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Formularies CHAPTER 18
If drugs are similar in terms of efficacy and toxicity
but have different potential for interaction, this could
be a deciding factor. Drugs with fewer possibilities of
interaction mean fewer problems in use.
Patient acceptability is an important factor, which
will be affected by efficacy and toxicity. If drugs do
not work, or if they cause side-effects, patients are
less likely to take them. For orally administered drugs,
palatability and ease of swallowing will contribute to
acceptability. Other considerations may also be important, such as the extent to which a dispersible
preparation actually disperses, or whether a modified-release tablet can be divided. Inhaled drugs are
available in many different formulations and their
selection will depend to an extent on what patients
will or can use properly,to achieve maximum efficacy.
For topical products, such as creams and ointments,
patient acceptability is particularly important.
A local formulary may simply list drugs which
are recommended or it may specify particular dosage forms of those drugs. Patient acceptability is
likely to influence the different formulations selected for inclusion in a formulary mor e than the
drug entities. However, the range of formulations
available, which will in turn affect patients’ acceptanceofdrugtherapy,maybeafactorindeciding
which drugs to include. If a drug is available in a
wide range of formulations, it may be a better
choice than one which has very few. It is simpler
for the prescriber to remember one drug name
when a particular class of drug is required, rather
than to have to choose different drugs because they
come in different f ormulations.
Many formularies exclude all combination products which include two or more drugs in fixed ratio.
This is because it is impossible to increase the dose of
one drug without also increasing the dose of the other
drug(s). Some patients may receive higher doses of
one of the constituents than they require as a result.
However, combination products are more favoured in
primary care, where they are considered to improve
patient compliance and also reduce prescription
charges for the patient. Combination products may
be useful if the pharmacokinetic characteristics of the
components are compatible and it can be shown that
patients require and obtain benefit from all the components individually, in the same ratio as the combination product. Unfortunately, very few combination
products are used in this way. Their inclusion in a
formulary will depend on local preferences and appropriate use will subsequently depend on individual
prescribers.
Cost considerations are also important, but the aim
of a formulary is to encourage rational and costeffective prescribing, not primarily to save money.
Cost-effective prescribing involves the use of the drug
with the lowest costs which is also effective, has minimal toxicity and is acceptable to patients. The cheapest drugs may not be the most acceptable, or of
adequate efficacy. For some groups of drugs, prescribing costs may actually rise as a result of using a local
formulary, since the optimum drugs may be the most
expensive. However, where efficacy, toxicity and
patient acceptability are equal, cost should be the
deciding factor in drug selection. As described above,
both hospital and community costs of drugs should be
considered when selecting drugs for a hospital formulary, as the bulk of the cost is likely to be borne by
primary care. The purchase price of a drug may not be
the only factor to be taken into account when considering costs. Pharmacoeconomic evaluations, which
take account of the costs of the consequences of treatments, may also be necessary (see Ch. 19).
All drugs included in a formulary should be easily
available, so ‘specials’, drugs available in hospital only,
or on a named patient basis, should be avoided. Generic availability is a bonus, as it usually means costs
are lower than for drugs which are only available as
branded formulations. Most formularies specify that
prescribing should be generic, where appropriate. The
use of computer systems for prescribing, which automatically change prescriptions to the appropriate
generic name, increases the proportion of generic
prescriptions considerably. This should also reduce
costs.
As part of their role in formulary development,
pharmacists frequently provide unbiased information
about any differences in efficacy, toxicity and cost
between drugs. Some useful sources of information
are the National Prescribing Centre in Liverpool or
the Scottish Medicines Resource Centre in Edinburgh
and Drug and Therapeutics Bulletin.
Use of prescribing data
All the factors mentioned so far can also be applied to
the selection of drugs for individual patients. A further factor which may be considered when selecting
drugs for populations is current prescribing habits.
The main reason for this is that it is much easier to
encourage use of a formulary if it involves few changes
of habit. However, if the commonly prescribed drugs
are not efficacious, or have a high incidence or severity
179
SECTION THREE Pharmacy prescribing and selection of medicines
of toxicity, it is better not to include them. Frequent
use does not necessarily imply appropriate selection.
