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PubMed1999

Planning and analysis of repeated measures at key time-points in clinical trials sponsored by pharmaceutical companies.

In this paper we explore the possible reasons why medical papers reporting clinical trials sponsored by the pharmaceutical industry often analyse repeated measures data at certain key time-points instead of employing sophisticated models of repeated measures proposed by many statisticians. A survey indicated that the priority reason in the industry for having repeated measures in clinical trials is to monitor the trial and to utilize the early results for strategic decision making. We discuss what the common statistical methods do and do not offer for analysis of repeated measures in such clinical trials. We advocate the need to improve the understanding of the medical interest in conducting longitudinal trials in the industry, and to plan and analyse the repeated measures accordingly. We address the medical interest by formulating the problem and give illustrative examples for both phases II and III trials.

Alendronate↗
PubMed2006

Needle-free injection of DNA vaccines: a brief overview and methodology.

The development of needle-free injection originally stemmed from a general apprehension of needle injections, disease transmission by accidental needle-sticks, and the need for effective mass immunization. Naked DNA vaccines, as attractive and universal as they appear, have not produced robust immune responses in test systems. However, proof of principle for DNA vaccines has been validated with a number of vaccine candidates in a variety of test systems, and the concept of DNA vaccines as a generic platform for vaccines still remains viable and attractive. Many avenues are being explored to enhance the immunogenicity of DNA vaccines. The easiest and most straightforward approach that can be quickly transitioned to a clinical trial setting is vaccine delivery by a needle-free jet injector. This approach has shown much potential in a number of cases and should become the lead method for enhancing DNA vaccines. This approach requires no additional development, and with an expanding market and willingness from jet injector manufacturers to produce prefilled syringes, the technique should become feasible for larger phase II/phase III trials.

Animals↗
PubMed2000

No clinically important effects on intraocular pressure after short-term administration of sildenafil citrate (Viagra).

PURPOSE: To assess the short-term effects of sildenafil citrate on intraocular pressure in healthy male volunteers and participants in clinical trials. METHODS: Intraocular pressure and pupil diameter were measured in two placebo-controlled studies. Oral doses of sildenafil citrate (VIAGRA; Pfizer Inc, New York, New York) ranged from 10 mg to 150 mg. RESULTS: No major changes in intraocular pressure or pupillometry were detected at any time (1.0-24 hours) after administration of sildenafil. Additionally, of 36 subjects with a medical history of increased intraocular pressure in the sildenafil safety database, none were reported to have a clinically significant increase of their intraocular pressure. During clinical trials, two glaucoma cases were listed as serious adverse events, but were not considered treatment related. CONCLUSION: No clinical abnormalities were observed in intraocular pressure or pupil diameter in subjects receiving sildenafil. Currently, no evidence suggests that long-term treatment with sildenafil has an effect on intraocular pressure or is associated with the development or worsening of glaucoma.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2005

Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients.

PURPOSE: A new generation of molecularly targeted agents is entering the definitive stage of clinical evaluation. Many of these drugs benefit only a subset of treated patients and may be overlooked by the traditional, broad-eligibility approach to randomized clinical trials. Thus, there is a need for development of novel statistical methodology for rapid evaluation of these agents. EXPERIMENTAL DESIGN: We propose a new adaptive design for randomized clinical trials of targeted agents in settings where an assay or signature that identifies sensitive patients is not available at the outset of the study. The design combines prospective development of a gene expression-based classifier to select sensitive patients with a properly powered test for overall effect. RESULTS: Performance of the adaptive design, relative to the more traditional design, is evaluated in a simulation study. It is shown that when the proportion of patients sensitive to the new drug is low, the adaptive design substantially reduces the chance of false rejection of effective new treatments. When the new treatment is broadly effective, the adaptive design has power to detect the overall effect similar to the traditional design. Formulas are provided to determine the situations in which the new design is advantageous. CONCLUSION: Development of a gene expression-based classifier to identify the subset of sensitive patients can be prospectively incorporated into a randomized phase III design without compromising the ability to detect an overall effect.

Antineoplastic Agents↗
PubMed1992

Phase II and III studies with carboplatin in small cell lung cancer.

Carboplatin is one of the most active agents in untreated small cell lung cancer (SCLC) (11% complete response [CR], 59% CR plus partial response [PR]). Combination carboplatin/etoposide/vincristine (CEV) (phase II trial) led to an overall remission rate of 84% in patients with limited disease (LD), with 52% CRs. The median survival time with this combination was 14 months in patients with LD and 9.5 months in those with extensive disease (ED). The 30-month survival rates are 30% in LD and 10% in ED, which represents a plateau of the survival curve. This regimen is highly effective and exhibits low toxicity in SCLC. To evaluate the role of carboplatin in combination chemotherapy in patients with extensive SCLC, a phase III trial was performed. In this ongoing trial comparing CEV and etoposide/vincristine in ED patients, CR and overall response rates to date are higher in the CEV arm (CR, 20% versus 15%; CR plus PR, 83% versus 65%), but as yet the differences are not statistically significant. In summary, chemotherapy regimens containing platinum compounds are among the most active in the treatment of SCLC. The use of the new compound carboplatin instead of cisplatin has led to similar or increased remission rates and is preferable because it has fewer side effects. Preliminary results from this ongoing, prospective, randomized phase III trial are presented.

