House of Commons - Ensuring access to working antimicrobials

Ensuring access to working antimicrobials - Science and Technology Committee Contents

3 Antibiotics for the future

61. Antibiotic resistance is a natural process. When a microbial population is exposed to a toxic substance, there is an evolutionary pressure to develop a means of reducing the impact of that substance on that population. Often, the microbial population acquires the ability to destroy the substance or to ignore its effects. As a consequence, the only way to ensure long term access to functioning antibiotics is to continually find new antimicrobial agents.

62. Historically, new antimicrobial compounds have most often been developed by large pharmaceutical companies. However, Jeremy Farrar, Director of the Wellcome Trust told us that that while "20 or 25 years ago, there might have been 18 or 20 major pharma players in that space. There are now four".[184] The Wellcome Trust[185] highlighted that "since 2000, 22 new antibiotics have been launched, only 5 of which are new classes and very few of which are effective against gram-negative bacteria".[186]

63. We considered the challenges associated with the development and commercialisation of antibiotic drugs and technologies, the state of UK research activity in this area and potential alternatives to traditional anti-microbial chemistry.

The failing antibiotic pipeline

64. Kush Naker, Universities Allied for Essential Medicines UK, told us that "probably the key to driving antibiotic research in the UK is making sure that it is commercially viable for big pharma to get involved".[187] The Association of the British Pharmaceutical Industry (ABPI), wrote that companies were "reluctant to invest in antibiotic R&D" because the returns were "significantly lower" than for other areas,[188] leading to many pharmaceutical companies exiting the market. On average it requires an investment of "£1 billion" and "10 to 12 years" to develop a new medicine.[189] Several factors make this commercially unattractive:

· Limited use: New antibiotics were often reserved as drugs of "last resort"[190] and used "sparingly" for "short" courses of treatment.[191] In contrast, treatments for mental illnesses or cancer may last for several weeks, months or even years, providing greater opportunity for those treatments to deliver a return on investment.

· Low price: Professor Sir Anthony Coates, Antibiotic Discovery-UK, told us that "antibiotics are very cheap. The most expensive anti-cancer drugs are tens of thousands of dollars, even $100,000, per course, whereas antibiotics are much cheaper at less than £100".[192]

· Short lifespan: Antibiotics can have a short working lifespan, as resistance may develop to compounds in a relatively short period of time, sometimes at the clinical trial stage. This was a challenge which was "unique" to antibiotic development.[193]

· Clinical trials: The ABPI reported that it was particularly difficult to conduct clinical trials of antimicrobials because it was often not clear which disease was affecting a patient and diagnosis time could be lengthy.[194]

65. The Government's 2013-2018 Strategy, acknowledged the "need to do more to address the commercial viability and market failure issues that are hampering investment in antibiotic development". The Strategy clearly expects that the pharmaceutical industry will contribute in the effort to tackle antimicrobial resistance [see Appendix 1] but does not identify any means to promote that contribution, other than "corporate or social responsibility".

66. As the development of new antibiotics and new technologies is dependent on private enterprise working closely with academia, we were disappointed to find that the membership of the Government's High Level Steering Group for the Strategy did not incorporate voices from industry or learned societies. We recommend that the membership of the High Level Steering Group be expanded to include those voices.

Potential market incentives

67. Witnesses offered a range of suggestions for addressing the market failure. These included addressing pricing mechanisms, clinical trial regulation, patent extension and alternative financing mechanisms.

PRICING MECHANISMS

68. The Association of the British Pharmaceutical Industry (ABPI) stressed that "alternative approaches to antibiotic pricing"[195] needed to be considered if new antibiotics were to be successfully developed. It particularly highlighted the need for sales volume to be "decoupled" from price "in a way that appropriately shares risk between the purchaser and industry".[196] GlaxoSmithKline (GSK) was also in favour of a reimbursement mechanism that did not "rely on volume of sales to reward innovation".[197]

69. At present, the price that the NHS pays for most branded pharmaceuticals is determined by the Pharmaceutical Price Regulation Scheme (PPRS)—a voluntary pricing agreement negotiated by the Department of Health once every 5 years. The 2014 PPRS[198] has recently been approved and differs from previous schemes by placing a cap[199] on the total annual NHS drugs bill, requiring companies to rebate any amount above this cap. When asked about the PPRS scheme, James Anderson, European Partnerships Director of GSK, pointed out that this would do little to incentivise antibiotic development:

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He added that while "some companies" were simply asking "for higher pricing for antibiotics", the inherent unpredictability of resistance meant that this was not the answer and that "simply having a potentially higher price for [antibiotics] does not help to predict the revenue that encourages you to make that investment"[201]

