Select Committee on Science and Technology Seventh Report


APPENDIX 6 (continued)

Length of course

71.    We put it to the FDA that their policy encouraged pharmaceutical companies to specify longer courses of antibiotics than were necessary, thereby adding to the general antibiotic load. Dr Goldberger replied that the FDA has no policy on length of courses; it relies on the manufacturer to decide what length to use for the trials leading up to licensing, and licenses the the drug on that basis. Under pressure from managed care (see below) to reduce costs, manufacturers are beginning to try shorter courses as a way to gain market advantage; the FDA requires to be convinced in each case that the short course is at least as effective as the longer one. Dr Siegfried of PhRMA commented that the manufacturer's view of the ideal length of treatment often changes once a drug reaches the market.

Antibiotics in old people's homes

72.    Nursing homes are big business in the USA, as in the UK. People at the Institute of Medicine said that they were under-regulated. Dr Siegfried at PhRMA drew attention to an invisible form of "drug abuse": informal and inappropriate pill-sharing by old people. ICARE staff at CDC told us of a case where the main source of resistant infections in a hospital turned out to be a nearby nursing home.

Antibiotics for export

73.    We asked the FDA about regulation of antibiotics manufactured for export. Antibiotics manufactured in the USA for export to a country with lower standards are not required to meet the high standards set by the FDA for drugs intended for use by Americans. However drugs may not be exported which have passed their "sell-by" date.

Antibiotics in farming

74.    "Antibiotic resistance is our most important issue just now," said Dr Stephen Sundlof, Director of the FDA Center for Veterinary Medicine; and its importance in the context of farming is recognised by politicians and the press.

75.    The flashpoint is the fluoroquinolones. In 1995 the FDA approved the prescription of sarafloxacin for the prevention of pneumonia in poultry, subject to resistance monitoring up and down the food chain. There was apparently some ambiguity in this decision: Dr Levy, who was involved, was left with the impression that approval would be provisional, but it turned out not to be. Then, early this year, a 'phone call from Colindale alerted FDA to the emergence of ciprofloxacin resistance in S. typhimurium DT104 in the UK. Since then, FDA has issued no more approvals for fluoroquinolones for animals; meanwhile, sure enough, 10 per cent resistance to fluoroquinolones has been found in Campylobacter, though none as yet in Salmonella. FDA are using DNA fingerprinting to see whether resistance in Campylobacter can be traced to poultry and sarafloxacin; they suspect so strongly, but have not yet proved it.

76.    FDA believe that lives are not at risk; but Dr Sundlof frankly admitted that they are not sure, and they are very concerned. At the same time, they have no intention to deprive agriculture altogether of the benefits of antibiotics; they have to balance the interests of agriculture against those of public health, and, as Dr Sundlof explained, this is not easy. Interestingly, he did not consider that this was an issue which could safely be put to the people. The FDA has seconded someone to the UK CVL and PHLS to learn from our experience of fluoroquinolone use. In discussion at FDA, someone took us aback by asking simply, why the UK continues to approve fluoroquinolones for animal use, when the USA has stopped doing so on advice from British scientists.

77.    Dr Tauxe expressed to us CDC's serious concern over continued veterinary use of fluoroquinolones. He told us how Congress recently blew a large hole in the Swann regime by legislating to permit any antibiotic approved for use in one species, including man, to be used in any other. This enactment was promoted by the veterinary profession; it was resisted by CDC, who succeeded only in winning exceptions for the fluoroquinolones and the glycopeptides.

78.    US agriculture uses around 16m lb of antimicrobials for animals every year, of which CDC believes 40-80 per cent to be unnecessary. In Dr Tauxe's view, antibiotics are being used as a "crutch" for otherwise impossibly intensive farming practices. He likened the modern farm to a nineteenth-century city before the revolution in sanitation and public health. He pointed to the example of Denmark, where by improved farming practice the level of Salmonella had been dramatically reduced without increasing costs.

79.    Like the EU, the FDA has prohibited the growth promoter avoparcin. Dr Sundlof was unable to reveal the reason, but said that it was not fear of fostering resistance to other glycopeptides including vancomycin, though this fear would now deter the FDA from approving animal use of any glycopeptide. The USA has plenty of vancomycin-resistant bacteria as it is (see above, VISA and VRE). Dr Sundlof blames this on overuse of vancomycin in human medicine; but Dr Siegfried of PhRMA, who is personally "appalled" at the amount of antibiotics fed to animals, believes that there is significant illegal use of vancomycin in US agriculture, while Dr Levy believes that VRE originally reached the USA from Europe.

