Document zQN0ROwgV8Og6r5anOK27Bg2R

Harrison. M.e. (Myron) From: Sent: To: Subject: George Woodall (Woodallg@api.org} Wednesday, February 07,2001 11 :14 AM Baruch Brody (E-mail); Lorraine Twerdok (E-mail); Lynn Russo (E-mail); Myron C. Harrison (E-mail); Norm Zeiser (E-mail); Otto Wong (E-mail); Patrick Beatty (E-mail); Rich Herold (E-mail); Richard Irons (E-mail); Robert Schnatter Ph. D. (E-mail) FW: Ethics Review Progress Report Benzene Study Ethics Workgroup; Below is a message forwarded from Baruch Brody summarizing the progress on the ethics review process. In subsequent calis with Dr. Brody and Dr. Irons, it was decided that a conference call will be set up for the morning of Wednesday. February 21 fro1ll11:45 AM -1:15 PM (EST). (The logistics for the conference call will be sent later.) The subject of the call will be the review of the protocols for the Disease ProgressIon Study and the Molecular Epidemiology Study, which is anticipated to be made available to you either by the end of this week or early next week. Thank you, George M. Woodall, Ph.D. Senior Toxicologist American Petroleum Institute 1220 L Street, NW Washington. DC 20005 tel: (202) 682-8067 fax: (202) 682-8031 woodallg@api.org -----Original Message----From: Baruch A Brody [mailto:bbrody@bcm.tmc,eduJ Sent Saturday. February 03, 2001 1035 PM To: Woodallg@api.org Cc: pwbe@chevron.com Subject: Here is the text of my interim report which I promised I would send to you ASAP. Please distribute it to the stakeholders and others, as you see fit. BARUCH INTERIM PROGRESS REPORT ETHICS REVIEW PROCESS BENZENE SHANGHAI STUDIES Feb.4,2001 The ethics review process has been examining three proposed studies, the NHL-AML study (to be conducted by Dr, Wong and learn) and the Disease Progression and Molecular Epidemiology studies (to be conducted by Dr. Irons and team). This report summarizes the work done by the team up to a conference call held on January 22, the results of which were summarized to the Stakeholders Meeting at API Headquarters on January 26. NHL-AML Protocol I / I I HAZ-SHA-000048 At our meeting in Salt Lake City on October 26, 2000, we reviewed a draft of Dr. Wong's protocol and raised a number of issues of concern. He has addressed them in a series of revisions, culminating In a protocol dated January 11. 2001. It was the unanimous conclusion of the group that we were satisfied that the issues had been appropriately addressed, although there were two on which further work needed to be done by Dr. Wong and there was one on which there was still some disagreement. Let me review what was done, issue at a time: 1. enefits and burdens to subjects and to communil}'- this form of case control epidemiological study, which primarily involves a questionnaire interview of cases and controls and the gathering of exposure information, offers primarily the prospect of benefit to the public health in Shanghai by providing the basis for a scientifically sound formulation of better benzene exposure regulations, by identifying workplaces with unacceptable levels of exposure, and by identifying other risk factors. Dr. Wong has strengthened the potential for achieving these benefits through his contact with Dr. Liang. Except for concerns about confidentiality, there are no real risks to the subjects of the study. So the benefit-risk ratio is quite favorable. so long as Issues of confidentiality are addressed. 2. Confidentiality- the entire effort in Shanghai will involve three components: the diagnostic laboratory to be developed by Dr. Irons, Dr. Wong's study, and Dr. Irons's study. The databases for these three studies will be kept separate. Informed consent of subjects will be required to transfer information from one data base to another. Even when consent is obtained for such a transfer, only relevant information will be transferred. All this is spelled out very carefully in Section 2.10 of the protocol. 3. Jnformed Coa,;;ent- At the request of the ethics review process, there will be two separate consent forms, one for the cases and one for the controls. Each will clearly explam whether they are being asked to participate because they are cases with the disease in question or whether they are being asked to be controls. The consent forms are complete; what remains to be developed is..a summary information sheet which ex4p.lainEsxctheesssivtuedIynidnucaeCrnUeItoIltC~!3-"VThseenresiwtivaes fashion considerable"'discussion of the amount to pay the SUbjects. On the one hand, one did not want to exploit the Chinese subjects by paying them less than one would pay American subjects for participaing in a similar study. On the other hand, one did not want to make the inducement so good as to make the offer impossible to refuse. The group decided to emphasize the former value and to avoid concerns about exploitation by paying $30, an amount similar to what Dr. Wong pays subjects for such stUdies in the U.S. 5. QUestionnaire Development- In addition to asking about employment history, Dr. Wong proposes to administer a questionnaire to identify other poSSible risk factors, A concern was expressed about whether the questions which might be asked are inappropriate in the Chin~ cUltur.Lettiog The questionnaire rernaimi to be developed S. Control of ~sults- Although this is an industry sponsored study, it is important that the investigators retain final control over what is said in all publications to protect the integrity of the study and the acceptability of the results. This, and other aspects of a communication plan, are carefully outlined in Section 2.13 of the ~~L / Summary of What Remains to be Done- The information