Tobacco Documents Online

WSA Mission To understand the science of smoking and health, communicate with the scientific community, evaluate proposed product changes, and guide reduced harm product development fvGSVffiiio~usdl/ WSA mission statement

WSA PROCESS FOR REDUCED-HARM Goals - Organization - Process - Focus SCoR Commercialization Team Meeting February 9, 2001 The presentation provides information about the current goals for harm reduction, the organization of WSA, the general process for making claims, and some of the current project areas in WSA to bring PM closer to making this happen.

Dose Response (Toxicity) Assessment Review of the literature and experimental data to derive the amount of reduction in a particular smoke constituent that would result in a decrease in biological activity. In the absence of such an analysis, our current recommendation is to achieve reductions of 90% or greater. Y41115Cdlf~uimMniq FeGwWmlrvrywCdS The next stage of the Risk Assessment is the dose response or toxicity assessment. This involves ....

WSA. Organization I • INBIFO • Product Integrity (PI) • Human Studies (HS) • Product Assessment (PA) • Regional Units (EU/Asia) 66£BVLS80Z ' Fa Diicuedai Aspom Only

Acceptability Testing • Concern Level II -Level I + -Genotoxicity -Cytotoxicity -Smoke Chemistry R . ~. ~-. _ i~~ FuLim®MFA~Y The next level of concerrr(level II) would include the same testing as level one plus genotoxicity (damage to genetic blueprint of the cell), cytotoxicity (cell death) and smoke chemistry which consists of about 50 compounds found in smoke that have be identified by IARC and or the Consumer Products Safety Commission as probable or known human carcinogens

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WSA Organization • INBIFO • Product Integrity (PI) • Human Studies (HS) • Product Assessment (PA) • Regional Units (EU/Asia) uaisuc~~nw.,n7~n 5 Groups that make up WSA INBIFO - laboratory group does testing PI - reviews materials that make up products for approval HS - exposure assessment PA - rolls it (the above) all together Regional Units - deal with issues that arise in the EU and Asia regions -

Smoking and Harm Reduction "We agree with the overwhelming medical and scientific consensus that cigarette smoking causes lung cancer and other serious diseases: " w ~.o , ,om .ra "We take the pursuit of harm reduction as a priority. We are pursuing harm reduction in a responsible way. We welcome involvement of the public health community." R5A presentatlonlo WHO "We will develop and launch a conventional cigarette with a significant reduction in potentially harmful smoke constituents by the middle of 2002." Sbaem.a~~ Addr~.r~ ~M vsro~aaxcuiamnamamu.na raum.~rm+..ah Overhead shows PM's statements regarding Smoking and Harm Reduction. There has been an evolution over time and it is reflected here. The top quote is from the PM web site. The next three bullets are from Rick's presentation to WHO. The last is a statement made during Mike Szymanczyk's State of the Business Addresses, December 7, 8, 11, 2000 Also made public to Financial Investors.

Acceptability Testing ,~_ -- =tT =t+~~.~ • Concern Level I -Disclosure -Analysis for potential contribution to smoke by pyrolysis 29V1 $'MCmumiW~slwAMni FuLVmuaPUP'm'Vly The toxicity assessment is done in a tiered approach with the level of testing inereasing with the concern level. Concern level I is the lowest of the concern levels and would involve ....

r:.=. ;..a Exposure Assessment Substance Amount _ _ _-_,_ Fxposure Frequency Exposure Route 1 .. ~~...~.~~ _".~.- . PoNu;atiori Studies Switching Studies M, s~C~4a~ The exposure assessment portion of the risk assessment paradigm is something new for PM. Here we are looking at Human studies - the amount someone gets, how often, how long and how they are exposed (route). We are planning two types of studiespopulation and switching studies.

