Insights into Brain Health and Central Nervous System (CNS) Clinical Trials

Central Nervous System Clinical Trials, Central Nervous System
Brain Health, Michael Murphy

Brain health is one of 19 primary session topics that will be discussed at the Biotechnology Innovation Organization’s (BIO) annual conference. Neurological diseases are the leading cause of disability, according to a systematic analysis of data from 195 countries performed for the Global Burden of Disease Study 2015 (1). With 250.7 million years of healthy life lost due to death or disability caused by neurological disorders, this area of clinical research remains one of today’s most urgent challenges.

Brain Health, Michael Murphy

For perspective on brain health, we spoke with central nervous system (CNS) clinical trials expert Michael Murphy, M.D., Ph.D., Chief Medical & Scientific Officer of Worldwide Clinical Trials. With a career spanning over 25 years, Dr. Murphy’s work has emphasized the integration of medical and scientific ingenuity with operational excellence. He is board-certified in psychiatry and has a doctorate in pharmacology, with training at Tulane University, Stanford University and the Mt. Sinai School of Medicine.

The Editors of Talking Trials: How do we capture expertise among internal (sponsor) and external partners in central nervous system clinical trials to forge valuable partnerships for significant competitive advantage?

Dr. Murphy: The issue is one of process more than content, i.e., a method by which one first engages, then maximizes the contribution of individual team members, each of whom bring a different expertise to the R&D space. This is particularly important in earlier phase clinical research at the transition between preclinical and clinical investigations when an integrated approach is required to explore a compound’s potential attributes. For example, advanced therapy medicinal products, such as stem cells and gene-based therapeutics, will make significant demands upon the management of the investigational product and the clinical coordination required for both delivery and assessments.

Patient phenotypes in earlier phase clinical research additionally are significantly leveraged in order to maximize signal detection. This process accentuates elements of the patient’s presentation that are amenable to the presumptive mechanism of action of the test agent. Identification of possible linkages between nonclinical, usually in vivo, data that reflects the anticipated relevant mechanism of action and the clinical presentation of patients who will have signs and symptoms that are targetable is part of the exercise.

Finally, the structural elements of a proposed program require mastery of small-sample clinical trials both in operational as well as biostatistical dimensions. Like Archimedes, with a thousand patients one can rule the world, but this is untenable in earlier phases of development given the presumptive benefit to risk assessment and the level of investment that companies are willing to pursue. Constraining the sample; minimizing exposure to control where feasible, including assessments that are accessible but consistent with nonclinical data; and extracting signal against the background of noise is the art of translational research. Fundamentally, a team-based approach is necessary, extending across organizations to efficiently and effectively evaluate a potential therapeutic effect while maintaining the highest standards of clinical care.

Editors: What type of science compels the interest of Big Pharma investment in CNS clinical trials?

Dr. Murphy: Sentiments vary throughout the industry but customarily pivot around protecting and maximizing the intellectual property of a test agent, then subsequently maximizing value. At Worldwide, we view the environment as one that is dichotomized between small financial groups specializing in early phase funding and pharmaceutical companies seeking assets for further clinical development and marketing once proof of concept has been achieved. This perspective is based upon our client base, which tends to be small to midsize pharmaceutical and biopharmaceutical companies.

For example, small companies increasingly are the incubator of innovation, but they out-license products to experienced firms for later-stage drug development, regulatory affairs and review, and commercialization. The innovator company receives cash and or equity plus additional compensation based upon milestones or royalties. The company acquiring the asset obtains rights to develop and market a new compound and is compensated appropriately for that investment. The engagement between smaller and larger companies validates the science and the management acumen of both organizations.

In that setting, small to midsize financial investment groups may be looking for value inflection points, as much as specifics about the pharmacological attributes of a compound. Customarily, these organizations delve deeply into presumptive mechanisms of actions, and appreciating that risk during clinical development is largely a reflection of the competency of individuals designing and operationalizing the clinical program. In the experience of Worldwide, these investors impose key operational metrics at the onset of engagement, and the mantra “start on time, end on time, and stay in budget” is dominant.

Increasingly, these very experienced teams place a great deal of emphasis upon the pedigree of the management group that has generated the opportunity and the business model articulated by the company, as much as a compound’s presumptive pharmacological attributes – giving life to the axiom “one invests in management as much is in the compound.” Selecting a CRO that meshes with this corporate strategy is key and reflects upon the scientific, clinical, and operational acumen of the management. Key opinion leader sentiments, both preclinically and clinically, weigh heavily on decisions to anticipate “development to inflection points” and the ultimate addressable market. The clinical development team must demonstrate facility with this process and comfort in that environment.

In contrast, pharmaceutical companies engaged in licensing efforts appear to seek late-stage opportunities with more diligent quantitative assessments and manage risk against these metrics. In the last 10 years, this interaction appears to have moved from opportunistic to focused acquisitions, with individual companies weighing the new opportunity against their current portfolio carefully. During the acquisition process, the evaluations of data from drug discovery and clinical development within a small company are usually comprehensive and critical, requiring internal champions to advance the investment to closure. Contract Research Organizations who are a part of that process must execute clinical studies to impeccable standards and be conversational with the scientific rationale for the product mapped against the known pathophysiology of the indication.

Finally, evaluations appear to have shifted from exclusively scientific, marketing, and regulatory risk toward issues of reimbursement and IP control. This shift places greater emphasis upon strategic program design that generates data that will resonate with multiple stakeholders – a process that ensures the compound can compete on “value” as much as “novelty.”

Editors: Which emerging partnership models are paying dividends, and what could be done differently?

Dr. Murphy: Worldwide calibrates the effectiveness of a partnership in terms of dividends achieved in the process of clinical development. Broadly speaking, this implies informed, efficient programs that are capable of signal detection in early phase trials, with subsequent transition into predictable trial execution in more representative investigators and patients for late phase studies. Companion initiatives to ensure formulary placement with appropriate reimbursement at the time of market authorization have equal importance.

Worldwide begins by establishing a communication strategy that facilitates issue escalation and resolution. Functional governance committees (subsumed under the umbrella of project teams) consider commercial, quality issues, financial performance, and other aspects relevant to clinical study conduct. Subsequently, an operational steering committee evaluates outcomes each month to drive effectiveness and efficiency into the process. Quarterly executive steering committees participate in strategy discussions, given the increasingly competitive clinical development environment and the shifting sands of regulatory standards of efficacy and safety characterized by many novel indications.

Contract and payment models increasingly are important, particularly for small to midsize organizations. These models are characterized by flexibility in master service agreements; risk sharing with bonus-malus; and the creation of fixed-price, unit base, or milestone contracts.

In an ideal structure, each member of the partnership brings considerable pedigree to the table – illustrating the axiom that “the sum is always much greater than the parts.”

Further questions about CNS clinical trials?

Connect Dr. Murphy directly if you’d like to meet with him at BIO 2018 or discuss your CNS clinical trial.


  1. Collins TR. Neurologic diseases found to be the largest cause of disability worldwide. Neurology Today. 2017;17(22):1,32–35.

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