1216
USA: Therapeutic AIDS vaccine trial debated National Institutes of Health director Bernadine Healy convened a committee on Nov 5 to consider the proper scientific response to the Congress’ appropriation of$20 million for a clinical trial of the therapeutic use of a vaccine against AIDS. In an unprecedented move, Congress had earmarked$20 million in the Department of Defense appropriations bill that passed the full Congress on Oct 6 for a "clinical investigation of the gp 160 vaccine ... unless, within six months... the Secretary of Defense, the Director of the National Institutes of Health, and the Commissioner of Food and Drugs" object, in writing, giving their reasons; if they block the study, DoD would use the money for other AIDS research. Although the law does not seem to rule out the gpl60 vaccines for preventive purposes, the intent was to use the vaccine in the controversial and unproven role of therapeutic agent, to boost the immune response of HIV-infected individuals, thereby slowing or arresting the progress of the disease. The law represents the success of many years of lobbying by the leading producer of recombinant gp 160, MicroGeneSys, and its president Frank Volvovitz, through such high-powered lobbyists as Russell Long, senator from Louisiana from 1948 until 1986 (Science, Oct 23). Scientists, clinicians, and AIDS activists have been predictably critical of the process by which the legislation came about, but representatives of all groups at the meeting were in favour of the trial, and of including several other vaccine candidates that have been through phase I clinical studies.
By the usual criteria for vaccine development, no product is ready for a large-scale (phase III) trial, and only two are in the early stages of phase II trials. But those criteria were developed for preventive vaccination against diseases with mortality rates under 100%. So although several speakers, including David Kessler of the FDA, defended the traditional rules and funding of their agencies, others opined that we would probably learn nothing by waiting, that no other therapies were ready for a large-scale trial, and that this opportunity should be taken immediately. Noted researcher Howard Temin’s advice, "don’t let the best be the enemy of the good", was repeatedly invoked. The MicroGeneSys gpl60 product, a recombinant HIV envelope protein made in insect cells by use of a baculovirus vector, is the candidate HIV vaccine that has progressed the furthest through preliminary studies, and as such is an obvious choice for the trial, but there are several other companies producing candidate vaccines in mammalian cells. Genentech and Chiron/Biocine both produce gpl20, a truncated form of HIV envelope protein, and Immuno AG produces gpl60. Whole psoralen-inactivated HIV is available from Immune Research Corporation. All phase I trials of these products have so far shown them to be safe and immunogenic, and although they have not been tested in patients with advanced AIDS, they have been shown to enhance the immune responses of HIV-positive patients, with increased proliferation of lymphocytes and generation of antibodies to additional epitopes. There is some evidence that CD4 cell counts may be stabilised, but there has been no measurable decrease in viral burden. There are no data on the ability of therapeutic vaccination to slow the clinical progression of HIV disease in man, and in all the available animal models, including simian immunodeficiency virus infection, post-infection vaccination has shown no ability to retard disease progression or mortality. Some ascribe this to
the tendency of lentiviruses to undergo post-infection antigenic variation. Lawrence Corey of the University of Washington presented data suggesting that MGS gpl60 was the least good of the available products, possibly because production in insect cells results in abnormal glycosylation. At this, Frank Volvovitz responded from the audience with a long list of questions about comparability of data and data selection, claiming his product was not being given a fair hearing. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, commented that all these questions would have to be answered in writing, later, before the next meeting of the committee. Jesse Dobson, the only member of the panel to identify himself as a person with AID S, asked Volvovitz, "why are you wasting our time with this crap?" A consensus statement by 12 AIDS activist groups was read by Mark Harrington of the Treatment Action Group; it exhorted the agencies involved to put aside questions about the process by which the legislation was approved, to refrain from engaging in "turf wars", to take this opportunity to proceed with a large-scale trial, and to include several vaccines and placebo. Susan Ellenberg of NIH then presented a statistical estimate-for a large simple trial of three agents plus placebo that would include seropositive individuals with slight, moderate, and severe and that would measure only time of immunosuppression, to frank AIDS or time to mortality, a study of progression 30 000 people would yield results in 2-3 years. Several panel members said that they would like to see more detailed virological and immunological work done on a subset of the subjects, so that something would be learned even if the whole therapeutic vaccine idea fails. The committee is due to meet twice more, and to report to Healy by Dec 2. They will almost certainly recommend that a trial be conducted, and Volvovitz’s gp 160 will probably be among the agents to be tested. Paul M. Rowe
Germany:
New health-care law agreed
