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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Clinical trial design in metastatic breast cancer: a commentary.
Trial designs traditionally used in the development of new anti-cancer agents are usually categorized as phase I, phase II, phase III and phase IV. Such trials are often performed in patients with metastatic cancer. Phase I trials are conducted in small numbers of patients to determine a drug's maximally tolerated dose (MTD) and toxicity profile. In phase II studies, the anti-tumor activity of the new agent is tested in different tumor types. If a drug is found to be promising in phase II studies, it is then compared to standard therapy through a randomized trial design in phase III studies. In phase IV studies, the efficacy and safety profile of the drug are evaluated in a standard clinical setting. In the field of oncology, studies have been conducted in which agents already approved by the regulatory agency are combined with other anti-cancer drugs and evaluated for anti-tumor efficacy. These have also been termed phase II studies.
Antineoplastic Agents↗
Post-tympanostomy otorrhea: a randomized clinical trial of topical prophylaxis.
Myringotomy with the insertion of tympanostomy tubes has become the most frequently performed otolaryngologic procedure, and otorrhea is the most common post-tympanostomy complication. Many otolaryngologists routinely use prophylactic topical antibiotic solutions when performing tympanostomy tube placement. Relatively little has been written regarding early post-tympanostomy otorrhea and scarcely any examining the efficacy of such prophylaxis. The current study is a randomized clinical trial to critically evaluate the efficacy of prophylactic otic drops after tympanostomy tube placement. The ototoxic potential of these solutions, combined with constant pressures to decrease medication expenses and eliminate unnecessary use of antibiotics, makes determination of the shortest effective course of application paramount. Subjects were randomized at the time of surgery into one of three groups: one group received no prophylaxis, a second group received gentamicin otic drops immediately after tympanostomy tube placement in the operating room only, and the third group received an additional 48 hours of drops (4 drops in each ear, three times a day). All patients were seen within 2 weeks postoperatively. An overall early post-tympanostomy otorrhea incidence of 8.7% is documented with 12%, 8.8%, and 5.6% for each study group, respectively. While these findings may suggest possible efficacy of topical prophylaxis, a statistically significant difference between the treatment groups was not proved (p = 0.62). Further analysis by subdivision of the patients, on the basis of middle ear cavity finding at the time of surgery, reveals a highly significant statistical association of the occurrence of post-tympanostomy otorrhea in ears having mucoid effusions (p less than 0.001) as compared to ears without effusion or with serous effusions.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Topical↗
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↗
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↗
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↗
A randomized clinical trial of topical cysteamine disulfide (cystamine) versus free thiol (cysteamine) in the treatment of corneal cystine crystals in cystinosis.
In nephropathic cystinosis, corneal cystine crystals cause severe photophobia and corneal erosions. Topical cysteamine dissolves these crystals, but cannot be marketed because it rapidly oxidizes to the disulfide form, cystamine, at room temperature. Since cystamine itself could be used commercially, we compared the efficacy of cystamine and cysteamine with respect to cystine crystal dissolution in a randomized, double-masked clinical trial. One eye each of 14 patients with cystinosis was randomized to either cystamine or cysteamine, 0.5%, with 0.01% benzalkonium chloride; the companion eye was treated with the alternate preparation. Corneal crystals were photographed and a density score was assigned to each slide based on 13 standard slides. After 8-20 months, 6 patients showed significant reduction of the corneal crystal score in only one eye. In each case, the improved eye was the cysteamine-treated eye. Theoretically, cysteamine should dissolve both intracellular and extracellular crystals, whereas cystamine should dissolve only intracellular crystals because it must first be reduced to the free thiol by the cytoplasmic-reducing environment. Hence, the lack of efficacy of the disulfide cystamine suggests that some corneal cystine crystals in cystinosis patients are extracellular, and that another form of stable, topical cysteamine must be developed for cystinosis patients.
Administration, Topical↗
The first clinical trial of topical application of procyanidin B-2 to investigate its potential as a hair growing agent.