*se Response(Taxicity) Assessment Review of the literature and experimental data to derive the amount of reduction in a particular smoke constituent that would result in a decrease in biological activity. In the absence of such an analysis, our current recommendation is to achieve reductions of 90% or greater. I 6ZC8bLS80Z I 17777 'i-7 'ir _, 7I i'-7 1 i For Difcuwion Puvpau Only

Smo' i. .g and Harm Reduction "We agree with the overwhelming medical and scientific consensus that cigarette smoking causes lung cancer and other serious diseases." gww.nhiljp,morr(s.com "We take the pursuit of harm reduction as a priority. We are pursuing harm reduction in a responsible way. We welcome involvement of the public health community." WSA presentation to WHO "We will develop and launch a conventional cigarette with a significant reduction in potentially harmful smoke constituents by the middle of 2002." State of the Business Address 12/07/00 94£8VL980Z , F«amussim rurposa Only

Ir 5££81~L580Z ' Acceptability Testing Fa Disw.m Pn^µwa. Only

0 I Acceptability Testing ' Concern Level II -Level II + Pii:.3Lilk~i `,l3'.i: IN m -94-Day Inhalation L££8tiL580Z ~ 7„ I I I ~ ~ I Par Diwwrinn Pmpo.e. Only

Acceptability Testing ~- -- - - ~-Y _- ~ ' Concern Level II -Level II + -90-Day Inhalation NtT~ ]fdCmmxiffunlmAkavry The highest tier is concern level III that would include in addition to all the other tests a 90 day inhalation study using rats.

SCoR Product - Timeline • Begin INBIFO Evaluation of 1st Prototype January 2001 • Specifications for 2nd Prototype March 2001 • Make 2nd Prototype INBIFO Samples April 2001 • Begin INBIFO Evaluation of 2nd Prototype May 2001 • Results INBIFO Evaluation of 1st Prototype -January 2002 • Results from INBIFO short-term tests " • Results from INBIFO Evaluation of 2nd Prototype May 2002 • Launch July 2002 • Initiate Human Studies after May 2002 Let me end with the overhead on the timeline for SCoR

These are the steps in the typical risk assessment scheme. It is reasonable to think of the approach to harm reduction in these terms. Hazard identification is the finding of targets to address. In terms of disease categories they are: lung cancer, CVD, and COPD. This can also go beyond that to the identification of targets for reduction in chemistry and in biological tests. This step is conducted by all of WSA. Toxicity Assessment is more commonly known as dose-response assessment. This is the stage where we say how large of a reduction would be meaningful. This step is conducted by all of WSA. Exposure assessment is how much to people take in. This means doing human studies. This step is principally conducted by the human studies group. Risk Characterization is putting it all together. This step is conducted principally by Product Assessment.

Hazard Identification Provide recommendations in order to result in reduced-harm associated with major smoking-related diseases. • smoke constituent(s) targets for reduction/removal • appropriate biological tests. YA.a19GHMVwaWVtimAlmvV ~~~~H+~WN'.+~Y This is the first step-in the Risk Assessment paradigm. Hazard ID involves providing recommendations in order to result in reduced harm associated with major smoking related diseases. Specifically identifying smoke constituent targets to reduce or remove and determine the appropriate biological testing that should be done. A major point is that we are making product changes with the ultimate goal of affecting human health.

Process for Reduced-Harm Product Use and Claims MupYWliryTUb 1 -S~mY.flremhlry 1 -O~nbKFIIY -~~bX ry ~9~LNnanbinFebWn ~ Sp.d.IHCmnWictlen £ g~NVmqdueKn 1 Tab,i(n.aN : T..b,lii..GM 3 E ~ ffi ~ ~ -- ~ 8 euMkMw. TwtlnY . Po~ HumnE~n SM1mETmnHUm.n lmCTamH~~nun ~ V m Mx.~ NWNEILM81uNr ~ E~ Sd~~ € 1 -&wimk.nW ~` -9mewMUea B° EyYlpnbkpy .HemHnnlm F ~ 1 w r.a wtrq f7 6-12 Months 12-36 Months 12-36 Months 5-20 YBSPs iwm:Da~ma.~„~wa. icn.brb.unp~mleer.k~ur.nl wvoa.r..e.~~n This is the version submitted to the IOM. Overview of the process. Similar to FDA approach for drugs where look at safety and efficacy, we are looking at acceptability and reduced harm claims. As always acceptability test and subjective testing and adding additional work as part of claim and accessing human exposure EXAMPLE Provisional Product Claim- May reduce exposure to CO Product Claim - Reduced exposure to CO may decrease risk of CVD Confirmed Product - Claim reduced risk of CVD

