Inquiry Into Matters Relating to the Safety of Blood Products in New Zealand

Inquiry into Matters Relating to the Safety_of Blood Products in New Zealand

Wellington

December 1992

Department of Health TETARI ORA Mr. J. C. Lovelace Director-General of Health Department of Health Wellington

Dear Mr. Lovelace,

In accordance with the Terms of Reference of the Inquiry into matters relating to the safety of blood products in New Zealand, we have the honour to present our report.

00, 0

Dr Sue Morey Hon. Stan Rodger Member of the Inquiry Member of the Inquiry

WELLINGTON 15 December 1992 EXECUTIVE SUMMARY

REPORT OF THE INQUIRY INTO MATTERS RELATING TO THE SAFETY OF BLOOD PRODUCTS IN NEW ZEALAND

1 Issue which led to the Inquiry On 17 November, an article in the "Dominion" newspaper raised concern about the continued supply, after HCV screening was introduced in July 1992, of the blood product Factor IX (Prothrombinex) which was manufactured from blood unscreened for Hepatitis C, resulting in potential risk of Hepatitis C infection for haemophiliacs using Factor IX.

2 Establishment of Inquiry and Tennis of Reference The Director-General by letter dated 23 November 1992 appointed the Inquiry under Section 7 of the Health Act 1956 and Section 90 of the Area Health Boards Act 1983. Dr Sue Morey, Chief Medical Officer, New South Wales Department of Health, Australia and the Honourable Stanley Joseph Rodger, retired Member of Parliament and former Minister of the Crown, were charged as follows:

"Now pursuant to section 7 of the Health Act 1956 and section 90 of the Area Health Boards Act 1983 you are appointed and requested to do the following:

1 To determine the circumstances surrounding the continued supply after 1 July 1992 of a blood product which potentially exposed the users of that product to the risk of infection with Hepatitis C; and

2 To investigate what are the responsibilities and functions of the Office of the Minister of Health, the Department of Health, the Blood Transfusion Advisory Committee and the Regional Blood Transfusion Services and how those functions and responsibilities inter- relate in respect of: 2.1 The provision of policy advice to the Minister of Health regarding the risk of infection with Hepatitis C resulting from receipt of fractionated blood products; and 2.2 The facilitation of the efficient and effective and safe acquisition and distribution of fractionated blood products in New Zealand.

3 Report to the Director-General of Health on the results of your inquiry making recommendations as appropriate regarding: 3.1 Any changes to processes for the preparation and submission to the Minister of Health of policy advice relating to blood and blood products; and 3.2 Any changes to the responsibilities and functions between the office of the Minister of Health, the Department of Health, the Blood Transfusion Advisory Committee and the Regional Blood Transfusion Service and their inter-relationships that are necessary to facilitate the acquisition and distribution of blood and blood products in an efficient and effective and safe way (bearing in mind the Governments proposals for the reorganisation of the Blood Transfusion Service). 3 Procedure Adopted b y the Inquiry

3.1 The Inquiry reviewed the functions and responsibilities of the Office of the Minister of Health, the Department of Health (including changes arising from departmental restructuring), the Blood Transfusion Advisory Committee and the Regional Blood Transfusion Services. The roles and inter-related responsibilities of the Communicable Disease Control Advisory Committee and the Medicines Adverse Reactions Committee were also considered.

3.2 The Inquiry examined departmental files for all relevant correspondence, background papers and briefing papers to Ministers, the Minutes of the relevant advisory committees and interviewed departmental and ministerial office staff, in order to establish a chronology of events.

3.3 A number of interviews were held and submissions were received from a variety of organisations and individuals.

4 General Observations

Funding for screening of donated blood for Hepatitis C was provided from 1 July 1992. As a result of timing of approval and time required for the tendering process and implementation, screening of blood for Hepatitis C was not in place throughout the country until 27 July 1992.

Because the time difference between plasma collection and product return for Factors VIII and IX is up to nine months, from 1 July until 30 November 1992, blood products supplied for clinical use in patients with haemophilia continued to be that made from blood unscreened for Hepatitis C. In the case of patients with Haemophilia A, as the products had been subjected to high heat treatment (80°C), any Hepatitis C virus in the plasma used to make the product would have been inactivated. However, for patients with Haemophilia B (Factor IX deficiency) there was no - readily available product which could guarantee absence of potential exposure to the Hepatitis C virus.

Neither the Minister of Health nor senior officers of the Department of Health had been specifically alerted to the fact that, despite introduction of screening of blood donations, there was a small group of patients, ie those with Factor IX deficiency, who had not been previously infected with Hepatitis C (a total of between 10 and 15 patients) who were potentially exposed to the virus if they received Factor IX. This is clearly a small subsection of a very vulnerable group of patients, already carrying a significant burden of illness, and they warrant special attention.

Even if they had been specifically alerted to the fact that blood products derived from blood unscreened for Hepatitis C were still in use, no clearly defined and completely satisfactory alternative was available. High heat treated Factor IX (Prothrombinex H-T, PTX H-T) has not been available to either Australian or New Zealand patients because it is a new product which has not yet been approved by the Australian Drug Evaluation Committee, and there is a prohibition on the export of products which are not licensed. (This unlicensed product was however made available to New Zealand on 30 November 1992 at the request of the New Zealand Department of Health).

While the letter of 31 July 1992 to the Minister of Health written by Dr E W Berry on behalf of the Medical Advisory Panel of the New Zealand Haemophilia Society referred to the potential

2 problem for Factor IX deficient haemophiliacs associated with the lack of PTX-HT, the primary purpose of the letter was to request funding to import products from overseas. The Ministers reply of 4 September 1992 referred to the fact that Area Health Boards have the responsibility to provide services for the health needs of the people of their region. While any Area Health Board has the ability to buy commercial products which have been high heat treated (or equivalent new products) from overseas, the fact that these products are derived from unknown plasma which may contain unrecognised viruses is a cause for concern in scientific communities.

There is no doubt that much of the media attention to this issue has been inaccurate and misleading and has led to unnecessary anxiety for the New Zealand public.

Nevertheless, the circumstances surrounding events subsequent to 1 July 1992 can only be placed in perspective by acknowledging that there has been widespread community concern and debate regarding testing of donated blood for Hepatitis C in New Zealand since early 1990.

The Blood Transfusion Advisory Committee advised the Department of Health in June 1990 and the Communicable Disease Control Advisory Committee advised the Minister of Health in August 1990 that screening of donated blood for Hepatitis C should be introduced. The matter was refel-red to the Department of Health which commissioned a number of cost-effectiveness studies. The Department was apparently concerned that the sensitivity and specificity of the available test were not sufficiently high for this to be introduced at a time of significant budgetary problems for Area Health Boards. Approval in principle for the provision of central funding for the introduction of Hepatitis C screening was given by the Minister of Health on 30 July 1991. Additional funds were sought through normal budgetary processes, but this application for funding was rejected, with approval of funding only recommended if funding was available from reprioritisation within the Health Budget. Funds were withheld centrally from AHB Budgets to allow screening to commence in the 1992-93 financial year.

This two year delay was a cause of considerable concern to transfusion services, clinicians and the general community, and was the subject of ongoing representations to the Minister and the Department. It is not difficult to see how the larger group of transfusion recipients in general detracted attention from the greater risk posed to the much smaller number of potential recipients of unscreened, non high heat treated Factor IX . At no time was it clearly articulated that even the second generation screening test was only 98% sensitive, and would not detect 2 of every 100 infected donors. • Therefore, when up to 6,000 donations were pooled to make one batch of Factor IX, given the estimated prevalence of 0.31% of Hepatitis C in the donor population, 33% of batches are likely to contain Hepatitis C virus. In the absence of super heat treatment, over a period of time, all recipients of Factor IX are likely to become infected.

It is obvious that the complexities of the problem are unlikely to be recognised by those without a medical and scientific background. The fact that the Department of Health was undergoing a number of major restructures during the period and that there was no medical or epidemiological input from within the Department at decision making level, no doubt contributed to the delay in introducing screening. There was no clear channel of communication between the Ministers expert Advisory Committees and the Minister, and the Departmental structures for providing advice to the Minister on competing priorities lacked clinical input.

3 The devolution of responsibility and funding to Area Health Boards resulted in a failure to acknowledge that there are some clinical areas, blood transfusion being one, where strong national policy and national standards are essential. It is clear that at least in the foreseeable future, New Zealand will remain dependent on other countries for some blood products or recombinant products as they become available and that responsibility for negotiating and purchasing should be vested in an organisation with a clearly defined national responsibility in this area.

5 Findings

5.1 First Term of Reference

Blood and blood products can never be 100% safe - that is, there can never be a zero-risk blood supply.

HCV screening of blood reduces, but does not completely eliminate the risk of HCV infection in blood.

Supply of Prothrombinex, a complex Factor IX blood clotting product, which was made from plasma unscreened for Hepatitis C, continued after 1 July 1992.

Screening of blood for HCV, begun on 27 July 1992, would have reduced the risk but not eliminated the possibility of infection. As the screening test will not detect 2 in every 100 infected donors, and as up to 6,000 donations are pooled to make one batch of PTX, in the absence of super heat treatment, 33% of batches are likely to contain HCV.

HCV in Factor IX is partially inactivated if the blood product heated to 60°C and more fully inactivated if the product is high heat treated to 80°C.

No approved and licensed alternative Factor IX product (heated to 80°C) was available in either Australia or New Zealand on 1 July. An unregistered Australian product was provided under special conditions on 1 December 1992.

• The fact that Prothrombinex made from blood unscreened for Hepatitis C continued to be used after July 1, 1992 was not known either to the senior management of the Department of Health or to the Minister of Health or his office.

• There is no evidence of a deliberate attempt to withho ld information relating to this situation.

5.2 Second Term of reference

• There are no clearly defined lines of communication for transmission of policy advice to the Minister on issues relating to blood transfusion.

• BTAC was left without a Chairman or access to senior levels of the Department of Health or to the Minister of Health.

• As a result of numerous departmental reorganisations, there was no senior departmental officer with a knowledge of clinical issues, who was aware of the problems faced by BTAC and the complex scientific problems involved in maintaining a safe and effective supply of blood products in New Zealand.

• Responsibility for negotiation with CSL for the acquisition and distribution of fractionated blood products in New Zealand was loosely delegated to the Director of the Auckland RBTS.

• There is no formal contract between CSL and New Zealand for the supply of blood products worth over $6 million per year.

5.3 Third term of reference

• There should be a Committee charged with the development of national policy and standards for the Blood Transfusion Service. This Committee should comprise representatives from blood transfusion service directors, clinical haematologists, Regional Health Authorities, the Principal Medical Advisor, Department of Health and a consumer.

• The Committee should more appropriately advise the Director-General of Health rather than the Minister of Health in order to ensure that appropriate policy can be developed taking into account other competing priorities.

• Nevertheless, the Committee should retain the option to approach the Minister of Health directly on matters of concern.

• There are some distinctive features about Blood Transfusion Services which require them to be considered in a somewhat different context from most other health services.

• There is a need for the services to retain a local focus, firstly to facilitate donor recruitment and retention, and secondly to maintain close relationships with clinicians, the users of the products, in order to ensure appropriate usage and quality control.

There is also a need for a strong national focus.

- National standards for good manufacturing practice of blood and blood products need to be adopted and monitored.

- Decisions on policy for issues such as screening need to be made at a national level.

- There needs to be a clearly identified body which takes total responsibility for all issues relating to the acquisition and supply of blood and related products for New Zealand.

- There are likely to be financial as well as quality advantages in purchasing blood products nationally.

5 Transfusion medicine is a highly specialised and rapidly advancing field. It is important to limit responsibility for transfusion services to a small number of appropriately qualified staff whose expertise can be maintained and developed

Links should be maintained between any body charged with the development of national blood transfusion policy and the Principal Medical Advisor to the Department to ensure that senior departmental officers are aware of any developing issues requiring a policy response.

. A contract should be signed with CSL, with regular review at appropriate intervals, to formalise the arrangements between Australia and New Zealand.

6 Recommendations

There is a need for a national committee to take responsibility for the development of policy and standards, the monitoring of standards and the provision of advice to the Department and the Minister of Health on issues relating to blood and blood products.

2 The Principal Medical Advisor to the Department of Health should be responsible, within the Department of Health, for overseeing issues relating to blood and blood products.

3 A contract should be formalised with CSL for the supply of blood products for use in New Zealand.

4 The Department of Health should request the manufacture and supply of high heat treated Prothrombinex, sourced from New Zealand plasma screened for HCV, from CSL at the earliest practicable opportunity.

5 Steps should be taken by the Department of Health to ensure appropriate medical and technical input into health policy. To: The Director-General of Health

REPORT OF THE INQUIRY INTO MATTERS RELATING TO THE SAFETY OF BLOOD PRODUCTS IN NEW ZEALAND

Issue which led to the Inquiry

On 17 November, an article in the "Dominion" newspaper raised concern about the continued supply, after HCV screening was introduced in July 1992, of the blood product Factor IX (Prothrombinex) which was manufactured from blood unscreened for Hepatitis C, resulting in potential risk of Hepatitis C infection for haemophiliacs using Factor IX.

2 Establishment of Inquiry and Terms of Reference

The Director-General by letter dated 23 November 1992 appointed the Inquiry under Section 7 of the Health Act 1956 and Section 90 of the Area Health Boards Act 1983. Dr Sue Morey, Chief Medical Officer, New South Wales Department of Health, Australia and the Honourable Stanley Joseph Rodger, retired Member of Parliament and former Minister of the Crown, were charged as follows:

"Now pursuant to section 7 of the Health Act 1956 and section 90 of the Area Health Boards Act 1983 you are appointed and requested to do the following:

2.1 The provision of policy advice to the Minister of Health regarding the risk of infection with Hepatitis C resulting from receipt of fractionated blood products; and

2.2 The facilitiation of the efficient and effective and safe acquisition and distribution of fractionated blood products in New Zealand.

INQUIRY REPORT 3 Report to the Director-General of Health on the results of your inquiry making recommendations as appropriate regarding:

3.1 Any changes to processes for the preparation and submission to the Minister of Health of policy advice relating to blood and blood products; and

3.2 Any changes to the responsibilities and functions between the office of the Minister of Health, the Department of Health, the Blood Transfusion Advisory Committee and the Regional Blood Transfusion Service and their inter-relationships that are necessary to facilitate the acquisition and distribution of blood and blood products in an efficient and effective and safe way (bearing in mind the Governments proposals for the reorganisation of the Blood Transfusion Service).

The Inquiry was assisted by Mr Patrick Hoy, Auditor - Major Projects Group, Office of the Controller and Auditor General, Wellington.

Support was also provided by the following officials of the Department of Health, Dr Sharon Kletchko, Wendy Edgar, Alison Brieseman and Gina Inglis.

We record our warm appreciation for their strenuous efforts in assisting to bring this report to the stage of presentation at very short notice.

INQUIRY REPORT 2 3 Procedure Adopted by the Inquiry

3.3 A number of interviews were held and submissions were received from a variety of organisations and individuals. A list of those interviewed or who made submissions is attached as Appendix 1.

4 Clinical and Scientific Background Information

4.1 Transfusion-transmitted Infection and Reduction of Risk

Transfusion of human blood is not without risk. Certain infectious agents including malaria, syphilis, hepatitis A, B & C, HIV and cytomegalovirus can be carried in the blood and therefore transmitted during the transfusion process. In addition to these (described in Appendix 4), at different times it has been alleged that morbilli, varicella, variola, epidemic parotitis, influenza, filariasis, toxoplasmosis, Q-fever, tuberculosis, leptospirosis and "Chagas" disease have been transmitted by blood transfusion.

The number of infections that are potentially transmissable by blood transfusion seems daunting, however, the incidence of most of these infections in the general population is low.

Five key measures help improve the safety of blood transfusions:

Selection of donors - it is important that donors are interviewed in private by experienced interviewers, who will question the potential donor on relevant areas of their history and lifestyle. It is also important that there is an opportunity for a donor to request anonymously, subsequent to donation, that the blood not be used.

INQUIRY REPORT 3 2 Use, wherever possible, of autologous blood, that is blood donated by a person for their own subsequent use. This would include salvaging and re- infusion of blood during surgical procedures.

3 Education of providers to minimise use of blood transfusions as a treatment option unless the situation is life-threatening.

4 Screening of blood for known infections. Laboratory-testing can identify markers of infectious agents in donated blood. Tests include those for syphilis, hepatitis B and C viruses, HIV types 1 and 2, and human T-cell lymphotropic virus (HTLV) types I and II; in addition, selected blood components may be tested or processed to prevent the transmission of cytomegalovirus to susceptible patients.

5 Pooled plasma products can be subject to viral-inactivation procedures and research is under way on recombinant products and viral inactivation for cellular blood components.

The safety of the blood supply continues to improve. New screening tests are introduced from time to time. The sensitivity of current tests continues to improve. There is also an increased awareness amongst the donor population of their responsibility when donating blood.

The chances of contracting a serious disease or dying from transfusion are now much lower than with many other therapeutic interventions. However a zero-risk blood supply is virtually unachievable. Each step towards the goal of achieving a zero-risk blood supply absorbs more resources that, if diverted elsewhere, might have a greater impact on the health of the public.

