The potential of the biotechnology industry to provide blockbuster products is clearly demonstrated by examples like Enbrel (for the treatment of rheumatoid arthritis in adults and of active polyarticular-course juvenile chronic arthritis), Remicade (for the treatment of rheumatoid arthritis and Crohn's disease), and MabThera (for treatment of stage III-IV follicular lymphoma and CD20 positive diffuse large B-cell non-Hodgkin's lymphoma). The EvaluatePharma database1 indicates that at least 265 biotechnology products are currently marketed globally, more than doubling the figure from 1995. It is clear that there are many more blockbuster products to come, with an additional 100 biotechnology products currently in Phase III/preregistration, and a further 1000 reported to be in active development.

With this exponential growth in biotechnology product development, it follows that there is a corresponding increase in biotech clinical trial experience. Nevertheless, biotech clinical development continues to be a challenging exercise, particularly early on in anticipating the regulatory requirements for gaining approval to conduct a trial and in latter-stage clinical requirements for marketing approval.

In biotechnology forums, it is sometimes said that biotechnology product development by small- to medium-sized companies (called small- and medium-sized enterprises or SMEs in the EU) will be leaner and more efficient than for traditional "big pharma" drug development. Although many accept this concept, the reality is that this hypothesis is yet to be fully tested. Of the more than 265 biotechnology products marketed globally, the vast majority have come from big pharma, and a significant proportion of the product candidates have come from SMEs. Due to the prohibitive cost of clinical development, however, the clear majority of products were partnered or licensed to big pharma. In the future, we anticipate that biotech product development by SMEs will continue to be leaner and more efficient than big pharma. For broad applications, the cost of clinical development will continue to require SMEs to partner with big pharma. But for rare and serious orphan diseases, there is an opportunity for SMEs to fulfill the promise of independent, lean, and more efficient drug development.

Progress in EU regulatory guidance As more experience is gained with biotech product development, more and more guidance documents are being produced by both the EMEA ( http://www.emea.eu.int/index/indexh1.htm) and the ICH ( http://www.ich.org/UrlGrpServer.jser?@_ID=276&@_TEMPLATE=254). From the EU perspective, two of the more significant developments include the publication of European Commission Directives 2001/20/EC² and 2003/63/EC.³

Table 1. Areas to consider for the first clinical trial application

In accordance with Directive 2001/20/EC, all investigational medicinal products (IMP) in clinical development, even those in early development, will need to demonstrate Good Manufacturing Practice (GMP) in concordance with the phase of development, which will be a significant challenge for many independent investigators and start-up biotech companies. An additional regulatory procedure will also be introduced. Before submitting any documents to an ethics committee or to the national regulatory authority (defined in the legislation as a "competent authority"), it will be necessary to register with the EUDRACT database. This database is intended to facilitate both the exchange of information between the trial sponsor and the competent authority, the National Regulatory Authority, and between competent authorities of different Member States. To register in the EUDRACT database, it will be necessary for the sponsor to provide administrative information as well as information on the IMP, the trial protocol, and the envisioned countries and sites where the trial will take place. A unique EUDRACT identification number will then be allocated for each clinical trial entered by a sponsor, and this number will be requested for Ethics Committee and competent authority submissions. One benefit of this additional EUDRACT process is that the system may prefill for the sponsor the subsequent Ethics Committee and National Regulatory Authority trial application forms.

Once a sponsor has obtained the EUDRACT identification number, Ethics Committee and competent authority approval is still required. In practice, there are still likely to be differences between Member States, but overall it is expected that the process will be better harmonized. The applications for each will be very similar, including:

• Administrative data
• Protocol
• Investigator's Brochure
• IMP Dossier (all Quality, Nonclinical and Clinical data on the IMP, and a integrated summary with an overall benefit/risk assessment)
• Subject-related information (patient informed consent, recruitment methods)
• Protocol-related information (where is the trial conducted in EU and outside EU, any other trials conducted with the IMP)
• Manufacturing documents (GMP, TSE, Viral Safety, Certificate of Analysis)
• Financial data (insurance, compensation, agreements, and contracts).