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OvARTMlNT oF HcOtC)Ni D1VIStON oF RssPIRATORY DIltA![! GARY L. MUt[R, . M.D., CNI[F C Mailettg Address: •CTM ISRAEL MOSrITAL 830 >1ROOKLlM[ AVENUE WfTOM, MASSACMUiETTf 03l1s - 4617) 733-37ft December 25, 1977 William W. Shinn, Esquire Shook, Hardy & Bacon Mercantile Bank Tower 1101' Walnut Kansas City, Missouri 4106 Dear Bill, As we have discussed in several telephone calls and at various meetings, our animal inhalation facility has been; for the most part, inoperable for the past three'months. I am with this communication requesting through you supplementary funds in the magnitude of $489,955 from the grantors for the.purpose of renovating and upgrading our currently leased facility at Charlesgate West. Without these funds, the industry- supported tobacco and health research program cannot continue for much longer at Harvard University in a significant way. The monies awarded, if approved, will be used for the following purposes: Basic renovation and construction $322,500 Emergency generator system 25,000 Vacuum cleaning system 20,000 Sprinkler fire control system 23,000 Construction contingency (5%) 19,525 Additional Lorillard smoking machine 25,000 Additional animal cages 31,500 Additional animal laboratory equipment 20,430 Total $489,955 Of the monies requested, the vast majority ($410,000) is for direct renovation costs to upgrade the current facility to animal accreditation standards, with an estimated $390,500 in direct costs (outlined in the quotation from Walsh Brothers Construction Company, enclosed). As 0 recommended by the construction firm, a contingency allocation of 5% w ($19,525) is also included for revisions to scope and latent conditions ~ that may arise during the course of the renovation. These cost estimates D represent a overall renovation expenditure of under $40 per square foot vt for the Charlesgate West complex, a rate that is highly competitive in ~ this area. The remaining $79,930 requested is for the purchase of one additional Lorillard smoking machine, animal cages, and related equipment to permit our research staff to carry on simultaneous BETH ISRAEL HOSPITAL

William W'. Shinn, Esquire December 25, 1977 Page 2 sham exposure experiments concurrently with smoke inhalation studies, an option that is severly limited in our current facility. It may be helpful to review the history of the program, especially in regard to the facilities that have been available to us, relative to our current need for these renovation monies. The industry-sponsored. program was initiated in September of 1972, although not approved or made operational until January of 1973. The program started when we were at the Boston City Hospital, with no intent or even any hint at that time that we would have to change location. In February of 1973, for all practical purposes, it was evident that, on decisions made primarily in the office of the Mayor of Boston, the Harvard Medical Service at the Boston City Hospital, of which we were a part, would have to be relocated elsewhere. An ad hoc committee was formed to develop the best possible options for the resources of the Harvard Medical Service and Thorndike Laboratory, and a decision was eventually reached, on the basis of that committee's evaluations at the time, to transfer the majority of the resources existing at the Boston City Hospital to the Beth Israel Hospital. Those members of our clinical program, who were in essence without a place to function after July 1, 1973, moved to the Beth Israel in December of 1973. Our research staff completed the transition over the months of February through October of 1974. As you may recall, that was not an uneventful move in that the City of Boston impounded our equipment while it was on the trucks and prevented our transition on our first three attempts to leave. I will remember forever my confrontation with MACE- squirting guards in the BCH parking lot as I tried to remove my personal possessions. In the 18 months or so the program was primarily based in the Channing Laboratory,'of the Boston City Hospital, a relatively small, amount of project funds was spent on renovation so that acute tobacco smoke inhalation studies could be undertaken. The move to the Beth Israel was not an easy one for our program. Had we been the only ones moving from one Harvard institution to another perhaps more could have been expected, but the Beth Israel had to accomodate the majority of the individuals in a very large Department of Medicine transferring from Boston City Hospital. That was not an easy task for them. The construction of our new animal facilities and laboratories was delayed several months beyond the initially promised dates and the final cost was eventually several fold greater than initially approved through me and the industry sponsors.The Hospital had a very large n building program underway for clinical programs that took priority and CJ the difficulties we encountered were not unique to our project as several 4,1 other investigators and groups had similar problems. It took a special "P visit by Horace Kornegay and David R. Hardy to Boston, however, as well C!i as a very intense effort by all concerned at this end, to complete 'a before the first industry site visit to Harvard in the Fall of 1974 ~ renovatiomof what were then to be our animal facilities at the Beth Israel Hospial. It is important to recall there was great concern b~~- essentially all industry sponsors over the long initial delay, induced by the transition, in developing facilities to undertake the basic

