SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Therapeutic equivalence studies still present problems to regulatory reviewers from many perspectives. This paper is intended to discuss some of these concerns from the statistical viewpoint. There are, however, also some newer approaches which may be particularly useful for the investigation of therapeutic equivalence.
BACKGROUND: A Program of Therapeutic Equivalents (TEP) is here reported which was elaborated and is currently in force at a third level university teaching hospital. MATERIALS AND METHODS: Therapeutic equivalents were selected within the same pharmacologic group on the basis of approved indications and both efficiency and safety data. RESULTS: TEP considers: a) the substitution of drugs which are considered therapeutic equivalents; b) withdrawal of drugs which have not proved efficiency or are of no interest for inpatients; c) continuation of therapies when changes are not advisable, and d) indistinct use of homologous drugs. From August 1998 up to April 1999, TEP was applied in 505 occasions; it was accepted in 499 (99%) and rejected in 6 (1%). DISCUSSIONS: The substitution of therapeutic equivalents should be viewed in the context of selecting the most appropriate drugs to be used in the hospital setting. TEP should be a consensus document and supervised by the Pharmacy and Therapeutics Commission.
BACKGROUND: Although generic formulations of drugs are chemically equivalent, they may not be bioequivalent to the innovator. Since bioequivalence of intranasal corticosteroids has been difficult to demonstrate by pharmacokinetic methods, clinical trials have been necessary to compare generic and innovator agents. OBJECTIVE: We therefore designed a multicenter, randomized double-blind, parallel-group placebo-controlled study to examine the therapeutic equivalence of generic beclomethasone diproprionate to the innovator. METHODS: A total of 518 patients, ages 12 to 60, with ragweed-induced seasonal allergic rhinitis from eight centers were randomized to receive intranasal generic or innovator beclomethasone 42 microg, 84 microg or placebo twice daily for 6 weeks. Efficacy was assessed by means of rhinitis symptom scores as recorded in patient diaries. Adverse events were recorded throughout the study to assess safety. RESULTS: Mean rhinitis composite symptom scores (congestion, postnasal drip, runny nose, and sneezing) were significantly lower in patients receiving 42 microg (P = .0003) or 84 microg (P = .0001) beclomethasone twice daily compared with placebo. Generic beclomethasone was equivalent therapeutically to the innovator in alleviating nasal congestion (42 microg and 84 microg doses), postnasal drip (84 microg dose), runny nose (84 microg dose), sneezing (42 microg and 84 microg doses) and mean composite (42 microg and 84 microg doses) symptom scores during the 6-week study period. Similar and equivalent efficacy was also demonstrated during the 5-day period of peak pollen counts at each site. The type and incidence of drug-related adverse events were similar for both beclomethasone treatment groups and did not differ significantly from placebo in severity and frequency. CONCLUSIONS: Generic beclomethasone was therapeutically equivalent to the innovator in regards to both efficacy and side effect profile in the treatment of ragweed-induced allergic rhinitis.
Less than daily alendronate dosing has been identified as an attractive alternative to daily dosing for patients and physicians. A recent 2-year study found bone mineral density (BMD) changes caused by weekly alendronate dosing therapeutically equivalent to that caused by daily dosing. There are no methods that can be used to predict how long therapeutic equivalence will be maintained after the first 2 years of treatment. In addition, it is unclear if dosing less frequently than weekly also might be therapeutically equivalent to daily dosing. In this study we use a computer simulation to develop predictions of the therapeutic equivalence of daily and less than daily dosing over time periods as long as a decade. The computer simulation uses a cell-based computer model of bone remodeling and a quantitative description of alendronate pharmacokinetics/pharmacodynamics (PK/PD). The analyses suggest that less than daily dosing regimens do not increase BMD as much as daily dosing. However, model predictions suggest that dosing as frequent as weekly still may be therapeutically equivalent to daily dosing over periods as long as 10 years. In addition, the simulations predict dosing less frequently than weekly may be therapeutically equivalent to daily dosing within the first year of treatment but may not be therapeutically equivalent after 10 years. Hypotheses based on these simulations may be useful for determining which dosing regimen may be most attractive for clinical trials.
