Demonstrating similarity

In this chapter we will move away from superiority trials to look at methods for the evaluation of equivalence and non-inferiority. The setting in all cases here is the comparison of a new treatment to an active control where we are looking to demonstrate similarity (in some defined sense) between the two treatments. 

It should be clear from our earlier development, especially the discussion in Sections 9.2 and 9.3, that obtaining a non-significant p-value in a superiority evaluation does not demonstrate that the two treatments are the same a nonsignificant p-value may simply be the result of a small trial, with low power even to detect large differences. ICH E9 makes a clear statement in this regard. 

Unfortunately this issue is not well understood within the clinical trial community and the misinterpretation of non-significant p-values is all too common. See Jones et al. (1996) for further discussion on these points. 

Equivalence trials are, of course, routinely used in the evaluation of bioequivalence and the methodology there is well established, both European and FDA guidelines exist. More recently we have seen the need to establish therapeutic equivalence and Ebbutt and Frith (1998) provide a detailed case study in the development of an alternative propellant for the asthma inhaler. More usually, 

Statistical Thinking for Non-Statisticians in Drug Regulation Richard Kay 2007 John Wiley Sons. Ltd ISBN 978-0-470-31971-0 

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Two to three weeks of fluconazole or itraconazole solution are highly effective and demonstrate similar clinical response rates.32 Doses of 100 to 200 mg are effective in immunocompetent patients but doses up to 400 mg are recommended for immunocompromised patients. Due to variable absorption, ketoconazole and itraconazole capsules should be considered second-line therapy. In severe cases, oral azoles may prove ineffective, warranting the use of amphotericin B for 10 days. Although echinocandins and voriconazole are effective in treatment of esophageal candidiasis, experience remains limited. 

Activated carbon has high specific surface area with respect to its volume, and thus has high adsorption capacity. Activated carbon adsorption is considered to be one of the most versatile treatment technologies and can remove classical pollutants such as COD, TOC, BOD, and nitrogen, as well as toxic pollutants such as phenol, refractory organic compounds, VOCs, and soluble heavy metals.38 Activated alumina and peat have also demonstrated similar abilities. 

A family of linear Dy3 and Tb3 clusters, with almost identical structure to the Dy3 mentioned in the previous paragraph, was reported by Tong and coworkers in 2011 [42]. The Dy compounds demonstrate similar static and dynamic magnetic... 

In order to compare the specific activity of plant-derived C5-1 to that of the hybridoma-derived antibody, the antigen-binding capacity of antibodies produced in each system was assayed by enzyme-linked immunosorbent assay (ELISA). As shown in Table 1.2, antibodies from both sources demonstrated similar binding characteristics against human IgGs [8]. Furthermore, the stability of alfalfa-derived C5-1 in the blood stream of Balb/c mice was comparable to that of the hybridoma-derived IgG [8]. 

This study demonstrate similar ranking of each material independent of test method used. At this stage it is premature to choose one test as a better small scale model of full scale fires. Each method needs further elaboration. 

In Ref. 15, an optical MNF hydrogen sensor was demonstrated. Similar to the MNF sensor described in the Sect. 13.4.1, this sensor monitors variation of transmission power of an MNF representing a waist of a biconical taper. The sensor is shown in... 

Presently, the only commercially available dyes that are applied because of then-ability to form fluorescent aggregates are trimethine cyanines JC-1 and JC-9 (Fig. 11) [25], the first one being studied much more extensively than the second one. The dye JC-1 is known to form red-fluorescent (emission maximum at 590 nm) J-aggregates in mitochondria possessing strong intramitochondrial negative potential, while upon depolarization of the mitochondrial membrane, the dye monomer green emission (maximum at 527 nm) is observed [25]. JC-9 demonstrates similar properties [25]. Such properties permit the application of these dyes for, e.g., detection of apoptotic electrical depolarization of mitochondria [25]. 

In identical systems, uptake of aldrin (30, 300, 3000 yg/300 ml) has been demonstrated. Similarly, both uptake and elimination... 

In 1971, Edwards and Jones showed that non-specific non-immunological reactions occurred between plant extracts and normal human sera (31). Noweir (29) repeated studies in byssinotics similar to ones performed by Massoud and Taylor (11) and Taylor e al. (35), and demonstrated similar findings, i.e. normal, byssi-... 

DNA from any source can be utilized for pharmacogenetics research, including germline and tumor sources. Immortalized cell lines can provide an almost infinite DNA resource, and genotyping of Epstein-Barr virus (EBV)-transformed immortalized lymphoblastoid cells has demonstrated similar allele frequencies to equivalent... 

An interesting observation should be made concerning the dependence of the physical properties on molecular cyclicity, since it will have a significant effect on the formulation of electrolytes for lithium ion cells. While all of the ethers, cyclic or acyclic, demonstrate similar moderate dielectric constants (2—7) and low viscosities (0.3—0.6 cP), cyclic and acyclic esters behave like two entirely different kinds of compounds in terms of dielectric constant and viscosity that is, all cyclic esters are uniformly polar (c = 40—90) and rather viscous rj = 1.7—2.0 cP), and all acyclic esters are weakly polar ( = 3—6) and fluid (77 = 0.4—0.7 cP). The origin for the effect of molecular cyclicity on the dielectric constant has been attributed to the intramolecular strain of the cyclic structures that favors the conformation of better alignment of molecular dipoles, while the more flexible and open structure of linear carbonates results in the mutual cancellation of these dipoles. 

Gy of irradiation demonstrated a median survival duration of 21 mo (54). Using similar preoperative therapies, smaller studies demonstrated similar findings of improved survival (50,55,56). 

In summary, compared with earlier processes which utilize hazardous solvents and generate large waste streams, the carbonylation of chloropinacolone offers an environmentally and operationally advantaged process since it requires (r) very little excess amine or methanol, (fr) no extraneous reaction solvents, Hi) little or no extraction solvent, and (fr) the tributylamine coreactant and methanol components are readily recycled. This was accomplished while also demonstrating similar yields, shorter reaction times, and higher product concentrations which result in a significant reduction in the number of batches and time required to produce significant quantities of methyl pivaloylacetate. 

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