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David Thomson, BSc, MRPharmS, is
lead pharmacist for haematology,
and Toby Capstick, BSc, MRPharmS, is haematology pharmacist at
the Leeds Teaching Hospitals NHS Trust
Correspondence to David Thomson, Pharmacy Services,
The Leeds Teaching Hospitals NHS Trust, Leeds General Infirmary,
Great George
Street,
Leeds LS1 3EX
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The MRC Myeloma IX trial opened to recruitment in May 2003 and is the
first large, multicentre, national trial of thalidomide in a large patient
group. The trial is co-ordinated by the Northern and Yorkshire Clinical
Trials and Research Unit and two of its three principal investigators
are based in the Leeds Teaching Hospitals NHS Trust (LTHT).
A decision has been made in liaison with the Medicines and Healthcare
products Regulatory Agency to use a thalidomide product that incorporates
a risk management programme. Consequently LTHT, as the lead centre for
the trial, has been involved in trialling the risk management programme
for thalidomide and advising on the practicalities of the system.
We are now using the thalidomide product with a risk management programme
attached for all patients being dispensed thalidomide from LTHT, whatever
the indication. Thalidomide is being used within the trust as an unlicensed
treatment for erythema nodosum leprosum, graft-versus-host disease and
multiple myeloma.
Thalidomide — a history
Thalidomide was first marketed in West Germany in 1956 as a hypnotic
as well as a treatment for morning sickness. The drug was then
successfully launched in a number of countries, including Britain
in 1958, and was generally accepted as a safe and efficacious compound.
However, in 1961 it became clear that if it was taken during pregnancy
it could cause phocomelia, a rare congenital abnormality in which
the long bones fail to develop. At least 600 babies with phocomelia
were born in Britain and more than 10,000 throughout the world.
In the following year it was banned worldwide. The thalidomide
tragedy stunned health care professionals, the pharmaceutical industry
and public alike, resulting in an overhaul of the processes of
drug development and licensing. The Committee on Safety of Medicines
(CSM) was established in the UK in 1963, and similar groups were
set up all over the world.
Over the years some beneficial effects of thalidomide have been
recognised and it has been used as an unlicensed treatment for
various disorders such as multiple myeloma, erythema nodosum leprosum,
aphthous ulcers in HIV-infected patients, chronic graft-versus-host-disease
and a variety of tumours. In 1998 the US Food and Drug Administration
approved the marketing in the US of thalidomide for the treatment
of erythema nodosum leprosum, a complication of leprosy resulting
in painful skin lesions. When thalidomide was approved for use,
the FDA issued the following statement: “FDA today cleared
thalidomide for marketing ... while at the same time it imposed
unprecedented restrictions on the drug’s distribution. Because
of its well known potential for causing birth defects, thalidomide
will be among the most tightly restricted drugs ever to be marketed
in the United States.” |
Risk management programmes
When thalidomide was marketed in the US (see Panel above), the Food
and Drug Administration worked with Celgene, the thalidomide manufacturer,
to develop a risk management programme. The programme requires that only
licensed providers who are registered in the System for Thalidomide
Education and Prescribing Safety (STEPS) programme prescribe the
drug.
In addition, both male and female patients are required to follow
mandatory contraceptive measures and participate in a patient registry
and patient
surveys. Providers cannot prescribe thalidomide unless they have
had a written report of a negative pregnancy test. Following initiation
of treatment, pregnancy tests are conducted weekly for the first
month,
then monthly in women with regular menstrual cycles or bimonthly
in women with irregular cycles. Female patients have to acknowledge in
writing their understanding of reproductive warnings.
The prescribing physician is responsible for educating patients about
thalidomide and the STEPS programme. After this education, the patient
signs a multicopy informed consent form, which confirms his or her
understanding of the risks and benefits of treatment. Although pharmacists
do not have
a role in providing this patient education, the pharmacy has to register
with the manufacturer to qualify as a dispensing location. STEPS has
been successfully used in the US for monitoring approximately 80,000
patients over the past five years. There have been no known cases of
fetal exposure.