There is no consistent approach to dealing with this difficult question, but there remains a responsibility to educate the public about the risks and benefits associated with blood transfusion.

Patients are at a much greater risk if they do not have transfusions when they genuinely need them than they are from the possible complications of transfusion.

4.2 Hepatitis C

Hepatitis is an inflammation of the liver commonly caused by viruses and toxic agents such as alcohol and other drugs. Recent advances in the identification of the causative viral agents of hepatitis have clarified some of the issues and associated problems. The group of viruses causing hepatitis includes a range of very different and unrelated human pathogens. Hepatitis A, hepatitis B, Epstein-Barr. hepatitis (associated with glandular fever) and cytomegalic hepatitis were until recently the major identifiable forms of viral hepatitis. A further group was given the uncomfortable name of non A, non B hepatitis viruses.

INQUIRY REPORT 4 One of the major viruses causing non A, non B hepatitis is now designated Hepatitis C. It is the most common form of hepatitis following blood transfusion and can be spread in ways other than through blood. Hepatitis D virus (also referred to as Delta agent) can cause infection only in association with hepatitis B and therefore is of special significance because of the high level of hepatitis B infection in New Zealand. The most recent advance is the successful identification of the virus causing enterically transmitted non A, non B hepatitis, provisionally named hepatitis E virus (which has epidemiological and clinical features similar to hepatitis A).

The importance of sexual and perinatal transmission of Hepatitis C is uncertain. It is clear, however, that it is transmitted through blood and blood products in the same way as other blood-borne viruses, such as hepatitis B and human immunodeficiency virus (HIV). Hepatitis C occurs only occasionally in people who have received blood transfusions. It is a more common problem in people receiving a lot of blood and blood products. Since the end of July 1992 all donated blood in New Zealand has been screened for Hepatitis C, so blood transfusion has become safer.

It is thought that the majority of Hepatitis C infection in the community is caught through ways other than transfusion of blood and blood products (e.g. sharing of contaminated needles and syringes by injecting drug users). In many cases it is not possible to ascertain how the infection was acquired.

A great deal of information about Hepatitis C has become available internationally in the last two years. Although several research studies are in progress, there is limited knowledge of the epidemiology and clinical spectrum of the disease in New Zealand.

The majority of cases of non A, non B hepatitis transmitted through blood transfusions and a significant proportion of cases of sporadic (no identified risk factors) non A, non B hepatitis are thought to be due to infection with the Hepatitis C virus.

Modes of transmission of Hepatitis C virus (HCV) in New Zealand are similar to other parts of the world. A number of studies have been carried out to look at prevalence of infection, although no national seroprevalance study has been undertaken. All of the studies have investigated prevalence of antibody to Hepatitis C Virus (anti-HCV). The presence of anti-HCV indicates that the person has been exposed to the virus. It does not identify acute or chronic infection or whether the person is immune.

Some of the results of serological study in NZ population groups provided by the New Zealand Communicable Disease Centre are as follows:

Injecting drug users > 75% anti-HCV reactive (mostly those attending treatment clinics):

INQUIRY REPORT CLARIFICATION TO PARAGRAPH 3 ON PAGE 6 OF THE INQUIRY REPORT

Hepatitis C disease is not specifically listed in the First Schedule to the Health Act 1956 but would be included in the category of Hepatitis non A or B.

People in the Christchurch community 15% anti-HCV reactive with some liver dysfunction:

Patients with chronic liver disease: 10-20% anti-HCV reactive

STD clinic attenders: 7% anti-HCV reactive

Male prison inmates: 20% anti-HCV reactive

There were 585 laboratory-diagnosed anti-HCV positives in the first ten months of 1992. There were also 157 cases found to have HCV RNA (a marker for the virus and therefore of infectivity.) Many of the RNA positive cases will have been anti- HCV positive as well.

Hepatitis C is not a notifiable disease. However up to 31 October 1992, notification of hepatitis non A, non B, Hepatitis C or hepatitis acute type unspecified, numbered 78. The notifications were only 13 in 1990 and 22 in 1991. The increased reporting in 1992 is likely to be due to increased awareness of Hepatitis C.

Australian figures suggest that about 40% of patients with chronic HCV infection referred to clinics acquired the infection from transfusion of blood and blood products; compared with 40% by injecting drug use and 20% other factors (including tattooing and occupational exposure.) In contrast, information from the USA suggests that 10% of cases of non-A, non-B hepatitis is related to transfusion. The proportion of New Zealand cases of Hepatitis C associated with transfusion of blood or blood products is likely to be between these estimates.

Up to 50% of adults who are infected with HCV may become chronic carriers of the virus. This compares with hepatitis B, where up to 10% of adolescents and adults, and 50% or more of neonates and pre-schoolers infected develop a chronic carrier state.

Most patients with chronic HCV infection do not initially show any symptoms of illness (they are asymptomatic) but many gradually develop non-specific symptoms such as fatigue and malaise. Chronic carriers are rarely jaundiced.

Hepatitis C virus carriers have a substantially increased risk of developing chronic liver disease, including chronic persistent hepatitis, chronic active hepatitis, cirrhosis and primary hepatocellular carcinoma. Progression to chronic diseases is usually very slow, occurring over 1-3 decades.

Asymptomatic or symptomatic patients may have normal or intermittently abnormal blood biochemical findings and have specific inflammatory activity in the liver which can only be identified by liver biopsy. The latter is particularly important in relation to monitoring therapy with drugs such as Interferon.

INQUIRY REPORT 6 The outcomes of HCV infection may be influenced by other factors, such as alcohol.

4.3 Haemophililia

Haemophilia is a term which describes a congenital plasma clotting deficiency or defect which may result in bleeding into muscles, joints and body cavities, hours or days after an acute trauma.

Most of the inherited plasma coagulation disorders are due to defects in single coagulation proteins (those proteins responsible for helping blood to clot).

Two of the disorders, namely factors VIII and IX deficiency, occur in males but are carried by females (X chromosome-linked). These two disorders account for the majority of congenital coagulation disorders. That is, most people with haemophilia in New Zealand have one or other of these disorders. These patients merit special attention since they may have severe bleeding and chronic disability and require specialised medical therapy with pooled plasma products for either prophylaxis to prevent bleeding or to control bleeding.

Prothombinex has been a standard product for the management of patients with Factor IX deficiency for many years. It contains coagulation factors II, IX and X with atrace of VII.

4.4 Estimated Risk from Blood and Blood Products of Hepatitis C

A number of media reports have contained misleading figures regarding the potential risk of infection with HCV to New Zealanders. The following information attempts to put this risk into perspective.

There are 135,000 patients transfused per year who are at risk of infection. This means that 337,500 patients will have been transfused from February 1990 (when Australia began to screen) to 27 July 1992 (when New Zealand began to screen). Approximately 1048 (0.31 %) non-immune patients will have been exposed to a sero-positive unit based on the 1990 prevalence study by Dr D G Woodfield, Director of the Auckland Blood Transfusion Service. Of these approximately 733 (70%) will contract the Hepatitis C virus. Clinical acute Hepatitis C will develop within six to twenty-six weeks in approximately 183 (25%) patients and asnall number. 4.0l %) will develop fulminant Hepatitis C which will lead to death or liver transplant.

Of the 733 infected patients 323 (43.9%) will survive, the remaining 410 patients having died from other causes within two years. 160 patients will have no adverse consequences of the infection, while 163 will develop some liver disease. Of these 130 will have chronic low-grade disease (approximately half will have no adverse effects while the other half will have minimal disruption to daily living.) A total of

INQUIRY REPORT 7 33 patients will develop aggressive liver disease with cirrhosis and some may develop hepatocellular cancer an average of 15 years post transfusion

There are several estimates of the total number of haemophiliacs in New Zealand with the highest estimate being 535 Factor VIII and 95 Factor IX haemophiliacs. Of these, approximately 38% are severe, with a factor level of less than or equal to 5% of normal, thus having a greater use of blood products.

A study conducted in 1990 revealed that 70% of haemophiliacs were HCV positive. That is, infection took place for 70% of the at risk population before any screening tests were available.

It is more difficult to quantify the numbers of haemophilia patients recently exposed as pasteurisation to 60°C of pooled plasma products is effective in reducing the total number of infected batches as indicated by the Karolinska article (in Appendix III Lancet 1992: 340: 305-306). If pasteurisation was not effective at all, then one could expect that of the estimated 50 patients who have Factor IX deficiency and require concentrates on a moderately regular basis, an estimated total of 15 would not have been infected in 1990. Of these 15, 11 are at risk of developing Hepatitis C infection through receiving pooled plasma concentrates. A total of 5 patients would be predicted to develop chronic active hepatitis if there were no deaths from other causes and 2 would go onto developing cirrhosis and possibly hepatocellular carcinoma.

5 Blood Transfusion Services In New Zealand 5.1 Organisation of Services The New Zealand Blood Transfusion Service (BTS), as currently organised, deals with the recruitment of blood donors, the collection of blood (based on voluntary donations), the screening and accreditation of donated blood (eg HIV, Hepatitis B & C), the processing of donated blood into a variety of components, and the storage and dispensing of blood and blood products as requested by clinicians. Plasma separated from donated blood is frozen and pooled prior to dispatch to a centre where it is fractionated2 into specific components. Organisationally the New Zealand blood transfusion services tend to be part of Area Health Board pathology services, they comprise: blood banks in most large hospitals (these store, dispense and provide cross- matching services);

18 sub-regional centres (mainly for blood collection, some testing);

Accreditation: The process of testing blood and plasma donations for blood groups, relevant red cell antibodies and evidence of certain infections, and the final cceptance and labelling of the blood/plasma for clinical use -Fractionated blood products: Therapeutic blood products prepared from plasma by an integrated series of physico-chemical separation steps. Through letters of agreement with New Zealand, this process is undertaken at the Commonwealth Serum Laboratories (CSL), Victoria, Australia.

INQUIRY REPORT 8 six regional centres (provide full range of services, support sub regions and handle local distribution of Australian Commonwealth Serum Laboratories (CSL) products); some additional services provided by the Auckland regional centre (liaison with CSL, storage and distribution of CSL products, some purchasing). The Area Health Boards in which the six regional blood transfusion centres are based bear the major costs of supplying blood products to the users - ie. other boards and the private sector. Operating costs of the regional blood transfusion centres (including the supply of fractionated products by CSL from plasma produced in New Zealand) are estimated at around $20 million (direct costs). There is currently only limited formal co-ordination of the BTS at a national level - each regional centre is operated largely independently. There is a large degree of voluntary co-operation between regions. No charges may be made for blood and blood products (Part III A of the Health Act 1956). There is no national database of donors. Each of the regional centres has an independent system for donor management. In 1991, 167,6988 units of blood were donated in New Zealand. The six regional centres collected close to 30% of this blood at their donor centres, and 50% from mobile collections. Just over 20% of the blood was collected from the smaller centres. Average level of donations per 1000 population varies from a low of 46 in Wellington to a high of 55 in Auckland. More blood is collected than is required for whole blood and red cell usage because of the high demand for plasma derived products. Over 90% af all blood collected has the plasma retrieved for processing. In recent years the total blood requirement in New Zealand has declined due to increased efficiency in the use and processing of blood products. New Zealand is almost wholly dependent upon the CSL for the processing and supply of fractionated blood products. Frozen plasma is sent by the individual regional centres to the CSL in Melbourne for fractionation into various protein constituent products. The Auckland centre has a limited fractionation capability. which manufactured 4% of New Zealands requirements for Factor VIII in 1991/92. There are currently 6 medical specialists qualified in transfusion medicine in the New Zealand Blood Transfusion Service, equating to 4.5 full time equivalents. It is understood that reviews of the Blood Transfusion Services, 1987 and 1989, had considered the possibility of establishing a national agency but that this had not been supported.

5.2 New Zealand Links with Commonwealth Serum Laboratories (CSL) Since 1962, CSL in Melbourne has received plasma from New Zealand for processing into fractionated products. All plasma from New Zealand is sent by air,

INQUIRY REPORT directly to Melbourne from one of the three international airports in New Zealand. All finished products are air-freighted to Auckland for distribution. Approximately 30,000 litres were forwarded in the last year. In 1987, New Zealands arrangement with CSL was formalised by exchange of letters between the Director-General of Health and the Managing Director, CSL. The letters followed a review in New Zealand on the feasibility of establishing a full-scale fractionation plant in New Zealand. The then Minister of Health had decided against such a development in New Zealand on the grounds that it would be more economical to continue with the system of having CSL produce blood products from New Zealand plasma. The Director-Generals letter states "We agree also that it would be most desirable to establish an explicit and on-going commitment for the use of your facilities by an exchange of letters of intent and understanding rather than a formal contract". Initially, this arrangement maximised the benefits for both countries because blood from both New Zealand and Australia was pooled for fractionation processes. Following the HIV/AIDS risks in the early 1980s, the two blood streams were separated because HIV infection in New Zealand was significantly lower than in Australia. While increasing the safety of New Zealand fractionated products, the decision reduced the efficiencies in the arrangement. This agreement involves about $6.2m per year.

5.3 Blood Transfusion Advisory Committee

The Blood Transfusion Advisory Committee (BTAC) was established in 1963 under section 13 of the Hospitals Act 1957 to advise the Minister of Health on "technical aspects of blood transfusion". The medical directors of the six regional blood transfusion centres (Auckland, Hamilton, Palmerston North, Wellington, Christchurch and Dunedin) make up the Committee. In the 1970s and early 80s the Chairman was a medical officer from the Department of Health. Subsequently, up to December 1990 there was an independent Chairman. The Committee is serviced by the Department of Health. The BTAC has itself established three subcommittees: A Technical Working Party which advises BTAC on technical issues. Membership comprises charge technologists from each of the six regional centres. A Histocompatability Working Party which advises BTAC on tissue typing issues. Membership comprises a separate team of charge technologists from five of the six regional centres. A Donor Managers Working Party which advises BTAC on donor recruitment issues. Membership comprises the Donor Managers from seven centres.

INQUIRY REPORT 10 6 Summary of Chronological Events in relation to Hepatitis C

7/8 December 1989 BTAC minutes noted that tests have become available for Hepatitis C and that testing is likely to start in Australia in a few months. It was stated that the Department of Health should fund tests to determine the frequency of Hepatitis C in New Zealanders as a prelude to full-scale testing.

19 February 1990 HCV screening was introduced throughout Australia.

22/23 February 1990 The BTAC noted at its meeting that Australia had started testing for Hepatitis C (HCV) and reported that Abbott Industries had donated testing kits to conduct a trial in New Zealand to determine the positive rate for Hepatitis C in blood donors. BTAC also noted the Australian recommendation that all new haemophiliacs should be given super heat-treated Factor VIII. This was recorded in FLAG (Red Cross Fractions Liaison Advisory Group) minutes "it was believed that in the interests of responsibly providing the safest possible service, the (Red Cross) Society should endeavour to ensure that all newly diagnosed haemophiliacs or those not previously exposed to treatment with concentrate should be given high purity AHF concentrate if treatment with concentrate is required". BTAC noted that "While high purity Factor VIII is not in New Zealand yet, all Factor VIII used in New Zealand will eventually be of this type. Current UK experience suggests that since the introduction of the Elstree method, there have been no break-through cases of HIV or Hepatitis C in patients treated with this concentrate."

March 1990 The Minister of Health, Rt Hon Helen Clark, was advised that a trial was being conducted.

April 1990 Associate Professor C. Tasman-Jones, Department of Gastroenterology, School of Medicine, Auckland forwarded a paper supporting the case for blood screening for Hepatitis C to the Director-General of Health.

30 April 1990 Medical Director, Auckland RBTS visited CSL and reported to BTAC, "80°C heated material has been processed and the protocol for trial of this is in preparation. We can be involved in the evaluation if we wish. It has been used successfully in the UK and some is being used in the USA."

INQUIRY REPORT II May 1990 New Zealand Communicable Diseases Centre was asked by the Department to do a cost benefit analysis and comment on the technical aspects of testing. This was submitted to the Communicable Disease Control Advisory Committee (CDCAC).

4 June 1990 The New Zealand trial of Abbott first generation test kits was completed. The trial in 1990 indicated that HCV antibody was likely to be present in the blood of 0.47% of donors (taking false positives into account thisis likely to fall to approximately 0.31%). The current test to detect HCV antibody in blood did not identify all carriers of Hepatitis C. It would allow identification of approximately 86% of infected donors and the elimination of their blood from the blood supply. Second generation tests, with greater specificity, were expected to be available in the late 1990 year.

13 June 1990 Dr E W Berry, Chairman, Medical Advisory Panel, NZ Haemophilia Society, wrote to the Chairperson, BTAC suggesting that the following matters be considered at the 14/15 June 1990 meeting of BTAC. She advised that the panel had recommended that super heat (80°C) treated concentrates are considered to be a minimum standard of factor concentrate which should be available for the treatment of Haemophilia A and B (absence of Factor VIII and Factor IX). Further recommendations were that all blood donors be tested for HCV and that a representative of the Haemophilia Society become a member of BTAC.

