Penicillin: Government: COC


Committee on Chemotherapeutic
and Other Agents

This committee, entitled the Committee on Chemotherapeutic and Other Agents (COC), was one of the first committees founded by the Division of Medical Sciences (DMS) of the NRC in May 1940 as part of the army's program of " 'medical preparedness' " for war (Adams, 1991, 26). The COC members included chairman Perrin Long of Johns Hopkins University and Chester S. Keefer of Boston University, who was also director of Evans Memorial at the Massachusetts Memorial Hospitals. Keefer, who served as information coordinator for the COC's Subcommittee on Infectious Diseases, replaced Long as chairman in September 1942 after Long accepted a commission in the U.S. Army Medical Corps. Other COC members were physicians Francis G. Blake of Yale University, John S. Lockwood of the University of Pennsylvania, E. K. Marshall, Jr. of Johns Hopkins University, and W. Barry Wood of Washington University in St. Louis (Hobby, 110; Adams, 1991, 31-32). The government thus called on university-based scientists, physicians, and engineers to staff these and other wartime research agencies and committees in order " 'to utilize to the full potential the resources of the academic world' " given the threat of war (Adams, 1991, 56). [Although I have not come across an image of the Committee, this might be useful. Otherwise, Hobby does have a picture of Keefer on 111-can we find similar pictures for the other members?]

While the COC's initial responsibilities lay in examining the sulfonamides and other drugs in battle wound treatment, it later turned to the study of penicillin. Long recommended the consideration of penicillin in October 1940, perhaps having seen Florey's research in an earlier issue of the British Medical Journal (Adams, 1991, 29). Due to limited funding and availability of penicillin at that time, clinical investigation could not be conducted. The subsequent work of the Columbia group and other researchers revealed the therapeutic possibilities of penicillin, work which, along with Florey's visit to Richards in August 1941, contributed to the CMR's decision to take on the responsibility of examining penicillin's potential for large-scale production. After it designated the COC in charge of "[gathering] information on [penicillin] dosage, methods of administration, duration of treatment, and reactions" in January 1942, the CMR remained involved in penicillin distribution for the remainder of the war (Neushul, 383; Keefer, 719). [I had difficulty locating the British Medical Journal article cited above-has it already been scanned?]

Under Long, the COC began its penicillin clinical studies on staphylococcal infections in the spring 1942, albeit with still limited supplies of penicillin. The team that initially compiled this research data included Champ Lyons, who later treated patients after Boston's Coconut Grove Fire and conducted the Bushnell Hospital study discussed below, Keefer, Blake, Martin Henry Dawson, and Wesley Spink (Adams, 1991, 31). They continued their studies through the summer, enlarging the research program to include infections such as pneumococcal meningitis and empyema. The investigations continued into the fall, as Keefer transitioned into his role as chairman, and in mid-October 1942 he relayed to Richards the COC's findings to date. Specifically, he found that penicillin was particularly effective against "…staphylococcal infections and hemolytic streptococcal infections with bacteremia, chronic osteomyelitis, and chronic empyema. It had shown little clinical effect, however, against subacute bacterial endocarditis [SBE]" (Adams, 1991, 33). He thus recommended that the COC push forward with further studies on staphylococcal and sulfonamide-resistant gram positive infections. Further investigations, such as the work of Lyons at Massachusetts General Hospital under a CMR/OSRD contract in conjunction with the COC, supported earlier findings of penicillin's effectiveness. He treated over 170 patients, many of whom were injured during the late 1942 Boston Coconut Grove Fire, and concluded that penicillin's therapeutic effects were " 'impressive' " (Adams, 1991, 33). [The results of this investigation under a CMR/OSRD contract are found in the following document, taken from Adams, 1991, 33, note 29-Champ Lyons, "Committee on Medical Research of the Office of Scientific Research and Development: Final Report for the 12 Months Ending December 31, 1942," 17 March 1943, CMR, Record Group 227.]

Although in March 1942 there was only enough penicillin for one case, supplies had increased to provide enough for ten cases in June 1942 and for ninety cases in February 1943 (Richards, 442; Hobby, 145). This increase in supplies, made possible by the afore-mentioned production improvements at the NRRL and pharmaceutical firms, resulted in an increase in the number of "accredited investigators" authorized to conduct penicillin studies. These clinicians, whose number reached 22 in August 1943, included the U.S.'s leading infectious disease specialists who possessed relevant clinical investigation skills. They continued "…to test penicillin in proved cases of the infections then under investigation, [and the] reports of all cases were forwarded to a central office, so that all investigators, producers of penicillin, the [COC], and the [CMR] were familiar at all times with the results being obtained" (Keefer, 719). Keefer's office at the Massachusetts Memorial Hospitals in Boston served as this central office, where in the subsequent months Keefer and Donald Anderson, his assistant who also taught at Boston University School of Medicine, considered physician requests (Keefer, 720). The accredited clinicians received penicillin with the understanding that no physician or patient could buy or sell the penicillin; moreover, the investigators were required to submit progress reports to the COC for analysis (Keefer, 719). [Keefer fails to cite where one might find these progress reports-possibly in Record Group 227?]

