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INSTITUTIONAL RESPONSE TO THE HIV BLOOD TEST PATENT DISPUTE AND RELATED MATTERS

Staff Report
of the Subcommittee on Oversight and Investigations
Committee on Energy and Commerce
United States House of Representatives


VI. GALLO/HHS ON LTCB MATERIALS TRANSFERS

A. Practices at the LTCB

Immediately upon publication of the May 1984 Science papers, the LTCB received numerous requests for its IIIb-infected cell line, its "H9" uninfected cell line, and related reagents. According to commonly-accepted standards for scientific collaboration and exchange, these materials should have been readily and unconditionally provided to qualified scientists, since they had already been published. From a public health standpoint, one could even argue that the materials should have been unconditionally shared well before their May 1984 publication, considering the devastation of the AIDS epidemic and the potential benefits the materials had for AIDS/HIV research.

Dr. Gallo and his associates provided their cell lines and reagents to many who requested them. Dr. Gallo frequently recites the numbers of scientists who received these materials; the LTCB also has prepared several lists of scientists who allegedly received LTCB materials. On numerous occasions, these lists have been adduced as evidence of the generosity of Gallo et al.

But the lists of scientists who allegedly received LTCB materials (some scientists who were listed by the LTCB as recipients did not receive the requested materials) cannot obscure the reality that, at the same time as he provided materials to some scientists, Dr. Gallo withheld reagents and cell lines from others. Dr. Gallo also gave special treatment to some scientists, actually offering materials under favorable conditions to selected collaborators, while at the same time, he delayed responding to the requests of others less favored.

Most problematic of all, for some scientists, Dr. Gallo imposed conditions on transfers of materials that were blatantly at odds with accepted principles of conduct in research, at odds with Dr. Gallo's professed commitment to public health, and that apparently were driven at least in part by the intention to keep others from demonstrating the uniquely close genetic relationship of "HTLV-IIIb" and LAI.

Dr. Gallo was aware of and professed adherence to principles of free access to research materials. Dr. Gallo articulated those principles in 1981, during a deposition in the U.S. District Court of Maryland, in the lawsuit, Hoffman-LaRoche, Inc. v. David W. Golde, et al. The Roche/Golde et al. lawsuit focused on sharing of cell lines; Dr. Gallo, whose use and transmission of a disputed cell line was an important issue in the lawsuit, was questioned at some length about his understanding of accepted scientific practices relating to the sharing of research materials, and about his own conduct.

Dr. Gallo's answers in the deposition provide informative context for his later statements and actions. Asked if he freely gave out cell lines from his laboratory, Dr. Gallo said this:

"Yes. The policy is to make them available to everybody on publication who asks who's a qualified investigator, whether they work in any place, any affiliation, race, color, or creed, and so. The lines are available on publication" (7/15/81 deposition of Robert C. Gallo; transcript p. 90).

Later in the deposition, Dr. Gallo responded to questions about the rationale for the free exchange of research materials:

Q: "Is your sending out of cell lines or other things which you feel free in your laboratory to send out something that you do to further medical research or scientific research?

A: I mean, that's what we grew up -- when you're growing up, you get taught certain rules of behavior, and that was one of the rules of behavior in science that we sort of followed ...

Q: Is it also fair to say that one of the reasons why NCI has historically encouraged the sending out of cell lines and other things is to further medically useful research?

A: Of course. They have useful cooperation with outside people and useful interrelationships rather than any hostilities of holding this or holding that. I think that's obvious" (op cit., pp. 93-94).

The reality of Dr. Gallo's actions vis-a-vis his AIDS research materials was far different:

B. Practices at NCI, NIH and PHS

It is clear that the impetus for selective withholding and imposition of restrictive conditions of LTCB research materials came initially from Dr. Gallo. But it is equally clear that for a prolonged period, Dr. Gallo's superiors at the NCI, particularly Drs. Fischinger and DeVita, gave Gallo license to give and withhold his materials at will. It also is clear that at the PHS level, Dr. Lowell Harmison institutionalized the selective withholding of research materials, as a matter of political and commercial policy.

