Control , historical trials

Regional chemotherapy combined with systemic chemotherapy reduces hepatic progression and may improve 2-year survival significantly according to phase III trials (Kemeny et al. 1999). Neoadjuvant chemotherapy may improve survival and extent of surgery according to phase II and historical control trials (Tanaka et al. 2003 Wein et al. 2003). 

S.5.5.2.3 Historical controls Since many clinical trials are conducted in the same diseases, with the same control treatments there is an obvious desire to make the most use of this potentially valuable information. Can we compare the results of a new treatment in a group of patients with a group of control patients extracted from a historical database For example, suppose we are testing a new treatment for migraine headache and 60% of patients improve in the first 2 h post-treatment, compared to 30% in a group of historical control patients treated who had been treated with the current gold standard. Are we able to conclude that the new treatment is preferable to the gold standard ... 

To understand the context of these other techniques, one should put them in perspective. One can rank methods for obtaining information in order of increasing confidence that the conclusions are valid. The order would be a single memorable case, a series of memorable cases, and a series of consecutive cases. The control observations for these would be historical controls, either articulated by the observer or merely understood. The assumption with the use of historical controls is that the controls are comparable to the patients and that the outcome of the treated patients if not given the new treatment would be identical to the historical controls. Often initial therapeutic trials of new cancer drugs are done in a consecutive series of treated patients and compared to historical controls. In these studies, the controls are usually not articulated. The authors assume that the natural course of the disease is so predictable in these patients that change from the predicted course is due to the drug. The validity of this assumption must be carefully examined when one interprets any study that is a case series. 

In clinical trials the cumulative risk of death 35 days after starting treatment was 9% in the lepirudin-treated patients, compared with 18% in historical controls cumulative risk of new thromboembolic complications was 6% with lepirudin and 22% in historical controls... 

The issue of constancy concerns the conditions under which the current active control trial is being conducted compared to the conditions under which the active control was established historically. Things may well have changed. For example, the nature of the underlying disease or the effectiveness of ancillary care may be such that the active control performs rather differently now than it did when the original placebo-controlled trials were undertaken. This may well be true, for example, for antibiotics where populations of patients will have developed resistance to certain treatments. If this were the case then the current non-inferiority trial could lead to a misleading conclusion of effectiveness for the new active when in fact the comparator treatment is ineffective. 

E. Therapeutic response Thrombin-dependent tests show dose dependency [aPTT rise proportionally to dose of Refludan]. The key criteria of efficacy in two pivotal clinical trials from a laboratory standpoint were platelet recovery and effective anticoagulation. Seven days after the start of treatment with Refludan in patients with HIT, the cumulative risk of death, limb amputation, or new thromboembolic complication was substantially lower than in a historical control group. 

This chapter provides some historical perspective and describes the evidence provided by randomized, double-blind, placebo-controlled trials of several of the most commonly used agents in this class. Ephedrine, the active principle in Ma-huang, is discussed in Chapter 9. 

It has been proposed that the phenomenon of DWI lesion reversal means that patients without perfusion-diffusion mismatch may still benefit from thrombolytic therapy (Kidwell et al. 2000). However, others consider more research is needed before adopting such an approach into clinical practice (Schellinger et al. 2003). We have not found that non-mismatch patients benefited from thrombolysis compared to historical controls (Parsons et al. 2002a). The ongoing Australasian Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) has been designed, in part, to answer the question of whether non-mismatch patients benefit from thrombolysis (Parsons et al. 2002a). 

This herb is also known as St. Joan s wort, klamath weed, and goatweed. It has historically been used for many purposes, but most recently it is marketed as an antidepressant. In fact, it outsells all conventional antidepressants in Germany. The active constituent is hypericin that seems to act as a weak monoamine oxidase MAO inhibitor and a selective serotonin reuptake inhibitor (SSRI). Dopamine and norepinephrine uptakes are also mildly inhibited. St. John s wort is available in many forms, as a tablet, tea, tincture, and the raw dried herb. For best results, a tablet standardized to contain 0.3% hypericin should be taken Kira by Lichtwer Pharma is the most extensively studied. Randomized, placebo-controlled trials using 300 mg of St. John s Wort three times daily have found it to be superior to placebo in mild to moderate depression. Response rates are generally regarded as inferior to conventional antidepressants, including... 

The efficacy of triple therapy with bismuth plus amoxicillin and metronidazole has been assessed in an open trial in 26 children with duodenal ulcers associated with H. pylori (15). Helicobacter pylori was eradicated in 25 children and the ulcer was healed in 24. During a mean follow-up of nearly 2 years, the annual ulcer relapse rate was 9% (compared with 56% in historical controls, in whom the infection was not eradicated). Adverse events were reported by 13% of the children, and included diarrhea, dizziness, nausea, and vomiting. 

Although randomized, controlled trials form the basis for some of the most reliable assessments of drug safety, pregnant women usually are not eligible for participation in clinical trials. Other types of data often are used to estimate the risk associated with medication use during pregnancy, such as animal studies, case reports, case-control studies, prospective cohort studies, historical cohort studies, and voluntary reporting systems. 

Colonization of the nares with Staphylococcus aureus is a well-described SSI risk factor. Two small prospective trials suggest that eradication of nasal S. aureus with mupirocin significantly reduces the incidence of SSI when compared with historical controls in patients undergoing both cardiac and upper gastrointestinal surgery. Larger prospective trials, however, are needed before this therapy can be advocated routinely. Other factors shown to increase the risk of SSI include age, length of preoperative hospital stay, and obesity. ... 

Farly trials of HAI revealed objective response rates ranging from 30% to 88%, many of which were observed in previously treated patients, as well as increased survival rates compared to historic controls. Because supportive care alone is no longer considered standard care for metastatic disease, when HAI was compared to systemic chemotherapy, most comparisons did not yield a survival benefit. Furthermore, the majority of studies have allowed patients in the systemic therapy treatment groups to crossover to HAI upon tumor progression therefore the impact of these treatments on survival is difficult to interpret. 

The results of these trials suggest rates of adverse outcomes in high-surgical risk patients which approach those from the normal-risk CEA landmark trials, but are underpowered to draw significant conclusions. Subsequent studies that enrolled broader patient population with respect to surgical risk provide some of the additional numbers to aid in further comparisons with the CEA historical controls. 

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