In the planning phase of a therapeutic equivalence trial, a range has to be specified that defines the parameter region within which the treatments to be compared are considered equal for practical purposes. It is current practice in equivalence assessment to fix some value for limiting the equivalence range and to test the corresponding null hypothesis in confirmatory analysis. This procedure is unsatisfactory, if, for example, the drug to be investigated is not only equivalent but turns out to be even superior to standard. In this situation it would be desirable to test not only for equivalence but also for superiority. The paper presents an alternative approach that allows for a flexible handling of the problem. If therapeutic equivalence can be established the method additionally allows, under maintenance of the multiple level, for testing all null hypotheses that correspond to acceptable equivalence ranges and even of superiority. Because of the special structure of the hypotheses no alpha-adjustment is needed for these additional confirmatory analyses.
This paper reviews issues related to defining and demonstrating therapeutic equivalence. A set of guidelines are proposed to critically review clinical trials to determine whether there is sufficient evidence to conclude that an experimental therapy is therapeutically equivalent to a standard one. These guidelines include criteria for assessing whether imprecision pertaining to the measurement of outcomes impinges on the validity of an equivalence test.
Explore the source record for details and available documents.
Pharmacists are continually faced with drug product selection decisions. When is a generic drug product equivalent to the innovator product and, thus, a suitable candidate for generic substitution? The FDA policy has been that only drug products that are therapeutic equivalents are candidates for product selection decisions. This paper outlines the regulatory and scientific framework for the FDA's policies and requirements for generic drug products. The history and current status of the Drug Efficacy Study Implementation (DESI) project is described. Originally begun in 1966 as a review of about 3,400 drug products, the review in mid-1983 is more than 90% complete, but its impact has already affected more than 7,000 marketed drug products. The therapeutic equivalence policy and the manner in which decisions on therapeutic equivalence are communicated are reviewed. Regulatory policies for the approval of generic drug products are reviewed and specific litigation challenging the rights of generic drug manufacturers to produce generic "look-alikes" and challenging the FDA's policy that a generic drug product is a new drug requiring an approved New Drug Application for marketing is discussed. The conclusion reached is that the evaluation of regulatory requirements and science is leading to a point where all generic drug products will be known to be safe, effective and therapeutically equivalent, and pharmacists can be optimistic about the quality of products in the generic drug market.
Explore the source record for details and available documents.
We have evaluated the therapeutic equivalence of a beta-cyclodextrin-artemisinin complex at an artemisinin dose of 150 mg, with a commercial reference preparation, Artemisinin 250 at a recommended dose of 250 mg. One hundred uncomplicated falciparum malarial patients were randomly assigned to orally receive either beta-cyclodextrin-artemisinin complex (containing 150 mg artemisinin) twice daily for five days or the active comparator (containing 250 mg artemisinin) twice daily for five days. The patients were hospitalized for seven days and were required to attend follow up assessments on days 14, 21, 28 and 35. All patients in both treatment groups were cured of the infection and achieved therapeutic success. At day seven of treatment, all patient blood was clear of the parasites and the sublingual temperature of all patients was less than 37.5 degrees C. Moreover, the parasite clearance time in both treatment groups was similar, being approximately three days after initiation of treatment. Comparable plasma artemisinin concentrations were observed between patients in both treatment groups at 1.5 and 3.0 h, although slightly higher levels were obtained with patients in the beta-cyclodextrin-artemisinin complex-treated group. The beta-cyclodextrin-artemisinin complex at a dose of 150 mg artemisinin was therapeutically equivalent to 250 mg Artemisinin 250. Additionally, patients receiving beta-cyclodextrin-artemisinin complex showed less variability in their plasma artemisinin concentrations at 1.5 h post-dosing, which suggested a more consistent rate of drug absorption.