Procyanidin B-2 is a compound we have identified in apple which acts as a growth-promoting factor on murine hair epithelial cells. This report describes our investigation of the hair-growing effects of 1% procyanidin B-2 tonic after sequential use for 4 months. A double-blind clinical trial was performed, involving a total of 29 subjects (procyanidin B-2, 19 men; placebo, 10 men). No adverse side effects were observed in either group. In the procyanidin B-2 group, 78.9% showed an increased mean value of hair diameter, whereas only 30.0% in the placebo group showed any increase (p < 0.02, Fisher's exact probability test). The increased ratio of hairs measuring more than 40 microm in diameter after 4 months of procyanidin B-2 treatment was significantly higher than that of the placebo controls (p < 0.05, two-sample-t-test). The increase in number of total hairs in the designated scalp area (0.25 cm(2)) of procyanidin B-2 subjects after a 4 month trial was significantly greater than that of the placebo controls (procyanidin-B-2, 3.67 +/- 4.09 (mean +/- SD)/0.25 cm(2); placebo, -2.54 +/- 4.00/0.25 cm(2); p < 0.001, two-sample t-test). Procyanidin B-2 therapy shows potential as a promising cure for male pattern baldness.
Administration, Cutaneous↗
Scientific and ethical considerations in trial design for investigational agents for the treatment of human immunodeficiency virus infection.
The design of clinical trials for new antiretroviral agents poses unique challenges, given the availability of highly active antiretroviral therapy (HAART). These challenges include the selection of appropriate populations, the methods used to partition the effects of the study drug under observation from those of the other concurrently administered medications in early studies, performance of dose-ranging studies for disease states in which suboptimal drug exposure may lead to the development of viral resistance that limits future treatment options, and the need to fulfill the obligations of international regulatory agencies. Throughout, science and ethics are tightly woven elements in study designs for antiretroviral drug trials. Fast-track drug approval status and successful lobbying by advocates for patients with acquired immunodeficiency syndrome aimed at the US Food and Drug Administration, the National Institutes of Health, the Centers for Disease Control and Prevention, university teaching centers, pharmaceutical companies, and members of Congress undoubtedly contributed to the development and swift regulatory approvals of the 17 antiretroviral medications now available in the United States for the treatment of human immunodeficiency virus infection.
Anti-HIV Agents↗
[Production and diffusion of scientific results in oncology].
The production of data from oncological research must follow specific steps linked to the type of research carried out. Research can be subdivided into the following areas: translational research, clinical research (Phases I, II and III), pharmacoutilization research, meta-analysis, and guidelines. A topic for discussion is represented by levels of evidence (LOE) of research, considered necessary for the transferral of therapeutic approaches to clinical practice. These involve production times of scientific research, and, in particular, the end-points deemed necessary by the appropriate regulatory bodies to permit the commercialization of drugs (problem of surrogate end-points). The interrelation between researchers and pharmaceutical companies has also recently become an object of reflection and research to find solutions that will guarantee both the independence of research and the legitimate needs of companies. A particularly important issue is the correct transmission of scientifically relevant data to the public by mass media sources. The communication of therapeutic advances obtained through research and scientific innovations should not lead to unrealistic expectations in the general population, which rather serve to weaken the already fragile relationship between the official world of oncology and the diverse universe of patients and their families.
Biomedical Research↗
Taxol (paclitaxel): a novel anti-microtubule agent with remarkable anti-neoplastic activity.
Taxol (paclitaxel), an anti-microtubule agent extracted from the needles and bark of the Pacific yew tree Taxus brevifolia, has shown a remarkable anti-neoplastic effect in human cancer in phase I studies and early phase II and III trials thus far conducted. This has been reported primarily in advanced ovarian and breast cancer, although significant activity has also been documented in small-cell and non-small-cell lung cancer, head and neck cancers, and with lower activity in metastatic melanoma. The clinical utilization of Taxol had been previously somewhat restricted by its limited availability, a limitation that has recently been overcome by combined efforts of pharmaceutical, agricultural, and governmental agencies. In this review we shall address the pre-clinical data which have led to the use of Taxol in man, the main clinical results thus far obtained, the toxicities associated with its use, current ongoing trials and future clinical directions of this promising agent.
Animals↗
Innovative strategies in lymphoma therapy.
