Clinical Trials in The US

The relevant regulations governing the conduct of clinical trials in the U S are shown in Table 5.4. As they also reflect the principles of GCP, they are quite similar in requirements to those of the E U. However, because they apply to a single jurisdiction, they are framed to provide more prescriptive detail than can be found in the equivalent EU directives. Similarly, they are supported by the ICH- and FDA-specific guidelines. As most of the practices are the same as discussed in the previous section, the chapter will now just examine some of the aspects that are unique to the US regulations. 

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During placebo-controlled clinical trials in the US, a total of 0.26% pioglitazone-treated patients and 0.25% placebo-treated patients had ALT values 3 times or more the ULN. During all clinical studies in the US, 0.43% pioglitazone-treated patients had ALT values 3 times or more the ULN. 

Apocyanaceae, Ang./t p. alkal., approved in Europe and in clinical trials in the US... 

Like other potential biopharmaceutical products, FDA, Center for Biologies Evaluation and Research (CBER) regulates the production, testing and use of AAV vectors in human clinical trials, in the US. Many regulatory documents are available to help guide the researcher. These documents are available via the Internet on http //www.fda.gov.cber/guidelines.htm. Review of these documents prior to significant work towards production of vector for... 

These principles of GCP have been incorporated into regulations that govern the initiation and conduct of clinical trials. The process for undertaking clinical trials in the EU and the US shall now be examined. 

Globally, in excess of 500 candidate bio-pliarmaceuticals are undergoing clinical evaluation. The Pharmaceutical Research and Manufacturers of America (PhRMA), which represents the US drug industry, estimates that some 371 biotech medicines are undergoing trials in the US [27]. Of... 

In conclusion, the USA cGMP regulations apply to interstate commerce within the USA and to any facility worldwide, that exports pharmaceutical materials (drug products, APIs, or con wnents of these products) to the USA or, wishes to perform clinical trials in the USA. These facihties are open to inspection for cGMP compliance by US FDA inspectors and for those facilities found to be in non-compliance with these requirements the material will be deemed adulterated with respect to identity, strength, quality and purity. Products from these facilities will be refused entry for seU or use within the USA. Data from these facilities may not be accepted in support of regulatory filings. 

An IND application must be submitted to the FDA prior to the first clinical trial in the United States. In Europe, IMPD/CTA submission is required, and the content and expectations may vary country-to-country. For IND/IMPD EIH studies, the project team must plan for the manufacture and release of clinical trial materials as well as for the IND/IMPD documentation. A regulatory submission may not be required in certain ex-US/EU countries if the study is conducted in volunteers. For a study in volunteers not requiring an IND/IMPD, documentation needs are reduced but all other activities remain the same. 

Analytical methods and specifications must be established and validated so as to define and control the quality and purity of the raw materials, intermediates and the finished product. For many standard chemical raw materials, the development of specifications will not be necessary as they are already published in US and European pharmacopoeia (for example, standards for water, organic solvents and various excipients). The ultimate objective of these activities is to be able to manufacture the drugs required for clinical trials in accordance with good manufacturing practice (GMP). 

Requests for permission to conduct clinical trials with pharmaceuticals in the US are termed Investigational New Drug Applications (INDs). The applications are actually a request for an exemption to supply a drug without a marketing authorisation. A cover sheet (Form 1571) must accompany the application. This cover sheet should also be used with each subsequent communication with the FDA, with each form consecutively numbered, starting at 000 for the initial submission. A copy of the form is shovm in Figure 5.6. 

It is worthwhile to note that, in the US, where the applicant will just be dealing with a single authority, there is no need to re-submit data that was previously submitted as part of an IN D application to conduct clinical trials. Instead, the applicant can cross-reference the IND file. This does not apply in Europe, because clinical trial applications will have been submitted to individual Competent Authorities, whereas marketing authorisation applications are usually submitted either centrally to the European Medicines Agency (EMEA) or collectively to a number of Competent Authorities. Thus, the files need to be self-supporting. 

Genentech was founded in 1976 by scientist Herbert Boyer and the venture capitalist Robert Swanson. Headquartered in San Francisco, it employs almost 5000 staff worldwide and has 10 protein-based products on the market. These include hGHs (Nutropin, Chapter 11), the anti-body-based products Herceptin and Rituxan (Chapter 13) and the thrombolytic agents Ac-tivase and TNKase (Chapter 12). The company also has 20 or so products in clinical trials. In 2004, it generated some US 4.6 billion in revenues. 

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