Chapter 6 Official regulation of medicines
Basis for regulation
The principles of official (statutory) medicines regulation are that:
• No medicines will be marketed without prior licensing by the government.
• A licence will be granted on the basis of scientific evaluation of:
• A licence shall specify the clinical indications that may be promoted and shall be for a limited period (5 years), which is renewable on application. A regulatory authority may review the risk:benefit balance or safety of a drug at any time and restrict the licensing, or remove the drug from the market for good cause.1
• A licence may be varied (altered) by an application from the pharmaceutical company to update efficacy, safety and quality sections; safety and (less commonly) efficacy variations may be initiated by the regulatory authority.
Plainly manufacturers and developers are entitled to be told what substances are regulated and what are not,2 and what kinds and amounts of data are likely to persuade a regulatory authority to grant a marketing application (licence) and for what medical purpose. In summary, medicines regulation aims to provide an objective, rigorous and transparent assessment of efficacy, safety and quality in order to protect and promote public health but not to impede the pharmaceutical industry. Inevitably, an interesting tension exists between regulators and regulated.3
Historical background
The beginning of substantial government intervention in the field of medicines paralleled the proliferation of synthetic drugs in the early 20th century when the traditional and familiar pharmacopoeia4 expanded slowly and then, in mid-century, with enormous rapidity. The first comprehensive regulatory law that required pre-marketing testing was passed in the USA in 1938, following the death of about 107 people due to the use of diethylene glycol (a constituent of antifreeze) as a solvent for a stable liquid formulation of sulphanilamide for treating common infections.5
Other countries did not take on board the lesson provided by the USA and it took the thalidomide disaster6,7 to make governments all over the world initiate comprehensive control over all aspects of drug introduction, therapeutic claims and supply. In 1960–1961 in (West) Germany, the incidence of phocomelia in newborns was noted. The term means ‘seal extremities’ and is a deformity in which the long bones of the limbs are defective and substantially normal or rudimentary hands and feet arise on, or nearly on, the trunk, like the flippers of a seal; other abnormalities may occur. Phocomelia is ordinarily exceedingly rare. Case–control and prospective observational cohort studies in antenatal clinics where women had yet to give birth provided evidence incriminating a sedative and hypnotic called thalidomide; it was recommended for use in pregnant women, although it had not been tested on pregnant animals. The worst had happened: a trivial new drug was the cause of the most grisly disaster in the short history of modern scientific drug therapy. Many thalidomide babies died, but many live on with deformed limbs, eyes, ears, heart and alimentary and urinary tracts. The world total of survivors was probably about 10 000.
In the UK, two direct consequences were the development of a spontaneous adverse drug reaction reporting scheme (the Yellow Card system) and legislation to provide regulatory control on the safety, quality and efficacy of medicines through the systems of standards, authorisation, pharmacovigilance (see p. 52) and inspection (Medicines Act 1968). A further landmark was the establishment of the Committee on Safety of Medicines in 1971 (from 2006 renamed the Commission on Human Medicines) to advise the Licensing Authority in the UK. In 1995, the new European regulatory system was introduced (see below).
Despite these protective systems, other drug disasters occurred. In 1974 the β-blocking agent practolol was withdrawn because of a rare but severe syndrome affecting the eyes and other mucocutaneous regions in the body (not detected by animal tests), and in 1982 benoxaprofen, a non-steroidal anti-inflammatory drug, was found to cause serious adverse effects including onycholysis and photosensitivity in elderly patients. More recent examples that have gained wide public notice include the association of serotonin-specific reuptake inhibitors with increased risk of suicide behaviour and that of cyclo-oxygenase I and II inhibitors with cardiovascular disease (see p. 243).
Current medicines regulatory systems
All countries where medicines are licensed for use have a regulatory system. When a pharmaceutical company seeks worldwide marketing rights, its programmes must satisfy each of the following: the Food and Drug Administration (FDA) of the USA; the European regulations and guidance issued by the Commission and overseen by the European Medicines Agency8 (EMA); and the Japanese Pharmaceutical Affairs Bureau. The national regulatory bodies of the individual European Union members remain in place but work with the EMA, which acts as a single source of authority. National licences can still be granted through individual member states, which maintain particular responsibility for their own public health issues. Significant harmonisation of practices and procedures at a global level was also achieved through the International Conferences on Harmonisation (ICH) involving Europe, Japan and the USA.
In the European Union drugs can be licensed in three ways:
1. The centralised procedure allows applications to be made directly to the EMA; applications are allocated for assessment to one member state (the rapporteur) assisted by a second member state (co-rapporteur). Approval of the licence is then binding on all member states. This approach is mandatory for biotechnology products and for certain new medicinal products.
2. The mutual recognition (or decentralised) procedure allows applicants to nominate one member state (known as a reference member state), which assesses the application and seeks opinion from the other (concerned) member states. Granting the licence will ensure simultaneous mutual recognition in these other states, provided agreement is reached among them. There is an arbitration procedure to resolve disputes.
3. A product to be marketed in a single country can have its licence applied for through the national route.
The European systems are conducted according to strict timelines and written procedures. Once a medicine has been licensed for sale by one of the above procedures, its future regulatory life remains within that procedure. Safety updates have to be reviewed every 6 months for the first 2 years, then annually until 5 years. Thereafter, there may be a second renewal at 10 years, if safety issues demand.1 The renewal of a licence is primarily the responsibility of the pharmaceutical company, but requires approval from the regulatory authority. This provides the opportunity for companies to review, in particular, the safety aspects to keep the licence in line with current clinical practice. Any major changes to licences must be made by variation of the original licence (safety, efficacy or quality; see below) and supported by data, which for a major indication can be substantial.
Requirements
Authorisation for clinical trials in the UK
The EU Clinical Trial Directive 2001/20/EC harmonised the laws and administrative procedures relating to the regulation of clinical trials across Europe and replaced the previous legislation in each of the separate member states. It is implemented in the UK through the Medicines for Human Use (Clinical Trials) Regulations.9 All interventional clinical trials of an investigational medical product (so-called CTIMPs), including human volunteer trials, require regulatory approval through a Clinical Trial Authorisation (CTA) application that must include summaries of preclinical, clinical and pharmaceutical data. For most trials a response must be provided by the regulatory authority within 30 days, with a maximum of up to 60 days. There is a complementary process to allow for amendments to the original application, and there is a requirement to notify each involved regulatory agency when the trial is completed.
Regulatory review of a new drug application
A drug regulatory authority requires the following:
• Quality checks. Full information on manufacturing process including purity, stability, formulation.
tests carried out in animals to allow some prediction of potential efficacy and safety in humans (see Ch. 4).• Clinical (human) tests (Phases 1, 2, 3).
• Knowledge of the environmental impact of pharmaceuticals. Regulatory authorities expect manufacturers to address this concern in their application to market new chemical entities. Aspects include manufacture (chemical pollution), packaging (waste disposal), pollution in immediate use, e.g. antimicrobials and, more remotely, drugs or metabolites entering the food chain or water where use may be massive, e.g. hormones.
The full process of regulatory review of a truly novel drug (new chemical entity) may take months.
