Health Technology Assessment in the Context of Adaptive Pathways for Medicines in Europe: Challenges and Opportunities.

Adaptive pathways for medicines have gained momentum and, in Europe, adaptive pathways have recently been introduced into the European Medicines Agency (EMA) processes after a successful 2-year pilot. Although the concept, as initially proposed, contained several elements that would have required regulatory reforms, the adaptive pathways program has developed a more pragmatic scope (Box 1). In this article, we explore the main challenges and opportunities adaptive pathways pose from a European health technology assessment (HTA) perspective.

Quantitative in situ monitoring of an elevated temperature reaction using a water-cooled mid-infrared fiber-optic probe.

A novel water-cooled mid-infrared fiber-optic probe is described which is heatable to 230 °C. The probe has chalcogenide fibers and a ZnSe internal reflection element and is compact and fully flexible, allowing access to a wide range of standard laboratory reaction vessels and fume cupboard arrangements. Performance is demonstrated via the in situ analysis of an acid-catalyzed esterification reaction in toluene at 110 °C, and the results are compared with those from a conventional extractive sampling loop flow cell arrangement. Particular emphasis is given to the quantitative interpretation of the spectroscopic data, using gas chromatographic reference data. Calibration data are presented for univariate and partial least squares models, with an emphasis on procedures for improving the quality of interpreparation calibration and prediction through the use of focused reference analysis regimes. Subset univariate procedures are presented that yield relative errors of <5%, and bias-corrected partial least squares procedures are described that result in relative errors of interpreparation calibration and prediction consistently <3%. This paper demonstrates the considerable power of fiber-optic mid-IR spectroscopy combined with bias correction partial least squares procedures for the efficient in situ quantitative analysis of laboratory scale reactions.

Chromatographic approaches to the quality control of chiral propionate anti-inflammatory drugs and herbicides.

The chiral analysis of a range of propionate anti-inflammatory drugs and herbicides was accomplished by gas chromatographic separation of their R-alpha-phenylethylamide diastereomeric derivatives. Using a packed column (3% OV-l on Chromosorb G) good separations were obtained but analysis times were rather long. Examination of the same crystalline derivatives using a capillary column (bonded methylsilicone) resulted in good separations together with much reduced total analysis times. The technique was validated through the analysis of several derivatives prepared on a micro scale and examined directly by gas chromatography without any crystallisation step. Racemic materials all gave virtually 50:50 response ratios while the analysis of optically pure samples produced no evidence of significant racemization. Derivatives of phenoxyacetic acid and myristic acid were also prepared and chromatographed as potential internal standards.

Chiral high-performance liquid chromatographic studies of 2-(4-chloro-2-methylphenoxy)propanoic acid.

The direct enantiomeric resolution of the racemic herbicide 2-(4-chloro-2-methylphenoxy)propanoic acid (CMPP) was demonstrated on an Enantiopac (alpha 1-acid glycoprotein) chiral high-performance liquid chromatographic (HPLC) column. The HPLC separation of various amide derivatives of CMPP on a chiral "Ionic Pirkle" column comprising of N-(3,5-dinitrobenzoyl) (R)-(-)phenylglycine as chiral ligand, was also accomplished. These amides and racemic ibuprofen, however could not be separated on the Enantiopac system. The performance, stability and cost of the two systems were compared. Using optically pure CMPP enantiomers the elution order was determined and shown to reverse between the two systems. It was also shown that negligible racemisation occurred during derivatization.