Information about current prescribing is obtainable
for either hospital or primary care prescribers. National databases on hospital prescribing are being developed, but prescribing data from computerized
pharmacy supply systems are readily available which
usually relate to wards or directorates. In primary
care, data are available from the Prescription Pricing
Division in England, Health Solutions in Wales, the
Information and Statistics Division in Scotland and
the Central Services Agency in Northern Ireland.
The data can identify prescribing by an individual
GP or by a practice.
From data on the frequency with which different
products are prescribed it is usually possible to identify one or two drugs within each therapeutic class
which account for the bulk of prescriptions. These
should usually be considered for inclusion in a formulary, as little change in prescribing habits will be needed, providing they are efficacious and have minimal
toxicity. It may be possible to include only these drugs
in a formulary, or there may be a need for others to be
included on a more restricted basis. If the commonly
prescribed drugs are inappropriate on therapeutic
grounds, alternatives may be required.
Formulary management systems
A formulary needs to be flexible and dynamic. A
system must be devised which allows this. This is
known as the formulary management system and it
covers many other aspects of formularies.
Production, distribution and
revision
still incorporate colour and be attractively bound for a
professional appearance. However, if large numbers
are required, printing becomes more economical.
Distribution by mail with a covering letter may be
easiest for large numbers of people, but hand delivery,
with verbal explanation, may help to encourage interest and therefore adherence to a formulary’s recommendations. Launching of a new formulary (or indeed
a revision) can usefully be accompanied by a meeting
to explain its aims, describe how to use it and encourage discussion of its contents. Leaflets advertising the
benefits of using the formulary and educational material may be usefully developed to encourage prescribers to learn about why they should consider using it.
Electronic versions can obviously be easily distributed within an NHS trust, but require just as much
supplementary information to encourage their use.
Specialist IT support to ensure that the formulary
can be integrated with electronic prescribing systems
is a key factor in their successful use.
After all the effort which goes into producing a new
formulary has resulted in the final document, the
thought of revising it is likely to be far from popular.
However, because of the time taken to produce a
new formulary, it will soon go out of date. If this is
allowed to happen, respect for its content will decline.
Adherence to its recommendations may follow suit.
Revision should therefore be considered even before
the formulary is finished. The BNF is revised every
6 months, but most local formularies cannot hope to
achieve a similar frequency, because of the amount
of work involved. Annual or biennial revision should
be aimed at and specified at the launch. As new drugs
are coming onto the market all the time, even
6-monthly revision will not be adequate to keep a
formulary up to date. Some system, therefore, needs
to be devised to allow new drugs to be considered for
inclusion.
Producing a formulary is a very time-consuming task
which, although overseen by the ADTC, needs a driver to take responsibility for ensuring it is completed.
Usually this is a pharmacist, who will be involved in
collecting together the data on which the drug selection will be based (published evidence, prescribing
data and expert or all group members’ opinions),drafting material, reaching agreement on the format(s)
and design to be used and seeing it through to production. The ADTC should consider who will need a copy
and how it will be distributed. For paper versions,
photocopying is cheapest for small numbers and can
180
Responding to the needs of
practice
Change is the norm in the world of drugs. New drugs
are constantly becoming available, old drugs are removed from the market, new clinical trials provide
evidence for efficacy of existing drugs in novel indications and post-marketing surveillance provides constantly changing data on adverse effect profiles. An
awareness of all the facts this generates is essential, so
that the formulary does not go out of date and can
respond to the changes. In implementing a formulary,
Formularies CHAPTER 18
patients must not be deprived of the benefits of new
information and drugs. There will also inevitably be an
occasional need for patients to receive treatment outwith a formulary’s recommendations, since a formulary cannot be expected to cover all possible
situations. Methods are therefore needed to allow
drugs to be considered for inclusion in the formulary,
to allow drugs to be removed from the formulary and
to supply non-formulary drugs when these are appropriate.