Prccess'Fbr Reduced-Harm Product Use and Claims ., ~ AtosptabNity TWs - Smoke Chemistry I - (ien0toxlcity I - Cyiotoxicity I Sub chronicinhalation ( 8pec1N Harm R.ducHon E Speciai Harm Reduction T.sts, if needed ~ Tests, if needed e.g.OrgaN V E ~ System Teating ,5 cc a ~ v ~ Y L a ~ C ~ ~ Q Sub).ctiws T.sting > p, Smoke Paneis Human Exposure Short-Tenn Human Long Term Human M.asur~ro~nt Health ENect Studies Health Effects Studi Epidemiology I - Biomarkers d - Biomarkers of - Hartn Reduction I exposure I Effect Monitoring 6-12 Months 12-36 Months 12-36 Months 5-20 Years Time for testing, not development For Disnwion Purposes Only as! m 6Z£8ti1880Z

Proposed Human Study Design Study design: single crossover Number of groups: 3 • Test group: adult smokers switching • Reference group: cessation group • Control group: adult smokers Group size: 20 - 50 adults (>21 years of age) Duration: 9 months plus analysis and report writing NWI Y4Cwumniliutim We'q Here is what a human study should look like. The study design is a single crossover which means that the test subject is switching from one product to another. There are 3 groups the test changes (switches cigarettes), the reference group with stops smoking and the control which continue to smoke their regular cigarettes as is normal for them. Them group size is 20 - 50 adults smokers and the duration of the study is 9 months for data collection and additional time for analysis of the data and writing the final report. These test will be run under the strictest International guidelines (ICH, FDA and Helsinki accords). I.e. above and beyond what is normally required so that we can take the data anywhere and use it -

Acceptability Testing • Concern Level I -Disclosure -Analysis for potential contribution to smoke by pyrolysis 80Z , ~ £££8tiL5 I Fac DLuw.ion Pnrpoua Only ti I

Proposed Claims Substantiation Requirements Manufacturing and quality controls in place to assure the consistent production of a product upon which any claims are based. During Production: Change control system(s) in place to assure that: - if changes are made to any claims; that there continues to be valid supporting data and evidence to support such changes - if changes are made in suppliers, supplier requirements, production processes, or other manufacturing factors that such changes will not undermine the claims. Documentation: - literature%itations used with regards to any claim. - test methods to substantiate any claim. - experimental and human studies upon which the claim is based. Testing on final product design (marketable product). Discussion with public health authorities and other appropriate parties that the data and informaHon supporting any claim constitute valid scientific evidence. Yt0~9'dlCm:m3WUUmMay Fvquud.VUqauWy Making a claim involves a cultural change for PM. In past we have been able to make changes to our product rather freely. That is not the case with claims. With a reduced harm product we need to guarentee that all the products are reduced harm and that it is maintained therefore we cannot change it freely. Really talking about a change control system 1 - Change control 2 - Also need the documentation for the product (not a prototype) 3 - Discussions with public health authorities etc.

Proposed Human Study Schedule • New Product "Limited smoking" (cig./day), New Product No smoking r-6 rrronlhs rm~ vcx~ c,m,~a„u"s+udw n.uam~ox. Ta 3 m Ti 6 months T2 Determine biomarkers of exposure/effect in: Step 1: adult test smokers after normal smoking of their preferred brand style of conventional cigarette for at least 6 months (TO). Step 2: adult test smokers who switch to test cigarette and continue to smoke same number of cigarettes as before for 3 months ('9imited smoking") (T1). The control and reference groups are also tested at the same time points. Step 3: switchers who continue to smoke test cigarette without any restrictions for another 6 months ("normal smoking") (T2). Once again the control and reference group are also sampled.

WSA Focus 2001 • Identification of potential links between smoke constituents, host factors and the following disease endpoints - Lung cancer - Cardiovascular disease - Chronic obstructive pulmonary disease - - • Identification of smoke constituent targets • Identification of biomarkers (exposure, effect) • Plan and conduct human exposureleffect studies - Pilot and Total Exposure Study (TES) (July 01) - Accord JLI (Sept 01) - OASIS in Japan (Jan 02) - SCoR (2002) - Overhead shows the focus for WSA in the year 2001 Concentrating on 3 disease endpoints ID smoke consittuents - major Risk Assessment process ongoing, our priority is gas phase components (1,3-but., aldehydes, and CO) H) biomarerks Humand studies pilot will benchmark various classes of smokers (4 tar groups, look at various demographichs) what the smoker is getting today and validate assays. This is a population study and will involve 3,000 - 6,000 people. The remaining three studies are swithcing studies and will start with Accord. - - DATES SHOWN ARE TARGET START DATES. - N

