Drug Development Portfolio Research Articles

RES-Seq-a barcoded library of drug-resistant Leishmania donovani allowing rapid assessment of cross-resistance and relative fitness.

Visceral leishmaniasis (VL) remains the third largest parasitic killer worldwide, responsible for 20,000-30,000 deaths each year. Control and ultimate elimination of VL will require a range of therapeutic options with diverse mechanisms of action to combat drug resistance. One approach to ensure that compounds in development exploit diverse mechanisms of action is to screen them against highly curated cell lines resistant to drugs already in the VL pipeline. The identification of cross-resistant cell lines indicates that test compounds are likely acting via previously established mechanisms. Current cross-resistance screens are limited by the requirement to profile individual resistant cell lines one at a time. Here, we introduce unique DNA barcodes into multiple resistant cell lines to facilitate parallel profiling. Utilizing the power of Illumina sequencing, growth kinetics and relative fitness under compound selection can be monitored revolutionizing our ability to identify and prioritize compounds acting via novel mechanisms.

The role of intellectual capital in new product development: Can it become a liability?

ABSTRACTGiven the increasingly high cost of new product development (NPD), it is important for firms to terminate unsuccessful NPD projects as soon as possible. This article investigates the role of intellectual capital in the discontinuation of NPD projects. The three dimensions of intellectual capital (human, structural, and social capital) are posited to decrease the likelihood of discontinuation of NPD projects, while contextual factors such as the firm's discontinuation experience and the size of the drug development portfolio are expected to affect this relationship. The research model is tested using a unique data set of 1,168 drug discovery and development projects. The results suggest that NPD projects rich in all three dimensions of intellectual capital are less likely to be discontinued. The size of the firm's drug development portfolio, however, is found to mitigate these effects, while discontinuation experience enhances the relationship between intellectual capital and discontinuation duration. As only a fraction of new product development initiatives result in success, timely discontinuation of unsuccessful projects is critical for sustained performance of organizations. Our findings make an important contribution to this stream of work. By highlighting the role of intellectual capital in the discontinuation process, we offer an interesting twist to the literature that invariably assumes intellectual capital to be important for innovation.

Nanotracing and cavity-ring down spectroscopy: A new ultrasensitive approach in large molecule drug disposition studies.

New therapeutic biological entities such as bispecific antibodies targeting tissue or specific cell populations form an increasingly important part of the drug development portfolio. However, these biopharmaceutical agents bear the risk of extensive target-mediated drug disposition or atypical pharmacokinetic properties as compared to canonical antibodies. Pharmacokinetics and bio-distribution studies become therefore more and more important during lead optimization. Biologics present, however, greater analytical challenges than small molecule drugs due to the mass and selectivity limitation of mass spectrometry and ligand-binding assay, respectively. Radiocarbon (14C) and its detection methods, such as the emerging 14C cavity ring down spectroscopy (CRDS), thus can play an important role in the large molecule quantitation where a 14C-tag is covalently bound through a stable linker. CRDS has the advantage of a simplified sample preparation and introduction system as compared to accelerator mass spectrometry (AMS) and can be accommodated within an ordinary research laboratory. In this study, we report on the labeling of an anti-IL17 IgG1 model antibody with 14C propionate tag and its detection by CRDS using it as nanotracer (2.1 nCi or 77.7 Bq blended with the therapeutic dose) in a pharmacokinetics study in a preclinical species. We compare these data to data generated by AMS in parallel processed samples. The derived concentration time profiles for anti-IL17 by CRDS were in concordance with the ones derived by AMS and γ-counting of an 125I-labeled anti-IL17 radiotracer and were well described by a 2-compartment population pharmacokinetic model. In addition, antibody tissue distribution coefficients for anti-IL17 were determined by CRDS, which proved to be a direct and sensitive measurement of the extravascular tissue concentration of the antibody when tissue perfusion was applied. Thus, this proof-of-concept study demonstrates that trace 14C-radiolabels and CRDS are an ultrasensitive approach in (pre)clinical pharmacokinetics and bio-distribution studies of new therapeutic entities.

