8.6 THE SENATE ENQUIRY SECTION 7.
The AHPHP operation and accountability
7.1 Under the second term of reference, the Committee is required to report on whether CSL or CSL Ltd, the National Health and Medical Research Council (NHMRC), the Department of Health and Family Services (DHFS) or any other Commonwealth department, agency or employee failed to adequately protect public safety in relation to the Australian Human Pituitary Hormone Program (AHPHP).
7.2 In their submissions to the Committee, many recipients expressed disquiet at the way the AHPHP was conducted and raised issues of accountability. For example, one recipient submitted:
...all of the agencies that were connected with the Australian human pituitary hormone program are at fault. The revelations of the Allars inquiry are mind-boggling to say the least. The irony of all of this is that no one will ever be made accountable for their improper actions, actions that have left a number of people dead, others at risk and families devastated by a dreadful disease.
No-one from CSL - whose actions in harvesting the pituitary glands under completely uncontrolled conditions must border on criminal negligence - has ever been held to account. Nor have any members of HPAC, who sought kudos and career advancement ahead of prudent medical practice and patient safety.
Further, some recipients concluded that there were breaches of the law by persons involved in the program:
We believe that the report completed by Professor Allars, her executive summaries and Dr Lawrence's speech to the House prove beyond any question that there had been significant breaches of the law as it applies to a wide variety of areas. These include the manufacture of the hormone, including the collection of glands, distribution of the hormone by various agencies, including HPAC, CSL and others as detailed in the Allars report, and non-disclosure of possible side effects.
7.3 Other recipients expressed concern that CSL's manufacturing practices were `unsafe' and `negligent' and that they may have been treated with hormone that was not only potentially contaminated with CJD but hepatitis as well.
7.4 For many recipients lack of knowledge about the future implications for their children is a further source of anxiety:
As a human pituitary hormone recipient and as member of the Australian public, I feel that my life, my safety, has been jeopardised. I now have an increased risk of contracting CJD and it is not known to what extent all my 4 children (who were all breastfed) are also at risk of contracting CJD.
7.6 The Allars Inquiry report provided extensive detail on the government bodies and agencies involved in the AHPHP. Many recipients believe however, that the Allars Inquiry did not adequately address the issue of accountability because the terms of reference did not go to the question of liability. Professor Allars in her submission to the Committee noted:
Neither compensation nor the issue of criminal or civil liability of medical practitioners were part of my terms of reference. Consequently I made no recommendation on these issues. I make no comment now.
7.7 In considering whether there was a failure to adequately protect public safety in relation to the AHPHP, the Committee has relied extensively on the findings of the Allars Inquiry. Comments are provided in relation to the particular areas of :
the production of the product, including collection of pituitary glands; supervision of the product and program by government agencies including the Health Department, the National Biological Standards Laboratory and the Human Pituitary Advisory Committee; and action taken by the Department following the suspension of the program in 1985 in relation to tracing of recipients, information provided to recipients, epidemiological studies, and blood and organ donation.
7.8 The Allars Inquiry reported that from the commencement of the AHPHP, CSL and HPAC believed that there were two avenues for ensuring the safety of hormone product from viral contamination. Firstly, through the criteria established to exclude the collection of glands from certain cadavers and secondly, through the method of processing the glands.
Collection of pituitary glands
7.9 A brief summary of the very detailed account in the Allars Report of the development of the exclusion criteria is given in Chapter 2 of this report. The Committee also notes that a letter from the Director General of Health to CSL in June 1963 stated:
...that all medical superintendents of hospitals with pathology departments (and State authorities responsible for accident autopsies) should be induced to arrange for the collection of glands, the recording of particulars of all autopsies...and the regular transmission to a central depot.
The first instructions on the selection of glands was issued by CSL in 1966. Over the period of operation of the AHPHP the exclusion criteria were amended, but as Allars notes `in a reactive fashion as problems of possible sources of infection came to light'. Further, with one exception in 1971, HPAC took no action to keep abreast with current scientific knowledge of disease potentially affecting human pituitaries
7.10 Dr Whitten in his submission also noted that `in a surprising move NPA [the USA National Pituitary Agency] in early 1978 took the lead from Australia and excluded glands from patients with "viral dementia", one of the names used for CJD and kuru'.
7.11 Although exclusion criteria were established, the Allars Inquiry found that there was a failure to communicate the criteria to the pathologists and mortuary attendants who removed the glands. No one institution or individual was made responsible for the distribution of, or compliance with, the exclusion criteria. The Allars Inquiry found that most of the pathologists and mortuary attendants contacted by the Inquiry were unaware that any written exclusion criteria issued by HPAC existed. Most relied on verbal and self-imposed criteria to exclude unsuitable material.
7.12 The Allars Inquiry concluded that as screening of glands for compliance with the exclusion criteria could only be done by the pathologist at the time of removal, CSL and HPAC had no means of ensuring that glands within the exclusion categories would not be collected. This was particularly so when glands were removed by mortuary attendants without supervision, `as was usually the case'. Thus, as infected glands may have been forwarded for processing, the ability of the manufacturing process `to eliminate viruses and bacteria was essential to the production of hormones with the least amount of contamination possible'.
7.13 The Allars Inquiry noted that the glands were not removed by sterile technique, nor was the post-mortem room a sterile environment. The Inquiry also found that in most institutions no specific procedures were in place in relation to the sterilisation of the equipment or the handling of tissue. It was not until 1977 that CSL provided instructions for the removal of the gland. This arose from concerns about the presence of extraneous material with the gland and the impact of such material on CSL's estimations of hormone yield.
