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Surveys evaluating industry experience with performing pediatric studies under the Best Pharmaceutical for Children Act (BPCA) and Pediatric Research Equity Act (PREA) regulatory regime were conducted by Tufts Center for the Study of Drug Development (Tufts CSDD) in 2000, 2006, and 2016. These survey results are being used to assess the future impact of regulatory incentive programs on generating pediatric specific labeling information and development of age-appropriate drug formulations. A second perspective will be provided through the experience and expertise of neonatal/pediatric clinicians and researchers with a focus on the urgent need for the study of new and existing drugs in this vulnerable population (especially with 90% of drugs in neonates still being used off-label). This group will also address the impact of existing regulations and the likely trajectory of future pediatric drug development efforts after nearly 2 decades of regulatory incentives (both mandatory and voluntary). Finally, this review will provide input on approaches that are needed to continue to advance pediatric drug development with an emphasis on rare diseases.

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A host of challenges confront healthcare authorities worldwide. Topping the list is the demand for innovative new medicines to treat a range of both infectious and non-communicable diseases, while containing spiraling healthcare costs. The challenge is particularly great in therapeutic areas where, despite significant medical need and economic impact, the technical challenges and commercial risk of development serve as disincentives to drug sponsors. These areas include cardiovascular diseases as well as diseases and disorders of the central nervous system. Currently, the development and approval of new active substances, with its disproportionate focus on oncology, is not in alignment with healthcare needs in most geographic regions. In this article, we discuss the origins of this misalignment and suggest various approaches to address healthcare needs going forward.

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OBJECTIVE: We examine whether drugs' excluded versus recommended status on pharmacy benefit manager exclusion lists corresponds to evidence from cost-effectiveness analyses, lack of evidence, or rebates. DATA SOURCES: To find cost-effectiveness data for drugs on 2016 exclusion lists of CVS Caremark and Express Scripts, we searched the Tufts Cost-Effectiveness Analysis Registry and the peer-reviewed literature. STUDY DESIGN: For each excluded and recommended drug, we compared the mean cost-per-QALY, and we calculated the difference between the numbers of excluded and recommended drugs for which we could find no cost-effectiveness evidence. DATA COLLECTION: As keywords in our searches, we used the brand and generic drug name and "cost-effectiveness" and "cost-per-quality-adjusted life-year." Of 240 retrieved studies, 110 were selected for analysis. PRINCIPAL FINDINGS: The mean cost-per-QALY for excluded drugs was higher ($51,611) than the cost-per-QALY for recommended drugs ($49,474), but not statistically significant. We could find no cost-effectiveness evidence in the Registry or peer-reviewed literature for 23 of the excluded drugs, and no evidence for 5 of the recommended drugs. CONCLUSIONS: Cost-effectiveness does not correlate with a drug's excluded or recommended status. Lack of cost-effectiveness evidence favors a drug's excluded status.

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Social media has transformed how people interact with one another through the Internet, and it has the potential to do the same for orphan drug development. Currently, social media influences the orphan drug development process in the following three ways: assisting the study of orphan diseases, increasing the awareness of orphan disease, and playing a vital role in clinical trials. However, there are some caveats to the utilization of social media, such as the need to protect patient privacy by adequately de-identifying personal health information, assuring consistent quality and representativeness of the data, and preventing the unblinding of patient group assignments. Social media has both potential for improving orphan drug development and pitfalls, but with proper oversight on the part of companies, support and participation of patients and their advocacy groups, and timely guidance from regulatory authorities, the positives outweigh the negatives for this powerful and patient-centric tool.

