Clinical trial methods course in neurology

Collaborations among various players, including funding agencies, academic centers, and pharmaceutical companies, have helped in financial support and meeting the higher bars for regulatory compliance of clinical trials Patient advocacy groups and practicing neurologists also play an important role.

Role of the internet in clinical trials. The widespread use of the internet in the general population facilitates rapid recruitment of participants as well as instant collection of data in a secure and confidential manner.

Internet-based trial method is most suitable when the intervention is safe, the medical disorder can be confirmed by remote means, and the outcome measures can be applied by using electronically transmissible technologies. Within these parameters, the internet trial method offers opportunities for studying treatments quickly and efficiently. United States Government database of clinical trials. Registered clinical trials are openly accessible at www. This is the largest registry of clinical trials with plans, design, and contact information as well as current status.

As of March , it listed , trials with locations in all 50 states and in countries. Data are self-reported by trial sponsors or investigators worldwide through a web-based system. The registry was expanded in to include a database for reporting summary results. A publication analyzed data that were publicly available during a period of 1 year ending September and pointed out some of the limitations of the available information Although the database enables access to study results not otherwise available and allows examination of clinical trials, its ultimate usefulness depends on the submission of accurate and informative data by the investigators.

Drawbacks and limitations of clinical trials. Although randomized controlled trials have become the standard technique for changing diagnostic or therapeutic methods, the use of this method poses several problems. The results of well-conducted clinical trials are not being translated into practice for several reasons that include ignorance of patients as well as physicians, uncertainty as to the applicability of trials to individual patients, and financial considerations.

Some of the issues are as follows:. Disparity between the results of animal experiments and human clinical trials. This is well recognized because of failure of animal models to adequately mimic human diseases. An example is that of a corticosteroid, which showed benefit in animal models that could not be proven in clinical trials of human patients with head injury.

Significance of results for clinical practice. Randomized trials may lack relevance to clinical practice. The enrolled subjects are highly selected and unrepresentative of the general population affected by the condition under consideration.

Randomized clinical trials provide high-quality evidence about the benefits and harm of medical interventions but may not answer clinicians' questions about a specific treatment in the real-world practice of medicine. To balance this limitation, practical or pragmatic trials have been suggested that compare 2 or more medical interventions that are directly relevant to clinical care, even though they may lack the statistical power Outdated results.

Prolonged periods of planning, conduct, and analysis of clinical trials limits their ability to keep pace with advances in products and treatments that develop after initiation of trials. Surrogate biomarkers. High costs and time limitations of clinical trials may lead to reliance on surrogate biomarkers that may not adequately represent outcome of interest.

Multiplicity in clinical trials. This problem usually occurs in clinical trials with several objectives based on the evaluation of multiple end points or multiple dose-control comparisons, and many patient populations. Multiple comparisons in a clinical trial increases the likelihood that a chance association would appear causal.

Statistical strategies such as multiplicity adjustments based on clinical trial simulations are available to address various sources of multiplicity and the probability of an erroneous conclusion that the experimental treatment is effective Geographical variations of results of clinical trials.

Although most variations in results among countries are likely due to chance, they may also be due to differences among populations in the benefits of an intervention or in adverse reactions. If a randomized clinical trial shows marked variations in results among countries, additional supporting evidence should be sought to determine whether the observed results are real, a variation in methodology and analysis of trial, or simply due to chance Data from the Matrix and Platinum Science Trial show that endovascular aneurysm retreatment occurs with different frequency and at different times in different regions of the world, but clinical outcomes are similar When retreatment is a primary endpoint, it may or may not take place within the defined study follow-up period.

Differences in practice patterns between various countries must be accounted for when comparing outcomes between different trials. Ethical issues. Physicians participating in these trials are required to modify their commitment to their individual patients. The physician-patient relation of mutual confidence may be disturbed as the patient becomes the research subject for the interest of humanity in general. Protection of subjects in clinical trials. Several mechanisms have been instituted in the United States to protect the subjects in clinical trials, eg, informed consent and institutional review boards.

However, there has been no new regulation since , although the number of clinical trials and innovative therapies has increased considerably. Several changes and suggested improvements in oversight of clinical trials and informed consent are currently under discussion. Legislation designed to protect clinical trial study participants, close dangerous loopholes, and bring certainty and public transparency to life-saving research studies has been introduced in the United States House of Representatives.

