Report of the MMR Expert Group
4 Vaccine Testing and Monitoring
This chapter describes:
the roles and responsibilities of the Joint Committee on Vaccination and Immunisation, the Committee on Safety of Medicines and the Medicines Control Agency (paragraphs 4.1 to 4.6);
How vaccines are tested, and the monitoring of adverse effects (paragraphs 4.7 to 4.18);
the licensing of MMR vaccines (paragraphs 4.19 to 4.25); and
the scope for importing unlicensed products (paragraphs 4.26 to 4.29) and how that relates to measles and mumps vaccines (paragraphs 4.30 to 4.35).
4.1 The Expert Group was asked to describe the process of vaccine testing and the monitoring of adverse effects, having regard to the role and remit of the Joint Committee on Vaccination and Immunisation (JCVI), the Committee on Safety of Medicines (CSM) and the Medicines Control Agency (MCA).
4.2 The Joint Committee on Vaccination and Immunisation is a statutory expert Standing Advisory Committee established in England and Wales under the National Health Service Act 1977. The Committee has no statutory basis in Scotland or Northern Ireland, but fulfils the same role and has the same responsibilities. The Committee has no executive function. Its terms of reference are:
"To advise the Secretary of State for Health, the Scottish Ministers, the Northern Ireland Ministers responsible for health and the National Assembly for Wales on matters relating to communicable diseases, preventable and potentially preventable through immunisation."
The Committee as a whole has a responsibility to provide high quality and considered advice and recommendations to Ministers on the matters set out in its terms of reference. This includes giving advice and recommendations on matters of both a "routine" nature and also on any specific or special matters that Ministers may from time to time request. In formulating its advice and recommendations, the Committee must take into account the need for and impact of vaccines, the quality of vaccines and their safety and the strategies to ensure that the greatest benefit to the public health can be obtained from the most appropriate use of vaccines. Members are expected to make a full and considered contribution to this work.
4.3 The Committee on Safety of Medicines (CSM) is one of the independent advisory committees established under the Medicines Act. It advises the UK Licensing Authority (UK Health Ministers) on the quality, efficacy and safety of medicines in order to ensure that appropriate public health standards are met and maintained. The Committee members are appointed, for 3-year terms, by UK Health Ministers following a wide-ranging consultation process. There are two lay members. The Committee's responsibilities are, broadly, two-fold:
To give advice with respect to safety, quality and efficacy in relation to human use of any substance or article (not being an instrument, apparatus or appliance) to which any provision of the Medicines Act 1968 is applicable.
To promote the collection and investigation of information relating to adverse reactions for the purpose of enabling such advice to be given.
Summaries of the minutes of all meetings of Committee are published on the MCA website.
4.4 The UK Medicines Control Agency (MCA) is the executive arm of the UK Licensing Authority. It is an Executive Agency of the Department of Health. Its primary objective is to safeguard public health by ensuring that all medicines on the UK market meet appropriate standards of safety, quality and efficacy. Safety aspects cover potential or actual harmful effects; quality relates to development and manufacture; and efficacy is a measure of the beneficial effect of the medicine on patients.
4.5 The Agency achieves that objective through:
a system of licensing before the marketing of medicines;
monitoring of medicines and acting on safety concerns after they have been placed on the market;
variation and renewal of marketing authorisations and reclassification of legal status;
inspecting standards of pharmaceutical manufacture and wholesaling;
enforcement of medicines legislation;
regulation of product information and advertising.
4.6 The Expert Group acknowledges the help and support provided by all those organisations in collating the material that follows.
A Summary of the Process of Vaccine Testing and the Monitoring of Adverse Effects
4.7 The control of medicines in the UK is primarily through the system of licensing laid down in EC legislation, in the Medicines Act (1968), and in relevant subordinate legislation. This legislation covers, among other things, the systems by which licences to manufacture, market, distribute, sell and supply medicinal products are granted by Ministers or, in the new centralised licensing system, by the relevant Community institutions.
4.8 The MCA operates a system of licensing before the marketing of medicines. Medicines which meet the standards of safety, quality and efficacy are granted a marketing authorisation (previously a product licence), which is normally necessary before they can be prescribed or sold. This authorisation covers all the main activities associated with the marketing of a medicinal product. The MCA carries out pre-marketing assessment of the medicine's safety, quality and efficacy, examining all the research and test results in detail, before a decision is made on whether the product should be granted a marketing authorisation.
4.9 Before a product is marketed, experience of its safety and efficacy is limited to its use in clinical trials. The conditions under which patients are studied pre-marketing do not necessarily reflect the way the medicine will be used in hospital or in general practice once it is marketed. Consequently, there is a continued need for vigilance to detect adverse effects that become apparent after marketing and when the medicine is more widely used among a greater variety of patients.