A method for allowing drugs to be considered for
inclusion in a formulary should not be restricted to
newly available drugs. It must allow any user of the
formulary to propose a drug for consideration and
should be able to provide an evaluated response within a reasonable time. Evidence of any advantages the
proposed drug has over drugs already included, in
terms of efficacy, reduced toxicity or cost, will be
needed. This must be based on well-designed published clinical trials, the same basis as that used in
the initial formulary development. Many formulary
management systems require a form to be completed;
an example is given in Figure 18.3. The person making
the request must be informed as to whether the drug
will be included and, if so, whether any restrictions
will be placed on its prescribing. One option is to have
Figure 18.3*Example of a form which could be used to request new drugs to be considered for inclusion in a formulary.
181
SECTION THREE Pharmacy prescribing and selection of medicines
an appraisal period, say 6 months, during which prescribers can gain experience with a newly recommended drug. After this period the committee can
then review the status of the drug.
If a drug is accepted onto an existing formulary
between revisions, it is essential to inform all users
of the change. One way of achieving this is to issue
information bulletins, either by post or e-mail. A
similar method can be used to inform users of any
changes in the indications or doses of drugs which
may also occur during the life of a formulary. Similarly, if drugs are to be withdrawn from the formulary,
users must be kept informed. Regular bulletins issued
by the ADTC are therefore an important feature of
formulary management.
Withdrawals may occur because of manufacturers
ceasing production, product licences being withdrawn
or changes in manufacturers’ recommendations.
However, it may also be useful to consider withdrawing drugs from the formulary if they have not been
prescribed for a long time. Again, 6 months would be a
suitable time to study the prescribing of most drugs,
except those whose use is seasonal. This could be
done on a regular basis between major revisions, but
would require consultation with prescribers before
the withdrawal was implemented. The advantage of
a practice such as this is that it helps to keep the
number of drugs in the formulary to a minimum.
As there will be situations when a non-formulary
drug is requested for a patient, it may be necessary to
have a method of ensuring that the request is dealt
with promptly. In primary care, there should be no
problem in supplying a non-formulary drug, although
there may be a delay if it is not stocked by local
pharmacies owing to rare use. In hospital, however,
pharmacies tend to stock only a limited range of
drugs. Formulary drugs should always be easily available, but non-formulary drugs may need to be purchased specially. This will lead to delays in treatment.
Some formulary management systems, usually in hospitals, require completion of a form for every nonformulary drug which is prescribed. The purpose of
this is twofold: it acts as a deterrent to prescribing
non-formulary drugs and also allows monitoring to
see whether any drugs are frequently requested. Consideration may be given to including frequently
requested drugs in the formulary. Usually forms require a senior medical staff signature, but there is a
possibility that this requirement may be abused. Once
a form with the appropriate signature is received,
pharmacists should not simply assume that the request should be complied with. If this occurs, all that
has been achieved is an elaborate ordering system. For
the formulary system to operate effectively, all prescribers requesting a non-formulary drug should be
questioned to determine the reasons why a formulary
drug is not suitable.
One of the most frequent reasons for requesting a
non-formulary drug in hospital is that the patient was
taking the drug prior to admission and prescribers are
reluctant to change it. This can be viewed as an opportunity to review the medication, ensuring that it is
appropriate for the individual patient. If it proves to
be so, itmay bepossibleto usethe patient’s own supply
of the drug, providing there are systems in place to
ensure this is indeed required and fit for use. If this is
not an option, a decision must be made on whether the
requested drug will be supplied from the pharmacy.
The systems in place must ensure that this is a rapid
process, particularly if a special purchase is required.
The most common reason for using non-formulary
drugs in primary care is also that patients are already
taking them and either they or their GPs are reluctant
to change the prescription. Pharmacists can use the
opportunity of conducting medication reviews to consider the appropriateness of any non-formulary drugs
prescribed. Pharmacists also undertake regular review
of repeat prescribing in many practices, using the
techniques of drug utilization review, drug use evaluation and audit (see Ch. 19). Non-formulary prescribing can be assessed through these mechanisms and
therapeutic switching undertaken to address any
changes which would be of benefit.
The promotional activities of drug manufacturers’
representatives will need to be controlled to prevent
them from undermining the principles of a local formulary. Many NHS trusts have policies on which staff
representatives are allowed to see and what they are
allowed to supply. Manufacturers can be an extremely
useful source of information on their products, but
the inclusion of a drug in a formulary must be evidence based and unbiased. Making constructive use of
the visit from a pharmaceutical company’s representative can be a beneficial educational exercise to staff
involved in using a formulary.