7.14 In relation to the lawfulness of collection of the glands, the Allars Inquiry found that prior to the introduction of uniform human tissue legislation, the lack of hospital records meant that the Inquiry was unable to come to a firm conclusion as to whether glands had been collected lawfully or unlawfully. Following the introduction of uniform legislation, glands were generally not removed for the purposes of post-mortem examination but for the purpose of supply to CSL. Thus, the use of glands during the period of the human tissue legislation was unlawful.
7.15 In submissions and evidence before the Committee, many recipients expressed concern about the way in which the glands were collected and the lack of information provided to recipients about the source of the material:
The revelation of the way in which pituitary glands were collected for use in the AHPHP came as a great shock to many recipients and continues to be a source of great anger today. The pressure exerted on hospitals to increase the rate of gland collection; the incompetent, reactive and slow revision of exclusion criteria; the inadequate communication and monitoring processes that were employed and the unlawful removal of glands contribute to a situation where people want answers to a lot of questions and want people to explain their actions and be made accountable for the circumstances we find ourselves in today.
7.16 The CJD Support Group Network stated:
The focus of HPAC was on maximising collection. Scant regard was paid to the law or to basic measures to safeguard the health of endusers.
7.17 In its submission, the Department stated:
It is now recognised, with the benefit of hindsight, that the precautions taken by HPAC and pathologists were insufficient to completely rule out collection of a pituitary gland (or for that matter an organ or tissue) with the potential to infect a recipient with CJD. This is because a person carrying the CJD prion may, on clinical examination, show no symptoms of the disease. No level of protection could completely guard against collection of glands from people in the preclinical stage of CJD. The HPAC relied upon the professional expertise of pathologists in deciding whether a gland should or should not be released for therapeutic purposes. Through their medical training pathologists were aware that a cadaver likely to be infected with hepatitis, CJD or other viral or neurological diseases should be retained for microscopic examination. This was the standard medical procedure. The fact that the pathologist knew the gland was to be used for therapeutic purposes was a further incentive not to release the gland for extraction of the hormones. This same situation applied where dura mater, organs or tissues were also being collected for therapeutic purposes.
7.18 The Committee considers that the Department's statements above raise serious concerns about its understanding of the ethical matters and accountability issues raised by gland collection and the monitoring of exclusion criteria as detailed in the Allars Report. As the Allars Inquiry reported:
Nor was it an adequate excuse that on account of the incubation period for slow viruses scrupulous attention to the criteria would not have prevented a gland from a person who had incubated the disease from slipping through. Exclusion criteria were established to ensure the product was safe. Adequate steps should therefore have been taken to ensure compliance with them. HPAC failed to take those steps.
7.19 The Committee also notes that following the introduction of uniform tissue legislation, the Health Department failed to act to ensure that glands for the AHPHP were collected in a lawful manner. Not only did the Department have a role in oversighting the AHPHP, but it also had representatives on HPAC and should have ensured that legislation was complied with.
Processing of pituitaries
7.20 CSL processed glands using mainly the Ferguson method and, from late 1984, the Chapman method, although for some time CSL also produced hormone using the Brown/Catt method. Details of these methods are given in Chapter 2.
Concerns raised about the processing of glands
Screening of glands
7.21 From the Allars Report, it appears that until 1977 frozen pituitaries were received at CSL and ground with dry ice without any visual inspection. However, following concerns about yield estimates, a sample of glands were examined and it was found that 12 to 15 per cent of the tissue collected was extraneous matter. This led CSL to issue in 1977 instructions on the removal of glands. From July 1982, CSL began separating glands into four classes based on their appearance and those in the `poor' and `rejected' gland classes were not processed.
7.22 Allars reported that laboratory screening of pituitaries was not carried out by CSL because it would make the glands unavailable for processing. The Committee notes that the practice adopted in the UK was that small batches of pituitaries, eventually 100, were extracted and, if the extract proved positive for hepatitis, the batch was rejected.
Quality assurance and contamination
7.23 A summary of measures taken by CSL in relation to quality assurance and contamination is given in Chapter 2 of this Report. The Allars report also contains the list of batches processed by CSL and indicates those it believed were not distributed or withdrawn because they failed quality control.
7.24 In relation to contamination, the Allars Inquiry stated:
The proposition that the larger particles of viruses and bacteria would come off the column first in the Ferguson process, leaving the hormone product free from contamination was soundly based until the late 1970s.
7.25 In its submission to the Committee, CSL stated that:
The Ferguson gel filtration fractionation method as used by the Laboratories in the manufacture of hormones clearly demonstrated its effectiveness, and reinforced the trust placed in it by both the Commission and the HPAC, by excluding the hepatitis in the void volume of the four batches (082, 93, 100 and 128) referred to in the Allars Report which tested positive to hepatitis B antigen in the void volume.
7.26 The Allars Inquiry noted that in 1966, Dr Wes Whitten, then of NBSL, warned that because large particles, including viruses, would precede the hormone through the column, the line would become contaminated. In their submission to the Committee, Drs Whitten and McCullagh noted concerns about the sterility procedures in place at CSL to ensure that the products were `free from contamination by infectious agents and their products'. They commented:
We believe that procedures to maintain sterility were patently inadequate by the standards of the time and that CSL failed to recognize or to acknowledge this.
7.27 Dr David Howes, former NBSL officer, submitted that CSL and HPAC had an over simplistic and over optimistic view of the fractionation process and put forward the following points:
that only some of the virus particles and some CJD particles would be removed in the `void volume' of the process; that in the column of gel beads there were very small and acute angled crevices to trap various sized particles which could become dislodged later in the process to mix with the hormone extractions; and there could be cross-contamination of runs.