Politicians from the Christian Democrat and Liberal coalition and the opposing Social Democrats (who have the majority in the council of federal states) met in Lahnstein and reached a compromise on health reform. The original target of saving DM 11 -4 billion in 1993 is expected to be met. What’s new is the restructuring of the health insurance schemes. From 1997 everybody will be free to choose their statutory health insurance scheme. Imbalances between the expenditures of health insurance companies will be removed by payments between the companies, which will be calculated according to the health risks of their clients. Outpatient services (including day surgery) will be encouraged by a 10% increase in payment from the relevant health insurance company. Practitioners will no longer be paid for ordering laboratory tests; this money will instead be used to improve the patient care given by general practitioners. All other services by the doctor, including preventive medicine, will be covered by a fixed budget. There will also be a fixed budget for drug expenditure by health insurance companies in 1993. The expected overdraft of DM 560 million will be paid jointly by the doctors and the pharmaceutical industry. From 1994 there will be recommended limits on prescriptions, and if they are excluded the doctor’s prescribing behaviour will be
1217
investigated. Patients will not have to pay 10% as originally planned, towards the cost of drugs, but only DM 3, 5, or 7, depending on whether the package is for short, medium, or long term drug use. The health ministry will found a pharmaceutical institute to create a list of drugs acceptable for refund by insurance companies. To address the issue of the excess of doctors, from 1999 doctors will retire at age 68 if they have practised for at least 20 years. However, the outpatient services and polyclinics of the former East Germany will not have to be closed down by
1995, as previously proposed. The pharmaceutical industry has expressed fears that the drug list will result in the collapse of dozens of firms. Doctors complain about "state medicine" restricting patient care and putting patients at the mercy of the strengthened health insurance companies. Preventive medicine will suffer, since it will become uneconomical for doctors. There are plans to challenge the obligatory retirement age in the constitutional court. But these complaints are not expected to change the bill in any considerable way, since it has such a broad parliamentary backing.
Annette Tufts
Italy: National health service intact but charges rise This summer the Government fmally realised that it was high time to do something to put right the nation’s disastrous financial situation. One of its proposals then was tantamount to a dismantling of the national health service, at least for those families with a joint income of over 40 million lire ( £ 18 500). Since then the nation has been barraged with continually changing decisions from the Minister of Health. The contradictory nature of these changes highlights the contrast between the difficulty of introducing cuts and the ease of imposing new charges. Now, under the influence of the various lobbies, a new picture seems to be emerging, with proposals that charges over and above the basic NHS contribution be made for vouchers for various services. For people with a yearly income (before income tax) of 30 million lire if alone, 42 million lire (2 members), 50 million lire (3 members), or 55 million lire (4 members), the charges will be: 85 000 lire per year per family member to obtain assistance from practitioners (from Jan 1,1993); 40 000 lire per drug prescription + 10% of the difference between the total price and the 40 000 lire from March 1, 1993), except for lifesaving drugs; 100 000 lire for diagnostic examinations, physiotherapy, or thermal care + 10% of the difference between the total price and the 100 000 lire (from March 1, 1993). For people with gross income lower than the above, the charges will be: 4,000 lire per drug prescription or any other service; 2000 lire for each drug prescribed. All employees will have to pay an additional NHS contribution of 0 -% up to 40 million lire gross annual salary and 04% above that; all self-employed workers will be charged an additional NHS contribution of 0-4%. The charges have been approved by parliament but have yet to be discussed by Senate. The proposals have been severely criticised for putting the burden of health costs almost entirely on the shoulders of employees. The only reason for satisfaction is that the NHS has not been dismantled-the important principles remain
that no citizen is excluded from the NHS and that the NHS still includes all services, not just hospital care. The decisions taken by the government are not fair in terms of distribution of the burden. At present employees pay about 10% of their salary (before taxation) whereas self-employed workers pay only 5% for salaries up to 40 million lire/year and 4% from there up to 100 million lire/year to obtain the same services. The charges for the proposed vouchers are heavy because for a family of two with a net annual income of about 31 million lire would already have paid 4-6 million lire/year for the NHS on top of income tax (9-9 million/year). Additionally, the calculation of these charges is so cumbersome and the distinction between people who are exempt for reasons of poverty or because they have chronic diseases is so blurred that there is doubt about the efficacy of the new rules. The rumour is that the new charges will come into force from March, 1993, rather than January, 1993, as originally proposed. There is further risk that NHS hospital expenses will increase because patients will ask for hospital admission to avoid paying for the vouchers. The Government has ignored several measures that could help distribute the burden equally. It could gradually make the contributions of the independent and dependent workers equal; increase the number of hours worked by physicians in the NHS, for the same salary; slim down the national drug formulary; negotiate better discounts on bulk purchases of drugs; limit the reimbursement of expensive me-too drugs; and reduce the costs of distribution through pharmacies, which in Italy accounts for about 25% of all sales of drugs.