Froposed , Human Study Design Study design: single crossover i Number of groups: 3 • Test group: adult smokers switching • Reference group: cessation group • Control group: adult smokers Group size: 20 - 50 adults (>21 years of age) Duration: 9 months plus analysis and report writing Sti£8tiLS80Z 771",,, T., „r9 For Diicuwim Pwpwe. Only w

Process for Reduced-Harm Product & Claim(s) Ac2pt.b0ltyTeab ~ -9mohaChemb4y~ -Gewroxicily Lymaxidy specitl Hnm NeduMo Subabmnk Inheletb Tuh,iln.edM /' NBIF( N ...a.oru.d ~ CRC 8 sy.nm rrun u a ProouctProductlon f Humnn Evpneu Mee.unment a~srM..a WSP4NBIFO/CRC Months 12-36 Months 12-36 Months Time for wwe. mt dwebpment rsCtllCm,.mJ,uuwMrctlry Frcdw®vmpa..qilf 8-20 Years a PA/PUCRC/INBIFQare involved in this testing (point out area in slide)

SCoR Timeline • Begin INBIFO evaluation - SCoR 2 May, 2001 • Begin Pilot TES May, 2001 • Results Pilot TES Dec. 2001 • Begin TES - Jan. 2002 • Results INBIFO evaluation - SCoR 1 - Jan., 2002 • Results INBIFO evaluation - SCoR 2 May, 2002 • Begin Cross-over Study on SCoR product May, 2002 • Launch SCoR Product (no claims) July, 2002 • Results TES Jan.2003 • Results Cross-over Study for SCoR May 2003 (may provide data for provisional claim)

Exvasnre Assessment a Pvpulation Studies Switching Studies bb£8bL880Z 111I Iq ~1 7r7111 ,1 Far D'ncwria¢ Aayaoe. On1y I

• • • • • • Begin INBIFO Evaluation of 1st Prototype Specifications for 2nd Prototype Make 2nd Prototype iNBIFO Samples Begin INBIFO Evaluation of 2nd Prototype January 2001 March 2001 April 2001 May 2001 Results INBIFO Evaluation of 1 st Prototype Results from INBIFO short-term tests -January 2002 ******* • Rr~suits from INBIFO Evaluation of 2nd Prototype • Launch • Initiate Human Studies 65E8tiLS80Z i l I,'' ~I '11~1 '~' I I L I li I I d I I .. I . For Dirwaon Pi¢pom Only May 2002 July 2002 after May 2002

Process for Reduced-Harm Product & Claim(s) DnNOpmeM Acttpbb0iry Tev. SnnFeCAcm'ovy~ 1 Gymmv i~h 1 SPeelel H.Im Fauctia BubcblmklMblalkn TMb~HMedetl BIF( 9~o'M"" CRC ~ •syafemTwun rotlucl Prouction ] `m W6MNBIFpICRC 4 Months IMOISLbMCmmemo4utl®NUny ep.~xl H..m n.n.<u.~ Tene,xae.een NBIF E CRC ~ U ~ ~ ~ 6 Hunum Expw SIIOM1Tenn Humen tnnG Tmm Hum.n Meuunment HeeHb Etkcl Studl HeMN Ettecb 51udIeM HS Epidamloblry ~BmxMxaa/ -B/em.XUnuf _µe~qyi~ly~ EHxY ManecmG HS 12-36 Months 12-36 Months 5-20 Years Timelm 1mfmL. ~ dwebpmenl fvlYmiuPUpra0.lr m D In the process the hazard identification step is represented by the area to the left of the box. PA in coordination with INBIFO and WSA is responsible for this area.