4.10 "Pharmacovigilance" is the process of:
(a) monitoring medicines as used in everyday practice to identify previously unrecognised or changes in the patterns of their adverse effects;
(b) assessing the risks and taking account of the benefits of medicines in order to determine what action, if any, is necessary to improve their safe use;
(c) providing information to users to optimise safe and effective use of medicines; and
(d) monitoring the impact of any action taken.
4.11 "Pharmacovigilance" uses many different sources of information including spontaneous adverse drug reaction (ADR) reporting schemes, clinical and epidemiological studies, the world literature, morbidity and mortality databases. The MCA and the Committee on Safety of Medicines are responsible for the UK's spontaneous adverse drug reaction reporting scheme (called the 'Yellow Card' reporting scheme) to which doctors, dentists, pharmacists and coroners/procurators fiscal report suspected adverse drug reactions. Health professionals are requested to report only serious III suspected adverse reactions for established medicines, whereas it is requested that ALL suspected adverse drug reactions are reported for the newer "Black Triangle" medicines. In addition, health professionals are strongly encouraged to report ALL suspected ADRs that have occurred in children whether associated with a "Black Triangle" or established medicine. The scheme provides an important early warning of suspected adverse reactions to medicines by collating information required to assess the association between the suspected adverse reaction and the medicine. This scheme may identify previously unknown side-effects or indicate that certain known side-effects occur more commonly than previously believed. It may also identify at-risk groups of patients for particular adverse reactions. Such findings can lead to changes in the marketing authorisation, for example restrictions in use, refinement of dose instructions or the introduction of specific warnings of side-effects in product information, which allow medicines to be used more safely and effectively.
4.12 When a hazard is considered unacceptable, a medicine may have to be withdrawn from the market. When drugs are removed from the market, action is usually taken voluntarily by pharmaceutical companies, but there are powers for the licensing authority to compulsorily vary, revoke or suspend marketing authorisations.
4.13 A European system for drug regulation was introduced in January 1995. There are three systems for licensing medicines in Europe: the centralised system by which a single EU licence is granted; a mutual recognition procedure whereby a licence in one Member State is recognised by others, and a national procedure for medicines licensed in only one Member State.
The main value of spontaneous reporting schemes, like the Yellow Card Scheme, is in the early detection of previously unrecognised possible drug safety hazards. It is recognised that the Yellow Card Scheme is particularly useful for identifying rare adverse drug effects, especially disorders that do not have a high background incidence and which occur in close temporal association to administration of the drug. The Yellow Card Scheme is recognised to be one of the best spontaneous reporting schemes in the world in terms of the level of reporting and has a proven track record of identifying new drug safety hazards. Although spontaneous reports are useful in signal detection, there are often limitations to their use in signal evaluation. While spontaneous reporting systems serve to generate hypotheses, drug safety signals often need to be further investigated by other methods, such as epidemiological studies, to confirm and quantify any risk.
Medicines Control Agency
4.14 The Committee for Proprietary Medicinal Products (CPMP) is the advisory body which advises on matters relating to medicines in the EU. The Pharmacovigilance Working Party is a working party of the CPMP with representation from all Member States, which provides a forum for reaching consensus on drug safety issues and for promoting the development of common pharmacovigilance practices. The MCA takes a leading role in European Pharmacovigilance. As laid down in European Community legislation, the regulatory authorities of the European Member States exchange information and work closely together on drug safety matters.
4.15 The work of the MCA in pharmacovigilance is conducted in a world-wide context, with close links and increasing information transfer with other regulatory authorities, for example the Food and Drug Administration (FDA) in the USA.
4.16 The MCA, like any other medicines regulator, does not routinely, proactively encourage companies to seek licences for products.The Expert Group notes that, in this sense, regulatory authorities in medicines cannot be compared directly with conventional regulators, for example, the Office for the Regulation of Electricity and Gas (OFREG), in terms of powers, roles and responsibilities. The responsibility for bringing a medicinal product to the market, and collating the necessary evidence to support licensure rests with the manufacturer. It is therefore vitally important that the MCA licensing process remains, rigorous and demanding. The Expert Group acknowledges that the MCA operates within a very robust system of medicine legislation, which is largely European, and therefore applies equally to all Member States.
4.17 Some submissions presented to the Expert Group raised questions about the value of the Yellow Card reporting scheme. While acknowledging the main strengths of the Yellow Card system, the data are not expected to serve an important role in substantiating or eliminating concerns about potential contributory long-term effects of immunisation. The Expert Group recognised that the use of the scheme for detection is limited when, under near-universal application of immunisation, there are potential difficulties in a health care professional attributing suspicion to gradual or delayed changes in a patient.
4.18 The Expert Group considers it important that the Medicines Control Agency should continue to work closely with the European Union, and appropriate corresponding bodies in individual Member States, to improve collaboration and monitoring of vaccine safety issues. The Expert Group also recommends that the MCA should regularly review the operation, management and voluntary nature of the 'Yellow Card' system in the light of such developments.