Silvio Garattini
Europe: Review of short-acting benzodiazepines Short-acting hypnotics could be subject to strict new labelling and dose rules in December when European Commuity regulatory authorities end a year-long review of seven benzodiazepines, sparked by last October’s furore over Halcion (triazolam, Upjohn). A Committee for Proprietary Medicinal Products working party will finalise its report on Nov 16-17, before the full Committee meets on Dec 3-4. Whilst details of the report are confidential, both pharmaceutical industry and EC sources expect the working party to call for the same restrictions for these benzodiazepines as those CPMP recommended for Halcion in Oct, 1991. These were: that prescription should be limited to severe, disabling, or very distressful sleeping disorder; the initial treatment should not exceed two to three weeks and any subsequent treatment should be subject to a complete re-evaluation of therapy; the dose for most patients should be 0-125 mg immediately before retiring but could be increased to a maximum 0-25 mg for the most serious cases; elderly, debilitated people and those with liver function should receive only the lowest 0-125 mg dose; and, the product should never be prescribed to the under-18s or people with major psychiatric disorders. The review was intended to see whether there was any substance to Upjohn claims that the side-effects of Halcion are similar to those of other products in the class. The other benzodiazepines reviewed were brotizolam (used in Germany and Belgium), flunitrazepam (Germany and Ireland), midazolam (Spain and the Netherlands), temazepam (Italy and the UK), zolpiden (Greece and France), and zopicone (France and Portugal).
Sara Lewis
USA: Therapeutic AIDS vaccine trial debated National Institutes of Health director Bernadine Healy convened a committee on Nov 5 to consider the proper scientific response to the Congress’ appropriation of$20 million for a clinical trial of the therapeutic use of a vaccine against AIDS. In an unprecedented move, Congress had earmarked$20 million in the Department of Defense appropriations bill that passed the full Congress on Oct 6 for a "clinical investigation of the gp 160 vaccine ... unless, within six months... the Secretary of Defense, the Director of the National Institutes of Health, and the Commissioner of Food and Drugs" object, in writing, giving their reasons; if they block the study, DoD would use the money for other AIDS research. Although the law does not seem to rule out the gpl60 vaccines for preventive purposes, the intent was to use the vaccine in the controversial and unproven role of therapeutic agent, to boost the immune response of HIV-infected individuals, thereby slowing or arresting the progress of the disease. The law represents the success of many years of lobbying by the leading producer of recombinant gp 160, MicroGeneSys, and its president Frank Volvovitz, through such high-powered lobbyists as Russell Long, senator from Louisiana from 1948 until 1986 (Science, Oct 23). Scientists, clinicians, and AIDS activists have been predictably critical of the process by which the legislation came about, but representatives of all groups at the meeting were in favour of the trial, and of including several other vaccine candidates that have been through phase I clinical studies.
