Download The Medicare amendment adopted late last year contains a

Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper
Comparative Effectiveness of Medicines and Use
of Head-to-Head Comparative Trials
By Warren Kaplan, Ph.D., JD, MPH
7 October 2004
8.4-1
Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
Table of Contents
Executive Summary................................................................................................................................... 3
1. Introduction ....................................................................................................................................... 4
1.1 Comparative Effectiveness .................................................................................................... 4
1.2 Cost-Effectiveness ................................................................................................................... 5
2. Experiences with Comparative Effectiveness and Cost-Effectiveness ................................... 6
2.1 EMEA........................................................................................................................................ 6
2.2 National Institute for Clinical Excellence ............................................................................ 6
2.3 Australia ................................................................................................................................... 6
2.4 United States ............................................................................................................................ 7
2.4.1 Medicare Program ................................................................................................................ 7
2.4.2 `Prescription Drug Comparative Effectiveness Act of 2003’ .......................................... 8
2.4.3 Medicare Prescription Drug, Improvement, and Modernization Act (MMA) ............ 8
3. Comparative Effectiveness and the Need for Head-to-Head Clinical Trials ........................ 8
3.1 The Value of Comparative Clinical Trials ........................................................................... 9
3.2 Criticism of Comparative Clinical Trials ............................................................................. 9
4. Sponsoring Comparative Trials ................................................................................................... 12
4.1 Industry Sponsored Trials ................................................................................................... 12
4.2 Government-Sponsored Trials ............................................................................................ 12
5. Alternatives ...................................................................................................................................... 12
5.1 Partnerships Between Public and Private Sectors to Conduct Post Marketing Studies
................................................................................................................................................. 12
5.2 Electronic Prescribing and Comparative Effectiveness: The Future? ............................ 13
6. Conclusions...................................................................................................................................... 14
References ................................................................................................................................................. 15
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
Executive Summary
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Prescription drugs can be very expensive and their cost may be a barrier to universal
access. Governments of most developed countries have subsidy systems to achieve
equity of access to pharmaceuticals.
For a number of these medications at launch, we know little about their effectiveness
beyond comparison to a placebo. In most circumstances, this is the most scientifically
robust comparison available to demonstrate efficacy. The EMEA and other regulatory
authorities will find that a new product meets the statutory requirement for efficacy if
superior to placebo.
To estimate comparative efficacy between two medicines, large trials are needed since
there are often small differences between treatment outcomes when the interventions are
compared.
Regulatory agencies neither examine products under conditions of routine use nor
determine whether a product is better value for the money than alternatives (cost
effectiveness) although, for making reimbursement decisions cost effectiveness is very
important and many countries do incorporate some sort of economic evidence into their
reimbursement schemes.
The industry does conduct comparative trials after approval if they have not been
conducted during development. Nevertheless, it is certainly fair to say that
the
discovery that a new product, which has yet to establish a market, is no better than an
older and cheaper one could be commercially problematic..
Comparative trials can be expensive and take many years to complete.
There are at least two alternatives to having either the industry or the government pay
for comparative clinical trials. In one approach, private insurers and the government
would set aside some fraction of their annual drug spending to endow a new institute to
provide an independent source of reputable research into comparative effectiveness and
cost. The other approach relies on electronic prescription and medical databases to
conduct Phase IV and/or pharmacoepidemiologic studies to supplement or even take the
place of randomized, controlled, comparative clinical trials.
The EU is presently discussing so-called “e prescribing” and other IT approaches.
We see a great comparative advantage in the EU, as such electronic linkage of prescribers
and medical records is still fragmented in the United States.
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
1.
Introduction
From a public health and equity viewpoint, drugs are not normal items of commerce but are
“public goods” that should be distributed on the basis of "end user" need or ability to benefit
rather than "end user" ability to pay.1 Because many drugs are very expensive, availability on
the market is therefore not sufficient to ensure access for all the population. Governments of
most developed countries have subsidy systems to achieve equity of access to pharmaceuticals.