The Trial and Experimental Studies Transparency TEST Act of updates and expands the United States Government clinical trial registry data bank with stronger reporting requirements and requires that all foreign clinical studies meet the same registration and reporting requirements as domestic trials if they are used to support an application to market a product in the United States.

Eighty percent of the drugs entering the market in were clinically tested overseas, and a growing number of device trials are also being outsourced to other countries.

Many of these trials are not required to be registered with the clinical trials database. Institutional review board IRB delays. Start-up periods for multicenter clinical trials can be delayed because of multiple IRB reviews of the same protocol.

It is expected that use of this central IRB will decrease clinical trial start-up time Significance of information. Licensing trials may provide insufficient information on which to base clinical decisions particularly if the sample size is small, difference in effect is not marked, or adverse effects are common.

Limitations of intention-to-treat analysis. Intention-to-treat maintains treatment groups that are similar except for random variation. The primary goal of efficacy trials is to determine if a treatment works under ideal circumstances, which requires minimization of factors that can alter a treatment effect. Therefore, statistical analyses in efficacy trials frequently exclude patients that deviate from the protocol.

In clinical practice, however, factors such as compliance, adverse events, drug regimens, comorbidities, concomitant treatments, or costs all can alter efficacy. An analysis limited to subjects that complete the trial would not take these factors adequately into account.

The object of the randomized trial is to remove bias. This is only applicable in a situation where the physician has an opinion about the treatment.

Randomization is not applicable in the trial of a new, untested treatment for which a physician has not yet formed an opinion. This is difficult to maintain in certain conditions such as cancer and AIDS, in which the side effects of the treatment are evident.

This has most commonly been reported in the evaluation of results and, if undetected, may cause promotion of an ineffective and potentially harmful treatment. Adverse drug reactions. The collection of adverse event data is an important component of clinical trials, but it is controversial whether solicited or unsolicited collection methods are better at distinguishing drug effects from the effects of placebo.

Although solicitation produces higher reporting rates, spontaneous reporting provides larger drug-placebo differences. Rare adverse drug reactions with a frequency of occurrence less than may not be detected during clinical trials and may become a cause for concern some years after the introduction of the drug. Identification of rare but serious adverse effects of treatment often manifest only during postmarketing surveillance and long-term follow-up Seeding trials.

These are like clinical trials conducted by pharmaceutical companies. The purpose of seeding trials is not to advance research, but to make physicians familiar with a new drug for facilitating marketing. Statistical manipulation. In some types of data analysis, such as performance several subgroup analyses, data can be manipulated to give the result needed to support a hypothesis.

Using the definition of a significant p value as 0. If numerous statistical tests are used in situations where there is no real difference between 2 groups, some tests will give statistically significant results by chance. Furthermore, the number of tests can be increased to a point that a false positive result is obtained. Difficulties in demonstrating the slowing of progression of a disease.

Some interventions for chronic neurodegenerative diseases may not produce any improvement but merely delay the progression of the disease to clinically important end points. These require a long-term follow-up and the results are difficult to evaluate. A surrogate outcome measure such as cessation of formation of new lesions on MRI in multiple sclerosis with campath-1 is a sensitive measure of the biological effect of the treatment but a poor index of the clinical effect.

Publication of clinical trial data. In an industry-sponsored trial, the investigators may not have full access to the data or may not be allowed to reveal it in writing or presentations at conferences.

In , the International Committee of Medical Journal Editors proposed that as a condition of consideration for publication of a clinical trial report in its member journals, authors are required to share with others the de-identified individual patient data underlying the results presented in the article including tables, figures, and appendices or supplementary material no later than 6 months after publication.

Sharing of data generated by interventional clinical trials is considered to be an ethical obligation as participants have put themselves at risk Apart from improving the understanding of clinical trial results, this information will help avoidance of mistakes and repetitions in further clinical trials. Missing data. This is a serious problem that limits the drawing of any conclusions from clinical trials. A special report by members of the panel has analyzed the causes of missing data in clinical trials and offered suggestions to remedy it One of the causes is patient dropout from clinical trials.

It is important to design clinical trials carefully as there is no satisfactory way to fix this problem at the data analysis stage. Some analyses apply naive methods to adjust for missing data and make unjustified assumptions. The report concluded that the best approach is to prevent missing data by designing and carrying out the trial in a way that limits the problem. Nonreporting of negative results.

