• Canvas site: https://umich.instructure.com/courses/211772

• Grading:
  • HW (9 \(\times\) 7% = 63%)
  • Quizzes (2 \(\times\) 10% = 20%)
  • Anonymous Feedback (10%)
  • Participation in lectures, attendance (7%)

• Surveys available on Canvas after each lecture
• Immensely helpful for me
• Worthwhile for you

• I will try to post them by Friday morning
• Should be nearly identical to slides
• Not a substitute for attendance

• BA in Math, Political Science from Calvin College (Grand Rapids, MI)
• MS, PhD in Biostatistics from UM
• Early-phase cancer trials in hematology; other cancer research projects; Bayesian shrinkage methods; Combining data sources

• Your preferred name
• Your ideal job
• One diversion

• "Experiment testing a medical treatment on human subjects" (Piantadosi, 2017)
• "Prospective study comparing the effect and value of intervention(s) against a control in human beings" (Friedman, Furberg and DeMets, 2010)
• "the test of any therapeutic procedure applied to a sick person" (Hill and others, 1962)
• "A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes" (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html)

• https://www.pollev.com/philipboonst814

• text 'PHILIPBOONST814' to 22333 to join

Nuremberg Code (1947)

• Ten principles for permissible medical experiments
• Arose out of the Nuremberg Trials, including Nazi physician torture of concentration camp prisoners

https://history.nih.gov/research/downloads/nuremberg.pdf

Declaration of Helsinki (1964–2013)

• WMA developed "formal code of ethics for physicians engaged in clinical research"
• Controversy in subsequent updates; FDA stopped formally recognizing in 2008

Belmont Report (1978)

• National Research Act created a commission for basic ethical principles in human subjects research:

"identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles"

• Part of response to Tuskegee Syphilis Study

International Council for Harmonisation - Good Clinical Practice (1990–2015)

"GCP covers similar topics to the Declaration, but the focus of GCP is regulatory harmonisation, not the articulation of ethical commitments."

(Kimmelman, Weijer and Meslin, 2009)

• Guidlines are given here: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM464506.pdf

• See also (Brody, 2002)

1. Ethics

2. Study Design / Registration

3. Logistics

4. Proper Timing

Informed consent

"the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision"

The Nuremberg Code

Informed consent

• Tuskegee Syphilis Study (https://en.wikipedia.org/wiki/Tuskegee_syphilis_experiment)

Informed consent

• University of Pennsylvania Gene Therapy study (https://en.wikipedia.org/wiki/Jesse_Gelsinger)

Autonomy

We are interested in the main in the patient’s safety, not the patient’s virtue (Ashcroft et al., 1997)

Mental incapacitation, incarceration, and institutionalization limit autonomy, e.g. Jewish Chronic Disease Hospital, Brooklyn 1963: cancer cells injected into 22 elderly patients to look for immunological response

Beneficience

• No expectation of harm, including withholding medical care
• Good discussion in (Ashcroft et al., 1997)

1. Improving health outcomes (including identifying inferior treatments)
2. Decreasing cost of care delivery
3. Equitable distribution of burden-benefit ratio between study and target populations (justice)

Table 3.1 (Piantadosi, 2017)

• Societal
  • Direct and indirect benefits to the current population from past studies
  • Cost savings from new treatments for serious diseases
  • Use of appropriate risk-benefit considerations to develop new therapies
  • Proven therapies replace ineffective but seemingly low-risk ones, and not vice versa
• Individual
  • Altruism
  • Amelioration of disease or improved quality of life
  • Improved supportive care
  • Hope

Any clinical trial should be focused on answering a specific question, e.g. do subjects treated one way do better than those treated another, or what is the largest dose of a drug that may be safely administered?

