Charge Questions for SAB/SAP Joint Subcommittee on
Data from Human Subjects

The Agency is developing a fuller articulation of its position on the generation and use of data derived from research and testing on human subjects. That position is based upon inter-Agency and international discussions on the topic over the past several years; in particular, the Federal Policy on Protection of Human Subjects (Common Rule) (40 CFR Part 26) and the World Medical Association's Declaration of Helsinki (as reprinted in JAMA 277:925-6, 1997).

In the midst of this effort, some specific issues have arisen regarding the testing of human subjects in support of pesticide registrations. Both scientific and (primarily) ethical questions have been raised about the data, the manner in which they were developed, and the purpose to which they can or should be put.

As noted in the following, the Agency seeks advice from the SAB/SAP Joint Committee on a range of issues, but focusing on the practical questions confronting the Pesticide Program as it seeks to implement the Food Quality Protection Act.

1. The Value of Human Studies

Human studies provide a special type information that may contribute to the decision making process. The Agency seeks advice on the role that such data can play in evaluating a toxicological data base for purposes of regulatory decision making. Specifically,

What are the general arguments for the proper role of human studies in supplementing animal studies in making regulatory decisions about various environmental agents; e.g., water pollutants, air emissions, and pesticides?

2. Factors for Consideration

The Agency is confronted with question of how to determine what constitutes an appropriate human study for use in environmental decision making. There are similarities and difference between the use of such studies in reaching decisions in other areas; e.g., drug licencing. In all cases, the Agency recognizes that the scientific benefits must at least be commensurate with the risks involved.

a. What factors are relevant to consider when reaching a judgment on what constitutes an ethically appropriate human study?

b. How can these factors be used to make decisions in such cases? Please give some examples.

c. In using these factors, are there "benchmarks" that emerge that would clearly make a study appropriate (or inappropriate) for use? Please give some examples.

3. The Risks and Benefits to Subjects and Society

The Agency is concerned that the best scientific information be brought to bear in making its decisions. At the same time, the Agency is concerned that the studies they require/rely on to make those decisions should meet rigorous ethical standards. Specifically, the risks to the study subjects should be commensurate to the benefits for them personally and for society as a whole.

a. What are the benefits to subjects and to society from human participation in research studies; e.g., those supporting pesticide registration?

b. What is the impact of remuneration on this question of benefits to subjects and society?

c. Are there differences or distinctions that should be made for studies involving
pesticides versus those involving other environmental chemicals?

4. Application to specific situations

The Agency must make judgments on a wide variety of studies involving humans. Such studies include controlled ingestion of test compounds by test subjects, accident reports, and monitoring of exposure during routine activities. It would be helpful to have advice on how the guiding principles on human subject research and testing (i.e., the Common Rule and Declaration of Helsinki) might be applied across this broad range of studies, particularly as they might apply in the case of studies submitted in support of a pesticide registration:

a. How can/should this guidance be applied to

Studies conducted in the past, prior to the adoption of the Common Rule (1991), but may (or may not) have adhered to another ethical standard of another day?

Studies gathered from the open literature for use by the Agency?

b. Is it ethical to engage in the oral dosing of human volunteers with environmental toxicants (e.g., cryptosporidium, SOx, or organophosphates (OPs)) in order to establish a NOAEL?

5. Compliance

Even if the Agency has appropriate ethical standards in place, there is the question of determining compliance with those standards.

How can the Agency determine whether and to what extent its ethical standards have been met in a particular test with respect to the following aspects:

a. Informed consent

b. Voluntary participation

c. Institutional Review Board (IRB)

Scientific Advisory Panel (SAP)/Science Advisory Board (SAB) December 1998 Meeting