Clearly a lot of effort goes into operating a formulary and there are many advantages of a good formulary management system. The measure of success of
any formulary is in the extent to which it is used or
adhered to and the demonstration that prescribing is
more rational. It may be possible to show improvements in efficacy and reduced toxicity and also cost
savings, but these may be more difficult to achieve
and to demonstrate.
182
Formularies CHAPTER 18
Changing practice
Developing local formularies and treatment protocols
encourages good relationships between prescribers
and pharmacists. Building on this relationship is important to enable the changes to practice to be made
which will be necessary in implementing these.
Changing prescribing habits can be extremely difficult. Some prescribers dislike losing the freedom to
prescribe as they choose and may reject a formulary
and its concept. Often prescribers have developed
personal drug preferences over the years and, even if
they have no objection in principle to prescribing a
different drug, may easily forget when actually writing prescriptions. Incorporating the formulary into
electronic prescribing systems, which restrict choice
or at least highlight formulary drugs as preferred, is
therefore of great benefit. If agreement on what drugs
should be used has been difficult to achieve, the resultant formulary may contain a large number of
drugs. This can be more easily adhered to, but is less
likely to achieve rational prescribing or to reduce drug
costs. Conversely a formulary which is too restrictive
is more likely to be difficult to adhere to.
When a formulary is introduced, some patients will
be receiving medicines which are not included and
they, too, may be resistant to change. The doctors
who prescribe for these patients may also be unhappy
about changing individual patients’ drugs. This is especially likely if the patient is well stabilized on a
particular drug, with little adverse effects. As drugs
included in a formulary will have been selected on a
sound basis, it could be more suitable for a patient
than their current drug. Change may therefore be of
benefit. Education of prescribers and patients may be
necessary to convince them of potential benefits and
can be supported by educational packages, as already
mentioned. Pharmacists are often those most actively
involved in educating and persuading prescribers to
carry out changes. They are also well placed to implement formulary recommendations themselves within
their roles as prescribers. Even without changing individual patients’ drug therapy, if the drugs recommended in a local formulary are used for all patients
starting new therapy, most prescriptions will in time
include formulary drugs.
Research has shown that for clinical guidelines,
visits to prescribers to provide education, involving
local opinion leaders in educational meetings and interactive educational workshops are successful methods of changing behaviour. The same is likely to apply
to formularies. A strategy should be developed which
ideally includes a mixture of methods, because the
more frequent the reminder, the more likely it is that
practice will change. Constant reminders may be
necessary to maintain prescribing within the recommendations of a formulary. However, feedback on
adherence to the formulary is another important
mechanism for reminding prescribers about it.
Auditing performance
Providing feedback to prescribers on whether they
follow formularies is essential. Because formularies
encourage rational prescribing, the extent of their
use can be used as one indicator of the quality of
prescribing. For other types of prescribing indicators,
see Chapter 19. The simplest way to gauge whether a
formulary is being used is to look at the same type of
prescribing data used to help develop the formulary.
Computerized prescribing data can easily be studied
to assess whether formulary drugs are being prescribed. However, this type of data provides no information about the patients for whom the drugs have
been prescribed. It cannot, for example, identify why
patients have received prescriptions for non-formulary
drugs. Nor can it be used to determine whether the
formulary drugs were prescribed appropriately or
whether formulary drugs were used within local
guidelines or treatment protocols. For this, drug utilization review or clinical audit is required (see Chs 11
and 19).
For data to be of any use, they must be easy to
interpret, accurate and up to date. They must also
be of direct relevance to the prescriber to whom they
are given and may allow comparison either to earlier
prescribing or to the prescribing of others. Comparing
the prescribing of several GPs or hospital doctors to
each other is known as peer review. Comparison to a
‘norm’ of prescribing practice, or to the practices of
others in the same peer group, often increases the
desire of prescribers to conform to the ‘norm’ or
the peer group. However, it is important to ensure
that the ‘norm’ is desirable.