Challenges and Benefits of Repurposing Products for Use during a Radiation Public Health Emergency: Lessons Learned from Biological Threats and other Disease Treatments.

The risk of a radiological or nuclear public health emergency is a major growing concern of the U.S. government. To address a potential incident and ensure that the government is prepared to respond to any subsequent civilian or military casualties, the U.S. Department of Health and Human Services and the Department of Defense have been charged with the development of medical countermeasures (MCMs) to treat the acute and delayed injuries that can result from radiation exposure. Because of the limited budgets in research and development and the high costs associated with bring promising approaches from the bench through advanced product development activities, and ultimately, to regulatory approval, the U.S. government places a priority on repurposing products for which there already exists relevant safety and other important information concerning their use in humans. Generating human data can be a costly and time-consuming process; therefore, the U.S. government has interest in drugs for which such relevant information has been established (e.g., products for another indication), and in determining if they could be repurposed for use as MCMs to treat radiation injuries as well as chemical and biological insults. To explore these possibilities, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop including U.S. government, industry and academic subject matter experts, to discuss the challenges and benefits of repurposing products for a radiation indication. Topics covered included a discussion of U.S. government efforts (e.g. funding, stockpiling and making products available for study), as well unique regulatory and other challenges faced when repurposing patent protected or generic drugs. Other discussions involved lessons learned from industry on repurposing pre-license, pipeline products within drug development portfolios. This report reviews the information presented, as well as an overview of discussions from the meeting.

Mixed news for AstraZeneca’s drug development portfolio

Mixed news for AstraZeneca’s drug development portfolio

Meta-Analysis of Clinical Dose–Response in a Large Drug Development Portfolio

This article reports the results of a meta-analysis based on dose–response studies conducted by a large pharmaceutical company between 1998–2009. Data collection targeted efficacy endpoints from all compounds with evidence of clinical efficacy during the time period. Safety data were not extracted. The goal of the meta-analysis was to identify consistent quantitative patterns in dose–response across different compounds and diseases. The article presents summaries of the study designs, including the number of studies conducted for each compound, dosing range, the number of doses evaluated, and the number of patients per dose. The Emax model, ubiquitous in pharmacology research, was fit for each compound. It described the data well, except for a single compound, which had nonmonotone dose–response. Compound-specific estimates and Bayesian hierarchical modeling showed that dose–response curves for most compounds can be approximated by Emax models with “Hill” parameters close to 1.0. Summaries of the potency estimates show pharmacometric predictions of potency made before the first dose ranging study within a (1/10, 10) multiple of the final estimates for 90% of compounds. The results of the meta-analysis, when combined with compound-specific information, provide an empirical basis for designing and analyzing new dose finding studies using parametric Emax models and Bayesian estimation with empirically derived prior distributions.

The Impact of R&D Cooperations on Drug Variety Offered on the Market. Evidence from the Pharmaceutical Industry

Our study puts special attention to the fact that R&D cooperations in the pharmaceutical industry are formed at different stages throughout the drug development process. We study if the timing to engage in R&D cooperations in the pharmaceutical industry has different impacts on the technology and product markets. Using a comprehensive dataset on the pharmaceutical industry, and estimating a heterogeneous treatment effects model (Heckman et al., 2006) our results show that R&D cooperations formed at the early stages increase the number of R&D projects and the number of drugs launched on the product market. Most interestingly, late stage R&D cooperations significantly reduce the number of drugs launched on the market, even though they increased firms’ activity in the technology markets. This result highlights the fact that firms re-optimize their drug development portfolio to avoid wasteful duplication and cannibalizing the sales of the jointly developed drug in R&D cooperations. Our study show that firms cooperating in late stage collaborations re-optimize their individual drug development portfolios, which significantly reduces the number of drugs offered on the market.

