Showing papers by "Tufts Center for the Study of Drug Development published in 2009"

Drug development costs when financial risk is measured using the Fama–French three‐factor model

Abstract: In a widely cited article, DiMasi, Hansen, and Grabowski (2003) estimate the average pre-tax cost of bringing a new molecular entity to market. Their base case estimate, excluding post-marketing studies, was $802 million (in $US 2000). Strikingly, almost half of this cost (or $399 million) is the cost of capital (COC) used to fund clinical development expenses to the point of FDA marketing approval. The authors used an 11% real COC computed using the capital asset pricing model (CAPM). But the CAPM is a single factor risk model, and multi-factor risk models are the current state of the art in finance. Using the Fama-French three factor model we find that the cost of drug development to be higher than the earlier estimate.

European Medicines Agency workshop on biosimilar monoclonal antibodies: July 2, 2009, London, UK

Abstract: The European Medicines Agency (EMEA) workshop on biosimilar monoclonal antibodies (mAbs), held July 2, 2009 at the EMEA headquarters in London, was a harbinger with potentially far-reaching implications for all groups interested in antibody therapeutics development. These groups include not only regulators and the innovator and generic biopharmaceutical industries, but also physicians, patients and payers. The objective of the workshop was to discuss and assess the feasibility of the development and authorization of mAbs using EMEA’s biosimilar regulatory pathways. The workshop sequentially focused on questions relevant to three areas: 1) chemistry, manufacturing and controls (CMC); 2) non-clinical issues; and 3) clinical issues, including outcome measures. Proceedings of the workshop are presented in Part 1 of this report, and discussed within the context of the legal, regulatory, and business environments of the European Union, Asia, and the United States in Parts 2, 3 and 4, respectively

Translational Medicine: An Engine of Change for Bringing New Technology to Community Health

Abstract: Bringing a new medical technology from the lab to the clinic is a daunting prospect, but making sure that same innovation is available to the average patient has proven to be even more challenging. Translational medicine is a movement intended to help bench researchers and bedside clinicians learn from each other for the benefit of patients. This goal can best be accomplished if a patient-centered focus is incorporated throughout the R&D continuum and changes are made so that biomedical innovation serves the broadest needs within the shortest period of time. All sectors of the biomedical enterprise must be engaged and committed for these changes to occur. If actions are taken in concert, we should see real change in one generation.

New challenges to medicare beneficiary access to mAbs

Abstract: Precision binding of monoclonal antibodies (mAbs) to biological targets, their relative clinical success, and expansion of indications following initial approval, are distinctive clinical features. The relatively high cost of mAbs, together with the absence of a regulatory pathway to generics, stand out as distinctive economic features. Based on both literature review and primary data collection we enumerated mAb original approvals, supplemental indications and off-label uses, assessed payer formulary management of mAbs, and determined new challenges to Medicare beneficiary access to mAbs. We found that the FDA has approved 22 mAbs and 30 supplemental indications pertaining to the originally approved mAbs. In addition, there are 46 off-label use citations in officially recognized pharmaceutical compendia. Across Part B carriers and Part D plans, we found considerable variation in terms of coverage and conditions of reimbursement related to on- and off-label uses of mAbs. Our results point to four major challenges facing mAb developers, health care providers, Medicare beneficiaries, payers and policymakers. These include administrative price controls, coverage variation, projected shift from physician- to self-administered mAbs, and comparative effectiveness. We suggest more systematic use of "coverage with evidence development" as a means of optimally addressing these challenges.

Global antibody development trends

Abstract: Although monoclonal antibodies (mAbs) have long been staples of biotech research and development (R&D), the study of mAb therapeutics has recently attracted a great deal of attention by the pharmac...