The penicillin supplied for these tests of just 100 patients between June 1942 and February 1943 came from pharmaceutical companies free of charge. Except for the penicillin that the companies needed for their own investigations, they turned over all of the penicillin to the CMR, who then gave the supplies to the COC for clinical testing. By February 1943, however, "…the unfairness of this plan was apparent, so that from that time on the government, [via an OSRD contract with penicillin producers, on CMR recommendation,] paid for all the penicillin used in clinical investigation under [the COC's] direction and supervision…" (Keefer, 719). Expanding these studies, however, required increased penicillin quantities. While work continued at the NRRL and at pharmaceutical plants, Keefer stressed that " '[we] must all push its production as hard as possible [italics in original]' " (Adams, 1991, 35). He wanted to press forward with penicillin studies, given the potential shown thus far, and was particularly enthusiastic about extending investigations to the armed forces-an intention that Keefer shared with Richards in March 1943. [For the document that includes Keefer's above-mentioned quote as well as his intentions to extend studies to the army, locate Chester S. Keefer to A. N. Richards, 22 March 1943, CMR, Record Group 227 (Adams, 1991, 35, note 35).]

This desire was in line with COC and wartime bureaucracy's goals of conducting research studies that supported the war effort (Adams, 1991, 67). The opportunity to advance knowledge of penicillin's actions, specifically in battle wounds that were unreceptive to other treatments, presented itself in the spring 1943. Major Frank B. Queen, a Bushnell Hospital medical officer in Brigham, Utah, requested that Keefer initiate a pilot study at the hospital on the "…application of penicillin among military casualties" (Adams, 1991, 35). Keefer supported the proposal, and asked Richards to discuss the matter with both penicillin producers and with the surgeon general in order to gain military approval. Richards approved the study, believing that Bushnell Hospital served as a terrific opportunity to advance penicillin study. This decision emphasizes Richards's ongoing support for the penicillin project as well as his role in COC activity. Upon hearing from Richards, Keefer informed Major Queen that the COC's Lyons would be conducting the Bushnell studies beginning in April 1943. Lyons and the hospital's staff worked well together, and his initial results, which showed the effective treatment of several patients with penicillin, demonstrated the importance of the drug to the army. In June, Lyons began work at Halloran Hospital in New York, where he was in charge of training medical officers in the use of penicillin; this program later included other army hospitals as well (Adams, 1991, 36-38; Keefer, 719-720; and Richards, 443). [For Richards's go-ahead response to Keefer's inquiry regarding the Bushnell study, find A. N. Richards to Chester S. Keefer, 24 March 1943, CMR, Record Group 227 (Adams, 1991, 36, note 40). Also, locate Lyons's JAMA progress report, 18 December 1943 (mentioned in Richards, 443).]

"The Bushnell studies represented a turning point in the clinical evaluation of penicillin by the COC" (Adams, 1991, 38). The army now recognized the value of penicillin. Not only did it extend its medical officer training program to nearly a dozen other army hospitals, but due to the initial observations of John Mahoney of the U.S. Public Health Service on the applicability of penicillin to syphilis and gonorrhea, the army also adopted penicillin for the treatment of venereal diseases (Keefer, 720). The army's decision to use penicillin "…left accredited investigators with far less of the drug available for civilian patients" (Adams, 1991, 38). Richards, concerned by this prospect, announced in JAMA that "[unless] penicillin production increased,…supplies for civilians would become even more scarce"-a prediction echoed by Keefer in his memorandum to the accredited investigators (Adams, 1991, 39). [Elder cites a 1943 CMR investigative report entitled "Penicillin Therapy for Septic Compound Fractures in a Military Hospital," finding that this report "…was the spark which triggered the accelerated program" (Elder, 3). He does not, however, provide further information as to where to find this report. We have Richards' JAMA statement. For Keefer's statement, locate Chester S. Keefer, "Memorandum on Penicillin Distribution," 25 May 1943, CMR, Record Group 227 (Adams, 1991, 39, note 48).]

These supplies began increasing substantially in 1943, for just as the army was impressed by penicillin's performance at Bushnell and other army hospitals, so, too, was the WPB, whose involvement in penicillin production is discussed in detail in The War Department section. Moreover, noting that in the COC's trials to date penicillin "…not only fulfilled [its] early expectations but exceeded them, the [WPB] consented in June 1943 to become responsible for the program of commercial production" (Keefer, 720). Following his May 1943 statement in JAMA, Richards had asked the WPB "…to assume ownership of all penicillin in this country and allocate it to the armed services, to the manufacturers for their own research purposes, to the OSRD for investigations as recommended by the CMR, and to the Public Health Service" (Swann, 161). This allocation order, official as of July 16, 1943, although initially reducing the amount of penicillin available to the COC, as noted in The Public section, subsequently allowed for larger amounts of penicillin available for civilian use. Specifically, by mid-1943, the WPB allocated more penicillin to the OSRD, who then released it to the COC, given the strides in penicillin production discussed in The Pharmaceutical Companies section (Keefer, 720).