By the usual criteria for vaccine development, no product is ready for a large-scale (phase III) trial, and only two are in the early stages of phase II trials. But those criteria were developed for preventive vaccination against diseases with mortality rates under 100%. So although several speakers, including David Kessler of the FDA, defended the traditional rules and funding of their agencies, others opined that we would probably learn nothing by waiting, that no other therapies were ready for a large-scale trial, and that this opportunity should be taken immediately. Noted researcher Howard Temin’s advice, "don’t let the best be the enemy of the good", was repeatedly invoked. The MicroGeneSys gpl60 product, a recombinant HIV envelope protein made in insect cells by use of a baculovirus vector, is the candidate HIV vaccine that has progressed the furthest through preliminary studies, and as such is an obvious choice for the trial, but there are several other companies producing candidate vaccines in mammalian cells. Genentech and Chiron/Biocine both produce gpl20, a truncated form of HIV envelope protein, and Immuno AG produces gpl60. Whole psoralen-inactivated HIV is available from Immune Research Corporation. All phase I trials of these products have so far shown them to be safe and immunogenic, and although they have not been tested in patients with advanced AIDS, they have been shown to enhance the immune responses of HIV-positive patients, with increased proliferation of lymphocytes and generation of antibodies to additional epitopes. There is some evidence that CD4 cell counts may be stabilised, but there has been no measurable decrease in viral burden. There are no data on the ability of therapeutic vaccination to slow the clinical progression of HIV disease in man, and in all the available animal models, including simian immunodeficiency virus infection, post-infection vaccination has shown no ability to retard disease progression or mortality. Some ascribe this to
the tendency of lentiviruses to undergo post-infection antigenic variation. Lawrence Corey of the University of Washington presented data suggesting that MGS gpl60 was the least good of the available products, possibly because production in insect cells results in abnormal glycosylation. At this, Frank Volvovitz responded from the audience with a long list of questions about comparability of data and data selection, claiming his product was not being given a fair hearing. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, commented that all these questions would have to be answered in writing, later, before the next meeting of the committee. Jesse Dobson, the only member of the panel to identify himself as a person with AID S, asked Volvovitz, "why are you wasting our time with this crap?" A consensus statement by 12 AIDS activist groups was read by Mark Harrington of the Treatment Action Group; it exhorted the agencies involved to put aside questions about the process by which the legislation was approved, to refrain from engaging in "turf wars", to take this opportunity to proceed with a large-scale trial, and to include several vaccines and placebo. Susan Ellenberg of NIH then presented a statistical estimate-for a large simple trial of three agents plus placebo that would include seropositive individuals with slight, moderate, and severe and that would measure only time of immunosuppression, to frank AIDS or time to mortality, a study of progression 30 000 people would yield results in 2-3 years. Several panel members said that they would like to see more detailed virological and immunological work done on a subset of the subjects, so that something would be learned even if the whole therapeutic vaccine idea fails. The committee is due to meet twice more, and to report to Healy by Dec 2. They will almost certainly recommend that a trial be conducted, and Volvovitz’s gp 160 will probably be among the agents to be tested. Paul M. Rowe
Germany:
New health-care law agreed
Politicians from the Christian Democrat and Liberal coalition and the opposing Social Democrats (who have the majority in the council of federal states) met in Lahnstein and reached a compromise on health reform. The original target of saving DM 11 -4 billion in 1993 is expected to be met. What’s new is the restructuring of the health insurance schemes. From 1997 everybody will be free to choose their statutory health insurance scheme. Imbalances between the expenditures of health insurance companies will be removed by payments between the companies, which will be calculated according to the health risks of their clients. Outpatient services (including day surgery) will be encouraged by a 10% increase in payment from the relevant health insurance company. Practitioners will no longer be paid for ordering laboratory tests; this money will instead be used to improve the patient care given by general practitioners. All other services by the doctor, including preventive medicine, will be covered by a fixed budget. There will also be a fixed budget for drug expenditure by health insurance companies in 1993. The expected overdraft of DM 560 million will be paid jointly by the doctors and the pharmaceutical industry. From 1994 there will be recommended limits on prescriptions, and if they are excluded the doctor’s prescribing behaviour will be
1217
investigated. Patients will not have to pay 10% as originally planned, towards the cost of drugs, but only DM 3, 5, or 7, depending on whether the package is for short, medium, or long term drug use. The health ministry will found a pharmaceutical institute to create a list of drugs acceptable for refund by insurance companies. To address the issue of the excess of doctors, from 1999 doctors will retire at age 68 if they have practised for at least 20 years. However, the outpatient services and polyclinics of the former East Germany will not have to be closed down by
1995, as previously proposed. The pharmaceutical industry has expressed fears that the drug list will result in the collapse of dozens of firms. Doctors complain about "state medicine" restricting patient care and putting patients at the mercy of the strengthened health insurance companies. Preventive medicine will suffer, since it will become uneconomical for doctors. There are plans to challenge the obligatory retirement age in the constitutional court. But these complaints are not expected to change the bill in any considerable way, since it has such a broad parliamentary backing.
