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PubMed1998

Intervention trials in general practice.

The best way to establish the place of interventions including pharmaceuticals, physical therapies, counselling, and surgery in general practice is by a trial. When undertaking such trials, care must be taken to ensure the reference population is appropriate, that recruitment strategies and the conduct of the trials do not introduce systematic bias, that adequate numbers of subjects are included to prove or disprove the question being researched and that the trial is ethical.

Double-Blind Method↗
PubMed2001

Ethical issues arising in pharmacoepidemiologic research in a community hospital in Crete, Greece.

This paper presents the various issues encountered in planning, designing, performing, and reporting pharmacoepidemiologic research. Five hundred and fifty-one indigent patients insured by Social Care visited the Hospital Pharmacy of Chania General Hospital, and were compared with 551 patients insured under Social Security funds who visited three community pharmacies. The study had no external funding. Before we started the study, we officially sought approval from the Scientific Committee of our Hospital and from the local Pharmaceutical Association. We asked also for approval from the Medical School of the University of Crete. Patient privacy was of great concern in the design and performance of the study. The law in Greece, according to the directives of European Union, affects the way we use records in hospitals and protect patient rights. After these studies were completed, we made proposals to the authorities concerning continuous health education for both patients and health workers. Pharmacoepidemiologic research is difficult in hospitals outside universities or institutions, because of the lack of adequate funding and grants to support research staff.

Bioethics↗
PubMed2006

Bioequivalence of a novel high-dose oral formulation of alpha-dihydroergocryptine.

The plasma pharmacokinetics of alpha-dihydroergocryptine (DHEC, CAS 14271-05-7) were investigated in 24 patients with Parkinson disease after the administration of repeated oral doses of 40 mg DHEC twice daily by means of a novel 40 mg DHEC tablet (Almirid 40 mg test T) and an established 20 mg DHEC tablet (Almirid 20 mg - reference R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design; steady-state was established by means of a stepwise up-titration from 5 to 40 mg b.i.d. from day D01 to D19; investigational treatments (40 mg DHEC b.i.d. by means of formulation R and T) were administered on day D20 and D21 according to a randomised, period-balanced within-subject cross-over; treatment with DHEC was down-titrated in stepwise fashion from day D22 to D34. Morning doses of 2 x 20 mg DHEC (reference) yielded a fast and relatively short lasting peak with a geometric mean Cmax of 2157 pg/mL (CV: 0.978) after a median tmax of 1.00 h. Cmin throughout the first 12 h was on average 189 pg/mL (CV: 0.908). There was a quite distinct diurnal effect: evening doses of 2 x 20 mg DHEC (treatment R), yielded a relatively lower exposure with geometric mean Cmax, Cav- and Cmin-values of 800 pg/mL (CV: 0.870), 389 pg/mL (0.813) and 177 pg/mL (CV: 0.942). In contrast, there was relatively little within-subject distinction between the two formulations: for the day profile after the morning dose, the estimated ratios of the true means (Pr:R) for Cmax Cmin and Cav were 1.18 (90% CI: 0.96 to 1.43 - CVm: 0.394), 0.96 (90% CI: 0.86 to 1.09 - CVm: 0.230) and 1.06 (90% CI: 0.93 to 1.21 - CVm: 0.254); for the night profile after the evening dose, the estimated ratio of the true means (muT:muR) for Cmax, Cmin and Cav were 1.11 (90% CI: 0.91 to 1.35 - CVm: 0.395), 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.232) and 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.220). In view of important medical-ethical constraints not to expose an unreasonably high number of subjects, these findings could be accepted as a sufficient demonstration of bioequivalence.

Aged↗
PubMedDate not supplied

Economic, clinical, and humanistic outcomes: a planning model for pharmacoeconomic research.