80.    We raised at FDA the case of virginiamycin, which was approved for animal use before human use of cognate antibiotics became a possibility. Dr Sundlof replied that the FDA could not block all veterinary drugs for fear of compromising possible human uses of substances cognate to the drug in question but as yet undeveloped. They are trying to find ways to predict resistance in advance of approval, by examining data from clinical trials; but these are of limited predictive value. As Dr Sundlof put it, such cases present a "difficult regulatory challenge"; Dr Levy regards this issue as a major weakness in the Swann regime.

81.    Until 1991, FDA approved most animal drugs for sale over the counter. All approvals since then have been for prescription only. The most vocal protesters have been the fish-farmers. We encountered widespread concern about the use of antibiotics in aquaculture (fish-farming); Dr Levy commended Norway for best practice in moving from overuse of antibiotics towards vaccines.

82.    Several of those we met commended the conclusion of the recent WHO meeting on this issue in Berlin, that growth promoters should be progressively removed from the agricultural scene. Dr Levy described the meeting as a "historic moment". In his view, the low-level long-term use of growth promoters is much more damaging than veterinary prophylaxis. He told us how Sweden banned all growth promoters at a stroke, without destroying Swedish agriculture. Sweden is a rich country, with a highly centralised agricultural industry; Dr Levy acknowledged that such a step would be much harder for, say, China. The agricultural industry has for too long "refused to admit that we are on the same planet", and hidden behind the difficulty of proving that resistant strains induced in animals are the same as those which cause human disease (the "show me a dead body" argument)—though Dr Levy has proved this to his own satisfaction in the case of E. coli. The Berlin meeting was particularly important because it included industry representatives.

Resistance markers in genetically modified organisms (GMOs)

83.    Dr Beru of FDA gave us the US position on resistance markers in GMOs. The FDA adopted a regulatory policy in 1992. For foods derived from GMOs, FDA believes evaluation of resistance markers should be based on three questions:

      (i)  How toxic is the enzyme generated by virtue of the resistance gene?

      (ii)  Could the enzyme act directly on antibiotics?

      (iii)  Could resistance be transferred from the GMO?

84.    The first case to come forward was the "Flavr Savr" tomato. The enzyme was not toxic, and could not act directly. There was a very remote possibility of transfer; but even in the worst case scenario the effect would have been trivial. After 4 years of review, the tomato was approved. Since then FDA has finalised consultations on 30 GMOs, mostly with resistance markers, all of them plants. One was Ciba-Geigy's GM maize, which was also approved by the EU; the UK ACNFP approved it for processed products but not for unprocessed products.

Biocides in domestic articles

85.    Dr Levy drew our attention to the new phenomenon of domestic articles—kitchenware, soap, even children's toys—which are advertised as containing antibacterials. To the extent that this is true, he regards it as a further serious threat to normal bacterial ecology. Such products appeared in the USA in 1995, and are just beginning to appear in the UK.[82]

TO SEE OURSELVES AS OTHERS SEE US

86.    People we met were generally coy about commenting on the UK's performance in the fight against resistance; some frankly admitted to knowing little about the UK scene. Dr Levy suggested that the UK was perhaps a little complacent, possibly because rates of the main resistant strains are lower than in the USA. Regarding antibiotics for animals, he suggested that the UK had relied on the Swann regime for too long; as noted above, we were challenged at FDA on the licensing of enrofloxacin.

87.    Over lunch in Boston, Dr O'Brien spoke highly of PHLS's system for surveillance of Salmonella, which drew early attention to the problem of S. typhimurium DT104; and Dr Medeiros and Dr Gorbach observed that the UK has tools of control which the USA lacks, e.g. the NHS, the British National Formulary, the prescribing data compiled by the Prescription Pricing Authority, and a culture less averse to regulation.

 "TAKE-HOME MESSAGES"

88.    The following are the messages which came over to us most strongly during the visit:

      (i)  Antimicrobial resistance can be seen as a subset of a series of threats to public health posed by emerging and re-emerging infections. (See above, paragraph 5.)

      (ii)  UK hospitals should expect before long to have as much trouble with VRE as US hospitals do already. (Paragraph 15.)

      (iii)  The USA has paid a heavy price, in money and lives, for letting down her guard against TB; the UK must not make the same mistake. (Paragraph 17.)