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The morbidity and mortality toll of pediatric cancer affects the public health of children worldwide, but despite the gains in the fight against cancer, more progress needs to take place against this disease, which is a leading cause of death and chronic disability in children. In response, leading regulatory authorities in the developed world have been ratcheting up their efforts to induce the private sector to expand their research and development focus during drug development for adult cancers to include children. In mid-May 2016, the Center for the Study of Drug Development at Tufts University held a roundtable workshop on pediatric oncology to explore how companies could maximize the efficiency of pediatric assessment of adult cancer indications while minimizing resource expenditures to comply with regulatory requirements under the European Medicines Agency and the U.S. Food and Drug Administration. Although worldwide a child is diagnosed with cancer every 3 minutes, pediatric cancer is a rare disease, and trial participants are hard to come by. Thus, the market hardly sustains research and development expenses, advances in pharmacogenomics are not reaching down the age scale, and even in the public sector, basic research funding for pediatric cancer pales in comparison to the amount spent on cancer overall. The goal of the roundtable was to acknowledge these problems, and more importantly, to raise the level of awareness of potential solutions, including: more efficient use of the data hierarchy of informative events in clinical trials; new innovative clinical trial platforms for rapid assessment of new drugs in children; new developments in formulation technology; and optimization of speed in pediatric drug development through a multi-stakeholder network collaboration separate from the adult development plan.

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Four challenges to the adoption of personalized medicine were identified in the mid-2000s - adherence to the blockbuster model, the lack of a supportive regulatory environment, the dysfunctional payment system and physician barriers. In this article, we report on our study findings based on interviews with 24 senior executives from leading drug and diagnostics companies to assess progress made in addressing those challenges over the last decade. Overall, we found that even with payer pushback and adjusting to new business models, the majority of developers expected their business to increase over the next 5 years. Several factors that unexpectedly helped to shape the personalized medicine landscape, such as the growth of support in genomic medicine from the public sector, are also discussed.

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BACKGROUND: With available funding from the public sector decreasing while medical needs and scientific complexity increase, private-sector collaborations with academia and government have become increasingly key in furthering medical innovation. Nonetheless, some skeptics diminish the contribution of the private sector to the discovery and development of truly innovative drugs on the one hand, while on the other hand they assert that research and development (R&D) of new medicines could and should be exclusively within control (at least financially) of the government. This begs the question, How much government funding would be needed to replace industry new drug R&D spending? METHODS: We address the respective roles of the private and public sectors in drug development by examining a diverse array of evidentiary materials on the history of 19 individual drugs, 6 drug classes, and 1 drug combination identified as the most transformative drugs in health care over the past 25 years by a survey of over 200 physicians. RESULTS: Only 4 of the individual drugs appear to have been almost completely researched and developed by one sector. One sector or the other, however, did dominate particular phases of the R&D continuum. For example, 54% of basic science milestones were achieved predominantly by the public sector and 27% by the private sector. For discovery milestones, it was 15% by the public sector and 58% by the private sector. The private sector was also dominant in achieving the major milestones for both the production and drug development phases (81% and 73% of the drugs reviewed, respectively). For 19% to 27% of the case histories for the various categories, dominance of one sector versus the other could not be determined. On the question of replacing industry's spending on the R&D of medicines, we estimate quite conservatively that the amount that would have to be spent by government would be nearly double the budget of the National Institutes of Health just to maintain the flow of the most innovative drug approvals and would have to increase nearly 2.5 times that level to maintain the development of all new drugs. CONCLUSIONS: Our analysis indicates that industry's contributions to the R&D of innovative drugs go beyond development and marketing and include basic and applied science, discovery technologies, and manufacturing protocols, and that without private investment in the applied sciences there would be no return on public investment in basic science.

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BACKGROUND: Regenerative medicine (RM) is a game-changing technology with the potential to repair damaged tissues and organs, but its introduction into the clinic is complicated by the fact that Europe, Japan, and the United States are struggling to make appropriate regulatory decisions about advanced technologies that are highly promising but also uncertain and potentially risky. They have adopted the new approach of regulatory science (RS), applying science-based approaches and standards to support regulatory decision making, to address the challenge. METHODS: Is RS the right approach for harmonizing the regulatory mechanisms needed to integrate RM into the mainstream of the development continuum for medical products? If so, what are the prospects for harmonization? We examine the current state of the art for RM and RS in the 3 major drug development regions to answer these questions. RESULTS: Among the practical obstacles to harmonization is the fact that the 3 regions represent different legal jurisdictions and health care systems, with disparate regulatory and reimbursement requirements. However, the regulatory regimes are not without commonalities. Thus, it is not the practical differences that should be debated but rather how best to enhance collaboration. CONCLUSIONS: Just as consistent and predictable regulatory support founded on common principles in regulatory science provide the confidence and certainty required to bolster investment in regenerative medicine, harmonization is essential to building that framework on a global scale.