Dr Howes concluded that `virus contamination was unavoidable'. Further, he stated:
In relation to the CJD and hepatitis B contaminations of pituitary hormones, the failure of both CSL and HPAC to subject the gel chromatography technique to a very detailed critical analysis in relation to the possibility of contamination with viruses as a general problem was, in my view, a major contributor to the disaster.
7.28 The matter of hepatitis B contamination was also raised in submissions and evidence. Issues canvassed include that:
HPAC was advised before the screening for hepatitis B commenced in 1978 of the risks of hepatitis and failed to act. First in 1973, then by the Assistant Director-General of Health in 1975 and also by CSL's Production Manager in 1976. Although the Allars Inquiry reported that a batch of hormone tested positive for hepatitis B, but not to a sufficient level to fail quality control, the Senate Community Affairs Legislation Committee had been told by the Department at an estimates hearing that `there is no safe level for hepatitis contamination, and that it would be illegal to distribute products that were contaminated with hepatitis'. Hormone prepared in the UK was extracted from batches of 800 glands and later sub-batched to 200 and then 100 glands because of hepatitis contamination. CSL knew of this but did not employ the same strategy and continued to use pools of 1,350 glands. CSL tested the final product before ampouling and not the homogenate as was done in the UK. Only two batches of hGH were tested for hepatitis. CSL underestimated the risk of hepatitis B by using a chimpanzee infectious dose to constitute a human infectious dose.
7.29 In evidence before the Committee there was extensive discussion concerning batch 128. In the Allars Report it is stated that hPG batch 128 was not distributed. However, this batch was distributed and received by APQ and it is now acknowledged in submissions to have been distributed. CSL suggested this discrepancy in the Allars report was a `transcription error'.
7.30 Dr Peters in evidence asserted that CSL records show that batch 128 tested positive for hepatitis B. An internal CSL memo indicated that tests of batch 128 resulted in a positive test in the column charge and negative in the void volume. Reference was also made to batches 003, 004 and 024 as being non-sterile but distributed. Dr Peters stated:
In my submission of 12 July I attached the batches received by a number of recipients, with the names removed to protect liability. This shows that batch 24, which was a non-sterile batch, had been given to a recipient.
7.31 In its submission to the Committee, CSL stated that `at no stage did the Commission distribute any product known to be contaminated with a pathogen'. Further, all material issued by the Commission `was considered acceptable by the HPAC adopted and introduced'. CSL went on to state that:
Of these batches [which tested positive for hepatitis in the void volume] 082 was withheld from distribution; Batches 93 and 100 were combined and reprocessed into Batch 110, however this batch was withheld from distribution because it failed pyrogen testing; Batch 128 was released following further tests for hepatitis. 40
7.32 In evidence, Mr Kaufman of CSL, commented further:
[batches 82 and 93] tested positive in the void volume which is that peak that comes out first where the viruses will be concentrated selectively into the void volume. That is the part that tested positive. The fractions that have come off the column have not tested positive, did not test positive from the start of hepatitis testing in the program, which really validates the separation efficiency of the column. We know that in batches 82, 93, 100 and 128 we could detect it in the early phase of the separation. It was not present in later fractions.
7.33 Mr Kaufman also gave a detailed explanation of the processing of batch 128. He concluded by stating that:
Having reviewed the results recently, I would still come to exactly that same conclusion. So there is no question of batch 128 having been issued despite it being positive for hepatitis because it was not positive for hepatitis.
7.34 In relation to hepatitis in recipients, CSL stated:
No hormone recipient in Australia (or in the world for that matter) has been reported as being hepatitis B positive (or HIV positive) as a result of receiving pituitary hormone therapy.
7.35 This statement was questioned by Dr Howes who stated:
A much more recent flaw in CSL's knowledge and reasoning can be seen in its attempt, in the department's submission, to establish that recipients were demonstrably not at risk of hep B infection. It is said that one hormone recipient had been tested for hep B antibodies and that the test was negative. Most hep B infections are acute, and the woman tested had been treated with hormones many years earlier, but antibody levels decline progressively over time and some infections may come to test negative as a result. It also uses the argument that no cases of hep B infection have been reported. That begs the question of who has looked and what proportion of those at risk have been checked.
7.36 In answering a question on tracing recipients to test for hepatitis B, the Committee was told that there had not been any attempt to ascertain the hepatitis status of recipients. Further, Mr Kaufman of CSL stated `I think, Senator, there are no potential contaminated batches as far as hepatitis B goes' based on CSL's testing. Tracing of recipients is discussed later in this Chapter.
7.37 Mr Kaufman also replied to concerns about pool size. He stated:
We had a look at the UK practice. The fact remains that we had at least two steps in the process that were capable of eliminating virus.
7.38 Following the Committee's hearing on 13 August 1997, CSL provided further detailed information concerning the above matters raised by Drs Peters, Whitten, Howes and McCullagh. This information included:
the test results of batch 128; that batch 003-1 failed sterility test and was reprocessed as batch 003-2 which was sterile; that the records of batch 004 do not show sterility problems; that there are no records that batch 24 was issued; and that hGH was tested for hepatitis B.
7.39 The CSL's response to evidence was further responded to by Dr Howes. He provided evidence in relation to the pool of fractions used to produce batches 121 and 128, the testing for contamination with hepatitis B antigen, invalid tests for hepatitis B antigen in hormone samples and reduction in risk of contamination of batches of pituitary hormones with infectious hepatitis virus. Macedones also provided the Committee with further comments regarding the processing of batch 003-2.
7.41 The Melbourne achives documents of Gajdusek may demonstrate that this section is incorrect in tis assumption that little was know at the time.