William W. Shinn, Esquire December 25, 1977 Page 3 chronic animal inhalations on which all aspects of the program, including the studies involving human smokers, are based. That concern was appropriate and understandable. We did not have a facility in which we could initiate our first chronic smoke inhalation studies until we moved into the Kirstein Annex of the Beth Israel Hospital in the early winter of 1974, almost two years after funding was approved by the sponsors. The need to move from the Boston City Hospital certainly could not have been anticipated and I think all parties concerned would have been understanding if our problems with animal quarters had ended with the opening of the Kirstein Annex facility. In retrospect,'the development of the Kirstein Annex animal complex for our inhalation studies was a great and tragic mistake, for which all of us at this end, including myself, must take a certain share of responsibility. At the time, it was the only identifiable option available to our program. There were the pressures from the industry to "get_ going", so to speak, and that was rightfully so." As it turned out, however, the theoretical number of animals that could be housed and studied in the Kirstein Annex on paper could never be implemented in reality. Unfortunately, it took for all of us the experience of constructing the facility and trying to make it work to learn that. The air handling system just was not appropriate and was inadequate. After six months of what Dave Hardy called "courageous endeavors" by our research staff, and after scrapping essentially all research data generated because of one catastrophe or.another, a decision was reached that the Kirstein facility simply could not ever meet the needs of our program. In the spring of 1975, two and one half years into the program and with the Kirstein complex closed, industry sponsored funding was stopped until a solution for acceptable animal quarters could be developed and implemented. It was clear at the time that no alternative for us within the Beth Israel complex existed, and in that our clinical program was based in this institution a decision was reached to lease additional off-campus space through the Hospital. After on-site evaluation of over 50 potential locations, the current facility at Charlesgate West was identified as the best possibility. I met with Dave Hardy and you in New York in the spring of 1975 to present with both of you the two options to the industry for continuing forward, and I think it is important not to lose sight of those options and the decision that was reached at that time. Both options involved renovating Charlesgate West as the only satisfactory site available to the program. The first option, as developed by Dr. Melvin First of the Harvard School of Public Health, was a "minimum investment" option O to give a facility wherein we could satisfactorily conduct tobacco ~' inhalation studies and demonstrate to our sponsors that we were capable „a of doing the kind of research initially proposed. Reluctancy by the 1z sponsors to expend more than the "minimum" appeared reasonable, for we ~ had been supported for 2h years and had not been able to conduct any ~ satisfactory chronic inhalation studies, and perhaps several people were rightfully questioning our ability to do so. I certainly had confidence at the time that our group could be successful in this regard, if we had

William W'. Shinn, Esquire December 25, 1977 Page 4 an appropriate place in which to work,-and the results since then have more than supported that confidence. The second option considered in the spring of 1975, as developed by Clifford Douglas Stewart and Assoicates and the Beth Israel Hospital, was a'"maximum investment" option to develop an '"optimum" animal inhalation facility at Charlesgate West. The proposed costs for the two options were essentially a log apart in magnitude. The "minimum investment" option was budgetable within the then-existing monies already awarded to Harvard and the "maximum investment" option would have required major supplemental funding. The industry reached the decision to go with the recommendations of Dr. First. That was, at the time, my recommendation, as well, in that I felt it would have been wrong to ask for more money at•the particular time. I may well have been wrong in the recommendation viewed from the current perspective, but I do not think any of the industry sponsors were in any mood to consider providing additional funds under the then existing set of circumstances and problems. After all, the funding was stopped. Funding was reinstituted, the "minimum investment" option for an animal facility was implemented, and Charlesgate West opened in October of 1975 for chronic tobacco inhalation studies. Until we closed it voluntarily in September of 1977, a total of 4,500 animals were successfully studied at Charlesgate West, with 2,650 animals exposed to tobacco smoke for periods of one month to over six months without problems over that two year period. We accomplished a great deal with those two years of operation. Good people, as we have in our group, working together can achieve a lot. We had a very-successful site visit by the industry a year and a.half ago. Several important scientific contributions have