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PURPOSE: Meeting marketplace demands for proving the value of new products requires more data than the industry has routinely produced. These data include evidence from comparative effectiveness research (CER), including randomized, controlled trials; pragmatic clinical trials; observational studies; and meta-analyses. METHODS: We designed and conducted a survey to examine the industry's perceptions on new data requirements regarding CER evidence, the acceptability of postapproval study types, payer-specific issues related to CER, communication of data being generated postapproval, and methods used for facilitating postapproval evidence generation. FINDINGS: CER is being used by payers for most types of postapproval decisions. Randomized, controlled trials were indicated as the most acceptable form of evidence. At the same time, there was support for the utility of other types of studies, such as pragmatic clinical trials and observational studies. Respondents indicated the use of multiple formats for communicating postapproval data with many different stakeholders including regulators, payers, providers, and patients. Risk-sharing agreements with payers were unanimously supported by respondents with regard to certain products with unclear clinical and economic outcomes at launch. In these instances, conditional reimbursement through coverage with evidence development was considered a constructive option. The Food and Drug Administration's initiative called Regulatory Science was considered by the respondents as having the most impact on streamlining the generation of postapproval research-related evidence. IMPLICATIONS: The biopharmaceutical industry is faced with a broad and complex set of challenges related to evidence generation for postapproval decisions by a variety of health care system stakeholders. Uncertainty remains as to how the industry and payers use postapproval studies to guide decision making with regard to pricing and reimbursement status. Correspondingly, there is uncertainty regarding whether the industry's investment in CER will have a positive return on investment in terms of reimbursement and market access.

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There have been several major problems that have plagued biopharmaceutical development since the end of the 1990s, but two in particular have reached the point where they are impacting the economic viability of the industry: the lack of efficacy of new drugs and increasing competition among therapeutics that broadly attack certain common diseases and disease areas. The US FDA has noted that the era of one-size-fits-all treatment may well be reaching its end days as companies increasingly adopt approaches that involve biomarkers (there are now commercial databases that purport to track over 11,000 of them). Pharmacogenomic biomarkers in particular are used to create diagnostics that help to differentiate or stratify the likely outcomes a patient will experience with a drug, which can now be said to be targeted or tailored to patients with particular traits (i.e., personalized), leading to an era of so-called precision medicine. As more is understood about diseases and the why and how of their effects on people through advances in biomarkers and genomics, personalized medicine is becoming a natural result of biomedical science and a natural trajectory for the innovation-based biopharmaceutical industry. The focus of this article is to examine an apparent divergence in that trajectory engendered by a growing differentiation in the approaches to personalized medicines in terms of their accompanying diagnostics: companion diagnostics are typically linked to a specific drug within its approved label, while complementary diagnostics are associated more broadly, usually not with a specific drug but with a class of drugs, and not confined to specific uses by labeling, with consequent ramifications for economic, regulatory and strategic considerations.

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BACKGROUND: Despite considerable disincentives for conducting drug studies in children, 15 years ago the Food and Drug Administration, pediatric health advocates and congressional sponsors created a carrot-and-stick policy approach of voluntary and mandatory programs to encourage the pharmaceutical industry to include children in the drug development process. After several rounds of reauthorization of the laws on a temporary basis, the enabling statutes have been made permanent. OBJECTIVE: The purpose of this analysis is to review the advances that resulted from the law and the areas where further progress is needed. METHODS: A brief review of the history and results of the pediatric studies initiative was conducted by the authors and a determination made about the accomplishments of the law and remaining challenges. RESULTS: Indicators of the changes that resulted from this pediatric studies initiative are both indirect, such as the increase in the number of indication supplements for new populations, and direct, such as the decrease in the percentage of medicines used off-label in children. Although the pediatric studies initiative has significantly improved therapeutic options for children, concern still exists that drug companies are reluctant to include children in drug development unless continuously incentivized, whether positively or negatively. Two challenges are particularly problematic: neonatal studies and child-friendly formulations. CONCLUSION: Although the latest round of legislation should provide opportunities to address these problems, significantly more effort will be needed to achieve real culture change. Ultimately, the solution will require full program implementation by the Food and Drug Administration and close collaboration by many key stakeholders to ensure that pediatric studies become a routine part of the drug development process.

