APPENDIX 18
Memorandum by Professor Les Toop and Dr
Dee Richards (PI 49)
CONTENTS
Summary of Recommendations
Background
Drug Innovation
The Conduct of Medical Research
The Provision of Drug Information and Promotion
Professional and Patient Education
Regulatory Review of Drug Safety and Efficacy
Product Evaluation
Conclusion
RECOMMENDATIONS
1. Incentives need to re-aligned to encourage
innovation in areas of public health need (eg newer antibiotics)
rather than in areas of consumer want and company profit (eg anti-ageing
and lifestyle).
2. Any and all clinical RCTs involving a
new product should be registered with a central agency. Failure
to register an RCT prior to it starting would rule its findings
inadmissible as evidence in a subsequent licensing or funding
application.
3. Marketing of products under the guise
of post marketing phase 4 research should be much more closely
scrutinised by ethics committees as an explicit part of their
brief.
4. Trials that are industry-funded and which
have not gone through an independent peer review process should
have independent and rigorous scientific scrutiny to be judged
ethically sound.
5. Direct to consumer advertising of prescription
medicines should continue to be banned and regulation of disease
awareness promotion strengthened and enforced.
6. Funding should be provided for an independent
consumer medicine and health information service free of commercial
interest.
7. Rational use of medicines should be promoted
though provision of high quality, balanced and independent information
coupled with feedback to prescribers on utilisation and be matched
with meaningful incentives to change behaviour.
8. Provision of free samples by pharmaceutical
companies should be banned and instead a mechanism provided for
prescribers to provide a short trial courses of medicines.
9. Funding of licensing bodies should not
be directly linked to the number of user pays applications in
order to minimise perverse incentives.
10. The organisation charged with determining
medicine subsidisation from public funds needs to be separated
from political and industry influence.
11. Conflicting and competing interests
of members of these committees should be made more transparent
and explicit rules to ensure independence.
12. Licensing criteria should be strengthened
with consideration of rigorous criteria of fast track licensing,
explicit consideration of added therapeutic value in licensing
and subsidisation decisions and facilitation of generic introduction.
13. Drug safety should be centrally managed
and preferably at arms length from the licensing body. A more
robust system for pharmaco-vigilance needs to be developed which
includes facilitation of a process for patient self-report.
BACKGROUND
1. The influence of the pharmaceutical industry
on health systems occurs at multiple levels. Over recent years
this influence has become increasingly pervasive and has seen
a trend to the "pharmaceuticalisation" of health in
the developed world. These influences act in the following broad
areas:
Licensing
2. Current user pays arrangements in many
developed countries mean that the pharmaceutical industry is effectively
the main funder and therefore the "client" of licensing
agencies. Requirements for licensing do not encourage balanced
disclosure of research allowing proper assessment of safety and
efficacy.
Direct to doctor promotion
3. This is very effective at influencing
prescriber behaviour and increasing sales. This promotional activity
includes visits, gifts and other inducements, subsidisation of
conference attendance, free samples etc.
Education
4. Pharmaceutical companies provide significant
funds for sponsorship and have undue influence on the content
of continuing education for prescribers. This takes the form of
meeting sponsorship, the provision of "free lunches"
through to initiation of education meetings with "expert
speakers" discussing the benefits of company products.
Direct to patient promotion
5. This also takes many forms and in addition
to brand advertising includes disease awareness advertising, thinly
disguised brand advertising, funding of disease specific consumer
groups, patient education and sophisticated campaigns run by public
relations companies. It also includes high profile media coverage
of "important breakthrough treatments" or "diseases"
with "patients" and interviews with company sponsored
"experts".
Research
6. Pharmaceutical companies are a major
funding source for research. This creates conflicts of interest
for investigators, skewing of research towards pharmaceutical
treatments and publication bias resulting in a relative decrease
in research into non-pharmaceutical and preventative treatments.
DRUG INNOVATION
7. True innovations in pharmaceutical development
do occur. However, they are the exception rather than the rule.