sheet for the consent process and the questionnaire about other factors need to be developed by Dr. Wong. in close collaboration with his Chinese COlleagues and a Chinese bioethicist, and the final results need to be reviewed 10 the ethics advisory process. One other issue remains to be resolved in that process: is there any place in this study for interim review of results (to insure that any convincing results of great pUblic health interest are released 2 HAZ-SHA-000049 if firmly established). or is that unnecessary in a case control study (in which no participants are put at risk by their continued participation). Although there is work to be done, this study is ready to move forward from the perspective of an ethics review, Disease Progression Study At our meeting in Salt lake City, Dr. Irons presented his original ideas about this study. They have been modified and developed extensively since that time, and what we now have available is part (not aft) of the "front-end" of the protocol. Still. the group felt that we had enough information to make a tentative evaluation of the protocol from an ethics perspective. Once more, this will be done on an issue by issue basIs: 1. Benefits and burdens to sU0ect~!!l!Y- This study requires theaeve~oT an OK ro:aated@gnOStiGlil'p.QrEt!:uy and the training of local personnel to do"t e diagnostic work, This alone represents a major contribution to Shanghai since the laboratory and the trained personnel will remain after the study is complete. In addition, - this will im rove the dia ~ndl\I.kI.uaL@tjents, and this may be of dinic va ue to them, especially for cases wtilCh will be follo~R six mQlltb intervals (the cases of 8P, AA, and MDS). All of this is spelled out In Section IV of the protocol. As the major risks to the subjects involve questions of confidentiality, the benefit-risk ratio of this protocol is quite favorable, so long as these issues of confidentiality are addressed. 2. Confidentiallty- Although this remains to be spelled out more fully, it is our belief that there will be no problems here because of the basic principles of separation of databases and consent for transfer of information oullined above. 3. Informed Consent- We have not yet received the consent documents for review, although we have been assured that there Will be separate consent forms for the different populations in this complex study. 4. Excessive Inducements- The question ofthe amount to pay the subjects was different in this study, because it was fell that we needed to take into account standard Chinese practice in connection with donations of blood, since such a donation has a different cultural meaning in the Chinese setting. Dr. Irons has proposed a payment schedule which ranges from $30 for control subjects for completing an interview (see analysis above) to $200 for those who donate blood and undergo a bone marrow biopsy and aspiration (this being comparable to what the Chinese receive for donating blood for transfusions). 5. Questionnaire Development- An analysIs of confounders will be done (Section 20) by use of a questionnaire. A concern was expressed about whether the questio,ns ~clJ...l:Dight.bQ..asked..ar.e.joappr.Qp.Liate.in. the Chinese cultural setting. The 'questionnaire remains to be developed. 6. Control of Results- - Although this is an industry sponsored study, it is important that the investigators retain final control over what is said in all publications to protect the integrity of the study and the acceptability of the results. A communication plan, built around this principle, remains to be developed. 7. Other Issues- Two issues remain to be addressed in appropriate sections of the protocol not yet developed: (a) how clinicians/subjects will be informed of clinically significant information discovered in the disease progression foJlow up visits and how public h Icials will be infq[r]J~QJlboY!Jhe resulg;5!tworl<QLace visits ind atingun~..cQ!1ditiqIlS~Jbrno~.!J1aterial will be YS~ter /' studies, inc;:I!J{1i!l9_genetic studies. What we have heard from Dr. Irons makes us feel confident that these issues will be dealt with appropriately. .",...- Summary of What Remains 10 be Done The ethics revIew process needs to 3 HAZ-SHA-OOOOSO .' review the completed "front-end" of the protocol once it is available (probably, in later February). In addition, a series of consent forms, and the questionnaire about other factors, need to be developed by Dr. Irons in close collaboration with his Chinese colleagues and a Chinese bioethicist, and the final results need to be reviewed in the ethics advisory process. One other issue remains to be resolved in that process: is there any place in this study for interim review of results (to insure that any convincing results of great public health interest are released if firmly established), or is that unnecessary in a case control study (in which no participants are put at risk by their continued participation). Although there is more work to be done from an ethics perspective on this study than on the previous study, we believe that it will certainly meet all of the remaining issues and be ready to move forward from the perspective of an ethics review. Molecular Epidemiology Study The ethics review process has not yet seen any part of this protocol. From the discussions with Dr. Irons, there is no reason to believe that there will be any insurmountable problems from an ethics perspective with this planned study, but saying anything more would be inappropriate until we can review the "front-end" of this protocol. 