The published results in the medical journals deal mostly with positive outcomes. The negative results are published rarely. An attempt was made to remedy this by public registration of all clinical trials to ensure that information about all clinical trials undertaken would be available regardless of whether their results were positive or negative.

The FDA Amendments Act of required that new clinical trials conducted in the United States post summaries of their results at www. The first open audit of the process, covering all clinical trials registered in , found that 4 out of 5 trials covered by the legislation had ignored these reporting requirements No fine was levied. Another study found that despite ethical and legal obligations to disclose findings promptly, most clinical trials that were highly likely to be subject to the FDA Amendments Act did not report results to ClinicalTrials.

Compliance was higher in industry-funded trials than in trials funded by the NIH or other government or academic institutions. These findings provide a rationale for policy reforms aimed at promoting transparency, ethics, and accountability in clinical research.

A proposed legislation in the United States House of Representatives called the Trial and Experimental Studies Transparency TEST Act of would require that results from all clinical trials be posted to the database within a year of the trial's end Also, the trials would need to be registered prior to enrolling any participants, and the NIH as well as the FDA would have to report to Congress on new database standards.

Systematic posting of full protocols and statistical analysis plans, which is now required at www. Nevertheless, several opportunities for analyzing the data more systematically as a basis for key decisions by investigators, funders, institutional review boards, and others remain unexploited.

In a follow-up to this statement, the authors endeavor to support researchers and institutions in maximizing the value of their efforts and those of the research participants as well as the overall value of the ClinicalTrials.

Sharing of data from clinical trial s. It is generally recognized that sharing of data from clinical trials is useful, but some of the issues under discussion currently are the amount and format of data to be stored and shared as well as how to protect the privacy of the trial participants. Merely depositing the data somewhere is not enough, but it should be possible for others to find and reanalyze the data. One concern is that it would be difficult to get someone to enter the clinical trial field and spend years collecting data if others could simply obtain the finished data effortlessly.

A more important concern is that secondary analysis without involvement of the primary investigators might yield erroneous results. To address these concerns, it may be better to define a core set of data that can be freely accessed from all trials and to allow sharing of the more complex data for specific diseases only through collaborations, which are already an accepted practice in global health care A workshop on sharing data from clinical trials made the following observations and suggestions 42 :.

Reporting of randomized controlled tria ls. For accurate assessment of a trial, the published report should contain complete, clear, and transparent information on its methods and findings, but this is not always available. Because of the high rate of unpublished clinical trials, one needs to search www. According to the FDA Amendments Act of and the NIH policy, all parties responsible for clinical trials need to ensure that their systems as well as procedures promote complete and timely clinical trial reporting; summary results information must be posted publicly on the following website: ClinicalTrials.

Publication of clinical trial results in nonindexed journals. Such sources need to be searched manually to obtain a comprehensive controlled trials register. Placebo-controlled studies. It is a general belief that placebo interventions induce powerful effects.

Several randomized trials that compared placebo-treated to untreated patients found no evidence that effect of placebo exceeds that of active therapeutic intervention.

The ethics of performing placebo-controlled studies of new medications in neurologic disorders where treatment is already available is questionable. Nevertheless, there are ethical reasons that justify study designs that use placebo, provided that the rights and safety of participants are adequately safeguarded. If placebo effect interferes with evaluation of results of clinical trials, particularly those of antidepressants, sequential parallel comparison design can enrich the study population to be less responsive to the placebo by removing placebo responders between the first and second phases of a trial The final summary statistic in this type of trial is then based on a weighted combination of effects from the 2 stages.

Furthermore, adaptive designs in clinical trials were found to recover unnecessary resources spent in the traditional sequential parallel comparison design with overestimated initial sample sizes and provide moderate gains in power. Nocebo effect.

This term is used when an otherwise harmless drug produces effects that are perceived to be harmful by a subject and lead to treatment discontinuation. Nocebo effects are driven by expectancy and contribute to variations of outcome in both placebo and active treatment arms of clinical trials.

A study that analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate treatment-emergent adverse events in placebo arms found that they were commonly due to nocebo effect with no evidence to associate them with adverse clinical outcomes Evaluation of nonpharmacological therapies. The randomized placebo-controlled trial was developed to test new drugs. It may lead to negative results in nonpharmacological therapies such as acupuncture.