Adult↗
PubMed2001

Clinical trials: are they a good buy?

PURPOSE: Concern that clinical trials may be too costly has been used to justify traditionally restrictive insurer policies regarding clinical trials. Additionally, fear of insurer reimbursement denial can be a significant barrier to clinical trial participation. In this study, we reviewed the empirical data on costs of clinical trials versus standard care and summarized the current status of policy initiatives related to clinical trial insurance reimbursement. METHODS: Electronic and print data sources were searched for studies on the costs of oncology clinical trials. Information on policy initiatives for clinical trial reimbursement was obtained from the American Society of Clinical Oncology, the American Society of Hematology, and the Coalition of National Cancer Cooperative Groups and from searches of World Wide Web sites. RESULTS: Five pilot studies provided information for 377 patients on phase II/III clinical trials matched with controls on standard care. Cost estimates ranged from 10% lower to 23% higher costs/charges for clinical trials in comparison to standard medical care. Medicare, 14 states, and several private insurers now cover the costs of patient care in "qualifying" clinical trials. CONCLUSION: Findings from small pilot studies suggest that phase II and III clinical trials result in at most modest increases in cost over standard treatment costs. Also, an increasing number of policy makers have decided to support clinical trial reimbursement initiatives. It is hoped that economic data from large observational studies will facilitate widespread and permanent decisions that support reimbursement for phase I, II, and III clinical trial participation.

Clinical Trials as Topic↗
PubMed2005

Biostatistical methods for demonstrating efficacy in the regulatory setting. An epistemological approach to adaptive designs.

Adaptive designs are one of the most promising developments in statistics with applications to clinical trials. Obviously the knowledge at the beginning of a clinical trial will always be limited. In consequence it may be considered necessary that the knowledge from accumulating information should be used to optimize the design of the trial. This paper discusses conditions under which this may be possible in phase III clinical trials where the principle aim is confirmation of hypotheses that have been developed in earlier stages of drug development.

Biometry↗
PubMed2003

Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis.

OBJECTIVE: To review the data supporting drotrecogin alfa (activated) for severe sepsis treatment. DATA SOURCES: Published research and data from the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. DATA EXTRACTION AND SYNTHESIS: The coagulation cascade and intense inflammation play a central role in the development of organ failure due to severe sepsis. Drotrecogin alfa (activated) has anti-inflammatory, antithrombotic, profibrinolytic, and other properties that may explain the beneficial results seen in both animal models and humans with severe sepsis. Drotrecogin alfa (activated) produces a robust reduction in the mortality rate of patients with severe sepsis that is evident across nearly every subgroup examined in the phase III clinical trial and has an acceptable safety profile with bleeding during infusion as the only significant risk associated with therapy. The relative risk reductions for mortality seen in Gram-negative, Gram-positive, pneumonia, abdominal sources, shock, and nonshock are similar to the intent-to-treat population, 19.4%. Treatment also increases days alive and free from mechanical ventilation and shock. CONCLUSIONS: Coagulopathy and systemic inflammation are almost universal in patients with severe sepsis. Treatment of this disorder with drotrecogin alfa (activated) directly addresses these derangements and substantially reduces morbidity and mortality rates with potential for bleeding during infusion as the only known risk.

Animals↗
PubMed1995

Phase I study of paclitaxel as a 3-hour infusion followed by carboplatin in untreated patients with stage IV non-small cell lung cancer.

Preliminary results of a phase I study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given by 3-hour infusion, followed by carboplatin in chemotherapy-naive patients with stage IV non-small cell lung cancer indicate that both agents can be combined at clinically relevant single-agent doses. The paclitaxel (mg/m2)/carboplatin area under the concentration-time curve (mg.min/mL) dose level of 225/7 is projected to be the maximally tolerated and recommended phase II dose level for future evaluations. Dose-limiting neutropenia, thrombocytopenia, and nausea and vomiting preclude treatment with carboplatin doses estimated to target an area under the concentration-time curve of 9 mg.min/mL when given with paclitaxel 225 mg/m2. The heterogeneous nature of the principal toxicities, as well as the ability to administer clinically relevant single-agent doses of both agents in combination, also indicate that further dose escalation of paclitaxel and carboplatin using hematopoietic growth factors would not be feasible. The preliminary antitumor activity noted to data, as well as the safety associated with the clinically relevant single-agent doses that can be given in combination, indicate that phase II/III evaluations of this regimen are warranted in patients with both advanced and early stage non-small cell lung cancer.

Adult↗
PubMed1993

[Are phase II or phase II antidepressive drug studies still feasible considering currently required inclusion and exclusion criteria?].