Such subsidy systems involve delicate balancing acts. Given the costs to provide and deliver
health care today, as costs rise, the need to look for every opportunity to extract “value” has
become much more important.1
1.1
Comparative Effectiveness
Unfortunately, for most of these medications at the time they are launched, we know little about
their effectiveness beyond comparison to a placebo. This is because, for the most part, the ability
of a medicine to provide “efficacy” is still derived from randomized clinical trials and, under the
current licensing regulations of major industrialized countries, the manufacturer must show
clinical trial evidence from placebo-controlled trials. Thus, a sponsor must show absolute, not
comparative, efficacy in scientific terms to achieve marketing approval. So long as a new
product is more effective than placebo, barring other issues, the FDA and the EMEA will find it
meets the statutory requirements.i
Comparator studies may be set up to statistically demonstrate “superiority” to the comparator
or as a a “non-inferiority” trial which occurs when a new drug is tested against a standard
treatment with similar efficacy and the trial must be designed to show that the new treatment is
equivalent to, or not worse than, the standard therapy.2 If one cannot reasonably determine
what the absolute effect of a standard treatment is in a study (sometimes referred to as the
equivalence or non-inferiority margin), it is not possible to interpret a non-inferiority study.
Defining the effect of the standard treatment control is more difficult where the effect of the
standard therapy is relatively small (e.g., increased survival by 2-3 months). A risk in any given
study population is that the standard therapy control actually had no absolute effect and that a
new treatment that was indistinguishable from control might have no effect either.
To estimate comparative efficacy or to show equivalence studies that are much larger than the
usual placebo controlled studies are needed. 3 Comparative benefit can be determined without
placebos, indeed placebo-controlled trials are not possible in some cases, because when an
efficacious treatment already exists it is unethical to assign placebo treatment to patients as it
violates the ethical principle of equipoise, a state of uncertainty regarding which of the
treatments studied is better.2
On the other hand, FDA does consider relative safety, and will refuse to approve a new product that has
a distinctly less favorable risk-benefit ratio than already marketed products.
i
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
Industry has a preference for comparison with placebo as the main determinant of efficacy for
regulatory approval.4 Currently in most major drug regulatory authorities, a requirement for
active treatment comparative studies is still the exception, although requests for active
comparator studies are increasing.
Indirect comparisons involve creating a comparison between drugs A and B when there are two
placebo controlled trials: A v. placebo and B v. placebo.5 Another type of indirect study involves
a review of clinical trials between A v. B and C v. B to enable a comparison between A versus C.
6 Such indirect comparisons are problematic. 5, 6 Biases may arise due to differences in
methodology, outcome measurement, or the populations included in studies of the two drugs.
The best information will come from large, properly constructed randomized trials, using valid
outcomes, and done in a way that is meaningful to clinical practice. Data from trials prone to
bias because of faulty design will not be of use and may give rise to misleading conclusions.
Sufficient numbers of patients and events are required to overcome any random effects.
1.2
Cost-Effectiveness
Moreover, the systems for pharmaceutical evaluation in most countries do not allow for studies
to determine whether the product is better value for the money than alternatives (cost
effectiveness. Generally, the assessment of comparative cost has not been germane to scientific
assessment in the regulatory process.
In making reimbursement decisions, however, cost effectiveness is very important. Several EU
countries , including the Netherlands, Portugal, Finland, Denmark and the UK, have all
introduced procedures in reimbursement decisions to use some economic evidence.7
Many other EU countries do not mandate cost effectiveness data for reimbursement, however it
is implicit that manufacturers need to include this evidence in the reimbursement dossier.
Additionally other EU countries (France, Italy, Spain) require or strongly encourage economic
evidence for pricing rather than reimbursement.
One source of cost-effectiveness research is the pharmaceutical industry itself. However, public
and private managers of drug benefits might not consider research by manufacturers a sound
basis for decisions about which drugs to favor. 8, 9 The objectivity of manufacturer-sponsored
research seeking to justify claims that a drug is better than its competition can be questioned.
There is evidence that studies sponsored by drug companies are more likely to have findings
favoring the sponsor’s drug than are those having other sponsors.8, 9, 10 Conversely, large
purchasers and insurers have also shown interest in sponsoring research on the relative value of
different drugs, but the potential bias of their results also could be raised, especially by
manufacturers or patients and their physicians.8
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
2.
