The new article highlights the key points related to the controls in comparative clinical outcome studies.

The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to the design considerations for pivotal clinical studies. The document outlines specific aspects related to different types of studies and describes the approach to be applied to ensure the accuracy and reliability of study results. It is also important to mention that provisions of the guidance are non-binding, nor are intended to introduce new rules or impose new obligations, but rather to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered by medical device manufacturers, study sponsors and other parties involved to ensure compliance thereto. 


Controls in Comparative Clinical Outcome Studies: Key Points 

According to the existing legislation, there are four types of controls, and the study protocol should contain a comparison of the results with a control. Furthermore, a study protocol should contain detailed enough information regarding the control used, together with the description of methods used to minimize potential bias appearing when the clinical data is being collected and analyzed. This should also include information regarding the methods used for masking (blinding). Regulation 21 CFR 860.7(f)(1)(iv) describes the following four types of controls:

  1. Not treatments. Where objective measurements of effectiveness are available and the placebo effect is negligible, a comparison of the objective results in comparable groups of treated and untreated patients;
  2. Placebo control. Where there may be a placebo effect with the use of a device, a comparison of the results of the use of the device with an ineffective device used under conditions designed to resemble the conditions of use under investigation as far as possible;
  3. Active treatment control. Where an effective regimen of therapy may be used for comparison, e.g., the condition being treated in such that the use of a placebo or the withholding of treatment would be inappropriate or contrary to the interest of the patient;
  4. Historical control. In certain circumstances, […], the results of the use of the device may be compared quantitatively with prior experience historically derived from the adequately documented natural history of the disease or condition in comparable patients or populations who received no treatment or who followed an established effective regimen (therapeutic, diagnostic, prophylactic).

Apart from the ones listed herein, the authority also distinguishes an additional one – “Subject Serving as Own Control”. 

It is important to mention that in the context of the guidance, the term “intervention” is often used to replace “treatment” concerning specific procedures falling within the scope of diagnostic, therapeutic, and aesthetic interventions. 

The authority further explains that each of the controls described in the guidance has its advantages and limitations when applied in the course of an investigation. Under the general rule, concurrent controls allow for minimizing bias more efficiently in comparison to non-concurrent ones. 

Control Types in Detail

The document also provides a table that describes in detail the existing types of controls and highlights the key points associated with each of them. According to the table, the four main types outlined in the regulation are concurrent ones, while the “Subject as own control” proposed by the FDA is a non-concurrent control. The latter provides a comparison of the initial condition of the study subject (baseline) to the condition of the same subject after the intervention (assessing the study outcomes and evaluation of the endpoints). However, the authority acknowledges that the said approach will be inappropriate for most types of studies since the results could be affected by numerous factors that are not related in any way to the medical device in question, hence, will not be reliable and accurate to the extent required. 

The table also describes a non-concurrent historical control which provides that clinical data used derives from another group treated in the past. The main concerns related to the use of such controls are associated with compatibility between two groups, as well as the adequacy of treatment methods used for the initial group (they may become no longer relevant due to medical technology development). Some of these concerns could be addressed by applying statistical methods of analysis; however, the final results remain sensitive to the evaluation methods, as well as the quality and scope of data available concerning the initial investigation used as a baseline. 

The table also contains a detailed description of all four main types of controls, including the key considerations associated thereto. 

  1. Active Intervention Control (“Active”) stands for the approach when the control group is provided with a different intervention, while the effect of such intervention is known in advance. Hence, the approach will demonstrate whether the results achieved with the use of the device in question are better in comparison to the ones achieved for the control group. At the same time, the effectiveness of this control depends on the knowledge regarding the treatment used for the control group and the possibility to predict it with sufficient accuracy. 
  2. Placebo Control (“Sham”) provides that the medical device used for the control group has no effect. Even though such an approach is quite efficient in situations when the placebo effect may take place, sometimes it is difficult to ensure the device having no effect operates like the one which does. The authority also mentions that in some cases, it may be unethical to randomize subjects to a placebo that will provide no known effect.
  3. “No Intervention” Control provides that no intervention applies to the control group. This approach could be challenging as it requires study subjects to be involved who will not receive any treatment. 

In summary, the present FDA guidance describes in detail the main types of controls to be used in the context of clinical outcome studies. The document highlights the key points related to each type of the studies and outlines the most important aspects study sponsors should pay attention to. 



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