1. All trials must have protocol pre-specifying all aspects of trial and how the question will be answered. This is a "living" document
2. Federally sponsored and/or regulated research are required to be approved by an "Institutional Review Board"" (IRB)
3. Trial must be actively monitored by IRB or IRB-delegated independent safety committee for as long as subjects are participating
4. If drug or device is to be marketed (and paid for by insurance), regulatory agency, i.e. FDA in the US, must ratify findings of trial
5. Many sponsors and journals require that trial be registered on https://clinicaltrials.gov/

Modern clinical trials require financial sponsorship to pay for

1. the experimental drug, device, or therapy
2. facilities / staff
3. care for subjects
4. compensation

Sponsor may be industry, government agency, non-profit organization

• In first-in-human studies, must have sufficient but not too much knowledge about safety of intervention

• In a comparison trial, must have equipoise about efficacy of treatments

Accelerated approval of eteplirsen based upon single arm 12 patient study of novel therapy Duchenne muscular dystrophy

The [FDA] had urged Sarepta, which is based in Cambridge, Mass., to do a larger study with a placebo control to better determine whether the drug worked. But the company argued that doing so would be unethical and impractical, since early hints of effectiveness meant that parents would no longer enroll their sons in a trial where they might not get the drug. Instead, Sarepta compared the data from the 12 boys in the trial to historical data from patients in Italy and Belgium who were as closely matched as possible in disease characteristics.

https://www.nytimes.com/2016/09/20/business/fda-approves-muscular-dystrophy-drug-that-patients-lobbied-for.html

https://content.iospress.com/download/journal-of-neuromuscular-diseases/jnd170272?id=journal-of-neuromuscular-diseases%2Fjnd170272

Which of these are necessary features of clinical trials?

1. Intervention applied in controlled environment

2. Involves human subjects

3. Placebo controlled

4. Attempt to minimize extraneous influences

5. Clinical response measured (as opposed to biological)

6. At least 20 subjects enrolled

7. Limited to drugs or devices

Pure Food & Drugs Act (1906)

• Drugs and medicines had to have accurate labels, and amount of eleven specific ingredients (including alcohol, heroin, cocain, and cannabis) had to be listed
• https://www.fda.gov/AboutFDA/WhatWeDo/History/Origin/ucm054819.htm

Food, Drug and Cosmetic Act (1938)

• Response to unregulated sale of a poison marketed as an antibiotic
• https://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SulfanilamideDisaster/default.htm

Kefauver-Harris Amendments (1962)

• In Europe, thalidomide, a morning-sickness alleviation, was causing severe birth defects.
• Requires proof of both safety and efficacy
• https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4227B1-02-02-FDA-Appendix1.pdf

(Piantadosi, 2017)

• In vitro studies of cell lines
• In vivo animal studies
• Many dead ends
• Simple, initial assessment of toxicity, efficacy

Translational

• Sub-therapeutic dose levels administered to humans
  • Look at pharmacokinetics (how agent is absorbed, metabolized, excreted) and pharmacodynamics (how agent impacts patient)
  • Measure biomarkers

Dose-Finding (DF)

• Small (\(<25\))

• Safety trial. Main outcome is toxicity

• Sometimes:
  • First-in-human study of agent that has completed preclinical studies
  • Study of agent for new indication
  • Study of novel combination of approved agents

Safety-Activity (SA)

• Larger (\(20-100\))
• Carry forward recommended dose from phase 1
• Seeking to establish evidence of activity
• Sometimes controlled
• Practice for phase 3

Comparative Treatment Efficacy (CTE)

• Active comparison to standard of care (randomized)
• Multi-center
• Definitive, rigorous endpoints
• Most often precede regulatory approval

Expanded Safety (ES)

• Post-approval surveillance
• Large-scale safety study, specifically for rare events

• Walk through chronology of phases 1–3
• Learn accompanying statistical methodology

• How to design and analyze clinical trials
  • Statistical ideas related to design, analysis
  • Software for simulations
  • Intersection of clinical trial ethics and statistical methodology
• Understanding controversies, challenges in clinical trials from a biostatistician's perspective