DaCCoTa�Introduction to Clinical-Translational Research�Leaping from Bench to Bedside�

Sabha Ganai, MD, PhD, MPH, FACS, FSSO

Associate Professor of Surgery�August 5, 2022

Land Acknowledgment

Today, the University of North Dakota rests on the ancestral lands of the Pembina and Red Lake Bands of Ojibwe and the Dakota Oyate - presently existing as composite parts of the Red Lake, Turtle Mountain, White Earth Bands, and the Dakota Tribes of Minnesota and North Dakota. We acknowledge the people who resided here for generations.

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Today, NDSU and the City of Fargo rests on the traditional lands of the Oceti Sakowin (Dakota, Lakota, Nakoda) and Anishinaabe Peoples in addition to many diverse Indigenous Peoples still connected to these lands.

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We honor with gratitude Mother Earth and the Indigenous Peoples who have walked with her throughout generations. We will continue to learn how to live in unity with Mother Earth and build strong, mutually beneficial, trusting relationships with Indigenous Peoples of our region.

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We will continue to build upon our relations with the First Nations of the State of North Dakota - the Mandan, Hidatsa, and Arikara Nation, Sisseton-Wahpeton Oyate Nation, Spirit Lake Nation, Standing Rock Sioux Tribe, and Turtle Mountain Band of Chippewa Indians.

Disclosures

• Castle Biosciences (Advisory Board)
• Stryker (Educational Course)

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• There are no conflicts of interests relevant to the content of this presentation.

Funding Statement

• This conference is supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number U54GM128729. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Clinical Research

1. Patient-oriented Research

- direct interaction with human subjects

• Mechanisms of human disease
• Therapeutic Interventions
• Clinical Trials
• Development of New Technologies

2. Epidemiologic and Behavioral

Studies

3. Outcomes research and � Health Services Research

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1997 NIH Director’s Panel on Clinical Research

Translational Research (NIH)

1. Process of applying discoveries generated during research in the laboratory and in preclinical studies to the development of trials and studies in humans.
2. Research aimed at enhancing the adoption of best practices.
• Population-health / public health
• Implementation sciences

“Translation”

• The process of turning observations in the laboratory, clinic and community into interventions that improve the health of individuals and the public — from diagnostics and therapeutics to medical procedures and behavioral changes.

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• Translational science: The field of investigation focused on understanding the scientific and operational principles underlying each step of the translational process.

Lost in Translation?

• $Billions have been spent on basic science research!
• <25% of highly promising biomedical discoveries result in an RCT
• <10% of highly promising biomedical discoveries are established in clinical practice within 20 years

Translational Roadblocks

• T1 = Basic Science to Clinical Efficacy
• T2 = Clinical Efficacy to Effectiveness
• T3 = Effectiveness to Adoption and Health Improvements

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Drolet BC and Lorenzi NM. Translational Res 2011; 157: 1-5.

Clinical Trials

• Pre-clinical animal studies
• Phase I – Safety and Pharmacokinetics (n<50)
• Phase II – Efficacy (n<100s)
• short- and medium-term side-effects
• Phase III – Randomized clinical trial (n=100-1000s)
• Phase IV – Real-world Effectiveness (post-FDA monitoring)
• long-term side-effects, PROs, cost-effectiveness

Efficacy

• Results under structured experimental conditions.
• Randomization
• Blinding
• Placebo or gold-standard controls
• Inclusion/exclusion criteria
• Standardized therapy with monitored compliance
• Per protocol analysis
• Causal Inference
• Minimizes bias and confounding
• High internal validity

Effectiveness

• Results under real-world conditions, accounting for variability in response or adherence to therapy.
• Less rigid inclusions/exclusions
• Intention-to-treat analysis
• Focuses on external validity

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• Barriers – Access, cost, toxicity, timing, infrastructure
• Facilitators – health system, resources

SMART Goal Setting

Research to Clinical Practice

• Effective?
• Feasible?
• Pragmatic?
• Economical?
• Anatomically sound?
• Physiologically sound?
• Behaviorally sound?
• Competing Therapies?
• Ethical?

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Human Subjects

• Risks to subjects, and adequacy of protection from risk
• Potential benefits to subjects and others
• Data and safety monitoring plan (clinical trials)
• Inclusion of Women, Minorities and Children
• Justification of inclusions and exclusions in respect to scientific goals and research strategy of study

NIH Review

“Significance”

• Does the project address an important problem or critical barrier to progress in the field?
• Is there a strong scientific premise for the project?
• If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved?
• How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

“Overall Impact”

• Composite Score Integrating Core Review Criteria
• Significance
• Investigator
• team?
• Innovation
• “novel” enough? paradigm shift?
• Approach
• Strategy, methodology, analyses?
• Environment
• resources? support? populations?

Clinical Collaborations

• Clinicians
• Access to patient populations
• Access to human tissue
• Relevant expertise

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• Pitfalls
• Rare diseases
• Referral biases
• Time limitations
• Clinical Productivity vs. Academic Priorities
• Expectations