14115 June 1990 The BTAC minutes record that the letter was tabled, and discussion centred only on the membership of BTAC. BTAC recommended at its meeting the introduction of HCV screening. The minutes also noted that Dr S Martindale, Advisor (Science), Therapeutics Section, Department of Health, advised BTAC that super-heat treated Factor VIII is a medicine requiring Ministerial consent before it can be legally used and distributed in New Zealand.

27 June 1990 The NZCDC report was submitted to the CDCAC, advising "that the CDCAC recommend to the Minister of Health the immediate funding of a nationwide screening programme of blood for tranfusion for Hepatitis C antibodies".

29 June 1990 The BTAC Chairpcson, Mr G K Chapman, wrote to the Department of Health about the BTAC recommendation, urging the immediate introduction of screening and setting

INQUIRY REPORT 12

out reasons for doing this and the consequences of not proceeding.

11 July 1990 An internal departmental request for advice from the Departmental Legal Services Section resulted in advice that

12 July 1990 The CDCAC considered a paper by Professor C Tasman- Jones on Hepatitis C, at the request of the Minister of Health. They also tabled a paper by Dr N Wilson, NZCDC, "Cost-effectiveness of screening for HCV antibodies in blood for transfusion".

CDCAC agreed that advice to the Minister should be as follows:

"Mandatory testing for the presence of HCV antibody hould be introduced for all blood and blood products for transfusion.

On scientific grounds it is difficult to disagree with Professor Tasman-Jones other four conclusions: - Surveys should be made to show the relative incidence of Hepatitis C in selected populations. - Interferon should be made available for treatment of Hepatitis C in controlled clinical research units. - The relative importance of Hepatitis C in chronic liver disease should be ascertained by appropriate research. - A national policy on liver transplantation should be developed."

- 27 July 1990 A letter from Abbott Diagnostics to the Minister of Health, noted "they understand a decision has been made to screen all donors for HCV".

12 August 1990 Dr Stewart Reid, Chairman of CDCAC, wrote to the Minister of Health advising that the committee was unanimous in its agreement that mandatory testing for HCV should be introduced. This was one of a number of issues raised with the Minister of Health. (NB. Normal procedure in processing Ministerial correspondence involves the immediate referral of letters by a clerk in the Office of the Minister to the Department of Health for the preparation of a draft reply. A period of one month is normally allowed unless an urgent reply is requested.)

INQUIRY REPORT 13 26 August 1990 The Minister of Health noted the CDCACs recommendation and requested a full briefing from the Department. The Inquiry found no record of that briefing being given.

28 August 1990 The Minister of Health replied to Abbott Diagnostics, stating "I understand that at a meeting in July the CDCAC considered a recommendation that blood be screened for Hepatitis C but I have not yet been advised of any recommendations arising from this meeting".

28 September 1990 An issues paper from the Manager, Health Services Policy was tabled by the Department of Health Corporate Management Group. It considered legal and cost- effectiveness issues relating to Hepatitis C screening. There is no record of any resolutions made on the issues raised in this paper.

September 1990 The Medical Director, Auckland RBTS reported on his attendance at the Australian Red Cross Blood Transfusion Services executive committee held on 19/20 September 1990 and the National Blood Transfusion Meeting, 20 September 1990. His report noted that three batches of Prothrombinex heated at 80°C had been prepared and were awaiting clinical evaluation.

24 October 1990 The Minister of Health replied to the Chairman CDCAC, thanking the committee for considering issues in relation to Hepatitis C and these would be "followed up by the Department".

27 October 1990 General election and change of Government.

2 November 1990 New Government took Office. Hon. Simon Upton was sworn in as Minister of Health.

There is no reference in the Department of Healths Briefing Papers to the incoming Government to the issue of Hepatitis C.

29/30 November The BTAC meeting minutes noted: 1990 "Members concern over their legal position regarding the non-introduction to date of Anti-HCV testing as previously recommended by the BTAC and CDCAC. Dr Faed notified the meeting that he intended writing to the General Manager Otago Area Health Board advising that due to the continuing delay in introducing Anti-HCV testing

INQUIRY REPORT 14 of the blood supply, he was no longer prepared to accept responsibility for patient safety. Regional Directors concurred with this action. Jill Stringer advised that people contracting Hepatitis C from contaminated blood would be eligible to apply for ACC benefits."

BTAC agreed to write to the Director-General requesting:

"(a) response to the recommendations on Anti-HCV testing contained in a letter from the BTAC dated 29 June 1990. Clarification of Regional Directors legal position if patients contract Hepatitis C from the blood supply was sought also. Include statement advising that CSL are currently refusing to accept blood that has tested HCV positive.

(b) In addition a letter should go to the Director-General recommending that "the New Zealand Communicable Disease Centre establish confirmatory testing procedures for HCV positive specimens, plus an external quality assurance system for all laboratories involved in HCV Ab testing".

(c) Members agreed that after confirmatory testing, HCV positive donors should be retired from the donor panel and referred for appropriate medical investigation and counselling."

1 December 1990 Resignation of BTAC Chairperson, Mr Chapman took effect.

5 December 1990 The New Zealand Medical Association (NZMA) Assembly recommended that funds should be made available by Government for mandatory screening.

12 December 1990 The NZMA wrote to the Minister of Health, advising of this recommendation.

21 December 1990 Secretary, BTAC wrote to the Director-General of Health reminding him of the June recommendation from BTAC that screening of blood donations for Hepatitis C be introduced, and noted BTACs concern about the need for an urgent decision.

19 March 1991 The Medical Director, Auckland RBTS reported to BTAC on his annual visit to CSL. He noted that "High heat treatment for Prothrombinex is not yet finalised, partly due to the need to add ATIII to the product for stability purposes. No date has yet been set for its availablility". A new product, mono

INQUIRY REPORT 15 component Factor IX concentrate, "Haemostat IX", is to be prepared. No dates have been set for its release.

20 March 1991 The General Manager Services, Department of Health attended a South Pacific Commission Regional Heads of Health Services Conference in Noumea on 11-15 March 1991, and reported that Dr Gary Schatz from the Communicable Disease Centre, Atlanta spoke on Hepatitis C and had indicated the screening tests then available had a high false positive rate. Dr Schatz is reported to have commented "that anyone under pressure to use the current generation of kits should wait for the next generation products which should be available in 6-12 months". He also recommended Dr Miriam Alter for expert comment.

8 April 1991 3 April paper from Manager, Health Services Policy to Corporate Management Group, proposed that "screening for HCV be introduced and asked CMG to note that there are a number of issues to be resolved." CMG agreed that a paper should be prepared for the Minister, recommending that screening be introduced, after the issues of test specificity and funding had been investigated by Policy Group.

11 -12 April 1991 Mr John Dagger of the Haemophilia Society, attended the BTAC meeting. The minutes noted:

"BTAC members responded to the specific concerns of the Haemophilia Society as follows:

Hepatitis C testing of blood donations.

• currently no guarantee can be given that donated blood will be screened before transfusion to haemophiliacs.

• the Standards for the BTS being prepared by the BTAC contain an obligatory requirement to screen donated blood for Hepatitis C.

• the availability of a new and more specific test for the Hepatitis C virus is anticipated for the very near future.

• the option exists for the Haemophilia Society to lobby the Minister direct on the issue of introducing Hepatitis C screening of the blood supply."

Other issues discussed included:

INQUIRY REPORT 16 • present supply of Coagulation Products, and the phasing out of the use of Cryoprecipitate.

• national supply of Coagulation Products under Area Health Boards.

future availability and use of Recombinant Factor VIII.

The minutes also noted:

"Anti-HCV Testing: Confirmatory Testing

Dr Woodfield (Medical Director, Auckland RBTS) reported receiving written advice from Dr Martin Tobias, ManagerNZ Communicable Disease Centre, that Anti-HCV confirmatory testing is now available at the Centre."

19 April 1991 The Morbidity and Mortality Weekly Report from CDC, Atlanta published "Public Health Service Interagency Guidelines for Screening Donors of Blood, Plasma, Organs, Tissue and Semen for Evidence of Hepatitis B and Hepatitis C". These guidelines recommended that all donations of whole blood and components for transfusion be tested for anti-HCV by EIA (enzyme immuno assay).

7 May 1991 CSL wrote to the Director-General of Health, advising that Australia had introduced screening for HCV in February 1990. The letter noted the importance of eliminating HCV from the starting plasma. CSL requested comments and advice on when New Zealand would be in a position to introduce screening.

15 May 1991 The Department advised the Minister of Health of its support of the CDCAC recommendation and that any final decision should be deferred until the specificity of the then available test had been investigated and further work on cost estimates and on blood transfusion services funding had been completed.

20 May 1991 Minister of Health approved the recommendation that

"You note:

1. that the Department supports the CDCAC recommendation that screening of donated blood for Hepatitis C antibody should be introduced;

INQUIRY REPORT 17 2. that the Department considers the final decision on funding should be deferred until the specificity of the currently available test has been investigated and further work on cost estimates and on blood transfusion services has been completed;

3. that a paper will be prepared for you on future options for blood transfusion services by 30 June 1991."

30 May 1991 A letter from Dr H W H Pullon on Manawatu Regional Blood Transfusion Services letterhead and signed as Consultant Haematologist and Regional Transfusion Director to the Associate Minister of Health, Hon Katherine ORegan, reiterated the advice of BTAC that HCV screening should commence forthwith, and offered BTACs assistance to advise in any way possible to clarify any doubts or concerns which politicians may have as regards this matter.

June 1991 Abbott second generation test kits were released for marketing in New Zealand. Limited screening of blood began on the initiative of some Regional Blood Transfusion Centres (eg, Otago).

June 1991 The Department of Health requested information from NZCDC about technical developments in testing.

13 June 1991 NZCDC advised on improved performance characteristics of the second generation screening test, as well as developments in confirmatory and supplemental testing. The availability of second generation tests in New Zealand was also mentioned.

17 June 1991 Letter from Mr M R Mapperson, President, New Zealand Haemophilia Society to the Minister of Health re-emphasised the need for testing of blood donors.

1 July 1991 Hon Katherine ORegan replied to Dr Pullon, advising that there was no need for BTAC to meet with Ministers on this issue and pointing out that the proposal for Hepatitis C testing has to be considered fully in the context of other pressing priorities for funding.

10 July 1991 Dr E Berry wrote to the Minister of Health, copying the letter to the Acting Director-General of Health, expressing the concern of the Medical Advisory Panel of the New Zealand Haemophilia Society about the supply and funding of specialised factor concentrates for patients with bleeding disorders. Dr Berry noted the complete lack of budgetary

INQUIRY REPORT 18

provisions and commented that the prospect of a viral free product is extremely desirable.

The Department referred this letter to BTAC. (it was considered at the 28129 November 1991 meeting of BTAC.)

25 July 1991 Dr H W H Pullon of the Manawatu Regional Blood Transfusion Service wrote to the Minister of Health on behalf of all Regional Transfusion Directors advising that they "are appalled and dismayed that there has still been no decision on the funding of Hepatitis C testing of blood donations within New Zealand. We now regard this as an extremely urgent matter, and of great public concern." (NB - an extract from a two page letter.)

30 July 1991 The Department of Health prepared a comprehensive briefing to the Minister recommending that he:

1. agree in principle to the provision of central funding for the introduction of Hepatitis C screening;

2. note that the maximum cost in a full financial year would be $2 million, but that it is expected that this cost could be reduced;

3. instruct the Blood Transfusion Advisory Committee to meet as soon as possible to provide the Minister with options for the introduction of screening.

The Minister of Health approved this on the same day.

31 July 1991 The Minister of Health replied to Dr H Pullon:

"I appreciate that this is a matter which is of considerable concern for those involved with blood transfusion services and that from your perspective action on the introduction of Hepatitis C screening has been slow. I have a responsibility, however, to carefully consider the implications and relative priority of all proposals which call on the limited health dollar.

I am now able to advise you that I am prepared to support in principle the provision of central funding for Hepatitis C screening.

I am concerned, however, at the high cost of the screening programme, and wish to see the cost estimate of $2 million

INQUIRY REPORT 19 per annum reduced if at all possible. This may require some trade-off in terms of what is optimal. I am advised that the Blood Transfusion Advisory Committee is best placed to provide expert advice on this issue.

I am therefore instructing the Department of Health to arrange a meeting of this committee as soon as possible, in order to provide me with options for the introduction of a screening programme."

August 1991 A letter was received by the Minister of Health enclosing an undated newsbrief of the New Zealand Haemophilia Society which explained the nature of Hepatitis C. It contained a section on the safety of blood products which stated: "Some blood from New Zealand donors is pooled and sent to CSL in Australia for processing into Factor VIII and Factor IX concentrates. This Factor VIII is heat treated to 80°C which seems to eliminiate the Hepatitis C and HIV virus. Factor IX concentrate (Prothrombinex PTX) is heat treated to 60°C which inactivates HIV, but not the Hepatitis virus. Some blood from New Zealand donors is processed in New Zealand and made into Factor VIII concentrates. This Factor VIII is heat treated to 60°C which inactivates only the HIV virus. Future productions later this year will probably be heated to 80°C, inactivating the Hepatitis C virus also."

5 August 1991 Letter from Dr H Pullon to the Minister of Health - on Manawatu Blood Transfusion Service letterhead and signed as Regional Transfusion Director - clearly writing on behalf of the Medical Directors, as members of the National Transfusion Advisory Committee "We are uncertain as to which Health Department officials are involved in overseeing transfusion matters, and indeed organising Transfusion Advisory Committee meetings". He suggested a date for a BTAC meeting to consider options for screening and requested the presence of senior Health Department officials at the meeting.

8 August 1991 Hon. M Williamson, on behalf of the Minister of Health, replied to Mr Mapperson, "I am pleased to advise you that I have now approved the provision of central funding for Hepatitis C screening. The Blood Transfusion Advisory Committee is to meet in the near future to provide me with options for the implementation of the screening programme."

8 August 1991 Hon. Simon Upton, replying to a letter dated 11 July 1991 from Dr Berry about testing for Hepatitis C, stated "I am pleased to advise you that I have now approved the provision

INQUIRY REPORT 20 of central funding for Hepatitis C screening. The Blood Transfusion Advisory Committee is to meet in the near future to provide me with options for the implementation of the screening programme."

24 August 1991 Hon. Simon Upton, replied to Dr. Pullons letter of 5 August 1991 with suggested meeting date and stating that the Personal and Public Health Section of the Departments Policy Group will be involved in overseeing blood transfusion services matters.

5 September 1991 BTAC members and departmental representatives met to develop HCV screening costing options.

1 October 1991 The Medical Director, Auckland RBTS reported on his attendance at the Australian Red Cross Blood Transfusion Services executive sub-committee held on 30 September 1991. His report noted that "an application for high heat treated PTX is being prepared for submission to the Australian Therapeutic Goods Administration. VFX H-T (800) will be supplied in February 1992, if all goes well. It is available on IPU (that is, named patient use). We need to use up our Prothrombinex before high HT material becomes available. (The report uses s and underlining to indicate matters relevant to New Zealand.)

2 October 1991 The Medical Director, Auckland RBTS reported on his 2 October visit to CSL, noting that CSL is to advise the New Zealand Department of Health of the trends in overseas fractionation units of not accepting HCV antibody plasma and that CSL will soon be requiring this as a standard criterion for acceptance of plasma for fractionation.

28/29 November 1991 The BTAC meeting minutes noted that:

"Anti-HCV Testing: Confirmatory Testing

Confirmatory testing for anti-HCV was not being done at the New Zealand Communicable Diseases Centre yet."

and

Hepatitis C testing

Russell Ritchie reported that the paper on funding options for Hepatitis C screening was shortly (following week) to go to the Minister. A decision should be made shortly. Directors reiterated their concerns over the delay of introducing

INQUIRY REPORT 21 screening and the ethical problems associated with issuing untested blood.

Concern was also expressed over the implication of the new ACC Bill (Accident Compensation and Rehabilitation Insurance Bill) and Directors were encouraged to look over the proposed legislation and make submissions.

ACTION REQUIRED: Secretary to find out the closing date of submissions and inform Directors.

Supply and funding of specialised factor concentrates for patients with bleeding disorders

The issue referred to BTAC by the Department was raised in a Dr Elizabeth Berry letter on behalf of the NZ Haemophiliac Society. Also raised in a previous BTAC meeting, the issue was whether the Department of Health or the Blood Transfusion Services directly supplied factor concentrates for the treatment of haemophiliacs. It was generally agreed that although specialised factor concentrates were a non-human product and there was no specific budget for its procurement, channelling it through BTS was preferred, as the Services were part of the overall treatment of haemophiliacs. BTS could also act as a control mechanism against unnecessary usage". (This letter was replied to on 2 April 1992.)

29 November 1991 A briefing paper prepared by the Department for the Minister, setting out three fully costed options for HCV screening of donated blood, recommended that the Minister:

1. agree that option 1 be implemented i.e all donated blood should be screened for HCV at an estimated cost of $1.642million in 1992/93 and $1,590,200 in. succeeding years.

2. note that the preferred second option is option 2, ie to test all donors once annually at an estimated cost of $1.534 million in year 1, $1,340,885 in subsequent years.

3. note that option 3 is least safe and the least preferred option: to test 50 % of all donations at a cost of $1.733 millon in a year 1 and $1,293 million in subsequent years.

