Economics of new oncology drug development.

PURPOSE: Review existing studies and provide new results on the development, regulatory, and market aspects of new oncology drug development. METHODS: We utilized data from the US Food and Drug Administration (FDA), company surveys, and publicly available commercial business intelligence databases on new oncology drugs approved in the United States and on investigational oncology drugs to estimate average development and regulatory approval times, clinical approval success rates, first-in-class status, and global market diffusion. RESULTS: We found that approved new oncology drugs to have a disproportionately high share of FDA priority review ratings, of orphan drug designations at approval, and of drugs that were granted inclusion in at least one of the FDA's expedited access programs. US regulatory approval times were shorter, on average, for oncology drugs (0.5 years), but US clinical development times were longer on average (1.5 years). Clinical approval success rates were similar for oncology and other drugs, but proportionately more of the oncology failures reached expensive late-stage clinical testing before being abandoned. In relation to other drugs, new oncology drug approvals were more often first-in-class and diffused more widely across important international markets. CONCLUSION: The market success of oncology drugs has induced a substantial amount of investment in oncology drug development in the last decade or so. However, given the great need for further progress, the extent to which efforts to develop new oncology drugs will grow depends on future public-sector investment in basic research, developments in translational medicine, and regulatory reforms that advance drug-development science.

Design of Scheduling Algorithms Using Game Theoretic Ideas

Scheduling a set of jobs over a collection of machines to optimize a certain quality-of-service measure is one of the most important research topics in both computer science theory and practice. In this thesis, we design algorithms that optimize {\em flow-time} (or delay) of jobs for scheduling problems that arise in a wide range of applications. We consider the classical model of unrelated machine scheduling and resolve several long standing open problems; we introduce new models that capture the novel algorithmic challenges in scheduling jobs in data centers or large clusters; we study the effect of selfish behavior in distributed and decentralized environments; we design algorithms that strive to balance the energy consumption and performance.

The technically interesting aspect of our work is the surprising connections we establish between approximation and online algorithms, economics, game theory, and queuing theory. It is the interplay of ideas from these different areas that lies at the heart of most of the algorithms presented in this thesis.

The main contributions of the thesis can be placed in one of the following categories.

1. Classical Unrelated Machine Scheduling: We give the first polygorithmic approximation algorithms for minimizing the average flow-time and minimizing the maximum flow-time in the offline setting. In the online and non-clairvoyant setting, we design the first non-clairvoyant algorithm for minimizing the weighted flow-time in the resource augmentation model. Our work introduces iterated rounding technique for the offline flow-time optimization, and gives the first framework to analyze non-clairvoyant algorithms for unrelated machines.

2. Polytope Scheduling Problem: To capture the multidimensional nature of the scheduling problems that arise in practice, we introduce Polytope Scheduling Problem (\psp). The \psp problem generalizes almost all classical scheduling models, and also captures hitherto unstudied scheduling problems such as routing multi-commodity flows, routing multicast (video-on-demand) trees, and multi-dimensional resource allocation. We design several competitive algorithms for the \psp problem and its variants for the objectives of minimizing the flow-time and completion time. Our work establishes many interesting connections between scheduling and market equilibrium concepts, fairness and non-clairvoyant scheduling, and queuing theoretic notion of stability and resource augmentation analysis.

3. Energy Efficient Scheduling: We give the first non-clairvoyant algorithm for minimizing the total flow-time + energy in the online and resource augmentation model for the most general setting of unrelated machines.

4. Selfish Scheduling: We study the effect of selfish behavior in scheduling and routing problems. We define a fairness index for scheduling policies called {\em bounded stretch}, and show that for the objective of minimizing the average (weighted) completion time, policies with small stretch lead to equilibrium outcomes with small price of anarchy. Our work gives the first linear/ convex programming duality based framework to bound the price of anarchy for general equilibrium concepts such as coarse correlated equilibrium.

Equilibrium structure of the hydrogen bonded dimer H2O ⋯ HF

The equilibrium structure of the hydrogen bonded complex H2O HF has been calculated ab initio using the CCSD(T) method with basis sets up to sextuple- quality with diffuse functions and taking into account the basis set superposition error correction. The calculations carried out confirm the importance of diffuse functions and of counterpoise correction to obtain an accurate geometry. The most important point is that the basis set convergence is extremely slow and, for this reason an accurate ab initio structure requires a very large basis set. Nevertheless, the ab initio structure is significantly different from the experimental r0 and rm structures. Analysis of the basis set convergence and of the approximations used for the determination of the experimental structures indicates that the ab initio structure is expected to be more reliable.