4 HAZ-SHA-000051 Harrison. M.e. (Myron) From: Sent: To: Subject: George Woodall [Woodallg@api.org] Wednesday, February 07,2001 11 :14 AM Baruch Brody (E-mail); Lorraine Twerdok (E-mail); Lynn Russo (E-mail); Myron C. Harrison (E-mail); Norm Zeiser (E-mail); Otto Wong (E-mail); Patrick Beatty (E-mail); Rich Herold (E-mail); Richard Irons (E-mail); Robert Schnatter Ph. D. (E-mail) FW: Ethics Review Progress Report Benzene Study Ethics Workgroup; Below is a message forwarded from Baruch Brody summarizing the progress on the ethics review process. In subsequent calls with Dr. Brody and Dr. Irons, it was decided that a conference call will be set up for the morning of Wednesday, February 21 from 11 :45 AM - 1:15 PM (EST). (The logistiCS for the conference call will be sent later.) The subject of the call will be the review of the protocols for the Disease ProgressIon Study and the Molecular Epidemiology Study, which is anticipated to be made available to you either by the end of this week or early next week. Thank you, George M. Woodall, Ph.D. Senior Toxicologist American Petroleum Institute 1220 L Street, NW Washington, DC 20005 tel: (202) 682-8067 fax: (202) 682-8031 woodallg@api.org -----Original Message----From: Baruch A Brody [mailto:bbrody@bcm.tmc.edu] Sent: Saturday, February 03, 2001 1035 PM To: Woodallg@api.org Cc: pwbe@chevron.com Subject: Here is the text of my interim report which I promised I would send to you ASAP. Please distribute it to the stakeholders and others, as you see fit. BARUCH INTERIM PROGRESS REPORT ETHICS REVIEW PROCESS BENZENE SHANGHAI STUDIES Feb. 4, 2001 The ethics review process has been examining three proposed studies, the NHL-AML study (to be conducted by Dr. Wong and team) and the Dis~ase Progression and Molecular Epidemiology studies (to be conducted by Dr. Irons and team). This report summarizes the work done by the team up to a conference call held on January 22, the results of which were summarized to the Stakeholders Meeting at API Headquarters on January 26. NHL-AML Protocol HAZ-SHA-000048 At our meeting in Salt Lake City on October 26, 2000, we reviewed a draft of Dr. Wong's protocol and raised a number of issues of concern. He has addressed them in a series of revisions. culminating In a protocol dated January 11, 2001. It was the unanimous conclusion of the group that we were satisfied that the issues had been appropriately addressed, although there were two on which further work needed to be done by Dr. Wong and there was one on which there was still some disagreement. Let me review what was done. issue at a time: 1. .enefits and burdens to subjects @d to community- this form of case control epidemiological study. which primarily involves a questionnaire interview of cases and controls and the gathering of exposure information, offers primarily the prospect of benefit to the public health in Shanghai by providing the basis for a scientifically sound formulation of better benzene exposure regulations, by identifying workplaces with unacceptable levels of exposure. and by identifying other riSK factors. Dr. Wong has strengthened the potential for achieving these benefits through his contact with Dr. Liang. Except for concerns about confidentiality. there are no real riSKS to the subjects of the study. So the benefit-risk ratio is quite favorable, so long as Issues of confidentiality are addressed. 2. Co.n!identiality- the entire effort in Shanghai will involve three components: the diagnostic laboratory to be developed by Dr. Irons, Dr. Wong's study, and Dr. Irons's study. The databases tor these three studies will be kept separate. Informed consent of subjects will be required to transfer information from one data base to another. Even when consent is obtained for such a transfer, only relevant information will be transferred. All this is spelled out very carefully in Section 2.10 of the protocol. 3. Informed Consent At the request of the ethics review process,there will be two separate consent forms. one for the cases and one for the controls. Each will clearly explain whether they are being asked to participate because they are cases with the disease in question or whether they are being asked to be controls. The consent forms are complete; what remains to be developed is ill summary information sheet wlJich explains the study in a cu1turpll;: seosjtive tashioo " 4. Excessive 1nduceme~- There was considerable discussion of the amount to pay the subjects. On the one hand. one did not want to exploit the Chinese subjects by paying them less than one would pay American subjects for participaing in a similar study. On the other hand. one did not want to make the inducement so good as to make the offer impossible to refuse. The group decided to emphasize the former value and to avoid concerns about explOitation by paying $30, an amount similar to what Dr. Wong pays subjects for such studies in the U.S. 5. Questionnaire Development- In addition to asking about employment history, Dr. Wong proposes to administer a questionnaire to identify other pOSSible risk factors. A concern was expressed about whether the questions which might be asked are inappropriate in the Chinese cultural' ionnaire ra . . -----. . ontrol of ~ults- Although this is an industry sponsored study, it is imporfunt that the investigators retain final control over what is said in all publications to protect the integrity of the study and the acceptability of the results. This, and other aspects of a communication plan, are carefully outlined in Section 2.13 of the protocol. /' Summary of What Remains to be Done The information sheet for the consent process and the questionnaire about other factors need to be developed by Dr. Wong, in close