A new approach to assess drug development performance

This article suggests that successful innovation in biopharmaceuticals is strongly related to the ability of firms to move compounds forward along the drug pipeline, relatively to other companies, within the same therapeutic area. We used this intuition to build indicators of performance at the firm-level and use them to conduct empirical analysis that relies upon a comprehensive database. We consider the effect of various factors on drug development performance, including R&D funds allocation across therapeutic areas and the proportion of biological molecules in the drug development portfolio. Subsequently, we show that a correlation exists between our performance variables and the per-capita growth of biopharmaceutical firms' revenues.

A mathematical model for maximizing the value of phase 3 drug development portfolios incorporating budget constraints and risk

We describe a value-driven approach to optimizing pharmaceutical portfolios. Our approach incorporates inputs from research and development and commercial functions by simultaneously addressing internal and external factors. This approach differentiates itself from current practices in that it recognizes the impact of study design parameters, sample size in particular, on the portfolio value. We develop an integer programming (IP) model as the basis for Bayesian decision analysis to optimize phase 3 development portfolios using expected net present value as the criterion. We show how this framework can be used to determine optimal sample sizes and trial schedules to maximize the value of a portfolio under budget constraints. We then illustrate the remarkable flexibility of the IP model to answer a variety of 'what-if' questions that reflect situations that arise in practice. We extend the IP model to a stochastic IP model to incorporate uncertainty in the availability of drugs from earlier development phases for phase 3 development in the future. We show how to use stochastic IP to re-optimize the portfolio development strategy over time as new information accumulates and budget changes occur.

Proteomics profile of cellular response to chiral drugs: Prospects for pharmaceutical applications

Chiral drugs account for a large proportion of drugs available in the market. There is increasing awareness of the importance of drug chirality and the role it plays in explaining the oftentimes dramatic differences in biological activities in the current drug development portfolio. Using recently developed chiral drugs-cell interaction system, several examples of protein profiles induced by chiral drugs were illustrated in detail on the platform of 2-D LC interfaced with MS/MS system. In addition, the background of chiral drug investigation from which contemporary drug chirality research has emerged, the techniques involved in proteomics technology, the application of proteomics in this exciting area, and the perspectives in future applications are also discussed.

Review of the performance of the 3T3 NRU in vitro phototoxicity assay in the pharmaceutical industry

Based on current regulatory guidelines a substantial proportion of drug development portfolios within the pharmaceutical industry trigger the requirements for photosafety testing i.e. absorb light in the range 290–700 nm, and are either applied locally/topically, or ‘reach’ (EMEA)/‘significantly partition to’ (FDA) the skin or eyes. There has been growing concern within the pharmaceutical industry over recent years regarding the performance of the in vitro photosafety tests with respect to in vivo predictivity (in animals and in humans). Therefore, the Safety Ad hoc Group (SAHG) of the European Federation of Pharmaceutical Industries and Associations (EFPIA) commissioned a survey of member companies to better understand the triggers for photosafety testing and how in vitro hazard characterisation translated to in vivo risk (both in animal models and in humans). Data were collated for 361 compounds from 10 EFPIA member companies and the results of the phototoxicity survey are reported. Based on these results, it appears that the in vitro photosafety assays are substantially over predicting animal photosafety hazard in vivo and also human photosafety risk in the clinic. This raises concern regarding the use of in vitro photosafety assays for the assessment of chemical photosafety of pharmaceuticals for regulatory purposes. At the very least, a review of the current guidance documents for the photosafety evaluation of pharmaceuticals should be undertaken urgently.

Drug Development Portfolio and Spending Practices after Mergers and Acquisitions

The recent volume of merger and acquisition activity in the biopharmaceutical industry has been high and is expected to accelerate in 2009 and 2010 due to global economic conditions. In order to understand changes following merger and acquisition (M&A) in clinical research investment and activity, Tufts Center for the Study of Drug Development analyzed development pipeline and spending data for 24 of the largest independent M&As occurring between 1998 and 2004 that each exceeded $1 billion in transaction value. Organizations that had experienced a merger or acquisition were evaluated across three time periods and compared with industry benchmarks: 2 years prior to an M&A announcement, and 2 years and 4 years after the transaction was announced. The results indicate that following a transaction, companies initially limit R&D spending growth to accommodate integration challenges, uncertainty, and instability. However, 4 years post-transaction M&A companies rapidly increase R&D spending across a significantly consolidated portfolio of late-stage (phase 2 and 3) development projects. Due to resource constraints and integration uncertainty, phase 1 and 3 product attrition rates for M&A companies are higher than the industry average. Statistically significant differences are observed in development pipeline and spending practices between small and large acquirers and between companies undergoing mergers versus acquisitions. The results of the study offer biopharmaceutical executives and financial professionals insights into better forecasting of drug development productivity and resource requirements following M&A transactions.