8. It is not well understood that the way
in which medicines are developed means there is no reason to suppose
that a New Chemical Entity (NCE) will be automatically better
than older medicines in the treatments of common chronic conditions.
There is good evidence from systematic reviews of the last 20
years of innovation carried out by separate groups in France and
Canada that less than 10% of all new products coming to market
represent significant advance on currently available therapy.1,2
The pharmaceutical industry has demonstrated a tendency to ignore
and hide evidence of non-superiority choosing instead to invest
heavily in promoting newer patented "me toos" and lifestyle
drugs. This has resulted in prescription choices being driven
by commercial rather than by rational prescribing principles.
An excellent individual and recent example is the ALLHAT study,3
which examined older and newer treatments for hypertension. It
found that the older (and very, very much cheaper) medicines were
more effective than newer heavily promoted products at preventing
the serious long-term complications of raised blood pressure.
This is not just of fiscal concern. Of necessity, long term safety
data, (particularly of rare and serious or fatal adverse reactions)
cannot be known in the early life of medicines. Over recent decades
as many as 13% of new medicines have subsequently been withdrawn
or had serious safety caveats imposed on their use.4 Prudent and
rational prescribing would dictate that newer agents are used
cautiously and conservatively only when it is likely that there
will be truly significant added clinical benefit for the patient.
Such listings should be monitored by publicly funded and independent
pharmaco-vigilance. This rarely happens. Instead newer medicines
are often heavily promoted and prescribed with unwarranted enthusiasm
and little proactive monitoring.
9. The majority of true innovation occurs
in state funded and usually small private research institutions.
In the opinion of many, pharmaceutical companies have become little
more than sophisticated marketing organisations. Despite claims
to the contrary, in our opinion it appears that in many instances
the high prices of branded patented medicines (largely paid for
by the taxpayer) are more likely to sustain expensive marketing
and PR campaigns and shareholder profit, than be used for reinvestment
into research and development of medicines addressing areas of
public health need. Limiting marketing excesses and reducing prices
with purchasing strategies such as reference pricing would free
up resource for more publicly funded innovative research targeted
to areas of health need, and provide incentive for pharmaceutical
companies to channel their efforts and profits into development
of truly innovative drugs. The public money saved would also pay
for robust independent consumer health information to counter
the covert (and not so covert) direct to consumer promotion which
is gaining momentum in the guise of disease awareness advertising
and funding of patient groups.
RECOMMENDATION
10. Incentives need to re-aligned to encourage
innovation in areas of public health need (eg newer antibiotics)
rather than in areas of consumer want and company profit (eg anti-ageing
and lifestyle). This will never be achieved using conventional
"market forces."
CONDUCT OF
MEDICAL RESEARCH
11. The majority of clinical trials (and
therefore the agenda and often the research design) are now funded
by the pharmaceutical industry. They are naturally very adept
at designing studies to show their products in a good light. Space
precludes fuller detail—many editorials in august journals
have highlighted some of the greater excesses. Most forms of scientific
half-truth and fraud have been uncovered and published in recent
years, and a variety of dubious research practices are cause for
ongoing concern. Companies do not use placebo controls or appropriate
comparator drugs for their trials—comparator drugs tend
to be those least likely to be efficacious and most likely to
provoke adverse effects, rather than being the current most effective
treatment. Doses chosen for the comparator drug are frequently
not equivalent to those of the new drug. These practices result
in overestimation of efficacy and safety of the newer drug. Other
common practices include non-publication of trial data showing
negative effects. Partial publication of data with suppression
of negative data, and selection of large numbers of outcomes of
dubious clinical significance which, with a currently accepted
"statistical significance" level of p=0.05, results
in at least one in 20 showing improved outcomes by chance alone.
12. One of the most flagrant lawful abuses of
the scientific method relates to the selective minimum evidence
accepted as evidence of efficacy by licensing authorities. Consider
a company with a new product (perhaps an antidepressant) which
it wishes to license. It commissions several trials, only two
of which show any statistically significant efficacy against placebo,
indeed one or two actually show the drug may have no effect or
even negative effects. Only the two positive trials are put forward
for publication and for subsequent proof of efficacy. In this
way a product which may have almost no efficacy gains a license.
