Statistical Methodology for Characterization of Macromolecular Similarity

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PROJECT SUMMARY/ABSTRACT As with any drug, approval of generic versions of macromolecular drugs requires rigorous evaluation of therapeutic equivalence to the reference drug in order to assure similar efficacy and safety. Compared with drugs that are small organic molecules, the chemical composition and characteristics of macromolecular drugs—typically proteins or polysaccharides—are inherently more variable because of the way these molecules are produced and isolated. It would be advantageous to have a way to determine molecular similarity and, by implication, equivalence without using costly in vivo testing in animals and humans. The specific aim of the proposal is to develop and test a robust data-driven statistical methodology for assessing similarity among distinct samples of therapeutic macromolecules, whether from different batches or altered processes, or even if produced by different entities entirely. The methodology is based on a genetic algorithm designed to extract relevant features from large, complex datasets. The hypothesis guiding the work is that with proper data interpretation and modeling, therapeutic equivalence can be inferred from molecular similarity determined using spectroscopic and chromatographic measurements that reveal the critical molecular attributes ultimately responsible for important properties of the generic and reference macromolecules: efficacy, side-effects, stability, and so on. Even without knowing how these attributes specify these properties, the fact that they do specify them means that this data is where equivalence can best be determined without going to in vivo testing. Data introduced into the model will be collected for multiple lots and batches of protein and polysaccharide drug substances and products. The data will come from an assortment of high-resolution mass-spectrometry methods, high-field nuclear magnetic resonance spectroscopy analyses, and several other spectroscopic and chromatographic methods used to characterize macromolecules in solution. Biological activity data will be obtained from outsource testing labs that have established assays in place. The outcome of the proposed research will be a working methodology for evaluation of similarity between generic and reference versions of any macromolecular drug. This will lead towards faster approval of generic versions of macromolecular drugs, and thereby to broader access and lower cost for these drugs which are critical to treating many serious diseases.