The present policy of pharmaceutical companies to aim at perfectionistic, and therefore inflexible protocols for clinical drug-trials renders patient recruitment increasingly difficult or even impossible, and may result in an increasing number of non-completed studies. It appears that many of today's inclusion and exclusion criteria are not sufficiently assessed in terms of their scientific basis and clinical usefulness. Sense and nonsense of these criteria are discussed. The tendency to adhere to streamlined protocols to certify the needs of drug regulators will severely impair the feasibility and validity of antidepressant drug trials in psychiatric in-patients.

Adolescent↗
PubMed2004

COLAL-PRED Alizyme.

COLAL-PRED (prednisolone sodium metasulfobenzoate), which is targeted to the colon by COLAL colonic drug delivery technology, is being developed by Alizyme for the potential treatment of inflammatory bowel disease. Alizyme expect to initiate a phase III trial in 2005.

Animals↗
PubMed2001

Paclitaxel added to the cisplatin/etoposide regimen in extensive-stage small cell lung cancer -- the use of complete response rate as the primary endpoint in phase II trials.

Obtaining a complete response (CR) is the most powerful predictor of survival in extensive-stage small cell lung cancer (SCLC). Improvements in long-term survival in extensive-stage SCLC can be made if the proportion of complete responders to induction therapy can be increased. We performed a phase II trial of the feasibility of adding paclitaxel to standard cisplatin/etoposide (EP regimen) in extensive-stage SCLC. The primary endpoint for this trial is the proportion of patients (pts) obtaining a CR rather than overall response. The null hypothesis for this trial consists of the absence of a CR rate >20%. Paclitaxel was given at doses of 135 (3 pts) or 170 mg/m(2) i.v. over 3 h on day 1. Cisplatin 60 mg/m(2) was given on day 1. On days 1-3 etoposide 80 mg/m(2) per day i.v. was given. G-CSF was used from days 5 to 14 of each cycle. Cycles were repeated q21 days. A two-stage design was used for patient accrual, based on the occurrence of complete responses. Initially, 16 patients were to be accrued. If more than three complete responses were to occur, a further 20 patients would be accrued to the study (Simon's optimal two stage design). Sixteen patients were enrolled. Two patients had a CR (13%) and nine patients had a partial response (56%) for an overall response rate of 69%. The trial was suspended due to the low CR rate. Review of the literature for paclitaxel based front-line treatment combined with EP therapy, in extensive stage SCLC, consistently shows a CR rate <20% but high overall response rate is maintained (thus most responses are partial). As virtually all long-term survivors in extensive-disease SCLC have had a CR to induction therapy and CR remains the strongest predictor of survival for this disease, this may suggest that paclitaxel added to standard EP may improve progression-free survival (and possibly median survival) but is unlikely to significantly improve long-term survival. Initial randomized phase III data confirm the absence of impact on survival for this triple-drug regimen compared to EP therapy alone. Furthermore, other regimens comparing favorably to the EP regimen have all shown consistent CR rates >20% in the phase II setting. In conclusion, consideration should be given to the use of CR rate as a phase II endpoint to determine if a particular regimen should be compared to the standard in a phase III setting for extensive-stage SCLC. A two-stage phase II design based on a minimum required completed responses for further patient accrual is recommended.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

What are the reasons for negative phase III trials of molecular-target-based drugs?

The results of molecular-biological studies of cancer are changing the way we diagnose and treat cancer. Target-based drug discovery selects agents for development based on their mechanisms of action. The interaction between target-based drugs and their targets can be described by classical drug-receptor theory. Clinical trials have demonstrated that some effective target-based drugs induce apoptosis, even though they are considered to be cytostatic. Numerous phase III trials of target-based drugs have been conducted. Although some have yielded strongly positive results, the majority of the results have been negative. This article seeks to clarify the value of molecular-target-based therapy and to discuss the reasons for negative results in phase III trials. The importance of proof-of-principle studies is stressed throughout preclinical and clinical trials of molecular-target-based drugs.

Antineoplastic Agents↗
PubMed2003

The Prostate Cancer Prevention Trial: design, status, and promise.

The Prostate Cancer Prevention Trial is the first phase III (randomized, placebo-controlled, prospective) population-based study to determine whether the risk of prostate cancer can be reduced. Between 1994 and 1997, 18,882 men were randomized to either finasteride or placebo at 219 sites in the United States. The study design included annual digital rectal examination and PSA determinations with PSA performed centrally with reports provided to sites corrected for treatment arm (as finasteride lowers PSA level). Because of a number of potential biases that could confound disease ascertainment all patients were scheduled for an end-of-study prostate biopsy. End-of-study prostate biopsies began in 2000, and the final biopsy is expected in 2004, with results of the study anticipated shortly thereafter. The high participant interest and extensive data collected for this study demonstrate the extraordinary opportunity for chemoprevention trials of prostate cancer in the United States

Clinical Trials as Topic↗
PubMed2003

Sumanirole Pharmacia.

Sumanirole is a dopamine D2 agonist under development by Pharmacia Corp (formerly Pharmacia & Upjohn) for the treatment of Parkinson's disease. The compound is currently undergoing phase II trials in Japan and phase III clinical trials in the US.

Antiparkinson Agents↗