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
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.
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.