4. agree that the Auckland Area Health Board should manage the letting of the tender for HCV test

INQUIRY REPORT 22 kits, payment for the on-going supply of test kits and the national donor information supplies.

5. agree that HCV screening of blood should be undertaken only by the six regional laboratories which currently undertake HIV screening.

5 December 1991 The Minister of Health agreed with option 1, "subject to the 1992/93 budget round" (an annotation in his own hand- writing), ie screening of all donated blood for HCV at an estimated cost of $1.642 million in 1992/93 and $1,590,200 in succeeding years. He also noted recommendations 2-3 and agreed to recommendations 4-5 above. The Minister directed the Department to address the issue of funding.

7 February 1992 Dr H W H Pullon, Regional Director, Palmerston North BTS wrote to the Director-General of Health on behalf of all of the Medical Directors urging urgent action to introduce HCV screening.

"We ask that this matter be expedited and that the funding arrangements for Hepatitis C antibody screening be finalised now. We continue to endorse the previous recommendation that all blood donations collected within New Zealand be tested for Hepatitis C antibodies.

As you are aware, the Transfusion Advisory Committee will be meeting in mid March 1992, and we hope that a final decision about funding for Hepatitis C antibody testing will have been made by that time. If testing is to be commenced at the beginning of the next financial year it will be necessary for the Hepatitis C antibody test tender to be put out in late March/early April 1992. It should then be possible to perform test kit evaluation and make a decision on which test kit is to be used during May 1992. Any delay in the timetable outlined will further delay introduction of testing beyond the start of the next financial year." (NB - Extract from a two page letter.)

27 February 1992 A briefing paper was provided to the Director-General on the issues raised in Dr Pullons correspondence and a response was attached for his snature, outlining that the Minister had already received the Department of Health paper (29/11/91) and that the Minister was expecting to announce a decision soon.

INQUIRY REPORT 23 10 March 1992 The Minister announced that he was seeking funding in the 92/93 Budget for the HCV screening programme.

19/20 March 1992 The BTAC meeting minutes noted that:

"HEPATITIS C

Sheryl Small reported that the Minister of Health is seeking Government approval for funding in the 1992/93 Budget round. The issue is now awaiting Government approval.

There was concern over the lag-time between funding approval and implementation. Dr Gibbons suggested that the tendering process start in anticipation of Government approval. The BTAC selected Drs Gibbons and Woodfield as its representatives on the Committee involved with the tendering and evaluation of the test kits.

A press release from the Minister of Health stated that the screening programme would be conducted by the six Regional Blood Transfusion Centres. It was suggested that this be clarified: screening would be made in each region under the direction of the regional director.

ACTION REQUIRED: Secretary to draft a letter to the Department of Health recommending that in view of the time required for the evaluation of test kits that a tender be established for Hepatitis C testing."

25/26 March 1992 NZCDC held a Hepatitis C workshop and the Minister was invited to open it and announce the Governments decision re funding for the HCV screening. The Minister declined the invitation.

27 March 1992 Medical Director, Auckland RBTS reported on his visit to CSL, noting that "application for registration by the TGA is expected by mid-April 1992, but that PTX H-T (80°C) could be released immediately under Section 29, Medicines Act 1981 (for a period up to two years) and that a section 23 application could be lodged".

March/April/May A series of letters was exchanged between Dr Berry, the 1992 Auckland RBTS, the Auckland Area Health Board, the Department of Health and the CSL about the process for making individual named patient applications and obtaining PTX H-T. The reasons that this exchange of letters did not result in the availability of any of these products relate to the complexities of legislative provisions and administrative

INQUERY REPORT 24 procedures associated with the use of unlicensed products both in Australia and New Zealand.

2 April 1992 The Secretary, BTAC replied to Dr Berrys letter of 10 July 1991, stating "The BTAC appreciates your concerns and acknowledges the special circumstances of haemophiliacs. It noted, however, that there was no specific budget for the procurement of specialised factor concentrates.

As you would be aware, Area Health Boards currently fund the blood transfusion services from the population based grant boards receive from the Department of Health. This allocation is determined having regard to competing claims of other services on a boards resources. The funding the blood transfusion services receive is not tagged for any particular activity within the scope of the services they provide. The BTAC noted your suggestion and agreed that the blood transfusion services are better placed for channelling specialised factor concentrates, providing funding was made available."

22 April 1992 The Medical Director, Auckland RBTS wrote to CSL requesting unregistered 80°C P1X H-T on behalf of three Hepatitis C antibody negative patients. He stated " It seems that it must be near the time when we should make a batch of New Zealand plasma into the high heat treated material. What is the possibility of this and will it be possible to release some Australian sourced high heat treated Prothrombinex for our use in at least (named patient)?"

6 May 1992 A fax was sent from CSL to the Medical Director, Auckland RBTS, stating that he would have to ask the New Zealand Department of Health whether they are prepared to issue an IPU approval for the product which has not yet been registered by the Australian TGA. CSL also indicated they would consider the feasibility of making a batch of PTX H-T from New Zeland plasma. They noted they would first need to make some antithrombin (AT III).

7 May 1992 A letter to Dr G R Boyd, Manager, Therapeutics, Department of Health from Dr Woodfield asked for advice on how to proceed with a request from Dr Berry to import Prothrombinex HT fro- CSL for some of her young patients not yet exposed to Hepatitis C.

8 May 1992 The Officials Committee on Expenditure Control considered a request by the Minister of Health for new funding for

INQUIRY REPORT 25 Hepatitis C testing, and recommended to Cabinet, on Treasury advice, that approval only be given if funded from reprioritisation within Vote: Health. Treasury had argued that funding should come from existing AHB operating grants as Boards are the major beneficiaries of reduced health care costs due to screening. Cabinet minutes (CAB (92) M20/13k) subsequently record that Cabinet agreed that the costs of Hepatitis C testing of $1.847m in 1992/93.. .be absorbed in the existing Area Health Board grants.

14 May 1992 BTAC wrote to the Director-General urging that the test kit tendering process be commenced in anticipation of funding being approved.

25 May 1992 In a letter from Dr Boyd to Mr D King, General Manager, Auckland Area Health Board, in reply to the letter of 7 May 1992 from the Medical Director, Auckland RBTS, Dr Boyd advised Mr King of the sections of the Medicines Act 1981 (Sn 29 and Sn 25) under which which Prothrombinex - HT could be legally used. This letter was copied to the Medical Director, Auckland RBTS.

12 June 1992 The Medical Director, Auckland RBTS wrote to CSL stating that PTX H-T could be legally used in New Zealand. He was unsure "what IPU approval is", as he did not recall ever having to use it in relation to other new products produced by CSL. He suggested that if there was a problem, CSL should contact the New Zealand Department of Health.

He also commented "We will be very glad when you make a batch of PTX H-T for us. It will be very welcome."

19 June 1992 The Department prepared a briefing paper to the Minister seeking approval for the Departments plan for implementation of the Hepatitis C (HCV) screening programme. The Department view was that screening should be administered nationally and provided by Regional Blood Transfusion Centres as was the case with HIV testing.

The paper recommended that the Minister:

1. note the rationale for the Departments plan.

2. reconfirm that funding will come from the Area Health Board POBOC as approved by Cabinet (92) M 20/13k.

INQUIRY REPORT 26 3. approve that testing will be carried out by the six Regional Blood Transfusion Centres.

(The Ministers response to the briefing paper has not been located.)

June 1992 National tender for second generation test kits was let.

9/10 July 1992 The Department consulted the BTAC on the tenders. A decision was made on the successful tender. (NB - The draft minutes of the BTAC meeting became available on 15 December 1992.)

27 July 1992 HCV screening commenced nationally and the fol1oiing initiatives were undertaken by the Department:

(i) press release prepared (ii) HCV educational materials produced (disseminated in September 1992) (iii) kits provided to all BTS (iv) NZCDC contracted to provide confirmatory testing (v) circular letter to medical practitioners prepared announcing Hepatitis C screening.

Funding for the purchase of test kits was met from Area Health Board base allocations.

31 July 1992 Dr Berry wrote to the Minister of Health stating that "the only Factor IX concentrate available in New Zealand is heat treated to only 60°C which inactivates HIV but not Hepatitis viruses and is thus able to continue infecting new patients.

Supplies of 80°C heat treated Prothrombinex from CSL have still not eventuated and haemophiliacs with Factor IX deficiency and others requiring this product are faced with the dilemma of leaving haemorrhages untreated or risking Hepatitis C infection. Commercial Factor IX products which do not transmit Hepatitis viruses are now available but are expensive, and no budgets have been developed in the Transfusion Service to buy such products."

Dr Berry concluded by saying "The main purpose of this letter is to request the necessary funding to purchase supplies of safe Factor IX concentrate until such time as appropriate local products come on stream". (NB. Normal procedure in processing Ministerial correspondence involves the immediate referral of letters by a clerk in the Office of the Minister to the Department of

INQUIRY REPORT 27 Health for the preparation of a draft reply. A period of one month is normally allowed unless an urgent reply is requested. Hon Simon Upton replied on 4 September.)

6 August 1992 The Medical Director, Auckland RBTS wrote to CSL asking whether CSL performs HCV testing on Prothrombinex. He indicated that he had done HCV testing and found them to be negative.

21 August 1992 Secretary BTAC wrote to Dr R Fong, Director, Wellington RBTC, stating "Following your inquiry, I consulted Todd Krieble about the issue of retrospective testing of blood for Hepatitis C.

Todd said that the the issue of retrospective testing of blood already in stock was discussed at the meeting where Dr Woodfield mentioned Aucklands intention to carry this out. It was budgeted for and there is a Ministerial expectation that blood in stock will be tested.

Call me if you wish to discuss this."

(NB Mr Todd Krieble was Board Liaison Manager, Area Health Board Contracts, Department of health)

21 August 1992 CSL replied to the Medical Director, Auckland RBTS outlining that tests on present PTX stocks would be a waste of time because HCV antibodies are proteins, and the plasma pooling process for producing PTX diluted the protein content to such an extent that screening tests would be unable to detect the presence of immune globulin protein.

4 September 1992 The Minister of Health replied to Dr Berry, noting that blood transfusion services are currently funded through Area Health Board bulk grants. In addition, he noted "the Department of Health makes an annual grant to the Auckland Area Health Board for purchasing, on behalf of the country, fractionated products from CSL in Australia. Apart from that specific allocation, the funding that blood transfusion services receive is not tagged for any particular activity. The blood transfusion services, through the Area Health Boards, have the responsibility to provide services that meet the health needs of people in their regions. I understand the distribution and the monitoring of usage of Factor VIII and other products for the treatment of haemophiliacs is already handled through the six regional blood transfusion centres. I consider that

INQUIRY REPORT 28 your organisation should discuss any issue related to the treatment of people with bleeding disorders with the regional directors of the blood transfusion services. I will also refer your letter to the Blood Transfusion Advisory Committee for comment."

October 1992 The Secretariat of the PTAC wrote to Professor V S Chadwick, President of Society of Gastroenterology listing the current approved indications of Interferon and asked for Guidelines on which indications should be funded and whether the Society would endorse funding for Interferon for Hepatitis C and provide guidelines for its use. The response was requested by 8 December to be tabled at the next meeting of the PTAC.

The Society of Gastroenterology advised that this deadline date could not be met.

19 October 1992 CSL wrote to the Auckland RBTS requesting advice of the dates when screening of plasma was started at all regional centres.

29 October 1992 Dr E Berry wrote to the Acting General Manager, Auckland Area Health Board, stating "This letter is to bring to your urgent attention that PTX, the only Factor IX concentrate available in New Zealand has not been treated to inactivate Hepatitis viruses. Risk of infection transmitted from this product is estimated to be over 70%. Appropriately inactivated products are widely available internationally and could be obtained for NZ patients. Such a product was expected to be available from CSL over a year ago but has still not been delivered." Dr Berry commented that she had no budget to supply appropriate product to clients. Dr Berrys letter was referred to the Board Solicitor for advice about Board liability.

Over the ensuing two weeks discussions and communication occurred between the Board solicitor and Dr Berry.

17 November 1992 In response to reports in the Dominion newspaper of that day - "Blood product feared to contain Hepatitis C", Dr Joan Baas, Therapeutics Section, Department of Health telephoned Dr Peter Schiff, clinical Senior Manager, Blood Products Division CSL to obtain background information on Factor IX to prepare a paper for the Minister.

INQUIRY REPORT 29 18 November 1992 Dr Arvind Pate! and Dr Joan Baas of the Department of Health telephoned Dr Woodfield to discuss issues relating to the Factor IX products produced by CSL. Dr Woodfield faxed some questions for CSL and Dr Baas agreed to telephone Dr Peter Schiff regarding these questions.

A telephone conversation with Dr Schiff confirmed that

• an immediate supply of some Prothrombinex (60°C) from Australian blood could be supplied following an approval from the Australian Red Cross.

• A supply of super heat treated product (80°C) from Australian blood (currently subject to approval for clinical trial) could be supplied, if requested by the New Zealand Department of Health, following approval from Red Cross and the Therapeutics Goods Administration, the Australian Authority.

• Dr Schiff agreed to contact Dr Woodfield regarding supply of these products.

18 November 1992 Dr E Berry wrote to the General Manager, Auckland Hospital stating that the Auckland Area Health Board solicitor recommended the purchase of a supply of commercial product as soon as possible to cover the interim period until CSL can process New Zealand plasma appropriately.

19 November 1992 A facsimile was sent by Dr Baas to Dr Woodfield to confirm details of an earlier conversation on 18 November 1992 with Dr Schiff. Dr Baas asked Dr Woodfield:

• to advise when the Australian sourced product would arrive in New Zealand, which product and quantity.

• to recall to consumer level the current Prothrombinex and advise how this was to be put in place.

Dr Baas advised Dr Woodfield that "there should be no arrangement for the supply of Factor IX product to New Zealand manufactured from unscreened blood unless agreed by the Minister".

20 November 1992 Facsimile from Dr Woodfield to Dr Baas advised that a supply of test 300 units of high heat treated Factor IX are being consigned to New Zealand today. Regional Directors

INQUIRY REPORT 30 have been asked to quarantine all existing stocks of Factor IX.

CSL telephoned the Department of Health, asking for authorisation for export listing of the high heat treated Factor IX. Export listing is required by TGA as the product is not registered in Australia. -

This meant that this product could not be consigned to New Zealand until listing had occurred. Therefore Dr Baas asked "CSL to immediately supply Prothrombinex (60°) to ensure a safe supply of Factor IX was immediately available".

A letter was faxed on behalf of the Department of Health, New Zealand to both TGA and CSL acknowledging that New Zealand would receive Prothrombinex H-T, even though the product is not a registered product in Australia. 300 units of high heat treated Factor IX are to be dispatched to New Zealand in the next two weeks.

A facsimile was received from CSL to confirm that 100 bottles of Prothrombinex (60°C) would arrive in New Zealand on 21 November 1992.

A facsimile was sent from the Department of Health to Dr Schiff, CSL, confirming that the next batch of Factor IX to be made from New Zealand blood will be prepared from screened plasma.

The foregoing is a selection of the more notable items pertaining to the matters under inquiry amongst the substantial volume of material made available to the Inquiry.

INQUIRY REPORT 31 7 First Term of Reference ff To determine the circumstances surrounding the continued supply after 1 July 1992 of a blood product which potentially exposed the users of that product to the risk of infection with Hepatitis C"

7.1 Introduction of HCV Screening of Donated Blood

The Committee was advised that the date of 1 July 1992 was selected on the basis that funds for testing of donated blood had been made available for the 1992-93 financial year, commencing on that date.

Official notification of the commencement of HCV screening, dated July 1 1992, from the Department of Health was forwarded to all Area Health Board General Managers. Second generation EIA test kits were received from the supplier in all Regional Blood Transfusion Centres during the week up to 27 July 1992, the delay being associated with the tendering process. Full screening of blood for HCV commenced throughout New Zealand on July 27 when the kitsets were provided to all regional Blood Transfusion Services.

Partial screening had begun in some areas on their own initiative (Otago, Southland, Hawkes Bay, Taranaki, Rotorua) as early as mid 1991, when the second generation test became available.

Screening of existing stocks of blood was undertaken in the Auckland, Palmerston North, and Otago Regional Blood Transfusion services within one week of starting to screen new blood donations. Wherever possible, existing blood was not used. In Canterbury, including Timaru and Greymouth, unscreened blood was quarantined and not used. Wellington began screening existing blood stocks on 23 September 1992. Existing blood stocks were not screened in Waikato, but all products issued after 27 July 1992 were screened.

7.2 The Reasons for Continuing Risk

High heat treatment of blood products had been introduced in England by the Elstree Laboratories in 1987. The methodology for these products was obtained by CSL in 1989. However, concerns developed relating to the potential increase in concentrations of activated clotting factors as a result of this heat treatment, leading to complications of thrombosis in patients receiving this product.

It was therefore necessary to modify the methods used to produce PTX H-T through the addition of Antithrombin III. A high heat treated Factor VIII (inactivating HCV) was produced by CSL and available for use in New Zealand from mid-1990. The development of a safe and effective high heat treated Factor IX proved more difficult and was not available for trial in Australia until March 1992.

