Editing Paclitaxel (section)

==History==
The discovery of paclitaxel began in 1962 as a result of a NCI-funded screening program.<ref name=NCI2016/> A number of years later it was isolated from the bark of the Pacific yew, ''Taxus brevifolia'', hence its name "taxol".<ref name=NCI2016/>

The discovery was made by [[Monroe E. Wall]] and [[Mansukh C. Wani]] at the [[Research Triangle Institute]], [[Research Triangle Park]], North Carolina, in 1971.<ref>{{cite journal | vauthors = Wall ME, Wani MC | title = Camptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award Lecture | journal = Cancer Research | volume = 55 | issue = 4 | pages = 753–760 | date = February 1995 | pmid = 7850785 | url = http://cancerres.aacrjournals.org/content/55/4/753.long | url-status = live | archive-url = https://web.archive.org/web/20161124171818/http://cancerres.aacrjournals.org/content/55/4/753.long | archive-date = 24 November 2016 }}</ref> These scientists isolated the natural product from the bark of the Pacific yew tree, determined its structure and named it "taxol", and arranged for its first biological testing.<ref>{{cite journal | vauthors = Donehower RC |date=1996 |title=The Clinical Development of Paclitaxel: A Successful Collaboration of Academia, Industry and the National Cancer Institute |url=https://academic.oup.com/stmcls/article/14/1/25-28/6390626 |journal=Stem Cells |language=en |volume=14 |issue=1 |pages=25–28 |doi=10.1002/stem.140025 |pmid=8820947 |issn=1066-5099}}</ref> The compound was then developed commercially by BMS, who had the generic name assigned as "paclitaxel".{{citation needed|date=June 2014}}

===Plant screening program===
In 1955, the NCI in the United States set up the Cancer Chemotherapy National Service Center (CCNSC) to act as a public screening center for anticancer activity in compounds submitted by external institutions and companies.{{sfn|Goodman|Walsh|2001|p=17}} Although the majority of compounds screened were of synthetic origin, one chemist, Jonathan Hartwell, who was employed there from 1958 onwards, had experience with natural product derived compounds, and began a plant screening operation.{{sfn|Goodman|Walsh|2001|p=22}}

After some years of informal arrangements, in July 1960, the NCI commissioned the [[United States Department of Agriculture]] (USDA) botanists to collect samples from about 1,000 plant species per year.{{sfn|Goodman|Walsh|2001|pp=25,28}} On 21 August 1962, one of those botanists, Arthur S. Barclay, collected bark from a single Pacific yew tree in a forest north of the town of [[Packwood, Washington]], as part of a four-month trip to collect material from over 200 different species. The material was then processed by a number of specialist CCNSC subcontractors, and one of the tree's samples was found to be [[cytotoxic]] in a cellular assay on 22 May 1964.{{sfn|Goodman|Walsh|2001|p=51}}

Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall in Research Triangle Park, North Carolina, began work on fresh ''Taxus'' samples,  isolating the active ingredient in September 1966 and announcing their findings at an April 1967 [[American Chemical Society]] meeting in [[Miami Beach]].<ref>{{cite journal | vauthors = Wall ME, Wani MC | title = Camptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award Lecture | journal = Cancer Research | volume = 55 | issue = 4 | pages = 753–760 | date = February 1995 | pmid = 7850785 }}</ref> They named the pure compound taxol in June 1967.{{sfn|Goodman|Walsh|2001|p=51}} Wall and his colleague Wani published their results, including the chemical structure, in 1971.<ref>{{cite journal | vauthors = Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT | title = Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia | journal = Journal of the American Chemical Society | volume = 93 | issue = 9 | pages = 2325–2327 | date = May 1971 | pmid = 5553076 | doi = 10.1021/ja00738a045 | bibcode = 1971JAChS..93.2325W }}</ref>

The NCI continued to commission work to collect more ''Taxus'' bark and to isolate increasing quantities of taxol. By 1969, {{Cvt|28|kg|}} of crude extract had been isolated from almost {{Cvt|1200|kg|}} of bark, although this ultimately yielded only {{Cvt|10|g|}} of pure material,{{sfn|Goodman|Walsh|2001|p=81}} but for several years, no use was made of the compound by the NCI. In 1975, it was shown to be active in another ''[[in vitro]]'' system; two years later, a new department head reviewed the data and finally recommended taxol be moved on to the next stage in the discovery process.{{sfn|Goodman|Walsh|2001|pp=79,81}} This required increasing quantities of purified taxol, up to {{Cvt|600|g|}}, and in 1977 a further request for {{Cvt|7000|lb|}} of bark was made.