70. The ABPI highlighted a range of models that might provide suitable approaches to decouple sales volume from unit price, including "insurance premium type arrangements, the upfront purchase of novel antibiotics by national governments upon successful regulatory approval, or license fee models agreed at a national level".[202] AstraZeneca, supported the license fee model and outlined the following benefits:

removal of local budget pressures, ensuring that prescribing decisions could be made purely on the appropriate clinical use of a new antibiotic

a manageable and predictable impact on healthcare expenditure

incentivises research into antibiotics to treat rarer resistant pathogens, which could become the major causes of bacterial diseases in the future.

enables a more appropriate way to assess the value a new antibiotic brings to the healthcare system

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CLINICAL TRIAL REGULATION

71. Clinical trials are experiments conducted on humans with the aim of testing the effectiveness of new drugs, or other health interventions, before they are actively used to treat disease or infection. Witnesses highlighted the particular difficulties in conducting antimicrobial clinical trials:

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72. Public Health England[206] indicated that Phase III clinical trials[207] were effectively only available through large pharmaceutical companies due to the costs involved. GlaxoSmithKline suggested antibiotic trials be made easier to conduct and Public Health England indicated that costs should be reduced but the Universities Allied for Essential Medicines indicated that any review of regulatory systems should bear in mind safety concerns.[208] Some limited attempt has already been made by the Government: the 'Early Access to Medicines Scheme', a project which was considered by the MHRA until 2009[209] and launched by the Department of Health in March 2014, grants patient access to medicines which are still in the second phase of clinical trials.[210]

PATENT EXTENSION

73. Witnesses raised concerns about the impact of patent time limits on the development of new antibiotics. AstraZeneca said that "antibiotics typically reach peak sales after 13 years, compared to just six for other drugs, by which time, they are no longer covered by the initial patent and so the company can struggle to recoup their investment".[211] Professor Peacock, University of Cambridge, told us that "some of the off-patent antibiotics are very cheap. If we do not charge as much for a new antibiotic as a cancer drug", antibiotics are "not such an attractive thing to produce".[212] John Hardcastle, Chief Executive Officer of Novolytics, recommended that the Government "think about changing when the patent time starts ticking. Rather than it being when you apply for a patent, you need to tie it to when you can sell the medicine".[213] The British Society of Antimicrobial Chemotherapy (BSAC) agreed that patent extensions could be used to "increase return on investment", and "to balance the risk benefit ratio companies' face when developing antibiotics".[214] Professor David Livermore, University of East Anglia, said that the GAIN Act in the US, which included policy to extend the patent life of new antibiotics was "stimulating considerable interest".[215] However, Dr Leong, ABPI explained that "the demand is for [antibiotics] to be available, not necessarily to be used. Therefore, extending the patent term might help only to a certain extent, because there would not be the high volume to recover that"[216] and so "patent extension alone will not help".[217]

PUBLIC-PRIVATE PARTNERSHIPS

74. The Royal Society of Chemistry advocated a "joint approach" to funding antimicrobial research. It suggested a model of Public-Private partnerships (PPP) to provide an effective financial risk-sharing mechanism to encourage involvement in R&D and cited the Structural Genomics Consortium as an example of an R&D PPP in the UK "supported by several private investors and public funders including, amongst others, GlaxoSmithKline (GSK), Janssen, Takeda, Pfizer, the Wellcome Trust and the Canadian Institutes for Health Research".[218] John Fitzgerald, Secretary General, Responsible Use of Medicines in Agriculture Alliance, thought that the PPP model "was a good area to explore"[219] and GlaxoSmithKline thought that the UK Government should do more to "support Public-Private Partnerships for antibiotic R&D".[220] AstraZeneca, while acknowledging that the PPP model had a "high profile" in the USA and Europe and "could play an important role", considered that PPPs could only "be one part of the solution".[221]

Research collaboration

75. The importance of research collaboration was heavily emphasised throughout the inquiry. Durham University stated that "clinicians, veterinarians and other healthcare professionals [needed] to work in closer collaboration with industry".[222] The Medical Schools Council and Association of UK University Hospitals said that "stimulating academic: industry consortia or collaborations could be particularly beneficial".[223] We were informed about a wide range of work undertaken by the Technology Strategy Board (TSB) to encourage research in antimicrobial technologies[224] and were told by the BioIndustry Association that the TSB had already proved itself to be "a valuable UK asset in supporting medical research".[225]

76. The Government's 2013-2018 Strategy identified enhanced collaborative efforts, as a key area for future action, including "better identification and prioritisation of antimicrobial resistance research" and "better access to and use of surveillance data" as well as "developing new drugs, treatments and diagnostics through better collaboration between research councils, academia, industry and others".[226] Professor Dame Sally Davies, Chief Medical Officer, told us that "the expertise may lie in different universities" and emphasised the need to set up "networks" and further "collaborations".[227]

77. It is unclear, however, how the departments will co-ordinate their activities. The body, identified within the Strategy, to be responsible for ensuring "key stakeholder involvement and communications at all stages of the programme including wide clinical/scientific/user involvement in supporting the work programme"[228] is the High Level Steering Group. However, this group will meet only twice a year "to oversee delivery against strategic aims".[229] Professor Sharon Peacock, University of Cambridge questioned who, below the level of the High Level Steering Group was actually going "to take action and corral the efforts".[230] The Governance structure suggested by the Strategy indicated that Public Health England, Defra and the Department of Health would all have their own programmes and groups tasked with bringing together relevant partners.