INQUIRY REPORT 32 In March 1992, the Medical Director, Auckland RBTS, in a report of a visit to CSL, stated "It appears that all products could be registered under Section 23 of the Act, although final registration required section 20 specifications to be met.....It was suggested that Prothrombinex (high heat treated) should be released immediately under Section 29 and that a Section 23 application should be lodged, but that would be unlikely to be completed until the end of 1992".

CSL had made inquiries about what approvals would be required in Australia to allow an unapproved product (ie, PTX H-T) to be issued to New Zealand patients on an individual patient usage (IPU) basis. CSL were advised that the product required listing on the Australian Register of Therapeutic Goods as an "export only" product and that this could not be achieved until the New Zealand Department of Health gave informed consent.

Successive contacts with CSL during 1992 reinforced the expectation that access to Prothrombinex H-T from Australia was imminent.

Nevertheless the product has still not been approved by the Therapeutic Goods Administration in Australia and is available for use in Australia only under the Australian Special Access Scheme.

Relevant New Zealand legislation, Section 29, Medicines Act 1981 states that an exemption allows a distributor to supply a product not otherwise covered under other provisions of the Act. In effect, it allows individual medical practitioners to request a distributor to provide a product for named patients. If a product is supplied, the distributor must report at the end of each month to the Director- General of Health on the name of the product supplied, the practitioner requesting the product and the patient to whom the product is supplied.

In the context of Section 29, a request to purchase CSL manufactured PiX H-T would be directed or referred to the Auckland Regional Blood Transfusion Service, by virtue of its apparent responsibility to purchase CSL products on behalf of the country. That is, the Medical Director, Auckland RBTS is the "distributor". The Medicines Act 1981 does not oblige the distributor to provide requested products.

Section 25 of the Medicines Act 1981 also provides for individual medical practitioners to sell, or supply, or procure for supply, products not currently covered under the Act. In effect, this allows any practitioner to go direct to CSL or to other overseas suppliers. Under the circumstances, no central funding was available, and Area Health Boards had the responsibility to fund the purchase of the product.

There was no risk of Hepatitis C associated with other blood products, ie Immunoglobulin products, SPPS, Albumin or !actor VIII concentrates.

INQUERY REPORT 33 7.3 Level of Recognition of this Continuing Risk

The fact that Factor IX made from blood unscreened for Hepatitis C continued in use was clearly recognised by BTS Directors and clinicians.

7.3.1 BTS Directors:

It is said that the continued use of Prothrombinex made from plasma not screened for HCV was discussed at the July 1992 meeting of BTAC, although this is not recorded in the draft minutes first made available to the Inquiry on 15 December 1992, at its request.

Given that the circumstances were clearly well known to this group, it could reasonably be expected that if any members of the group had considered that the products should have been withdrawn, they would have sought to have this recorded in the proceedings of the meeting.

We were advised in writing by the Medical Director, Auckland RBTS that: In July 1992, a similar situation developed with the blood services in New Zealand as with the Australian Red Cross Society Blood Transfusion Services in February 1990. There was little scientific or financial logic in withdrawing or discarding all non-screened HCV plasma collected in the first half of 1992 and excluding it from the production of a product like Prothrombinex. Indeed, this would have probably led to a major supply crisis and would not have substantially reduced the infectivity of Prothrombinex for routine use.

Therefore, in view of the Australian experience .... and in the absence of a high heat treated product, no change in the procedures was made, ie, there was no withdrawal of stocks of Prothrombinex made from non screened plasma. There was also no withdrawal of plasma in process for the production of Prothrombinex.

7.3.2 Clinicians:

Clinicians using the blood products were also aware of the problem which had been ongoing for 2 1/2 years. The product information sheet for Prothrombinex from CSL clearly stated that heating to 60°C did not inactivate the Hepatitis C virus. In addition it is said that a leaflet had been produced and circulated widely within hospitals in New Zealand to ensure that medical and nursing staff were aware of the risk, and a Haemophilia Society newsletter had also drawn attention to the fact. Dr Elizabeth Berry has stated that she always advised her patients of the risks.

Dr Berry, repesenting the Medical Advisory Panel to the Haemophilia Society, had been seeking funding and clarification of the process for importing alternative, safer products for uninfected patients with Factor IX deficiency haemophilia since July 1991.

INQUIRY REPORT 34 7.3.3 Department of Health:

There is no indication that any senior official in the Department of Health had been alerted to the fact that Prothrombinex made from unscreened blood continued in use in New Zealand.

The 31 July 1992 letter from Dr E W Berry, when referred to the Department for the preparation of a draft reply for the Minister, drew to the attention of some departmental officers, the continuing risk of infection associated with the lack of availability of high heat treated Prothrombinex, but any potential relationship between this and the introduction of whole blood screening for HCV was not identified.

7.3.4 Minister of Health:

There is no indication that the Minister or anyone in his office had become aware of the fact that Prothrombinex made from unscreened blood continued in use in New Zealand after 27 July 1992.

On 31 July 1992 Dr E W Berry wrote to the Minister of Health, alluding to the problem that PTX from CSL, which remained heat treated only to 60°C and not to 80°C, could contain HCV and could continue infecting new patients. Dr Berry referred to the availability of other commercial Factor IX products which do not transmit Hepatitis C, but noted that "no budgets have been developed in the Regional Blood Transfusion Service to buy such products". She concluded: "The main purpose of this letter is to request the necessary funding to purchase supplies of safe Factor IX concentrate until such time as appropriate local products come on stream."

The 4 September 1992 reply to Dr Berry from the Minister of Health, submitted in draft by the Department of Health on 31 August 1992, noted that blood transfusion services are currently funded through Area Health Board bulk grants. In addition, the reply noted "the Department of Health makes an annual grant to the Auckland Area Health Board for purchasing, on behalf of the country, fractionated products from CSL in Australia. Apart from that specific allocation, the funding that blood transfusion services receive is not tagged for any particular activity. The blood transfusion services, through the Area Health Boards, have the responsibility to provide services that meet the health needs of people in their regions. I understand the distribution and the monitoring of usage of Factor VIII and other products for the treatment of haemophiliacs is already handled through the six regional blood transfusion centres. I consider that your organisation should discuss any issue related to the treatment of people with bleeding disorders with the regional directors of the blood transfusion services. I will also refer your letter to the Blood Transfusion Advisory Committee for comment."

The issue that the blood product was a potential source of infection was not addressed in the reply from the Minister.

INQUIRY REPORT 35 7.4 The Inquiry finds that

Blood and blood products can never be 100% safe - that is, there can never be a zero-risk blood supply.

HCV screening of blood reduces, but does not completely eliminate the risk of HCV infection in blood.

Supply of Prothrombinex, a complex Factor IX blood clotting product, which was made from plasma unscreened for Hepatitis C, continued after 1 July 1992.

Screening of blood for HCV, begun on 27 July 1992, would have reduced the risk but not eliminated the possibility of infection. As the screening test will not detect 2 in every 100 infected donors, and as up to 6,000 donations are pooled to make one Latch of PTX, in the absence of super heat treatment, 33% of batches are likely to contain HCV.

HCV in Factor IX is partially inactivated if the blood product heated to 60°C and more fully inactivated if the product is high heat treated to 80°C.

The fact that Prothrombinex made from blood unscreened for Hepatitis C continued to be used after July 1, 1992 was not known either to the senior management of the Department of Health or to the Minister of Health or his office.

There is no evidence of a deliberate attempt to withhold information relating to this situation.

ENQUIRY REPORT 36 8 Second Term of Reference ff To investigate what are the responsibilities and functions of the Office of the Minister of Health, the Department of Health, the Blood Transfusion Advisory Committee and the regional Blood Transfusion Services and how those functions and responsibilities inter-relate in respect of.

2.1 The provision of policy advice to the Minister of Health regarding the risk of infection with Hepatitis C resulting from receipt of fractionated blood products; and

2.2 The facilitiation of the efficient and effective and safe acquisition and distribution offractionated blood products in New Zealand.

( 8.1 Responsibilities and Functions:

8.1.1 Minister of Health

According to "Parliamentary Practice in New Zealand" by David McGee, now Clerk of the House of Representatives, "The Minister in charge of each Department is responsible for the conduct of the affairs of that Department"

Ministers are appointed by the Governor-General on the advice of the Prime Minister. Ministers are also members of Cabinet which, while having few if any legal powers itself, makes many decisions of a political or administrative nature which are then implemented by ministers in their individual capacities.

In practice, many other day to day policy and administrative matters are managed by Ministers without reference to other Ministers.

Prior to November 1990, the Minister of Health was Rt. Hon Helen Clark.

Since the current Government assumed office, the Minister of Health, Hon Simon Upton, has been assisted by two Associate Ministers. Their identified responsibilities are respectively: Hon Simon Upton - Overall strategic direction of health sector. - Interim Targeting Regime. - Determination and structure of Vote:Health and expenditure priorities. (This includes expenditure priorities for Area Health Board and independent service provider contracts and health benefits). - Core concerns relating to the Health/Welfare Interface. - Health research. - Environmental health.

INQUIRY REPORT 37 Hon Katherine ORegan

- Child and adolescent health. - Health of older people. - Mental health. - Womens health - Communicable disease control. - Non-communicable diseases. - Health consumer rights. - Workforce issues. - Food and nutrition.

Hon Maurice Williamson

- Information technology and information systems. - Pharmaceutical and therapeutics. - Alcohol and drug abuse. - Smoke-free Environments Act. - Day-to-day management and signing of Area Health Board and independent service provider contracts. Each minister as a small number of policy advisers and support staff in his/her office.

8.1.2 Depwlinent of Health:

Section 7, Health Act 1963 states: "The principal functions of the Department of Health shall be - (c) to prevent, limit and suppress infectious and other diseases: (g) generally, to take all such steps as may be desirable to secure the preparation, effective carrying out, and co-ordination of measures conducive to the public health:

The Director-General of Health has a performance agreement with the Minister on the outcomes expected from the Department during the financial year. This performance agreement is harmonised with the Mission Statement and Business Plan of the Department of Health.

The mission statements of the Department of Health in 1990/91, 1991/92 and 1992/93 outline the Departments responsibility "to be the Governments principal agent and advisor on health .....

The Department of Health has undergone three restructurings since 1989. The first, completed in February 1990 marked a major transition for the Department towards becoming a policy Ministry. A number of functions of a service delivery nature were devolved to Area Health Boards. Subsequent reorganisations in July 1991 and October 1992 were to focus the Department more sharply in its policy advice role.

INQUIRY REPORT 38 Organisational charts indicate successive changes of structure, function and responsibility. As a result of the structural changes, different sections have been successively responsible for policy advice on blood transfusion services and for providing secretarial support to the above advisory committees.

As a result of restructuring to focus the Department of Health as a policy ministry, service provision functions were separated from policy advisory functions. Some key staff with medical/technical expertise were transferred to the Services Group. This resulted in a significant dearth of medical, technical or epidemiological input to the development of policy advice.

8.1.3 Blood Transfusion Advisory Committee (BTAC)

BTAC was established by the Minister of Health in 1963 under section 13 of the Hospitals Act 1957 to advise the Minister of Health on technical aspects of blood transfusion.

The members of BTAC are the Medical Directors of the six Regional Blood Transfusion Services. The Chairpersonship, a Ministerial appointment, is currently vacant. Since the resignation of the last Chairperson, effective 1 December 1990, four Departmental officials, responsible under successive Departmental restructurings for this function, have chaired BTAC meetings.

BTAC has three sub-committees to advise on matters of donor management and recruitment, tissue typing, and technical matters relating to blood transfusion.

BTAC is an advisory committee to the Minister of Health. In past practice, it has reported in writing to the Minister of Health and the Director-General of Health.

The work of two other advisory committees is also relevent to the Inquiry: - Communicable Disease Control Advisory Committee (CDCAC) - Medicines Adverse Reactions Committee (MARC)

CDCAC was established by the Minister of Health in December 1984 under Section 9A of the Health Act 1956 to advise the Minister of Health on general matters relating to - communicable disease control - sexually transmitted disease control - immunisation procedures and practices.

MARC was established by the Minister c Health in 1985 under Section 8 of the Medicines Act 1981 - to advise the Minister of Health on matters concerning adverse reactions to medicines

INQUIRY REPORT 39 - to oversee the collection and dissemination of information on adverse reactions to medicines - to keep the medical and dental professions informed on adverse reactions to medicines.

The area of mutual interest to all three advisory committees is the monitoring and control of infectious diseases. Within the Department of Health, there are no formal linkages, accountabilities or advisory mechanisms between these three bodies. The principal line of communication is through Departmental officials communicating with colleagues on matters they perceive to be relevant to other committees.

8.1.4 Regional Blood Transfusion Services (RBTS)

There are six regional blood transfusion centres under the direct responsibility of Area Health Boards, organised geographically alongside the major providers of acute trauma/surgical/medical/oncology care in Auckland, Hamilton, Palmerston North, Wellington, Christchurch and Dunedin. The six regional centres organise blood donation/collection activities locally and supply appropriate blood and blood products to meet local requirements. They also provide advisory and other specialist, services and co-ordinate the transfer of plasma to CSL, and the distribution and supply of fractionated and rare blood products.

BTS Directors are employed by the Area Health Boards.

The Auckland RBTS acts as the co-ordination centre for some "national" services including the maintenance of banks of frozen rare blood types. It is also responsible for maintaining New Zealands links with CSL and is the co-ordinator and distributer of CSL products throughout New Zealand.

From the perspective of the issues under inquiry, it is difficult to separate the roles of the Regional Blood Transfusion Services and the BTAC.

8.2 The provision of policy advice to the Minister of Health

8.2.1 Policy Advice and BTAC

BTAC is a Ministerial Advisory Committee.

The minutes of meetings of that Committee have not, at least in recent years, been submitted to the Office of the Minister (or to Associate Ministers) or to the Director-General of Health. From time to time, the Chairmen of this Committee and of CDCAC have written directly either to the Minister or to the Director- General on major areas of concern. At other times, it appears that letters to the

INQUIRY REPORT 40 Minister or to the Director-General were drafted by the secretary who is a departmental officer.

In May and June 1991, Dr H W H Pullon wrote both to the Hon Mrs Katherine ORegan and the Hon Simon Upton, on Manawatu RBTS letter-head and signed in his capacity as Regional Transfusion Director, regarding issues which clearly represented the opinions of BTAC rather than Dr Pullon as an individual. On 25 July 1991, Dr Pullon wrote, signing on behalf of the Medical Directors of the RBTS, stated "If funding for Hepatitis C is not forthcoming, then we as Regional Transfusion Directors will publicly absolve ourselves from the responsibility for the safety of the blood supply in New Zealand".

The reasons that advice was provided by members of BTAC in their individual capacities without the Committees formal letterhead no doubt related to the failure to appoint a permanent Chairman to replace Mr G K Chapman who resigned in Decembr 1990.

This, in turn, could be attributed to the review of Ministerial Advisory Committees which was conducted in early 1991 at the request of the Minister of Health. This review recommended that BTAC be disbanded and its functions devolved to Area Health Boards. The response to these recommendations is not known. Departmental restructuring, taken together with the review, may have contributed to the lack of priority given to BTAC affairs.

It is clear from the chronology recorded earlier that issues relating to the screening of donated blood for Hepatitis C were brought to the attention of the Minister by the Department and a number of external individuals and organisations.

8.2.2 Policy Advice and the Depamnent of Health

The Department of Health provided policy advice to the Minister on the issue of screening throughout the period under inquiry. The Department used a number of sources of information in the formulation of its policy advice to the Minister. These sources included BTAC, CDCAC and the New Zealand Communicable Disease Centre (NZCDC). Their recommendations were considered in the light of available resources.

It is clear that from early 1990 there was a view commonly held by departmental managers that the first generation EIA test was "not reliable enough ". It appears to the Inquiry that the concepts of sensitivity and specificity of tests were not well understood, and that considerable emphasis was placed on the number of false positives rather than on the fact that screening would enable 86% of the cases of Hepatitis C to be eliminated from the donor pool. This view was reinforced in March 1991 after the meeting of the General Manager, Services, with an official of the Centers for Disease Control, Atlanta and seems to have contributed to the approach taken by the department to policy formulation in respect of testing donated blood for Hepatitis C. This view was contrary to that of the BTAC, CDCAC, and

INQUIRY REPORT 41 published guidelines of CDC Atlanta as well as cost effectiveness studies produced in New Zealand.

Another factor influencing departmental policy was the process of devolution of responsibility and budget to Area Health Boards and the view of Ministers of Health that it would be inappropriate to direct Area Health Boards on health priorities for their local populations.

Senior departmental officers could have been more aware of the level of concern among medical and professional groups regarding the failure to introduce screening, if a senior medical member of the staff of the Department had been asssigned the responsibility for broad oversight of the operations of BTAC.

BTAC minutes from 1991 record the committees discussions of progress reports tm screening for Hepatitis C, the availability of PTX H-T from CSL and other issues relating to the treatment of haemophiliacs. In the BTAC minutes of 11 April 1991, it was noted that " all haemophiliacs who are not known to be infected should be treated solely with super heat treated concentrates". However, there is no record of further action on this statement.

Since the resignation as Chairman of BTAC of Mr G.K. Chapman in December 1990, each BTAC meeting was chaired by a different departmental officer.