Limitations of clinical trials for personalized medicine. Average treatment effects shown by clinical trials cannot be reliably applied to an individual patient or even patient subgroups, leading to treatment of patients for whom the treatment is not effective and may be harmful. Better stratification of patients by genotyping, disease stage, or baseline risk of relevant outcomes is more likely to identify those who will benefit and those who will be harmed by an intervention, leading to the development of appropriate diagnostic and treatment thresholds, which will reduce overdiagnosis as well as overtreatment This approach is in line with personalized medicine.

P values. Physicians are not always taught how to interpret clinical trial results and detect flaws. Many would accept the results of a randomized, double-blind, placebo-controlled study in which p values are quoted as proof that 2 treatments led to different results. However, p values convey meaningful information only if they are put into a clinical context. A p value of 0. A confidence interval usually consists of 2 values, an upper and a lower limit, attached to a level of probability.

Confidence intervals can be used to indicate the clinical significance of a p value. This is important because a small clinical difference may be statistically significant because of large sample size, whereas a clinically important effect may appear statistically insignificant if the number of subjects studied is too small. The use of confidence levels as well as the plotting of clinical significance curves and risk-benefit contours has been proposed to provide degrees of probability of both the potential benefit of treatment and the risk due to toxicity These should be incorporated in reports of clinical trials to provide clinicians with a mechanism of translating the results of studies into treatment for individual patients and to facilitate the clinical decision-making process.

Intention-to-treat analysis. Such an analysis is the most rigorous that can be performed on clinical trial data and includes all the patients who were randomized to a study.

If the number of patients analyzed is less than the number randomized such as in subgroup analyses , there can be a serious bias as the randomization ensures that the groups are similar in terms of patient characteristics.

Errors occur when one incorrectly evaluates the difference in outcomes between the placebo and the treatment groups. Type 1 error false-positive signal is the erroneous conclusion of difference when in fact no difference exists. The probability of a type 1 error alpha is usually set at 0. Type 2 error false-negative result occurs when a false conclusion is made that the 2 outcomes are not significantly different when they are.

A type 2 error can result from erroneously failing to reject the null hypothesis. The probability of a type 2 error beta decreases as the sample gets larger or the statistical power 1-beta increases. With knowledge of clinical trial results, a physician can make a more informed decision about appropriate treatment.

Some well-executed clinical trials, the results of which have been published in high profile medical journals, have resulted in significant changes in medical practice. This impact, though, is not consistent because the factors that influence the patterns of practice are complex. Physicians do not necessarily change their prescribing habits following the introduction of new drugs, despite the reported success of clinical trials, especially in cases for which several drugs are available, as in epilepsy.

More cautious physicians tend to observe the drugs for longer periods in the postmarketing phase and review the results of meta-analyses before forming opinions about adopting a new drug in their practice. Explanatory versus pragmatic clinical trials.

Although explanatory trials confirm a physiological or clinical hypothesis, pragmatic trials form the basis of a decision by providing evidence for adoption of the intervention into the real world clinical practice. Very few trials can be fully pragmatic, and some novel interventions can have a significant impact on clinical practice without being pragmatic. A practical approach to pragmatism is to adopt the features of pragmatic trials whenever feasible without compromising trial quality and the ability to answer the clinical question of interest Randomized clinical trials are the best evidence considered by consensus conferences that also determine the practical importance of the trials.

Common features of consensus conferences and clinical trials are an impersonal nature and objectivity. Consensus is the opinion and recommendations of a group, not an individual. Metaanalysis of clinical trials. Some problems with the translation of clinical trials into real life practice are revealed by metaanalysis of randomized, placebo-controlled trials to determine the efficacy and adverse effects of atypical antipsychotics for the management of agitation, aggression, delusions, and hallucinations in patients with Alzheimer disease.

Although small statistical effect on symptom rating scales support the evidence for the efficacy of atypical antipsychotics, it is limited by incomplete reporting, dropouts, and adverse effects. It leaves the decision up to the physician to prescribe atypical antipsychotics within the context of medical need and the efficacy and safety of alternatives.

Standard systematic reviews and meta-analyses rely on published aggregate data to provide robust clinical conclusions. A study found that hazard ratios from published aggregate data were most likely to agree with those from individual participant data when the information size was large Based on these findings, Tierney and colleagues provide guidance for determining systematically when standard meta-analysis of published aggregate data will likely generate robust clinical conclusions and when the individual participant data approach will add considerable value.