If hospital data generated by the pharmacy computerized stock control system refer to drugs issued to
wards or directorates, care must be taken to determine whether this equates to drugs prescribed. Any
drugs which were not issued through the computer
system, such as patients’ own drugs, may not show up
in these data. Electronically incorporating the formulary into prescribing systems should make the measurement of formulary adherence relatively simple.
183
SECTION THREE Pharmacy prescribing and selection of medicines
In primary care, prescribing data represent the
number of prescriptions dispensed, excluding only
prescriptions written which have not been presented to pharmacies and dispensed. They cannot,
however, distinguish between formulary and nonformulary drugs. This must be done manually and a
figure for adherence can th en be calculated, again
taking the quantities of each drug into account.
Another source of data in primary care is the practice computer, which can again incorporate formulary drugs within its programs. However, if a
practice does not generate or record all its prescriptions via the computer, the prescribing patterns
obtained will not show the full picture. The number of prescription s written usually differs from
those dispensed, so a different picture of formulary
adherence may be found if data from dispensed and
written prescriptions are compared.
When providing feedback to prescribers based on
prescribing data, care should be taken to ensure that
the quantities of the different drugs used are taken
into account in some way. For example, if 180 tablets
of a formulary drug and 20 tablets of a range of four
other non-formulary drugs are used, adherence
should be quantified as 90% (180 out of 200 tablets
used in total). It could also be calculated that adherence was only 20% if the range of drugs were used
(one out of a range of five), but this would not be a
reasonable representation of the overall prescribing.
Another source of valuable data for the formulary
pharmacist is the request forms for non-formulary
drugs, if they are used. Review of these can indicate
the extent of non-formulary prescribing. These
should also explain the reasons why non-formulary
drugs were used. Records of clinical pharmacists’
interventions made during routine prescription review or medication review which relate to nonformulary prescribing can also be studied.
Regular provision of information on performance is
an essential part of formulary management. Any data
which are presented to prescribers as a means of
informing them of adherence to formulary recommendations will need to be attractive and easy to
use, just like the formulary itself. Graphics and colour
can be used to highlight important points. Finally,
evidence of cost savings, if they have been achieved,
may help to encourage use of the formulary. This is
probably best expressed as actual expenditure compared to expected expenditure had the formulary not
been used. If formulary adherence is found to be low,
then this is an important result, which needs to be
investigated to determine whether the formulary
best serves the needs of the population or requires
revision.
All this feedback should be provided in the same
formats as the formulary – paper, electronic or both. It
can be incorporated into regular published bulletins
from the ADTC. This highlights the continuing importance of the formulary and should be an indication
of the committee’s willingness to update the formulary in the light of changing needs. Pharmacists can
also use discussion of feedback information as another
opportunity to market a formulary and gain the support of prescribers in its use.
KEY POINTS
*
A formulary is a list of drugs which are
recommended and available for prescribing
*
A formulary may contain prescribing policies,
which detail the use of drugs in specific medical
conditions
*
Local formularies are used in conjunction with
clinical guidelines and treatment protocols to
encourage rational and cost-effective prescribing
*
Compiling a formulary is a valuable educational
exercise
*
Pharmacists should work with others to compile a
formulary
*
Drugs are selected for inclusion in a formulary on
the basis of efficacy, toxicity, patient acceptability
and cost
*
Use of a formulary containing a restricted number
of drugs may reduce the incidence of adverse drug
reactions, interactions and lack of efficacy
*
For a formulary to be accepted, there should be
widespread consultation on its content
*
A formulary should be easy to use, professionally
presented in paper or electronic (or both) formats
and revised at least every 2 years
*
A formulary management system is required to
provide systems for considering the inclusion of
new drugs, deleting drugs and supplying nonformulary drugs
*
Feedback information should be provided to
prescribers on their adherence to a formulary to
encourage its use
*
Prescribing data can be useful in both developing a
formulary and feeding back on performance
*
Ideally a mixture of methods should be used to
encourage use of a formulary
184
Chapter Nineteen
Drug evaluation and
pharmacoeconomics
Janet Krska and Dyfrig A. Hughes
19
STUDY POINTS
*
Safety, efficacy and economy
*
Pre-marketing studies
*
Post-marketing studies
*
Pharmacoeconomic evaluation of medicines
*
Drug utilization review and evaluation
Safety, efficacy and economy
The volume, complexity and costs of modern medicines are increasing. The need to compare the therapeutic efficacy (i.e. benefits) of medicines with their
potential to cause harm (i.e. risks) and the economic
implications of these is of paramount importance to
the pharmaceutical industry, to healthcare providers
and to society. Pharmacists play a major role in the
evaluation of the safety, efficacy and economics of
medicines use.
