2 Kisicki, J. (2009) “Re: Ethics Review of Chlorpyrifos Human Toxicity Study”. Unpublished letter dated June, 23, 2009 to K. Racke of Dow AgroSciences, responding to EPA Ethics Review of MRID 44811002 dated May 29, 2009. 7 p.

Anon. (1998) Attachment to June 23, 2009 J. Kisicki letter to K. Racke with subjects de-identified. Unpublished Screening Logs dated September 21, 1998 and October 6, 1998, used by MDS-Harris La boratories in the execution of the study reported in MRID 44811002. Submitted to EPA on July 1, 2009. 18 p.

I have reviewed the documents cited above, including the study report, the previous EPA ethics reviews, the 2009 report from the Huma n Studies Review Board, and the additional information submitted by Dow Agrosciences in connection with the HSRB’s 2009 review of the study. Based on the HSRB’s recommendations and my independent considerat ion of the relevant documents, I have concluded that EPA may rely on this study in actions under the Federal Insecticide, Fungicide, or R odenticide Act (FIFRA) or the Federal Food, Drug, and Cosmetic

Act (FFDCA).

Background

May 2009 ethics review by John Carley, EPA

The ethical conduct of this research wa s reviewed by EPA in May 2009 (memorandum by John Carley to Anna Lowit dated May 29, 2009). In that review, Carley raised a number of concerns, the most significant of which related to the consent process. In particular, Carley believed that some subjects may have undergone screening procedures, such as providing medical history, submitting to a physical examin ation, or providing blood and urine samples, prior to providing informed consent. Belo w is an excerpt from Carley’s review.

“As noted earlier in this review, by th e time of check-in—October 1, for phase I— subjects had given blood and urine samples, provided medical and surgical history, and been subjected to a physical examination at screening, had visited the clinic 48 h before

check-in to obtain urine collec tion containers, and had been collecting their urine for two days. Notwithstanding that the QA Unit re ported study initiation on October 1...in my judgment the subjects should all have provided written informed consent at or before the time of screening, which for phase I subj ects was reported in Appendix 4.6.1 ... as September 23 or 30.” (p. 6-7)

Primarily on the basis of his belief that so me subjects may have given blood and/or urine samples and personal information prior to providi ng informed consent, Carley concluded that the consent process was significantly deficient relative to the standards that prevailed at the time the study conducted (FDA regulations at 21 CFR 50. 20 and 50.25). He also concluded that the consent process did not meet the requirements in FIFRA §12(a)(2)(P) for fully informed, fully voluntary participation because he felt that study initiation may have preceded consent for some subjects.3 Other concerns about the consent process that contributed, to a lesser extent, to Carley’s

conclusions related to the conten t of the consent form. The followi ng concerns were detailed in Carley’s memo:

“The consent form includes extensive technical language taken directly from the protocol which was unlikely to be understood by subjec ts. The Flesch-Kincaid Grade Level score for the first full paragraph of the consent form is 17.7, equivalent to an advanced graduate student. The form is poorly organized and diffi cult to follow, shifting suddenly from the first to second persons and back again, and in cluding both dire warnings of “very serious consequences for [subject’s] well-being” and reassurances that uni dentified MDS Harris

medical consultants think the risks invol ved should not deter the subjects from participating.” (p. 7)

Carley’s May 2009 ethics review was provi ded to the study sponsor and the HSRB in May 2009; the study was reviewed by the HSRB at its public meeting on June 24, 2009.

Additional Information Provided by th e Study Sponsor prior to HSRB Meeting

On June 23, 2009, one day prior to the HSRB’s June 24 th meeting, Dow Agrosciences submitted a copy of a letter from Dr. James C. Ki sicki (the study director) to Kenneth D. Racke of Dow Agrosciences. In the letter, dated June 23, 2009, Dr. Kisicki provided details about the candidate screening process that were not clear in the study report, and he addressed the issues discussed in Carley’s May 29, 2009, ethics review. A copy of Dr. Ki sicki’s letter was provided to the HSRB members, and the description in the le tter of the candidate screening procedure was read aloud to the HSRB during the meeting.

The relevant portions of the letter are as follows:

“In 1998, when this study was conducted, our internal standard operating procedure (SOP) for screening was as follows:

When potential subjects arrived at the rese arch facility, they were given a packet of information about the study. The packet contained a copy of the IRB-approved Informed Consent Form. Prior to any sc reening procedures, the subjects were required to sit and listen to an audio ta pe of the Informed Consent Form and follow along with the written document. An associate was available to answer any questions. Documentation is available of the subject signing a log indicating that they had listened to the audio tape of the Informed Consent Form, they understood it, and that they had no further questions.” (p. 5-6)

HSRB Meeting

The study was reviewed by EPA’s Human Studies Review Board at its public meeting on June 24, 2009. During the meeting, Carley presen ted his review and conclusions. The Board discussed the consent process a nd other aspects of the study thor oughly, and ultimately indicated disagreement with the conclusion in the Carley review that the study wa s significantly deficient

relative to the sta ndards governing its ethical conduct.4 Additional Information Provided by th e Study Sponsor after the HSRB Meeting

On July 1, 2009, approximately one week afte r the HSRB meeting, copies of the subject sign-in logs referen ced in the June 23 rd letter, with the signatures redacted, were submitted to EPA and provided to the HSRB members for their consideration in developing their recommendations and drafting the HSRB report.

