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Each reviewer then prepares a review report. This is forwarded to their supervisory officers, who undertake a second review. All of the reports are then sent to the division director who, in turn, recommends rejection or approval, or asks the sponsor to provide more information. On average, this entire process takes 12 months.
Even when the NDA is approved and the product goes on sale, the sponsor must provide the FDA with further occasional reports. These can be in the form of scheduled annual reports, but unscheduled reports are also required in instances such as the occurrence of an unexpected adverse response to the drug.
A similar general approach is taken by CBER with regard to drugs being developed under their auspices. The CBER ‘licensing process’ for a new drug consists of three phases: the IND phase (already discussed), the pre-marketing approval phase (licensure phase) and the postmarketing surveillance phase. The pre-marketing approval phase (i.e. clinical trial phase) aims to generate data which proves the potency, purity and safety of the product. Upon completion of clinical trials, the sponsor collates the data generated and submits it to the FDA in the form of a biologics licence application, which must provide a comprehensive description of both the product and product manufacture (including methods of QC analysis, product stability data, labelling data and, of course, safety and efficacy data).
A small number of biotechnology products are classified as medical devices and hence are regulated by the Center for Devices and Radiological Health. The first approved biotech product to come under the auspices of the CDRH was OP-1 implant. Marketed by Stryker
Biotech, OP-1 implant is a sterile powder composed of recombinant human osteogenic protein-1 (OP-1) along with bovine collagen. It is used to treat fractured bones that fail to heal. The product is mixed with sterile saline immediately before application, which entails surgical insertion of the paste into the fracture.
The overall philosophy behind granting a marketing authorization for a new drug is broadly similar in the USA and Europe. There are, however, major differences in the systems by which these philosophies are implemented in the two regions.
The European Union (EU) is currently composed of 15 member states and a total population of 371 million (compared with 249 million in the USA and 124 million in Japan — the other two world pharmaceutical markets). The total European pharmaceutical market value stands at ˆ70 billion, representing almost 33% of world sales (the US and Japanese figures are 31% and 21%, respectively). Annual expenditure on European pharmaceutical R&D stands at about ˆ17 billion.
Prominent within the EU organizational structure is the European Commission. The Commission is composed of 20 commissioners (with at least one being from each member state) and several thousand civil servants. The major function of the European Commission is to propose new EU legislation and to ensure enforcement of existing legislation (European drug law, therefore, comes under the auspices of the Commission).
Two forms of legal instrument can be issued from the centralized European authorities: a ‘regulation’ and a ‘directive’. A regulation is a strong legal instruction which, once passed, must be implemented immediately, and without modification, by national governments. A directive is a looser legal term, and provides an individual member state with 18 months to translate the flavour of that law into national law. Pharmaceutical law within the EU has been shaped by both directives and regulations, as discussed later.
National regulatory authorities
In all European countries, there exist national regulatory authorities. These authorities are appointed by the government of the country in question and are usually located in the national Ministry of Health. They serve to apply national and European law with regard to the drug development process. In many countries, different arms of the regulatory authorities are responsible for authorizing and assessing clinical trials, assessing the resultant drug dossier and deciding on that basis whether or not to grant a (national) marketing authorization/product licence. They are also often responsible for issuing manufacturing licences to companies (Chapter 3).
In the past, a company wishing to gain a marketing licence within Europe usually applied for separate marketing authorizations on a country-by-country basis. This entailed significant duplication of effort, because:
• the drug dossiers needed to be translated into various European languages;
• national laws often differed and, hence, different expectations/dossier requirements were associated with different countries;
• the time scale taken for dossier assessment varied from country to country.
Attempts to harmonize European pharmaceutical laws were accelerated in the 1980s. From 1985 onwards, a substantial number of European pharmaceutical directives have been adopted.