Biography

While a graduate student at The University of Texas, Austin, Dr. Lindner took extensive coursework, including practicums, in cognitive and neuropsychological assessments of children and adults. The clinical courses and practicums, as well as numerous courses on research methods, design and statistical analyses, included extensive training in blinding and other control procedures commonly used to prevent the effects of experimenter bias. While these control procedures are commonplace in clinical research, they are not a part of the standard of practice in preclinical research.

Early industry experience was obtained as a Post-doctoral Research Fellow at Bristol-Myers Squibb Pharmaceutical Research Institute, where he worked to develop and validate animal models of dementia, global ischemia and amnesia, for drug discovery and development. He spent considerable time trying to validate models of dementia using what were then clinically-approved compounds for treating dementia, the nootropics. Despite demonstrating the sensitivity and reliability of his methods, his experiments did not detect therapeutic effects with these compounds. These compounds were never approved by the FDA and have been taken off the market in Japan for lack of clinical efficacy.

Dr. Lindner later accepted an offer to move to a small biotech company, CytoTherapeutics, where he managed preclinical in vivo studies and personnel, assessing the therapeutic efficacy and safety of novel treatments in animal models. Dr. Lindner’s research failed to detect any therapeutic potential of intrathecal adrenal chromaffin cells for treatment of neuropathic pain, but the company in-licensed this technology based on numerous publications of robust efficacy in preclinical models. This treatment attracted a corporate partner, and CytoTherapeutics devoted its resources to the clinical trials that ensued. Unfortunately, consistent with the negative results produced in Dr. Lindner’s preclinical group, the results of the randomized, placebo-controlled, double-blind clinical trial failed to detect analgesic effects of intrathecal adrenal chromaffin cells and CytoTherapeutics had to close its doors.

During his 15 years in the pharmaceutical/biotech industry, Dr. Lindner has seen that carefully controlled, thorough and objective assessments of the therapeutic potential of novel treatments often suggest that novel compounds have little or no evidence of therapeutic potential, and yet many of these same novel compounds are advanced anyway, on the basis of whatever positive data can be obtained. Since assessments of potential efficacy are probabilistic, even ineffective compounds will almost always produce some evidence consistent with therapeutic potential. The current standards of practice across the industry virtually insure that, so long as novel compounds meet acceptable PK/PD criteria in terms of their molecular target, whatever evidence of therapeutic potential is available will be used to promote these novel compounds into clinical trials. This accounts in part for why so many things seem to produce therapeutic effects in preclinical models only to fail in clinical trials due to lack of efficacy.

This happens, not as the result of intentional deceit or fraud on the part of drug discovery scientists, managers and executives, but as a consequence of the effects that current corporate organizational and management processes and systems have on human judgment and decision-making. The expectations and demands now placed on drug discovery scientists, managers and executives, must be changed so that their objectives are more closely aligned with the goals of the company. So long as drug discovery personnel are rewarded for the number of compounds they advance into clinical trials, and so long as they are required to advance more and more compounds into clinical trials, with little or no regard for ultimate clinical success rates, flawed judgment and decision-making practices can be expected to continue unchanged.