules, such as those that control axon guidance, will require a great deal of basic and applied research before they can be developed into useful drugs. With so many potential therapies for spinal cord injury, investigators must carry out efficient preclinical tests to ensure that the most effective therapies proceed as rapidly as possible to clinical trials and, ultimately, to proven safety and usefulness. New animal models and better ways to monitor the success of treatments are essential to this process.

Clinical Trials

Randomized, controlled human clinical trials are the “gold standard” for revealing the benefits and drawbacks of a therapy. However, such trials are usually very expensive, and they are unlikely to yield useful results without adequate preclinical study. Clinical trials that do not yield clear answers are an enormous waste of resources. Physicians conducting clinical trials also must ensure that they do no harm to the patients in their study. The Belmont report of 1978, which guides human medical research ethics in the United States, reaffirmed that the rights of individuals participating in clinical trials must take precedence over the potential benefit to society as a whole. This restricts randomized trials to those therapies that have shown potential usefulness in systematic preclinical studies. Only with good preclinical data can researchers predict which treatment regimens might be useful and whether new therapies can be combined with standard therapy.

A clinical trial involves hundreds of components, all of which are important to its success. Seven components essential to a good trial include the rationale, or reasons the trial should be carried out; the design, which should compare different therapies (or therapy and placebo); the inclusion and exclusion criteria determining which patients should enter the trial; the use of randomization or bias control measures; the number of patients to be tested in order to produce clear results; carefully defined outcome events (that is, measures of how well patients recover); and the analysis of the data. For a clinical trial to be justified, physicians should ideally be in a state of “equipoise” in which they are not sure whether a treatment works or not. If they are certain a treatment works, it is unethical to withhold it from patients. Yet, without a reasonable expectation that patients will benefit, it is difficult to justify the risks.

There are three phases of systematic clinical testing in the United States. Phase I trials determine the criteria for safe and effective use of the therapy. These trials usually involve small numbers of patients and test the therapy in a range of doses. It is important to make this phase as extensive as necessary to eliminate unknown factors that can confound the results of later, more expensive phase II and III trials. Phase II trials establish whether the therapy, at safe and optimal doses, works for the disease. These trials should also help define factors such as which patients might benefit from the therapy. Finally, Phase III trials compare the new therapies to other therapies and/or to placebo. These trials are usually very large, as they must involve enough patients to reasonably show the drug’s benefits and potential adverse reactions. A company must obtain phase III data before applying for FDA approval of a new drug.

The NASCIS trial that established the benefits of methylprednisolone is a model of an efficient phase III clinical trial for spinal cord therapy. This efficiency resulted from the trial’s design, which used one placebo control group compared to two therapies: methylprednisolone and naloxone. This design made optimal use of resources, with a minimal number of patients given placebo. The NASCIS II trial also revealed that most patients improve somewhat, regardless of whether or not they receive methylprednisolone — knowledge that is important for designing future clinical studies. Because methylprednisolone reduces Disability, clinical trials can no longer use placebo controls because it would be unethical to withhold the drug from patients. Instead, new therapies must be compared to methylprednisolone, the best standard therapy.

A special problem in testing therapies for spinal cord injury is that most studies thus far have found combination therapies to be the most effective strategies. The need to test several therapies together complicates and can confound traditional clinical trial strategies. Investigators must find effective ways to deal with this problem to test many of the promising therapies for spinal cord injury.

Conclusion

Researchers have identified a wide variety of potential therapies for spinal cord injury. To efficiently evaluate these therapies, however, investigators need to carry out well-designed, preclinical and clinical studies. Key elements include cooperation between multiple independent research centers, strategic trial design, and well-defined criteria for selecting potential therapies to be tested. The success of the methylprednisolone trial and advances from the basic science realm have stimulated the pace of research on treating spinal cord injury. With properly designed trials, potential therapies can be efficiently tested so they can help people with spinal cord injuries as soon as possible.