The documentary record from early Summer 1984 shows that NCI and NIH officials were aware of problems concerning Dr. Gallo's failure to unconditionally share his research materials. Minutes of the June 18, 1984 meeting of the NIH AIDS Executive Committee show that NIH Director Dr. James Wyngaarden ordered Dr. Gallo to "immediately" furnish the uninfected H9 cell line to Malcolm Martin and CDC. Dr. Gallo provided the line to CDC; he did not obey the order to provide the cell line to Dr. Martin.

Dr. Wyngaarden also ordered Drs. Gallo and Fischinger to prepare a response concerning Gallo's provision of LTCB materials to other scientists. Dr. Fischinger's memorandum transmitting Dr. Wyngaarden's order to Dr. Gallo was typical of the boosterism Fischinger typically displayed toward Gallo:

"If you did not honor an isolated request, you may state your reasons. As we discussed, it seems reasonably clear that your past concerns can be easily validated" (6/19/84 Fischinger-to-Gallo memorandum; p. 1).

Fischinger also told Gallo that:

"Dr. J. Wyngaarden was highly supportive of your stated position and defended your perspective over the objections of Dr. K. Sell [of NIAID] at this meeting" (op cit., p. 1).

But Dr. Wyngaarden told Subcommittee staff his support for Dr. Gallo extended only to his (Gallo's) position regarding his desire to obtain samples from CDC. Dr. Wyngaarden said he would never have supported Dr. Gallo's actions in imposing conditions like those imposed on James Mullins and the scientists at the CDC, or conditions like those Gallo attempted to impose on Malcolm Martin.

No document prepared by Gallo in response to Dr. Wyngaarden's directive was ever provided to the Subcommittee. Dr. Wyngaarden told Subcommittee staff that he questioned Gallo about the matter, but according to Wyngaarden, Gallo "insisted he was sharing his samples as fast as he could." Moreover, said Wyngaarden, Gallo showed him a "two-inch thick" list of names of scientists to whom he supposedly sent his cell lines and reagents. According to Dr. Wyngaarden, Dr. Gallo told him there was only one person to whom he had refused to send materials, i.e., Malcolm Martin. Restrictive conditions on materials, apparently, were not discussed.

On July 2, 1984, at a follow-up meeting to the June 18 meeting of the NIH AIDS Executive Committee, Dr. Peter Fischinger presented to the Committee the "Policy on Requests for the Distribution of NIH Cell Lines Used in AIDS Research and Development." According to minutes of the July 2 meeting,

"Dr. Fischinger, who prepared the Policy, said that it was discussed at a meeting of Drs. Wyngaarden, DeVita, Chabner, Gallo and Harmison on July 2 ..."

The "Policy" actually institutionalized and/or provided cover for some of Dr. Gallo's more arbitrary actions relative to withholding and/or restricting use of LTCB materials. The two most problematic provisions of the July 1984 Policy were these:

(1) Concerning the "IIIb"-infected cell line,

"... all further transfer (sic.) to non-profit organizations should also include a signed confidential disclosure agreement" (p. 2).

(2) Concerning the uninfected cell line:

"Release of the uninfected cell line to non-profit concerns shall presently be at the discretion of Dr. Robert Gallo, LTCB, NCI, with a discussion of the resulting collaborative plan. The standard caveats of non-release to third parties for commercial purposes, and the prudent containment practices on infection shall be heeded as per the required confidential disclosure agreement" (emphasis added; p. 2 ).

The "confidential disclosure" provisions of the NCI/NIH transfer agreement were as follows:

"It [the recipient institution] will maintain in confidence all information relating to these materials and not disclose this information to others without specific written permission, in advance, from the Director, National Cancer Institute, or his designee... It is understood that you will obtain secrecy agreements from all employees to whom the proprietary materials or information will be made available as may be necessary to insure their compliance with the terms of the agreement."

Prospective imposition of these conditions, especially in academic research settings, was bad enough. But in August 1984, when NCI attempted to impose the conditions retrospectively, the result was a series of strong protests from officials of those organizations, protests both at the infringement on academic freedom and the attempted suppression of information in the fact of an devastating epidemic. By March 1985, NCI Director Vincent DeVita had found it necessary to prepare a form letter to respond to the protests. DeVita's letter included this:

"If you interpret that the 'Confidentiality Research Agreement' may preclude publication in scientific literature without NCI's prior approval, you are overly restrictive.