~.v~.w z~aw.~.~ ~mowM .eaw .rows + ~ ' mr O AMHU.a J F PyM J J Mna 0.Y J F AW p~ AY J J kq 06 J F fy~ Mf J Y Ra/fctC.WY.w IOx1 f Cberele.hM[L /r.k. mm~ Mrn~asm~..m~ n~s e~ns~e~ oww. ~ e cmae@.m... z.te ~ e wpoeo.w.n izw~:. .._....`..._ - _ . Mu.an +e.e.v ~ia,wM ~a.w. +e qut~tl5~preso, a w ~J 13 anapm... o»w. 11 16 6J~WiCmP6b Cnk e ~..y. 10 ~.N.OWery 13vk. ~ n s...ue.nn uoe.r +e mauiuf.u~ io... Sl wm~[asmm.an awln „ o~, a FMkip f+i.e. 10 Wu 9 B.WbnCmGkB 13Wa _ e. ryry~C.Hen IE.Ru a au .em..a~ amy m Mqe~ia`.ro. ie~ n cquwh.uea. e.v m lmwes~mnew. ~ senap:mw o..~. • ua~an~.e. - -xw o fi a~..,~cenous x n .ndx u. . y . . .n This overhead is included to give a feel for the time required to complete the various testing. These are the typical durations. They can be accelerated occasionally but not every study can be conducted on a reduced timeline. This include time for a gr- planning and post experiment documentation. The real message here is to start coordination with PA/PI EARLY. Subchronic inhalation study (90 day) really takes closer to 2 years. It takes so long for these test because they are done under GLP conditions to ensure worldwide compliance and the acceptability of the data.

~.,V_~ I~y ,_'.. ~~. :y.. Process for Reduced-Harm Product & Claim(s) PUPA pA Tmp4bpiryTeeY SnoknCM1SmeVy 1 -aamm.iciy bchmnylclnM1elancn 1 T 41.rcHarnmd~netluctbn ~ ® T.~e1.WHn..awnetlucuon BIF H sy.won.T..nn CRC U NBIF CRC ~ ~ 9 ~ U ~ a $ Pradua oevelopmem ProductPraduNOn Y a c 2 A a a` a 0 1 a` Humen Espo.c . SM1orl-T.nn Humen Lony Tam Humen Meeeunmenf HS HWNEHedStud HWM Eihet. 901tlN.r HS Epkemiobpy 1 eNmexwad -9bm.rbnor .wimR.aunqn en.n wniw~.w HS Months 1236 Months 12-36 Months 5-20 Years WSNINBIFO/CRC ~ znarxucc~mm.w.mmw~a Time br taelin9, mt dmnb~mmenl v " tw~car Hopefully now you see how this all fits together

Process for Reduced-Harm Product & Claim(s) P'7iu', DSw«•I;,~p,~r;, . Research ., P~IPA PA Acceptabliky Tesls Smoke Chemistry I ~ - Genotoxtoity -Cytotoxicity Special Hann Reduction E Special Harm Reduction - Sub-Otxonio Inhalatlon Tests, ii needed ~ Tests, H needed ivsiF( U raalF ", Sys • 4T CRC CRC ~ ~ t , . ati ~ v a ~ "' Product Production m 0 ~ a ~ R ~ C z 10 ~ L - , ; Market Surveillance I Q ~ a Human Expos Short -Tenn Human Long Term Human Measurement ~S Health Effect Stud Health Effects Stu HS Epidemiology ~ Biomarkers of - Biomarkers of - Harm Reduction I exposure Effect Monitoring I WSAIItJB6FO/CRC Months 12-36 Months 12-36 Months 5-20 Years Time for testing, not development LZ£8t~'LB8OZ F~ a~ ~~+~y diea! HS f V I

Process for Reduced-Harm Product & Claim(s) ProtlucY DevelopmeM Accephbility Teab ~ Smoke~ Genoloxklly CJmbaniry 9ubabrunk Inbalalbn ProEucY Productlon i ~ n w BpeuWHermNed Tea..une.aea , ' wS. OrpuV sy.rm ru VBIFI CRC E m 5 WSP/INBIFQ/CRC TlmekrlteUn9,not deeebpmenl rvdsa..omwp..aur 5-20 Years In our process, the human studies are represented (show area). The first arrow leading to provisional product claims involves looking at biomarkers of exposure (such as exhaled CO, carboxyhemagoblin, metals in urine) and may take 1 - 3 years, the next arrow leading to product claims looks at biomarkers of effect - here one is looking at markers that are believed to be early indicators of disease and changes in these markers directly corelate with disease state. The diseases we are concentrating on are CVD, Lung Cancer, and COPD. Also plan to save and store tissues for future analysis. The idea is that as the science progresses , we will have samples to test. The final arrow involves much longer term studies. Here one is actually determining if there is a decrease in the disease state. Therefore need to look at effects in human population Mumen E.po.u Meaunment HS 1 ~9imzrkaad 1 aqmure Months 12-36 Months 12-36 Months