7.44 The Allars Inquiry found that from 1971 (Dr McGovern's warning) to 1980 there was no record of discussion of unconventional slow viruses in the minutes of HPAC or its Subcommittees. The Committee's perusal of the minutes of HPAC and its Subcommittees similarly found no record of discussions of slow viruses until 1980. In 1980, the Chairman of HPAC, Professor Lazarus, and the Director of the Medical Research Council in the UK, discussed recent developments in the UK in regard to the possibility of slow virus infection in pituitaries. Professor Lazarus wrote to Dr Ferguson, Chairman of the Fractionation Subcommittee, about the problem. The Allars Inquiry noted that the Fractionation Subcommittee discussed the possibility of slow viruses at its meeting of 19 May 1980. The Subcommittee concluded that `as, at present, a slow virus is not positively linked with a disease present in the community and, moreover, as the technology did not now exist to detect a slow virus, acknowledgment of the potential dangers is all that is possible'. HPAC concurred with this conclusion.
7.45 The Allars Inquiry found that the Subcommittee's conclusion was incorrect in the light of scientific knowledge in 1980 as cases of CJD had been reported in Melbourne as early as 1963 and in Adelaide in 1965. Further, neither the Subcommittee nor HPAC sought expert advice or re-assessed the program. Although there was no technology to detect the virus, other options were available to the Subcommittee for re-assessing the safety of the product.
7.46 The Allars Inquiry also concluded that conferral on HPAC and the Fractionation Subcommittees the responsibility for monitoring all aspects of the production of the hormone was fundamentally flawed. Further, members:
..are not to be blamed for their lack of expertise or lack of familiarity with the developments in knowledge of CJD. They were not neuropathologists or virologists. They are to be blamed for their failure to recognise the limits of their expertise and the need to seek advice.
7.47 The Inquiry also noted that `like the Fractionation Subcommittee and HPAC, CSL failed in 1980 to consider or adopt options which were appropriate with regard to the risks of treatment with the hormones in the light of scientific knowledge at the time'.
7.48 The Committee notes that in a judgement handed down in regard to the UK growth hormone program, Mr Justice Morland, found that the UK Department of Health should have acted on warnings of CJD contamination and suspended the program from July 1977. In her submission to the Committee, Professor Allars, while noting the date of July 1977, stated:
7.49 The Committee received evidence on the awareness of CJD transmissibility and when HPAC should have become aware of the risk. Dr Peters submitted `Professor Allars implies that there was only limited knowledge of CJD in Australia until the late 1970s. This is incorrect'. He went on to note early work on the transmission of scrapie and that `the connection between scrapie and human diseases was postulated in 1956'. Dr Peters also noted that papers were published on kuru in the 1950s and 1960s and that CSL scientists published at least five papers on kuru between 1961 and 1972. Dr Peters also submitted `from 1973 onwards, Health Department files expressed concerns about the possibility of transferring CJD by medical goods and instruments. Some of these concerns were relayed to HPAC, which the files show ignored the warnings'. He concluded `there was sufficient knowledge about CJD within CSL, the Health Department and the medical profession to have required extreme caution about the hormone program even at the beginning'.
7.50 Drs Whitten and McCullagh submitted that there were recurrent reports of transmission of CJD between 1968 and 1973 in widely read medical and scientific journals, including Science and Nature. Further, they noted at one stage HPAC had included in the exclusion criteria neurological disease, and submitted that `its framing can only be construed as evidence that HPAC was aware, at an early stage, of transmissibility risks'. They went on to state:
We believe that it should have been apparent by the mid 1970s to biological scientists with a familiarity with the general scientific literature that CJD and related conditions were likely to be transmissible.
7.51 Recipients also raised the matter of knowledge of CJD by members of HPAC. Whilst not having scientific training, many recipients have made the effort to become as informed as possible as a way of diverting the impact of CJD risk awareness. In doing so, many recipients have reached an opinion on the HPAC's knowledge of the awareness of CJD:
Clearly, in the light of scientific knowledge, the Human Pituitary Advisory Committee failed to respond appropriately to the knowledge of the risks of treatment with hormones, and demonstrated incompetence and disregard for public safety. Those responsible for administering the program must be asked to explain their actions and be brought to account for the consequences. Matters of alleged illegality should be thoroughly investigated and appropriate action taken. The lives of so many people have been adversely affected as a result of their conduct.
7.55 Once the hGH and hPG had been produced it was tested for potency. CSL used bioassay and radioimmunoassay. Bioassay involved a sample of each batch of hormone being injected into a test animal and the response measured against a standard. The amount of response obtained indicated the amount of hGH or hPG in the sample. A potency value in international units (IU) was then assigned to each batch. Radioimmunoassay is the measurement of a radioactively labelled substance using as the measure the amount of antigen bound to an antibody.
7.56 The measure of potency was particularly important for hPG recipients where there was a risk of multiple pregnancies or hyperstimulation of the ovaries, a potentially fatal condition, if dosage was incorrect. CSL stated in its submission to the Committee that every single batch of pituitary product was assayed for potency. It also developed additional assays requested by HPAC, for example the luteinising hormone assay, introduced in 1972.