The Licensing of MMR Vaccines
4.19 A combined measles, mumps and rubella vaccine (MMR-I) was first licensed in the UK in 1972, but it was not actually used then, because combined measles, mumps and rubella vaccines were not introduced into the UK routine childhood immunisation programme until 1988, by which time MMR-II had replaced MMR-I (differing in the rubella virus strain only), and other similar combination vaccines had been licensed. Prior to 1988, the safety of measles, mumps and rubella combination vaccines was well established based on their world-wide use (over 500 million doses of MMR have been given since the mid-1970s); such vaccines had been routinely used in the USA since the early 1970s and in Scandinavia since 1982. Initially, a single dose was given, but a two-dose immunisation schedule with measles, mumps and rubella vaccine has existed in the UK since October 1996 (the first dose is given at 12-15 months and the second dose at 3-5 years).
Components/strains of MMR used since 1988:
From 1988 to present:
MMR II(Ender's Edmonston (measles), Wistar RA27/3 (rubella) and Jeryl Lynn (mumps) strains)
From 1998 to present:
Priorix(Schwarz (measles), Wistar RA27/3 (rubella) and RIT438 (derived from Jeryl Lynn (mumps) strains)
From 1988/89 to September 1992 (no longer used due to presence of Urabe mumps strain):
Pluserix (licence now cancelled) and Immravax(Schwarz (measles), Wistar RA27/3 (rubella) and Urabe Am 9 (mumps) strains)
4.20 Five combined measles, mumps and rubella vaccines have been licensed in the UK (including MMR-I). Three of these are still licensed and two (MMR II - Pasteur Merieux MSD and Priorix - GSK Biologicals) are routinely used in the national immunisation programme. Following the introduction of combined measles, mumps and rubella vaccine in 1988, sporadic case reports in the literature of mumps virus meningitis were reported in association with vaccines containing the Urabe Am 9 strain of mumps. Fewer cases were reported in association with combined measles, mumps and rubella vaccines containing the Jeryl Lynn strain. Since the Jeryl Lynn strain appeared to carry a lower risk of meningitis and meningo-encephalitis, only combined measles, mumps and rubella vaccines containing this strain were made available from 1992 (no licensing action has been taken against those containing Urabe Am 9 as the Committee on Safety of Medicines (CSM) concluded that the balance of risks and benefits remained positive).
4.21 In accordance with the principles of good clinical practice, the majority of clinical trials that supported licensure of these five MMR vaccines, similarly to other medicinal products, were sponsored by the company, were conducted by investigators experienced in the field, and were monitored by company personnel. The licensing procedure for the MMR vaccines was not different to that adopted for other vaccines or, indeed, for any other medicinal product.
4.22 Most of the studies enrolled children in the second year of life, although some enrolled children up to 13 years old. Details of adverse reactions were mostly recorded over 4-6 weeks post-injection, because children returned for assessment of their immune response to the vaccines around this time. A minority of children was followed for longer. However, post-marketing reporting of adverse reactions by the marketing authorisation holders and published studies of vaccine safety provide much additional information on the safety of these products.
4.23 In January 2001, an article by Mr Wakefield and Dr Montgomery in the journal Adverse Drug Reactions and Toxicological Reviews48 reviewed several papers which, the authors claimed, suggest that MMR vaccines are more harmful than the single component vaccines given separately and that MMR vaccine was licensed prematurely. These claims were thoroughly assessed, answered and rejected by CSM in January 2001 49.
4.24 The submissions presented to the Expert Group fully support the conclusion that MMR was appropriately and rigorously tested before introduction, consistent with standards and science relevant at the time. We note that the process has subsequently been formally reviewed by the MCA, who confirmed that licensing followed normal procedures, clinical trials met the satisfactory standards of the time and follow-up of patients was in accordance with usual practices on vaccine trials. The Expert Group also recognises that the MCA continually monitors the safety of MMR vaccines in clinical practice and, if necessary, updates the Marketing Authorisation and product information if and when new data become available. For example, the "signal" that idiopathic thrombocytopenic purpura (ITP) could be caused, very rarely, by vaccines has been examined. A recent publication 50 has shown that this signal is a genuine indication of a rare problem.
4.25 The Expert Group further recognised that the identification and analysis of conditions which appear to emerge some considerable time after the administration of any medicine, and which may or may not be connected, may require supporting epidemiological evidence.
Medicines Legislation and Policy: Unlicensed Products
4.26 The Medicines Act 1968 contains an exemption which allows the supply of unlicensed relevant medicinal products for human use (commonly known as "specials") in response to a genuine, unsolicited order, formulated in accordance with the specification of a doctor or dentist, and for use by his individual patients on the doctor's or dentist's direct personal responsibility. In the interest of public health the exemption is narrowly drawn, because these products, unlike licensed products, have not been assessed by the licensing authority against the criteria of safety, quality and efficacy.
