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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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76 BIOPHARMACEUTICALS
Table 2.6. Some clinical trial design types. Refer to text for full details
Randomized control studies (blinded or unblinded)
Historical control studies (unblinded)
Non-randomized concurrent studies (unblinded)
Cross over trial design
Factorial design
Hybrid design
Large simple clinical trials
Randomized control studies
This trial design, which is the most scientifically desirable, involves randomly assigning participants into either control or test groups, with concurrent testing of both groups. Randomness means that each participant has an equal chance of being assigned to one or other group. This can be achieved by, for example, flipping a coin or drawing names from a hat. Randomness is important as it:
• removes the potential for bias (conscious or subconscious) and thus will produce comparable groups in most cases;
• guarantees the validity of subsequent statistical analysis of trial results.
The trial may also be unblinded or blinded. In an unblinded (‘open’) trial, both the investigators and participants know to which group any individual has been assigned. In a single-blind trial, only the investigator is privy to this information, while in double-blind trials, neither the investigator nor the participants know to which group any individual is assigned. Obviously, the more blind the trial, the less scope for systematic error introduced by bias.
The most significant objection to the randomized control design is an ethical one. If a new drug is believed to be beneficial, many feel it is ethically unsound to effectively deprive up to half the trial participants from receiving the drug. One modification that overcomes the ethical difficulties is the use of historical control trials. In this instance, all the trial participants are administered the new drug and the results are compared to previously run trials in which a comparable group of participants were used. The control data are thus obtained from previously published or unpublished trial results. This trial design is non-randomized and nonconcurrent. While it bypasses ethical difficulties associated with withholding the new drug from any participant, it is vulnerable to bias. The trial designers have no influence over the criteria set for their control group. Furthermore, historical data can distort the result, as beneficial responses in the test subjects may be due not only to the therapeutic intervention but to generally improved patient management practices. This can be particularly serious if the control data are old (in some trials it was obtained 10-20 years previously).
Additional trial designs
Non-randomized concurrent clinical trials initially assign participants to a control or test group in a non-random fashion. These trials are run concurrently, but are unblinded. This introduces a danger that the control and intervention groups are not strictly comparable.
THE DRUG DEVELOPMENT PROCESS 77
Cross-over design trials represent an adaptation of randomized control trials in which each participant acts as his/her own control. In the simplest scenario, each participant will receive either a placebo or the test drug for the first half of the trial and will receive the alternative treatment for the second half. The order of placebo versus test drug for any individual is randomized. Hence, at any time point, approximately half the test participants will be receiving the placebo and the other half the test substance.
The major benefit of this design is the associated reduction in variability. This allows investigators to use smaller participant numbers to detect a specific response. This trial type, however, may only be used if there is sufficient evidence to show there is no carry-over effect from the first half to the second half of the trial. An extreme example of non-conformance to this requirement would be if the patient received the test drug during the first phase and was completely cured by it.
Factorial design represents yet another trial design of interest. This may be used to evaluate the effect of two or more interventions upon participants in a single trial (Table 2.7) and, hence, can be economically attractive.
Hybrid trial designs also have been used under certain circumstances. These generally combine elements of both historical and randomized control studies. They may be of particular interest if a substantial amount of control data are already available in the literature. Under such circumstances, a smaller proportion of the trial participants serve as control, whereas the majority of participants form the test group.
In some cases, the concept of a large, simple clinical trial has gained favour. This trial type would only be considered in cases where the intervention is easily administered and the outcome is easily measured. In such instances, simplified trial criteria are enforced, with the major prerequisites being recruitment of relatively large numbers of participants and randomization.
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