With heavy promotion it may even become a blockbuster!
RECOMMENDATIONS
13. Any and all clinical RCTs involving
a new product should be registered with a central agency (as indeed
they already are locally to obtain ethical consent). Failure to
register an RCT prior to it starting would rule its findings inadmissible
as evidence in a subsequent licensing or funding application.
One of the easiest ways this could be achieved
would be through ethical committees. Data from all registered
trials, even those that were either not completed or remain unpublished,
would have to be submitted (in a predetermined format) at the
time of any licensing application, together with a statement signed
by each of the investigators explaining why any studies were abandoned
or remain unpublished. This process should not slow down the normal
processing of applications, which already take several months
to complete. The stakes are high—blocking the licensing
of a single ineffective drug could save taxpayers hundreds of
millions of pounds/dollars. A model for such a global clinical
trial's register is already available in the Cochrane Collaboration
trials register.
14. Marketing of products under the guise of
post marketing phase 4 research should be much more closely scrutinised
by ethics committees as an explicit part of their brief.
"Studies" which are no more than marketing
exercises for newer "me-too" drugs should not receive
ethics approval. Information sheets in pharmaceutical trials should
include details of the amount of money the investigators will
receive per patient enrolled and/or donations to their research
trust funds and "unrestricted education grants".
15. Those trials that are industry funded
and which have not gone through an independent peer review process
(which public grant funded research bodies use) should have independent
and rigorous scientific scrutiny to be judged ethically sound.
Many of these poor quality studies offer little
hope of producing useful new knowledge and are in fact no more
than cheap promotional exercises for companies and money gathering
exercises for the multitude of investigators. Adequately funded
and independent pharmaco-vigilance would provide better data at
less cost.
THE PROVISION
OF DRUG
INFORMATION AND
PROMOTION, PROFESSIONAL
AND PATIENT
EDUCATION
Drug information for consumers
16. There is intense pressure to allow direct
to consumer communication or advertising by pharmaceutical companies
under the guise of "information". The concept of "public—private
partnerships which superficially appear attractive, carry very
real risks and provide further opportunities for industry capture.
Undoubtedly industry will claim that direct to consumer disease
awareness promotion is both educational and useful. However, there
is no demonstrable benefit for population health and there are
potential harms. There is no doubt that disease awareness promotion
results in increased use of particular products in the same way
as branded DTCA. For the reasons outlined above (see innovations
section) the heavy promotion of products still under patent is
least likely to result in cost effective health gains. Allowing
advertising by permissive legislation, lack of enforcement or
(as in the case of the US and NZ) by default, constitutes a public
health intervention. As with any public health intervention, there
should be evidence that benefits outweigh harms before
implementation. We have argued that advertising of prescription
medicines directly to the public is of net harm to the public
health. The evidence for this is clearly detailed in our report.
17. Non-enforcement of legislation by governments,
as a soft way of managing the pressure from industry, is widespread—this
occurs in the USA Canada and Australia. A government's failure
to enforce a ban of advertising by allowing loopholes to permit
advertising when a conscious decision has been made that DTCA
is of net harm is arguably inconsistent with democratic principles.
It is unclear whether this is deliberate policy to encourage industry
or whether it represents an inability or unwillingness to take
on the pharmaceutical industry in costly and time consuming legal
battles.
18. Our report (and update) on direct to
consumer advertising of prescription medicines in New Zealand
has already been made available to the inquiry. The main points
to note regarding regulation are that the New Zealand experience
shows that complaint driven self regulation of either brand or
disease awareness DTCA does not work. If the public is not to
be misled, technical (ie scientific) pre-vetting for accuracy
and fair balance is essential together with proactive monitoring.
Central regulation is not working in the US as it is reported
that the FDA have been instructed adopt a liberal attitude to
enforcement by the current administration who have been extensively
and effectively lobbied by industry.