collaboration with his Chinese colleagues and a Chinese bioethicist, and the final results need to be reviewed In the ethics advisory process. One other issue remains to be resolved in that process: is there any place in this study for interim review of results (to insure that any convincing results of great public health interest are released 2 HAZ-SHA-000049 if firmly established), or is that unnecessary in a case control study (in which no participants are put at risk by their continued participation). Although there is work to be done, this study is ready to move forward from the perspective of an ethics review. Disease Progression Study At our meeting in Salt Lake City, Dr. Irons presented his original ideas about this study. They have been modified and developed extensIVely since that time, and what we now have available is part (not all) of the "front-end" of the protocol. Still, the group felt that we had enough information to make a tentative evaluation of the protocol from an ethics perspective. Once more, this will be done on an issue by iSsue basIs: 1. Benefits and burdens to sul:>j~!uncLcomlIumj~- This study requires thelrevEiiOPilleiUof an up (oaa.ted~g noti.g @bo~~~9.~ and the training of local personnel to do'tile diagnostic work. This alone represents a major contribution to Shanghai since the laboratory and the trained personnel will remain after the study is complete. In addition, - this will imQrQif2:e ~.l!9~nd.i.lLidlJal~tients, and this may be ot clinica va ue to them. especially for cases whICh will be follo~ (the cases of BP, M, and MDS). All of this is spelled out in Section IV of the protocol. As the major risks to the subjects involve questions of confidentiality, the benefit-risk ratio of this protocol is quite favorable. so long as these issues of confidentiality are addressed. 2. Confidentiallty- Although this remains to be spelled out more fully, it is our belief that there will be no problems here because of the basic principles of separation of databases and consent for transfer of information outlined above. 3. Informed Consent- We have not yet received the consent documents for review, although we have been assured that there wlUbe separate consent forms for the different populations in this complex study. 4. Excessive Inducements- The question of the amount to pay the subjects was different in this study, because it was felt that we needed to take into account standard Chinese practice in connection with donations of blood, since such a donation has a different cultural meaning in the Chinese setting. Or. Irons has proposed a payment schedule which ranges from $30 for control subjects for completing an interview (see analysis above) to $200 for those who donate blood and undergo a bone marrow biopsy and aspiration (this being comparable to what the Chinese receive for donating blood for transfusions). 5. QUestionnaire Development- An analYSIS of confounders will be done (Section 2D) by use of a questionnaire. A concern was expressed about whether the questiops V!bict:unigblbe.as.ked-are.inapPf9pliate. in. the Chinese cultural setting. The questionnaire remains to be developed. 6. Control of Results- - Although this is an industry sponsored study. it is important that the investigators retain final control over what is said in all publications to protect the integrity of the study and the acceptability of the results. A communication plan, built around this principle. remains to be developed. 7. Other Issues- Two issues remain to be addressed in appropriate sections of the protocol not yet developed: (a) how Clinicians/subjects will be informed of clinically significant information discovered in the disease progression follow up visits and how public health officials will be infQrl'D~Qjlbo!:!.Ube resul~_QtWP[KQ.Lac.e visits ind~ating.lm~!!!LQo.!:I';'(b}llo~.!!!aterial will be u.s.edJol:.-later :/' studies, in~lugjl19_geDetjc studies. What we have heard from Dr. Irons makes us feel confident that these issues will be dealt WIth appropriately. Summary of What Remains to be Done- The ethics revIew process needs to 3 HAZ-SHA-OOOOSO review the completed "front-end" of the protocol once it is available (probably, in later February). In addition, a series of consent forms, and the questionnaire abOut other factors, need to be developed by Dr. Irons in close collaboration with his Chinese colleagues and a Chinese bioethicist, and the final results need to be reviewed in the ethics advisory process. One other issue remains to be resolved in that process: is there any place in this study for interim review of results (to insure that any convincing results of great public health interest are released it fIrmly established), or is that unnecessary in a case control study (in which no participants are put at risk by their continued participation). Although there is more work to be done from an ethics perspective on this study than on the previous study, we believe that it will certainly meet all of the remaining issues and be ready to move forward from the perspective of an ethics review. Molecular Epidemiology Study The ethics review process has not yet seen any part of this protocol. From the discussions with Dr. Irons, there is no reason to believe that there will be any insurmountable problems from an ethics perspective with this planned study, but saying anything more would be inappropriate until we can review the "front-end" of this protocol. 