The government's position has always been that general dissemination of new research information by publication is very much appropriate and that such information would only serve to ameliorate the current status of treatment and prevention of AIDS. Accordingly, please feel free to publish your research results. Should you want to consider alternative dissemination methods which could in some way adversely affect our current licensees, please contact us for further discussion."

It is unclear what "alternative dissemination methods" might have adversely affected HHS' five blood test licensees. But the mere inclusion of this provision in DeVita's letter is revealing with respect to NCI/HHS' motives in restricting access to the LTCB's research materials, i.e., to protect "our current licensees." Moreover, it is clear that in other significant respects, HHS was more-than-zealous in its protection of its licensees, even at the cost of public health (see below).

Concerning the policy on the uninfected cell line, the codification of the provisions that placed release of the line "at Dr. Gallo's discretion" clearly refutes Dr. Gallo's assertion that the materials transfer restrictions were forced on him by higher officials. The codification also is noteworthy, considering that Dr. Wyngaarden, at least, was on notice that there were problems with Dr. Gallo's inequitable release of the line. In light of Dr. Gallo's demonstrated inequitable conduct, the provision vesting authority for releasing the line at "Dr. Gallo's discretion" provision was clearly at odds with Dr. Wyngaarden's dictum, recorded in the minutes of the June 18 NIH AIDS Executive Committee meeting, that,

"... we need a tight and consistent policy, and ... we have to have objective criteria as soon as possible."

Consistency and objectivity vs. "at Dr. Gallo's discretion" -- these conditions were mutually exclusive. Yet, so far as is known, Dr. Wyngaarden made no objection to the NCI policy, when it was forwarded to him from Fischinger, through DeVita.

Whatever NCI/NIH officials said and did in 1984 concerning Dr. Gallo's actions vis-a-vis his reagents, in 1992-93, these officials professed dismay and indignation when they were confronted with the documented evidence concerning those actions. In 1993, when Dr. Wyngaarden was shown Dr. Gallo's transfer agreement mandating prepublication review and no-comparison restrictions for the CDC scientists, Dr. Wyngaarden's reaction was immediate and unequivocal:

"Clearly inappropriate."

Dr. Fischinger told Subcommittee staff he believed that Dr. Gallo, as a Federal employee, had a "special responsibility" to make his materials freely available. Dr. Fischinger said, concerning the restrictions Dr. Gallo placed on Malcolm Martin and CDC's receipt of his cell lines, "I wouldn't do it, but Bob must answer for himself." Dr. Fischinger was adamant on one fundamental point:

"DeVita, Wyngaarden and I all believed the reagents should go out!"

As for DeVita, he expressed himself more vividly, saying that "All restrictions are anti-science." Shown the restrictions Gallo placed on Malcolm Martin and the CDC scientists, Dr. DeVita's response was, "I think it's terrible."

C. The Unique Role of Dr. Lowell Harmison

Dr. Lowell Harmison alone, to this day, defends Dr. Gallo's imposition of restrictive conditions on his research materials, particularly relating to the CDC. Dr. Harmison's statements in this regard seemed to reflect Dr. DeVita's observation that by the Summer of 1984, Dr. Harmison had "assumed ownership of" Gallo.

When questioned by the Subcommittee in Executive Session, Dr. Harmison initially denied knowledge of the conditions imposed on the CDC scientists' use of LTCB materials. Yet when he was confronted with the actual transfer agreements the CDC scientists were forced to sign, Dr. Harmison defended them:

"At this period of time, no one knew the degree of infectiousness of this particular virus. There were very small quantities of this virus available. There were a limited number of people with detailed knowledge and experience in working in this area.

The most competent laboratory in this area was clearly that of Dr. Gallo's laboratory on retroviruses. The CDC did not have this capacity of the level of Dr. Gallo. CDC was not charged to do retroviral laboratory research...

So to me, as I look down over the seven conditions here, they are all very responsible and very logical when you did not know the nature of the infectious disease ... each one of these have a level of specific responsibility that would be required of any prudent scientific laboratory director. So I find no difficulty whatsoever in those conditions" (7/21/93 hearing of the Subcommittee on Oversight and Investigations; transcript pp. 54-55).