Changes in Medicine Status to "Over the Counter"
(OTC)
19. The licensing for provision of some
prescription drugs for sale "Over the Counter" has implications
for advertising in the UK. If a medicine is available OTC it can
then be advertised. It will not take long for consumers to realise
that it can be obtained more cheaply on prescription and for the
pressure on general practitioners to prescribe to begin. This
process may already have begun in the UK following the move of
statins to OTC status. There is evidence from the US and New Zealand
that GPs prescribe drugs they would not otherwise choose as a
result of patient demand driven by advertising. This is not surprising
given the "patient centred" model promoted as best practice
for doctor patient decision making. Commercial drivers should
not be allowed to intrude on this important therapeutic alliance.
RECOMMENDATIONS
20. That direct to consumer advertising
of prescription medicines should continue to be banned and regulations
around disease awareness should be strengthened and enforced.
21. Funding should be provided for independent
medicine and health information service free of commercial interest.
Drug information for prescribers
22. The rules on promotion and sampling
to physicians are regularly broken and it is time once again to
revisit the relationship between the medical profession and the
pharmaceutical industry. This promotion takes many forms; visits,
inducements, gifts, funding for conference attendance, travel
and provision of free samples. The influence of industry on research
and medical education at all levels is very significant and ultimately
driven by the need to increase sales of individual products. Despite
what individual doctors feel about the influence of industry on
their practice, there is no doubt that as a group, prescriber's
clinical practice is influenced by this promotional activity.
To some extent this situation has arisen as the industry had picked
up the shortfall from reduced central funding for both research
and education (particularly continuing medical education). The
irony is that allowing or indeed encouraging this influence in
the end costs the taxpayer more than appropriately funding these
activities centrally.
RECOMMENDATIONS
23. The keys to rational use of medicines
are threefold. The provision of high quality, balanced and independent
information coupled with feedback to prescribers on utilisation
must be matched with meaningful incentives to change behaviour.
There is research showing these are effective ways of promoting
rational prescribing. The most appropriate incentive in our view
is to involve prescribers in budget management with the autonomy
and ability to use savings to improve patient care locally.
24. Provision of free samples by pharmaceutical
companies should be banned and instead a mechanism provided for
prescribers to provide a short trial course for patients of any
licensed medication for a chronic condition.
REGULATORY REVIEW
OF DRUG
SAFETY AND
EFFICACY
25. Many countries have adopted a user (manufacturer)
pays approach to licensing. This leads to a system with processes
and importantly attitudes that accommodate industry as the principal
client, rather than acting principally as servants of the public.
Funding of licensing bodies should not be directly linked to the
number of user pays applications in order to minimise perverse
incentives.
26. Conflicting and competing interests
of members of licensing committees should be made more transparent
and explicit rules to ensure independence.
27. New drugs carry added risks and criteria
for fast track licensing need to be rigorous and only implemented
in unusual circumstances—for example a vaccine in an outbreak
situation or where there is urgent and clear health benefit likely
to accrue to a large number of users.
28. Licensing of new drugs should include
consideration of the ability of a manufacturer to provide evidence
of clinically significant added therapeutic value over existing
therapies. This would minimise the money wasted on large numbers
of heavily promoted "me too" products offering little
if any health gain at increased cost.
29. Licensing of generic drugs should be
facilitated. Loopholes, which allow extension of patents ("evergreening"),
are a significant barrier to generic introduction.
30. The same comments apply to decisions
around the state subsidisation of new drugs. The organisation
charged with determining medicine subsidisation from public funds
needs to be separated from political and industry influence. In
this way politicians are provided with some insulation from industry
when decisions are not commercially favourable.
31. Recent examples demonstrate that the
pharmaceutical industry cannot be relied on to responsibly report
safety concerns in a timely manner. Drug safety should be centrally
managed and preferably at arms length from the licensing body.
A more robust system for pharmaco-vigilance needs to be developed.
This should include the facilitation of patient self-report, which
is likely to be the most effective early warning system of problems.
RECOMMENDATIONS
32. Funding of licensing bodies should not
be directly linked to the number of user pays applications in
order to minimise perverse incentives.
