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".
The Wellcome Trust
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".
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".
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,
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.
factors make this commercially unattractive:
use: New antibiotics
were often reserved as drugs of "last resort"
and used "sparingly" for "short" courses of
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.
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".
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
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.
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
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
68. The Association of the British Pharmaceutical
Industry (ABPI) stressed that "alternative approaches to
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".
GlaxoSmithKline (GSK) was also in favour of a reimbursement mechanism
that did not "rely on volume of sales to reward innovation".
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 has
recently been approved and differs from previous schemes by placing
a cap 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:
our hope for the new PPRS scheme is that it will
enable a much more rapid uptake by the NHS of new products. In
every case, apart from antibiotics, that would make a big difference
to patients coming through. However, in antibiotics you almost
want the opposite. You do not want a rapid uptake of new products;
you want them to be used only by those patients who really need
them, for whom none of the other products will work.
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"
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".
AstraZeneca, supported the license fee model and outlined the
of local budget pressures, ensuring that prescribing decisions
could be made purely on the appropriate clinical use of a new
and predictable impact on healthcare expenditure
research into antibiotics to treat rarer resistant pathogens,
which could become the major causes of bacterial diseases in the
a more appropriate way to assess the value a new antibiotic brings
to the healthcare system
impact on company eNPVs
as revenues would be brought forward in the lifetime of a new
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:
When you do a clinical trial for an antibacterial
drug it is not the same as, say, a breast cancer drug. You know
that every patient in a breast cancer trial has breast cancer.
You also have several weeks in which to diagnose them accurately
and do personalised medicine, making sure the treatment is right
for them. We just do not have that with bacterial infections.
If a patient with a serious infectionsay, sepsisis
admitted to hospital, you have to treat them straight away[
For clinical trials, they would have to recruit hundreds of patients
to get the few they needed with the infection they are really
developing a drug for. If you are trying to develop a pneumonia
drug, many pathogens can give pneumonia. It is not like breast
cancer. If you are developing an antibiotic, you are developing
a drug to work at multiple body sites, and all the issues associated
with that. It is technically challenging
72. Public Health England
indicated that Phase III clinical trials
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.
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
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.
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".
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".
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".
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".
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".
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"
and so "patent extension alone will not help".
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".
John Fitzgerald, Secretary General, Responsible Use of Medicines
in Agriculture Alliance, thought that the PPP model "was
a good area to explore"
and GlaxoSmithKline thought that the UK Government should do more
to "support Public-Private Partnerships for antibiotic R&D".
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". 
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".
The Medical Schools Council and Association of UK University Hospitals
said that "stimulating academic: industry consortia or collaborations
could be particularly beneficial".
We were informed about a wide range of work undertaken by the
Technology Strategy Board (TSB) to encourage research in antimicrobial
were told by the BioIndustry Association that the TSB had already
proved itself to be "a valuable UK asset in supporting medical
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".
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
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"
is the High Level Steering Group. However, this group
will meet only twice a year "to oversee delivery against
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".
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".
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". 
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.
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.John
Hardcastle, Chief Executive Officer of Novolytics, told us that
"phages work [and] there is evidence that they work".
The advantage of phages was that in "the antibiotic development
] 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
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,
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".
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".
Patenting and the difficulty in commercialising was also highlighted
with respect to herbal remedies.
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".
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."
Professor Boriello, Chief Executive of the Veterinary Medicines
Directorate said that "everything is considered and everything
has to go through the same rigorous process".
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."
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
AMR0051, Para 15 [Wellcome Trust] Back
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
Q170 [Kush Naker] Back
AMR0014 [Association of the British Pharmaceutical Industry] Back
Q206 [Dr Leong] Back
AMR0054, para 8 [Academy of Medical Sciences] Back
Q206 [Dr Leong] Back
Q170 [Sir Anthony Coates] Back
Q218 [James Anderson] Back
AMR0014 [Association of the British Pharmaceutical Industry (ABPI)] Back
AMR0014, Para 3.1 Back
AMR0014, Para 3.12 [Association of the British Pharmaceutical
Industry (ABPI)] Back
AMR0029 [GlaxoSmithKline (GSK)] Back
Department of Health, Pharmaceutical Price Regulation Scheme
(PPRS): heads of agreement, November 2013 Back
"UK caps state drugs bill under new deal with industry",
Reuters UK Edition, 6 November 2013, accessed June 2014
AMR0014, Para 3.12 [Association of the British Pharmaceutical
Industry (ABPI)] Back
eNPV (expected Net Present Value) is a value a company calculates
to determine the likely profitability of a product or investment. Back
AMR0018, Para 38 [AstraZeneca] Back
Q36 [Professor Piddock] Back
AMR0027 [Public Health England] Back
Phase III studies are usually randomised, controlled, multicenter
trials on large patient groups (300-3,000 or more depending upon
the disease/medical condition studied) and are aimed at being
the definitive assessment of how effective the drug is, in comparison
with current 'gold standard' treatment. Because of their size
and comparatively long duration, Phase III trials are the most
expensive, time-consuming and difficult trials to design and run. Back
AMR0021 [Universities Allied for Essential Medicines] Back
Medicines and Healthcare products Regulatory Agency, Early
access to medicines scheme, accessed June 2014 http://www.mhra.gov.uk/Howweregulate/Medicines/MISGNewTechnologiesAdvisoryPanel/Earlieraccesstonewmedicinesintheuk/CON065736 Back
"Cutting-edge drugs to be fast-tracked to patients",
Department of Health press release, 14 March 2014 Back
AMR0018, Para 14 [AstraZeneca] Back
Q36 [Professor Peacock] Back
Q100 [John Hardcastle] Back
AMR0016 [British Society for Antimicrobial Chemotherapy] Back
AMR0049 [David Livermore] Back
Q212 [Dr Leong] Back
AMR0050, Para 11 [Royal Society of Chemistry] Back
Q151 [John FitzGerald] Back
AMR0029, Para 5.2[GlaxoSmithKline (GSK)] Back
AMR0018, Para 17 [AstraZeneca] Back
AMR0025, Para 4.1.7[Durham University] Back
AMR0006, Para 1.3 [Medical Schools Council & Association of
UK University Hospitals] Back
AMR0064 [Technology Strategy Board] Back
AMR0026, Para 25 [BioIndustry Association (BIA)] Back
Department of Health, Department of Rural Affairs, UK Five
Year Antimicrobial Resistance Strategy 2013 to 2018, September
2013, para 3.10 Back
AMR0069, Appendix A [Department of Health supplementary] Back
AMR0069, UK Five Year AMR Strategy implementation programme, governance
structure chart Back
Q4[Professor Peacock] Back
Q83 [Professor Lewith] Back
Q327 [Professor Dame Sally Davies] Back
Q91 [John Hardcastle] Back
236 Ibid. Back
Q81 [Professor Lewith] Back
Q91 [Professor Lewith] Back
Q230 [James Anderson] Back
Q93 [Professor Lewith] Back
Q15 [Professor Piddock] Back
Q161 [Catherine McLaughlin] Back
Q351 [Professor Borriello] Back