CHAPTER 6 NEW DRUG DEVELOPMENT
6.1 Another way round
the problem of resistance is by using new drugs. This approach
depends on the willingness of industry to invest in developing
new products in this area; their success in doing so; and the
ability to pay for any new patent medicines which emerge.
How hard is industry
trying?
6.2 Professor Reeves
of the AMM is under the impression that the pharmaceutical industry
are not currently investing much in antimicrobials, because the
chances of commercial return are small (Q 28). Several other
witnesses told the same story (e.g. Chopra p 402).
6.3 The ABPI (p 175;
QQ 314-320) tell a different tale. They acknowledge that
the 1980s saw little investment in new antimicrobials. However
this changed around 1990, partly because of the rise in resistance
(market pull) and partly because of the "explosion of information"
from bacterial genetics[62],
coupled with technological improvements in drug testing (science
push). "Most of the major pharmaceutical companies have invested
heavily in the last five years or so in the antibacterial area",
and antimicrobials are now the third largest therapeutic class
in R&D, accounting for 20 per cent of pre-clinical research
projects and 9 per cent of clinical development projects.
It is more than 20 years since the emergence of the last
major new class of antibiotics; but industry is now using genetics
to look for new drug targets and modes of action, including modes
of action which would either not give rise to resistance[63],
or even possibly reverse it. However, new antiviral and anti-parasitic
drugs are "lagging behind" antibacterials—with
the exception of drugs against HIV. Three British pharmaceutical
majors told us their own stories: see Box 10.
| Box 10
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| UK PHARMACEUTICAL INDUSTRY
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| EXAMPLES OF INVESTMENT IN ANTI-INFECTIVES
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| Glaxo Wellcome (p 405)
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| Since 1996, anti-infectives have been one of Glaxo Wellcome's priority areas for drug discovery, with increased investment, particularly in bacterial genomics, which in their view will "fundamentally swing the pendulum back" in favour of anti-infectives.
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| In 1994 Glaxo Wellcome launched "Action tb", a programme for collaborative research worth £2m p.a. for five years.
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| Glaxo Wellcome are major contributors to the Edward Jenner Institute for Vaccines Research (see Chapter 8).
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| Glaxo Wellcome have agents under development against penicillin- and cephalosporin-resistant pneumococcus and staphylococcus; resistant Gram-positive pathogens and TB; and azole-resistant fungal infections.
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| SmithKline Beecham (SKB) (p 473)
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| SKB hail the genomics "revolution": but they point also to developments in chemistry (combinatorial chemistry, and biotechnology) which have vastly increased the range of chemicals available for pharmaceutical applications; and to developments in screening, enabling the new chemicals to be tested faster for effects on the new targets identified by genomics.
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| SKB themselves claim to have "led the pharmaceutical industry" in investment in genome sequencing; and now have a joint venture with Glaxo Wellcome to sequence bacterial genomes. They have recently given their own antibacterial research special status and dedicated resources, under the tag "Manhattan Micro".
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| Despite all this effort, SKB warn of a "vulnerability window between 2000 and 2007, in which multi-resistant organisms will increase in clinical importance without parallel progress in the introduction of new antibiotic classes".
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| Zeneca Pharmaceuticals (p 544)
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| Zeneca has a "significant investment" in anti-infective discovery programmes, based on genomics, but does not expect results for "many years".
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6.4 The Chief Medical
Officer expressed satisfaction with the industry's efforts (Q 791):
"The fact that there are not lots of new drugs coming out
does not mean to say there is not a lot of work going on in this
area and a great deal of investment". Professor Finch said,
"[The pharmaceutical industry] have done a terrific job up
till now, and maybe the new genomics is going to open up new approaches".
But he warned, "We cannot always rely on [them] to come up
with new agents" (Q 386).
Licensing: fast-tracking
and "orphan drug" designation
6.5 The ABPI called
for accelerated licensing procedures, subject to the necessary
safeguards, for "new antibiotics that are acting by completely
novel mechanisms of action and are active against resistant organisms"
(Q 325; cp SKBp 484). The AMM make the same recommendation
(Q 60); and the Chief Medical Officer is in favour of speeding
up the process (Q 792). Professor Finch told us that the
United Kingdom Medicines Control Agency's procedure is now very
fast, and capable of responding to an application within 3-4 months.
The system can be made to work even faster, and has done so for
certain HIV treatments. There is also scope for compassionate
use in advance of licensing. The EU Medicines Evaluation
Agency takes rather longer (QQ 377-380).
6.6 If the prospective
market for a new drug is not sufficiently large or wealthy to
justify the cost of development, the drug is known as an "orphan".
Professor Finch was unable to envisage many situations where a
drug effective against a resistant infection would require orphan
status rather than the normal licensing regime (Q 381). However
the USA has a programme of incentives for orphan drugs, including
accelerated approval and extended patent protection, and the EU
is
consulting on a similar scheme. The
ABPI support it (Q 327); SmithKline Beecham, in particular,
recommend it as a way to encourage development of agents against
tropical parasitic diseases (p 485); the AMM call for a United
Kingdom scheme (Q 60), and Professors D A Mitchison
(p 432) and A R M Coates (p 470) of St George's
Hospital call for a scheme in respect of TB.
62
See the evidence of the Centre for Applied Microbiology and Research
(CAMR) (p 395), which also usefully surveys the leading edge
of completely novel approaches to antimicrobial resistance. Novel
approaches are also the subject of the evidence of Professors
Brian Henderson and Michael Wilson of the Cellular Microbiology
Group, Eastman Dental Institute, University College London (p 413),
and are noted by the Society for General Microbiology (p 493).
On bacteriophage in particular, see the evidence of Dr J Soothill
(p 510). On alternative approaches involving complementary
medicine, see the evidence of the Research Council for Complementary
Medicine (p 447) and J Hoare (p 420). See also
Appendix 6, paragraphs 49-50. Back
63
This "disease-based" approach is described by Glaxo
Wellcome (p 406). Professor Ian Chopra, Director of
a new Antimicrobial Research Centre at Leeds University, specifically
seeking to promote academic-industry collaboration in discovery
of antibacterial agents, warns (p 402) that there are "no
reports yet even of lead molecules". Back
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