Factors Associated with Multiple FDA Review Cycles and Approval Phase Times

Abstract: We examined the regulatory review histories of 298 approved new drugs and biologics with new drug applications (NDAs) or new biologic license applications (BLAs) submitted to the US Food and Drug Administration (FDA) during fiscal years 1996–2006 for factors that were associated with multiple review cycles and with longer or shorter total approval phase times (sum of FDA action and sponsor response times) for a given number of review cycles. Using logistic regression models, we found that the likelihood of multiple cycle review varied by therapeutic class, product type (odds ratio = 3.1 for BLAs), fast track status (odds ratio = 0.3), limited sponsor regulatory experience (odds ratio = 2.1 for first US approval), and more recent submissions (odds ratio = 1.7 for fiscal year 2000–2003 submissions compared to fiscal year 1996–1999 submissions). We also applied least squares multivariate regression analysis to explain the variation in total approval phase times with a number of drug, sponsor, and regulatory characteristics. After controlling for the number of review cycles and other factors, we found longer average approval phase times for more recent submissions (56% longer for priority rated compounds with multiple cycle reviews and submissions during a later period, P longer for multiple-cycle BLAs approved by CDER versus multiple-cycle CBER approvals, P = .0209), compounds with December submissions (18% longer for compounds with multiple cycle reviews, P = .0069), and compounds with advisory committee meetings (13% longer for compounds with a single review cycle, P = .0344). We found shorter average approval phase times for compounds with a fast track designation (21 % shorter for compounds with multiple cycle reviews, P = .0825) and accelerated approval status (24% lower for compounds with a single review cycle, P = .0010). Statistical models such as those presented here can help improve the precision with which drug developers and regulators predict approval times and assess the effectiveness of regulatory programs designed to speed the drug approval process.

Off-label use reimbursement.

Abstract: In this study, the authors examine factors underlying payer off-label use reimbursement policies. Updating a study published 14 years ago, presenting the results of the survey of 179 payers administering public (Medicare and Medicaid) pharmacy benefits. The focus is on payers administering pharmacy benefits in the public sector for two reasons: First, transparency; there is a tendency for such payers to reveal more about their decisionmaking processes than payers that exclusively deal with the commercial market. Second, Medicare and Medicaid set the pace in terms of specific policies on off-label use reimbursement, particularly with regard to anti-cancer agents and biologics. The authors investigate the role of primary and secondary sources governing reimbursement of unlabeled indications, including biopharmaceutical compendia, peer-reviewed literature, and clinical practice guidelines. The findings point to the continued variation of off-label use reimbursement policies across payers. Furthermore, the survey data shed light on payer efforts to design off-label use reimbursement strategies, including the use of cost-effectiveness.

Probabilities of success for antibody therapeutics.

Abstract: Probabilities of success (POS) play a key role in determining the distribution of resources by both investors and the pharmaceutical industry. Resources such as time, money and personnel are more likely to be directed toward programs in categories with acceptable rates of success. What is considered acceptable may, of course, vary between companies and other decision-makers. With the increased focus on development of antibody therapeutics, it is important for stakeholders to understand the utility, and limitations, of POS values such as cumulative approval success rates and clinical phase transition probabilities. A key point is that cumulative approval success rates are derived from data for only those candidates with known fates (either approved or terminated), but clinical phase transition probability calculations include data on the status of all candidates. POS values for various cohorts of monoclonal antibody (mAb) therapeutics have been reported previously. 1-6 For mAb POS, a key consideration is the source of the protein sequence. Data for humanized and human mAbs must be analyzed separately because, overall, these molecules display improved safety and efficacy profiles compared to murine and chimeric versions. Humanized mAbs comprise the ‘canonical’ cohort because a large number (>150) of these candidates have entered clinical study over the last two decades (1988–2008), and 12 have been approved (Table 1). However, ultimate fates (approval or termination) are known for only about half, and the cumulative approval success rate for the entire cohort of humanized mAbs will only be an estimate until the fates of all the molecules have been decided. The current cumulative approval success rate estimate for humanized mAbs is 17%. 2 It is important to note that time plays an essential role in POS calculations. In general, clinical study and regulatory review periods for therapeutics are lengthy, and mAbs are not exceptional in this regard. The mean (median) for the combination of the clinical and US Food and Drug Administration (FDA) approval phases for 23 mAbs (Table 1) is currently 8 (7) years. This has important implications for POS calculations for mAb cohorts that include high percentages of candidates that have entered clinical study within the past seven or eight years. Candidates that have entered clinical study since 2001 have not had sufficient time, on average, for approval, but might have been terminated for a variety of reasons. This suggests that there is a downward bias in cumulative success rates for cohorts that include candidates that recently entered clinical study. Indeed, the cumulative success rate for humanized mAbs changes dramatically when the cohort is divided into two groups: candidates that entered clinical study during 1988–1996 (n = 30; eight approved) and 1997–2008 (n = 125; two approved). Ultimate fates are known for 87% of the older candidates, and the cumulative success rate for the cohort is 31%. However, ultimate fates are known for only 33% of the newer candidates, and because many have not been in clinical study long enough to accumulate the

Finding value in the U.S. Food and Drug Administration's Fast Track program.

