Drug regulation seeks to ensure the quality of the whole process of making and using a new medicine. Thus there are strict regulatory requirements to adhere to on the synthesis, scale up and purity of the active ingredient of any medicine, alongside strict requirements to assess efficacy and safety before a medicine can be granted a licence for use in people (and indeed for use in veterinary medicine). The various control and regulatory mechanisms that regulate drug approval are pan-national and internationally adhered to during the preclinical and clinical development of a drug (which are summarized in Chapter 6, Chapter 7, Chapter 8, Chapter 9 ). These mechanisms aim to:
Protect the public from the conflict of interest between the necessity of drug companies to make a profit on their investment in developing a new medicine and the need of patients for beneficial medication.
Ensure standardized and agreed test panels for safety are used, and clinical efficacy testing is stringent.
Ensure the agreed pharmacopeia is adhered to with regard to purity and physicochemical properties (and therefore manufacturing processes).
Control access to drugs that require monitoring, and restrict access to drugs with abuse potential.
Drug Regulation for New Drugs
There are some differences in the approval processes between different bodies, for example the US Food and Drug Administration (FDA), the EU European Medicines Agency (EMA) and the Japanese Ministry of Health and Welfare. However there is also a process of harmonization (promoted by the International Council for Harmonisation of Requirements for Pharmaceuticals of Human Use (ICH), Chapter 9 ) attempting to make the regulatory processes more uniform across the world. The regulation processes for new drugs is described in Page et al., Integrated Pharmacology, 2nd edition pp. 83–87, and is condensed below.
In the United States, upon conclusion of a successful phase III clinical trial, the drug developer submits all preclinical and clinical data to the FDA in a New Drug Application (NDA) for review before a decision is made for approval for the drug to be used. The drug developer is required to create a ‘label’ that provides summarized details of the manufacturing process, pharmacokinetics, efficacy, toxicity and clinical trials and for which uses the drug is claimed to be of benefit. Once approved, the drug developer (company) is then given a licence for the drug to be marketed and used for the claimed indication(s). However, whilst the FDA has the power to approve the licencing and marketing of a drug for a particular indication, it cannot regulate use. Thus a physician may choose to use a drug on a patient for a non-approved disease indication which is termed ‘off-label’ use. If sufficient evidence is obtained from off-label use, this sometimes leads to the label being modified to reflect this broader use of the medicine.
In Europe, drug approval is currently regulated by both centralized and decentralized processes reporting to the EMA after clinical drug development is completed. A drug developer will summarize data in a ‘Summary of Product Characteristics’ (SmPC) file. Similar to the label in the United States, this will be reviewed before approval to market the drug is granted.
Centralized submissions in the EU are via the European Medicines Evaluation Agency (EMEA), with representatives from all member states, that appoints a rapporteur with a particular country’s regulatory agency that has responsibility for initial review on behalf of the member states. The rapporteur then submits an opinion to the Committee for Proprietary Medicinal Products (CPMP) to decide drug approval. Decentralized submissions in the EU occur via a member state initially, and the report and decision is then circulated to other member states to decide whether to adopt the decision in their own territories. Off-label use of a drug is less prevalent in Europe compared to the United States.
In Japan, the approval process is carried out under the authority of the Ministry of Health and Welfare (MHW) and the Central Pharmaceutical Affairs Council (CPAC), which consists of medical and pharmaceutical science experts. CPAC recommends a decision that is then implemented by the MHW. It is usually a requirement to make decisions from clinical trials conducted on the Japanese population, due to the perception that genetic variations in ethnic groups (for example Japanese compared to European or American populations) and cultural differences (that might influence preferred dosing regimens) require such tailored studies.
Rest of the world
Drug acceptance and use is regulated in most countries by other national agencies. Some may accept the decisions made in the United States, Europe and Japan, which have experienced and large regulatory authorities as a result of being the largest drug markets.