Pivotal studies

The penicillins are a class of compound having the general structure (1). Because of their unique effectiveness in the treatment of bacterial infections in humans, these compounds have been investigated intensively from the chemical, microbiological and clinical points of view since about 1940. The early history of these developments (see especially B-80MI51100, B-49MI51100) contains the following pivotal studies ... 

Efficacy. A pivotal study by Hurt et al. (1997) established the efficacy and safety of bupropion SRfor treatment of nicotine dependence, which led to its approval for this indication by the FDA in 1998. This study was a 7-week, double-blind, placebo-controUed, multicenter trial of three doses of bupropion SR (100 mg/day, 150 mg/day, or 300 mg/day in twice daily dosing). Patients were 6l5 cigarette smokers who smoked at least 15 cigarettes/day. The medication was administered in combination with weekly individual cessation counseling. End-of-trial 7-day point prevalence cessation rates were 19.0% for placebo and 28.8%, 38.6%, and 44.2% for the 100 mg/day, 150 mg/day, and 300 mg/day bupropion doses, respectively. At 1-year follow-up, cessation rates were 12.4% for placebo and 19.6%, 22.9%, and 23.1% for the 100 mg/day,... 

Yet the pivotal study on raloxifene has been the Multiple Outcomes of Raloxifene Evaluation (MORE), a randomized, double-blind, placebo-controlled trial... 

Acute, for example, implies a single exposure interval (of 24 h or less) or dose of test material. Using the second scheme (length of dosing), the objectives of the successive sets of pivotal studies could be defined as follows ... 

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. 

In pivotal studies, the actual blood levels of active moiety that are achieved will be determined so that correlations to later clinical studies can be made. 

Phase II studies encompass a detailed assessment of the compound s safety and efficacy in a larger patient population (a few-to-several hundreds of patients). It is important that any formulation selected for these studies must be based on sound biopharmaceutical and pharmaceutical technology principles. Phase III clinical studies, also referred to as pivotal studies, involve several thousands of patients in multiple clinical centers, which are often in multiple countries. The aim of these studies is to demonstrate long-term efficacy and safety of the drug. Since these studies are vital in the approval of the drug, the dosage form plays a very critical role. 

Phase III—Pivotal studies, multisite, 100s to 1000s of subjects, randomized, double-blinded... 

Application of a scientifically derived adjustment factor to the NOAEL, or LOAEL, of the critical effect established in the pivotal study. It is stated that if the database is inadequate, then human PNAELs cannot be derived scientifically. 

WHO/IPCS (1994, 1999) stated that a minimum data set considered adequate for an assessment will vary according to the purpose of the assessment. The major deficiencies in a toxicity database, other than those related to the pivotal study, which increase the uncertainty of the extrapolation should be recognized by the use of an additional UF. Since the quality and/or completeness of different databases vary, the additional UF will also vary. For example, a value of 1 would be applied to a database that was considered complete for the evaluation of the compound under consideration, but a factor of 1-100 might be necessary for limited databases. If minor deficiencies in the data exist with respect to quality, quantity, or omission, then an extra factor of 3 or 5 would be appropriate. An extra factor of 10 would be appropriate where major deficiencies in the data exist, e.g., a lack of chronic toxicity studies and reproductive toxicity studies. It was pointed out that inadequacies of the pivotal study could also be considered as a subset of inadequacies of the database and that the total factor for limitations of the pivotal study plus adequacy of the overall database should not exceed 100 since such a database is generally not acceptable for development of a TDI. 

Generally speaking, the FDA will require placebo-controUed studies wherever possible to demonstrate efficacy at the dose to be marketed and these are termed pivotal studies. Pivotal studies do not have to be placebo controlled, however, and in some areas, such as depression, the ICH guidelines suggest a three-arm study, with both an active comparator and a placebo control. The Declaration of Helsinki, revised in 2000, suggested that in some disease areas, placebo-controlled studies are to be examined very carefuUy for their ethical content. This includes areas where conventional best therapy is generally acceptable. In this case, great care needs to be taken with the choice of active comparator. 

It is widely accepted that two placebo-controlled pivotal studies are necessary, although it is not clear whether this is a mandatory regulation in the FDA or EMEA regulations. There is, however, a certain insurance in this approach as studies, even of drugs that are effective, can occasionally fail to show a statistically positive result if the treated population somehow deviates from the norm or if the placebo response is unexpectedly increased. In Europe the use of an active comparator in a pivotal study is more common. 

In more recent years, in an attempt to overcome these problems, it has become fashionable to include more centres than what 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 disease areas, it is often unreasonable to expect centres to recruit at the rate of more than 1-2 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, this mandates willingness on behalf of the investigator to participate in pivotal studies and to meet development deadlines, which, of course, assumes the existence of an appropriate patient population and facilities for the conduct of the study. 

The importance of identifying pivotal studies and studies on the critical path was discussed in a previous section, it is important that these studies are given the highest priority both in execution and reporting and that provision is made to identify early if there are problems recruiting patients so that appropriate remedial action can be taken. The studies of longest duration should be started first. 

It should be noted that our proposal goes considerably beyond the current proposal of FDA to create a looser Phase 0 stage for first-in-man pharmacokinetic and similar activities. Our proposal would cover all early human studies through clinical proof-of-concept, which usually occurs in Phase 2a. Only in the large pivotal studies (Phases 2b-3), when there is more assurance that the drug candidate has a solid chance of getting to an NDA submission, would the full formal IND filing be necessary. (These proposals are the opposite of what has been introduced by the EC Clinical trial Directive, see Chapter 17.)... 

First, the Office of Conformity Audit will conduct a compliance review to ensure that the dossier meets the standards of GCP, GLP and reliability. The GCP compliance check is based on the inspection of both study sites and sponsor. For the submission of new active substance usually four study sites are inspected. If the pivotal studies are conducted overseas, the inspection may be conducted by MHLW instead of PMDA. 

The list of subjects in the pivotal studies of dose setting/efficacy clinical studies... 

In addition to the pivotal studies, several publications (Table 6.2) used other methods to test the response of individuals with celiac disease who were introduced to oats. These studies did not fulfill the selection criteria of pivotal studies namely an in vivo oats challenge with an intestinal/skin biopsy to assess the biological response to the introduction of oats into an otherwise gluten-free diet. Instead, they used various in vitro techniques to assess the immune response to avenin, or serology without an intestinal mucosal biopsy. Most of the methods used duodenal mucosal cultures prepared from biopsies or intestinal T cell lines obtained from individuals with celiac disease. Other studies measured the immunogenic reaction in peripheral lymphocytes or measured the presence of various antibodies in individuals with verified celiac disease who included oats in their diet, in comparison with a reference group (Table 6.2). Some of these studies used patients that were previously included in pivotal studies. These studies are identified with an asterisk ( ) in Table 6.2. 

All pivotal studies, such as the main teratology study and any range-finding study performed to support the inclusion of women of childbearing potential in clinical trials, must be performed in compliance with Good Laboratory Practice. 

The CPMP (2001) Points to Consider on Application with 1. Meta-Analysis 2. One Pivotal Study indicates that it is good practice to write a protocol for the meta-analysis ... 

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