Clinical trials and evidence-based medicine. The practice of evidence-based medicine is the most judicious use of currently available medical evidence. It involves the integration of individual clinical expertise with the best external evidence from clinical trials and systematic reviews such as the Cochrane Collaboration.

The Cochrane Collaboration is a systematic review also called overview or metaanalysis of randomized trials and has 2 main components: 1 a systematic search for all relevant randomized clinical trials published or unpublished , and 2 the use of appropriate statistical methods to derive the best estimate of treatment effect. Industry sponsored reviews of drugs are less transparent, have fewer reservations about methodological limitations of the included trials, and have more favorable conclusions than the corresponding Cochrane reviews.

Some neurologic disorders are included in the Cochrane Database of Systematic Reviews. In relation to evidence-based medicine, emphasis is placed on the design of double-blinded randomized controlled trials, statistical power, and the level of significance.

Other significant aspects of trial quality—biological plausibility, reproducibility, and generalizability—that affect the validity of the findings should also be considered. In some instances, recommendations for treatment need to be made in the absence of definitive clinical trial data.

Limitations of recommendations of this type should be taken into consideration and treatment decisions can be based on a combination of careful clinical assessment of the patient and an objective evaluation of whatever clinical trial data are available. Instruments for measurement of outcome in management of neurologic disease with disability should be evaluated for clinical usefulness as well as scientific soundness.

Few instruments for measuring neurologic outcomes have been evaluated comprehensively. Many of the commonly used instruments, such as the Expanded Disability Status Scale, provide limited data about their scientific properties. The Barthel Index, which is a benchmark for measurement of disability, has incomplete psychometric data. Brain imaging provides objective documentation of several neurologic disorders.

Several brain mapping techniques are now available to enable the clinician to monitor disease progression and therapeutic effects of a drug in either the routine clinical setting or experimental clinical trials. Recruiting patients for clinical trials in neurology. Recruiting patients for clinical research studies in neurology is challenging. Distance, disability, and the need for frequent in-person visits are major barriers to participation in clinical trials.

Home visits may enable greater participation in clinical trials, but this is not practical in geographically diverse populations or for persons residing in nursing homes or not located near research centers. The Michael J Fox Foundation has a Fox Trial Finder online registry that identifies individuals with and without Parkinson disease who are willing to participate in future research studies. Despite some limitations, this approach may facilitate future clinical trial participation.

Because stroke is a complex condition with several clinical variables that compound care and influence outcome, few therapies will produce such a dramatic response that the medical community will accept the benefits of a treatment based solely on anecdotal, uncontrolled reports. Trial methodology in stroke can be problematic. Obtaining agreement on trial design, eligibility criteria, primary efficacy parameters, neurologic scales, and study sample size is not always easy to accomplish.

Application of proposed treatments in appropriate animal models is a prerequisite for interventional clinical trials in humans. Controlled clinical trials are expensive, and such projects should not be launched unless strong evidence from experimental and pilot clinical studies shows that there is reasonable chance for success.

Data from experimental studies should be clearly positive. The pharmacological properties of the drug should be known with a rational basis for the desired effect. Issues of safety and efficacy are best addressed by pilot clinical studies. In stroke clinical trials, the data safety and monitoring committee provides recommendations to the steering committee of the trial on whether to continue or to stop patient recruitment and on protocol amendments that may be necessary to protect the safety of the patients.

Because the stroke population is heterogeneous, treatment effect may be biased even in balanced randomized trials. Risk adjustment statistically addresses some of the heterogeneity and can reduce bias in the treatment effect estimate.

Estimation of number needed to treat in parallel design clinical trials is a useful measure of a treatment's clinical benefit or harm. Several randomized clinical trials have evaluated the long-term use of antiplatelet drugs in reducing the risk of new vascular events in patients with ischemic stroke and the results form the basis of various guidelines for the management of such patients in clinical practice.

A review of data from the Netherlands Stroke Survey showed that patients with ischemic stroke enrolled in randomized clinical trials are only partially representative of patients in clinical practice and suggested that less restrictive enrollment criteria could improve the selection of patients The information overlap that is misclassified in healthcare data from electronic medical records can be used to calibrate stroke risk factor management This enables more accurate reweighting of the trial findings for application to the target population.