Comparison of the experimental, semi-experimental and ab initio equilibrium structures of acetylene: Influence of relativisitic effects and of the diagonal Born-Oppenheimer corrections

The equilibrium structure of acetylene (also named ethyne) has been reinvestigated to resolve the small discrepancies noted between different determinations. The size of the system as well as the large amount of available experimental data provides the quite unique opportunity to check the magnitude and relevance of various contributions to equilibrium structure as well as to verify the accuracy of experimental results. With respect to pure theoretical investigation, quantum-chemical calculations at the coupled-cluster level have been employed together with extrapolation to the basis set limit, consideration of higher excitations in the cluster operator, inclusion of core correlation effects as well as relativistic and diagonal Born-Oppenheimer corrections. In particular, it is found that the extrapolation to the complete basis set limit, the inclusion of higher excitations in the electronic-correlation treatment and the relativistic corrections are of the same order of magnitude. It also appears that a basis set as large as a core-valence quintuple-zeta set is required for accurately accounting for the inner-shell correlation contribution. From a pure experimental point of view, the equilibrium structure has been determined using very accurate rotational constants recently obtained by a global analysis (that is to say that all non-negligible interactions are explicitely included in the Hamiltonian matrix) of rovibrational spectra. Finally, a semi-experimental equilibrium structure (where the equilibrium rotational constants are obtained from the experimental ground state rotational constants and computed rovibrational corrections) has been obtained from the available experimental ground-state rotational constants for ten isotopic species corrected for computed vibrational corrections. Such a determination led to the revision of the ground-state rotational constants of two isotopologues, thus showing that structural determination is a good method to identify errors in experimental rotational constants. The three structures are found in a very good agreement, and our recommended values are rCC 120.2958(7) pm and rCH 106.164(1) pm. © 2011 American Institute of Physics.

Existence, recurrence and equilibrium properties of Markov branching processes with instantaneous immigration

Attention has recently focussed on stochastic population processes that can undergo total annihilation followed by immigration into state j at rate αj. The investigation of such models, called Markov branching processes with instantaneous immigration (MBPII), involves the study of existence and recurrence properties. However, results developed to date are generally opaque, and so the primary motivation of this paper is to construct conditions that are far easier to apply in practice. These turn out to be identical to the conditions for positive recurrence, which are very easy to check. We obtain, as a consequence, the surprising result that any MBPII that exists is ergodic, and so must possess an equilibrium distribution. These results are then extended to more general MBPII, and we show how to construct the associated equilibrium distributions.

The role of economics in ecosystem based management: The case of the EU Marine Strategy Framework Directive, First lessons learnt and way forward

The EU Marine Strategy Framework Directive (MSFD) sets out a plan of action relating to marine environmental policy and in particular to achieving ‘good environmental status’ (GES) in European marine waters by 2020. Article 8.1 (c) of the Directive calls for ‘an economic and social analysis of the use of those waters and of the cost of degradation of the marine environment’. The MSFD is ‘informed’ by the Ecosystem Approach to management, with GES interpreted in terms of ecosystem functioning and services provision. Implementation of the Ecosystem Approach is expected to be by adaptive management policy and practice. The initial socio-economic assessment was made by maritime EU Member States between 2011 and 2012, with future updates to be made on a regular basis. For the majority of Member States, this assessment has led to an exercise combining an analysis of maritime activities both at national and coastal zone scales, and an analysis of the non-market value of marine waters. In this paper we examine the approaches taken in more detail, outline the main challenges facing the Member States in assessing the economic value of achieving GES as outlined in the Directive and make recommendations for the theoretically sound and practically useful completion of the required follow-up economic assessments specified in the MSFD.

The role of economics in ecosystem based management: The case of the EU Marine Strategy Framework Directive, First lessons learnt and way forward

The EU Marine Strategy Framework Directive (MSFD) sets out a plan of action relating to marine environmental policy and in particular to achieving ‘good environmental status’ (GES) in European marine waters by 2020. Article 8.1 (c) of the Directive calls for ‘an economic and social analysis of the use of those waters and of the cost of degradation of the marine environment’. The MSFD is ‘informed’ by the Ecosystem Approach to management, with GES interpreted in terms of ecosystem functioning and services provision. Implementation of the Ecosystem Approach is expected to be by adaptive management policy and practice. The initial socio-economic assessment was made by maritime EU Member States between 2011 and 2012, with future updates to be made on a regular basis. For the majority of Member States, this assessment has led to an exercise combining an analysis of maritime activities both at national and coastal zone scales, and an analysis of the non-market value of marine waters. In this paper we examine the approaches taken in more detail, outline the main challenges facing the Member States in assessing the economic value of achieving GES as outlined in the Directive and make recommendations for the theoretically sound and practically useful completion of the required follow-up economic assessments specified in the MSFD.