4 HAZ-SHA-OOOOSl Harrison. M.e. (Myron) From: Sent: To: Subject: George Woodall [Woodallg@apLorg] Wednesday, February 07, 2001 11:14 AM Baruch Brody (E-mail); Lorraine Twerdok (E-mail); Lynn Russo (E-mail); Myron C. Harrison (E-mail); Norm Zeiser (E-mail); Otto Wong (E-mail); Patrick Beatty (E-mail); Rich Herold (E-mail); Richard Irons (E-mail); Robert Schoatter Ph. D. (E-mail) FW: Ethics Review Progress Report Benzene Study Ethics Workgroup; Below is a message forwarded from Baruch Brody summarizing the progress on the ethics review process. In subsequent calls with Dr. Brody and Dr. Irons, it was decided that a conference call will be set up for the morning of Wednesday, February 21 from 11:45 AM -1:15 PM (EST). (The logistics for canthe conference call will be sent later.) The subject of the will be the review of the protocols for the Disease Progression Study and the Molecular Epidemiology Study, which is anticipated to be made available to you either by the end of this week or early next week. Thank you, George M. Woodall, Ph.D. Senior Toxicologist American Petroleum Institute 1220 L Street, NW Washington, DC 20005 tel: (202) 682-8067 fax: (202) 682-8031 woodallg@apLorg -----Ori9inal Message-- From: Baruch A Brody [mailto:bbrody@bcm.tmc.edu] Sent: Saturday, February 03,2001 10:35 PM To: Woodallg@api.org Cc: pwbe@chevron.com Subject: Here is the text of my interim report which I promised' would send to you ASAP. Please distribute it to the stakeholders and others, as you see fit. BARUCH INTERIM PROGRESS REPORT ETHICS REVIEW PROCESS BENZENE SHANGHAI STUDIES .._---- - - -.._---- - -~-... Feb. 4, 2001 _- ('_ .. " - - - - -- - - - - The ethics review process has been examining three proposed studies, the NHL-AML study (to be conducted by Dr. Wong and team) and the Disease Progression and Molecular Epidemiology studIes (to be conducted by Dr. Irons and team). This report summarizes the work done by the team up to a conference call held on January 22, the results of which were summarized to the Stakeholders Meeting at API Headquarters on January 26. NHL-AML Protocol HAZ-SHA-OO 1458 At our meeting in Salt Lake City on October 26, 2000, we reviewed a draft of Dr. Wong's protocol and raised a number of issues of concern. He has addressed them in a series of revisions, culminating in a protocol dated January 11, 2001. It was the unanimous conclusion of the group that we were satisfied that the issues had been appropriately addressed, although there were two on which further work needed to be done by Dr. Wong and there was one on which there was still some disagreement. Let me review what was done, issue at a time: 1. Be fits and burdens to sub'ects d to communi this form of case control epi emiological study, which primarily involves a questionnaire interview of cases and controls and the gathering of exposure information, offers primarily the prospect of benefit to the public health in Shanghai by providing the basis for a scientifically sound formulation of better benzene exposure regulations, by identifying workplaces with unacceptable levels of exposure, and by identifying other risk factors. Dr. Wong has strengthened the potential for achieving these benefits through his contact with Dr. Liang. Except for concerns about confidentiality, there are no real risks to the subjects of the study. So the benefit-risk ratio is quite favorable, so long as issues of confidentiality are addressed. 2. Confidentiality- the entire effort in Shanghai will involve thre~ts: the diagnostic laboratory to be developed by Dr. Irons, Dr. Wong's study, and Dr. Irons's study. The databases for these three studies will be kept separate. Informed consent of subjects will be required to transfer information from one data base to another. Even when consent is obtained for such a transfer, only relevant information will be transferred. All this is spelled out very carefully in Section 2.10 of the protocol. 3. Informed Consent- At the request of the ethics review process, there will be twoseparate consent forms, one for the cases and one for the controls. Each will clearly explain whether they are being asked to participate because they are cases with the disease in question or whether they are being asked to be controls The consent forms are complete; what remains to be developed i~jI summary information sheet ~xplai[]s the stUdy in a cultuq,lIy sensitive fashion '" 4. Excessive Inducemeo~- There was considerable discussion of the amount to pay the subjects. On the one hand, one did not want to exploit the Chinese subjects by paying them less than one would pay American subjects for participaing in a similar study. On the other hand, one did not want to make the inducement so good as to make the offer impOSSible to refuse. The group decided to emphasize the former value and to avoid concerns about exploitation by paying $30, an amount similar to what Dr. Wong pays subjects for such studies In the U.S. 5. Questionnaire Development- In addition to asking about employment history, Dr. Wong proposes to administer a questionnaire to identify other possible risk factors. A concern was expressed about whether the questions which might be asked are inappropriate in the Chinil.e cultur~ettlOg The Questionnaire remains IQ be deve!oped. - . - - 6. Control of ~sults- Although this is an industry sponsored -----.Stud,.,..it i~jmgprt'ant tQElt the investigators retain final control over what is said in all publicatrons to protect the integrity of the study an-a--- .... the acceptability of the results. This, and other aspects of a communication plan, are carefully outlined in Section 2.13 of the protocol. / Summary of What Remains to be Done- The mformatlon sheet for the consent process and the questionnaire about other factors need to be developed by Dr. Wong, in close collaboration with hiS Chmese