Recent initiatives and strategies to developing new drugs for tropical parasitic diseases

Background: Despite the toll of tropical parasitic diseases on human life in the developing world, present therapies still rely on drugs developed decades ago. In many cases, the clinical usefulness of these compounds is limited due to poor efficacy, toxicity and the constant attrition of drug resistance. The absence of a profit incentive regarding diseases afflicting the very poor has resulted in a lack of investment by the pharmaceutical industry in new chemotherapies. Objective: Given this background, this review addresses what alternative economic and scientific strategies have been implemented to procure novel drugs. Methods: The latest chemical, genetic and screening technologies to discover and develop drugs for tropical parasitic diseases are reviewed. In many cases these strategies are being implemented within the framework of public-private partnerships established to sustain dynamic drug development portfolios. Examples of public-private partnerships and their portfolios are discussed. Further, the contribution of dedicated academic screening centres to target discovery and preclinical prosecution of new small molecules is also highlighted. In every case, the latest scientific literature is cited, but also relevant press releases and website information to indicate the present vitality in the field. Conclusion: The tools, institutions and consortia are now in place and evolving to deliver new pharmaceuticals. Short-term results have already been realised in the clinic, mainly through the provision of new formulations of existing drugs. Long-term and consistent investment will be required, however, to identify, develop and clinically validate new chemical entities.

Successful anti-cancer drug targets able to pass FDA review demonstrate the identifiable signature distinct from the signatures of random genes and initially proposed targets

New efforts to guide and prioritize the selection of cancer drug targets are urgently needed, as is evident by the slow development of novel anti-cancer agents and the narrow therapeutic index of existing drugs. Given these limitations, the current study was conducted to explore the classification features defining the therapeutic success that can result from targeting a particular gene. Classification was based on extracting features specific to known successful anti-cancer targets and combining them in a linear classifier, resulting in calculation of an enrichment score for each gene. Extended description, the search tool used in this study, enriched existing drug target candidates by up to 10-fold at an approximately 50% recall rate, covering approximately 24 000 genes or approximately 80% of genome. More importantly, the target category with high attrition rate was classified from target category with low attrition rate, allowing to refine the drug development portfolios. Biological relevance of the parameters comprising the enrichment score was explored. Enrichment in cancer-specific effects was independently demonstrated by literature analysis. Imposing these enrichment scores on existing structural, pathway and phenotype-based procedures for prospective target selection may enhance the efficiency and accuracy of target identification and accelerate drug design. The software used in this work is available upon request.

The Probability of Registrational Success

Pharmaceutical industry drug development portfolios vary in breadth and depth. For each firm, however, the objective of improving the success rate of their marketing applications is paramount. Understanding some of the characteristics associated with marketing application success and alternatively some of the pitfalls associated with application failure may assist firms in developing more efficient drug development strategies. The purpose of this article is to review briefly some of the research that has been conducted, take note of current trends, underscore potential biases, and affirm the contribution that regulatory professionals can bring to the drug development process.

Current drug development portfolio for antimalarial therapies

In response to the emergence of parasite drug resistance to currently deployed antimalarials, the scientific community, in partnership with the pharmaceutical industry and public organizations, has fashioned an antimalarial drug development portfolio for the sustained development and registration of safe, effective and cheap antimalarial medicines. The management of this portfolio is being driven by MMV (Medicines for Malaria Venture), with a number of projects recently reaching the clinical end of this drug development pipeline.