1 EPA Human Studies Review Board Chair's Comments June 27, 2006 Celia B. Fisher, Ph. D.

Fordham University Chair HSRB 2 Responsibilities ° The Human Studies Review Board shall comment on the scientific and ethical aspects of research proposals and reports of completed research with human subjects submitted by EPA for its review and, on request, advise EPA on ways to strengthen its programs for protection of human subjects of research. 26.1603 ( b) 3 Charter 3. Objectives and Scope of Activities ° HSRB will provide advice, information and recommendations on issues related to scientific and ethical aspects of human subjects research.

° The major objectives are to provide advice and recommendations on:

  Research Proposals and Protocols   Reports of completed research with human subjects; and   How to strengthen EPA's programs for protection of human subjects of research. 4 Board Process Board members assigned as primary and secondary discussants will begin each board discussion 1. Answer questions posed by EPA 2. If applicable raise significant issues that were not posed by EPA 5 Board Process Science Evaluation followed by Ethics Evaluation Rationale:

° To be of benefit a study must be scientifically valid ( Nuremberg Code)

° Risk benefit ratio can only be calculated if there is benefit 6 Scientific Aspects of Research ° Did the research design and implementation meet scientific standards?

° Do the data generated by the protocol have implications for the Agency's Weight of the Evidence ( WOE) determination and when applicable aspects of the risk assessment. 7 Scientific Standards for Human Dosing Studies 8 Justification  Is scientific question worthwhile?

 Are human subjects necessary to answer the question?

 Is potential risk serious or irreversible? 9 Dose Selection  Sufficient to test the question? ( single dose in most cases is not sufficient)

 Based on appropriate data ( e. g. preclinical;

previous studies) 10 Endpoint Selection  Consistent with aim of the study?

 Appropriate to answer question about human responses ( e. g., sensitivity, accuracy, validity,

replicability)?

 Measured accurately and reliably with good quality assurance? 11 Participants  Characteristics generalizable to question asked?

 Appropriate inclusion/ exclusion criteria? 12 Method  Is sample size sufficient?

 Is selection of control and experimental groups appropriate?

 Is the staging of dose intervals, dose amounts,

and type of exposure sufficient to answer the question?

 Is there quality assurance for observations,

instruments and data? 13 Statistical Analyses  Can data be statistically analyzed?

 Is the statistical method appropriate to answer the question? 14 SINGLE DOSE LEVEL STUDIES 15 Single Dose Level Study Definition ° Individual study that uses one dose level irrespective of the number of subjects, frequency of dosing or inclusion of a control or placebo. 16 I. In general single dose level studies have limited utility ° Such studies cannot be used in isolation to establish a NOAEL or LOAEL ° In rare instances they may have utility if interpreted within the context of one or more supplementary studies that provide information at other dose levels under analogous conditions. 17 II. Single dose level studies may be able to answer a very focused question ° However in such instances its utility will depend upon the robustness of study design,

the rationale for the study and whether the study design was consistent with the rationale.

° Evaluation of robustness will include questions of: Control, relevant endpoints, evidence that measures can identify an adverse effect or detect a change, use of a surrogate marker that is quantifiable and recognized as an established function of the compound and other criteria for scientific validity. 18 III. A single dose level study may have utility if it provides evidence of adverse effects observed at lower levels than other studies have indicated. 19 Ethics Evaluation 1. Did the study fail to fully meet specific ethical standards prevalent at the time the research was conducted?

Examples ° FIFRA Section 12( a) 2( P)

° Declaration of Helsinki or other International Code of Conduct for Research or other well established International Ethics Code ° 1991 Common Rule 40CFR26 ( after 1991 International Codes must be at least equivalent to Common Rule standards) 20 If the study did If the study did not not fully meet ethical fully meet ethical standards prevalent at the time:

standards prevalent at the time: 21 2. Was the conduct of the study Fundamentally Unethical?

There is clear and convincing evidence that the research was intended to seriously harm participants or failed to obtain informed consent ( Final Rule 26.104) 22 3. Was the conduct of the study Significantly Deficient relative to the ethical standards prevailing at the time?

Is there is clear and convincing evidence that:

a. The deficiencies identified could have resulted in serious harm ( based on knowledge available at the time the study was conducted); or b. The information provided to participants could seriously impair informed consent