7.57 The Allars Inquiry reported that throughout the period of operation of the AHPHP treating practitioners found that batches of hPG varied in their potency. Treating practitioners also reported that some batches appeared inert and some were more potent than others. The FSH Subcommittee frequently made requests of CSL to improve the means of determining the potency of batches. 72
7.58 Dr Whitten submitted that `CSL was set an impossible task to bioassay hPG because it was a very impure and variable mixture of FSH and LH, and these two hormones may synergise or antagonise each other depending on the ratio in the mixture. Thus the potency is indeterminate'. Dr Whitten raised other matters concerning problems with potency: that assay for LH content, should have been carried out by the Parlow method; that degraded FSH (antiFSH) can assay as FSH using radioimmunoassay; batches were too small for economical standardization; vials were labelled as the equivalents to a fraction of a pituitary, thus origin, the quality of the storage and the efficiency of extraction would impact on potency; and hPG was not adequately standardised for LH. 73
7.59 In their submission to the Committee, Drs Whitten and McCullagh described the bioassay procedures applied by CSL to hPG as `incompetent (by the standards of the day)'. In a detailed review of CSL's bioassay procedures by Dr Whitten attached to the submission, he stated that evidence that CSL never overcame problems of bioassay of hGH is found in the minutes of the Fractionation Subcommittee meeting held in June 1981, which states `It is evident to the Subcommittee that the real issue of throughput for hGH was directly linked to bioassay'.
7.60 Drs Whitten and McCullagh also submitted that CSL concealed from practitioners these poor bioassay procedures. Product information distributed with the hormone `failed to convey a reasonable indication of the questionable value of data concerning potency'.
7.61 In evidence before the Committee, Dr Whitten went further:
The other aspect of that is that CSL's assays were almost incredibly primitive. They state in their submission that every single batch of pituitary product was assayed for potency. They do not say how accurate those assays were, and they do not say in what species they were assayed. But six members of HPAC or its committees published a paper which said clearly that they were assaying in the patients themselves. The patient was the guinea pig! That is the assay; an 'in-patient assay' they call it. They started the patients on a small dose of pituitary extract - FSH as they called it, although it was really hPG. Then they followed that patient for five days to see if her ovaries were producing oestrogens. In the early days these were measured in the urine and at a later stage by radioimmunoassay in the blood. If the patient did not respond, the dose was increased by a factor of 1.3. If she did not respond to that, it was increased again. These people clearly describe three patients who received, I estimate, between nine and 10 cycles of treatment. They started off with 0.3 or 0.5 and finished up getting a daily dose of three pituitaries for five days and, in this case, they decided that it was not the patient that was irresponsive, it was the hormone that was inactive. That was evidenced by a rather crude bioassay that had been done, but it was different from the radioimmunoassay that they had used. The radioimmunoassay that was used by CSL was such that it could not distinguish between FSH and inactive FSH - in other words, the work I had done earlier with the FSH. It is inactivated by enzymes that are present in many organisms and many tissues, and it is converted from an active FSH to an inactive one - in fact, it is an anti-FSH. The altered FSH sits on the receptors in the ovary and prevents the normal FSH from acting. I have said enough.
7.62 Dr McCullagh stated:
At page 30 [DHFS submission], for example, there is a specific reference to the effect that an assay system to determine the correct treatment regime for hPG patients was developed and resulted in fewer cases of multiple pregnancy and hyperstimulation. Fewer cases than what? We have already heard - and you can doubtless confirm this - about the pitiful state of bio-assay that was applied. It is an incredible statement. On the preceding page it is stated that a lower hyperstimulation rate was identified in Australia compared with results achieved overseas.
7.63 CSL responded to this evidence and disputed Dr Whitten's assumptions concerning the assays used by CSL and stated:
The assays used for both hPG and hGH were based on the standard British Pharmacopoeia [BP] biological assay. A full statistical analysis was done on each assay in exactly the manner recommended by Dr Whitten...The assay employed was a 2+2 design which (as pointed out by Dr Whitten) has some limitations in terms of testing for linearity - nevertheless it was the standard (and only) BP bioassay design for all products until the December 1980 edition of the Pharmacopoeia. The bioassays were subject to the normal variation seen in such assays, and were conducted in rats. CSL had a wide experience in bioassays across many different products - its expertise in this field was supplemented by regular assistance from NBSL.
Code of Good Manufacturing Practice (GMP)
7.64 In its submission to the Committee, CSL stated that it has always placed a high emphasis on quality manufacturing and had established an independent quality control section at the Laboratories as early as 1961. CSL submitted that this was before the Australian code was first published in 1970 but was consistent with WHO recommendations at the time `which demonstrates that the Commission was up to date in its thinking and prepared to accept advancements in manufacturing practice and regulatory aspects of the pharmaceutical industry'.
7.65 CSL went on to note that it had been actively involved in the development of the Australian Code and had a representative on the Therapeutic Goods Sub-Committee that had revised the Code in the mid 1970s. It also stated that NBSL inspected the Laboratories in 1971 and that by the time the Commission ceased in 1991 to become CSL Ltd, approximately twenty inspections had been conducted.
7.66 The Allars Inquiry reported that while it had been told by officers of CSL that it did submit itself to inspections pursuant to GMP, officers of the Department during the 1970s and 1980s told the Inquiry that `CSL strongly resisted having the Code applied to it, and this included a resistance to participating in inspections of its manufacturing premises pursuant to GMP'.
7.67 In evidence, Dr Peters stated:
I say in my submission that CSL resisted compliance with the Code of Good Manufacturing Practice. A reading of section 5 of the CSL submission gives the impression that CSL complied with the Code of Good Manufacturing Practice. This is incorrect. Documents on the CSL file say that CSL did not implement the Code of GMP because it would have been too expensive. Page 4 says that by the time the commission ceased in 1993 it had been inspected approximately 20 times. It did not say that most of these inspections were after 1985. As far as the hormone program was concerned there was only one inspection and this followed a complaint about labelling. There was never an inspection of the manufacturing program.
7.68 CSL responded by providing the Committee with a list of inspections between 1971 and May 1994. In all 27 inspections were conducted. 14 were made to June 1985, with one relating specifically to hormone products, that made in June 1974 concerning labelling of FSH. CSL also provided the Committee with documents relating to the preparation and approval of master formulae and manufacturing instructions.