Alternatives to antibiotics

78. The consequences of losing the ability to treat infections could be so serious that witnesses urged the Government to properly consider all potential avenues in addressing the issue of resistance and alternatives but that consideration should be led by good evidence of efficacy in any proposed treatment. One way to reduce the use of traditional antibiotics would be to increase use of evidence-based alternative treatments of infection, including vaccines, bacteriophages and herbal therapies. Professor George Lewith, University of Southampton, indicated that when considering alternatives to antibiotics "you need all of [them] in a co-ordinated way. You need phages when you have really bad infections in hospital. You need vaccinations for prevention. You need simple primary care approaches that stop over-prescription".[231] The potential for alternatives to obviate the need for antibiotic use was demonstrated several times during the inquiry. The Chief Medical Officer, Professor Dame Sally Davies told us how using vaccines in fish farming reduced antibiotic use "to 2% of what it used to be".[232] Dr McIntosh, global scientific affairs senior expert for Novartis Vaccines, revealed that the use of vaccines not only reduced the incidence of the infection they prevent but, in the case of influenza, also reduced the use of antibiotics for the secondary superinfections that often arise.[233] Dr McIntosh also pointed out that increasing capabilities to use genetic information would allow more specific targeting of vaccines against the gram-negative organisms, like E coli, that traditional antibiotics had failed to address.[234]John Hardcastle, Chief Executive Officer of Novolytics, told us that "phages work [and] there is evidence that they work".[235] The advantage of phages was that in "the antibiotic development arena […] there are lots of possible candidates and very few of them actually get through to being useful drugs. From [the phage therapy] perspective, we have a lot of good putative candidates already".[236]

79. Professor Lewith highlighted the role herbal remedies could play in reducing demand for antibiotics for example in averting antibiotic prescriptions for urinary and lower respiratory tract infections in primary care,[237] but acknowledged that "we need some harder studies to demonstrate that they really do control symptoms, and that they can be prescribed by GPs, or over the counter and made available by pharmacists, so that the GPs can feel they are doing something".[238]

80. There are challenges to the introduction and effective use of these alternatives. James Anderson, GlaxoSmithKline, told us that the use of bacteriophages had not received "the level of investment and investigation that it warrants, partially because of the challenges around securing the intellectual property".[239] Patenting and the difficulty in commercialising was also highlighted with respect to herbal remedies.[240] An important point about alternative approaches was raised by Professor Piddock, British Society for Antimicrobial Chemotherapy who warned, that while each of the alternatives may help in the short term, "bacteria can become resistant to those as well".[241]

81. Catherine McLaughlin, National Farmers Union, said that "if there is quality science coming out, we would certainly be happy to consider making recommendations on how it is interpreted and used."[242] Professor Boriello, Chief Executive of the Veterinary Medicines Directorate said that "everything is considered and everything has to go through the same rigorous process".[243] Jane Ellison, Minister from the Department of Health said that she would be "led by the evidence and by the guidance of my experts" and would "keep an open mind."[244]

Conclusions

82. Antimicrobial resistance has the potential to send medicine back to the early 20th century, severely limiting the use of what are now considered basic and routine surgical procedures. The best current defence against this scenario is a strong global pipeline of new drugs, possibly using a range of solutions as described above. But that is dependent on the infrastructure that provides financial incentive to the industries that deliver these technologies including means of compensating for the uncertainties inherent in research and development.

83. We agree with the Prime Minister that, if there is no change to the economic landscape for developing new antimicrobials, the pipeline of new antimicrobials will run dry. We also agree that the Government needs to work with researchers, investors, small and medium sized enterprises, large pharmaceutical companies and other Governments to urgently identify appropriate economic models that might encourage the development of new antimicrobials. We hope that the review, which will take almost two years to report back with recommendations, will not delay work on any pricing alternatives that could be agreed with the pharmaceutical industry over a shorter timescale.

184 Q170 [Professor Farrar] Back

185 AMR0051, Para 15 [Wellcome Trust] Back

186 Butler M. S., Blaskovich M. A. & Cooper M. A, "Antibiotics in the clinical pipeline in 2013", Journal of Antibiotics, vol 66 (2013), pp.571-591 Back

187 Q170 [Kush Naker] Back

188 AMR0014 [Association of the British Pharmaceutical Industry] Back

189 Q206 [Dr Leong] Back

190 AMR0054, para 8 [Academy of Medical Sciences] Back

191 Q206 [Dr Leong] Back

192 Q170 [Sir Anthony Coates] Back

193 Q218 [James Anderson] Back

194 AMR0014 [Association of the British Pharmaceutical Industry (ABPI)] Back

195 AMR0014, Para 3.1 Back