      (iv)  Multi-resistant Strep pneumoniae poses a most serious threat to public health outside the hospital, and the search for better vaccines is urgent. (Paragraph 26.)

      (v)  A surveillance system along the lines of ICARE would be a great asset to UK hospitals. (Paragraph 40.)

      (vi)  The key to controlling resistance is prudent use of antibiotics; and the key to prudent use is education—of policy-makers, professionals and the public. (Paragraph 57.)

      (vii)  As pre-school childcare becomes ever more prevalent in the UK, we should be mindful of the implications for the spread of infection and the use of antibiotics. (Paragraph 63.)

      (viii)  It is possible, and cost-effective, to educate and equip doctors to change their prescribing practices. (Paragraphs 67, 68.)

      (ix)  The licensing of enrofloxacin for animal use may have been a grave mistake, which must not be repeated. (Paragraphs 75, 76.)

SOULSBY OF SWAFFHAM PRIOR
5 December 1997

DIARY

MONDAY 17TH NOVEMBER, WASHINGTON

National Institutes of Health (NIH)

National Institute of Allergy and Infectious Diseases (NIAID)

89.    NIH is the US equivalent of the MRC. Within NIH, NIAID is responsible for conducting and supporting research into infectious diseases. NIAID's research budget for 1996 was $31m. We met:

      (-)  Dr Dennis Dixon, Chief of the Bacteriology and Mycology Branch

      (-)  Dr Amar Bhat, Programme Officer for Europe

      (-)  Dr Ann Ginsberg, Medical and Program Officer for TB, Leprosy and other Mycobacterial Diseases

      (-)  Dr Stephen Heyse, Medical Bacteriology and Antibacterial Resistance Program Officer

      (-)  Dr David Klein, Respiratory Diseases Officer

      (-)  Dr Dennis Long, Bacterial and Viral Enteric Diseases Program Officer

      (-)  Linda Scott, Policy Analysis Branch

90.    At the end of a wide-ranging discussion, we asked what were the top priorities in the fight against resistance. The answers were: genomics; vaccine development, especially for TB and HIV; epidemiology on the farm; and "Wash your hands!"

Ambassador's lunch

91.    Over lunch at the Ambassador's Residence, we met, among others:

      (-)  Dr Gail Cassell, Vice President of Infectious Diseases Research, Eli Lilly

      (-)  Donna Vogt, of the Congressional Research Service Science Policy Division

      (-)  Janet Shoemaker, Director of Public and Scientific Affairs, American Society for Microbiology

      (-)  Miss Stoiber, of the US Department of Health and Human Services

      (-)  Dr Polly Harrison, Institute of Medicine

92.    In discussion around the table, Dr Cassell stressed the importance of infectious diseases to the USA and to the world; and particularly the issue of food poisoning. She called for public and professional education, and for control of antibiotic use in farming. Miss Vogt indicated that Congress is well seized of the significance of food poisoning. Miss Shoemaker stressed the over-prescription of antibiotics to children, and the importance of basic hygiene. Dr Harrison noted that very worrying links are emerging between infections and chronic disease, for example cardiovascular disease and some cancers.

93.    Miss Stoiber drew attention to the growth of "managed care", whereby commercial "health management organisations" (HMOs) manage the healthcare of people with health insurance with a view to controlling cost to the insurers. The government is not involved in managed care, though during our visit the President announced a plan for a "Patient's Bill of Rights", a voluntary code for HMOs which may be modelled on the UK Patient's Charter. Miss Stoiber also mentioned food poisoning, for which she blamed intensive farming practices more than poor hygiene in the home.

White House Office of Science and Technology Policy (OSTP)

94.    OSTP is the US equivalent of OST; it is led by the President's Science Advisor, Dr Jack Gibbons, as OST is headed by the Chief Scientific Adviser, Sir Robert May. Its functions are advisory and managerial rather than executive. We met:

      (-)  Dr Laura Efros, Senior Research Analyst

      (-)  Rachel Levinson, Assistant Director for Life Sciences

Conversation turned mainly on the recent Presidential Directive on emerging infections.