The European Agency for the Evaluation of Medicinal Products (EMEA)
has said in the past that if a recommendation for the licensing of
thalidomide
is ever made, the terms of the licence would be extremely strict. A
risk management programme would also be put in place so that, in theory,
fetal
exposure to thalidomide could never occur. A marketing authorisation
for thalidomide for the treatment of multiple myeloma and erythema
nodosum leprosum is currently being applied for from the EMEA by Pharmion,
a
Cambridge-based company. This company has designed a risk management
strategy for the safe prescribing of thalidomide as an integral part
of its application. This strategy is called the Pharmion Risk Management
Programme and is based on STEPS. Why risk management is needed
A number of otherwise safe and effective products have been withdrawn
as a result of inadequate management of their known risks. In July 2003
cisapride was withdrawn from the UK market. Lack of efficacy was not
the reason for this product withdrawal but rather it was the result of
cardiac toxicity. It could prolong the QT interval, which could lead
to life-threatening arrhythmias. Certain medical conditions and the concomitant
use of other drugs that prolong the QT interval were known to increase
this risk. According to the CSM, cisapride was associated with 386 reports
of serious ventricular arrhythmias (including 125 fatalities) and 50
cases of sudden, unexplained death worldwide. The CSM communicated the
risks to health care professionals in August 1998. However efforts to
minimise the co-prescribing of cisapride with contraindicated medicines
had only a limited effect and serious cardiovascular reactions, including
fatalities, continued to be reported. The loss of this medicine deprived
patients and clinicians of a useful agent for the treatment of a condition
with significant morbidity and mortality.
Despite the well-known teratogenic potential of isotretinoin, a treatment
for severe acne, fetal exposure to the drug has occurred in the UK. It
has been reported that 76 pregnancies were electively terminated during
the five-year period from 1992–96 because of fetal exposure to
isotretinoin.1 The authors of the report indicated that the actual number
of pregnancy terminations was probably much higher because of significant
under-reporting of elective abortions following isotretinoin exposure.
In the US a voluntary risk management programme has failed to prevent
exposure of the fetus to isotretinoin. In 1988, an FDA advisory committee
considered removing isotretinoin from the US market, but relented when
Roche Pharmaceuticals designed the Roche Pregnancy Protection Programme
for Women on Accutane. However this is a voluntary risk management programme,
which has reduced the incidence of pregnancy during isotretinoin treatment
by approximately 10-fold.2 A total of 402 pregnancies occurred among
124,216 women treated with isotretinoin between 1989 and 1993 and a further
136 pregnancies occurred during the month after discontinuing treatment,
despite this risk management programme. Most of these pregnancies were
electively terminated, but birth defects were reported in eight out of
32 liveborn infants.
The known risk of thalidomide causing
severe, life-threatening birth defects cannot be allowed to be managed
as inadequately as the above studies suggest it might be. However there
is already evidence that the risks of thalidomide are not being managed
at present in the UK. The All-Wales Dermatology Audit Committee, in 2001,
set out to assess prescribing and monitoring practices for thalidomide
in Wales.3 A questionnaire was completed by 17 of 19 consultant dermatologists
concerning thalidomide usage in Wales. Eleven of the 17 respondents had
used thalidomide in 40 patients. Five consultants had a total of 12 patients
currently taking thalidomide. Four patients (33 per cent) had received
an information leaflet and four had signed a consent form. Seven patients
(58 per cent) were identified as women of potentially child-bearing age
and none of these seven patients had had a pregnancy test before starting
thalidomide. In four cases either the patient or her partner had undergone
laparascopic sterilisation or vasectomy.
The EMEA met with Thalidomide UK, a group which campaigns for the rights
of people affected by thalidomide, in January 2003. In the past, the
group has been critical of attempts to license thalidomide and has warned
that it was a “ticking time bomb” and should remain banned.
Discussion focused on whether it should be licensed to help in other
indications. The group thought that it could not stand in the way if
thalidomide could do some good. This decision means that there is a role
for pharmacists in managing the risks of thalidomide within the risk
management programme to ensure that a fetal exposure does not occur.
It should also serve to highlight the fact that thalidomide use, and
its particular well-known risks, will be examined more intensively than
for any other drug by media, support groups and public in the UK alike.