In 1978, two NCI researchers published a report showing that taxol was mildly effective in leukaemic mice.<ref>
{{cite journal | vauthors = Fuchs DA, Johnson RK | title = Cytologic evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison | journal = Cancer Treatment Reports | volume = 62 | issue = 8 | pages = 1219–1222 | date = August 1978 | pmid = 688258 }}</ref> In November 1978, taxol was shown to be effective in [[xenograft]] studies.{{sfn|Goodman|Walsh|2001|p=95}} Meanwhile, taxol began to be well known in the cell biology, as well as the cancer communities, with a publication in early 1979 by [[Susan Band Horwitz|Susan B. Horwitz]], a molecular pharmacologist at [[Albert Einstein College of Medicine]],  showing that taxol had a previously unknown mechanism of action involving the stabilization of microtubules. Together with formulation problems, this increased interest from researchers meant that, by 1980, the NCI envisaged needing to collect {{Cvt|20000|lb|}} of bark.<ref name="Goodman and Walsh p97">{{harvnb|Goodman|Walsh|2001|p=97}}</ref> Animal toxicology studies were completed by June 1982, and in November, the NCI applied for the [[Investigational New Drug|IND]] necessary to begin clinical trials in humans.<ref name="Goodman and Walsh p97"/>

===Early clinical trials, supply and the transfer to BMS===
[[phases of clinical research|Phase I]] clinical trials began in April 1984, and the decision to start [[phases of clinical research|Phase II]] trials was made a year later.{{sfn|Goodman|Walsh|2001|p=115}} These larger trials needed more bark and collection of a further 12,000 pounds was commissioned, which enabled some phase II trials to begin by the end of 1986. But by then it was recognized that the demand for taxol might be substantial and that more than 60,000 pounds of bark might be needed as a minimum. This unprecedentedly large amount brought ecological concerns about the impact on yew populations into focus for the first time, as local politicians and foresters expressed unease at the program.<ref name="Goodman and Walsh p120"/>

The first public report from a phase II trial in May 1988 showed promising effects in melanoma and refractory ovarian cancer.<ref>{{cite journal|vauthors = Rowinsky EK, Donehower RC, Rosenshein NB, Ettinger DS, McGuire WP|title = Phase II study of taxol in advanced epithelial malignancies|journal =  Proceedings of the Association of Clinical Oncology|volume = 7|pages = 136|year = 1988 }}</ref> At this point, Gordon Cragg of the NCI's Natural Product Branch calculated the synthesis of enough taxol to treat all the ovarian cancer and melanoma cases in the US would require the destruction of 360,000 trees annually. For the first time, serious consideration was given to the problem of supply.<ref name="Goodman and Walsh p120"/>
Because of the practical and, in particular, the financial scale of the program needed, the NCI decided to seek association with a pharmaceutical company, and in August 1989, it published a [[Cooperative Research and Development Agreement]] (CRADA) offering its current stock and supply from current bark stocks, and proprietary access to the data so far collected, to a company willing to commit to providing the funds to collect further raw material, isolate taxol, and fund a large proportion of clinical trials. In the words of Goodman and Welsh, authors of a substantial scholarly book on taxol, "The NCI was thinking, not of collaboration, ... but of a hand-over of taxol (and its problems)".<ref name="Goodman and Walsh p120">{{harvnb|Goodman|Walsh|2001|p=120}}</ref>