33. The organisation charged with determining
medicine subsidisation from public funds needs to be separated
from political and industry influence.
34. Conflicting and competing interests
of members of these committees should be made more transparent
and explicit rules to ensure independence.
35. Licensing criteria should be strengthened
with consideration of rigorous criteria of fast track licensing,
explicit consideration of added therapeutic value in licensing
and subsidisation decisions and facilitation of generic introduction.
36. Drug safety should be centrally managed
and preferably at arms length from the licensing body. A more
robust system for pharmaco-vigilance needs to be developed which
includes facilitation of a process for patient self-report.
PRODUCT EVALUATION,
INCLUDING ASSESSMENTS
OF VALUE
FOR MONEY
37. We suggest the committee look closely
at the functioning and effectiveness of the PBS in Australia and
PHARMAC in New Zealand. Value for money remains largely subjective.
Pharmacoeconomics is a young and still very imprecise science.
Different economists can and do make very different assumptions
and predictions on the same data sets. Many of the variables,
particularly opportunity costs, cannot be easily quantified. In
our view there is no obvious reason why the costs of medicines
should increase any more than general inflation. Compare the price
of innovation in the computer industry where with time we expect
more power, more memory and more data storage at a cheaper price.
The prices demanded (and paid) for many new medicines cannot be
justified on the basis of value added over existing products,
nor on the argument of research and development costs. In many
cases they do not represent good value for money. Prioritisation
frameworks for organisations which evaluate products (eg NICE)
should include public health needs in their prioritisation for
reviews to guard against a tendency to use these evaluations solely
as a counter to industry skewing the focus towards new chemical
entities.
RECOMMENDATIONS
38. We suggest the committee look closely
at the functioning and effectiveness of the PBS in Australia and
PHARMAC in New Zealand.
39. Prioritisation frameworks for organisations
that evaluate products (eg NICE) should include public health
needs.
CONCLUSION
40. There is intense pressure on politicians
and policy makers in all countries from powerful pharmaceutical
lobbyists. The common themes of this lobbying include:
— decreasing times to licensing;
— more liberal rules on advertising
directly to consumers;
— increase in patent protection times;
— increased barriers to introduction
of cheaper generic drugs through intellectual property and patent
protection; and
— limit access to data used to license
drugs on the grounds of "commercial sensitivity".
41. Drug company arguments for special commercial
consideration in these areas include the importance of their industry
and the high costs of research and development. There is no other
industry that receives commercial protection at such a high level.
Third party insurers (often the state) largely underwrite their
profits. In general the industry have not shown the extra responsibility
that would be expected to be associated with such a privileged
position. Indeed some would say they have abused this privilege.
Arguments, which promote high research and development costs as
a threat to viability of the industry, are not sustained by evidence.
The pharmaceutical industry globally is currently among the most
profitable. This does not suggest they are struggling with R&D
costs or that additional concessions should be considered.
42. Medicines generally are of enormous
value to the health of populations when used appropriately. The
pharmaceutical industry will understandably push the boundaries
as far as regulatory frameworks allow in order to maximise profits
for their shareholders. Many have observed that the pendulum has
swung too far in favour of the pharmaceutical industry. Governments
and regulatory authorities have a responsibility to enhance and
protect the health of the public, ensuring safe and effective
medicines are available whilst using taxpayers money wisely. To
achieve these aims incentives must be aligned to ensure that the
pharmaceutical industry serves the population and not the other
way around.
REFERENCES
1. Patented Medicine Prices Review Board.
Annual Report 2000. Compliance and excessive price guidelines.
Ottawa: PMPRB;2000. p 26-31.
2. A look back at 2000. Overabundance and
deregulation. Prescrire International 2001;10(52):52-54.
3. Major outcomes in high-risk hypertensive
patients randomised to angiotensin-converting enzyme inhibitor
or calcium channel blocker vs diuretic: The Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
JAMA 2002; 288:2981-2997.
4. Lasser KE, Allen PD, Woolhandler SJ,
Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings
and withdrawals for prescription medications. JAMA 2002;287(17):2215-2220.
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