Given these increasing supplies, the COC was able to extend its clinical testing program. Yet the scarcity of the drug nonetheless remained, requiring the COC to hold to its rationing policy of "[providing] penicillin only to patients suffering from illnesses where data could be of potential benefit to the war effort,…[while age,] gender, or other factors [continued to have] no effect on rationing decisions" (Adams, 1991, 77). By adhering closely to its rationing policy and by justifying its actions "…as being in the best interest of the nation" since its research supported the war effort, the COC "…insulated itself from legal problems" (Adams, 1991, 67). However, this did not preclude the COC from criticism-both from politicians, as in an example described in The Public section, as well as from physicians. For instance, the Mayo Clinic's Wallace Herrell, who had been studying and treating patients with penicillin prior to the allocation order's restriction of supplies, clashed with Keefer. Whereas Herrell believed that the COC's investigative program "stifled academic freedom," Keefer felt that an emphasis on "cooperative research" was essential (Adams, 1991, 82, 85). "Cooperative research," reflected in the COC's rationing policy, called for the study of penicillin "…according to a predetermined investigative protocol in order to insure uniformity of research methods and results…[and] helped guard against the possibility of bias on the part of a single researcher" (Adams, 1991, 85).

Another conflict, centering on physician use of penicillin for untreatable cases, likewise highlights the logic behind COC rationing policy. Martin Henry Dawson had " '…treated several [SBE] patients without first consulting the Committee [COC] and used penicillin which had been released to him for other purposes….' " (Adams, 1989, 206). Similarly, Leo Loewe, a New York physician, was studying penicillin's applicability to SBE patients; he obtained his penicillin supplies from John Smith, Pfizer's president, who knew of Dawson's work and was touched by Loewe's efforts to treat children and other patients suffering from SBE (Hobby, 167-168). Following the allocation order, Smith supplied the OSRD and WPB with vast quantities of penicillin while giving Loewe the eight million units permitted for the company's research program. This cooperation between Loewe and Pfizer in the study and treatment of SBE patients, while promoting penicillin use in a manner contrary to COC guidelines, eventually led to Keefer's recognition in 1945 of the applicability of the drug to SBE. Until this point, however, Keefer maintained that physicians and accredited investigators must adhere to COC policy in order to ensure the equitable distribution of penicillin and the "…orderly accumulation of knowledge" on penicillin (Adams, 1989, 208). Lockwood, who "… 'deplored' any deviation from Committee policy," emphasized this need for compliance: " 'Although we appear to assume a grave responsibility in certain individual cases,…it seems to me only by adhering to this course can we provide 'the greatest good to the greatest number' " (Adams, 1991, 80). [For this notable quote, locate John S. Lockwood to Chester S. Keefer, 12 August 1943, CMR, Record Group 227 (Adams, 1991, 80, note 43).]

Richards supported Keefer's decisions, reflecting their cordial relationship and their parallel thinking. As mentioned above, Richards and the CMR prompted the COC's involvement in clinical testing on penicillin. When Keefer became frustrated by his attempts at explaining COC rationing policy to the press, he turned to Richards for " 'advice and council' about [how he should handle] lay pressure for the drug" (Adams, 1989, 204). In addition, when Herrell tried to continue his work with penicillin according to his own protocol, he appealed to Richards in an attempt to circumvent Keefer. Richards, however, "…was unwilling to override Keefer's authority," and he "…fully supported Keefer's belief that policy should be maintained at all costs" (Adams, 1991, 82). Richards, in his capacity as chairman of the CMR, reinforced Keefer's decisions, strengthening the credibility of the COC's rationing policy. [For Richards's response to Herrell, obtain A. N. Richards to Wallace E. Herrell, 13 August 1943, COMM, National Academy of Science (Adams, 1991, 82, note 51).]

The COC's "…program of clinical investigation was continued until April 30, 1944, by which time a sufficient amount of information had been accumulated on the clinical value of penicillin in certain diseases to justify a revision of the program" (Keefer, 721). Moreover, pharmaceutical firms were producing enough penicillin to satisfy military needs. In fact, the amount of penicillin being produced became too large for efficient rationing by the COC such that the WPB transferred allocation responsibilities to the OCPD on May 1, 1944. The OCPD, which is discussed in The Public section and in The War Department section at length, assumed distribution responsibilities via a nationwide system of "depot hospitals" (Adams, 1991, 92). This meant that until December 1945, Keefer and the COC focused solely on clinical research without the distraction of civilian requests and media attention. [For an article on these "depot hospitals," see "Penicillin Comes to City Hospitals," New York Times (11 May 1944): 21, cited in my primary sources bibliography-we have this.]