National Academy of Sciences Institute of Medicine

95.    The National Academy of Sciences is the US equivalent of the Royal Society; the Institute of Medicine is its medical wing. We met:

      (-)  Dr Polly Harrison, Director, Forum on Emerging Infections, Institute of Medicine

      (-)  Philip Russell, Professor of International Health, Johns Hopkins University

      (-)  Stephen Morse, Assistant Professor of Epidemiology, Columbia University

      (-)  William James, Food Safety Inspection Service, US Department of Agriculture

      (-)  Andrew Pope, Senior Staff Officer, Institute of Medicine

      (-)  Rick Manning, Senior Program Officer, Institute of Medicine

      (-)  Tania Williams, Program Officer, National Academy of Sciences

96.    They told us about the Institute's report "Emerging Infections" of 1992, and actions to follow it up. The CDC produced a national plan, which has attracted Congressional funding, and established ICARE (see above). The American Society for Microbiology set up a task force on surveillance. The Institute itself established the Forum on Emerging Infections; the Forum has held two workshops, on encouraging drug development ("Orphans and Incentives") and on "Antimicrobial Resistance, Surveillance and Response". Another is planned, on the implications of changes in US healthcare; and an interdisciplinary project on the ecology and evolution of infections is being launched.

TUESDAY 18TH NOVEMBER, WASHINGTON

Food and Drug Administration (FDA)

97.    The FDA regulates food and drugs. Their role is essentially passive: when a company applies for something to be licensed for certain uses, FDA decides whether to license it or not; but it is not their role to suggest improvements to the product, or alternative indications for use. However they have a research programme for vaccines. We met:

      (-)  Donald Aronson, Associate Director for Europe;

      (-)  Dr Mark Goldberger, Director, Division of Special Pathogens and Immunologic Drug Products, Center for Drug Evaluation and Research (CDER), who talked about TB;

      (-)  Dr Alex Rakowsky, Division of Anti-Infective Drug Products, CDER, who described the FDA's systems for accelerated and emergency drug approval, and for Orphan Drug designation. Accelerated approval does not in itself reduce time to market by more than one or two years; much more time can be saved if the manufacturer is prepared to take the business risks of running trials simultaneously rather than in sequence, and of committing manufacturing capacity in anticipation, and if the patient community are prompt to enrol for clinical trials. The Orphan Drug system was set up in 1992 to encourage development of drugs with a potential US market of fewer than 200,000 patients p.a.; threats in Congress to rewrite the rules had a "chilling" effect, and put industry off the scheme;

      (-)  Dr Michael Brennan, Chief, Laboratory of Mycobacteriology, Center for Biologics Evaluation and Research, and his colleague Dr Sheldon Morris, who covered TB vaccines;

      (-)  Dr Stephen Sundlof, Director, Center for Veterinary Medicine, who spoke mainly about animal use of the fluoroquinolones. He set out the difference between the FDA's approaches to regulating human and animal drugs. The FDA puts people ahead of animals. Therefore, whereas with human drugs benefits may outweigh costs, drugs for food animals must show "reasonable certainty of no harm" to humans, regardless of benefits to the animal;

      (-)  Dr Linda Tollefson, Director of Surveillance and Compliance, Center for Veterinary Medicine;

      (-)  Dr Nega Beru, Consumer Safety Officer, Center for Food Safety and Applied Nutrition, who spoke about resistance markers in GMOs;

      (-)  Roxanne Shively, Division of Clinical Laboratory Devices, Center for Devices and Radiological Health.

Pharmaceutical Research and Manufacturers of America (PhRMA)

98.    PhRMA is the US analogue of the ABPI, except that it embraces only manufacturers who conduct R&D in the USA, and excludes purely generic producers. We met DrJohn Siegfried, Deputy Vice President for Regulatory and Scientific Affairs, and Dr Gillian Woollett, Assistant Vice President Biologics and Biotechnology.

WEDNESDAY 19TH NOVEMBER, ATLANTA

Centers for Disease Prevention and Control (CDC)

99.    We were welcomed first by Dr Claire Broom, Deputy Director of CDC. She explained that CDC supports the States in their responsibilities for public health. It conducts and supports applied research (basic research is the responsibility of NIH); it designs, manages and evaluates surveillance programmes, and receives notice of notifiable conditions; it gives grants to the States for public health programmes, and steers such programmes by means including guidance, targets (e.g. for disease reduction or vaccine coverage), incentive funds and league tables. CDC staff are to be found in the health department of every state. CDC's UK counterpart is PHLS.

