Clinical trials safety concerns

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

The exact role of rituximab in RA is not clearly defined, but it is indicated for patients with moderate to severe RA with a history of inadequate response to DMARDs and other BRMs. Rituximab carries a black-box warning of fatal infusion reactions and severe mucocutaneous reactions even though these events did not occur during the RA clinical trials. The benefits of rituximab must be tempered against the safety concerns reported with use of rituximab in the oncology setting. 

Additionally, there are specialized studies designed to address endpoints of concern for almost all drugs (carcinogenicity, reproductive or developmental toxicity) or concerns specific to a compound or family of compounds (local irritation, neurotoxicity, or immunotoxicity, for example). When these are done, timing also requires careful consideration. It must always be kept in mind that the intention is to ensure the safety of people in whom the drug is to be evaluated (clinical trials) or used therapeutically. An understanding of special concerns for both populations should be considered essential. 

Regulatory guidance for the conduct of clinical trials on vaccines is specific. Traditional phase I trials in normal volunteers are not conducted. Rather, all trials assess not only safety but also efficacy (or at least immunogenicity). Trials may well be challenge trials, that is, after immunization subjects are purposely challenged with exposure to the infective agent of concern. 

An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution s potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research. 

O Shaughnessy, J.A. et al.. Commentary concerning demonstration of safety and efficacy of investigational anticancer agents in clinical trials, /. Clin. Oncol., 9, 2225-2232,1991. 

An analysis of 656 Phase III clinical trials from 1990 to 2002 showed that 42% of them failed. Of the failed trials, 70 of them provided reasonably detailed data for further analysis. Out of these 70,50% failed on efficacy and 31% had safety concerns, with the remaining 19% being neither safer nor more effective than the current drugs. 

Supply on a particular patient basis encompasses various categories of unauthorised use of medicinal products. A product maybe imauthor-ised because it has been specially formulated for use it may be at the clinical trial stage of development, but be requested by doctors for use outside a trial it may have been authorised previously and then withdrawn from the market for commercial reasons, or because of safety, efficacy or quality concerns or it may be authorised currently, but for a different indication or patient population, or in a different country. 

The pharmaceutical industry presents many new challenges to such a person which include the interface with pharmacy and pharmacology, toxicological research, human volunteer studies, clinical trials and post-marketing surveillance to name just a few. Product safety is a factor which impacts on all of those endeavours and the pharmaceutical physician will be expected to work and provide advice within that framework. It will be clear to anyone that evidence of lack of safety in a medical product is not good news for the company concerned and that some level of protective action will often be required which in extreme circumstances may involve product withdrawal. It is, therefore, essential that the pharmaceutical physician should be absolutely clear what constitutes lack of safety in relation to the intended use of the product. 

Concerns about safety of the study drug may characterise the Japanese clinical trial, in a Phase 1 study, the dose escalation stops at the level of expected therapeutic dose or double dose of it, and is never escalated to identify any toxicity (except for anticancer drugs), if toxicity is observed in a Phase I study, even if it is at the highest dose or under experimental conditions, further study will be difficult. Everybody in the clinical trial is used to handle study drugs with no safety problems and there is the general concept that the drug must be safe. ... 

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