OBJECTIVE: To study the therapeutic equivalence of two formulations (innovator v. generic) of beclomethasone dipropionate (BDP) 400 micrograms twice daily administered per metered dose inhaler (MDI), in adults with moderate to severe asthma. METHODS: A double-blind randomised parallel-group trial was performed with a 2-week run-in and an 8-week treatment period. Thirty-six symptomatic adult asthmatics on a mean daily dose of 750 micrograms inhaled corticosteroids during run-in, a mean forced expiratory volume in 1 second (FEV1) of 70% predicted normal and a mean histamine concentration provoking a 20% reduction in FEV1 (histamine PC20) of 0.11 mg/l were randomised to one of the two treatment groups. Primary variables were morning peak expiratory flow (mPEF), FEV1 and histamine PC20. Secondary variables were beta 2-agonist use, symptom score and nocturnal awakening. The Schuirmann two one-sided tests procedure was used for the statistical analysis. Ninety-five per cent confidence intervals (CIs) were calculated for the differences in means. RESULTS: The mean differences end of treatment to baseline for the two formulations (Becotide and Beclate) respectively were: mPEF 5.6 l/min (CI - 16.4-27.6) and -22.3 l/min (CI -35.6(-)-9); FEV1 -2.9% (CI -11-5.2) and 0.2% (CI -4.8-5.2); Histamine PC20 -0.04 mg/ml (CI -0.15-0.06) and 0.02 mg/ml (CI -0.37-0.4). Changes in clinical variables were not conclusive. The mean differences with CIs for primary variables were contained within the limits set for equivalence. The sample size was sufficient to differentiate the groups for mPEF, but this was not of clinical significance. CONCLUSION: After 8 weeks of treatment the two formulations of BDP, delivered by MDI through a large-volume spacer, were therapeutically equivalent in moderate-to-severe asthmatic adults.
The problem of therapeutic equivalence or inequivalence cannot be solved by "ignoring facts and proclaiming opinions". The entire problem is multifarious and is not even clearly arranged although heart glycosides have been used for 200 years in the therapy of cardiac insufficiency. It comprises the physico-chemical properties of the drugs, its preparation and its pharmacolinetic behaviour in the organism. Therapeutic equivalence or inequivalence can primarily only be evaluated in connection with the disease and the symptoms of disease, respectively. Thus, manufacturers, pharmacists and physicians likewise are confronted with the problem. The differences in bioavailability of the individual cardiac glycosides show the necessity for: 1. The number of fixed combinations of heart glycosides should be limited in the interest of drug safety. 2. Only such drugs should be approved whose quantitative and qualitative equivalence has been demonstrated with regard to the monoglycoside. 3. When prescribing digoxin derivatives one should not only observe the bioavailability but take also into account the chemical stability and the pharmacolinetic behaviour.
The introduction of mycophenolate mofetil (MMF) represented a major advance in transplant medicine, although optimal use may be limited by gastrointestinal (GI) side-effects. An enteric-coated formulation of mycophenolate sodium (EC-MPS; myfortic) has been developed with the aim of improving the upper GI tolerability of mycophenolic acid. Therapeutic equivalence of EC-MPS (720 mg b.i.d.) and MMF (1000 mg MMF b.i.d.), with concomitant cyclosporine microemulsion (Neoral) and corticosteroids, was assessed in 423 de novo kidney transplant patients recruited to a 12-month, double-blind study. Efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow up) at 6 months (EC-MPS 25.8% vs. MMF 26.2%; 95% CI: [-8.7, +8.0]) demonstrated therapeutic equivalence. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and of BPAR alone was 22.5% and 24.3% for EC-MPS and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with EC-MPS and 9.8% with MMF (p=ns). The safety profile and incidence of GI adverse events were similar for both groups. Within 12 months, 15.0% of EC-MPS patients and 19.5% of MMF patients required dose changes for GI adverse events (p=ns). Enteric-coated-MPS 720 mg b.i.d. is therapeutically equivalent to MMF 1000 mg b.i.d. with a comparable safety profile.