But there was no factual basis for Dr. Harmison's assertions supporting Dr. Gallo's restrictions on the CDC scientists. The claim that "there were very small quantities of this virus available" is directly contradicted by the fact that as early as March/April of 1984, LAI/MOV and LAI/IIIb were being grown in liter quantities at the LTCB contractor, Biotech Laboratories. Likewise, Dr. Harmison's claim that the CDC did not have the required competency to work with the AIDS virus is simply absurd, considering that by the Spring of 1984, when they sought Dr. Gallo's cell lines, the CDC scientists had been working with the IP virus and their own isolates, for nearly one year.

Dr. Harmison even defended Dr. Gallo's proscription of CDC's publishing without his (Gallo's) prior approval, although Dr. Harmison was not able to explain why this condition, like the "no comparisons" condition, should have been uniquely imposed on the CDC and Malcolm Martin's laboratory. Dr. Harmison acknowledged that the "prior approval" condition was "an absolute constraint" on publication, yet he maintained, "I think that was appropriate at this time..."

Dr. Harmison also promulgated and, to this day, adamantly defends, HHS' withholding of LTCB materials from foreign governments and from any commercial firms other than the five HHS blood test licensees, three of whom, (both at the time of their selection and thereafter) were contractors of the LTCB. The 1984 NCI/NIH policy actually incorporated protection of the HHS licensees as an overarching principle, placing patents and potential financial rewards above public health. The policy included these elements (concerning the uninfected cell line):

"Because patent protection does exist on this cell line, and because a number of ongoing useful experiments are taking place within NCI which could lead to further patents by the Government, release of this cell line to non-license for-profit organizations shall not take place at this time.

An additional reason is that a number of parallel uses of this cell line, which could readily lead to analogous AIDS blood tests, is obvious. It is considered prudent that the effectiveness and rapidity of the realization of the AIDS blood test by the existing licensees should not be compromised by additional competing technological thrusts" (p. 3).

In other words, by NCI/NIH policy, competition in developing the best HIV blood test was to be artificially constrained by restricting the availability of a uniquely permissive cell line for growing the virus.

HHS officials and Dr. Gallo himself asserted that their strategy for commercializing the LTCB blood test, including limiting the number of licensees, was first and foremost a means for ensuring that only quality tests would be developed. Thus, in late Summer 1984, in denying a request from the Commonwealth of Australia for a license to scale up production of "IIIb" to make a government-issue HIV antibody blood test, Dr. Edward Brandt (the letter was actually written by Lowell Harmison) said this:

"With regard to your request for permission to scale up production of the HTLV-III antigen for non-research purposes ... in June of this year we entered into licensing agreements with five organizations ... These five licensees were selected after scientific and technical reviews ... This licensing process has now been completed and we do not contemplate any further licensing, at least for the time being ...

"We think that the shortest pathway to obtaining accurate, sensitive, and highly selective blood test data is through the process that we have established for the assay. It should provide a reliable and effective screening tool in assuring a safe supply of blood and blood products. These assays will be made available through our licensees for use as specified in the product license to be issued by the Food and Drug Administration. Thus, the benefits of these efforts would offer to you a quality assay in minimal time" (Brandt-to-McCarthy; undated).

Dr. Gallo said this about the U.S. Government policy of restricting access to LTCB HIV-related materials:

"Now, there are things that we had to be certain about. Remember I could get in trouble for sending this out to anybody. The Government was concerned about fraudulent blood tests, unfair blood tests by somebody else, by some companies, quote. The Government was also concerned that I would give somebody AIDS by mailing this stuff out. So, we were under reasonable restrictions about who we could give it to. They had to show that they had the right facilities to grow the virus, enough technical competence and that they weren't about to make a test with it. Okay. This was not something I had full control over" (8/3/90 OSI interview; transcript pp. 124-125).

Dr. Harmison, during the July 21, 1993 Subcommittee hearing, also asserted the "quality control" argument as a rationale for restricting commercial firms' access to the LTCB materials:

"The issue as it emerged in late August of 1984 hinged on the following point. When you grant a license to a company or to any organization, you have granted them a license to do something. In return they have committed to do something. During the period of late August, the virus was going from research labs out, and different organizations were coming up to try to produce different blood tests without getting the proper clearances for those blood tests.