Experiences with Comparative Effectiveness and Cost-Effectiveness
2.1
EMEA
New pharmaceutical legislation for the EMEA came into force on 20 May 2004. 11 The new
legislation made it clear that, although “…[M]ember States have developed an evaluation of the
comparative efficacy of medicinal products aimed at positioning a new medicinal product with
respect to those that already exist in the same therapeutic class… this evaluation should not be
conducted in the context of the marketing authorization for which it is agreed that the fundamental
criteria should be retained.“11 (italics added). Thus, it would appear that the EMEA is still
considering safety and efficacy using placebo-controlled trials. However, comparator studies are
often requested on grounds of assessment of risk/benefit.
2.2
National Institute for Clinical Excellence
The National Institute for Clinical Excellence (NICE) was established in 1999 and now regularly
bases its decisions regarding drugs on evidence- based evaluation of their comparative
effectiveness and cost effectiveness, comparing their costs, and benefits with other treatments.12
Manufacturers can be requested by NICE to provide quantitative comparisons with other forms
of treatment, so that data comparing the new product with current standard therapy “head tohead” is sometimes available by the time NICE reviews the product. It is incumbent upon
manufacturers to provide everything to NICE, which would include comparator information.
2.3
Australia
The Pharmaceutical Benefits Advisory Committee (PBAC), a statutory committee established
under the National Health Act of 1953, consists of family and specialist medical practitioners,
pharmacists, and a consumer representative. The PBAC is charged with making
recommendations to the minister for health and aged care about which drugs and medicinal
preparations should be listed for subsidy. 1 The PBAC must consider comparative effectiveness
and cost in making its recommendations. To fulfill this requirement, cost-effectiveness
requirements were phased in during 1991 and 1992 and became mandatory in 1993. The choice
of an existing treatment with which the new drug will be compared is critical.1 The most
prescribed pharmacological analogue used for the same indication is usually preferred. If the
drug is in a new pharmacological class, the drug most prescribed on the Pharmaceutical Benefits
Scheme (PBS) for the same indication is the comparator.1 If no currently listed drug is available,
the main comparator usually is the standard medical (nondrug) management. The industry has
argued that using these criteria could disadvantage new drugs, as they are compared with
cheaper old drugs that are off-patent. PBAC prefers (but does not require) randomized trials
that directly compare the proposed drug with the main comparator. Since head-to-head
comparisons are rarely available, an analysis of two sets of randomized trials involving a
common reference will often be acceptable (i.e., drug A v. comparator and drug B v. same
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
comparator). The clinical evidence is supposed to indicate whether a drug is better than, no
worse than, or worse than the comparator and guides the type of economic analysis. Drugs that
are worse overall than the comparator are generally not subsidized.1
Australia’s system, has been criticized by the drug industry. It is one model for how to obtain
value for money in prescription drugs. Compared with other countries Australia pays a lower
price for drugs and across all categories of drug it pays less than half the price paid in the
United States.1
2.4
United States
Individual states of the USA have begun to use economic analyses as part of their state Medicaid
programs. For example, in 2001, the Oregon legislature directed the state’s Department of
Human Services to consider the effectiveness and relative cost of different drugs. Under
contract, researchers at the Oregon Health and Science University have conducted evidencebased reviews of published and unpublished studies on drugs in four therapeutic classes:
gastrointestinal medications, two types of pain medications, and cholesterol-lowering drugs.