At a macro level, the pharmaceutical industry
decides which line of drug development would best
serve its financial and philanthropic interests. The
few molecules out of the hundreds tested which
show promise must be studied in clinical trials before they can be marketed as medicines. After products are licensed and marketed, society and its
healthcare systems are then faced with difficult
decisions on which specific patient populations to
treat, or which new medicines to approve for use.
Increasingly, decisions are based on economic evaluations, which attempt to calculate benefit:risk ratios for medicines in potential patient populations.
In some countries, only medicines which have a
clear cost-effective advantage over existing treat-
ment are funded by government. In the UK, various
organiz ations work in differing ways to examine this
aspect of medicine evaluation. At a micro level,
clinicians (doctors, pharmacists or nurses) must
then assess the relative risks and benefits of each
medicine for individual patients. This involves consideration of factors which can affect drug disposition, efficacy and safety, such as concurrent disease
states or other medicines, while also weighing up
the risk of untreated disease and potential affordability. As pharmacists become more involved in
selecting treatments, the importance of skills in
evaluating all these factors to make individual clinical decisions increases. Furthermore, pharmacists
are frequently required to evaluate the use of medicines in individual patients prescribed by others.
This involves the further skills of drug use review
and evaluation.
There are many techniques used in the evaluation
of medicines for safety, efficacy and economy at
pre- and post-marketing stages, as summarized in
Table 19.1.
Pre-marketing studies
In most countries, evidence of safety, efficacy and
quality must be presented to government-appointed
regulatory authorities before a new product can be
marketed. In the UK, this role is undertaken by the
Medicines and Healthcare products Regulatory
Agency (MHRA), who must be satisfied with such
evidence before a marketing authorization (formerly
called a product licence) can be granted. It is the
responsibility of the MHRA to assure the public
SECTION THREE Pharmacy prescribing and selection of medicines
Table 19.1 Methods of evaluating medicines in humans
Method Subjects Outcome
Clinical trials
Phase I Usually healthy volunteers
(60 adults)
Phase II Selected and limited target
patient population
Phase III Larger numbers of target patients
(1000–2000 patients)
Post-marketing pharmacoepidemiological studies
Post-marketing surveillance
(Phase IV)
Pharmacoeconomic evaluations Variable numbers of patients
Drug utilization studies or reviews Variable numbers of patients
Drug utilization review programme
or drug use evaluation
or clinical audit
Up to 10 000 patients Less common and unpredictable ADRs
using the medicine in routine
clinical practice
using the medicine in routine
clinical practice
Variable numbers of patients
using the medicine in routine
clinical practice
that all medicines which reach the UK market have
been assessed for safety, efficacy and quality. Cost
issues are not taken into consideration. Efficacy has
to be balanced against toxicity for each product and,
while the MHRA’s evaluation includes the active
ingredients of a product and its formulation, final
decisions must also take into account the nature of
the disease to be treated and the duration of the
treatment. What is an acceptable benefit to risk ratio
may differ for a medicine used to prolong survival in
terminal conditions compared to a prophylactic treatment which needs to be taken for life.
Prior to clinical trials in humans, the pharmacokinetics and pharmacodynamics of any new drug are
studied in animals to indicate therapeutic and possible
toxic effects. However, there are often substantial
differences between species in drug handling and in
drug response, so new drugs must be screened in more
than one animal species. The poor relationship between the effects of drugs in animals and humans also
means that great caution is needed before progressing
to ‘first time in man’ trials.
