# Presentation: 670337

## Summary ofEPA Ethics Review

- Campbell, J. (1984) A Comparison of the metabolism of 14-C Amitraz in rat, mouse, baboon and human.  Unpublished study performed by FBC Ltd., Chesterford Park Research Station, UK, under project number Metab/84/01.  20 p.  MRID 00160964.
- Campbell, J.; Needham, D. (1984) Urinary Excretion of (Carbon 14)-Amitraz by Two Humans Following a Single Oral Dose of 0.25 mg/kg Bodyweight: M70. Unpublished study performed by FBC Ltd., Chesterford Park Research Station, UK, under project number Metab/84/10, 17L. 12 p.  MRID 46249601

## Amitraz 84 Metabolism Study

- Conducted at FBC Ltd., Chesterford Park Research Station in UK in 1984
- Component of multi-species study of comparative metabolism

## Amitraz 84 “Framework”

- Value
- Not published or disseminated
- Societal value not addressed in reports
- Scientific Validity: Defer to others
- Subject Selection
- Adult male volunteers from unknown pool
- Subjects may have been lab employees

## Amitraz 84 “Framework” -- 2

**Risk-Benefit Ratio**
- No information relevant to assessing the relation of research risks and benefits was reported
- Neither risks to subjects nor their minimization was discussed
- The rationale for dose selection at 1/40 the animal dose was not reported
- Neither societal benefits nor their relation to subject risks is discussed

## Amitraz 84 “Framework” -- 3

- Independent Ethics Review
- No mention of ethics oversight or independent review
- No standard of ethical conduct cited
- Informed Consent
- “Two healthy adult human males volunteered to participate in the experiment and consented to the administration of the radio-active dose.”

## Amitraz 84 “Framework” -- 4

**Respect for Subjects**
- Subject confidentiality was not compromised in the report.
- No mention was made of whether they were free to withdraw.
- The failure to monitor subjects until pulse and blood pressure returned to normal, and the disturbing report of adverse effects persisting beyond the period of observation, suggest less than full commitment to the welfare of the subjects.

## Amitraz 84 Prevailing Standard

- Research conducted in UK in 1984
- No standard of ethical conduct cited
- Declaration of Helsinki (1983) assumed to have prevailed

## Comparison to DoH

**Basic Principle #2:**  “The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted to a specially appointed independent committee for consideration, comment and guidance.”
**EPA Comment:** The protocol is not available.  There is no indication that it was transmitted to a specially appointed independent committee for review.

## Comparison to DoH -- 2

**Basic Principle #3:** “The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent.”
**EPA Comment:** The investigators’ failure to extend the period of observation until all signs of effects had returned to normal, and their report of effects which persisted beyond the period of observation, suggest that responsibility was inappropriately placed on the subjects to monitor and report effects.

## Comparison to DoH -- 3

**Basic Principle #5:**  “Every . . . project . . . should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others.”
**EPA Comment:**  If a careful assessment was conducted it was not reported.

## Comparison to DoH -- 4

**Basic Principle #9:** “. . . Each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The physician should then obtain the subject’s freely-given informed consent, preferably in writing.”
**EPA Comment:**  The study reports that the subjects volunteered and consented to receive the radio-labeled dose, but is silent with respect to what they were told

## Comparison to DoH -- 5

**Basic Principle #12:** “The research protocol should always contain a statement of the ethical considerations involved and should indicate that the principles enunciated in the present Declaration are complied with.”
**EPA Comment:** No protocol was included in the report.  Neither the Declaration nor any other standard was cited, nor was there any discussion of ethical considerations

## Amitraz 84 Summary

- There are many gaps in the record, but gaps are not “clear and convincing evidence”.
- There is no evidence that the research was fundamentally unethical.
- Some deficiencies are apparent relative to the cited 1964 Declaration of Helsinki.
- We welcome the Board’s advice on the significance of those deficiencies.