These reviews serve as input into a public process through which the state identifies preferred
drugs for its Medicaid plan.13 Individual states are using clinical and economic analysis as part
of the Medicaid program. Evidence based practice centers are established in the USA (in which
Oregon is one) and Canada to develop evidence reports and technology assessments based on
rigorous, comprehensive syntheses and analyses of the scientific literature .The Academy of
Managed Care Pharmacy which has ‘guidelines’ (a format for submission to Formularies) for
clinical and economic evaluation which is often used by managed care firms, pharmacy benefit
managers, and hospitals in the US. 14
2.4.1
Medicare Program
The U.S. Medicare law reads, in part: “No payment may be made under [Medicare] for any
expenses incurred for items or services [that] are not reasonable and necessary for the diagnosis
or treatment of illness or injury or to improve the functioning of a malformed body member…”15
In 1989 the agency administering the Medicare program prepared a set of criteria, including
cost-effectiveness.16 This later factor was not officially adopted. The Medicare program has
developed a process by which national coverage decisions are made.17 These decisions affect all
Medicare beneficiaries. The process relies on the evaluation of scientific evidence and can rely
on outside technology assessments and the opinion of a newly created Medicare Coverage
Advisory Committee. The question presented to the technology assessment body or to the
advisory committee is generally, “is the evidence sufficient to demonstrate that the item or
service provides a net health benefit compared to standard or accepted treatment.” The issue then
is one of comparative benefit and that benefit requires an evidence basis. In practice, however,
the level of evidence becomes directly proportional to the fiscal impact of the service
resulting in a de facto cost-effectiveness.8
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
2.4.2
`Prescription Drug Comparative Effectiveness Act of 2003’
In 2003, proposed legislation would have enabled the Director of the National Institutes of
Health, in coordination with the Director of the Agency for Healthcare Research and Quality
(AHRQ), to “conduct research, which may include clinical research, to develop valid scientific
evidence regarding the comparative effectiveness, cost-effectiveness, and, where appropriate,
comparative safety of covered prescription drugs relative to other drugs and treatments for the
same disease or condition.”18 This proposal found its way into law later in the year (most likely
a compromise between the two U.S. political parties) as the Medicare Prescription Drug,
Improvement and Modernization Act (MMA).19 (See Section 2.4.3).
2.4.3
Medicare Prescription Drug, Improvement, and Modernization Act (MMA)
This law (Pub. L. No. 108-173, § 1013, (2003)) was passed in late 2003. As we have mentioned,
controlled multi-centered clinical trials that sponsors conduct for FDA approval purposes often
do not generate the comparative data needed to judge whether the new item or service is
medically necessary to treat the Medicare population in a clinical setting. Under the MMA, $50
million is authorized in 2004 for the Agency for Healthcare Research and Quality (AHRQ) to “…
conduct and support research with a focus on outcomes, comparative clinical effectiveness
and appropriateness of health care items and services (including pharmaceutical drugs),
including strategies for how these items and services are organized, managed and delivered.” 18
(emphasis added)
This provision seems to imply that there is a lack of relevant data in this regard. It thus seems
inevitable that the AHRQ will be asked to conduct and support comparative clinical
effectiveness research. Whether this means actual head-to-head clinical trials remains to be seen.
The MMA is not explicit in requiring head-to-head comparative trials but one could easily read
into the language such an implication.
3.
Comparative Effectiveness and the Need for Head-to-Head Clinical
Trials
In principle, comparative effectiveness of drugs and other interventions can help to build
government capability to understand and evaluate marginal “value” by acting as a precursor for
cost effectiveness studies. In this view, which is not universally shared but which is of public
health importance, the industry, government and purchasers act as the arbiters of value. The
industry provides medical evidence – clinical trials, head-to-head trials. The government
compares the evidence, validating conclusions on comparative outcomes. The purchasers pay
for therapeutic “value”.
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
3.1
The Value of Comparative Clinical Trials
Many would take the position that head-to-head studies should be mandatory. A good recent
example is the “antihypertensive and lipid lowering to prevent heart attack” trial (ALLHAT) of
different antihypertensive drugs.20 See Textbox. ALLHAT tested an inexpensive diuretic versus
an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium-channel
blocker (DHP-CCB), both of which are much more expensive than diuretics. ALLHAT
recommended that diuretics be prescribed first, rather than the more expensive drugs. The
authors estimated that the USA health care system would have saved US$3.1 billion dollars
between 1982 and 1992, had this recommendation been followed.20 No similar analysis has been
done for the EU.