Pharmacokinetics of drug
Tolerability and toxicity profile (SAFETY)
Optimal dosage range (EFFICACY)
Balance between safety and efficacy (THERAPEUTIC RATIO)
Comparative safety and efficacy of medicine
Identification of common adverse
drug reactions (<1:250 incidence)
Identification of patients at risk
Comparative cost minimization, cost-effectiveness,
cost-utility or cost-benefit
Quantitative studies ! patterns of drug use
Some qualitative studies ! appropriateness
of drug utilization
Clinical, social and economic consequences
of drug utilization
Phase I trials
These first trials are carried out in healthy adult volunteers, to determine the drug’s toxicity profile and to
assess tolerability. A dosage range is tested initially
with a stepwise increase in drug dose being given to
successive volunteers. Subjects in Phase I trials are
intensively monitored to determine the nature and
severity of any predictable dose-related adverse
effects. Pharmacokinetic data are usually generated
from both single- and multiple-dose studies. These
may be used to assist in deciding the best method of
administration.
These trials provide only limited safety data, because the subjects are healthy adults and unlikely to
have any compromised drug handling ability. Thus
the potential risks of using the drug in patients at
extremes of age, or in those with poor hepatic or renal
function, are not known. There are also few subjects
(e.g. 50–60), so only very common adverse drug reactions (ADRs) are detected.
186
Drug evaluation and pharmacoeconomics CHAPTER 19
Phase II trials
These commence while Phase I studies are still running. They are carried out in relatively small groups of
target patients, usually within hospital departments
specializing in particular areas of medicine. Their
main aims are to establish efficacy and to confirm an
effective dose in closely monitored and controlled
conditions. Phase II studies give the first indication
of the likely value of the drug in patients, i.e. its
efficacy. There is less emphasis on safety assessments
during this phase, but the results will enable a therapeutic ratio (i.e. the balance between efficacy and
safety) to be determined. Double-blind randomized
controlled trials use a control group with a matching
placebo to assess the effectiveness of new therapies.
Phase II studies also inform the design of Phase III
studies which are more comprehensive. Phases II and
III combined may study 1000–2000 patients. The
regulatory authorities closely control Phase II and
Phase III studies, for which clinical trial certificates
or exemptions are required.
Phase III trials
These trials examine safety and efficacy. They are
generally large-scale studies comparing a new medicine with other treatments or placebo. Where possible, they should have a randomized controlled design,
which is generally accepted as the best method of
conducting clinical research. Assigning each patient
randomly to either the new treatment or control helps
to prevent bias. For other aspects of the design of
clinical trials, see Chapter 17.
Phase III trials are the main source of the information which appears in the summary of product characteristics (SPC) for the product. The conduct of
clinical trials is subject to guidelines which cover ethical issues, the trial design, the roles of the various
investigators and sponsoring company and the storage
and analysis of data. Forevery clinical trial which takes
place, approval must be obtained from either a local or
a multi-centre research ethics committee. This committee will scrutinize the design of the trial, the information given to the patients and the procedures for
obtaining consent, and that adequate compensation
and insurance are available.
Safety is assessed by close monitoring of clinical
signs and symptoms during scheduled clinical examinations and consultations, complemented by relevant
laboratory investigations. Baseline pre-treatment data
are compared with data obtained during periods of
treatment with the study medicine. However, systematic assessment of symptoms experienced by the
patients included in the trials is not always carried out
and a systematic checklist for patients to complete has
been suggested. Even with the numbers of patients
involved in Phases II and III, these trials can only
identify type A ADRs that affect 1 in 250 patients.
Type B ADRs, which are neither pharmacologically
predictable nor dose related, tend to be rare, so they
are more likely to be detected in post-marketing surveillance studies.
Post-marketing studies
Once the MHRA is satisfied that a product is safe,
efficacious and of suitable quality, it grants a marketing authorization, which means that the product can
then be promoted to prescribers. This means that
there is likely to be a large increase in the numbers
of patients using the product and it is important that
the authority continues to monitor its safety. The
MHRA operates a system of post-marketing surveillance which involves spontaneous reporting of suspected ADRs, similar to that in many other
countries. It is known as the Yellow Card system
and all prescribers, pharmacists and patients can report suspected ADRs directly to the MHRA (see Ch.