Although the offer was widely advertised, only four companies responded to the CRADA, including the American firm [[Bristol-Myers Squibb]] (BMS),
which was selected as the partner in December 1989. The choice of BMS later became controversial and was the subject of Congressional hearings in 1991 and 1992. While it seems clear the NCI had little choice but to seek a commercial partner, there was also controversy about the terms of the deal, eventually leading to a report by the [[General Accounting Office]] in 2003, which concluded the NIH had failed to ensure value for money.<ref>{{cite web|url=http://wyden.senate.gov/leg_issues/reports/taxol.pdf|title=Technology Transfer: NIH-Private Sector Partnership in the Development of Taxol|url-status=dead|archive-url=https://web.archive.org/web/20070726000303/http://wyden.senate.gov/leg_issues/reports/taxol.pdf|archive-date=26 July 2007|access-date=17 July 2016}}</ref> In related CRADAs with the [[USDA]] and [[Department of the Interior]],  Bristol-Myers Squibb was given exclusive first refusal on all Federal supplies of ''Taxus brevifolia''.
This exclusive contract lead to some criticism for giving BMS a "cancer [[monopoly]]".<ref name="monopoly">{{cite web| vauthors = Nader R, Love J |url = http://www.findarticles.com/p/articles/mi_m1295/is_n2_v57/ai_13417481|title = Looting the medicine chest: how Bristol-Myers Squibb made off with the public's cancer research|work = [[The Progressive]]|date = February 1993|archive-url = https://web.archive.org/web/20040924184528/http://www.findarticles.com/p/articles/mi_m1295/is_n2_v57/ai_13417481|archive-date = 24 September 2004 }}</ref>
Eighteen months after the CRADA, BMS filed a [[new drug application]] (NDA), which was given FDA approval at the very end of 1992.
<ref name="Goodman and Walsh p120"/>
Although there was no patent on the compound, the provisions of the [[Waxman-Hatch Act]] gave Bristol-Myers Squibb five years exclusive marketing rights.

In 1990, BMS applied to trademark the name taxol as ''Taxol(R)''. This was controversially approved in 1992. At the same time, paclitaxel replaced taxol as the generic ([[International Nonproprietary Name|INN]]) name of the compound.  Critics, including the journal ''[[Nature (journal)|Nature]]'', argued the name taxol had been used for more than two decades and in more than 600 scientific articles and suggested the trademark should not have been awarded and the BMS should renounce its rights to it.<ref>{{cite journal | vauthors =  | title = Names for hi-jacking | journal = Nature | volume = 373 | issue = 6513 | pages = 370 | date = February 1995 | pmid = 7830775 | doi = 10.1038/373370a0 | s2cid = 31510966 | bibcode = 1995Natur.373..370. | doi-access = free }}</ref> BMS argued changing the name would cause confusion among oncologists and possibly endanger the health of patients. BMS has continued to defend its rights to the name in the courts.{{sfn|Goodman|Walsh|2001|p=170}}
BMS has also been criticized for misrepresentation by Goodman and Walsh, who quote from a company report saying "It was not until 1971 that ... testing ... enabled the isolation of paclitaxel, initially described as 'compound 17".<ref>Bristol-Myers Squibb, The development of TAXOL (paclitaxel), March 1997, as cited in {{harvnb|Goodman|Walsh|2001|p=2}}</ref> This quote is, strictly speaking, accurate: the objection seems to be that this misleadingly neglects to explain that it was the scientist doing the isolation who named the compound taxol and it was not referred to in any other way for more than twenty years. Annual sales peaked in 2000 (the same year that several of BMS’s Taxol patents were invalidated via legal challenge from generic manufacturers<ref name="e669">{{cite journal | last=Rogers | first=Ron | title=Bristol-Myers Squibb loses Taxol patents | journal=Chemical & Engineering News Archive | volume=78 | issue=10 | date=2000-03-06 | issn=0009-2347 | doi=10.1021/cen-v078n010.p013a | pages=13–14}}</ref>), reaching [[US$]]1.6 billion; paclitaxel became available in generic form in 2000.<ref name="h410">{{cite web | title=In the Matter of Bristol-Myers Squibb Company | website=Federal Trade Commission | date=2000-11-21 | url=https://www.ftc.gov/sites/default/files/documents/cases/2003/03/bristolmyersanalysis.htm | access-date=2025-03-10}}</ref>