It is almost certainly true that drug comparisons will grow in importance. Biotech companies
have been developing expensive new drugs that cost many thousands of dollars a year and such
price pressure is likely to increase the call for comparative trials against the best available
treatment(s). In short, the typical argument is that more and better information about how well
a medication works compared to existing treatments and other medications will promote more
rational adoption of medicines and help to control health care costs. Some patients will respond
better to drug A than drug B and vice versa. Research to be better able to identify which patients
are more likely to benefit would have considerable value.
3.2
Criticism of Comparative Clinical Trials
The reluctance of companies to perform comparative trials during drug development is easily
explained. Traditionally, there has been little pressure from regulators to compare their products
with those of their competitors. Trials of active treatments have to be large to detect small
differences, which will add to the costs and time of conducting clinical trials. From a commercial
standpoint, the discovery that a new product which has yet to establish a market, is no better
than an older and cheaper one could be disastrous , and companies may try to avoid this by not
selecting candidates at early phases of development that they deem are unlikely to have
worthwhile clinical benefit. The reluctance could also be based on lack of guidance as to the
comparator (i.e., what is and what is not a clinical “benefit” and who makes this decision) That
is, since different products are in use in the markets of the world, it may often be very difficult
to define one or two “gold standard” medications that would be accepted as such across a range
of markets. We note that this reluctance does not extend beyond approval, when marketing
departments make claims about the superiority of their products. Companies make claims based
on indications agreed to by regulators and on the balance of the evidence, but often there is
minimal data.3
As we alluded to above, comparative effectiveness reviews (whether by clinical trials, literature
review or other method) serve as the empirical underpinning for cost effectiveness analyses. The
pharmaceutical industry in particular, appreciates that such a distinction may be more apparent
than real and that mandating comparative trials is essentially creating a de facto basis for cost
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
effectiveness. To be sure, the goal is improved patient care and efficiency, not just budget
cutting21
An additional argument, based on the logic that comparative effectiveness is de facto cost
effectiveness, is that comparative effectiveness studies will make the role of drug regulatory
authories (e.g., the EMEA) more ambiguous as the EMEA would now be performing economic
studies. Conversely, it can be argued that administrative agencies outside the EMEA should
not do cost effectiveness studies as they are merely “second-guessing” the regulators with
regard to efficacy and will end up becoming medical decision makers.
Another criticism is that the ability accurately to assess the full value of a treatment takes many
years. This is particularly so in relation to the treatment of chronic illness where surrogate
endpoints often have to be used. For instance, by its very nature, long-term survival data for
new cancer treatments will initially be lacking. A fundamental issue is whether available data
could reasonably be extrapolated for a 10-year, 20-year or longer period.20
A further argument is that comparative efficacy data, are only valid when the most recent study
is published, and never provide an up-to-date overview of the most recent clinical experience.
It seems clear that requiring the industry to conduct head-to-head trials before or even after
market approval is going to be quite expensive. The latest estimate for the average cost of
researching and developing a new prescription drug is US$802 million, spread over 10 to 15
years.22 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT) trial cost US$125 million23 and studied only one calcium channel blocker and one
ACE inhibitor. See Textbox 1. For example British Columbia’s provincial Pharmacare lists 8
ACE inhibitors and 5 DHP-CCBs on its list of drugs reimbursed. 24 Given the costs of ALLHAT,
head-to-head trials for each of them and one diuretic would cost an additional $800 million.
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
Textbox 1. The ALLHAT and ANBP2 Trials
The ALLHAT trial enrolled more than 40,000 older Americans. The results showed that generic
diuretics, previously introduced in the 1950s, were slightly superior to the more expensive calcium
channel blockers and angiotensin converting enzyme (ACE) inhibitors. The participants in the trials
who took diuretics suffered slightly fewer heart attacks and strokes than comparable groups on the
other medicines. Specifically, the overall findings of the trial, showed that coronary heart disease
(CHD) risk was not improved for any of the newer agents compared with the diuretic (represented by
chlorthalidone) and that total mortality was similar for ALL groups. However, diuretic-based therapy
was superior to alpha-blocker– based, ACE inhibitor– based, and calcium-channel blocker– based
therapy in preventing 1 or more major forms of cardiovascular disease (CVD), including stroke and
heart failure. Results were consistent for all outcomes by age, sex, diabetic status, and ethnicity, except
for stroke and combined CVD. See Davis, BR et al. 2004. ALLHAT: Setting the Record Straight. Ann
Intern Med. 141:39-46. The developers of this trial recommended that first line treatment of
hypertension should be the thiazide-type diuretics, rather than the more expensive treatments.
