From clinical trials to clinical practice: Generalizing from participant to patient

This paper uses the report of the Lipid Research Clinics Coronary Primary Prevention Trial as an example of how clinicians apply the results of clinical trials to their practice. Clinical trials influence practice primarily to the extent that they eventually become incorporated into the generally accepted standard of medical care. To a lesser extent, physicians are influenced by their own interpretation of clinical trial results. Since physicians usually do not have the leisure or the technical expertise to evaluate primary data critically, their conclusions are heavily influenced by the authors' sometimes overoptimistic interpretation of the results. Therefore, practicing clinicians often overestimate the benefits of a therapy and generalize the results of a trial too broadly. Ideally, physicians should base treatment decisions on their knowledge of the pathophysiology of the disease, the mechanism of action of the proposed treatment, and the clinical characteristics of the individual patient while informing their decision with a critical understanding of the results of relevant trials.     

Hypertension from Framingham to ALLHAT: translating clinical trials into practice

Despite decades of observational and clinical data about the effectiveness of treating hypertension, most Americans are still not being adequately treated. It makes little sense that much of our efforts are directed toward performing large trials to find out whether newer, more expensive agents are superior to conventional therapy, especially when little evidence shows any benefit to the newer drugs. Rather, our priority should be to treat more patients and to treat them more aggressively.     

Quality of Japanese clinical trials estimated from good clinical practice audit findings

To describe qualitatively recent changes in the Japanese clinical trial environments, we compared the results of the Good Clinical Practice (GCP) audits conducted from April 1997 to March 2000 (FY1997 to FY1999) with those from April 2002 to March 2003 (FY2002). In addition, the audit results were compared between the United States and Japan. The audit findings in the former period were based on the official audits by the Organization for Pharmaceutical Safety and Research (OPSR) that covered 331 hospitals and 775 trials. The audits by the OPSR in the latter period targeted 136 hospitals and 226 trials. The total number of deficiencies detected in the Good Clinical Practice audits in the former 3-year period (FY1997 to FY1999) was 1529, and the number in the single year (FY2002) was 1627. The total number of deficiencies detected and reported was about 3-fold on an annual basis between the periods. By category of deficiencies, there were 2 remarkable changes in the OPSR's audit findings between FY1997-FY1999 and FY2002. One was an increase in the proportion of protocol deviations from 14.7% (225/1529) in FY1997-FY1999 to 48.2% (785/1627) in FY2002, and the other was a decrease in the proportion of case report form-related deficiencies from 43.6% (666/1529) to 16.0% (260/1627). The high prevalence of protocol nonadherence and the relatively few findings of informed consent errors were important characteristics of Japanese trials inferred from the audit result reported by the OPSR in FY2002. In the United States, relatively high proportions of protocol nonadherence and informed consent errors were observed in the audit finding reported in 1997. Although the audit results for clinical trials between the United States and Japan are not strictly comparable, our results suggest that protocol deviations are a compelling issue for quality improvement in the conduct of clinical trials for the 2 regions.     

Designing clinical trials to evaluate mucus clearance therapy

Mucoactive therapy is meant to improve quality of life by making it easier to breathe and reducing the need for hospitalization and antibiotic therapy. There are a number of challenges when designing a clinical trial to test the effectiveness of potentially mucoactive therapy. These challenges can be categorized as understanding the mechanism of action for the intervention, understanding the disease being treated, and recognizing relevant outcomes that can be accurately measured. Dose, duration, route of administration, and effectiveness of a therapy are all influenced by mechanisms of action. Mucoactive therapy may not change sputum expectoration volume, expiratory airflow, or dyspnea sensation, although these are commonly measured. While clinically relevant outcomes are most informative, surrogate outcomes can be of value. The natural variability of the outcome measure in question in the population being studied must be known in order to design an appropriately powered study. The natural course of the disease being studied and the ability to accurately measure disease severity must be known in order to choose whether studies are conducted during periods of disease stability, at the time of an exacerbation, or immediately following successful therapy for an exacerbation. This information is also critically important in identifying an appropriate control group. These challenges can be met to advance our knowledge and to develop truly effective therapy for mucus clearance disorders.     

Adherence in clinical trials and in clinical practice

The degree of patient adherence is increasingly recognized to be a key factor in the success of highly active antiretroviral therapy (HAART). HAART regimens are also among the most complex ever prescribed and low adherence is directly related to treatment complexity. Physicians prescribing HAART need to make adherence a priority both in clinical practice and in the design and interpretation of clinical trials if HAART really is to succeed in the long term.     

Antiplatelet therapy in acute coronary syndromes: implications for nursing practice

The care of cardiovascular patients experiencing a myocardial infarction (MI) has evolved from simple bed rest and relief of pain to complex interventions and multiple medications that target both the short- and long-term risks associated with atherosclerosis and ischemia. Even the terminology has changed, from MI to acute coronary syndromes (ACSs). The term, acute coronary syndrome, refers to the clinical symptoms resulting from acute myocardial ischemia; it encompasses unstable angina, non-ST-elevation MI, and ST-elevation MI. Antiplatelet therapies are critically important in the management of patients with ACS. Antiplatelet therapies interfere with platelet aggregation and platelet activation both acutely and chronically and thus impact the development of acute MI. Thus, they are prescribed for millions of patients with ACS. As a result of this progress in treatment, nursing management of persons with ACS has also evolved. This article reviews the pathophysiology of ACS, the role of antiplatelet therapies, their effects on platelet adhesion, and the role of the nurse in caring for patients with ACS who are prescribed these important therapies.     

Migraine prevention trials and optimized acute therapy: Translating lessons learned into clinical practice

Different classes of drugs, discovered by serendipity, have been used successfully for migraine prevention for more than 40 years. The progressive knowledge of migraine pathophysiology, brain hyperexicitability, and the specific neurotransmitter systems involved in pain perception has driven the attempts at targeting two crucial mechanisms: the restoration of nociceptive dysmodulation and the inhibition of cortical hyperexcitability. The success of modern research trials with preventive migraine agents (mainly neuromodulators) and optimized treatment of acute attacks with drug combinations aimed at low serotonergic function, neurogenic inflammation, and central sensitization has translated into better outcomes for patients and physicians. Trials combining preventive migraine agents with nonpharmacologic behavioral headache management have yielded additional benefits over either approach alone. With the clinical application of this updated information from clinical trials, migraine impact on productivity, quality of life, and suffering will certainly be diminished. We hope that these achievements will create a stable path of management to benefit our patients, without interruption, into the foreseeable future.     

Good clinical practice in clinical trials: training clinicians,incentives to apply good clinical practice and assessment of compliance

Fourteen years after the concept was created, it seemed important to assess how well investigators actually apply Good Clinical Practice. Various sources of information have revealed a general deficiency in their application: "investigation by the working group, Afssaps (French Agency for the Safety of Health-Care Products) inspections, industrial data". The deficiencies identified stem from different factors: lack of professionalization, lack of training, lack of motivation, the large numbers of poorly conducted studies. The working group drew up proposals intended to improve the training of investigators, to dissuade investigators from pursuing inadequate procedure and to verify the level of compliance. However in this respect, the investigator is not the only one at fault. Improved practice unavoidably requires better assistance on the part of the sponsors, more consistent supervision of monitoring, and greater vigilence by the authorities involved in the control and use of trials.     

Generalizing from clinical trials

Although randomized controlled clinical trials have become the “gold standard” for evaluating new treatments, only a small subset of the population considered for treatment participate in randomized clinical trials. To what extent is it reasonable to generalize beyond the boundaries of a specific clinical trial? This paper argues that several pieces of information are necessary to determine the extent of extrapolation or generalization warranted in a specific clinical trial. The necessary items of information are derived from basic science laboratory studies; animal studies; genetic studies (where applicable); observational, clinical, and epidemiological studies; and other randomized clinical trials in similar settings or with similar treatments. An example from the field of cholesterol reduction is presented.     

Antiplatelet therapy - ticagrelor

Ticagrelor, a cyclopentyltriazolopyrimidine (CPTP), is the representative of a new chemical class of P2Y(12) receptor inhibitors that differ from thienopyridines (ticlopidin, clopidogrel, prasugrel) as ticagrelor is not a prodrug requiring active biotransformation by cytochromes in the liver and thus is characterized by a more rapid, more effective and more consistent platelet inhibition than ticlopidin or clopidogrel. An extensive study program for dose finding and safety for AZD6140 (DISPERSE studies) and a large-scaled phase III trial (PLATO) were undertaken on more than 18,000 patients for validation of efficacy and safety. In the PLATO trial, patients presenting with the broad spectrum of ACS, i.e. unstable angina, non-STEMI or STEMI, were randomized to ticagrelor (Brilique, Brilinta) or clopidogrel within 24 hours after onset of symptoms, regardless whether they were allocated to a planned invasive or conservative treatment. Compared to clopidogrel, ticagrelor reduced rates of the primary endpoint consisting of cardiovascular death, non-fatal MI, or stroke, without an excess of the primary safety endpoint that was PLATO-defined major bleedings. Results from the pre-specified confirmatory subgroup of patients undergoing planned invasive treatment was consistent with PLATO main trial. In addition, the primary endpoint, as well as CV death and all cause death were consistently reduced with ticagrelor in numerous exploratory subgroups including STEMI patients, those planned for non-invasive treatment, patients undergoing CABG, patients with renal failure, and those with diabetes mellitus, although patients were pretreated before coronary angiography and patients with clopidogrel pretreatment were not excluded. CONCLUSIONS: The pharmacological properties and convincing study results of the PLATO trial have stimulated a paradigm change for dual antiplatelet therapy. The new ESC guidelines on the management of ACS without ST segment elevation recommend the use of clopidogrel only when a new antiplatelet drug, e.g. ticagrelor or prasugrel is not available or contraindicated.     

Anti-angiogenic drugs: from bench to clinical trials

Angiogenesis, the generation of new capillaries through a process of pre-existing microvessel sprouting, is under stringent control and normally occurs only during embryonic and post-embryonic development, reproductive cycle, and wound repair. However, in many pathological conditions (solid tumor progression, metastasis, diabetic retinopathy, hemangioma, arthritis, psoriasis and atherosclerosis among others), the disease appears to be associated with persistent upregulated angiogenesis. The development of specific anti-angiogenic agents arises as an attractive therapeutic approach for the treatment of cancer and other angiogenesis-dependent diseases. The formation of new blood vessels is a complex multi-step process. Endothelial cells resting in the parent vessels are activated by an angiogenic signal and stimulated to synthesize and release degradative enzymes allowing endothelial cells to migrate, proliferate and finally differentiate to give rise to capillary tubules. Any of these steps may be a potential target for pharmacological intervention. In spite of the disappointing results obtained initially in clinical trials with anti-angiogenic drugs, recent reports with positive results in phases II and III trials encourage expectations in their therapeutic potential. This review discusses the current approaches for the discovery of new compounds that inhibit angiogenesis, with emphasis on the clinical developmental status of anti-angiogenic drugs.     

Prostate cancer gene therapy clinical trials.

Despite recent advances in early detection and treatment, prostate cancer is still the second leading cause of cancer death in men in the United States, and approximately 27,000 men will die from it this year. Better treatments are needed for aggressive forms of localized disease and hormone-refractory metastatic disease. Recently, several gene therapy strategies have generated provocative results in early-stage clinical trials, raising the possibility that gene therapy may have the potential to affect both localized and metastatic disease. Much work lies ahead. Nevertheless, for the time being, these studies provide hope that gene therapy may someday earn a place in the management of prostate cancer.     

Regulatory issues for clinical gene therapy trials

Gene therapy trials are among the most heavily regulated clinical trials. In this review, the basic tenets of human subject research are discussed in the context of the regulatory bodies which oversee this work. The challenges faced by academic research are outlined, including new and proposed regulations which impact human gene therapy investigators.     

Lessons learned from recent lipid-lowering trials: Why physicians should change clinical practice

In the past decade there has been an explosion of data on the beneficial role of cholesterol reduction in the prevention and treatment of cardiovascular disease (CVD). While earlier clinical trials focused primarily on patient populations with very high cholesterol levels, more recent studies have also included individuals with somewhat lower, or “average,” cholesterol levels. What is becoming clearer is that many patients with so-called “average” cholesterol levels may benefit from cholesterol reduction therapy to reduce the risk of cardiovascular events. Recent studies, such as the Heart Protection Study, provide further evidence for cholesterol reduction in the prevention and treatment of CVD and offer valuable lessons about cardiovascular risk reduction.     

Progress and prospects: hurdles to cardiovascular gene therapy clinical trials

Several gene therapy approaches have been designed for the treatment of cardiovascular diseases. A positive finding is that the safety of cardiovascular gene therapy has been excellent even in long-term follow-up. However, several hurdles to this field are still present. A major disappointing feature of the trials is that while preclinical and uncontrolled phase-I gene therapy trials have been positive, none of the randomized controlled phase-II/III cardiovascular gene therapy trials have shown clinically relevant positive effects. Low gene transfer efficiency seems to be associated with several trials. A sophisticated efficient delivery method for cardiovascular applications is still lacking and only low concentrations of the gene product are produced in the target tissues. Only a few gene therapy vectors can be produced in large scale. In addition, inflammatory reactions against vectors and inability to regulate gene expression are still present. Furthermore, a strong placebo effect is affecting the results in gene therapy trials, and long-term trials have become more difficult to conduct because of the multiplicity of therapies applied simultaneously on the patients. This review summarizes advances and obstacles of current cardiovascular clinical gene therapy trials.