For example, if in the overlapped part of the target population, 1 of 3 individuals have false-positive results and 2 of 3 have false-negative results, the same proportion of corrections is expected in the whole target population when measurements are calibrated, ie, 8 of 24 are false-positive, meaning no transient ischemic attack, and 14 of 21 are false negative-meaning transient ischemic attack.

The traditional approach to acute stroke clinical trial design has been problematic on several levels. There is a need to validate surrogate biomarkers, particularly brain imaging, and designs need to be developed for combination therapies of stroke.

Evaluation of restorative and regenerative therapies for stroke requires functional imaging such as fMRI and PET for assessment. Functional imaging for measuring tissue function introduces some complexities not encountered in structural imaging as the effectiveness of these interventions is influenced by factors such as activity However, imaging measures may also serve as a biomarker of treatment effect, which might secondarily guide restorative trial design. The trial was halted because of the results of a prespecified interim analysis that suggested high probability of success.

A discussion of the results assured that the positive outcome of the trial was not due to complex statistical maneuvering or the use of an unconventional end point that involved a utility-weighted modification of the usual Rankin scale Even with the use of basic parametric statistics and an end point that is typically used in stroke trials, the DAWN trial had strikingly positive results.

The trial required evidence of a small infarct core on diffusion-weighted imaging and no evidence of an infarct on fluid-attenuation inversion recovery imaging; this combination of findings indicates that the onset of stroke symptoms which were observed at awakening most likely occurred less than 4 hours earlier.

Multiple sclerosis. Signs and symptoms of multiple sclerosis are subjective and difficult to measure. Fatigue and numbness can only be assessed by self-reports because objective neurologic examination cannot measure this experience.

Current clinical research and outcomes rely heavily on outcome assessment that is influenced by ambulation. These parameters may be insensitive to some therapeutic measures. Possible adverse reactions to drugs produce another complicating factor. The unpredictable natural history of multiple sclerosis is a problem concerning evaluating the results of clinical trials.

Patients are selected for clinical trials of multiple sclerosis based on criteria designed to identify patients with high event or treatment failure rates. The power of the clinical trial is determined by the event rate in the control group on a short-term basis. The aim of the treatment, however, is modification of the long-term outcome such as time to reach the Expanded Disability Status Scale. Baseline Expanded Disability Status Scale and the duration of the disease should be taken into consideration in designing clinical trials of progressive multiple sclerosis.

A phase 2b placebo-controlled study of imilecleucel-T, an autologous T-cell immunotherapy for multiple sclerosis, showed no statistically significant clinical or radiological benefit, but a prospective analysis of subjects with more active disease favored immunotherapy in terms of annualized relapse rate An analysis also found a possible beneficial effect of prior disease-modifying treatment, which might explain the lower relapse rate in the placebo group and suggests limitation of future trials to treatment-naive patients.

The placebo group has other problems as well. In some studies, placebo groups have fared better than expected. Determination of the magnitude of placebo effect in multiple sclerosis patients would require randomization of patients, with 1 group receiving no therapy and another group receiving an inactive placebo.

The placebo effect is usually short-lived and does not produce a significant change in disability scales. This content does not have an Arabic version. Sections for Neurology Department home Sections Request an appointment.

Below are current clinical trials. Request an Appointment at Mayo Clinic. Share on: Facebook Twitter. Mayo Clinic, Rochester, Minn. Doximity Residency Navigator Neurology. Doximity, Inc. Accessed Dec. News Best Hospitals Mike Boland. Enterprise analytics. March 28, Leading NIH's Lewy body dementia initiative. Neurosciences Update. Mayo Clinic. Find an epilepsy center. National Association of Epilepsy Centers. Emergency stroke center locations.

National Stroke Association. The ALS Association certified centers and clinics. Good design and conduct of clinical trials can provide the necessary knowledge for the generation of definitive answers about the effectiveness of new therapeutic approaches.

In contrast, poorly designed or administered trials may provide misleading results, subject patients to unnecessary risk, waste considerable resources, and potentially diminish the interest of the research community and the public in the clinical trials enterprise.

The need for more medically-trained researchers with appropriate methodological training has been identified as an important limiting factor in the scope and quality of clinical research overall and specifically in neurology.

It is anticipated that this annual course will yield a group of talented, dedicated neurology researchers who will consequently be in a position to obtain funding for their own high quality clinical research.

If the program is successful, it is anticipated that students will return to their academic departments where they will take a prominent role in advancing local research priorities in neurology.