The second Australian National Blood Pressure Study (ANBP2) (Wing LM et al., 2003. A comparison of
outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly.
NEJM 348: 583-592) seemingly contradicted the ALLHAT results in that the ANBP2 trial suggested that
ACE-inhibitor regimens were actually superior to diuretics. The differences between the results were
likely due to design differences and conduct of the trials. See Turnbull F. & Neal B. 2004. Resolving the
differences between ACE inhibitors and diuretics- ALLHAT and ANBP2, Aust. Prescr. 27: 98-101.
The lesson of ALLHAT is not that one drug worked "better" than another but that several classes of
medicines worked just about the same. The lesson from a comparison of ALLHAT and ANBP2 is
actually a clinical one, i.e., regardless of which medicine one uses, good blood pressure control is
important. The ALLHAT results emphasize that pharmaceutical "innovation" should be judged based
on head-to-head trials and not just on placebo-controlled trials.
Head-to-head trials are more expensive than placebo trials because they require many more
subjects. This gives the trial more statistical power, which is required to observe the small
differences when the two drugs may have similar effects. According to US Food and Drug
Administration regulations, Phase III trials (the final stage before approval) must have at least
1,000 to 3,000 people. ALLHAT had over 33,000 people. ALLHAT started recruiting in February
1994 and closed on March 31, 2002. Adding another 8 years to the time required to approve a
drug for sale, or determine if components of a drug class are cost effective post marketing, is not
good policy.
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
4.
Sponsoring Comparative Trials
4.1
Industry Sponsored Trials
From the industries’ point of view, postmarketing clinical trials designed to show product cost
effectiveness as well as clearly improve therapeutic outcomes will be needed to win preferred
status among formularies and to motivate consumer loyalty even when the patients have to
cover out-of pocket charges.
Head-to-head clinical trials may be too expensive for individual European private companies to
undertake as the level of pharmaceutical industry investment is generally less than that of the
United States.8 Some classes of drugs cost the healthcare system tens or hundreds of millions of
dollars annually.20 Having the industry spend some fraction of these costs in a trial could
provide invaluable information on which to base policies, although one would have to find an
equitable base (i.e., some fixed percentage of their net profit or sales or R&D allocation for that
year) and other incentives to participate. Certainly, the industry would have to counter the
obvious conflict-of-interest such sponsorship entails.
4.2
Government-Sponsored Trials
Government-subsidized sponsorship of comparative trials is an option and governments could
support postmarketing randomized trials to answer unresolved questions regarding the clinical
and economic performance of new drugs. 3 However, governments will likely value some
clinical outcomes differently than will firms responding to consumer needs. Governments may
not share the preferences of consumers for certain aspcts of medication (e.g., convenience of use
or increased quality of life may be valued more by consumers than by the government). 3
Generally, private firms will be better informed about the potential value of innovations to
consumers and providers. Further, under a centralized system of comparative clinical research
expenditures, lobbying by those groups that are better organized politically can distort the
direction of research to better suit their particular needs.
5.
Alternatives
5.1
Partnerships Between Public and Private Sectors to Conduct Post Marketing
Studies
Professor Uwe Reinhardt of Princeton University has called for private insurers and the
government to set aside 1 percent of their annual drug spending to endow a new research
institute to provide an “authoritative, independent source of reputable research into whether
new, improved drugs are, indeed, significantly new and improved.”25, 26 At least in the U.S, this
formula would generate about $1 billion for research, an amount roughly one-third of the
$3.4 billion in total U.S. philanthropic spending on health in 2001.27, 28 Non-profit foundations
cannot easily reach the $1 billion amount. A European counterpart to this may be a useful
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
approach, although it would likely generate less money and be difficult to do on a European
wide basis as comparators and doses differ as do medical practice, e.g., treatment as a day case
or in patient, length of hospital stay, doctors and nursing costs and the like
5.2
Electronic Prescribing and Comparative Effectiveness: The Future?
