Tobacco Documents Online

29-10-1997 17 = 03 1=P.OM QI P.OUAL I TY PNAP.MAhIALYS I S TO Lam19mA27i12991 P. la 1 w covaM'CE-.--"~ TME DEYE6OPMENT SERVICES COfAPAMY Datc_ 29 Uctot,c.t 1997 From: Mark 13ent[ey FAX Covance Laboratories Ltd. nrlay R'narf Harrogate Morth Yorlechiro LIG3 tPY United Kingdom Tel: +44-(0)-1423-500011 Fax: +44-(0)-1423-508745 To: Dr Bruce Davies Fax Number: 00 1 804 274 2891 Philip Morris Copy to: K Phillips, C Swinton Dr R Carchman, Philip Morris (please copy internally) Re: Proposed Smoking Study Pages (including cover): 3 Dear Dr Davies Further to your recent enquiry regarding an investigation to determine whether the addition of ammonium compound.5 to cigarettes enharcPS the availability of nicotine to the smoker, it is proposed that a pilot investigation should be pcrfornied in thc first iFista.ncc, rzs outliulcd below :- • For this pilot study subjects would be recruited from employees at this site. Ethical approval for the study will be sought from our clinical research unit based in the City of Leeds, 15 miles from our Harrogate facility. • Volunteers will be required to give informed consent for participation and will be screened for height, weight, age and respiratory function to ensure that they are within normal limits. • The study will be a blind, 4-way crossover design with six subjects recruited, smoking each test cigarette (eg control + 3 modified units, A-D) i.ti duplicate. Subject 1 2 3 4 5 6 DAY I DAY 2 DAY 3 DAY 4 A B C D A B D A B C D A C D A B C U B C D A B C Using this regime, each subject will smoke two cigarettes of each type under test conditions (8 cigarettes in total). (bafidentiality Notice: This facsimile transmi3sion m,ty contain confidontial or logally privilaged infi rrnation which is intendod only for thc use ofthe individual or entity nautad on this trattsmittal shccx. If you are not the intended recipient. you are hereby notified that any disolosure, copyittg. distribution, or reliance upon the contents of this f<tcsimilo is strictly prohibitcd. Tf you have received this facsimitc tr.utsmission in otror, plcase notify us immediately by tclcphone so that we can arrange for the retum of the transmitted matorialc to us at no cost to you. N O t}S W ~ O CW -p N `~3

29-10-1997 17:04 FROM AIRQUALITY PHARMANALYSIS TO 001B042742891 P.02 r 29 October 1997 Page 2 • -sklbJects shoulct be alloyved to accllmatlze to smoiCing me test elgarettes, ror a perioa of a few days to a week, prior to the test period_ However, since there will be several ekiend'~tie t-igarPttP °`hrnncl" nncler te-;t (control) prior to testing- all the cigarette types. Subjects will be required to refrain from alcohol consumption for a period of 24 hours preceding the test period and will bc; rc;striclrCd tc smoking two test cigarettes o.u thc day of testing until the f nal blood sample has been taken. • Two test cigarettes will be smoked by each subject on each testing occasion (day) and will be smoked at approximately 4-hour intervals. • Smoking procedure :- - test cigarettes wili be stored in a controlled environment (22°C, 60%R1-I) for at least 24 hours prior to use. each test cigarette will be smoked using a puff prof le analyser capable of determining puff volume, puff interval, flow rate and pressure change. following each puff, a fixed volume of air will be inhaled (eg 500 mL) drawn from an air filled bag and held for 2 seconds prior to normal exhalation through an acidif ed Cambridgc filter. the test cigarette will be smoked at a rate of I puff per minute for a total of 7 puffs, all post-puff exhalations passed through the same Cambridge filter. • Blood samples (5 mL by venepuncture of ante-cubital veins) will be taken at the follow-ing times =- I minute prior to the f:rst puff 30 and 55 seconds after the first puff 30 seconds after puff 4 1, 15, 30 and 60 minutes after puff 7 Blood samples will bc co.llcctcd into tubcs containing lithium hcparin anticoagulant and centrifuged; the separated plasma will be transferred into polypropylene tubes and stored frozen (nominal -20°C) prior to analysis. • Puff profiles recorded for each test cigarette 'smoking' will be used to machine smoke identical cigarettes and hence determine `total' nicotine delivery. Carrying out these procedures, as described above, will provide the following information :- • the total amount of nicotine delivered by each cigarette to each subject on each smoking occasion. Confidentiality Notice N This facsimilc tratumission tnay contain confidential or legally pfivileged inforntation which is intrndcd only for the u_sc of the individttal or entity tu3mad 0 uu thi.ttmJourittui .hcct. ICyou a.e riot iIie iuteadtd recirittnt, you am 1.•creFy notit5cd that any d'ucloatuc, wpyiag, diatribution. or rcaiunco upoo tho (Tti ~rn~mnc. .•.f tlt;n far.ain:ile is strieety pmhibitcd. tFyou hnva rwoived thu Rtcaimil4 IrnnGmia;.ion in crror. nlcn.ec notify ua immodietol•; by ielaohone Go that ~ we can arrange fbr the rtttun of thc transmitted rnaleriAls to trs at no COst to you Q`t 0 W ~ R1 oz

