Synergy in Action


ISCTM Historical Perspectives: Milestones, Measures and Methods Series

Episode #1: History of clinical trials

Randomized clinical trials are an evolving technology that aims to provide an evidence base with which to distinguish justified belief from opinion. 
Our discussion focuses on the roots of clinical trials which date from Lind’s 17th century comparison of dietary supplements for scurvy. Over time, innovations such as random assignment, placebo control and blinding added progressive methodological rigor and became essential features of modern clinical trial design and set the stage for the first modern controlled clinical trial in 1948, streptomycin for pulmonary tuberculosis.

Episode #2: Emil Kraepelin: Foundation of modern CNS diagnosis

We discuss the impact and enduring value of Emil Kraepelin’s insights, which owe much to the methods he used to assess and classify patients. His great insights resulted from moving beyond current signs and symptoms to age of onset and course of illness. This enabled him to distinguish the three major division of psychiatric illness: dementia (Alzheimer’s disease), Mood disorder (manic-depressive insanity, and Thought disorders (dementia praecox/Schizophrenia).

Episode #3: Pseudo-Specificity in CNS Research

FDA raised concerns about pseudo-specificity in the mid-1900s. Sian Ratcliffe talks about how she coped with regulatory concerns about specificity for treatments for PTSD independent of antidepressant effects. Working with in-house statisticians and external collaborators enabled her to bring the clarity required to support a distinct indication.

Episode #4: Foundations of Modern Psychopharmacology

This cast discusses the era of modern psychopharmacology from seminal bench pharmacology research in the 1950s through to development of SSRIs. Bill Potter shares his own work on recognition of toxic metabolites and his interactions with pioneers like BB Brody, Julius Axelrod, and Arvid Carlson. His recollections of studies which began in the National Heart and Lung Institute and progressed to the NIH and industry provides prospective and insight on the co-evolution of biochemical psychopharmacology and clinical trials.

Episode #5: The Bayesian Estimation of Conditional Probability

Thomas Bayes “Essay Towards Solving a Problem in the Doctrine of Chances” (1763) was published posthumously in the Philosophical Transactions of the Royal Society. LaPlace made Bayes theory practical/applicable and that work eventually became the basis of a statistical technique, now called Bayesian estimation, for calculating the probability of the validity of a proposition on the basis of a prior estimate of its probability and new relevant evidence. Judith Jaeger guides our discussion of conditional probability and describes her novel application of Bayesian statistics using “posets” to classify and analyze data on cognitive states.

Episode #6: The Role of Organizations in Advancing Clinical Trial Methodology

Bill Potter has been a leading voice in both neuropharmacology and clinical methodology. We discuss how governmental organizations such as the NIMH’s Early Clinical Drug Evaluation Unit (ECDEU) and New Clinical Drug Evaluation Unit (NCDEU) meetings helped advance the science of clinical trial methodology necessary to advance psychopharmacology. Dr Potter traces the roots of pre-competitive collaboration and credits governmental initiatives, especially NIMH staff for convening meetings which bridged the competitive silos which often stymied the efforts of academics, industry, and regulators. Dr Potter points out an unexpected consequence: Successful clinical trials sometimes spurred success in marketing which can motivate development of me-too drugs. Notably sponsorship of meetings carrying on aspects of the mission of NCDEU has passed from NIMH to non-governmental organizations, ASCP and ISCTM.

Episode #7: The Founding of ISCTM

Dr. A. George Awad, founding President, discusses the founders concerns and objectives at the inception of ISCTM. He stresses the important of following democratic principles, assuring participation of multiple stakeholders and assuring the organization guard against being captured by special interests and recognition from the beginning that the society’s work would be progressive but not too slow and never finished. Dr. Awad recommends being bold and not leaving innovations to the private sector only.

Episode #8: Developing Innovative Scales and Study Design

Important clinical questions often go unanswered due to the lack of methodological tools needed to address them. Over Dr. Larry Alphs’ career, he has repeatedly responded to this daunting problem by developing the tools and establishing the psychometrics necessary to bring high-quality data to the discussion of burning questions related to psychosis, suicidality, negative symptoms and the use of clozapine. He is currently working on an improved approach to CGI rating based on capturing more of the patient’s voice using a standardized interview.

Episode #9: Development of Legacy Rating Scales

Dr. Schooler shares her perspective on the development of the first generation of scales such as the CGI and the BPRS. She notes Gerald Klerman’s work on the CGI is an example of a successful scale that came into widespread use with no data behind it. While acknowledging these and other legacy scales as “lead” rather than “gold” standards she notes that they have facilitated differentiation of efficacious treatment from placebo and can be regarded as having divergent validity. Dr Schooler also highlighted the distinction between scale content and the quality of the clinical interview.

Episode #10: Approaches to Precision Medicine

How do we know what the right choice is for a given patient? As a drug developer for over 30 years and as a founder of ISCTM, Dr Garibaldi has endeavored to find methods necessary to bring a more Personalized Treatment for patients with CNS diseases. Moving the field away from development of treatments for all-comers, requires a will to do better, a good understanding of the biology of disorders, and managing the fears associated with adopting a different business model. Ultimately, he reminds us that our ability to find new therapeutics requires creating novel tools and listening to what is important to patients. As a founder, George stressed ISCTM’s tradition of sharing and learning from negative results.

Episode #11: Desperate clinical need spurs the search for better treatments

Our clinical practices constantly remind us of the need for better therapeutics. Dr. Atul Mahableshwarkar’s efforts to meet the needs of a chronically manic patient reminds us of the classic manner in which many treatments have come into use. The desire to help this patient caused Dr. Mahableshwarkar to consult experts about off-label use of available agents. He was encouraged by Fred Quitkin’s reported use of high-dose fluphenazine and eventually presented a poster with results from his case series on IV administration of antipsychotics medication. When this kind of approach to clinical innovation is advanced in a thoughtful, responsible manner and the results shared, it can encourage a fully powered RTC and might even lead to regulatory approval.

Episode #12: Advances in the ISCTM Era

Dr. Carla Canuso reflects on progress made over the 20 years since ISCTM’s founding. She highlights recent approvals of novel treatments targeting Alzheimer’s disease as well as rapidly acting antidepressant therapies. These developments have been facilitated by an ecosystem of methodologies for selecting the right patients and measuring potential benefits. The inclusion of patients at risk for suicide in clinical trials has proven to be safe. Digital measures such as speech analysis and facial expression have promise for advancing phenotyping as well as outcome measurement. She is hopeful that psychedelics will lead to therapeutics that can be part of a precision medicine approach and be can available to patients in an equitable manner. Dr Canuso notes the importance of fostering the next generation of ISCTM leaders and offers some sage career advice.

*The content of each podcast represents individual opinions and not that of the institution, agency, company affiliation of participants or ISCTM.