7.69 Concerns were also expressed about the mixing of batches. CSL responded that there is nothing in the GMP to preclude batch mixing if the manufacturing protocol allows for it, and provided documentation to enable tracing is maintained.
7.70 The possible hepatitis contamination of hGH and hPG produced by CSL and the general questions raised about CSL's production method and standards of production are of great importance to many in the recipient community. For the information of recipients, the Committee has provided an outline of both the evidence received from Drs Peters, Whitten, Howes and McCullagh and CSL's response to that evidence.
7.71 The Committee does not have the expertise to make an authoritative evaluation of the detailed technical information provided in evidence. It considers that to make such an evaluation would require a panel of independent scientific experts. The Committee considers that an epidemiological study of recipients would be of use in establishing the impact of possible contamination, other than CJD contamination, on recipient health. This was discussed in Chapter 3.
7.72 In relation to awareness of the risk of CJD by HPAC and its Subcommittees or CSL, the Committee acknowledges that information on CJD generally, and its transmissibility, was available in leading scientific and medical journals. However, coming to a decision on whether or not the link between treatment with human pituitary hormone and CJD should have been made earlier is difficult. Such a decision involves making a personal judgment about the level of knowledge and individual understanding held at various times between 1965 and 1985, as well as the degree to which that knowledge was disseminated within the key groups of decision-makers.
7.73 The Committee does however make the following comments. First, the Committee's perusal of the minutes of HPAC and its Subcommittees also indicates that there was concern about the need for accurate information about the potency of the hormones produced by CSL during much of the period of operation of the AHPHP.
7.74 Secondly, the Committee is concerned about the quality of the information provided to the Allars Inquiry about batches. It has now been confirmed that batch 128 was distributed and according to CSL was not contaminated by hepatitis. The Allars Inquiry reported that this batch was contaminated and not distributed. The Committee finds it difficult to accept that this was simply a `transcription' error. Likewise, CSL has now indicated to the Committee that batch 003 was reprocessed as batch 003-2. CSL indicated that 003-2 was sterile and that batch 004 had no problems with sterility and was issued. The Allars Inquiry lists batches 003 and 004 as being not distributed or withdrawn.
7.75 The publishing of incorrect information in relation to batches 003, 004 and 128 can only have added to the anxiety of recipients already reeling from the knowledge that they were at risk of CJD and who realised that they had in fact received these batches of hormone. It would also have raised doubts in the minds of recipients as to the reliability of other information contained in the Allars report concerning batches. The Committee considers that the supply of incorrect information to the Allars Inquiry may require further review in the light of the information now available. See paragraph 7.181.
Supervision of the product and the program
7.76 The Allars Inquiry Report provides an in depth examination of the role of relevant government agencies in relation to the production and use of hPG and hGH. The following highlights the findings of the Allars Inquiry in relation to government agencies.
National Biological Standards Laboratory (NBSL)
7.77 In June 1964, the Pharmaceutical Benefits Advisory Committee (PBAC) recommended to the Minister that the addition of new preparations to the list of benefit be subject to satisfactory analytical reports being received from NBSL. From 1966, compliance with a specific or general standard was legally required for goods for therapeutic use which were supplied as pharmaceutical benefits.
7.78 The Allars Inquiry found that NBSL had first become involved with human pituitary derived hormones in 1966. At that time the Health Department requested NBSL involvement in certain matters concerning the hormone. Consequently, Dr Whitten, then an NBSL officer, warned of the problem of viral contamination in the preparation of the hormones. While there was action arising from this warning, the Allars Inquiry reported that the product was not tested by NBSL. NBSL's next involvement with the hormones was not until 1979 when NBSL contacted CSL about labelling of the product. In 1984 NBSL again became involved over the proposed supply of hGH processed in New Zealand and the need to improve manufacturing and quality control standards for hPG and hGH.
7.79 The Allars Inquiry found that the reason for failure by NBSL to test hormones for standard compliance was: an absence of an official standard; difficulty in developing a standard until the radioimmunoassay technique had been further developed; and poor communication and coordination within NBSL.
7.80 The Allars Inquiry found that there was a lack of initiative on the part of NBSL to develop an official standard, although the HPAC saw the need for this and undertook a project in the 1970s and 1980s to isolate highly purified hormones for the purpose of developing a radioimmunoassay. Further:
The Director-General of Health had a discretion in making arrangements for the testing of pharmaceutical benefits. In the case of the pituitary hormones, prior to the listing of the product, the Assistant Director-General made a particular request for involvement by the NBSL. This is another indication of how the pituitary hormone product was dealt with in a manner inconsistent with the normal course of listing and testing of a pharmaceutical benefit. NBSL failed to respond to advice. The Director-General failed to insist that the advice be provided prior to making the recommendations to the Minister that the hormones be listed.
7.81 The Allars Inquiry also reported that NBSL was involved in evaluation of commercial hGH in 1978 and 1981. Advice on the product from NBSL drew attention to hepatitis and slow viruses and raised the issue of a warning upon the labelling. The product was not approved for marketing in Australia. 90
7.82 In evidence, Dr Howes stated, in relation to NBSL's role:
In my submission I told how the viral products section of NBSL was often prevented from exercising its statutory responsibilities. I want to add to my submission a postscript about a statement to a Senate committee in 1994 made by Dr Geoffrey Vaughan, then head of TGA. It appears to confirm my story. I quote:
The relationship with the then National Biological Standards Laboratory was such that the government elected not to regulate CSL through the National Biological Standards Laboratory. Regulation of CSL and blood products did not take place until the enforcement of the Therapeutic Goods Act of 1989, which came into activity in February 1991.
I think that is highly relevant.