These groups will undoubtedly regard, due to its history, a fetal exposure
to thalidomide as far more serious than the adverse effects of other
agents. The health service cannot afford the legal implications of a
fetal exposure to thalidomide nor can we deny patients the use of a drug
that appears to be extremely useful in the treatment of a variety of
very serious conditions because of a failure to manage the risks appropriately. Arguments against a risk programme
A number of problems, however, do remain with the concept of the risk
management programme. The fact that patients are required to provide
sensitive personal information to a central registry could open up
the potential for breach of privacy. Informed consent forms could be
interpreted by the legal system as the patient’s written acceptance
of all risks associated with the product, which could limit their legal
options. The signing of an informed consent form in order to receive
thalidomide could be seen as a type of coercion: the patient must sign
the form to obtain a beneficial medicine. However, how the legal system
would view these points will probably not be known unless fetal exposure
is not prevented, resulting in legal action. Using a risk management
programme can only reduce the risk of this happening.
The US experience has seen the STEPS risk management programme being
used as a template by the FDA for the regulation of other high-risk medicines.
Risk management programmes exist for isotretinoin, cisapride and dofetilide.
This creates a number of shortcomings. There is lack of consistency for
different programmes making compliance difficult, due to health care
professionals being required to learn details of a number of different
programmes. Setting up a unique drug distribution and management system
for a high-risk medicine can also increase product costs and, certainly
in the UK, the thalidomide product with a risk management programme attached
is substantially more expensive than the alternative products that have
no risk-management system attached. In addition the cost associated with
developing and implementing these programmes could dissuade manufacturers
from developing useful therapies with serious but avoidable risks.
It is to be hoped that the EMEA, if it does issue a recommendation for
the use of a risk-management programme with thalidomide, will develop
a set of criteria to determine a drugs risk and whether it is enough
to warrant a special risk management. Without specific criteria to determine
risk, the future may involve many if not all medicines requiring some
form of risk management programme. This would be unworkable for patients,
health care providers and the pharmaceutical industry alike. Imagine
a scenario where all chemotherapeutic agents had to be prescribed and
dispensed via risk management programmes! The Leeds experience
The pharmacy department at LTHT plans to support the risk management
programme through the use of a specialist pharmacist, a pharmacist
who will be dedicated to the issue for at least the first six months
of implementation. We see the role of this pharmacist as being multifaceted.
It is essential that within our trust there are standard operating
procedures in place to ensure the safe supply of thalidomide and, of
course, this will lead to a requirement to educate both pharmacists
and doctors within our organisation. This will be an important role
and would also involve sharing the approaches used in Leeds with other
organisations.
One of the dangers of the risk management programme is that it focuses
the patient and clinician on the teratogenicity of thalidomide and the
need for contraceptive measures to be taken. While mentioning the other
substantial side effects of thalidomide, the risk management programme
does not focus on them as intently as it does on the teratogenicity.
These side effects include dose-limiting neuropathy, sedation and constipation.
The patient should be educated to report signs of adverse events, take
thalidomide in the evening three to four hours before going to bed and
maintain a good fluid intake. We plan for the pharmacist to undertake
the patient education on these specific issues and to investigate the
role of pharmacists in patient education and acquiring patient consent
generally.
Pharmacists’ supplementary prescribing has now been approved, and
we will also be considering the role of the supplementary prescriber
in the supply of thalidomide in the future. We see this risk management
programme as an opportunity for pharmacists because they are regarded
as a crucial element in the process. It is essential therefore that we
use this opportunity to make sure our views on risk management programmes
and their implementation are heard both locally and nationally.
Although we agree with the need for a risk management programme for thalidomide,
there is an alternative argument that thalidomide should not be treated
specially and that each pharmacy should be capable of putting systems
in place locally to manage the risks of all the drugs they dispense.
The advent of the thalidomide risk management programme should therefore
also have the effect of making us review our practices and policies for
all medicines, ensuring all risks are appropriately managed. Indeed the
only way to prevent high-risk medicines coming under the restrictive
rules of a risk management programme will be for pharmacists to continue
taking the lead in the day to day management of all medicines. References
1. Holmes SC, Banowska U, Mackie RM. The prescription of isotretinoin
to women: is every precaution taken? British Journal of Dermatology 1998;138:450–5.
2. Lary JM, Daniel KL, Erickson JD, Roberts HE, Moore CA. The return
of thalidomide: can birth defects be prevented? Drug Safety 1999;21:161–9.
3. Chave TA, Finlay AY, Knight AG. Thalidomide usage in Wales: the need
to follow guidelines. British Journal of Dermatology 2001;144:310–5. |
The
Pharmaceutical Journal