Treatment of malignant non-Hodgkin lymphomas (NHL) in the 21st century has been revolutionized by novel biological agents offering targeted approaches in addition to radio-chemotherapy. Monoclonal antibodies (MoAbs) against lymphatic surface antigens have been effective as monotherapeutic agents, and have already shown their superiority to conventional strategies when combined with chemotherapy. Radioimmunoconjugates are more effective than unlabelled antibodies. Specific inhibitors of neoangiogenesis as well as intracellular signal transduction pathways and antiapoptotic mechanisms have shown their efficacy in phase II studies. Long-term improvement in the setting of minimal residual disease has been observed after vaccination against surface antigens and non-myeloablative allogeneic stem cell transplantation is effective in controlling lymphoma growth. Novel specific antigens are currently identified using expression profiling of lymphomas. In the near future, combinations of biological agents will challenge conventional therapy. These exciting new strategies will improve the success rate in aggressive NHLs and may even challenge the paradigm of incurability of indolent lymphomas.
Alemtuzumab↗
Partial breast irradiation after breast-conserving surgery.
BACKGROUND: The standard technique of postoperative radiotherapy after breast-conserving surgery is percutaneous irradiation of the entire breast to a total dose of 45-50 Gy which is usually followed by a tumor bed boost. Since the majority of local recurrences in selected patients occur close to the former tumor bed, the question arises whether a sole tumor bed irradiation might be a therapeutic alternative to total breast irradiation. METHODS: A systematic review of relevant literature concerning partial breast irradiation (PBI) up to November 2004 was undertaken. Studies of any design were included for comparison and discussion. RESULTS: Nine unique brachytherapy studies using the multi-catheter technique, one the balloon technique (MammoSite), and eight particular intraoperative radiotherapy (IORT) trials were located of which only one was a randomized trial. Only minor postoperative complications were reported. Preliminary results are similar in terms of local tumor control, disease-free and overall survival. However, the current evidence base of IORT studies is poor. CONCLUSION: Despite controversies regarding PBI after breast-conserving surgery, results of phase I-II trials suggest that sole tumor bed irradiation might be an appropriate therapeutic alternative for selected breast cancer patients. However, more experience and data from ongoing phase III trials are required to define these new methods to be an appropriate treatment option. Therefore, total breast irradiation still remains the standard irradiation modality even in the treatment of early breast cancer, and PBI should be considered investigational.
Adult↗
Prospective clinical trials of biotherapies in solid tumors: a 5-year survey.
PURPOSE: To review the content and quality of prospective clinical trials of biotherapies in solid tumors. METHODS: Data were collected from the literature between 1990 and 2002 on general study characteristics, patient and disease factors, study methodology, and factors related to completeness of reporting. Quality of phase II studies was evaluated by an ad hoc questionnaire. Descriptive statistics, contingency tables, and the chi-square test were applied. RESULTS: A total of 334 studies were selected, of which about three quarters were multicenter, with 42.5% reporting phase I, 42.2% phase II or I/II, and 11.9% phase III or II/III studies. Only 13.7% were randomized, and a study design emphasizing statistical analysis was lacking in as many as one third. The assessment of biological endpoints was stated as the primary or secondary goal in half of these studies. Melanoma (17.1%), renal carcinoma (11.1%), gastrointestinal neoplasms (11.1%), and lymphomas (6.3%) were the most studied diseases. Immunotherapies accounted for 182 studies; the remaining 152 reported other biotherapies. Patients with (1) advanced disease (P = 0.003), (2) heavily pretreated neoplasms (P < 0.0001), (3) poor performance status (PS < 2) (P < 0.0001), were more frequently enrolled in studies of biotherapy. Biotherapies were less frequently evaluated in phase III studies (7/152) compared with immunotherapies (33/182) (P < 0.0001). A statistical study design was more frequently identified in biotherapy trials (127/152) compared with immunotherapy trials (98/182) (P < 0.0001). Biological endpoints were less frequently evaluated in phase III studies in both biotherapies (100% no vs 0% yes) and immunotherapies (81.8% no vs 18.2% yes) (P = 0.01, for biotherapies; P < 0.0001, for immunotherapies). Phase I immunotherapy studies more frequently applied biological or molecular criteria for patient selection (41.1%) than phase II (29.3%) and III (3.1%) studies (P < 0.0001). CONCLUSIONS: The very wide diversity in modalities of conducting and reporting clinical trials of biotherapies of solid tumors and the presence of some methodological pitfalls suggest that the methodological standards for conducting and publishing clinical trials in biotherapies should be improved to enhance the reliability of the body of published data.
