Extensive clinical trials

Attempts to improve the bioavailability of the organotin(IV) cations by the formation of water-soluble complexes or by their inclusion into )S-cyclodex-trin have also been reported. In spite of their widespread activity, these antitumor organotin(IV) complexes have not yet been subjected to extensive clinical trials in humans. 

Dobutamine (76), on the other hand, is a dopamine derivative which does not act centrally, but is of interest because of its coronary vasodilator properties. Such drugs are potentially of value in treatment of angina pectoralis. Further, it is now undergoing extensive clinical trials as an inotropic agent for use in heart failure. Its synthesis is effected by Raney nickel catalyzed reduction of methyl p-methoxyvinylphenylketone (75) to its dihydro analog followed by reductive alkylation with p-(3,4-dimethoxyphenyl)ethylamine. The ether groups are cleaved with HBr to complete the synthesis of... 

The 1962 Drug Amendment made three major changes in the manner in which new drugs could be approved (Merrill, 1994). First, and perhaps the most important, was that it introduced the concept of effectiveness into the approval process. An NDA had to contain evidence that the drug was not only safe, but also effective. The 1938 law contained no such specification. The effectiveness requirement necessitated that a drug company had to do more extensive clinical trials. The new law required that companies apply to the FDA for approval of its clinical testing plan... 

Adverse effects Extensive clinical trial studies for final products from oral or parenteral route Generally only known as a result of overexposure, accident, etc. 

Patent protection under general law usually lasts for up to around 20 years. This creates a difficulty in relation to medicinal products, as it can take some 12 years for the products to undergo research, development, the extensive clinical trials that are required in order to obtain a marketing authorisation and the authorisation process itself. These steps are also extremely expensive. The amount of time that remains during which the patent holder can exploit his patent and recoup his massive investment can be severely curtailed in relation to medicinal products. For this reason, the European Community has provided a form of additional patent-related protection for medicinal products authorised within the European Community, by means of a Supplementary Protection Certificate. A patent holder may apply for a certificate that takes effect at the end of the term of the basic patent, for a period equal to the period that elapsed between the date on which the application for the basic patent was lodged and the date of the first authorisation to place a product derived from the patent on the market in the Community, reduced by a period of 5 years. The maximum duration of the certificate is 5 years. The certificate applies to all medicinal products derived from the basic patent, but the additional time that can be obtained under the SPC is calculated in relation to the first product derived from the patent, authorised in the EU. 

The status of the extensive clinical trials of L-asparaginase against a number of forms of cancer, especially acute lymphatic leukemia, has been thoroughly treated in several recent reviews (106-109) and will not be dealt with here. 

Extensive clinical trials and premarketing studies were conducted before the Norplant (levonorgestrel) implant was registered and approved, in order to elucidate its... 

The development of the new class of compounds known as 5a-reduc-tase inhibitors has significantly advanced our understanding of androgen biology. Finasteride, a selective inhibitor of the human type 2 5a-reductase enzyme, was the first of this class of compounds in clinical development, and extensive clinical trials have established its usefulness... 

The most advanced of all the malaria, vaccine candidates is SPf66 (94,95). It is a synthetic polypeptide. The peptide represents several protective epitopes correlated to several proteins of the pre-erythrocytic and asexual blood stage of Plasmodianfalciporum. Extensive clinical trials with this vaccine have been carried out in South America and Africa (95—97). The efficacy of the vaccine varied in different regions, and generally lower than expected in a developed country. Consequently, the general application of the vaccine still generates much debate (98). However, this vaccine represents a major advance in the development of a malaria vaccine. 

Most recently, in a small double blind trial (Lane et al., 2008), sarcosine showed efficacy as monotherapy in acutely decompensated patients. Despite the small sample size, the monotherapy study represents a critical evolution of the NMDA-based therapeutic approach, which had up until then been limited to addon studies. In the study, no true placebo was used, although a lower dose of sarcosine was used as partial control and in order to evaluate the dose-dependence of findings. Obviously, more extensive clinical trials, as well as the introduction of high affinity, selective GLYT1 inhibitor compounds, are needed. 

Felix Hoffman worked for the manufacturers Bayer. His father suffered from arthritis and became sick when he took salicylic acid. He challenged his son to find a better alternative. Hoffman did this in 1893 when he made the compound acetyl salicylic acid. This compound went through extensive clinical trials and in 1899 it came on the market as aspirin (Figure 1.5). It proved to be a wonder drug and still is. 

Once the human safety and pharmacokinetic profiles are established the focus shifts to the design and conduct of early clinical trials that will confirm the hypothesized mechanism of drug action and characterize the differentiating features of the drug. These trials to establish mechanism of action and differentiation profile are the "killer experiments" that need to be conducted early in the program to provide the data to support a critically important Go/No-Go decision. It is essential to have answered the following four questions before proceeding to more extensive clinical trials in patients with the illness to be treated ... 

All short-course regimens include isoniazid, pyrazinamide and rifampicin. After extensive clinical trials, the following three have been found satisfactory ... 

Extensive clinical trials and premarketing studies were conducted before the Norplant (levonorgestrel) implant was registered and approved, in order to elucidate its mode of action, effectiveness, and adverse effects. However, none of these trials included either teenagers under 18 years of age or nulligravid women. 

The note for guidance CPMP/EWP/QWP/1041/98 on investigation of bioavailability and bioequivalence sets the criteria for showing pharmacokinetic equivalence and thus permits waiver of extensive clinical trials for demonstration of efficacy. 

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