P- 7rl l u. t Devp•l'i.)a.~l Rrc,duC: G0.ak:1a",., a P '+A for Reduced-Harm Product & Claim(s) ., Pb' PA PA Acwpta6ility Tasts - Smoke Chemistry 1 1 Genotoxicity Cytotoxk;ity Spacial Hanm Rrduction E Speaial Harm Reduction Sub-chsonie inhalaUon Tests, d` nNdedl Tats, If needed NBIF V NBIF 0 -a.q. orqaN CRG E ~ SysNm Taa t V ' Product PKOduction m 0 i a " " C 0 0 ~ ~ T ~ .' i iFTIMI 1 0 1 a 7 Human Expos Short-Tarm Human Lon IAwsursment r'-bS Heaith Effect Stud Hea E. ; b„ Epid ( -®iomarkers of - Biomarkam ot - Harm Reduction / 1 exposure E{fact Monitoring WSNINBIFaICRC Months 12-36 Months 12-36 Months 5-20 Years Time for testing, not development 6££8t~LS80Z I Fa~Ku" ~Pw~~ry i „

P•,, °h i.n-t [1gtvo,)o'r,enf WSAflNBIFQ/CRC ® - Smoke Chemistry . forRedHarm Pmduct & Claim(s) OPPA PA - Genotozic iy - Cytotoxicity Sp.oial Harm ;; - Sub-chronic IrhaBspion Tqh, it oaeY.d Pnociuct t'roch.tctiorv Pcst Hwnm Expos Measurement - Biomarkers of exposure 4BIFi CRC Market fii'Surveillanc e Months 12-36 Months i2-36 Months 5-20 Years Tpme for testing, not development Fur Dinewuan Pmpewu Only Si~£8ti1580Z i -a.tp. CkSaM ~ SysMm Ta a .. F'o,•t M,+!kt 1 k2r-,(,,arcif

Hazard Iden tification Provide recommeudadons in order to result in reduced-harm associated w*h major smoking-related diseases. • smoke constituent(s) targets for reduction/removal ' appropriate biological tests. SZ£8tiLS80Z II ~ '' ,, ' IIII'0. For Discu»Iq, Rrpases Only

WSA Focus 2001 • Identification of potential links between smoke constituents, host factors and the following disease endpoints - Lung cancer - Cardiovascular disease - Chronic obstructive pulmonary disease • Identification of smoke constituent targets • Identification of biomarkers (exposure, effect) • Plan and conduct human exposure/effect studies - Pilot and Total Exposure Study (TES) (July 01) - Accord JLI (Sept 01) - OASIS in Japan (Jan 02) - SCoR (2002) 95£8bLS80Z ' a n a i• uo~ a ryl. ,U

~~ Characte 4= 'Poxicity Assessment Purpose: Estimates the toxicity of a substance to huumans. •Smolae cFiae"ist.y •Genofoxiclly •Cyfofoxlclmy •Ankna1' MdNrlatJon Results: Determination of aoceptabiilty of ingredients, materials, and processes by estimating potential likelihood of biological endpoints relative to dose. Exposure Assessment Purpose: Estimate amounts of a substance to which someone is exposed. • Measures the amounts of substances in the body or other blomarkers. • Employs models of chemical behavior and models of human behavior Results: Determination of amount of the substance Ingested, Inhaled, or absorbed per unit of time by the exposed population. 4 Risk Characterization Purpose: Combines the results of toxicity assessments and exposure assessments to estimate potential risk. Results: Allows estimates of risk under actual conditions of use for determinations of reduced-harm products, product assessment and comparisons of products. 6~£8tiLS80Z '; fWiTiacupion FurpusetQn7