HSRB’s Report

In its report dated October 26, 2009, the Board co ncluded that there neither was clear and convincing evidence that the study was fundame ntally unethical, nor clear and convincing evidence that the study was significa ntly deficient relative to the ethical standards prevailing at

the time the research was conducted.

Not fundamentally unethical. The HSRB concluded that the Kisicki study was not fundamentally unethical because it was not intended to seriously harm participants, nor was there

a failure to obtain informed cons ent. The Board’s reported stated:

“...the information contained therein [in the supplementary material provided by Dow] do not meet the evidentiary standard of cl ear and convincing evid ence that the study was fundamentally unethical or significantly deficient relativ e to the ethical standards prevailing at the time. It is possible, for exam ple, that the deficiencies noted in the logs are the result of sloppy reco rd keeping rather than a serious impaired participant

recruitment, consent and screen ing process.” [p. 24 of 40]

Not significantly deficient. With regard to determining whether a study was significantly deficient relative to the ethical standards prev ailing at the time the research was conducted, the standard applied by the HSRB was wh ether or not any ethical defici encies identified could have resulted in serious harm based on knowledge av ailable to researchers at the time the study was conducted, or whether the information provided to study participants could seriously impair

informed consent. The HSRB concluded that ther e was not no clear and c onvincing evidence that the study was significantly deficien t. Based on toxicological data that was availa ble at the time for chlorpyrifos, study participants were unlikely to be at risk fo r serious side effects given the exposure doses used in the study. Furthermore, fr om the entirety of the evidence before the

HSRB, the Board concluded that that informed consent process was not seriously impaired.

Applicable Standards

Standards Applicable to th e Conduct of the Research

This research was initiated in 1998, before EPA’s amended Rule for the Protection of Human Subjects of Research became effective on April 7, 2006. It was co nducted in the United States by a Contract Research Organization laboratory, MDS Harris, and overseen by the5 laboratory’s in-house Institutional Review Board. The standards that were applicable to the conduct of this study are the U.S. Food and Drug Administration rules rela ting to the protection of human subjects, as codified at 21 CFR parts 50 and 56, as well as the Declaration of Helsinki (as amended in 1996). FIFRA §12(a)(2)(P) also applie d to this research because it involved the use of a pesticide.

Standards Applicable to EPA’ s Reliance on the Research

EPA submitted this study for review by the Human Studies Review Board (HSRB) in 2009 because 40 CFR §26.1604 requires HSRB review for pre-2006 studies intended for EPA

reliance that were conducted fo r the purpose of identifying or m easuring a toxic effect. This study meets those criteria.

The Agency’s rule (40 CFR part 26 subpart Q) defines standards for EPA to apply in deciding whether to rely on re search—like this study—involving in tentional exposure of human subjects. The applicable acceptance standard s from 40 CFR part 26 subpart Q are these:

§26.1703. Except as provided in § 26.1706, EPA must not rely on data from any research subject to this subpart invol ving intentional expo sure of any human subject who is a pregnant woman (and therefore her fe tus), a nursing woman, or a child.

§26.1704 EPA must not rely on data from any resear ch subject to this section if there is clear and convincing evidence th at: (1) The conduct of the research was fundamentally unethical (e.g., the research was intended to se riously harm participants or failed to obtain informed consent); or (2) The c onduct of the research was defi cient relative to the ethical standards prevailing at the time the resear ch was conducted in a way that placed participants at increased risk of harm (based on knowledge available at the time the study was conducted) or impaired their informed consent.

Compliance with Applicable Standards

All of the subjects in this study are age 19 or older. The thirty female subjects were not pregnant. Therefore, this rese arch did not involve intentiona l exposure of any pregnant or nursing female subjects or any children. EPA’s reliance on the research is therefore not prohibited by 40 CFR §26.1703.

The subjects provided written informed cons ent and the protocol underwent independent ethics review and approval. Based on these fact s, and the absence of any information suggesting that the research was fundamentally unethical or intended to harm participants, I conclude that

reliance on the research is not prohibited by 40 CFR §26.1704(1). Th is conclusion agrees with the recommendations of the HSRB in its October 2009 report.

I also conclude that there is no clear and convincing evidence that this research was deficient relative to the ethical standards prevaili ng at the time in a way that placed participants at increased risk of harm (bas ed on knowledge available at the time the study was conducted) or impaired their informed consent. Based on toxico logical data that was available at the time,6 subjects were unlikely to be at risk of harm given the exposure dose used in the study.

Furthermore, there is no clear a nd convincing evidence that any s ubject did not provide informed consent, or that the consent proc ess was seriously impaired. Based on these facts, I conclude that the study was not deficient relative to the prev ailing ethical standards in a way that placed participants at increased risk of harm or impaired their informed consent. Therefore, reliance on this study is not prohibited by 40 CFR §26.1704( 2). This conclusion agrees with the recommendations of the HSRB in its October 2009 report.

Conclusion

I find no barrier in law or regulation to reliance on MRID 44811002 in EPA actions taken

under FIFRA or §408 of FFDCA.