7.83 In his submission, Dr Howes also noted that:
In 1966, Dr Lazarus, the Chairman of HPAC, was advised by Dr Raby of NBSL, in writing, that the Ferguson fractionation technique could not be relied upon to remove virus infectivity during the production of pituitary hormones. HPAC evidently rejected that advice, for CSL continued to make these hormones and HPAC permitted their clinical use; in the IVF program in particular.
7.84 Dr Whitten also submitted, in relation to the Allars Inquiry comments on NBSL's failure to develop a standard, there were great difficulties with developing a standard and pointed out that the US Food and Drug Administration `did not produce standards but relied on collaboration with industrial firms such as Ely Lille to produce the US and the WHO Standards'.
Pharmaceutical Benefit Advisory Committee and listing of hPG and hGH
7.89 The Allars Inquiry concluded:
(a) on the listing
...the history of the listing of the hormones is one of circumvention of the PBAC and direct dealings between HPAC and the Director-General of Health and the Minister. These decision-makers determined the details of the scheme.
(b) on testing by NBSL:
PBAC proceeded to list the hormones without having followed the policy which applied to ensure appropriate exercise by the Director-General of his discretion under the National Health Act, namely to list as pharmaceutical benefits only those products which had been tested by NBSL.
(c) on the Guidelines
The distribution of the hormones under s.100 of the National Health Act appears to have been regarded by PBAC as a vehicle for delegating to the expert committees [of HPAC] its normal function of setting restriction for use of these pharmaceutical benefits. However, no formal delegation of the powers of HPAC were made. HPAC did not get PBAC's approval of the initial Guidelines...for approving patients for treatment with hGH or hPG.
(d) on the use of s.100
...it was sought to create a role for the expert committees which would be responsible for approving patients for treatment.
It was an improper purpose and the Minister's decision to list the hormones was an abuse of the power under s. 100.
(e) on the role of government decision-makers
The government decision-makers who established the scheme of regulation by expert committee must also take responsibility for having placed these medical practitioners and scientists [members of HPAC and its Subcommittees] in a position where they had such a responsibility, and where the normal mechanisms for testing and review by NBSL and other Departmental bodies, in the light of scientific knowledge, had been circumvented.
7.90 In relation to the Allars recommendation that s.100 be repealed and replaced with a different provision, the Committee has noted in Chapter 3 that the recommendation is still under consideration as part of a review being undertaken by the Attorney-General's Department.
Australian Drug Evaluation Committee (ADEC)
7.91 ADEC was established in 1963 with an advisory role in relation to the safety of drugs. From 1970 imported drugs had to be considered by ADEC. However, the Allars Inquiry found that ADEC could have played a role as the hormones were pharmaceutical benefits and PBAC could have requested that ADEC play a role. The Inquiry also found that the potential for effective regulation was undermined because of the leading role played by members of HPAC and its Subcommittees. For example, when ADEC needed advice as to the safety of imported hGH it sought advice from the Chairman of HPAC, Professor Lazarus, and when it considered biosynthetic growth hormone, it sought advice from the Endocrinology Subcommittee of ADEC, which was made up of members of HPAC.
Adverse Drug Reactions Advisory Committee (ADRAC)
7.92 From 1970 ADRAC undertook post-marketing surveillance of the safety of medicinal drugs. Unless it received an adverse drug report, ADRAC has no power to investigate. The Allars Inquiry reports that no report was ever made to ADRAC by HPAC or any health professional about adverse reactions to hPG or hGH.
National Health and Medical Research Council (NHMRC)
7.94 Allars reported that there is no general legislation in Australia regulating research conducted on human subjects. There is however general regulation through the funding of projects meeting requirements of the NHMRC as assessed by institutional ethics committees and the scheme for general marketing approval for new drugs.
7.95 The NHMRC funds research projects and requires grantees to comply with its Statement on Human Experimentation and Supplementary Notes as a condition of grants. The monitoring of compliance of research projects with the Statement and Supplements is undertaken by institutional ethics committees which have been established in hospitals and other research institutions.
7.96 The NHMRC released its first statement on Human Experimentation in 1966. The Statement was developed as a result of concerns that experimentation such as that revealed in the Nuremberg trial should not re-occur and concerns about the increasing incidence of medical negligence litigation in the USA. Allars found that the Statement did not make a distinction between therapeutic research in a clinical setting and non-therapeutic research conducted upon `normal' subjects. The Statement was presented for guidance only. Allars noted that the Statement was not referred to in any minutes of HPAC meetings.
7.97 The 1966 Statement was amended in 1973 in relation to consent; in 1976 to require all applicants for NHMRC grants involving human experimentation to have their applications submitted to institutional ethics committees for approval; and, in 1982 substantial amendments were made including in relation to the maintenance of records and consent involving children, the mentally ill and those in dependant relationships.
7.98 The Allars Inquiry found that there was need for a definition of what constitutes experimental medical treatment and it noted:
It is a dangerous situation if no attempt is made to draw the lines between ordinary exercise of clinical judgment, research, experiment and clinical trial, even if those lines be blurred lines. The absence of lines is most dangerous when new advances in medicine are being explored through new procedures, a particular problem in the field of reproductive technology, as is illustrated by the treatment regimes operating under the AHPHP and the Egg Project.
7.99 As a result, Allars recommended that the NHMRC review the Statement on Human Experimentation and issue a Supplementary Note on Reproductive Technology Procedures. Allars also recommended that the NHMRC review the General guidelines for medical practitioners on providing information to patients and revise the Code of Practice for Transplantation of Cadaveric Organs and Tissues. The implementation of these recommendations is discussed in Chapter 3.