been made, attempts to raise additional sources of grant support for the program have been successful, and as a group our investigators have jelled into the kind of cohesive and coordinated team that is needed to make progress in the difficult area of tobacco and health research. In September of 1977, I reached the decision that we had to close the facility as it now exists for further chronic smoke inhalation studies. We had not been able, particularly over the last several months of operation, to control the influx of outside rodents in the building and, with them, problems of infection in our study populations. We did not have these problems in the beginning. As is I think reasonable in the development of a program like ours, our initial chronic exposures to tobacco were of relatively short duration (1, 2, and 3 months). Perhaps because they were relatively short periods, we avoided some of the ~' significant problems that surfaced more recently. Our first attempts at ~ six-month exposure periods were also successful. As the duration of »"y exposures increased beyond that, however, so too by necessity did ~ the total number of animals involved. Our animal colony became infected, and in the end we lost some animals that we had been smoking for over OA eight months.

William W. $hinn, Esquire December 25, 1977 Page 5 Initially, I thought we could fumigate the facility, institute some additional rodent-control procedures and, so to speak, pick ourselves up and start all over again, with a discouraging but not insurmountable setback. In carrying out these plans, however, we faced some major new problems. We asked the Harvard veterinarians to evaluate the situation and make recommendations to us. I have forwarded previously to you their recommendations and enclose them again (attached herein as Exhibit A ). We have asked John Kennedy of Walsh Brothers Incorporated, a person in whom both Dr. First and I have a great amount of faith and respect without reservation, to provide us with an assessment of the costs required to implement the recommendations proposed by the Harvard veterinarians to bring the Charlesgate West facility up to standards that will meet animal accreditation (enclosed, Exhibit B). Up until fairly recently, the Beth Israel Hospital had not listed the Charlesgate West facility for accreditation inspection. Now that it is listed, and now that we have been informed by good consultants that there is no possible way the facility can be accredited as it currently exists, I am reluctant to undertake any major research in it. Any results we generate and share with the scientific community are open to considerable criticism to begin with, in part simply because we are working in the area of controversy that surrounds any tobacco and health research in general and, in addition, in part because the program is supported by industry. We have always done our best to keep our work above criticism of any kind, and I would not want to embarass either the industry or the University by having our animal inhalation facility closed by outside inspecting teams. We are now undertaking, however, some very short term (up to one month at most) inhalation studies of limited scope to answer a few questions that can be addressed under these kinds of conditions and circumstances. We cannot, in my judgement, undertake the Iong-term chronic inhalation programs that are vital to the program in the facility at this time. I am sorry to have taken this long to develop options for us to consider together. In part, I have been dependent on others to develop good information on which to base a recommendation to you and it has taken time to accumulate that information. I am grateful to Horace Kornegay for the information provided via the Department of Agriculture and especially to the understanding and patience that you and the industry sponsors have given us. In addition, I have tried to develop a definitive solution and that takes a lot of effort. In considering options, none of us connected with the program are very enthusiastic about requesting support fromthe grantors to improve a facility that inherently is not part of the University, that is not owmed by either the University or by the Hospital, and that is "ours" through a lease that has less than 2~ years to go and houses a programthat is funded only through mid-1980. In short, however, Dr. First and I both believe there is no other option that anyone here can identify at this time that will not result in a near-total disruption of the program. We leased the facility initially

William W. Shinn, Esquire December 25, 1977 Page 6 because there was no room for us in the Beth Israel Hospital, and there is even less space currently available there now. I have explored, on many different occasions, primarily through Mr. Meadow, but also through Dr. Epstein, Dr. Kass and others as well, potential options for occupancy by or development of a facility for the program within Harvard Medical School, but that option currently does not exist, either. Other possibilities have been explored. Harvard has recently purchased the S. S. Pierce Building, which is nearby, and Mr. Meadow is exploring renovating part of that for us in that it would be owned by Harvard. We actually had explored leasina that structure at the time we selected Charlesgate West, however, and it was not at the time considered a very good option. It would now be a much more expensive