Clinical development placebos

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

Tropane derivative tesofensine, also known as NS2330 (28), is reported to be a triple reuptake inhibitor. Its efficacy as a monotherapy in early Parkinson s disease was evaluated in a clinical trial however, it did not provide significantly greater benefits than placebo [90]. NS2330 is also reported to be in clinical trials for obesity [68]. NS2359 (GSK 372475, structure not disclosed), also a triple reuptake inhibitor, is reportedly in clinical development for depression and ADHD, as well as addictive disorders [68]. 

Within the past decade there has been significant interest in determining whether the use of clinical modeling and simulation software would increase the probability of conducting successful clinical trials (43). This approach incorporates the technique of pharmacokinetic-pharmacodynamic modeling that was discussed in Chapter 19 with the disease progression models described in Chapter 20. Although this type of a clinical development tool has considerable potential, the outcomes to date have been mixed. For example, this approach has identified the placebo-response rate for various disease states as an... 

Clinical development has to progress step by step, according to the general guidelines after each phase, the steering committee of investigators decided whether the study results justified whether or not to proceed to the next step. It was surprising to notice that the placebo was not considered as mandatory in dose determination studies (always mentioned in the protocols as placebo if necessary ), and it was never used in phase III studies, for ethical reasons, unless no reference treatment is available. This is still true today. 

Natural Products Bionovo reported phase II clinical development of MF-101, an ERp agonist, for the treatment of vasomotor symptoms in pre- and postmenopausal women. Two doses (5 and 10g) of MF-101 were more effective than placebo at reducing the frequency and severity of hot flashes. MF-101 is an aqueous ethanol extract of 22 herb species and showed selective ERp recruitment to target genes [105],... 

Phase 1/11 clinical studies The first-time-in-human PK and tolerability study likely will use the widest dose range and the highest dose ever in the clinical development. Therefore, it provides the unique opportunity to assess the clinical PK/PD data. A list of candidate surrogate markers both from preclinical studies or previous clinical experience should be established at this stage. The PK/PD information from the placebo controls should also be obtained because it is invaluable for future development. In addition, the interspecies differences in PK/PD responses should also be recognized. During Phase 11 development (especially proof-of-principle in Phase 11a), careful evaluation of PK/PD responses in both healthy subjects and patients should be performed to detect differences, if any. 

In the early clinical development phases, human subjects, who will usually be healthy, will be confined for varying periods of time while single or multiple doses of the product are administered and safety data are recorded. These subjects receive little in the way of benefit, except monetary compensation. When a reasonably safe and reasonably effective dose or dose range has been identified, the safety and efficacy of the product will be determined by studying patients with the indicated symptoms, condition or disease. Some of these patients will, of necessity, receive no treatment or treatment with inactive substances (placebo). 

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