Antineoplastic Combined Chemotherapy Protocols↗
[Pharmacological therapy for age-related macular degeneration. Current developments and perspectives].
Current therapeutic options for age-related macular degeneration are very limited and are, at best, only capable of slowing visual loss. Because of this an intensive search for prophylactic agents capable of inhibiting the progression of this disease from early into late forms, as well as for new therapeutic approaches has been undertaken. While neuroprotective substances are hoped to prevent cellular death in this disease process, multiple substances capable of inhibiting neovascularization, such as VEGF inhibitors, are in clinical trials. Inhibitors of matrix-metalloproteinases (MMP) and chemotherapeutic agents are also being clinically tested as novel therapies for AMD. Other targets include the inhibition of toxic compound formation in lipofuscin granules such as AZ-E. What follows is an overview of different substances and their stages of development in clinical trials.
Adrenal Cortex Hormones↗
Statistics in clinical trials.
Statistical developments over the past several years are described in this review. Efforts in phase I studies have focused on efficient estimation of maximum tolerated dose. Issues investigated for phase II trials include incorporation of multiple endpoints and randomization. For phase III trials, methods to reduce time or use the sample size more efficiently have been investigated. However, design innovations come with costs, including possible increased risk of incorrect conclusions. Other recent challenging statistical developments in clinical trials relate to use of complementary outcomes such as quality of life and to associated biologic questions, including the emergence of the field of genomics.
Clinical Trials as Topic↗
[Characteristics of clinical trials in oncology: pharmacist's implication].
French hospital pharmacists have been officially involved in the organization of clinical trials since 1988. New responsibilities included reception of clinical treatment units and nominative dispensation of these drugs. For quality assurance, they organized all the procedures to secure drugs utilization according to good clinical practices and ICH guidelines. The pharmacists can be participate in ethical counselling and training in methodology. For oncology trials, only a few pharmacies are involved because clinical trials for evaluation of cytotoxic drugs have been regulated by very strict standardized procedures since 1960 in accordance with international rules. Using these rules, Phase I studies determine the useful dose for human administration with tolerable toxicities. Phase II studies determine the efficacy in specific cancer localizations. Good response in a particular indication is usually followed by drug approval for Phase III. New clinical and biological end points are arising especially for new non-cytotoxic therapeutic agents. This activity is at the present time limited to inpatient treatments, but with the growing development of outpatient care networks, dispensary pharmacists will come to be more involved in the necessary research and development of new anticancer agents.
Antineoplastic Agents↗
5-fluorouracil/leucovorin versus capecitabine in patients with stage III colon cancer.
Capecitabine is an orally administered fluoropyrimidine carbamate that is preferentially converted to 5-fluorouracil in tumors relative to normal tissue. Three different dosing regimens were investigated in phase I studies: continuous monotherapy, intermittent monotherapy, and intermittent therapy supplemented with leucovorin. These studies defined the maximum tolerated dose for each regimen. Dose-limiting toxicities were diarrhea, hand-foot syndrome, and leukopenia. Each phase I study recommended a dose; these were directly compared in a phase II study. This phase II study showed that the intermittent regimen of capecitabine monotherapy was the most favorable on the basis of tumor response rates, time to progression, dose intensity, and toxicities. The intermittent regimen of capecitabine has been compared with the Mayo Clinic regimen of 5-fluorouracil/leucovorin in two large, phase III studies of patients with advanced colorectal cancer. The combined data from the two studies showed that capecitabine was superior to 5-fluorouracil/leucovorin in terms of tumor response rate (22% v 13%; P < .0001) and similar in terms of time to disease progression and overall survival. Capecitabine is now being compared with the Mayo Clinic regimen as an adjuvant treatment for patients with Dukes' C colon cancer.
Administration, Oral↗