When five companies had gone through a rigorous process to qualify the most expert and capable organizations to deliver that blood test acceptable to the Red Cross, acceptable to the FDA, and clean up the blood supply, so what was occurring, we had a lot of me-too organizations coming around all over the country wanting to get virus.

Suddenly they were testing a blood test. And that was infringement of the license granted. So when research quantities were moved out for research purposes, the only objective was to have that you have got to use it for commercial purposes, you have to come back and say, we would like a license now to commercialize, only to have a level playing field. That is the only basis upon which any conditions would have been applied to a virus, to my knowledge (transcript; pp. 49-50).

But the fact is that despite numerous requests, including requests from such reputable manufacturers as SmithKline Beckman, HHS adamantly refused to issue licenses beyond the initial five. Moreover, the whole "quality control" argument for limiting the licenses was bogus; quality control and reliability are the responsibility of the Food and Drug Administration (FDA), and only the FDA. No matter how many licensees developed an HIV antibody blood test, only the tests approved by the FDA could be marketed in the United States. There was nothing to substantiate that allowing more companies to develop antibody blood tests would result in lower quality tests. Indeed, logic suggests that greater competition would have spurred improvements in some of the worst performing of the first-generation U.S. tests developed by HHS' allegedly rigorously screened/carefully selected licensees, particularly the tests developed by Abbott Laboratories and Electro-Nucleonics. These tests embodied significant specificity deficits, and in the case of Abbott, significant sensitivity deficits as well.

Elsewhere in his Subcommittee hearing testimony, Dr. Harmison made it clear that the limited number of HHS licensees was a calculated strategy to reduce competition and thereby heighten the likelihood of profitable returns for the five licensees:

"... to get industry's effective participation, you must do something that offers them a grant or a contract. They must have within their hands the capacity to move forward. And that is basically removing the degree of uncertainty that you can remove" (op cit., p. 21).

Dr. Harmison also specifically invoked protection of the HHS licensees as the reason that foreign governments were denied licenses to make their own blood test:

"... you have to keep in mind that the participation of industry to invest -- and I am giving you my estimate -- something in excess of $10 to 12 million of their money, which wasn't available within the department to get this blood test available. The government went through a very elaborate process to license, I believe, five contractors ... and they had a license to practice this invention not just in the U.S. but worldwide" (op cit., p. 37).

Even in the face of clear documentary evidence to the contrary, Dr. Harmison denied that foreign governments' requests to use LTCB materials were refused. Following a question about whether Great Britain and Australia were denied licensing or permission to use the LTCB virus, (Canadian public health officials also were denied), there was this exchange:

A: "No, no. They were not denied. The U.S. license did not permit -- you can't give someone limited exclusive license or say to them, 'if you invest your money and take this blood test from a laboratory toy to a useful blood test that I can go down here to a clinic on the corner of X street and produce the virus, those companies invested their money and did those tests to get this approved to be marketed, with the hope of making some return on those investments.

We, the government, gave them that license. You can't then turn around and say, I am going to give this government the license or that government the license ... you are not being responsible to your agreements. So that is a big misunderstanding.

Q: You are not being responsible to these licensees?

A: "We absolutely were responsible to the governments and to the licensees. We were honoring the commitment the government made to have the virus and the license produced and marketed in this country, and that was part of international commerce. That is how it is done.

Q: That is how you did it.

A: No, that is how the department did it. That is the standard (op cit., p. 38).

It is important to note that Dr. Harmison's authority at HHS concerning these matters was absolute. Thus, Dr. Harmison's expression of his personal views was, in fact, a statement of HHS policy. But there is no substantiation for HHS/Harmison's assertion that in order to entice manufacturers to make HIV blood tests, it was necessary to limit the number of licensees. In June 1984, when HHS announced the availability of licenses, it was inundated with dozens of applications, at a time when there was no mention that the number of licenses would be limited. Moreover, when the limitation policy was announced, manufacturers demanded that HHS issue additional licenses. Any company that could manufacture a reliable test, at a competitive price, stood to make money. All the HHS/Harmison policy achieved was to enable a select few companies, most notably Abbott Laboratories, to make a great deal of money on the HIV antibody blood test, because competition had been artificially restrained.

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