Abstract: The U.S. Food and Drug Administration's (FDA) Fast Track program, created in 1997, was designed to facilitate the development and expedite the review of drugs and biologics intended to treat serious or life-threatening conditions, and that demonstrate the potential to address unmet medical needs. Although the intent is laudable, the significance of designations and effectiveness of the program have recently come into question. Tufts Center for the Study of Drug Development has collected data on fast track candidates since 1998. We analyzed the current dataset of 344 fast track candidates granted nearly 400 designations, representing approximately 70% of the fast track designations granted by FDA, to address questions regarding common metrics. We found that fast track candidates were widely diverse in characteristics and development histories. The complexity and limitations of the data introduced biases in metrics such as clinical phase lengths and phase transition probabilities, although these could be determined for subsets of the candidates. Our results suggest that evaluation of the Fast Track program requires a nuanced approach, and estimates of the program's value should include assessment of the resulting marketed products.

Can translational medicine bring us out of the R&D wilderness?

Abstract: After 50 years of wandering among new discovery technologies and a worrying antiquated development process, the research and development (R&D) enterprise may finally have found a way out of its wilderness through the auspices of translational medicine. For that to happen, a number of problems have to be confronted. Most prominent is the traditional problem credited with giving rise to translational medicine - the lack of a feedback loop from bench to bedside. However, there are equally significant roadblocks to be confronted at every turn along the R&D pathway, from basic research through discovery and preclinical testing and, finally, into the clinic. Translational medicine is now beginning to encompass other powerful and promising innovations such as personalized medicine, bioinformatics, advanced imaging and biomarkers to help move beyond these roadblocks. Although translational medicine has attracted significant financial support in recent years, the economics of the movement are still challenging, as public and private sector funding are both difficult to come by due to the economic downturn. Some of the dearth of monies has been redressed by foundations and public-private partnerships, which combine resources and, hence, divide the risk to the benefit of all. More recently, the inherent tension among the traditional roles of 'big pharma', biotechs and the public sector, which had waned somewhat in the wake of the Bayh-Dole legislation in the USA, has re-emerged owing to the furor over conflicts of interest. Translational medicine may help alleviate these tensions by its example of successful precompetitive collaboration, such as the Predictive Safety Testing Consortium and its effective use of project management techniques in multidisciplinary, multiphasic, multisectoral projects to bring the discipline necessary for the efficient functioning of consortia. Changing a research paradigm that has remained substantially unchanged for half a century will require considerable time, money and effort. However, there is reason to be optimistic that translational medicine is the right solution for the right problem at the right time.

Second International Conference on Accelerating Biopharmaceutical Development: March 9-12, 2009, Coronado, CA, USA.

Abstract: The Second International Conference on Accelerating Biopharmaceutical Development was held in Coronado, California. The meeting was organized by the Society for Biological Engineering (SBE) and the American Institute of Chemical Engineers (AIChE); SBE is a technological community of the AIChE. Bob Adamson (Wyeth) and Chuck Goochee (Centocor) were co-chairs of the event, which had the theme “Delivering cost-effective, robust processes and methods quickly and efficiently.” The first day focused on emerging disruptive technologies and cutting-edge analytical techniques. Day two featured presentations on accelerated cell culture process development, critical quality attributes, specifications and comparability, and high throughput protein formulation development. The final day was dedicated to discussion of technology options and new analysis methods provided by emerging disruptive technologies; functional interaction, integration and synergy in platform development; and rapid and economic purification process development. © This meeting report was written for and published by Landes Bioscience in the journal, mAbs. Reichert JM, Jacob N, Amanullah A. Second International Conference on Accelerating Biopharmaceutical Development: March 9–12, 2009, Coronado, CA USA. mAbs 2009 1(3); http://www. landesbioscience.com/journals/mabs/article/8491 Biotechnol. Prog., 2009

Second International Conference on Accelerating Biopharmaceutical Development: March 9-12, 2009, Coronado, CA USA.

Abstract: The second International Conference on Accelerating Biopharmaceutical Development was held in San Diego, California. The meeting was organized by the Society for Biological Engineering (SBE) and the American Institute of Chemical Engineers (AIChE); SBE is a technological community of the AIChE. Bob Adamson (Wyeth) and Chuck Goochee (Centocor) were co-chairs of the event, which had the theme “Delivering cost-effective, robust processes and methods quickly and efficiently.” The first day focused on emerging disruptive technologies and cutting-edge analytical techniques. Day two featured presentations on accelerated cell culture process development, critical quality attributes, specifications and comparability, and high throughput protein formulation development. The final day was dedicated to discussion of technology options and new analysis methods provided by emerging disruptive technologies; functional interaction, integration and synergy in platform development; and rapid and economic purification proce...