ההתייחסות בהנחיה בינלאומית מוכרת ICH-E10
CHOICE OF CONTROL GROUP AND RELATED ISSUES IN CLINICAL TRIALS (2001)
סעיף 2.5.3 עוסק באופן פרטני בשאלה האתית של ניסוי בטיפול במחלות קשות עם קבוצת ביקורת, כאשר התוצאות הראשוניות בתרופה נראות מבטיחות בהצביען על יתרון לעומת הטיפול המיועד לקבוצת הביקורת. ניכרת בו התלבטות ערכית בין שמירה על טובת החולה לבין הרצון לבחור בשיטת ניסוי שתניב תוצאות ברורות. מול הטענה האתית של טובת החולה מועלית טענה אתית נגדית, שניסוי שמראש לא יכול להניב תוצאה נחשב "לא אחראי או לא אתי".
מועלית גם הטענה שבמקרים רבים הציפיות שנתלו בתחילה בתרופות חדשות התבדו בעת שהגיעו לניסויים מול קבוצת ביקורת.
בנוסף לכך, בסעיף 2.5.7נטען שהניסיון מלמד שקיימת נטיה קבועה להעריך את האפקט שמתקבל בניסויים עם "קבוצת ביקורת היסטורית" (ללא קבוצת ביקורת עכשווית) מעל ערכו האמיתי.
לפיכך, בסעיף 2.5.4 ממליצים להגביל את הוויתור על קבוצת ביקורת עכשווית
(concurrent control group) למקרים שהאפקט מאד ברור וקיימים תנאים טובים להשוואה עם הטיפול החלופי (או אי טיפול).
מתוך המסמך ICH-E10 מ 2001
CHOICE OF CONTROL GROUP AND RELATED ISSUES IN CLINICAL TRIALS
External Control (Including Historical Control) (1.3.5)
An externally controlled trial compares a group of subjects receiving the test treatment with a group of patients external to the study, rather than to an internal control group consisting of patients from the same population assigned to a different treatment. The external control can be a group of patients treated at an earlier time (historical control) or a group treated during the same time period but in another setting. The external control may be defined (a specific group of patients) or non-defined (a comparator group based on general medical knowledge of outcome). Use of this latter comparator is particularly treacherous (such trials are usually considered uncontrolled) because general impressions are so often inaccurate. So-called baseline-controlled studies, in which subjects' status on therapy is compared with status before therapy (e.g., blood pressure, tumor size), have no internal control and are thus uncontrolled or externally controlled (see section 2.5).
Ethical Issues (2.5.3)
When a drug is intended to treat a serious illness for which there is no satisfactory treatment, especially if the new drug is seen as promising on the basis of theoretical considerations, animal 28 data, or early human experience, there may be understandable reluctance to perform a comparative study with a concurrent control group of patients who would not receive the new treatment. At the same time, it is not responsible or ethical to carry out studies that have no realistic chance of credibly showing the efficacy of the treatment. It should be appreciated that many promising therapies have had less dramatic effects than expected or have shown no efficacy at all when tested in controlled trials. Investigators may, in these situations, be faced with very difficult judgments. It may be tempting in exceptional cases to initiate an externally controlled trial, hoping for a convincingly dramatic effect, with a prompt switch to randomized trials if this does not materialize.
Alternatively, and generally preferably, in dealing with serious illnesses for which there is no satisfactory treatment, but where the course of the disease cannot be reliably predicted, even the earliest studies should be randomized. This is usually possible when studies are carried out before there is an impression that the therapy is effective. Studies can be monitored by independent data monitoring committees so that dramatic benefit can be detected early. The concurrently controlled trial can detect extreme effects very rapidly and, in addition, can detect modest, but still valuable, effects that would not be credibly demonstrated by an externally controlled trial.
2.5.4 Usefulness of externally controlled trials and validity of inference in particular situations
An externally controlled trial should generally be considered only when prior belief in the superiority of the test therapy to all available alternatives is so strong that alternative designs appear unacceptable and the disease or condition to be treated has a well-documented, highly predictable course. It is often possible, even in these cases, to use alternative, randomized, concurrently controlled designs (see section 2.1.5). Externally controlled trials are most likely to be persuasive when the study endpoint is objective, when the outcome on treatment is markedly different from that of the external control and a high level of statistical significance for the treatment-control comparison is attained, when the covariates influencing outcome of the disease are well characterized, and when the control closely resembles the study group in all known relevant baseline, treatment (other than study drug), and observational variables. Even in such cases, however, there are documented examples of erroneous conclusions arising from such trials. When an external control trial is considered, appropriate attention to design and conduct may help reduce bias (see section 2.5.2).