colleagues and a Chinese bioethicist, and the final results need to be reviewed In the ethiCS adVISOry process. One other issue remainS to be resolved in that process: IS there any place in this study for interim review of results (to insure that any convinCing results of great public health interest are released 2 HAZ-SIIA-OO 1459 if firmly established), or is that unnecessary in a case control study (in which no participants are put at risk by their continued participation). Although there is work to be done, this study is ready to move forward from the perspective of an ethics review. Disease Progression Study At our meeting in Salt Lake City, Dr. Irons presented his original ideas about this study. They have been modified and developed extensively since that time, and what we now have available is part (not all) of the "front-end" of the protocol. Still, the group felt that we had enough information to make a tentative evaluation of the protocol from an ethics perspective. Once more, this will be done on an issue by issue basis: 1. Benefits and burdens to subects uni - This study requires the 'evelopmen 0 _0 ate diagnostic labora\o.ry and the training of local personnel to dolne diagnostic work. This alone represents a major contribution to Shanghai since the laboratory and the '/----- trained personnel will remain after the study is complete. In addition, -/'" this will im rove the dia no . e . . . I atients, and this may be of clinica va ue to them, especially for cases which will be follo~n six montb intervals (the cases of BP, M, and MDS). All of this is spelled out in Section IV of the protocol. As the major risks to the subjects involve questions of confidentiality, the benefit-risk ratio of this protocol is quite favorable, so long as these issues of confidentiality are addressed. 2. Confidentiality- Although this remains to be spelled out more fully, it is our belief that there will be no problems here because of the basic principles of separation of databases and consent for transfer of information outlined above. 3. Informed Consent- We have not yet received the consent documents for review, although we have been assured that there will be separate consent forms for the different populations in this complex study. 4. Excessive Inducements- The question of the amount to pay the subjects was different in this study, because it was felt that we needed to take into account standard Chinese practice in connection with donations of blood, since such a donation has a different cultural meaning in the Chinese setting. Dr. Irons has proposed a payment schedule which ranges from $30 for control subjects for completing an interview (see analysis above) to $200 for those who donate blood and undergo a bone marrow biopsy and aspiratIon (this being comparable to what the Chinese receive for donating blood for transfusions). 5. Questionnaire Development- An analysis of confounders will be done (Section 2D) by use of a questionnaire. A concern was expressed about whether the questio.Q~.~lch might be a!Oked:are iDaIlPLQIIDateJn.the Chinese cultural setting. The questionnaire remaius_ to be developed. 6. Control of Results- - Although this is an industry sponsored study, it is important that the investigators retain final control over what is said in all publications to protect the integrity of _ the stud}' and the acceptability of the results. A communication plan, built around this principfe:remams tooeaevelopecr:---- ----.- - - - - - - - - - - - - - - 7. Other Issues- Two issues remain to be addressed in appropriate sections of the protOCOl not yet developed: (a) how clinicians/subjects will be informed of clinically significant information discovered in the disease progression follow up visits and how puelic health official~1 be InfQIm~.!9bout the S~QCW.9Llq~Lace..visits indicating ..!:lQsaj.e..c~.9!J.s";,,(b o~...!!1aterial Will Qf!..J.!~ed.lo~ater studies, inch,J.Qlfl9_genetic.studies. What we have heard from Dr Irons ,/ .)v?' ,lttvJ-~.J /Ar'/ . .~ makes us feel confident that these issues will be dealt with appropriately. Summary of What Remains to be Done- The ethiCS review process needs to 3 HAZ-SHA-001460 .. review the completed "front-end" of the protocol once it is available (probably, in later February). In addition, a series of consent forms, and the questionnaire about other factors, need to be developed.by Dr. Irons in close collaboration with his Chinese colleagues and a Chinese bioethicist, and the final results need to be reviewed in the ethics advisory process. One other issue remains to be resolved in that process: is there any place in this study for interim review of results (to insure that any convincing results of great public health interest are released if firmly established), or is that unnecessary in a case control study (in which no participants are put at risk by their continued partiCipation). Although there is more work to be done from an ethics perspective on this study than on the previous study. we believe that it will certainly meet all of the remaining issues and be ready to move forward from the perspective of an ethics review. Molecular Epidemiology Study The ethics review process has not yet seen any part of this protocol. From the discussions with Dr. Irons, there is no reason to believe that there will be any insurmountable problems from an ethics perspective with this planned stUdy. but saying anything more would be inappropriate until we can review the "front--end" of this protocol. ------------------- <1 HAZ-SHA-OOl461 ----_ .._ - - Harrison. M.e. (Myron) -------------------- From: Sent: To: Subject: George Woodall [Woodallg@api.org] Wednesday, February 07, 200111:14 AM Baruch Brody (E-mail); Lorraine Twerdok (E-mail); Lynn Russo (E-mail); Myron C. Harrison (E-mail); Norm Zeiser (E-mail); Otto Wong (E-mail); Patrick Beatty (E-mail); Rich Herold (E-mail); Richard Irons (E-mail); Robert Schnatter Ph. D. (E-mail) FW: Ethics Review Progress Report Benzene Study Ethics Workgroup; Below is a message forwarded from Baruch Brody summarizing the progress on the ethics review process. In subsequent calls with Dr. Brody and Dr. Irons, it was decided that a conference call will be set up for the morning of Wednesday, February 21 from 11:45 AM -1:15 PM (EST). (The logistics for the conference call will be sent later.) The subject of the call will be the review of the protocols for the Disease Progression Study and the Molecular Epidemiology Study I which is anticipated to be made available to you either by the end of this week or early next week. Thank you, George M. Woodall, Ph.D. Senior Toxicologist American Petroleum Institute 1220 L Street, NW Washington, DC 20005 tel: (202) 682-8067 fax: (202) 682-8031 woodallg@apLorg :, 'I / 1' / j/ I ---Original Message--From: Baruch A Brody [mailto:bbrody@bcm.tmc.edu] Sent: Saturday, February 03, 2001 10:35 PM To: Woodallg@api.org Cc: pwbe@chevron.com Subject: Here is the text of my interim report which I promised I would send to you ASAP. Please distribute it to the stakeholders and others, as you see fit. BARUCH INTERIM PROGRESS REPORT ETHICS REVIEW PROCESS BENZENE SHANGHAI STUDIES ---. ---_._------ ----- -_._-- ----------- Feb. 4, 2001 The ethics review process has been examintng three proposed studies, the NHL-AML study (to be conducted by Dr. Wong and team) and the Disease Progression and Molecular Epidemiology studIes (to be conducted by Dr. Irons and team). This report summarizes the work dona by the team up to a conference call held on January 22, the results of which were summarized to the Stakeholders Meeting at API Headquarters on January 26. NHL-AML Protocol 1 HAZ-SHA-OO 1458 At our meeting in Salt Lake City on October 26, 2000, we reviewed a draft of Dr. Wong's protocol and raised a number of issues of concern. He has addressed them in a series of revisions, culminating in a protocol dated January 11, 2001. It was the unanimous conclusion of the group that we were satisfied that the issues had been appropriately addressed, although there were two on which further work needed to be done by Dr. Wong and there was one on which there was still some disagreement. Let me review what was done, issue at a time: 1. ~eo.e.fits and burdens to subjects apd to community- this form of case control epidemiological study, which primarily involves a questionnaire interview of cases and controls and the gathering of exposure information, offers primarily the prospect of benefit to the public health in Shanghai by providing the basis for a SCientifically sound formulation of better benzene exposure regulations, by identifying workplaces with unacceptable levels of exposure, and by identifying other risk factors. Dr. Wong has strengthened the potential for achieving these benefits through his contact with Dr. Liang. Except for concerns about confidentiality, there are no real risks to the subjects of the study. So the benefit-risk ratio is quite favorable, so long as issues of confidentiality are addressed. 2. Confiden~lity- the entire effort in Shanghai will involve three components: the diagnostic laboratory to be developed by Dr. Irons, Dr. Wong's study, and Dr. lrons'sstudy. The databases for these three studies will be kept separate. Informed consent of subjects will be required to transfer information from one data base to another. Even when consent is obtained for such a transfer, only relevant information will be transferred. All this is spelled out very carefully in Section 2.10 of the protocol. 3. Informed Consent- At the request of the ethics review process, there Will be two separate consent forms, one for the cases and one for the controls. Each will clearly explain whether they are being asked to participate because they are cases with the disease in question or whether they are being asked to be controls The consent forms are complete; what remains to be developed is...a summary information sheet wl'ich explains the study in a cultllrally sensitive fashion ,/ 4. Excessive lnducemeo~- There was considerable discussion of the amount to pay the subjects. On the one hand, one did not want to exploit the Chinese SUbjects by paying them less than one would pay American subjects for participaing in a similar study. On the other hand, one did not want to make the inducement so good as to make the offer impOSSible to refuse. The group decided to emphasize the former value and to avoid concerns about exploitation by paying $30, an amount similar to what Dr. Wong pays subjects for such studies In the U.S. 5. Questionnaire Development- In addition to asking about employment history, Dr. Wong proposes to administer a questionnaire to identify other possible risk factors. A concern was expressed about whether the questions which might be asked are inappropnate in the Chinese cultural s ionnaire re . to be developed. - . _ - . ontrol of ~sults- Although this is an industry sponsored ---.Stuc4'.,Jt is..i!!1l2.ort'ant th9t the investigators retain final control over what is said in all publicabons to protect the integrity of the study ana-- the acceptability of the results. This, and other aspects of a communication plan, are carefully outlined in Section 2.13 of the protocol. ,/ Summary of What Remains to be Done- The information sheet for the consent process and