One pivotal study

For meta-analyses where these requirements are not fulfilled it will prove difficult to get a regulatory acceptance  

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. 

The two trial rule, for example in a placebo controlled setting, effectively translates into a very stringent requirement for statistical significance. In a single trial the conventional two-sided type I error rate is 0.05. It follows that in order 

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. 

CPMP (2001) Points to Consider on Application with 1. Meta-Analysis  

---

In cases where the confirmatory evidence is provided by one pivotal study only, this study will have to be exceptionally compelling, and in the regulatory evaluation special attention will be paid to ... 

Clarifying the definition of substantial evidence of efficacy to include only one pivotal study, provided there is adequate confirmatory evidence. This had long been used for the approval of oncology drugs, but was now able to be applied more widely. 

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],... 

It is necessary to work in a species capable of responding to the principal activity. Interferons are notorious for their species specificity, but most other lymphokines at least are more generally active. Work in a primate may be required, but it depends on the substance to be tested. There may be no point in using more than one species in pivotal studies. 

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. 

Based on these initial phase II results, an expanded worldwide phase II pivotal study was performed to assess the efficacy and safety of trastuzumab monotherapy (249). This study enrolled 222 metastatic breast cancer patients whose tumors had HER2 overexpression and who had progressed after one or two prior chemotherapy regimens. As with previous trastuzumab studies, HER2 overexpression was determined by a centralized IHC assay, in which HER2 staining was required to be 2+ or 3+ on a 0 to 3+ scale. Patients received trastuzumab intravenously as a 4 mg/kg loading dose followed by 2 mg/kg weekly maintenance. 

Pivotal Studies In clinical trials, a Phase III trial that is designed specifically to support approval of a product. These studies are well-controlled (usually by placebo) and are generally designed with input from the FDA so that they will provide data that is adequate to support approval of the product. Two pivotal studies are required for drug product approval, but usually only one study is required for biologies. 

A check on the data should be performed to ensure that dosage forms produced from different manufacturers are equivalent. To demonstrate equivalence, at least one batch of the drug product should be manufactured for each source of the new drug substance to verify for bioequivalence against each clinical batch used in the pivotal studies. 

A follow-up to these pivotal studies was published in 2002 [28]. One hundred twenty-eight subjects continued in open-label trials for up to 2 years at the conclusion of the controlled studies. Evidence suggests that the clinical benefit of therapy continued to be exhibited. Patients receiving inhaled tobramycin had improvements in FEVj of 14.3% compared to 1.8% in placebo patients, and active treatment significantly reduced sputum density of P. aeruginosa (p =. 0001). 

In more recent years, in an attempt to overcome these problems, it has become fashionable to include more centres than may be necessary in a study on the basis that some will be successful at recruiting whereas others will not. All, of course, have to be assessed to ensure that they can operate within the principles of GCP. It is important to be realistic in estimating the speed at which recruitment will occur, and even in common diseases areas it is often unreasonable to expect centres to recruit at the rate of more than one to two patients per month. Nevertheless, the geographical distribution of clinical research is of major commercial concern because involvement of influential clinicians in the evaluation of a product is vital. It necessarily follows that involvement of influential clinicians in potentially large markets is of prime importance. Studies should therefore be conducted in these areas as first choice. However, that mandates a willingness on behalf of the investigator to participate in pivotal studies, a willingness to meet development deadlines and, of course, assumes the existence of an appropriate patient population and appropriate facilities for the conduct of the study. 

No serious adverse events related to rAHF-PFM were reported in the Pivotal study. In total, 19 non-serious adverse events in seven patients were judged to be product-related these included taste perversion, headache, fever, diarrhea, dizziness, hot flashes, pain in upper abdomen, pain in lower chest, shortness of breath, sweating, nausea, rigors, and itching in the arm used for the infusion [8]. Five non-serious drag-related events were mild, 12 were moderate, and two (one high fever and one severe headache, reported concurrently in one patient) were severe. No patient withdrew from the study because of any study-drag-related adverse event [8, 25, 27-29],... 

The 108 treated patients in the PTP Pivotal study accrued a median of 117 exposure days. During the entire study, only one patient tested positive for a low titer (2.0 BU) inhibitor to FVIII following 26 exposure days to rAHF-PFM. This patient, a 5 5-year-old man with severe hemophilia A, displayed no symptomatic evidence of an inhibitor. The inhibitor was undetectable in a blood sample collected and tested 8 weeks later [8, 29]. 

Shun Z, Chi E, Durrleman S, Fisher L (2005) Statistical consideration of the strategy for demonstrating clinical evidence of effectiveness - one larger vs two smaller pivotal studies. Statistics in Medicine 24 1619-1637 discussion 1639-1656. 

This approach to the pivotal points needs to be checked, ideally not just for this curve, but for application in other studies. That is, it is wise to keep the piece components as few as possible, because the idea is to create a model that can be used across studies, not just for one particular study. Technically, one could fit each value as a piecewise computation until one ran out of degrees of freedom, but this is not useful. 

---