Departmental officials servicing the committee had insufficient medical/technical knowledge to identify the issues. As a result, they were not alerted to communicate with other knowledgeable officials in the Department.

Therefore, the Director-General of Health was not explicitly advised by Departmental officials that there was a continuing risk of infection and was not in a position to advise the Minister.

8.2.3 Policy Advice and the Regional Blood Transfusion Services

It is noted that two letters to the Minister of Health, written on behalf of the Directors of the Regional Blood Transfusion Services, raised the issue of screening. There is no other indication of policy advice from the RBTS directly to the Minister of Health.

8.3 The Facilitation of the Efficient, Effective and Safe Distribution of Fractionated Blood Products in New Zealand

8.3.1 Relationship with CSL

The great majority of fractionated blood products are supplied from CSL in Australia. A very small amount (4%) of Factor VIII is manufactured in Auckland.

INQUIRY REPORT 42 It is notable that the agreement between CSL in Australia and the New Zealand Department of Health has never been formalised beyond an exchange of letters between Ministers in 1962 and the Director-General of Health and Managing Director of CSL in 1987.

Responsibility for negotiation with CSL is with the Director of the Auckland Blood Transfusion Service. It is unclear under what authority he has been given this responsibility, other than as the designated liaison officer from the Blood Transfusion Advisory Committee. In this role he has visited CSL on an annual basis and reported back to BTAC on any matters relating to the supply or development of blood products. The Auckland Area Health Board requires the Regional Transfusion Director to develop a yearly budget for blood products based on assessments of the needs of each region. Information is obtained from individual regional transfusion directors and collated, costed and forwarded to the Auckland Area Health Board which then negotiates with the Health Department as to the availability of funding. The budget for purchase of blood products from CSL has been added to the budget of the Auckland Area Health Board, although reference to this in the contract of the Auckland AHB is not detailed.

The Directors lines of responsibility for this activity remain unclear. His major responsibility for the Auckland Regional Blood Transfusion Service is to the Auckland Area Health Board which, although in receipt of tagged funding, has not been formally given responsibility for negotiating with CSL.

No senior departmental officer has been identified as having any responsibility for the oversight of the negotiations with CSL, and therefore, apart from his reporting to BTAC, no clear channel of communication between the Director of the Auckland RBTS and the Department of Health exists in respect of his national responsibilities.

It is apparent that apart from information obtained at BTAC meetings by those acting as Chairman, issues relating to the delay in production of 80°C treated Prothrombinex by CSL have not been brought to the attention of the Department.

The Director of the Auckland RBTS has thus assumed responsibility for the efficient, effective and safe acquisition and distribution of fractionated blood products in New Zealand. The exchange of letters in 1987 bound him to a continued dependence on CSL for supply of these products.

There is currently no indication of whether the present arrangement for supply of fractionated blood products is the most efficient, effective or safe.

The possibility of developing a plant in Auckland which would allow New Zealand to be self sufficient has been previously considered and rejected. Obviously this option could be explored again if circumstances change.

There is no information available to indicate whether other countries would be able to provide a more efficient or effective service than Australia.

INQUIRY REPORT 43 It is known that a high heat treated Prothrombinex was first trialled in the United Kingdom in 1987 but that this product is not available for export.

It is noted that in 1989, Dr Woodfield wrote to the Chairman of BTAC indicating that he had explored alternative ways to obtain blood products and sought advice on whether such alternatives would be acceptable. He specifically mentioned a very attractive offer from France to process NZ cryoprecipitate into a high quality product at a price, conservatively, one third less than that charged by CSL. While no reply to this suggestion has been located, it would appear that it was not followed up.

It is understood that Factor IX deficient haemophiliacs are still using routine PTX made from Hepatitis C screened plasma.

It is also noted in November 1992 that communications between the Auckland RBTS and CSL recognised that haemophiliacs were demanding the import of American products. It is also clear that this option was viewed with considerable concern by many clinicians as well as transfusion specialists, on the grounds that commercial products derived from purchased plasma which has caused problems in the past, may carry yet undetected viruses.

The close professional links with Australia and communication issues provide a number of advantages which are unlikely to be matched by any other country which may offer a product at lower price.

Nevertheless it is obviously essential that a contract be developed between CSL and a New Zealand body which has a clear national responsibility in relation to blood products.

It is understood that a draft contract has been drawn up and is currently being considered by BTAC.

8.3.2 licensing Under the Medicines Act

Another issue of continuing concern is the fact that fractionated blood products have not been registered as Medicines under the Medicines Act 1981. Blood and blood products are required to be registered as medicines, although the Inquiry is aware that there has been on-going debate about the desirability of this classificiation. In order for registration to occur, blood processing centres need to be licensed under the Medicines Act, for the manufacture of medicines. The purpose of such licensing is to demonstrate that processing centres have the appropriate facilities and processes for the collection and manufacture of blood and blood products. The licensing requirement was to have been implemented by August 1985, later extended to August 1986. Because of difficulties in preparing agreed standards of the collection and manufacturing processes, no processing centre has yet been licensed.

INQUIRY REPORT 44 The Inquiry understands that the Department of Health is considering the adoption of the Australian Standards for Good Manufacturing Practice as applied to the licensing of blood processing centres and that licensing will commence in 1993.

Blood products from CSL used in New Zealand are required to be, but are not at present, registered under the Medicines Act 1981. Submissions on each product have been recieved from CSL, and are still in the process of assessment by the Therapeutics Division of the Department of Health.

8.4 The Inquiry finds that

• There are no clearly defined lines of communication for transmission of policy advice to the Minister on issues relating to blood transfusion.

• BTAC was left without a Chairman or access to senior levels of the Department of Health or to the Minister of Health.

• Responsibility for negotiation with CSL for the acquisition and distribution of fractionated blood products in New Zealand was loosely delegated to the Director of the Auckland RBTS.

• There is no formal contract between CSL and New Zealand for the supply of blood products worth over $6 million per year.

INQUIRY REPORT 45 9 Third term of Reference

"Report to the Director-General of Health on the results of your inquiry making recommendations as appropriate regarding:

3.1 Any changes to processes for the preparation and submission to the Minister of Health ofpolicy advice relating to blood and blood products; and

3.2 Any changes to the responsibilities and functions between the office of the Minister of Health, the Department of Health, the Blood transfusion Advisory Committee and the Regional Blood Transfusion Service and their inter-relationships that are necessary to facilitate the acquisition and distribution of blood and blood products in an efficient and effective and safe way (bearing in mind the Governments proposals for the reorganisation of the Blood Transfusion Service)."

9.1 Proposals for reorganisation of BTS The National Interim Provider Board was commissioned to study the future options for organising blood transfusion services in New Zealand, within the context of the overall health sector reforms. The government has made decisions based on the findings and recommendations of this consultancy project. Four regional blood trusts will be formed which will be responsible for obtaining the required products on contract from BTS organisations, and ensuring their supply to health service providers. They will be not-for-profit, charitable trusts, administered by separate boards of trustees. Each trust will determine its own executive staffing and accommodation arrangements. The trusts will have the same boundaries as regional health authorities (RHAs) and may develop close relationships with RHAs. The trusts are expected to be very small, employing only a small number of staff. It is envisaged that they will cooperate with each other to develop a joint contract with CSL for fractionated products. The Ministry of Health will be responsible for setting, monitoring and enforcing minimum safety and quality standards. The Minister of Health will have the power to grant permits for the collection of blood to the trust on therms directed by the Minister. The trusts will then arrange for the collection of donated blood within the agreed collection area and for testing, processing and storing blood and blood products. A national BTS committee will be formed to supervise and monitor the BTS as a whole and oversee the overall operation of each trust. It will report to the Director- General of Health and will also advise on BTS policy matters. BTS centres and sub-centres will remain in CHEs and they will contract with the blood trusts. Over time, other organisations such as private laboratories and voluntary organisations may also contract to provide BTS services.

INQUIRY REPORT 46 9.2 Proposals for Change

It is important that any proposals for change to responsibilities and functions relating to blood transfusion services or to systems for the supply and distribution of blood products are compatible with the general health reforms taking place in New Zealand.

The Inquiry has had access to the final report to the National Interim Provider Board on "Future Configuration Options for Blood Transfusion Services" prepared by Coopers and Lybrand Consultants and to the submissions made to the consultants. The extensive work undertaken by the Consultants is recognised and obviously the Inquiry has not in any way been able or even attempted to consider the issues in the detail undertaken by the Consultants.

The Inquiry has, however, highlighted a number of issues which need to be taken into account in the proposed reorganisation.

9.3 Term of Reference 3.1 - Policy Advice to the Minister

The Inquiry finds that

• Nevertheless, the Committee should retain the option to approach the Minister of Health directly on matters of concern.

9.4 Term of Reference 3.2

The Inquiry finds that

• There are some distinctive features about Blood Transfusion Services which require them to be considered in a somewhat different context from most other health services.

INQUIRY REPORT 47 • There is a need for the services to retain a local focus, firstly to facilitate donor recruitment and retention, and secondly to maintain close relationships with clinicians, the users of the products, in order to ensure appropriate usage and quality control.

There is also a need for a strong national focus.

- National standards for good manufacturing practice of blood and blood products need to be adopted and monitored.

- Decisions on policy for issues such as screening need to be made at a national level.

- There needs to be a clearly identified body which takes total responsibility for all issues relating to the acquisition and supply of blood and related products for New Zealand.

- There are likely to be financial as well as quality advantages in purchasing blood products nationally.

Transfusion medicine is a highly specialised and rapidly advancing field. It is important to limit responsibility for transfusion services to a small number of appropriately qualified staff whose expertise can be maintained and developed

Links should be maintained between any body charged with the development of national blood transfusion policy and the senior medical advisor to the Department to ensure that senior departmental officers are aware of any developing issues requiring a policy response.

A contract should be signed with CSL, with regular review at appropriate intervals, to formalise the arrangements between Australia and New Zealand.

INQUIRY REPORT 48 10 RECOMMENDATIONS

2 The Principal Medical Advisor to the Department of Health should be responsible, within the Department of Health, for overseeing issues relating to blood and blood products.

3 A contract should be formalised with CSL for the supply of blood products for use in New Zealand.

5 Steps should be taken by the Department of Health to ensure appropriate medical and technical input into health policy.

INQUIRY REPORT 49 APPENDIX 1

Those whom the Inquiry met and/or received submissions from:

Dr J W Baas Advisor (Science) Therapeutics Department of Health

Mr N H Barrett Partner Coopers & Lybrand Consultants Auckland

Dr E W Berry Physician-in-Charge (and Barrister W G C Templeton) Haemophilia Centre Auckland Hospital

Dr G R Boyd Manager, Therapeutics Department of Health

Mrs .L Caroll National Director of Services KIDS FOUNDATION

Rt Hon H Clark Member of Parliament for Mt Albert Former Minister of Health

Ms A M Dixon Manager Health Sector Provider Policy

Dr J M Faed Regional Transfusion Director

Dr Garry Forgeson Chairman New Zealand Clinical Oncology Group

Emeritus Professor F N Fastier Member, Toxic Substances Board

Mrs J M Glackin Analyst

ENQUIRY REPORT 50 Disability Support Services Department of Health

Dr L F Haas Honorary Secretary New Zealand Committee The Royal Australasian College of Physicians

MrDKHunn Commissioner State Services Commission

Mr L losefa Analyst Personal Health Services Department of Health

Mr I T Johns General Manager Policy Department of Health

Mr A Jones Policy Advisor Office of Minister of Health

Mr J C Lovelace Director-General of Health (26/1/92 - present)

Mr M R Mapperson President (and Barrister W G C Templeton) New Zealand Haemophilia Society Inc

Mr J Martin Senior Lecturer in Public Policy Victoria University Wellington

Dr J R D Matthews President Auckland Division New Zealand Medical Association

Mr I H Miller Acting Director-General of Health (1/4/92 - 26/1/92)

INQUIRY REPORT 51

Dr P A Ockelford President New Zealand Society for Haematology

Hon K V ORegan Associate Minister of Health

Dr A C Patel Senior Advisor (Community Medicine) Health Regulation and Protection Group Department of Health

Dr R B Ellis-Pegler Infectious Disease Physician Auckland

Mr R Ritchie Former Manager Health Services Policy Department of Health

Dr G C Salmond Former Director-General of Health (1985 - 28 March 1991)

Dr P Schiff Clinical Services Manager Blood Products Division CSL Ltd (Australia)

Dr A J Scott Chairman of Assembly New Zealand Medical Association

Associate Professor C Tasman-Jones Department of Medicine University of Auckland

Mr G V Taylor Deputy Commissioner Auckland Area Health Board

Mr M Templeton Chief Executive Officer Institute of Environmental Health and Forensic Science

INQUIRY REPORT 52 Mr W G C Templeton Barrister, Auckland

Hon S D Upton Minister of Health

Dr D G Woodfield Medical Director Department of Transfusion Medicine Auckland Regional Blood Service

Hon M Williamson Associate Minister of Health

ENQUIRY REPORT 53 APPENDIX 2

HEPATITIS C SCREENING OF BLOOD DONATIONS

A CHARACTERISTICS OF THE SCREENING TEST

The two basic characteristics of a screening test are its sensitivity and specificity.

Sensitivity tells us how good a test is at correctly Identifying people who have antibodies to Hepatitis C. For example, a sensitivity of 80% means that 8 out of every 10 people who truly do have the antibodies will have a positive test, and two will have a negative test.

Specificity tells us how good a test is at correctly excluding people who do not have antibodies to Hepatitis C. For example a specificity of 99% means that 99 out of every 100 people who truly do not have antibodies will have a negative tes, and the remaining person will have a positive test.

Sensitivity = True positives I true positives plus false negatives

= True positives / all those with the disease

Spec jflcity = True negatives I true negatives plus false positives

= True negatives / all those without the disease

Sensitivity (in percent) = A / A+C X 100

Specificity (in percent) = D I B+D X 100

B FIRST GENERATION HCV ANTIBODY (anti-HCV C100) ASSAYS:

Abbott specifications gave:

sensitivity: in acute cases 62%

(i.e. 62 out of 100 cases of acute Hepatitis C had a positive test while 38 patients who also had Hepatitis C, had a negative test)

in chronic cases 85.7%

INQUIRY REPORT 54 (i.e. approximately 86 patients out of 100 with chronic Hepatitis C had a positive test while 14 who also had chronic hepatitis had a negative test)

specificity 98.9%

(i.e. approximately 99 out of 100 patients without Hepatitis C infection will test negative; however one patient , without Hepatitis C,will test positive.)

SECOND GENERATION anti-HCV EIA ASSAYS;

sensitivity in acute cases 68.6%

(i.e. approximately 69 patients out of a 100 with acute Hepatitis C infection had a positive test while 21 patients also with acute Hepatitis C tested negative)

in chronic cases 98.0%

(i.e. 98 patients out of 100 with chronic Hepatitis C infection had a positive test while 2 patients who also had chronic hepatitits C tested negative)

specificity 99.5%

(i.e. almost 100 patients out of 100 without Hepatitis C infection will test negative)

LIKELIHOOD OF BLOOD PRODUCTS BEING INFECTED WITH AN AGENT EXPRESSED AS A PERCENT OF BATCHES PREPARED

Hepatitis C Number of Blood Donations Pooled toge batch Prevalence 500 1,000 2,000 4,000 1:100 99% >99% >99% 100% 100% 1:500 63% 87% 98% >99% >99% 1:1,000 39% 63% 87% 98% >99% 1:2,000 22% 39% 63% 87% 95% 1:5,000 10% 18% 33/5 55% 70% 1:10,000 5% 10% 18% 33% 45% 1:15,000 3% 7% 13% 23% 33% 1:30.000 >2% 3% 6% 13% 18%

INQUIRY REPORT 55 APPENDIX 3

SUMMARY OF RESEARCH CONSIDERED BY THE INQUIRY

1. Aust. N.Z.J. Med. (1982( 12, pp. 268-271

Prospective study on 94 patients, urban New Zealand. Analysis of sera with 26(27%) acute HB; 22(23%) had acute HA and 25(26%) had acute NANBH; 9 (10%) had EBVH (Epstein-Barr Hepatitis) and 1 (1%) had CMVH (cytomegalovirus infection).

2. Berlin: Springer, 1982:24-32

Hepatitis B virus markers were found in all patients treated with annual doses of 10,000 or more Factor VIII units.

3. Br. J. Haematol 1985; 60:469-79

There was a 100% prevalence of NANBH, diagnosed by the presence of raised aminotransferase levels after infusion and by the exclusion of other causes of hepatitis, in patients who were at high risk of infections because they had not previously received any blood or blood-product

4. Am J Haemato 1986; 23:295-305

The almost constant occurrence of post-transfusion hepatitis in patients given unheated pooled concentrates of plasma, and concern about the transmission by blood products of the HIV, have prompted manufacturers to develop procedures (usually based on various methods of heating the concentrate) for inactivating viurses with little loss of labile Factor VIII activity.

5. NZ Med J 1987; 100: 99-102

303 cases of viral hepatitis identified over 4 month period. 49(16.2%) HA, 88 (29%) HB, 80 (26.4%) NANBH, 81(26.6%) EBVH, 5 (1.6%) CMVH. Incidence of acute symptomatic viral hepatitis was 78 cases/105 I per year for the Auckland region.