Annette Tufts
Italy: National health service intact but charges rise This summer the Government fmally realised that it was high time to do something to put right the nation’s disastrous financial situation. One of its proposals then was tantamount to a dismantling of the national health service, at least for those families with a joint income of over 40 million lire ( £ 18 500). Since then the nation has been barraged with continually changing decisions from the Minister of Health. The contradictory nature of these changes highlights the contrast between the difficulty of introducing cuts and the ease of imposing new charges. Now, under the influence of the various lobbies, a new picture seems to be emerging, with proposals that charges over and above the basic NHS contribution be made for vouchers for various services. For people with a yearly income (before income tax) of 30 million lire if alone, 42 million lire (2 members), 50 million lire (3 members), or 55 million lire (4 members), the charges will be: 85 000 lire per year per family member to obtain assistance from practitioners (from Jan 1,1993); 40 000 lire per drug prescription + 10% of the difference between the total price and the 40 000 lire from March 1, 1993), except for lifesaving drugs; 100 000 lire for diagnostic examinations, physiotherapy, or thermal care + 10% of the difference between the total price and the 100 000 lire (from March 1, 1993). For people with gross income lower than the above, the charges will be: 4,000 lire per drug prescription or any other service; 2000 lire for each drug prescribed. All employees will have to pay an additional NHS contribution of 0 -% up to 40 million lire gross annual salary and 04% above that; all self-employed workers will be charged an additional NHS contribution of 0-4%. The charges have been approved by parliament but have yet to be discussed by Senate. The proposals have been severely criticised for putting the burden of health costs almost entirely on the shoulders of employees. The only reason for satisfaction is that the NHS has not been dismantled-the important principles remain
that no citizen is excluded from the NHS and that the NHS still includes all services, not just hospital care. The decisions taken by the government are not fair in terms of distribution of the burden. At present employees pay about 10% of their salary (before taxation) whereas self-employed workers pay only 5% for salaries up to 40 million lire/year and 4% from there up to 100 million lire/year to obtain the same services. The charges for the proposed vouchers are heavy because for a family of two with a net annual income of about 31 million lire would already have paid 4-6 million lire/year for the NHS on top of income tax (9-9 million/year). Additionally, the calculation of these charges is so cumbersome and the distinction between people who are exempt for reasons of poverty or because they have chronic diseases is so blurred that there is doubt about the efficacy of the new rules. The rumour is that the new charges will come into force from March, 1993, rather than January, 1993, as originally proposed. There is further risk that NHS hospital expenses will increase because patients will ask for hospital admission to avoid paying for the vouchers. The Government has ignored several measures that could help distribute the burden equally. It could gradually make the contributions of the independent and dependent workers equal; increase the number of hours worked by physicians in the NHS, for the same salary; slim down the national drug formulary; negotiate better discounts on bulk purchases of drugs; limit the reimbursement of expensive me-too drugs; and reduce the costs of distribution through pharmacies, which in Italy accounts for about 25% of all sales of drugs.
Silvio Garattini
Europe: Review of short-acting benzodiazepines Short-acting hypnotics could be subject to strict new labelling and dose rules in December when European Commuity regulatory authorities end a year-long review of seven benzodiazepines, sparked by last October’s furore over Halcion (triazolam, Upjohn). A Committee for Proprietary Medicinal Products working party will finalise its report on Nov 16-17, before the full Committee meets on Dec 3-4. Whilst details of the report are confidential, both pharmaceutical industry and EC sources expect the working party to call for the same restrictions for these benzodiazepines as those CPMP recommended for Halcion in Oct, 1991. These were: that prescription should be limited to severe, disabling, or very distressful sleeping disorder; the initial treatment should not exceed two to three weeks and any subsequent treatment should be subject to a complete re-evaluation of therapy; the dose for most patients should be 0-125 mg immediately before retiring but could be increased to a maximum 0-25 mg for the most serious cases; elderly, debilitated people and those with liver function should receive only the lowest 0-125 mg dose; and, the product should never be prescribed to the under-18s or people with major psychiatric disorders. The review was intended to see whether there was any substance to Upjohn claims that the side-effects of Halcion are similar to those of other products in the class. The other benzodiazepines reviewed were brotizolam (used in Germany and Belgium), flunitrazepam (Germany and Ireland), midazolam (Spain and the Netherlands), temazepam (Italy and the UK), zolpiden (Greece and France), and zopicone (France and Portugal).
Sara Lewis