HPAC and its Subcommittees
7.100 The Allars Inquiry investigation of the HPAC and its Subcommittees exposed a number of matters of concern. These concerns and others raised in submissions are highlighted below.
7.101 `Research allocations': Supply was approved for a number of research projects some of which involved the clinical use of hGH and hPG in breach of Guidelines for approved patients, for example the `Egg Project' and women suffering from infertility due to reasons other than anovulation. HPAC also did not insist upon submission of a research protocol in relation to some projects. Further, HPAC generally did not seek to reassure itself that the consent of the subjects of the research had been obtained in accordance with the NHMRC Statement on Human Experimentation which was in place from 1966.
7.102 Ethical considerations: The FSH Subcommittee failed to have sufficient regard to ethical considerations in regard to a number of matters including: the approval of the use of out of date hPG for ovarian stimulation tests in spite of CSL's disclaimer of responsibility; failure to sanction adequately practitioners who failed to forward treatment sheets, failed to return hormone when their participation in the program was suspended or treated patients without approval; and its consideration of the problem of hyperstimulation.
7.103 Conflict of interest: The Committee notes that some members of the FSH Subcommittee were also treating practitioners and in 1973, the FSH Subcommittee resolved that out of date hPG be issued to members of the Subcommittee for patient use. Further, the CJD Support Group Network noted `the conflict of interest in having a Subcommittee consisting largely of treating doctors was never acknowledged or addressed'.
7.104 Knowledge of CJD: As described above, HPAC failed to respond appropriately to the knowledge of the risk of CJD. Members of HPAC and its Subcommittees failed to recognise the limits of their expertise in relation to unconventional slow viruses. However, the Allars Inquiry concluded that some of the blame for this must also be shared by government decision-makers who established the regulation of the scheme by expert committee.
7.105 Exclusion criteria: As already noted, the Allars Inquiry found that HPAC's response was reactive and it failed to keep abreast of developments of scientific knowledge. The Committee also notes that it appears that even some members of the Subcommittees did not know that there were restrictions on the collection of glands. (See paragraph 2.23)
7.106 Regulatory role: Allars stated that although the expertise of the medical practitioners who comprised HPAC and its Subcommittees made them eminently qualified to provide advice on clinical and research issues, their expertise disqualified them from serving in the role of regulator. Allars found, for example, that HPAC failed in its regulatory role as it did not act to stop the unregulated production of hormone by Dr Brown in Melbourne. Further, the Inquiry found that in establishing HPAC and its Subcommittees, the Minister, on the advice of the Director-General of Health, `placed in the hands of those who ought to have been the subject of regulation the very power of regulation itself'. Power to regulate quality control was conferred on the Fractionation Subcommittee, in effect assuming the role which normally ought to have been performed by NBSL. The Chairman was Dr Ferguson, whose process was used to extract hormones, and members included Dr Brown and representatives of CSL. Thus `CSL's representative participated equally in the decision-making of the Subcommittee which was CSL's regulator'.
7.107 The Committee considers that the Allars Inquiry raises serious concerns about the role of government agencies in the establishment, control and accountability of the AHPHP. Recipients have also pointed to the lack of proper control over aspects of the AHPHP:
Reading the Allars report is a chilling experience if you are an Australian who thinks we have a really good health system with lots of checks and balances, that people cannot do things that are unsafe, that all clinical trials are regulated and that the left hand does know what the right hand is doing. Reading Allars is just horrific. It was really Dracula in charge of the blood bank after 1976. Four people who were intimately involved with the program are actually controlling the program. The regulation of product is being conducted by somebody who works for the organisation who is controlling the product and who invented the process. There were no checks and balances. There was no independent review. There was no scope of expertise. It was a very narrow, a very self-interested group, who were running the Australian human pituitary hormone program.
7.108 The Committee considers that there is evidence to suggest that treatment under the AHPHP was of a more experimental nature than has previously been suggested. In this regard, the Committee notes that: HPAC made a number of research allocations of hormones to projects outside the Guidelines; HPAC also allocated to its members out of date hormone for therapeutic use on patients and for stimulation tests; hormone was used in patients who were not approved under the program; did not insist on the return of unused hormone; HPAC failed to insist upon submission of a research protocol in relation to some projects; HPAC generally did not seek to reassure itself that the consent of the subjects of the research had been gained; and anecdotal evidence of witnesses concerning the information provided to them, the method by which the treatment was undertaken, especially in the case of hGH where recipients described the methods of assessment used during their treatment.
7.109 Comments by Allars regarding the role and operation of HPAC and its Subcommittees have been noted in paragraphs 2.82-83. In addition to those comments, the Committee notes the following matters arising from the Committee's examination of the minutes of HPAC and its Subcommittee. The HGH Subcommittee minutes contain detailed discussion of difficult cases and cases under review and the recommendations arising from those discussions. The FSH Subcommittee minutes do not record discussions of problems to the same extent. Further, the HGH Subcommittee invited observers to its meetings in order to foster understanding of the Subcommittee and its methods of working. The FSH Subcommittee did not undertake this practice. The Committee also notes that the HGH Subcommittee met quarterly, while the FSH Subcommittee met twice a year to 1979 and only annually from 1980 with its last meeting before the cessation of the program being in December 1983. There also appears to have been a lack of a consistent approach to issues between the Subcommittees, for example, the FSH Subcommittee approved the use of out of date hormone by its members while the HGH Subcommittee did not.
7.110 Further, the Committee considers that the Department's comments about the decision-making process in relation to the AHPHP and the matters addressed by the Allars Inquiry concerning the role of government agencies and accountability issues raise doubts as to whether the Department understands its responsibilities in this area. The Committee notes that in her opening statement on 13 August 1997, Professor Whitworth, Chief Medical Officer, stated: