How pharmacogenomics will impact the federal regulation of clinical trials and the new drug approval process.
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Clinical Trials as Topic↗
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Drug research: from the idea to the product.
The path of a new drug from the idea to product may be divided into 2 phases, namely drug discovery and drug development. In drug discovery a dramatic change is taking place. Due to a remarkable progress in understanding and explaining the underlying cause of many diseases by identifying and sequencing the genes encoded within DNA, it has become possible with new methods, like molecular biology or gene technology, to develop simple test assays by which a large number of compounds may be tested in regard to their biological efficacy. Automation of these test systems utilizing computer-controlled robotic systems has made it possible to evaluate up to 1 million substances per robot per year on their biological effect. While the classical medicinal chemistry cannot produce such a large number of new compounds, combinatorial chemistry may offer the opportunity to screen large numbers of novel compounds rapidly and to reduce the time taken to identify drug candidates substantially. Overall, it is estimated that combinatorial chemistry techniques have resulted in a reduction in the time taken to identify drug candidates of between 18-24 months. In drug development 2 partly overlapping phases can be differentiated, namely the preclinical and clinical phase. During the first part of drug development necessary requirements for first use in man are met by performing preclinical pharmacological, toxicological, and pharmacokinetic investigations in the animal and in in vitro testing. These investigations are playing a central part for the benefit/risk evaluation of new drugs. Only if the risks connected to the clinical study are medically justifiable in relation to the likely therapeutic benefit of the compound, the clinical trial may basically take place under consideration of the legal requirements of the country in which the study is carried out. In drug research clinical pharmacology is the connecting link between preclinical and clinical research. Clinical pharmacology produces the necessary basis for the clinical trial of a new substance in the patient with the target indication. After a first clinical-pharmacological profile of the new substance has been established during phase I on the basis of which a decision for the continuation of the clinical trial and the probable effective dose range and dosing interval is made, the aim of phase II-IV is now to answer the important questions of the therapeutic efficacy and tolerability in a large number of patients with the target indication. Only with a very careful drug investigation during phase I-IV it is really possible to register the therapeutic risk and benefit of a new drug and to control resulting serious problems. An analysis of registered drugs during the last years shows that despite enhanced efforts and dramatically rising development costs the innovation potential of the classical approach is steadily decreasing. Therefore, it is absolutely necessary to develop new innovative drugs with the help of new technologies like molecular and cell biology, gene technology, or immunology as well as combinatorial chemistry and robot supported substance screening.
Animals↗
[Drug clinics. Clinical drug trials: the importance and role of the general practitioner].
Clinical trials are an essential step in the development of a drug. They must be conducted according to strict rules called "Good Clinical Practice" or GCP. GCP requirements aim to guarantee a perfect methodology in the planning, realization and interpretation of clinical trials. The latter can be divided in four phases: phase 1 aiming to demonstrate the safety and to investigate the pharmacokinetics/metabolism of the drug in healthy volunteers; phase 2 aiming to study the intrinsic activity (generally versus a placebo) and safety of the compound in a rather small number of (hospitalized) patients; phase 3 aiming to confirm the comparative efficacy (versus a placebo or a reference drug) and safety of the pharmacological agent in a quite large number of (ambulatory) patients; and phase 4 carried out after commercialization, to verify the clinical utility of the drug in conditions of daily practice. Because he/she occupies a crucial position in the recruitment and follow-up of outpatients, the general practitioner should play a more active role in clinical trials, provided that he/she could work in collaboration with academic centers specialized in clinical pharmacology which can help to perform studies in accordance with GCP requirements.
Academic Medical Centers↗
Clinical trial designs for targeted agents.
With an increasing number of targeted agents available for testing, clinical trials must be rationally designed based on sound knowledge of the molecular mechanisms linking target and disease, fortified by strong preclinical data demonstrating how this relationship is modified by the targeted agent. Patients and resources are precious and should be expended judiciously on clinical trials that are well planned. Although traditional trial designs and endpoints may not be adequate for developing contemporary targeted drugs, transiting directly from phase I to phase III testing should be avoided except in distinct circumstances. Increased research efforts should be spent on the prospective evaluation and validation of novel biologic endpoints and innovative clinical designs, such that promising targeted agents can be effectively developed to benefit the care of cancer patients.
Animals↗
A phased approach to clinical testing: criteria for progressing from Phase I to Phase II to Phase III studies.
The overall intent of clinical testing is to establish, in a series of phased studies, the clinical tolerance and acceptable "safety" of the candidate vaccine, as well as the type, level and persistence of the immune response after its inoculation, to a representative target population, according to a convenient administration schedule. The final stages involve the direct or indirect demonstration of protective efficacy, if possible in the population(s) for which the vaccine is intended. In addition, consistency of production must be demonstrated. At all these stages, the amount of prior information from preclinical and other studies affects and informs the objectives and design of subsequent studies. Progression from one testing phase to the next is dependent upon attaining the pre-set objectives of each series of studies. The precise objectives to be met will be decided on a case-by-case basis. The earliest assessments in humans (Phase I) involve evaluation of short-term clinical tolerance as measured by local and general reactogenicity, and gross assessments of immunogenicity, in a small number of highly selected individuals in an idealised situation. The selection of "optimal" dose and schedule are the result of further dose-ranging investigations (Phase II), involving more volunteers, with longer, more detailed follow-up assessments. It is at this stage that the accumulated evidence on its immunogenicity profile should be sufficient to assess whether or not the vaccine is worthy of further development. The next level of investigation (Phase III) aims to measure with greater precision the vaccine protective efficacy in the intended target population(s) by comparison of infection and/or disease attack rates in vaccine and placebo recipients. In consistency studies different production lots, manufactured at commercial scale, are tested to demonstrate consistency of manufacture. Additional bridging studies to establish similarity of lots at different production scales, or studies of the duration of the immunity conferred, are conducted in parallel with the progression of the studies in the different phases mentioned above. These latter types of studies are usually carried out concurrently with Phase III studies. This progression continues into the post-marketing period (Phase IV) with surveillance of long term efficacy and observational studies of possible rare adverse events to establish "safety" with more confidence. This paper examines, in general, the aims and designs of studies in each phase as an introduction to the more specific publications that follow.
Clinical Trials as Topic↗
Clinical profile of glimepiride.
In order to achieve appropriate blood glucose control, the treatment of non-insulin dependent (NIDDM) Type II diabetes usually starts with diet and exercise. If this still results in insufficient metabolic control, oral hypoglycaemic drugs or insulin are added to the non-pharmacological measures. Sulphonylureas have been used successfully as oral hypoglycaemic agents since the 1950s but there are aspects where medication could be better adjusted to the patients' needs. Preclinical investigations on animals and in vitro studies with glimepiride (HOE490), a new sulphonylurea, suggested some benefit over sulphonylureas currently available, including lower dosage, rapid onset and long duration of action, lower insulin and C-peptide levels, possibly due to less stimulation of insulin secretion and more pronounced extrapancreatic effects. The clinical relevance of these findings were studied in clinical trials. 19 phase II and 4 phase III clinical studies, in a total of about 3750 Type II diabetic patients, established efficacy and safety of glimepiride in comparison to placebo and glibenclamide and showed its therapeutic value. 1 mg per day induced a marked blood glucose reduction (FPG 2.4 mmol/l; HbA1c 1.2%) which could be enhanced by increasing the dose to the maximum effective 4 and 8 mg daily. In patients, glimepiride had a more rapid onset of action than glibenclamide, with a long duration of action. Glimepiride achieved metabolic control with the lowest dose (1-8 mg daily) of all the sulphonylureas. In addition, it maintained a more physiological regulation of insulin secretion than glibenclamide during physical exercise, suggesting that there may be less risk of hypoglycaemia with glimepiride.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
Monitoring and safety assessment in Phase I to III clinical trials.
Safety issues play an important role for registration of new vaccines due to growing awareness of regulators and growing safety concerns of the general public, whether they are justified or not. Safety of a vaccine implies much more than merely monitoring and reporting adverse events, but relies on a holistic view including control of manufacturing, surveillance of possible long term effects, epidemiological data, the vaccination schedule and signals from post marketing surveillance. Vaccine safety has scientific and organisational implications. To achieve a balanced risk-to-benefit evaluation the input of a central safety department is recommended from planning of a clinical development to post-marketing phase. The concept of data evaluation and data assessment should be medically driven in close cooperation with the biometricians. An integrated safety plan with standardized procedures improves the likelihood of detecting a realistic AE-profile, prior to marketing a vaccine. The unique opportunity of a controlled clinical trial should be taken advantage of by optimizing both the organisation and the scientific methods. Further development of methodology of safety monitoring and assessment should be given the same importance as proving efficacy and complying with the regulatory requirements.
Biometry↗
[Dilated cardiomyopathy and growth hormone].
The data from animal and human in vivo studies suggest that cardiac function is dependent in part on the normal function of the GH/IGF-1 axis (growth hormone/insulin-like growth factor-1). So far encouraging results from phase II and III clinical trials evaluating the effects of intermittent GH treatment in patients with chronic congestive heart failure (CHF) due to dilated cardiomyopathy (DCM) have been published. In these studies, growth hormone (i.e., DNA-derived recombinant human growth hormone) was not used alone but in addition to standard optimal therapy for CHF. The following rationale is the basis of this new approach for the treatment of CHF due to DCM: According to Laplace's Law cardiac wall stress (i.e., the force acting per unit of cross-sectional area of the ventricular wall) is directly related to intraventricular pressure and ventricular radius and inversely related to ventricular wall thickness. Cardiac (ventricular) wall stress is increased in DCM (mainly because of the dilatation of the ventricles and to a minor extent because of the relative reduction in ventricular thickness). GH is capable of increasing ventricular wall thickness in DCM thus reducing cardiac wall stress which in turn leads to an improvement in systolic cardiac performance.
Adult↗
Induction therapy of adult acute lymphocytic leukemia without the use of vincristine or prednisone.
In the last 30 years, a multitude of treatment regimens for adult acute lymphocytic leukemia (ALL) has been developed. Essentially, all of these regimens use an induction therapy vincristine, prednisone, and an anthracycline intensified with L-asparaginase or cyclophosphamide. Though such regimens induce most patients to enter a remission, relapse is frequent, and most adult patients ultimately die of their disease. The author postulated that further refinements in this approach to induction therapy were unlikely to markedly improve treatment results in this disease. Therefore, the author is studying a new intensive strategy using cytarabine with a single very high dose of mitoxantrone (without vincristine or prednisone) as induction therapy for adult patients with ALL.
Adolescent↗
Analysis of the safety and efficacy of intra-arterial thrombolytic therapy in ischemic stroke.
BACKGROUND AND PURPOSE: Intra-arterial thrombolytic therapy (IAT) may be a treatment option for patients with ischemic stroke. We analyzed the safety and efficacy of IAT on the basis of published data. METHODS: We searched computerized databases for studies using IAT in >/=10 patients with ischemic stroke. Some studies had control patients for comparison. Data were collected on age, stroke territory, time to treatment, medication, site of arterial occlusion and recanalization on angiogram, outcomes, and symptomatic intracranial hemorrhage (SICH). RESULTS: The analysis included 27 studies with 852 patients who received IAT and 100 control subjects. There were more favorable outcomes in the IAT than in the control group (41.5% versus 23%, P=0.002), with a lower mortality rate for IAT (IAT, 27.2%; control group, 40%, P=0.004). The IAT group had an odds ratio of 2.4 (95% CI, 1.45 to 3.85) for favorable outcome. SICH was more frequent in the IAT group compared with the control group (9.5% versus 3%, P=0.046). The subgroup of patients receiving a combination of intravenous thrombolytic therapy and IAT had more favorable outcomes than the IAT alone subgroup, but this trend did not reach statistical significance (53.6% versus 41.5%, P=0.1). Among the patients treated with IAT, those who had supratentorial strokes were more likely to have favorable outcomes than those with infratentorial strokes (42.2% versus 25.6%; P=0.001; odds ratio, 2.0; 95% CI, 1.33 to 3.0). CONCLUSIONS: IAT for ischemic stroke appears efficacious but carries an increased risk of SICH. Further prospective studies are needed to prove the safety and efficacy of IAT in stroke.
Aged↗
Tirilazad mesylate in acute ischemic stroke: A systematic review. Tirilazad International Steering Committee.
BACKGROUND AND PURPOSE: Tirilazad is a nonglucocorticoid, 21-aminosteroid that inhibits lipid peroxidation. Studies in experimental models of ischemic stroke had suggested that tirilazad had neuroprotective properties. As a result, clinical studies were undertaken to assess the safety and efficacy of tirilazad in the treatment of acute ischemic stroke. We performed a systematic review of randomized, controlled trials that assessed the safety and efficacy of tirilazad in patients with acute ischemic stroke. METHODS: Trials of tirilazad were identified from searches of the Cochrane Library and communication with the Pharmacia & Upjohn company, the manufacturer of tirilazad. Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and corrected QT interval were extracted by treatment group from published data and company reports and analyzed by using the Cochrane Collaboration meta-analysis software REVMAN. RESULTS: Six trials (4 published, 2 unpublished) assessing tirilazad in 1757 patients with presumed acute ischemic stroke were identified; all were double-blind and placebo controlled in design. Tirilazad did not alter early case fatality (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). A just-significant increase in death and disability, assessed as either the expanded Barthel Index (OR 1.23, 95% CI 1.01 to 1.51) or Glasgow Outcome Scale (OR 1. 23, 95% CI 1.01 to 1.50) was observed. Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (expanded Barthel Index) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low-dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a nonsignificant worse outcome was also seen in patients with mild to moderate stroke (OR 1. 40, 95% CI 0.99 to 1.98). CONCLUSIONS: Tirilazad mesylate increases death and disability by about one fifth when given to patients with acute ischemic stroke. Although further trials of tirilazad are now unwarranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischemic stroke.
Aged↗
Sildenafil citrate (VIAGRA): overall safety profile in 18 double-blind, placebo controlled, clinical trials.
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Adolescent↗
Activity of telithromycin against key pathogens associated with community-acquired respiratory tract infections.
OBJECTIVES: To investigate the correlation between in vitro susceptibility of isolates and clinical outcomes with telithromycin in respiratory tract infections. METHODS: The activity of telithromycin was determined by in vitro susceptibility testing of key respiratory tract pathogens isolated from patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute maxillary sinusitis enrolled in 14 Phase III/IV clinical trials evaluating the clinical efficacy of telithromycin. RESULTS: In this pooled analysis, telithromycin mode minimum inhibitory concentration (MIC) and MIC90, respectively, were: 0.016 and 0.03 mg/l against Streptococcus pneumoniae (n=626); 0.03 and 0.5 mg/l for penicillin-resistant S. pneumoniae (n=56); 0.03 and 1 mg/l for erythromycin-resistant S. pneumoniae (n=81); 2 and 4 mg/l against Haemophilus influenzae (including beta-lactamase producers; n=627); both 0.12 mg/l for Moraxella catarrhalis (n=159) and both 0.25 mg/l for Staphylococcus aureus (n=124). Telithromycin (5 or 7-10 days) resulted in overall clinical and bacteriologic success rates of 88.1% (1593/1808) and 89% (1593/1789), respectively. CONCLUSIONS: High levels of in vitro susceptibility to telithromycin are paralleled by high rates of clinical cure and bacteriologic eradication.
Acute Disease↗
Phase III and Phase IV trials: noninvasive assessment of efficacy endpoints in vessel walls.
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Carotid Artery, Common↗
Effect and efficacy--on the function of models in controlled phase III trials and the need for prospective pharmacoepidemiological studies.
While the "effect" of a drug can be observed or deduced from observational data, the concept of "therapeutic efficacy" represents mainly a theoretical construction of a high degree of abstraction which is inconceivable without reciprocal combination with other theoretical constructs. The "therapeutic efficacy" of drugs can be investigated only via clinical-pharmacological or clinical "models". Several examples are given and discussed against the background of the actual considerations for shortening phase III studies and extending pharmacoepidemiological phase IV studies for scientific, practical and economic reasons. Of special relevance is the question whether study data of phase III allow an extrapolation to the wider patient population which it is intended to treat. Thus, it is well known that the criteria for representativeness in the investigated population are rarely achieved in phase III studies. Furthermore, observations have shown that various intervening moderator variables, such as the investigated subgroup or the trial setting (e.g. Inpatient or respectively out-patient treatment), might influence therapeutic efficacy and the possibility of generalizing the results. This again raises the crucial question of clinical relevance of significant effects. Possible ways of overcoming this unsatisfactory situation are suggested.
Clinical Trials, Phase III as Topic↗
Safety of the calcium antagonist lacidipine evaluated from a phase III-IV trial database.
OBJECTIVE: We reviewed the clinical safety profile of lacidipine with the help of the rather comprehensive datafile of the manufacturer. Although a number of prospective, randomly allocated trials under way at present are investigating the effects of treatment with calcium antagonists on cardiovascular morbidity and mortality, these results are not yet available. Therefore, the present approach may be useful. A fuller account of this work has been published in Blood Pressure. DESIGN: Since 1985,50 phase III-IV trials have been performed to investigate antihypertensive efficacy in patients with hypertension; 32 were controlled trials with comparison treatment and 18 were open studies of lacidipine treatment. Only data from trials completed before 1 January 1995 are presented here. SUBJECTS: In all, 16590 patients were treated with lacidipine; 13419 in open studies and 3171 in double-blind comparative trials. A total of 1810 patients were given active comparative treatment and 451 were given placebo. Altogether, 5124 person-years of data were obtained. MAIN OUTCOME MEASURES: Numbers of both fatal and non-fatal cardiovascular events were estimated. Efficacy (change in blood pressure and heart rate), adverse event rates and drop-out rates were compared for the different treatment regimens. RESULTS: In all trials, 2-6 mg lacidipine was effective in lowering blood pressure. In the controlled trials, systolic/diastolic blood pressure fell from 166/102 to 144/85 mmHg and the heart rate fell from 75.6 to 74.1 beats/min. The estimated event rate for a possible myocardial infarction in all studies was 5.46/1000 person-years; the fatal (all-cause) event rate was 5.27/1000 person-years and the estimated fatal cardiovascular event rate was 2.93/1000 person-years. There were 21 malignant events during treatment with lacidipine, for all studies yielding a crude incidence of 4.10/1000 person-years. In patients treated with lacidipine, the age-standardized (according to the world population) incidences were 1.49 (men) and 0.79/1000 person-years (women) compared with 2.74 (men) and 2.09/1000 person-years (women) in the European Community in 1990. The overall incidence in the comparative studies of one or more adverse events included 30.3% for lacidipine, 43.8% for other calcium antagonists, 18.7% for diuretics, 48.7% for beta-receptor blockers, 10.4% for angiotensin converting enzyme inhibitors and 15.7% for placebo. The adverse effects of lacidipine were, as expected, headaches, flushing, pedal oedema and palpitations. CONCLUSIONS: Lacidipine proved to be an effective and well tolerated drug in almost 19000 hypertensive patients. It displayed a reasonable adverse profile that was typical of a calcium antagonist of the dihydropyridine group. This analysis has two obvious limitations: (1) it is a retrospective analysis; and (2) the data were obtained from a large cohort of patients, but most were treated with lacidipine for a relatively short period of time. Although we found a lower fatal event rate than that reported by Collins et al., their meta-analysis included 10 times more person-years than our analysis, and therefore our event rate may be less accurate. Further prospective studies are under way at present to determine whether these drugs can produce reductions in atherosclerosis or in the incidence of cardiovascular disease.
Adolescent↗
Substantiating the concerns about recombinant human activated protein C use in sepsis.
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Clinical Trials, Phase III as Topic↗
Data from regulatory studies: What do they tell? What don't they tell?
Phase III studies of antiepileptic drugs (AEDs) are specifically designed to satisfy strict regulatory criteria. As they are conducted in protocol-restricted patient populations over short treatment periods and employ fixed study designs and dosing schedules, they are not fully representative of 'real-life' clinical practice. Therefore, in order to provide an overall assessment of clinical performance, regulatory studies must be backed up by post-marketing clinical experience. Phase IV studies provide information on a drug's performance in a setting more closely representing real clinical practice, with broader patient populations and a more flexible approach to individual treatment. Prospective long-term studies allow the determination of efficacy and safety (and cost-effectiveness) over extended treatment periods; these studies and audit data provide a means of assessing idiosyncratic side effects, unusual interactions and the effects of an AED in rare patient groups. By complementing regulatory evidence with real-life clinical experience, a comprehensive assessment of the risks and benefits of an AED can be made.
Adverse Drug Reaction Reporting Systems↗