Medical, ethical, and societal concerns about costs, access, and quality of care are causing health care practitioners to consider a more comprehensive model for medical decision making. Consequently, interest in research to assess the outcomes of health care has been increasing. The purpose of this paper is to explicate a theoretical framework for identifying, collecting, and using outcomes data to assess the value of pharmaceutical treatment alternatives. Causal relationships between disease, health outcomes, and decisions about medical care interventions (eg, treatment with pharmaceutical products and services) are proposed to address limitations inherent in the traditional medical decision-making model. The Economic, Clinical, and Humanistic Outcomes (ECHO) model depicts the value of a pharmaceutical product or service as a combination of traditional clinical-based outcomes with more contemporary measures of economic efficiency and quality. This integrated approach provides a theoretical basis for considering potential trade-offs among economic, clinical, and humanistic variables in optimizing the allocation of health care resources. The ECHO model is a preliminary step to modeling outcomes from pharmaceutical treatments and services. Data collection instruments need to be developed, and the proposed relationships among outcomes variables should be established empirically. The ECHO model should assist health services researchers in planning, conducting, and evaluating pharmaceutical products and services from a multidimensional perspective.

Causality↗
PubMed2006

Addressing the issue of channeling bias in observational studies with propensity scores analysis.

Randomized Clinical Trials (RCTs) remain the gold standard for determining the utility of pharmaceuticals especially from a safety and efficacy standpoint. However, restrictive entry criteria and stringent protocols can be barriers to generalizing RCT findings to real world practices and outcomes. Observational studies overcome these limitations of RCTs since they are representative of real world populations and practices. Nonetheless, attributing causality remains a major limitation in observational studies, due to the non-random assignment of subjects to treatment. Non-random assignment can lead to imbalances in risk-factors between the groups being compared and thus bias the estimates of the treatment effect. Non-random assignment can be particularly problematic in observational studies comparing older versus newer pharmaceuticals from similar therapeutic classes due to the phenomenon of channeling. Channeling occurs when drug therapies with similar indications are preferentially prescribed to groups of patients with varying baseline prognoses. In this manuscript we discuss the phenomenon of channeling and the use of a statistical technique known an propensity scores analysis which potentially adjusts for the effects of channeling. During the course of this manuscript we discuss tests for determining the quality of the derived propensity score, various techniques for utilizing propensity scores, and also the potential limitations of this technique. With the increasing availability of high quality pharmaceutical and medical claims data for use in observational studies, increased attention must be given to analytic techniques that adjust optimally for non-random assignment and resulting channeling bias. For research studies using observational study designs, propensity score analysis offers a reasonable solution to address the limitation of non-random assignment, especially when RCTs are too costly, time-consuming or not ethically feasible.

Bias↗
PubMed2006

FDA update.

This report addresses: (1) a general update of FDA activity in areas relevant to AED development; (2) an update on issues relevant to the development of AEDs in the pediatric population; and (3) an update on the Agency's approach to the evaluation of AEDs as monotherapy. FDA ACTIONS: Since January 2002, 47 Approval actions for 10 AEDs were issued, but none for a new chemical entity. Nine of the ten Approvable actions taken were relatively minor changes to existing applications. An Approvable letter was issued for Lyrica (pregabalin) for the treatment of post-herpetic neuralgia, painful diabetic neuropathy, and partial seizures in adults. The primary issue to be addressed in the face of post-marketing reports of adverse events is one of causality. The FDA has requested that sponsors search their databases for selected problems under review (e.g., suicidality). PEDIATRICS: The Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) require studies in pediatric patients for those indications granted for adults that are relevant for the pediatric population. Current FDA policy asks sponsors to undertake a development program in pediatric patients essentially analogous to that for adults. MONOTHERAPY TRIALS: Establishing the effectiveness of AEDs as monotherapy continues to be desirable, but problematic. Problems include the difficulty of performing monotherapy trials, ethical issues, designation of patients as "newly diagnosed," and endpoints. Historical controls may be acceptable if: (a) there is a consensus that it is essentially impossible to conduct controlled trials designed to demonstrate a difference between treatments; (b) there is an adequate historical database against which the seizure rate seen with the new drug can reasonably be compared; and (c) there is evidence from adequate and well-controlled trials that the treatment is effective as adjunctive therapy. FDA is Agency is reviewing analyses describing historical controls.