The introduction of mycophenolate mofetil (MMF)--the morpholino ester prodrug of mycophenolic acid (MPA)--has improved graft and patient survival, but its use has been linked with the occurrence of adverse events, particularly gastrointestinal (GI) side effects. These can be sufficiently severe to require dose reductions or discontinuation, which may lead to acute rejection episodes or graft failure. An enteric-coated formulation delivering mycophenolic acid-enteric-coated mycophenolate sodium (EC-MPS)-has been developed with the aim of improving upper GI tolerability. Therapeutic equivalence of EC-MPS 720 mg b.i.d. vs MMF 1000 mg b.i.d. has been established in a pivotal phase III, 12-month, international, randomized, double-blind, parallel group study, involving patients undergoing de novo renal transplantation. The incidence of efficacy failure (composite variable of biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow-up) was similar between the two groups at 6 months (EC-MPS 25.8% vs MMF 26.2%; 95% CI [-8.7, +8.0]), demonstrating therapeutic equivalence. Efficacy failure remained similar between the two treatment groups at 12 months. The overall incidence of adverse events and GI side effects were also comparable between treatment groups throughout the 12-month study period, although fewer patients in the EC-MPS group experienced study drug discontinuations, interruptions, or dose reductions (12 months: EC-MPS 15.0% vs MMF 19.5%). Subgroup analysis revealed similar safety profiles for EC-MPS and MMF in elderly patients and patients with diabetes at baseline. The EC-MPS 720 mg b.i.d. and MMF 1000 mg b.i.d. show therapeutic equivalence in de novo renal transplant patients. Therefore, EC-MPS offers transplant physicians and their patients an alternative MPA therapy that is as effective and safe as MMF.
With an increasing number of available treatment options, clinicians must frequently evaluate whether comparable therapies are equivalent in terms of efficacy and safety. Two methodologically distinct study designs are used to establish therapeutic equivalence: standard superiority trials and true equivalence trials. In either study design, clinician-readers assess equivalence by examining both the statistical significance and the clinical importance of the study results (as defined by the minimally important difference, the smallest difference in patient outcome that would lead to an important difference in patient health status). Once therapeutic equivalence has been established, clinicians may select one therapy as the preferred treatment option because it offers other clinical benefits, such as a lower cost or a more convenient drug administration schedule.
We discuss in this paper some issues related to the use of the ratio or the odds ratio of cure rates in therapeutic equivalence clinical trials with binary endpoints. Some two one-sided tests procedures are proposed and their fixed sample performances evaluated by Monte Carlo simulations. Sample size formulas are derived for most of these procedures. The consequences of applying acceptance limits proposed for pharmacokinetic responses in bioequivalence studies to clinical endpoints in therapeutic equivalence clinical trials are also described.
The number of studies designed specifically to demonstrate therapeutic equivalence or alternatively non-inferiority of pharmaceutical treatments has increased dramatically in recent years, during which time awareness of the methodological issues has increased. Regulatory authorities have been quick to recognize the need for specific support and have either published or initiated the creation of relevant guidance. Common misconceptions prevail however regarding sample size estimation and the choice of the most appropriate patient population to analyse while other areas such as equivalence margin specification and covariate adjustment have been neglected. This paper challenges some of the regulatory advice and the interpretation that others have made of this guidance with the aim of stimulating further debate.
OBJECTIVE: To explore the way for testing of multivariate in therapeutical equivalence. METHODS: By improved Hotelling T(2) test, the mean vector of two groups was tested. The information of each variable could then be obtained by deducting the their correlations. "Clinical Equivalence of Drug A and Drug B for Postmenopausal Bone Looseness" was used in this research. The primary measure of efficacy was regarded as the improvement rate of four variables with predefined limit of equivalence (2%) with the results of univariate test and multivariate test compared. RESULTS: Under P > alpha, all the variables were nonequivalent. Under P </= alpha, it was necessary to filtrate the variables of unequivalent until the residuals were equivalent. The method of multivariate test was a remedy to the shortage of univariate test. CONCLUSION: With the combination of the filtration of nonequivalent variables and the improved Hotelling T(2) test, the test of multivariate could be done. The method is reasonable and practical.