29-10-1997 17:04 FROM AIRQUALITY PHARMANALYSIS TO 001B042742E91 P.03 .,: r 29 October 1997 Page 3 • concentration profiles Iar nicotine in plasma during and following each smoking occasion enabling the calculation of pharmacokinetic parameters (t,,, tmnx, Cn,;,x, AUC (0-t, t-oo, 0-0o)) • total amount of nicotine exhaled immediately follow-ing puff inhalation. Statistical evaluation of the information provided will be performed to evaluate any potential differences in nicotine availability to the smoker between each of the test cigarettes investigated. A provisional cost of £25,600 has been estimated for this pilot investigation, as described, to include the following elements Ethical approval Subject remuneration (6 subjects) Sampling costs (3 persons @ 4 days) Sample analysis, plasma nicotine (384 samples) Pharmacokinetic analysis Statistical analysis Management Reporting # Analysis of mainstream. (MS) tar and nicotine as smoked on study (48 samples) # Analysis of exhaled nicotine (48 samples) # Analysis of test cigarette ammonium phosphate (`salt') content # Analysis of test cigarette MS tar and nicotine yields # NB Covance Laboratories Ltd do not have a puff profile analyzer or a smoking machine suitable for determining MS tar and nicotine yields. The analyses highlighted above may be performed by another facility on our behalf (eg LABSTAT Inc). The above cost estimate does not include the cost for these highlighted analyses. I hope that this draft proposal meets with your approva.#l and look forward to receiving your comments on the ideas that have been put forward. Once you have had a chance to review the contents of the proposal, perhaps it would be appropriate to arrange another conference call, or a meeting to further discuss your requirements in more detail. Please give Carolyn Swinton, Keith Phillip's secretary, a call to arrange a suitable i'orum at your convenience. At Keith's request, please can you make sure that Richard Carl:chman receives a copy of this communication. Many thanks and kind regards Mark Bentley BSc CChem MRSC Study Director Department of Air Quality Monitoring for Covance Laboratories Ltd Confidentiality Notice This 1lcsimilt transmission may contain conrsdential or Iogally privilcgcd information which is intcndcd only for the use of the indiv iduaf or entity named on this transmittal sheet, if you are not the inrcndcd recipient, you are hereby notiGed that any disclosure, copying, distribution, or reliance upon the eontcnt4 ofthis facsimile is strictly ptohibiteei, if,you have received this f:tcsimile traiLSmigsion in ctmr, please notifjy us immediately by tclephone so that we can arrungc for the rcttun of the transmitted materials to us at no cost to you