the questionnaire about other factors need to be developed by Dr. Wong, in close collaboration with hiS Chinese COlleagues and a Chinese bioethicist, and the final results need to be reviewed In the ethiCS adVISOry process. One other issue remains to be resolved in that process: IS there any place in this study for interim review of results (to insure that any convincing results of great public health interest are released 2 HAZ-SHA-0014S9 jf firmly established), or is that unnecessary in a case control study (in which no participants are put at risk by their continued participation). Although there is work to be done, this study is ready to move forward from the perspective of an ethics review. Disease Progression Study At our meeting in Salt lake City. Dr. Irons presented his original ideas about this stUdY. They have been modified and developed extensively since that time, and what we now have available is part (not all) of the "front-end" of the protocol. Still, the group felt that we had enough information to make a tentative evaluation of the protocol from an ethics perspective. Once more, this will be done on an issue by issue basis: 1. Benefits and burdens to sub'ects un; w This study requires the "evelopmen 0 __0 ate diagnostic la..boratoll' and the training of local personnel to do the diagnostic work. This alone represents a major contribution to Shanghai since the laboratory and the /.---- trained personnel Will remain after the study is complete. In addition, -.-/ this will im rove the die no . re . . . I atients, and this may be ot clinica va ue to them, especially for cases which will be f01l0~R six lllQoth inte[Vats (the cases of BP, AA, and MDS). All of this is spelled out in Section IV of the protocol. As the major risks to the subjects involve questions of confidentiality, the benefit-risk ratio of this protocol is quite favorable, so long as these issues of confidentiality are addressed. 2. Confidentiality- Although this remains to be spelled out more fully, it is our belief that there will be no problems here because of the basic principles of separation of databases and consent for transfer of information outlined above. 3. Informed Consent- We have not yet received the consent documents for review, although we have been assured that there will be separate consent forms for the different p0pulations in this complex study. 4. Excessive Inducements- The question of the amount to pay the SUbjects was different in this study, because it was felt that we needed to take into account standard Chinese practice in connection with donations of blood, since such a donation has a different cultural meaning in the Chinese setting. Dr. Irons has proposed a payment schedule which ranges from $30 for control subjects for completing an interview (see analysis above) to $200 for those who donate blood and undergo a bone marrow biopsy and aspiration (this being comparable to what the Chinese receive for donating blood for transfusions). 5. Questionnaire Development- An analysis of confounders will be done (Section 20) by use of a questionnaire. A concern was expressed about whether the questio.!!~_~ . . r ro..the Chinese cultural setting. The questionnaire remaios_ to be developed. 6. Control of Results- - Although this is an industry sponsored study, it is important that the investigators retain final control over what is said in all publications to protect the integrity of --.;'-bu:"t:h:;ei~lsttaurdoyu'nadndthtishepraincccieppleta, breilimtyaoinfsthteoroeseualtse. vAecolompmeunaic.a-t-io-n-p-la-n,.- - - - - 7. Other Issues- Two issues remain to be addressed in appropriate sections of the protocol not yet developed; (a) how clinicians/subjects will be informed of clinically significant information discovered in the disease progression follow up visits and how public hec:illb..Qfficia'~ be InfQ!med about the suits OCW..9r.~Q.La;6e_visits indlcating.!:!!!sal.a..c~lJ.s..;.Jb o:-t.!..!!laterial Will Qsl..J!s.ed.lo~ater studies: inch,J,gID.9_genetic.stOOies. What we have heard from Dr Irons ,/' !tyJM-~'J~/ ' ~ makes us feel confident that these issues will be dealt with appropriately. Summary of What Remains to be Done- The ethICS review process needs to 3 IU\Z-S~-OOl460 , review the completed "front-end" of the protocol once it is available (probably, in later February). In addition. a series of consent forms, and the questionnaire about other factors, need to be developed.by Dr. Irons in close collaboration with his Chinese colleagues and a Chinese bioethicist, and the final results need to be reviewed in the ethics advisory process. One other issue remains to be resolved in that process: is there any place in this study for interim review of results (to insure that any convinCing results of great public health interest are released if firmly established), or is that unnecessary in a case control study (in which no participants are put at risk by their continued participation). Although there is more work to be done from an ethics perspective on this study than on the previous study. we believe that it will certainly meet all of the remaining issues and be ready to move forward from the perspective of an ethics review. Molecular Epidemiology Study The ethics review process has not yet seen any part of this protocol. From the discussions with Dr. Irons, there is no reason to believe that there will be any insurmountable problems from an ethics perspective with this planned study, but saying anything more would be inappropriate until we can review the "front-end" of this protocol. ---_.--------------------------- ------ ---.... _------- -------..- - - 4 HAZ-SHA-001461