6. NEJM 1987; 316; 918-22

Post-transfusion hepatitis is frequent among patients with haemophilia who are treated with concentrated Factor VIII prepared from pooled plasma. A multicenter prospective sutdy to learn whether post-transfusion hepatitis would occur in previously untreated patients with haemophilia who were given infusions of a commercial Factor VIII concentrate that had ieen heated in solution (wet-heated) at 60°C for 10 hours in the presence of substances that stabilize Factor VIII activity was undertaken. This heating process, commonly called pasteurisation, is known to eliminate the risk of transmission of infection from blood products, such as albumin

INQUIRY REPORT 56 and plasma protein fraction, that are less labile than Factor VIII. In this study, no hepatitis occurred after infusion of 32 batches indicating that pastuerisation minimizes the risk of post-transfusion hepatitis.

7. TRANSFUSION 1987; 27, No. 6:447-448

The availability of a testing technology or a donor screening methodology does not necessarily mean the resources to implement such procedures should be expended. Unless the efficacy of the procedure has been firmly established, these monies would be better invested in improving the way in which we do things of proven efficacy in reducing transmission of HIV-1 and other infectious agents through blood transfusions.

8. Science 1989;244:359-62

Choo et al created a complementary DNA library from a concentrate of plasma taken from chimpanzees infected with NANBH. By screening approximately one million clones agaist sera of patients clinically infected with NANBH, the investigators isolated a single complimentary DNA and called it the "C100 antigen".

9. Science 1989;244:362-4

A radioimmunoassay was found to be positive in six of seven patients with chronic NANBH and negative in patients without disease. A colorimetric enzyme-linked immunosorbant assay (ELIZA) screening test was developed and introduced. A patent was taken out by the Chiron corporation.

10. Hepatitis C Antibody results in Sydney blood donors, Sept. 1990

Incidence of approximately 0.8% of Sydney blood donors to be repeat reactives (a positive result initially and on repeating the test) using the Abbott ELISA C100 screening test.

In Queensland and Northern Territory the Ortho ELISA C100 test showed an incidence of approximately 0.6% of blood donors to be repeat-reactive.

Discrepancies between the Abbott and Ortho tests are mostly in the low S/CO range (less than 2) and it seems likely that these discrepant repeat reactives arefalse positives. Results in Sydney have shown approximately more than half of Abbott repeat reactives in the low S/CO range to be negative by the Ortho Elisa Test.

A confirmatory test known as the Chiron Strip RIBA Test has been developed and is being marketed by Ortho. Results on Abbott ELISA C100 positive donor samples collected in Sydney have shown approximately 25% to be positive by the RIBA confirmatory test.

INQUIRY REPORT 57 Anti-HCV in Sydney Blood Donors

TEST NO. NO. % REACTIVES TESTED REPEAT IN DONOR REACTIVE POPULATION Abbott Elisa C100 Test 46,734 362 0.77 Ortho Elisa C100 on Abbott 362 237 0.5 Reactives RIBA confirmatory Test on Elisa 156 37 0.2 C100 reactivce samples from 16,998 donations

11. Post Transfusion NANBH in New Zealand, 1990 DG Woodfield, Medical Director Auckland Regional Blood Centre

The rate of detecting HCV antibody in random New Zealand blood donors is 0.47%. Personal communication with Abbott laboratories suggests on the basis of confirmation assays that the true figure may be 1/3 lower, i.e. 0.31%.

In New Zealand approximately 103,000 units of blood are transfused yearly. 319 units would therefore test HCV antibody positive. It is known that 50-90% of HCV-infected blood units will transmit this infection. Assuming that 70% of HCV antibody positive blood units are infective, and each patient receives 1 unit of HCV antibody positive blood, there would be 223 patients (70% of 319) infected.

Approximately half these patients will be deceased within 1-2 years from other causes leaving 112 patients who are infected with the virus. Only 28 (25%) of these patients would have clinical evidence of acute post transfusion hepatitis C.

Given that 50% of patients who receive infected units of blood will develop chronic hepatitis, and 20% of these cirrhosis, this means that 56 patients per year may develop chronic active hepatitis and 11 patients cirrhosis.

Some groups of patients, e.g. haemophiliacs, are treated with pooled blood products. Such persons are at greater risk of infection and sutdies have shoen a very high prevalence of HCV infection (over 75%). Such groups of patients will this eventually show an even higher frequency of chronic hepatitis and cirrhosis.

Prevention by HCV antibody screenign of all donor blood would seem an important option if confidence in the safety of the blood donor system is to be maintained.

The alternative will be a substantial increase in expensive autologous and directed transfusion programmes, a shortage of volunteer blood and the development of a lower standard of blood transfusion in New Zealand.

INQUIRY REPORT 58 12. Discussion Paper for CDCAC Dr. N Wilson, NZCDC, 27 June, 1990

The results of this analysis suggest that screening is a very cost effective intervention compared to many other comon activities in the haelath sector. The other benefits of screening in terms of preventing suffering and preventing loss of confidence in the blood supply, were considered to far outweigh potential adverse effects.

Although the benefits to the reipeients of specialised blood products (e.g. haemophiliacs) were not quantified, these were also considered to be significant.

Recommendations:

1 that the CDAC recommend to the Minister of Health the immediate funding of a nationwide screening programme of blood for transfusion for hepatitis C antibodies.

2 that it be recommended that the funding for screening be in addition to current Area Health Board funding so that screening can be implemented rapidly and uniformly across the nation.

3 that further research be recommended on the legal issues of not screening and the ethical issues related to informing donors infected with hepatitis C.

4 that as a general measure to reduce transfusion acquired infections, the CDCAC recommend that Area Health Boards pay more attention to quality assurance and audit in the area of blood transfusion.

13. Recommendations for Testing for Antibody to Hepatitis C Virus encoded antigen (anti-HCV) in Blood Establishments, Division of Transfusion Science, Laboratory of Blood Bank Practices. November 1990, FDA.

I. Performance of anti-HCV testing

1. a single EIA test should be performed on a donor sample for each unit of whole blood or component intended for transfusion (the initial test).

2. if the initial test is nonreactive the donor sample is considered negative for anti-HCV.

3. if the initial test is reactive, the donor sample is considered to be initially reactive. The sample should be retested in duplicate in a single test run, using a test kit from the same manufacturer of the kit used for the initial test.

INQUIRY REPORT 59 a. if both duplicate repeat test results are nonreactive, the test is considered to be negative for anti-HCV

b. if either one or both of the duplicate repeat test results are reactive, the test is considered to be repeatedly reactive for anti-HCV and the products should not be used for transfusion.

II. Plasma for further manufacture

Source Plasma: The FDA does not currently recommend that Source Plasma donors be tested for anti-HCV. Plasma from thousands of donors is pooled for the manufacture of plasma derivatives; although current tests identify the majority of HCV carriers, the testing of individual units for anti-HCV will not eliminate all hepatitis C virus contribute to the safety of certain plasma fractions, such as Immune Globulin and Immune Globulin Intravenous. The safety of immune globulin products experimentally manufactured from anti-HCV-depleted plasma pools is being studied.

VII. Other Measures against Post-transfusion Hepatitis

Anti-HCV testing is not expected to eliminate all case of post-transfusion hepatititis C. Therefore, the FDA suggests that blood establishments continue all measures implemented previously to reduce the risk of post-transfusion hepatitis.

14. SCIENCE, vol. 248; 4 May 1990:559-564

Advances in low-level risk detection threaten to engulf us with information. Regulators typically respond to each newly highlighted risk, whether painstakingly uncovered through scientific investigation or divulged with fanfare by the media, on an ad hoc basis. This response makes it hard to relate disparate risks to the overall risk level and impedes intelligent risk reduction, which must consider the costs and benefits involved.

We needto acknowledge that risks to life and limb are inherent in modem society— indeed in life itself—and that systematic strategies for assessing and responding to risks are overdue. Such strategies will involve significant reassignment of decision- making responsibilities. Individuals should do more for themselves, paying greater attention, for example, to their diets and driving habits. Governments should focus less on microscopic contingencies, and more on human mistakes and misdeeds, the source of far greater risks.

15. JAMA, November 7, 1990;Vol 264, No. 17:2231-2235

This study indicates that HCV is responsible for the majority of NANBH in the United States. Most cases are not associated with blood transfusion, and only half have a defined parenteral exposure. Further definition of the role of sexual

INQUIRY REPORT 60 transmission and inapparent sources of infection is needed to develop preventative measures that will have an impact on disease outside of the transfusion setting.

16. Hepatology 1990 12:671-75

These data suggest the slow, sequential progression from acute hepatitis C virus related NANBH through chronic hepatitis and cirrhosis to hepatocellular carcinoma and support a causal association between hepatitis C virus and hepatocellular carcinoma.

17. NZ Med J 12 Sept 1990; Vol 103, No 897:421-422

There is this evidence that: (1) NANBH and hence almost certainly hepatitis C is an issue in New Zealand, (2) Hepatitis C can be transmitted sporadically and by transfusion; (3) While it may cause an acute hepatitis, subclinical infection also occurs, (4)There is a high incidence of chronic active hepatitis, cirrhosis and hepatocellular cancer following exposure to the hepatitis C virus, (5)Hepatitits C may be pivotal in determining the outcome of excess alcohol in damaging liver, (6)A hepatitis C antibody diagnostic test is available. Preliminary studies suggest that it is a reliable test for diagnosing current infection and evaluating treatment. (7) Alpha interferon may have a place in the management of patients with chronic hepatitis C. (8) liver transplant may be the only therapeutic option for some patients with chronic hepatitis C infection.

Early consideration should be given to: (1) Mandatory testing of all transfusion blood and blood products for the presence of HCV antibody, (2) Surveys should be made to show the relative incidence of hepatitis C in selected populations, (3) Interferon should be available for treatment of hepatitis C in selected clinical research units, (4) The relative importance of hepatitis C in chronic liver disease should be ascertained by appropriate supported research. (5) A national policy on liver transplantation should be developed.

18. NFJM 1990;322:1107-1112

This paper was reviewed in GASTROENTEROLOGY Vol. 100, No.3:March 1991: 839-841

Comment stated that the NEJM study clearly demonstrates that HCV infection can occur as a consequence of transfusion with anti -HC V -negative blood. Therefore, the current anti-HCV ELISA (C100) test is not sufficiently sensitive to detect all infectious donors. The observation that longitudinal testing of anti -HCV -negative

INQUIRY REPORT 61 donors implicated in HCV transmission uncommonly shows late seroconversion indicates that implicated donors may be viraemic for prolonged periods without detectable anti-HCV. Better assays for detection of HCV-infective donors are needed.

19. Blood Reviews (1991) 3, 234-239

The incidence of post-transfusion hepatitis (PTH) varies over an order of magnitude in different parts of the world. For example, prospective studies from Spain and the UK reveal rates of PTH of approximately 10 and 0.5% respectively. Similarly the association of a history of transfusion in patients with chronic liver disease varies widely; in Japan, with high rates of PITH, the association appears obvious whereas in the UK less obvious. These factors must be taken into account when assessing the cost-effectiveness of pre-transfusion screening for HCV. A useful approach to assessing the vaue of screening donors for anti-HCV is to study prospectively the correlation of anti-HCV and PTH. In carefully selected cases of PTH, the correlation of anti-HCV and PTH in donor-recipient sets of samples may be very high. However, the predictive value of first-generation assays for anti- HCV in routine studies of unselected cases of PTH may be less than 20% in countries with low rates of transfusion-transmitted NANBH.

The anti-HCV screening tests and supplementary assays are continually evolving. More recent assays incorporate structural as well as non-structural antigens in both types of ELISA used for screening and in the supplementary tests such as the recombinant based immunoblots. The polymerase chain reaction (PCR) is also valuable for confirmation of viraemia but a negative result does not rule out the possibility of the presence of antibody in the absence of virus; nor can it rule out the presence of virus in very low levels in the blood stream, although virus may be present at a higher level in the liver or other tissues. However, these highly sophisticated supplementary assays are very expensive and their value as components of mass screening programmes must be assessed for each individual country before they are implemented.

20.THE LANCET vol 338: Oct 26, 1991:1040-1041

Screening for HCVAb clearly contributed to the decrease in PTHC even though the HCVAb screening kit that we used is not sensitive enough to identify all units infectious for HCV. In the hope of providing more complete protection against PTHC, we are now investigating more sensitive screening tests with other HCV- antigens.

21. Annals of Internal Medicine 15 Oct 1991; Vol 115; No. 8:596-600

In our study, the relative risk for hepatitis in recipients of anti-HC V-positive blood was almost 20 times greater than that in recipients of seronegative blood. Exclusion of anit-HC V-Positive blood could have prevented 80% of case of PTH.

INQUIRY REPORT 62 15% of our patients who develped NANBH had received transfusions of anti-HCV- negative blood. Our findings indicate that some infectious HCV carriers escape detection by ELISA (C 100) and suggest that more sensitive tests are needed to improve efficacy of screening blood donors for HCV.

22. Hepatology 1991; 14:90 A (abstract)

Half of acute NANB TAH (transfusion associated hepatitis) cases are reported to advance to chronic hepatitis with histologic sequelae of chronic active hepatitis in 50% and cirrhosis in 20%. Hepatocellular carcinoma appears also to be an endpoint, particularly in Japan. In the United States, the natural history of NANB TAH is not well defined. Our study concludes that mortality from cirrhosis and hepatocellular carcinoma in patients with NANB TAH is not increased an average of 18 years after hepatitis. Alcohol may effect liver-related mortality.

23.NEJM Feb 7, 1991; Vol 324 No. 6: 370-384

We identified 3.7 % of randomly selected patients (from hospital records) with disabling injuries caused by medical treatment. The proportion of adverse events due to negligence was highest for diagnostic mishaps (75%), noninvasive therapeutic mishaps ("errors of omission") (77%), and events occurring in the emergency room (70%). Errors in management were identified for 58% of the adverse events, among which nearlyhaif were attributed to negligence.

We conclude that although the prevention of many adverse events must await improvements in medical knowledge, the high proportion that are due to management errors suggests that many others are potentially preventable now. Reducing the incidence of these events will requeire identifying their causes and developing methods to prevent error or reduce its effects.

24. The Western Journal of Medicine Jan 1991;154:91-92

Approximately 0.4% to 1.5% of volunteer blood donors have a reaction with this test [ELISA C100-3]. It is estimated that the use of this screenign test will further decrease the rate of transfusion-transmitted NANBH by at least 50%.

As many as 40% to 60% of the reactions in blood donors are false-positive—that is, unrelated to hepatitis C. Among populations at high risk for NANBH, however, such as persons with haemophilia, almost all reactions are confirmed. Preliminary data suggest that the results of these confirmation tests correlate with infectivity.

25. Report of Hepatitis C Workshop NZCDC, March 1992

Testing • first generation assays only identified an antibody to a non-structural (C100) protein of the virus. • these assays were useful in drawing attention to hepatitis C but were not sensitive or specific enought to accurately determine prevalence rates.

INQUIRY REPORT 63 • "second generation" assays now available detect antibodies to structural and non-structural viral proteins. They have increased sensitivity and specificity, but are still imperfect. New assays are being developed. • "confirmatory" antibody assays are also available. These decrease the possibility of false-positive results. • a positive antibody result indicates that the patient has been exposed to HCV but cannot reliably distinguish between acute, chronic or resolved infection. • a polymerase chain reaction (PCR) based assay for detection of HCV RNA has been developed. This is a sensitive marker for viraemia and can therefore provide further information about the hepatitis C status of an infected individual.

Recommendations Blood Transfusion Services • it is recommended that all donations of whole blood intended for homologous or autologous transfusion be tested for anti-HCV. • testing of blood donations and donors should be kept under regular review by the Blood Transfusion Advisory Committee. • a regualr review of HCV test usage should be performed by the BTAC and major laboratories to define indications for testing of blood donors and other members of the community, and ensure that tests of apporpriate sensitivityand specificity are being used. • (FDA recommendations) • a policy based on objective evidence should be established by the BTAC on whether HCV marker-positive units of plasma may be used for manufacture of any specified fractionated blood product.

26. The Journal of the American Blood Resources Association April 23, 1992, FDA Memoranda Re: Testing Whole Blood for Anti-HCV

Supercedes the recommendations of November 1990. The FDA Blood Products Advisory Committee recommends that all donations of Whole Blood and blood components intended for transfusion, and Source Plasma and Source Leukocytes intended for further manufacture, be screened by a licensed test for anti-HCV and that no products repeatedly reactive for anti-HCV be used. The use of a multi- antigen test in the testing of Whole Blood and blood components for transfusion should be implemented as soon as is feasible. Inventories of blood and blood components for transfusion that were collected before the multi-antigen test implementation date should also be tested using the multi-antigen test if possible. Inventories of products intended for further manufacture and collected before the test implementaiton date need not be tested retroactively.

27. NZ Med J 27 May 1992 Vol 105, No. 934:195-196

Patients with chronically disturbed liver funcion tests of uncertain cause are a common clinical problem. We have found a prevalence of antibodies to HCV of 26% in a sample of such patients. Although our cases were highly selected it would appear that GCV is a significant cause of chronic liver disease in New Zealand.

