The most commonly performed clinical trials evaluate new drugs, medical devices, biologics, or other interventions on patients in strictly scientifically controlled settings, and are required for regulatory authority (in the USA, the Food and Drug Administration; in the EU, the European Medicines Agency) approval of new therapies. Trials may be designed to assess the safety and efficacy of an experimental therapy, to assess whether the new intervention is better than standard therapy, or to compare the efficacy of two standard or marketed interventions. The trial objectives and design are usually documented in a clinical trial protocol. In USA there is a 50% tax credit on clinical trials.

To be ethical, they must involve the full and informed consent of participating human subjects. They are closely supervised by appropriate regulatory authorities. All interventional studies must be approved by an ethics committee (in the USA, this body is the Institutional Review Board) before permission is granted to run the trial.

The study design that provides the most compelling evidence of a causal relationship between the treatment and the effect, is the randomized controlled trial. Observational studies in epidemiology such as the cohort study and the case-control study are clinical studies in that they involve human participants, but provide less compelling evidence than the randomized controlled trial. The major difference between clinical trials and observational studies is that, in clinical trials, the investigators manipulate the administration of a new intervention and measure the effect of that manipulation, whereas observational studies only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. These are fundamental distinctions in evidence-based medicine.

Currently some Phase II and most Phase III drug trials are designed to be randomized, double-blind, and placebo-controlled. This means that each study subject is randomly assigned to receive one of the treatments, which might be the placebo. Neither the subjects nor scientists involved in the study know which study treatment is being administered to any given subject; and, in particular, none of those involved in the study know which subjects are being administered a placebo. Of note, during the last ten years or so it has become a common practice to conduct "active comparator" trials (also known as "active control" trials) - in other words, when a treatment exists that is clearly better than doing nothing (i.e. the placebo) for the subject, the alternate treatment would be a standard-of-care therapy.

While the term clinical trials is most commonly associated with large randomized studies, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. Other clinical trials require large numbers of participants followed over long periods of time, and the trial sponsor is more likely to be a commercial company or a government, or other academic, research body. It is sometimes necessary to organize multicenter trials. Often the centres taking part in such trials are in different countries (in which case they may be termed international clinical trials).

The number of patients enrolled in the study also has a large bearing on the ability of the trial to reliably detect an effect of a treatment. This is described as the "power" of the trial. It is usually expressed as the probability that, if the treatments differ in their effect on the outcome of interest, the statistical analysis of the trial data will detect that difference. The larger the sample size or number of participants, the greater the statistical power. However, in designing a clinical trial, this consideration must be balanced with the greater costs associated with larger studies. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated and control groups. For example, a trial of a lipid-lowering drug with 100 patients per group, might have a power of .90 to detect a difference between active and placebo of 10 mg/dL or more, but only have a power of .70 to detect a difference of 5 mg/dL.

Rochester researchers join federal initiative to improve drug safety

Heart signals give clues about potential drug toxicity

The University of Rochester Medical Center will participate in a unique research partnership with the National Institutes of Health and the U.S. Food and Drug Administration (FDA) to develop new methods to assess the safety of drugs in clinical trials with greater speed and certainty.

The research, to be directed by Rochester researcher Jean-Philippe Couderc, Ph.D., will, for the first time, give scientists access to a huge FDA database of electrocardiograms (ECG) for the purpose of identifying early predictors of cardiac risk. This project is part of the "Critical Path" initiative launched two years ago by the FDA to accelerate the process of bringing medical breakthroughs to patients while at the same time ensuring safety and reducing drug development costs.

"Cardiac toxicity is a major issue for the pharmaceutical industry," said Couderc. "In recent years, many drugs have been pulled from the market because of concerns that they may cause adverse cardiac events. And this is not just limited to cardiac drugs; it also includes antibiotics, anti-psychotic, heartburn, and anti-histaminic drugs among others."

The most common form of this toxicity manifests itself in a drug's impact on cardiac repolarization – a split-second period between the heart's contraction and recovery phase. A drug-induced prolongation of this period, called the QT interval prolongation, can significantly increase risk for developing fatal arrhythmias and sudden cardiac death.

Beginning last year, the FDA required companies to submit ECG data from clinical trials in electronic form. The result has been the creation of a large – 500,000 and growing – electronic warehouse of ECGs. Couderc and his team will be the first outside researchers to gain access to this database.

Of particular interest to Couderc is a specific set of control data. The FDA requires drug companies to include ECGs from subjects who have been administered the drug moxifloxacin, an antibiotic that is known to prolong the QT interval. Because there is currently no standard measurement, the drug is used to demonstrate that the methods used by the drug companies to measure the QT interval are precise.

Couderc will use this and other data from the FDA to further refine a software program he has developed that enables researchers to precisely analyze ECG data. The software, called COMPAS (Comprehensive Analysis of Repolarization Signal), was designed to accurately identify ECG abnormalities, while taking into consideration other factors that may influence a person's heart activity, such as eating and stress. The goal of Couderc's research is to develop new measurements – or biomarkers – to identify cardiac risks associated with new drugs.

"The measurement of the QT interval is helpful wein lexikon but it is not a perfect surrogate marker of drug toxicity," said Couderc. "There is a crucial need for other ECG markers that would be more sensitive and more reliable and that is what we are aiming to provide with this technology."

Couderc believes that one potential new biomarker resides in the morphological analysis of the T-wave. Subtle changes in the shape or morphology of the T-wave – which comes at the end the QT or repolarization interval – could be a better indicator that a drug is interfering with ion channels in the heart's cells. The ion channels are protein structures that control the flow of ions responsible for producing the electrical activity of the heart. Interference with these structures diminishes the cells' ability to "recharge" between contractions, which, over time, may lead to lethal electrical dysfunctions of the heart.

Rochester is home to particular expertise in this field. The Heart Research Follow-up Program is an international leader in the science of heart arrhythmias and a rare genetic condition associated with an abnormal QT interval, called the congenital Long QT Syndrome (LQTS). The University keeps an International Registry for LQTS, and follows thousands of families who have this inherited condition. One of the genetic forms of the QT prolongation syndrome is similar to the drug-induced syndrome, and the University's work focuses on developing the tools to identify individuals with either condition.

Ultimately, more precise indicators of cardiac toxicity will not only improve the safety of new drugs, they will enable pharmaceutical companies to determine more quickly which new compounds pose a potential risk. This information could represent significant savings for drug companies; it is estimated that it costs, on average, $900 million to bring a new drug from the laboratory to the doctor's office.

Consequently, technology that is more precise and more consistent in detecting cardiac toxicity has a tremendous commercial potential. Earlier this year the University licensed the COMPAS software to iCardiac Technologies, Inc., a Rochester-based company founded by Couderc that is positioning itself as a leading provider of advanced cardiac safety analysis technologies.

External Links:
CDER Drug and Biologic Approval Reports
What is a Clinical Trial
Food and Drug Administration
Declaration of Helsinki
Declaration of Tokyo
Good Clinical Practices
Pharmaceuticals and Medical Devices Agency
WHO Model List of Essential Medicines
Clinical Data Interchange Standards Consortium
Nuremberg Code

theworldccr.org Clinical Research - Drugs, Health, Medical, Safety

Rochester researchers join federal initiative to improve drug safety

Heart signals give clues about potential drug toxicity

theworldccr.org
Clinical Research - Drugs, Health, Medical, Safety