100.    We were also welcomed by Dr Jim Hughes, Director of the National Center for Infectious Diseases, and colleagues.

101.    Next we met Dr Bruce Levin and colleagues, from Emory University School of Medicine. Dr Levin's field is population biology; he finds antibiotic resistance interesting in its own right, since it shows evolution in action. He gave us his reasons for believing that resistance is a one-way street: even if antibiotic use were cut back sharply, resistance would wane slowly if at all; even moderate use still imposes heavy selective pressure; and, if use were resumed then resistance would rise again more rapidly than before. As he put it, "We are committed to an arms race"; disarmament is not an option. He contemplated a future without effective antibiotics: infectious diseases could still be controlled by traditional means, as they were before the 1940s; but transplants, cancer chemotherapy and other modern medical techniques which depend on antibiotics would be impossible.

102.    Then, from the Division of Bacterial and Mycotic Diseases, we met Dr Mitchell Cohen, Director, Dr Ben Schwartz, and Dr Robert Tauxe, Medical Officer.

103.    We were entertained to lunch at the Houston Mill House by the National Foundation for the CDC: Charlie Stokes, Executive Director; Subie Green, Director of Development; and Nicole Kruse, Development Officer. The Foundation raises funds to help CDC to operate on the edges of its mandate, by supporting pilot projects, overseas projects, health education, IT, international fellowships etc. It has no analogue in the UK; some of what it does would fall to the major medical charities.

104.    From the Division of Parasitic Diseases, we then met Dr Daniel Colley, Director, Dr Peter Schantz (once a pupil of Lord Soulsby at the University of Maryland), Dr William Collins, Dr Trenton Ruebush and Dr Peter Bloland.

105.    Finally we met Robert Baldwin, Assistant Director for International Health Liaison. He explained that CDC has no mandate to work overseas; when they do so, it is therefore on a consultancy basis, by invitation.

THURSDAY 20TH NOVEMBER, ATLANTA

Centers for Disease Prevention and Control (CDC) (continued)

106.    From the Hospital Infections Program, we met William Jarvis, Director, and Dr Lennox Archibald.

107.    From the National Center for HIV, STD and TB Prevention, we met Dr Bess Miller, Dr Todd Weber, Dr Dale Hu and Dr Marisa Moore.

108.    We then met Dr John Livengood, Director, and colleagues from the National Immunization Program. They discussed the paradox that, if a vaccine is successful, the rate of disease may fall below the rate of adverse reaction to the vaccine, provoking an irrational loss of public confidence.

109.    Over lunch we also met Dr John McGowan, Professor of Infectious Diseases at Emory University.

110.    Our visit to CDC was meticulously organised by Linda Ford, Chief of International Visitors Activity. We were surprised to find that CDC is in part a uniformed service.

BOSTON

Consul-General's dinner

111.    Over dinner at the Somerset Club, kindly hosted by Mr Jim Poston, HM Consul-General, we met Dr Stuart Levy, Director of the Center for Adaptation Genetics and Drug Resistance at Tufts University School of Medicine and founding President of the international Alliance for the Prudent Use of Antibiotics; and Dr Thomas O'Brien, Medical Director of the Microbiology Laboratory at Brigham and Women's Hospital, Director of the WHO Collaborating Center in Boston, and creator of WHONET.

112.    Dr Levy, a lively and long-standing campaigner on this issue, expressed delight that it was receiving attention at Westminster. He declared himself an optimist—if only because, in the USA, the present position is so bad that major improvement would be relatively easy to achieve.

113.    Dr O'Brien expressed "amazement" at the ability of bacteria to evolve. He regards the recent emergence of 2-300 resistance genes, under the artificial selective pressure of antibiotics, as an evolutionary "disorder". The challenge, as he sees it, is to mobilize the information about resistance which microbiologists already have.

FRIDAY 21ST NOVEMBER, BOSTON

Alliance for the Prudent Use of Antibiotics (APUA)

114.    In the Sackler Library at Tufts University we met Dr Levy again, and colleagues from APUA.

Working lunch

115.    Over lunch, we met Dr Levy; Dr O'Brien; Dr Michael Bennish, Associate Professor of Paediatrics at Tufts University; Dr Anton Medeiros, Professor at Brown University School of Medicine; and Dr Sherwood Gorbach, Professor of Immunology, Molecular Biology, Microbiology and Community Health at Tufts University.

116.    Finally, after lunch, we met Dr Jerry Avorn, Assistant Professor of Medicine at Harvard Medical School, who told us about his work on doctor and patient behaviour.


82   See the evidence of the Royal Pharmaceutical Society (p 457) and the British Association for Chemical Specialities (p 545). Back


 
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