Pivotal trial

Fig. 1 Sustained virologic response rates from pivotal trials in patients with chronic hepatitis C according to treatment regimen and HCV genotype. For references see text...

Patients infected with HCV genotype 1,4, 5 or 6 are treated with peginterferon-a in combination with ribavirin for 48 weeks (Table 3). In the pivotal trials, sustained virologic response rates achieved with patients infected with these genotypes were 46-51% with peginterferon-a2a and ribavirin and 42-48% with peginterferon-a2b and ribavirin. Different baseline parameters (female gender, age <40 years, low body... 

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

Phase lib. Well-controlled trials to evaluate efficacy (and safety) in patients with the disease or condition to be treated, diagnosed, or prevented. These clinical trials usually represent the most rigorous demonstration of a medicine s efficacy. Sometimes referred to as pivotal trials. 

Finally, one of fhe most recent and most interesting approvals of a new formulation of paclifaxel was fhe approval of the agent ABl-007 (Abraxane ) (Abraxis Oncology, Schaumburg, IL, U.S.A.) (paclifaxel protein-bound particles for injectable suspension [albumin-bmmd]). It is indicated for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. The endpoint for that pivotal trial of Abraxane vs. paclitaxel was a... 

Campath was given accelerated approval on the basis of response rate. The pivotal trial was a study in 93 pahents who had been previously treated with an alkylating agent and whose disease had progressed on treatment with fludarabine. The FDA requested a follow-up sfudy for full approval of Campafh by randomizing patients between Campath and chlorambucil (Leukeran) as front-line therapy This trial is ongoing. Thus, Campath has had a convenhonal development approach. 

Another creative trial design was performed for the pivotal trial for approval of the monoclonal antibody cetuzimab (Erbitux). The clinical trial was based on the preclinical evidence. Erbitux was synergistic in animal model systems. 

Erlotinib (Tarceva) took a differenf approach to a pivotal trial. In the study of Tarceva for patients with advanced, previously treated non-small cell lung cancer, where survival was the primary endpoint, patients were randomized to receive either Tarceva or placebo. Tarceva clearly prolonged overall survival (6.7 vs. 4-7 months, p = 0.001). In addition, Tarceva improved progression-free survival, and improved fime-fo-deferiora-tion of patients reported symptoms (cough, dyspnea, and pain). Obviously, this was a definitive trial (drug vs. placebo) however, it could be a controversial trial as it was a survival trial with no provisions to crossover to the active Tarceva. It is doubtful fhaf many trials with this noncrossover design (with a survival endpoint) will be done in the future. 

Mass RD, Sanders C, Charlene K, et al. The concordance between the clinical trials assay (CTA) and fluorescence in situ hybridization (FISH) in the Herceptin pivotal trials. ProcAm Soc Clin Oncol 2000 19 75 (abstr). 

The logistics of large phase 3a trials are extremely complicated and require considerable manpower in the headquarters and in the field. Full compliance to Good Clinical Practice (GCP) as well as scientific integrity are prerequisites for the acceptability of these trials to the regulatory authorities, and the pivotal trials undergo detailed inspection to safeguard these... 

A discussion of the two pivotal trial rule and under what conditions sponsors may be allowed to deviate from that requirement is included in the CPMP (2001) Points to Consider on Application with 1. Meta-Analysis 2. One Pivotal Study paper that covers meta-analysis, as there are some common issues. 

In therapeutic settings where there are practical reasons why two trials cannot be easily undertaken or where there is a major unfulfilled public health need, it may be possible for a claim to be based on a single pivotal trial. The regulatory authorities do allow this, but only under certain conditions. 

This guideline defined the role of meta-analysis within a regulatory submission (see Section 15.5.1) and indicated the circumstances where a single pivotal trial might be acceptable as the basis for registration (see Section 15.5.2). 

The Liebowitz Social Anxiety Scale (LSAS) measures fear, anxiety and avoidant behavior in 24 commonly feared social situations and performances. There are 13 performance-related items and 11 items that rate the social situations (Heimberg et al, 1999). The LSAS is the standard established outcome measure in most of the pivotal trials for social anxiety. Cut-offs of 30 for social anxiety disorder and 60 for its generalized subtype on the LSAS total scores represent a balance of specificity and sensitivity. There are two valid versions of the LSAS a clinician-administered version and a self-rating version (Fresco et al.. 2001). 

Freidlin and Simon (10) have shown, however, how one pivotal trial can be used potentially for both purposes—if the set of patients used to develop the classifier is kept distinct from the set of patients used to evaluate treatment benefit. Generally, however, the studies should be kept separate. Developmental studies are exploratory, though they should result in completely specified binary classifiers. Studies on which claims of drug benefit are based should be non-exploratory, but should instead test prospectively defined hypotheses about treatment effect in a pre-defined patient population. 

Privitera M Efficacy of levetiracetam A review of three pivotal trials. Epilepsia 2001 42(Suppl 4) 31. 

Category 4 vendors are sole-source API manufactures. First-time clinical trial supply manufacturers, offshore single pivotal trial clinical sites, and... 

Collet JR Montalescot G, Fine E, et al. Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials. J Am Coll Cardiol 2003 41 8— 14. 

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