Adult↗
PubMed2003

[Clinical trials on medical products for human use in the case of acutely incapacitated patients within the fields of neurology and neurosurgery; implications of the new European legislation].

To comply with the European directive on clinical trials on medical products for human use, an amendment to the Dutch Medical Research Involving Human Beings Act was formally submitted in the Netherlands on the 27th February 2003. The objective is harmonisation of legislation and the protection of patients participating in clinical trials within the European Union. An important element of the directive is additional protection for incapacitated patients. In the fields of neurology and neurosurgery much research, mainly phase III, is conducted into the safety and efficacy of pharmaceutical products in emergency situations such as traumatic skull-brain injury or an acute cerebral infarct. Future emergency research in patients with acute cerebral disorders will be hindered by the (shortly legal) requirement that prior proxy consent is mandatory and the fact that individual patients must directly benefit as a result of their participation. This unintended negative effect may be considered contrary to the ethical principals for conducting good scientific research to improve treatment results. Also, it may lead to a scientific backlog compared to countries outside of the European Union. In the case of emergency phase-III research among acutely incapacitated patients we recommend that the Central Committee on Research Involving Human Subjects [Dutch acronym: CCMO] tests the research, that trials have an independent committee to monitor the data and safety, that an independent physician may grant consent for the patient to participate and that the consent of the patient's representative(s) is obtained within 24 hours of the patient being included in the trial.

Clinical Trials, Phase III as Topic↗
PubMed1999

Gender-related differences in pharmacokinetics and their clinical significance.

In this review I have attempted to summarize gender differences in pharmacokinetics involving the cytochrome P450 (CYP) isozymes of young and mature adults, excluding the effects of the menstrual cycle, use of oral contraceptives and pregnancy. Sex differences in drug metabolism and elimination are mainly related to steroid hormone levels. CYP3A4, responsible for the metabolism of over 50% of therapeutic drugs, exhibits higher activity in women than in men. Nonetheless, the absence of a sex difference has been reported by some workers. The activity of several other CYP (CYP2C19, CYP2D6, CYP2E1) isozymes and the conjugation (glucuronidation) activity involved in drug metabolism may be higher in men than in women. Drug metabolism in women is affected by sex-specific factors (menopause, pregnancy and menstruation) in addition to the cigarette smoking, drug ingestion and alcohol consumption that are more commonly observed factors in men. Furthermore, they are affected by physiological factors such as drug absorption, protein binding and elimination. Thus, careful attention should be paid to the side-effects and toxicity arising from sex differences in drug metabolism in clinical situations. Although there are specific ethical considerations regarding carrying out drug trials in women, the relationship between the side-effects and toxicity that may be influenced by hormones during drug metabolism and drug treatment needs further study.

Cytochrome P-450 Enzyme System↗
PubMed1985

Factors influencing the sample size, exemplified by studies on gastroduodenal tolerability of drugs.

The necessary number of subjects to be included in a clinical trial depends on different factors. Exemplified by clinical trials on gastroduodenal tolerability of NSAID, we show how the sample size increases when the significance level decreases, the detection level increases, or the clinically relevant difference decreases. The sample size also increases when the trial design is changed from a cross-over to a parallel-group design. It is concluded from an ethical and statistical point of view that the sample size must be calculated when planning a study.

Clinical Trials as Topic↗
PubMed1999

[50 years of clinical trials; a new direction in medicine].

In 1998 the medical community commemorated the completion of the first truly randomised trial, the Medical Research Council Streptomycin Study. This invention is at least as important as Harrison's clocks, which in the 18th century solved the problem of measuring longitude at sea. Naturally the idea of randomised controls had evolved from previous notions. Obtaining informed consent remains essentially a matter between patient and physician, but in the meantime four other interested parties have joined in: governing bodies, the pharmaceutical industry, medical journals, and the mass media. In order to keep all these forces in check, lawmakers should protect the weakest parties against the more powerful ones. There is a great deal to be done in the next 50 years.

Ethics, Medical↗