consideration. Dr. Epstein has suggested our exploring with you the building of 16,000 square feet of research floor space on top of a currently existing building at'the Beth Israel Hospital. That would provide a.permanent long-term solution and house our entire program in one unit contained within a major Harvard institution, all of which are extremely desirable However, it would cost $2 million and be three years or so before we could use it. No other options can be identified at Harvard at this time. We need about 10,000 square feet of floor space at a minimum for the animal inhalation part of the program, and preferably more. That is a lot of space and Harvard is not the kind of institution where unused space of any magnitude sits uncommited for any length.of time. It might be possible to build new space, somewhere else, as was our original plan at the Boston City Hospital, but that option would take, from where we are starting now, a good year or two at a minimum, and probably longer in reality, to implement. The cost for other options, even if a realistic one could be identified, would also be high. That really leaves us with Charlesgate West, unless you or someone else can come up with an alternative suggestion. I would welcome and strongly encourage, as you have suggested, having a group of industry representatives help identify our options and possible solutions. Furthermore, I sincerely hope they could help us come up with a better solution than I can identify for you now. Should a decision be made to go forward with the Charlesgate West renovation plan, I would strongly recommen&that the lease be signed directly between Harvard University, to wh=the tobacco grant is awarded, and the owners of the building. Alternatively, the grantors, perhaps through the Tobacco Institute, maght desire to undertake the lease directly. Dr. First and I have met with the owners, and the option for outright w purchase of the facility does exist, and the possibility is there for %J developing that facility and part of the adjacent one into a final ~ definitive solution. Whatever the final decision, I would strongly LM suggest the development for relatively long-term options so that any Winvestment in renovation or purchase can be utilized over a number of O years, and with maximum return to the grantors. I have little choice but to recommend to our sponsors that the industry approve this request for funding for this renovation. Quite

William W. Shinn, Esquire December 25, 1977 Page 7 . frankly, I am as tired as you are of the many recurrent problems we have had over the past five years in trying to find a lasting home for our research team. It has been frustrating, disheartening and, at times, most demoralizing to all of us here connected with the program. In the now 5-~ years of funded support, for example, we have had only two years of operating time for chronic smoke inhalation studies. That does not provide for a very effective utilization of our grantors monies, nor a very effective outlet for some very talented people who are giving their section of our program, including future plans, under separate correspondence. I believe this program has taken, in the past two years, one of the biggest steps ever in the history of tobacco-related research and we do have the resources to provide definitive answers to a number of crucially vital, questions in this area in the next few years, providing only that we have an acceptable facility in which our investigators can work. It would be a great tragedy to stop or significantly delay any further our efforts at this time. .very best effort inihelping us with a difficult research challenge. There are several ways to evaluate a research program, and I am not sure I should be the one to say that our program is scientifically excellent or not. I believe it is. In the past five years, I have traveled the world over and seen what is being done elsewhere in tobacco research. I think we have the best program anywhere, in spite of the problems we have experienced. Part of what we accomplished was presented to the industry at the site visit last year, and we have requested, before this current trouble developed, another site visit for the coming spring to present our considerable progress in the past year. More importantly, now we also have some specific new observations on the biologic effects of tobacco smoke on the lung, and some key information on~the potential mechanisms by which those effects are mediated, that never existed before. .I personally do not want to be put in the position that we irreversibly stopped research at such an important phase because we can no longer expose our animals. I have reviewed for you each I am very grateful to the tobacco industry for the research opportunities and support they have given to me and to our investigators, and I hope in return they appreciate that I have done our best to fulfill their expectation in implementing the agreement. In every contact I have had to date iniregard to our program, every component of the industry has been responsible in supporting,-either with funding, technical assistance or other resources, their stated commitment to finding answers to the tobacco and health controversy through research. Our program now has a vital need, and I hope you and the industry can help us develop the best solution possible. Sincerely yours, Gary L. Huber, M.D., Chief Respiratory Diseases GLH/far A