Linking data on prescriptions and diagnoses from large administrative databases is invaluable in
quantifying adverse effects. Arguably, using administrative databases will be useful for
evaluating the comparative effectiveness of drugs. Commentators have mentioned that small
genuine differences between active treatments are likely to be swamped by the confounding
effects of differing indications, the characteristics of patients, and choices by doctors.3 Thus, very
large databases will be required.
With these caveats in mind, information could be potentially available in electronic prescription
and medical databases to conduct Phase IV and/or pharmacoepidemiologic studies to take the
place of, or supplement, randomized, controlled, comparative clinical trials. With electronic
prescribing linked to medical records databases, it will in principle be possible to conduct
cohort, case control and other observational, post marketing studies.

Electronic prescribing linked to medical records can give physicians, patients, payers and
regulators objective, comparative information about the efficacy of treatment alternatives
and about the tradeoffs between cost, efficacy and adverse effects.29 Insurers and
employers are shifting more and more of the out-of-pocket burden to patients,
particularly for newer, more expensive, brand name prescriptions. Asked for higher copays for brand name products, consumers will want to know if the product is three times
as effective as the $5 or $10 choices.

E-prescribing tools, supported by patient-specific formulary information, plus up-to-date
information about clinical results and therapeutic indications, can benefit physicians and
shape the set of prescribing options they consider.29
The goal is to help make evidence about the comparative effectiveness and ineffectiveness of
medical technologies and interventions available.

The adoption of such electronic systems in the United States has been slow because of
the fragmentation of service payment systems across federal and state governments as
well as the many private insurers and large corporate self-insurers.30 Without a central
payer, such as the UK's National Health Service, to drive use and to set data and
workflow standards, US adoption has been limited to larger group practices and
hospital-focused delivery communities.29

There is enormous potential for a comparative advantage over the U.S. in terms of
expansion of electronic prescribing systems within the EU, although some of the more
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Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
obvious restraints to introducing electronic process include significant investment in
hardware, software, implementation, and concerns about confidentiality.
In April 2004, the European Commission made a strong policy statement that better use
of IT and e-Health and e-Government technology will be necessary – and interoperable
across EU member states.31 The package proposed by the Commission comprises three
elements, the most relevant for the present discussion being an action plan on e-Health
addressing the crucial role of new technologies and new ways of delivering health care
in improving access to, quality and effectiveness of care. The action-plan takes a twin
track approach: making the most of new information and communication technologies
in the health sector and better integrating a range of e-Health policies and activities. In
practice, this means making a reality of interoperable health care information systems,
on-line and digital patient records; and new services such as teleconsultation and eprescribing.30
6.
Conclusions
Comparative clinical trials are important to determine whether two medicines are similar in
their clinical effectiveness, supplementing the basic definition of efficacy from placebo studies.
Although such trials demand many participants, can take a long time, and can be very
expensive if there are many medicines to compare. From a commercial viewpoint, the
pharmaceutical industry is acting rationally by being reluctant to place their products at risk by
conducting head-to-head comparisons. In a practical sense, head-to-head trials can delay
approval. The government may not be the best entity to perform these tests either.
One proposal has the government and private sector insurers contributing to fund a research
institute that would study clinical effectiveness and cost effectiveness. In the United States, the
agency that is responsible for the Medicaid program does have such a research organization,
although it is not a truly independent entity.
The European Commission supports use of an action plan on electronic Health addressing the
crucial role of new technologies and new ways of delivering health care in improving access to,
quality and effectiveness of care. This plan would better integrate health care information
systems, on-line and digital patient records; and new services such as teleconsultation and eprescribing. We propose to use this action plan as a way of creating post-marketing
pharmacoepidemiologic studies to better understand comparative effectiveness and cost
effectiveness. In the long run, it will be much less expensive than creating new comparative
clinical trials de novo.
8.4-14
Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-toHead Comparative Trials
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