Pivotal clinical trials

The first study to demonstrate the activity of enfuvirtide in HIV-infected patients (Kilby et al. 1998) showed that patients receiving the maximum 100 mg intravenous dose had maximum median declines in HIV-1 RNA of -1.96 logjo copies/mL through 14 days. Several additional studies (Kilby et al. 2002 Lalezari et al. 2003a, b) further demonstrated the safety and efficacy of enfuvirtide and led to the selection of twice-daily subcutaneous injections of a 90 mg nominal dose for testing in the TORO (T-20 vs. optimized regimen only) pivotal clinical trials. 

In Phase III, the final dosage formulation has been established and the pivotal clinical trials are being conducted. Degradation products have been identified, so the method selectivity should be reevaluated to ensure that all degradants can be detected and quantitated. The analytical methods are completely validated, and appropriate for routine quality assurance and control purposes. The type and frequency of system suitable testing (SST) should be determined, and an excellent publication on SST for chromatography systems is available [47],... 

Available grant to support pivotal clinical trials. 

Available scientific data evaluating the introduction of pure oats in the gluten-free diet of patients with celiac disease and dermatitis herpetiformis indicates that moderate amounts of pure oats are well tolerated by the majority of these individuals who are either in remission or newly diagnosed. The term "pure oats" is used to indicate oats uncontaminated with gluten from other cereal grains, like wheat, barley, and rye, as detected by current test methods. Based on pivotal clinical trials in the published literature, the amount of pure oats considered within safe limits is 50-70 g/day for adults and 20-25 g/day for children. 

E. Therapeutic response Thrombin-dependent tests show dose dependency [aPTT rise proportionally to dose of Refludan]. The key criteria of efficacy in two pivotal clinical trials from a laboratory standpoint were platelet recovery and effective anticoagulation. Seven days after the start of treatment with Refludan in patients with HIT, the cumulative risk of death, limb amputation, or new thromboembolic complication was substantially lower than in a historical control group. 

Simon R. Designs and adaptive analysis plans for pivotal clinical trials of therapeutics and companion diagnostics. Expert opinion on Medical Dignostics (in press). 

This guidance iccoimnends that the minimum batch size for the NDA pivotal clinical trial batch or the ANDA/AADA biobatch be at least 100 kg or 10% of a production batch, whichever is larger. Deviations from this recommendation should be discussed with the appropriate agency review division. All scale changes should be properly validated and may be inspected by appropriate agency personnel. 

Change in batch size, up to and including a factor of ten times the size of the pivotal clinical trial/biobatch, where (1) the equipment used to produce the test batch(es) are of the same design and operating principles (2) the batch(es) is manufactured in full compliance with cGMPs and (3) the same standard operating procedures (SOPs) and controls, as well as the same formulation and manufacturing procedures, are used on the test batch(es) and on the full-scale production batch(es). 

In addition, the Office of Scientific Investigations (CDER) conducts biomedical audits of clinical investigator s sites. These investigations focus primarily on sites involved in pivotal clinical trials, but may also involve other sites. Investigators should be informed that they should contact the applicant when the FDA notifies them of an upcoming inspection. The spon-sor/applicant is generally not permitted to be involved in an FDA inspection of an investigator s site. Refer to Chap. 3 for an extensive overview of the FDA s expectations of clinical trial activities. 

The optimized formulation then is prepared for phase III pivotal clinical trials. Followed by manufacturing process optimization and scale-up, the three batches of the dmg product are manufactured for primary stability evaluation at product launch sites. The information on the manufacture, scale-up, control, and stability is used for product registration with regulatory agencies. 

While phase 1 trials often include patients of different treatment backgrounds and, depending on the mechanism of action of the experimental therapeutic, may include many different tumor types (e.g., an all-comers scenario), pivotal clinical trials are more tightly controlled in order to maximize the opportunity to detect an efficacy signal. As mentioned previously, the earliest pivotal clinical trials compare SOC alone and SOC in combination with experimental therapy to determine whether the experimental therapeutic provides additional patient beneht. Once this incremental beneht is demonstrated, additional clinical trials may be conducted to determine whether the experimental therapy is benehcial in earlier stage disease (e.g., the adjuvant... 

Recently, there has been active labeling to accept a single pivotal clinical trial as the basis for approval. This thrust is based on the FDA Modernization Act (FDAMA) of 1997. Section 115 of FDAMA states that the substantial evidence of efficacy requirement may be satisfied by one adequate and well-controlled clinical investigation supported by confirmatory evidence. The FDA issued a guidance on when one phase 3 trial would suffice in May 1997. 

Researchers may apply for grant funds to support pivotal clinical trials. As noted later on, this may be for up to 200,000 for a phase II or III study. 

Change in batch 1 process of combining phases Batch size changes upto 10 times of pivotal clinical trial or... 

A thorough and extensive review has summarized five pivotal clinical trials comprising 3252 patients (7). In some studies olanzapine has failed to show efficacy in treatment-resistant schizophrenia (8,9). 

FDA approval. Usually evidence of efficacy from two or more adequate and well-controlled clinical trials along with safety information is required for the regulatory approval of a new indication for a drug. The idea is that replication of the results of a single trial is needed to rule out the possibility that a finding of efficacy in a single trial is due to chance. This example describes the application of exposure-response analysis to establish an FDA-approvable claim of drug efficacy based on a dose-reponse relationship that was obtained from two pivotal clinical trials that used different final-treatment doses. 

In three pivotal clinical trials of mycophenolate mofetil in kidney transplant recipients, adverse effects were in accordance with the known antiproliferative effect of mycophenolate, namely gastrointestinal disorders, leukopenia, and opportunistic infections, in particular cytomegalovirus tissue invasive disease (SED-13, 1130) (SEDA-20,346). Nephrotoxicity was not observed in clinical trials, and renal function significantly improved in six patients converted to mycophenolate for ciclosporin nephrotoxicity (8). 

A good rule of thumb is that pivotal clinical trials for registration purposes ought to be conducted with the same formulation and manufacturing process that is proposed to be taken to market. Although the nuances of pharmaceutical constructs are described in Chapter 5, it is important to understand the sometimes grave consequences when this rule of thumb is not observed. 

GENERAL INEORMATION REGARDING SAFETY AND EFFICACY (INCLUDING PIVOTAL CLINICAL TRIALS)... 

Discuss and evaluate risks and benefits based on the conclusions of pivotal clinical trials and include interpretations of how safety and efficacy results support the proposed dose(s) and target indication(s) include also an evaluation of how prescribing information will optimize benefits and manage potential risks. 

Bioavailability studies provide information regarding the performance of the formulation and subsequently are a means to document product quality. Bioequivalence studies provide a link between the pivotal and early clinical trial formulation, a link between formulations used in the pivotal clinical trial and the stability studies, the pivotal clinical trial and the to-be-marketed drug product, and other comparisons as appropriate. 

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