Risk Characterization Toxicity Assessment Exposure Assessment Purpose: Estimates the toxicity of e substance to Purpose: Estimate unounts of a substance to which humans. someone Is exposed. •Bmoke chemistry • Measures the amounts of substances in the •Genotaxlclty body or other blomarkers. •Lytotoxlclty • Employs models of chemical behavior and •Anlmallnhalat(an models of human behavior Results: Determination of acceptability of ingredients, Results: Determination of amount of the substance meterlals, and processes by estimating potentlel Ingested, Inhaled, or absorbed per unh of time by the likelihood of biological endpoints relative to dose. exposed population. Risk Characterization Purpose: Combines the results of toxicity assessmente and exposure assessments to estimate potantlal risk. Results: Allows eslimates of risk under actual conditions of use for determinations of reducad-herm products, product assessment and comparisons of products. This overhead attempts to roll the risk assessment all together. Toxicity assessment looks at how much is need to do harm (done by PUINBIFO/CRC; the exposure assessment looks at how much a person is exposed to (done by_human studies) and the risk characterization attempts to combine these (done by PA). Example: Assume there is a toxin that will kill you if you ingest a teaspoon full. I can take that teaspoon full and put it in a teaspoon or a cupof water or a bathtub full of water. The toxicity will be the same but the amount you are actually exposed to would be different because the likelihood of ingesting the entire amount is different with the different conditions. A risk characterization would look at this and probably determine that your risk is high with the teaspoon (because it would be pretty easy to get the toxic dose), moderate with the cup (because you may not be able to finish the cup) and low with the bathtub (because it is unlikely that you would be able to ingest the entire tub.

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14- P'roposed , Human Study Schedule Sample ooIlection: r`Nornnsl smoking" • Preferred brand O O To = :Switch .~. .lT., ~. . Control group t- T 1- • New Product "Limited smoking" (cig./day), New Product No smoking Lti£8b1S80Z ~ ;+Im~i„~, i , ~ .. ~~ir~,~~s ~; IIlilii ~ ~wiLreY4®1 =1Lz7ififivao!doliiu i-L >=6 months To 3 m Ti 6 months T2 For Discuepim Rapwm Only

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• Begin INBIFO evaluation - SCoR 2 May, 2001 • Begin Pilot TES May, 2001 • Results Pilot TES Dec. 2001 • Begin TES -Jan. 2002 • Results INBIFO evaluation - SCoR 1 - Jan., 2002 • Results INBIFO evaluation - SCoR 2 May, 2002 • Begin Cross-over Study on SCoR product May, 2002 • Launch SCoR Product (no claims) July, 2002 • Results TES Jan. 2003 • Resufts Cross-over Study for SCoR May 2003 (may provide data for provisional claim) 49£MS80Z FI7771777A ~ N 1I i "i l11 011 For Diacumian Rrtporce On1y

Summarizes what I have been talking about. The Risk Assessment involving ID, acceptability testing and human studies PA is responsible for pulling the information together. There is input from society and the public health authorities and also looking at comparative risks. Green area really represent managing and would include outside groups to make claims and perhaps most importantly coming up with a way to effectively comrnunicate internally and externally. If we can not communicate effectively then even the best work in the other areas may prove meaningless. Beta has a communication team that is looking at this and will hopefully lay the ground work for this communication for all reduced harmproducts.

4 WDUCEWILARM CLAIMS APPROACH H Assessment - Management - Communication Risk Assessment I Ow ® E x{,~-SUrF Assessment LS£8VL580Z Toxicity Assessment Ir Comparative Risk Non-Risk Analyses For Diicw®an Pmpo.es Only Claims L" ffi!CtZVL' Communieation a a~

wd O*'nqsi $ubst.antiaafia~>~; I~equ.i~e.me>~.ts~ • Manufacturing and quality controls in place to assure the consistent production of a product upon which any claims are based. During Production: Change control system(s) in place to assure that: - if changes are made to any claims; that there continues to be valid supporting data and evidence to support such changes - If changes are made in suppliers, supplier requirements, production processes, or other manufacturing factors that such changes will not undermine the claims. • Documentation: - literature/citations used with regards to any claim. - test methods to substantiate any claim. - experimental and human studies upon'which the claim is based. Testing on final product design (marketable product). • Discussion with public health authorities and other appropriate parties that the data and information supporting any claim constitute valid scientific evidence. Fa Dimuuion Fsvp~.Only £SESbLS80Z I d 777•.,1