4.27 Responsibility for deciding whether an individual patient has "special needs" which the licensed product cannot meet is a matter for the doctor responsible for the patient's care.
4.28 A medicinal product should be regarded as a "pharmaceutical equivalent" if:
it contains the same amount of the same active substance(s, or in the case of liquid dosage forms the same concentration;
it is in the same dosage form; and
it meets the same or comparable standards considered in the light of the clinical needs of the patient at the time of use of the product.
4.29 These restrictions on the import of unlicensed medicines are needed because, as already established, the unlicensed medicines known as "specials" have not been assessed by the licensing authority against the criteria of safety, quality and efficacy. To protect public health, manufacturers and importers of unlicensed "specials" must hold licences for the purpose and comply with their licence conditions. Importers' licence conditions include the requirement that they must notify the MCA on each occasion that they intend to import an unlicensed "special". Importation may proceed unless the importer has been informed by the MCA within 28 days that it objects to importation. The MCA may object, and prevent importation, if it has concerns about the safety or quality of the product, or because there is an equivalent medicinal product available, and it is not satisfied that there is a "special need" for the supply to an individual patient.
Importation Policy Specific to Measles, Mumps and Rubella Vaccines
4.30 Combined MMR is the licensed medicine recommended for immunisation of children against measles, mumps and rubella. There are single component measles, mumps and rubella vaccines licensed in the UK. The licensed measles and mumps vaccines are not currently marketed by their licence holders in the UK. However, rubella vaccines are available in the UK, and are used mainly for the immunisation of women of child-bearing age who have been found to be non-immune either before or between pregnancies.
The Medicines (Standard Provisions for Licences and Certificates) Amendment Regulations 1999 (SI 1999/4)
4.31 However, as set out above, existing legislation allows a licensed importer to import an unlicensed mono-component vaccine and supply it in response to a doctor's prescription to meet the "special needs" of an individual patient, on the doctor's direct personal responsibility. The process is summarised in the flow charts shown.
4.32 The Scottish Executive Health Department's Deputy Chief Medical Officer, Chief Nursing Officer and Chief Pharmaceutical Officer provided relevant guidance for all NHS health professionals in December 2000. A letter about the MMR vaccination programme stated that "unlicensed medicines may be imported for use in private practice or the NHS... in accordance with the provisions of the Marketing Regulations".
4.33 The MCA has confirmed that the importation of unlicensed monocomponent vaccines is not uncommon. The figures for 2001 are shown below. These unlicensed vaccines have not been assessed by the MCA against the criteria of safety, quality and efficacy.
Data for total numbers of doses of unlicensed imported monocomponent measles and mumps vaccines notified to MCA-I&E in 2001 (UK)IV
Qty Imported (No. Doses)
Moraten Berna ~ Vaccination
Jeryl Lynn strain
4.34 The choice of strain(s) of virus in vaccines is part of the childhood vaccination programme. While specifications of vaccines derived from similar strains might be expected to be broadly equivalent, the purpose of licensing, in part, is to assure that equivalence through the specification of manufacture, storage and testing of the individual product.
Importation Monitoring Process
4.35 Taking all of that into account, the Expert Group considers that vaccination records relating to individual patients should always include details of the name and batch number of the vaccine administered. The Expert Group recommends that the Scottish Executive should:
make this a standard requirement for vaccination records;
progress the concept of a lifelong vaccination record which would allow identification of the immunisation status of an individual throughout the health service - irrespective of age group and independent of setting;
require NHS Health Boards to put in place adequate quality assurance mechanisms to ensure accuracy and completeness of recording of vaccination data.
Chapter 4 - Summary of Key Points
MMR vaccines licensing followed normal procedure and was based on the provision of satisfactory data regarding safety and efficacy in adequate numbers of children. MMR vaccines were not licensed prematurely.
The safety of combined measles, mumps and rubella vaccines has been reviewed repeatedly by the Committee on Safety of Medicines and others. All of these expert groups have concluded that the evidence does not support an association between combined measles, mumps and rubella vaccines and inflammation of the bowel or autism. It is not that there is no evidence, but that the available evidence does not show an association.
UK legislation allows a licensed importer to import an unlicensed monocomponent vaccine and supply it in response to a doctor's prescription to meet the "special needs" of an individual patient, on the doctor's direct personal responsibility. Whether an individual patient has a "special need" which a licensed equivalent may not meet is a matter of clinical judgement by the prescriber.
The Expert Group has recommended that the MCA should continue to work closely with equivalent bodies across the world, and that, in Scotland, vaccination records relating to individual patients should always include details of the name and batch number of the vaccine administered.