INQUIRY REPORT 64 28. Blood Vol 80 (July 15), 1992:540-543

It has been known since the early 1970s that haemophilia patients who frequently infused coagulation factor concentrates manufactured from pooled plasma had intermittently elevated liver aminotransferases [enzymes indicating inflammation of liver]. These abnormalities were attributed mainly to NANBH. Cohort studies of haemophiliacs have shown that using the first-generation anti-HCV ELISA C100 tests that at least 80% of haemophilia patients are positive. By Postransfusion follow-up studies, seropositivity seems to indicate ongoing infection with the virus and not immunity (NEJM 321:1494, 1989).

Our study shows that with the increased diagnostic capability of the newer serologic assays for anti-HCV, an increased prevalence of 2.7% may be found in high-risk cohorts. However, the prevalence of HCV-infected partners of haemophilic index patients still remained low, indicating that HCV was not efficiently transmitted by the heteroseuxal route and perhaps less effectively than other sexually transmissable viruses such as HIV.

29. NZ Med J , 23 Sept 1992 Vol 105, No 942: 376-377

The relative frequency of viral agents causing acute hepatitis was Epstein Barr virus 52%, Cytomegalovirus 5%, HAV 15%, HBV 13% and HCV 15%.

30. NEJM Vol 327; Aug 6, 1992, No 6: 369-373

Of the 912 patients who received transfusions before donors were screened for surrogate markers, 35 seroconverted to HCV, for a risk of 3.84 % per patient (0.45% per unit transfused). For the 976 patients who received transfusions after October 1986 with blood screened for surrogate markers, the risk of serocnversion was 1.54% per patient (0.19 % per unit transfused). For the 522 patients receiving transfusions since the addition in May 1990 of screening for antibodies to HCV, the risk was 0.57% per patient (0.03% per unit transfused). The trend toward decreasing risk with increasingly stringent screening of donors was statistically significant (P <0.001). After we controlled for the method of donor screening, the risk of seroconversion was strongly associated (P <0.001) with the volume of blood transfused, but not with the use of particular blood components. We conclude that the incidence of PTH has decreased markedly since the implementation of donor screening for surrogate markers and antibodies to HCV. The current risk of PTHC is about 3 per 10,000 units transfused.

31. THE LANCET Vol 340: August 1, 1992:305-306

We report a case of Hepatitis C (HCV) transmission via pasteurised plasma product. The has only received substitution of factor VII with Haemate P, and had no other exposure. After thorough investigation we could exclude the transfusion of any other plasma products to our patient. Thus, our case demonstrates that a Factor VIII concentrate, which has undergone viral inactivation through pasteurisation (60°C for 10 h in solution), may still occasionally transmit HCV. That this is a

INQUIRY REPORT 65 rare complication is illustrated by the fact that no other case of HCV transmission has been definitely connected to Haemate P over 10 years. Moreover, 7 of our patients, who have been treated only with Haemate P and who have received material from at least one of the two positive batches half a year ago or more, remain anti-HCV negative. (Karolinska Hospital, Sweden)

32. NEJM Ed. 6 Aug 1992, Vol 327, No. 6: 419-421

Four key measures help keep the use of blood safe: 1. all who prescribe blood should try to limit the frequency of homologous transfusion by responding only to patients physiologic needs and by using alternatives such as autologous transfusion and intraoperative blood salvage. 2. the selection of safe donors provides the greatest safety. 3. laboratory testing can identify the vast majority of donations from infected persons. 4. pooled plasma products routinely undergo viral-inactivation procedures. Any contemplated additional measures to prevent transfusion-transmitted infection must have demonstrable benefit. Preventive measures have the greatest value when the threat to recipients is increasing, but for the infectious agents of known concern to transfusion recipients in the United States the risk appears to be declining. Avoiding unnecessary use of blood and using autologous transfusion aggressively are economical measures that will increase safety further.

The chances of contracting a serious disease or dying from transfusion are now much lower than with most therapeutic methods, and the objective of a zero-risk blood supply is virtually unachievable. Each step toward that goal absorbs more resources that, if directed elsewhere, might have a much greater impact on the health of the public. Are continued efforts to reduce the risk of transfusion- transmitted infections commensurate with the risk itself, or with societys perception of the risk? As has been persuasively argued elsewhere, there is no consistent approach to dealing with this difficult question, but we should accept it as our responsibility to educate the public about the real risks.

33NFJM Vol 327, 26 Nov 1992; No.22: 1601-1602

The second generation EIA detected I additional donor per 1000 tested who had potentially infectious HCV. Previous data indicate that 78 to 88 percent os such donors are likely to transmit HCV infection. The ability of the second- generation EIA to detect these potential HCV carriers, when combined with the already low frequency of HCV transmission (before the introduction of this improved anti-HCV test, the risk was 1 per 3300 units) establishes that the current risk of the transmissin of HCV by blood that is negative by the second- generation EIA is very low. The use of the second-generation EIA will prevent 64% of the instances of HCV transmission that occur with the transfusion of blood judged to be anti-HC V-negative on the basis of the first generation EIA. We estimate that the current risk of HCV invection per unit of blood transfused ranges from 1 in 2000 (0.05%) to 1 in 6000 (0.017%)

INQUIRY REPORT 66 APPENDIX 4

TRANSFUSION-TRANSMITTED INFECTION

1. Introduction

The support given by blood transfusion services to health care programmes is unique and essential for modern medical practice. They have played a considerable part in lowering maternal mortality during childbirth and in the development of cardiac surgery. The transfusion of blood or its components can correct many deficiencies (even if only temporarily) and in most cases this effect can be acheived without any untoward effects.

It is theoretically possible that any infectious disease associated with the presence of the causative organism in the bloodstream may be transmitted from donor to recipient by blood transfusion. Nevertheless disease transmission is not common, because in general bacteraemia or viraemia produces constitutional symptoms and blood donors do not give blood when they are ill.

Agents transmitted by blood transfusion often possess a combination of some or all of the following properties:

• They are present in the blood for long periods, sometimes in high titres.

• They have the ability to cause subclinical infections or only mild symptoms.

• They have long incubation periods (sometimes years) before clinical signs appear.

• They may exist in a latent or carrier state, or both.

• They are stable in blood stored at 40C.

2. Organisms transmitted through blood/blood products

a) Bacteria

Bacterial complications of transfusion are rare because of the use of sterile, disposable collection sets and clean phlebotomy techniques. When they do occur, however, they can rapidly be fatal, principally as a result of endotoxic shock. Exogenous contaminants can be introduced into the blood during collection or (rarely) during processing, preparation and storage. At present most blood components are prepared in closed systems; blood is collected in multiple packs and the possibility of microbes entering the packs is negligible. Components prepared in an open system (such as washed cells

ENQUIRY REPORT 67 or filtered blood) need to be processed in sterile rooms and given a limited (24 hours) shelf life.

Common environmental contaminants that have been reported as causing serious (and often fatal) bacterial infections include pseudomonas, achromobacters, and coliforms (ie Gram negative bacteria that grow preferentially at 4-80C or at room termperature, but not at body temperature of 37°C).

Reactions to the transfusion of bacterial contaminated blood usually develop within minutes, with alarming signs and symptoms such as chills, rigors and fever.

Bacteria that may cause low grade or asymptomatic infections in the donor (such as Salmonella or Yersinia species) are sometimes an endogenous source of contamination. Bacteria that do not grow well in blood stored at 40C will grow rapidly in platelet concentrates that are routinely stored at 20- 22°C. Fatal salmonella septicaemia has been caused by contaminated platelet concentrates.

b) Syphilis

Syphilis can be transmitted by fresh blood and platelets because the organism T. pallidum is only inactivated by refrigeration for 72 hours. It is not transmitted by products fractionated from pooled plasma such as Factor VIII. The incubation period varies from four weeks to four and a half months, the average being nine to ten weeks. It is only rarely transmitted by transfusion and responds to treatment with antibiotics, usually a course of benzylpenicillin.

Screening for the antibody is required, and is usually by the cardiolipin assay or the (more specific) Tpallidum haemagglutination assay. In early primary syphilis, at the height of infectivity, screening tests may be negative. The detection rate is low because those who have had the infection have usually been treated. Donors with acute or latent infection are rare.

c) Malaria

Transmission of malaria is not uncommon in countries where malaria is endemic, but it may also occur in nontropical countries if former residents of the tropics are used as blood donors. Benign tertian (p. vivax) and malignant tertian (p. falciparwn) are rarely transmitted if the donor has been away from a malarial country for two years, not suffered malaria during the two years, and has not been taking drugs in that time that suppress malaria.

INQUIRY REPORT 68 Plasmodium falciparum is the most dangerous of the human malarial parasites; the others are Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. The organsims are restricted to red blood cells but may contaminate components such as platelets. Freezing plasma will lyse any contaminated red cells, but malaria parasites can survive storage of blood at 40C for at least a week. The incubation period is from one week to one month, but for the P malariae it may be several months.

In a malarial country the possibility of malarial transmission should be anticipated with every transfusion and a curative course of malarial therapy instituted. In a non-malarial country the occurence of intermittent pyrexia and rigors commencing six or more days after a transfusion should suggest the possibilily of malarial infection and blood should be examined for the presence of parasites.

d) Hepatitis B

The hepatitis B virus is plasma borne and easily transmitted by all blood components and any non-inactivated blood products. It is not transmitted by pasteurised albumin or immunoglobulins. The chance of transmission is enhanced when plasma is pooled for the manufacture of blood products. The incubation period ranges from two to six months but is usually about four. Although it is extremely infectious when injected, the number of transfusion transmitted cases has been drastically reduced by donor screening. The few cases that do occur are caused by non-inactivated compounds. Inactivation of pooled plasma products (600C for 72 hours) has proved effective in reducing the frequency of hepatitis B following transfusion.

Screening for hepatitis B surface antigen (HBsAg) is essential. Screening for the delta agent is unnecessary as the delta agent depends on hepatitis B virus to provide its surface antigen. Screening for antibody to HBeAg can be used to identify donors whose plasma is suitable for the preparation of hepatitis B immunoglobulin. Vaccine is available for protecting recipients of the products of pooled plasma who are negative for hepatitis B (for example, previously untreated haemophiliac patients) and for patients who need regular transfusions (for example, those with thalassaemia).

The incidence of post-transfusion hepatitis B has fallen significantly since the introduction of sensitive screening tests for the hepatitis B surface antigen. Donor blood found to be antigen positive is not used for transfusion but can be used to manufacture hepatitis B vaccine.

The risk of transmitting hepatitis B is much less with an individual unit of blood than with blood products made from pools of plasma taken from a large number of donors. Some products such as albumin solution are also made from large pools of plasma, but they are heated at 600C for 12 hours

ENQUIRY REPORT 69 during preparation so that any virus present is destroyed. Immunoglobulins are not known to have transmitted hepatitis B as prepared in Australasia. Prothrombinex and Factor VIII Concentrate will withstand heating at 600C for 72 hours and this inactivates HIV and hepatitis B viruses. Immunoglobulin preparations appear to be free of risk, and this may be due to their content of antibodies to hepatitis, as well as processing procedure.

e) Hepatitis A

Hepatitis A virus is the agent usually responsible for the disease known clinically as infectious hepatitis, although it is now known that up to one- third of cases previously diagnosed as infectious hepatitis may have been due to the hepatitis B virus. Infectious hepatitis due to the A virus has an incubation period of 20-40 days; the incubation period of the B virus is 40- 160 days.

Hepatitis A is most commonly spread by the faecal-hand-mouth route or by contaminated food and water rather than by blood transfusion. Present opinion is that the hepatitis A virus is very infrequently the cause of post- transfusion hepatitis. This may be due to the fact that the virus is present in the blood stream for only a short time, and the carrier state is a rare occurence. Some products made from large pools of plasma may be occasionally infected with the virus.

f) Non-A Non-B Hepatitis

Since the introduction of screening tests for hepatitis B surface antigen in donor blood it has become apparent that the majority of cases of post- transfusion hepatitis occuring are due to neither the A nor the B virus.

There may be at least two different viruses that transmit non-A, non-B hepatitis. Recently tests have been developed in which cloned peptides can react with antibody to the non-B agent now called Hepatitis C. Most of the non-A, non-B hepatitis that develops as a result of transfusion is now thought to be due to Hepatitis C. Detail on Hepatitis C is covered elsewhere.

g)HIV

HIV-1 was transmitted by transfusion before screening was introduced in 1985 and before donors at high risk started excluding themselves from giving blood. HIV-2 occurs mainly in West Africa. Before screening was introduced, HIV had been transmitted by whole blood, red cell components, platelet concentrates and fresh frozen plasma. It can contaminate Factor VIII and Factor IX concentrates, but it is inactivated by specific methods of

INQUIRY REPORT 70 heat treatments and chemicals. It has not been transmitted by albumin or immunoglobulins. The length of time before seroconversion is rarely longer than three months.

New Zealand screens for HIV-1 and HIV-2 as the test kits used are sensitive to both viruses.

Transmission of HIV by transfusion has been extremely rare since the introduction of screening, but if it occurs in infants it leads more rapidly to serious disease than in adults. Only one donation from a seronegative donor is known to have transmitted HIV infection in the United Kingdom since screening started in 1985. No cases have been identified in Australasia since 1985. The virus can be inactivated in blood products by treatment with heat or chemicals, but blood and blood components (for example platelets) cannot be treated in either of these ways. In New Zealand no donors with a positive HIV test have been detected since 1989.

h) Adult T Cell Leukaemia; Human T Cell Leukaemia Virus

Human T cell leukaemia virus (HTLV-I) is a retrovirus. The importance of HTL V-Il is not clear. In the developed world it is associated with intravenous drug use and has been found in a few cases of hairy cell leukaemia. It is associated with white cells and not transmitted in plasma. The incubation period for adult T cell leukaemia is about 20 years, but even I then only about I% of patients who are seropo. si tiv- d develop the disease. HTLV-I can also (rarely) cause tropical spastic paraparesis, which seems to have a shorter incubation period than adult T cell leukaemia. The infection is endemic in the Caribbean, parts of Africa, and Japan where 3-5% of the population are seropositive and where, before manadory screening, transmission by transfusion was quite common. It is also difficult to differentiate between the antibodies to HTLV-I and HTLV-II unless advanced (and expensive) technology, such as the polymerase chain reaction, is available. No cases of HTLV I or II have yet been detected in New Zealand, either as patients or donors. Limited screening is at present performed on donors who have been living in endemic areas.

(i) Post-transfusion mononucleosis

The main features commence three to five weeks after a transfusion usually of fresh blood in large quantities. The cause is thought to be infection with cytomegalovirus or Epstein-Barr virus, the syndrome is usually benign.

INQUIRY REPORT 71 (j) Cytomegalovirus

Cytomegalovirus (CMV) is a common viral infection and usually causes few symptoms in healthy adults. The virus is one of the herpes family and derives its name from the appearance of infected mononuclear cells which are grossly enlarged with "cows eye" inclusions in the nucleus. Apart from mononucleosis and occasional reports of mild liver damage following transfusion, CMV cannot be considered a harmful pathogen in immunocompetent individuals. However, in neonates and in immunosuppressed patients the virus may cause an overwhelming infection and death may occur, usually from interstitial pneumonitis.

The incidence of antibody to CMV in the population increases with age to about 75% in those over 60 years of age. The presence of CMV antibodies indicates that the person has been exposed to the virus and in a majority of such cases the virus is believed to remain in the infected individual in a latent form.

Blood transfusion has been shown to transmit CMV infection from CMV antibody positive donors to recipients, and the risk is greatest with leucocyte concentrates. Removal of leucocytes from blood reduces the risk of transfusion-transmitted CMV infection.

The incubation period is up to 12 weeks, and blood transfusion can cause primary infection, reactivation of an endogenous latent infection, or reinfection with a different strain of the virus.

Because severe (and sometime fatal) cytomegalovirus disease may occur only after transmission to immunosuppressed patients, selective screening of donors is sufficient to fulfil the demands of, in particular, recipients of bone marrow transplants and low birthweight premature infants.

Granulocyte transfusions that are seropositive for cytomegalovirus are especially likely to transmit the virus.

Components from which the white cells have been particularly or totally removed (for example, by special filters) have a reduced risk, and frozen red cells (from which the glycerol has been removed) and washed red cells tend not to transmit cytomegalovirus because of their low white cell content.

(k) Parvovirus

Serum parvovirus is not usually pathogenic when transmitted by transfusion, although B19 can lead to an apl:stic crisis in a patient with chronic haemolytic anaemia (such as sickle cell anaemia) because of its inhibitory effect on red cell precursors. The risk of transmission by transfusion of non- pooled components is minute because there is no carrier state and the period

INQUIRY REPORT 72 /

of viraemia is short. The titre of virus during the period of viraemia, however, is high and infectious units of plasma can contaminate batches of Factor VIII; over 90% of recipients of untreated Factor VIII are likely to be seropositive. Heat treatments of freeze dried Factor VIII at 800C for 72 hours may inactivate the virus, although recent data indicates that inactivation may not be complete.

73 INQUIRY REPORT WH 460 IQ) 1992 89378 .I.N QUIRY into matters rel.at_: inst..hesafetyo..lood p roducts in New Zealand

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