INTENTIONAL HUMAN DOSING STUDIES (IHDS)

1. INTENTIONAL HUMAN DOSING STUDIES (IHDS) Under what conditions can such studies be justified for non-pharmaceutical and non-nutritional substances?

2. WHY EVEN CONSIDER IHDS? • Limited utility of animal studies for certain endpoints • Limitations of observational studies in humans • Need to improve basis for extrapolation of animal data to humans However… There are serious scientific and ethical constraints on the conduct of IHDS. THUS…

3. NATIONAL RESEARCH COUNCIL, 2004 • “AN INTENTIONAL HUMAN DOSING STUDY CANNOT BE ETHICAL UNLESS IT IS…” • Justified, in advance, as necessary and scientifically appropriate to addressing an important science or policy question that can not be resolved on the basis of [other] data • Designed to yield data adequate to resolve the question • Conducted in accordance with good clinical practices, with appropriate safety monitoring AND is otherwise in conformance with contemporary ethical standards

4. TYPES OF IHDS THAT MAY HAVE BOTH SCIENTIFIC AND ETHICAL JUSTIFICATION • (IN ORDER OF POTENTIAL INCREASING RISK) • Low-Dose Pharmacokinetic studies – PB/PK model-building, etc. • Low-Dose Pharmacodynamic studies involving biomarker responses not likely to be adverse • Studies involving doses sufficient to produce clinically detectable adverse effects – • Must be clearly reversible • Are most easily justified, IF: • they involve exposures that can be encountered in normal environment • If they can be shown to have a public health (as opposed to a purely commercial) benefit

5. ETHICAL CRITERIA MUST BE SATISFIED • Scientific justification and adequate design and conduct • Acceptable balance of risks and benefits • Sufficient preclinical data to ensure safety • Equitable selection of subjects • Informed consent Etc. Federal Policy for the Protection of Human Subjects “The Common Rule”