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AIM: Personalized medicine is entering its second decade, yet the role it will play in addressing the biopharmaceutical industry's productivity gap and the rising cost of healthcare is still a matter of speculation. So what does the biopharmaceutical industry itself say about the business prospects for personalized medicine? MATERIALS & METHODS: The authors conducted interviews with 20 science and business experts from 13 companies to find out. In this article, particular attention is paid to drug-diagnostic codevelopment, so-called companion diagnostics. RESULTS: The results of the interviews are discussed in light of perspectives from various stakeholders available from the literature in the public domain. In brief, biopharmaceutical acknowledges the many difficulties that plague this path to product development with particular concern for knowledge gaps in the scientific base, the timing of studies during development, as well as the regulatory, reimbursement and commercial hurdles that can thwart approval, launch and market uptake. CONCLUSION: Nonetheless, personalized medicine in general and companion diagnostics in particular are believed to be an increasingly sustainable business proposition with expectations for rapid market growth in the near term.

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Implementation of REMS began in March 2008 and by mid-2011 close to 200 New Molecular Entities (NMEs) and New Drug Applications (NDAs) (i.e., NMEs plus new doses and formulations of drugs) approved by FDA were required to have a REMS. As the REMS program expands, there has been an increasing chorus of stakeholders who have expressed a range of concerns and criticisms about the program's impact on the health care system. Yet, these impacts still remain underexplored by academic study. The authors conducted a series of qualitative interviews with individuals representing the experiences and opinions of five stakeholder groups involved in various aspects of REMS programs. The groups were comprised of representatives of biopharmaceutical companies, payers, health care providers (HCPs), pharmacists, and patient advocacy organizations. Questions were organized around the following themes: REMS implementation and administration; REMS components (i.e., medication guides, communication plans, and elements to assure safe use); effects on patient access and delivery of care; program outcomes; and, issues specific to each stakeholder group. What was most surprising was not that respondent groups with such divergent perspectives and diverse roles within the REMS program disagreed on certain points, but rather that they agreed on so many points. There was general agreement that the program is burdensome and not an improvement over previous risk management programs. Respondents also concurred almost unanimously that the patient information is weighted much too heavily on the risk end of the risk/benefit scale. Similarly, there was general concern from all the responder groups about uncompensated time and resources expended by HCPs and pharmacists. While some positive aspects were noted, these tended to be viewed as opportunities for improvement rather than actual benefits of the REMS program as currently implemented. As PDUFA V draws ever nearer, it's clear that FDA is attempting to address the program's shortcomings but it is clear that more needs to be done.

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Expanding government purchases of prescription medicines increase the likelihood of public policies constraining prices and/or the formulary choices available to the beneficiaries of government programs. This can be predicted to reduce private sector incentives for the research and development of new and improved medicines. One response to that argument has been the premise that most of the important scientific advances that yield new and improved medicines do not result from private sector research, but instead are the fruits of research efforts financed or conducted by public agencies, the National Institutes of Health foremost among them. This study addresses that argument by examining the development histories of 32 drugs and drug classes deemed important in the scholarly literature along with three additional specific drugs that have figured prominently in the public discussion of the role of the private sector in drug development. We find that for the discovery and/or development of virtually all of the 32 drug classes, the scientific contributions of the private sector were crucial; and the same is true for the three drugs that have received widespread attention. All or almost all of the drugs discussed would not have been developed-or, at best, would have been delayed significantly-in the absence of private sector scientific discoveries. More generally, both National Institutes of Health-sponsored and private sector pharmaceutical research are crucial for the advancement of pharmaceutical science and the development of new and improved medicines.

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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.