47). Such schemes provide early warning signals of
potential problems and can lead to hypotheses about
associations between a medicine and an effect. These
can then be tested using retrospective (e.g. casecontrol studies) or prospective studies (e.g. cohort
studies). The main problems with spontaneous
reporting schemes are under-reporting, difficulty in
identifying new ADRs and the fact that incidence
cannot be calculated, since there is no information
on the number of patients exposed to the medicine.
The benefits of patients reporting their ADRs to the
MHRA are currently being evaluated, but in other
countries it has been found that patient reports add
to the usefulness of data obtained through reports
submitted by healthcare professionals.
Case-control studies retrospectively identify
patients who have developed a particular ADR and
determine their level of exposure to the suspected
medicine. This is then compared to a control group
of patients without the ADR of interest. Case-control
studies are smaller, much less expensive and generate
results more quickly than cohort studies. They are
used to investigate suspected ADRs identified by
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SECTION THREE Pharmacy prescribing and selection of medicines
other means, e.g. cohort studies or spontaneous
reporting, and are particularly useful for confirming
type B ADRs. They are capable of establishing whether an ADR is caused by a medicine, but cannot measure the incidence of ADRs.
Cohort studies measure the incidence of ADRs in a
group of patients exposed to a medicine over a period
of time and compare this with the incidence in a
similar control group who have not been exposed to
the medicine. They are useful where a wide range of
ADRs are associated with a single medicine, but are
less useful for studying rare suspected ADRs. This is
because large numbers of patients are required and
must be followed up for prolonged periods of time,
which is very expensive and may result in patients
being lost to follow-up.
Safety assessment of marketed
medicines (SAMM studies)
Formal studies to evaluate the safety of medicines
which are sponsored by the pharmaceutical industry
are known as SAMM studies. A SAMM study is defined as a formal investigation conducted for the purpose of assessing the clinical safety of marketed
medicines in clinical practice. The conduct of these
studies is also subject to guidelines. SAMM studies
use the standard methods of case-control and cohort
studies, but may also involve further randomized clinical trials.
Further clinical trials against
other drugs/treatments
Most products are marketed having been subject to
clinical trials in relatively few patients, which may
have excluded certain patient groups. Furthermore,
trials may have been conducted against placebo to
demonstrate efficacy, but there may be no data on
the comparative efficacy of a new product versus an
existing treatment for the same condition. In addition,
basic research may highlight new theories of how diseases may be treated which require older medicines to
be tested for efficacy in conditions where they have
not been used previously. Examples of this are the
trials required to assess the efficacy of aspirin for
prophylaxis against stroke and beta-adrenoceptor
blockers in heart failure. As with any other clinical
trial, the design is important and the randomized controlled design is considered the most appropriate.
Evaluation of medicines in
children
While medicines used in adults must have undergone
this rigorous testing before reaching the market and
coming into widespread use, this is not the case for
medicines used in children. Since there are many
differences in both pharmacokinetic and pharmacodynamic aspects of medicines between children
of different ages and adults, there are now increasing
efforts to ensure that medicines to be used in children
are also tested in children. This may involve production of specific formulations but should ensure the
increased availability of medicines which have been
specifically adapted and licensed for use in children,
as well as providing more relevant information about
efficacy and toxicity.
Herbal and homoeopathic
medicines
Most herbal remedies are not licensed medicinal products and therefore no evaluation is required before
they are marketed. Some, however, hold a marketing
authorization similar to other medicines and so must
have fulfilled the same criteria of safety, quality and
efficacy (or effectiveness) and be accompanied by a
patient information leaflet. A new process of regulation has recently been introduced covering ‘traditional herbal medicines’ which will assess safety and
quality (see Ch. 20).
Homoeopathic remedies may be registered under
a scheme which again only assesses quality and safety,
and does not allow indications to be specified. A new
scheme has recently been introduced which does permit indications (minor ailments only) to be included
as part of the registration process for some products.
Pharmacoeconomic evaluation of medicines
Once a product is licensed, decisions must be made
about whether it should be used. Local decisions
may be made by drug and therapeutics committees
(see Ch. 18). On a larger scale, decisions on whether
new treatments should be available on the NHS
in England and Wales are made by the National
Institute for Health and Clinical Excellence (NICE)
and the Scottish Medicines Consortium in Scotland.
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