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Durable cell and gene therapies potentially transform patient lives, but payers fear unsustainable costs arising from the more than 1000 therapies in the development pipeline. A novel multi-module Markov chain Monte Carlo-based model projects product-indication approvals, treated patients, and product revenues. We estimate a mean 63.5 (54-74 5th to 95th percentile range) cumulative US product-indication approvals through 2030, with a mean 93000 patients treated in 2030 generating a mean US$24.4 billion (US$17.0B-35.0B, US$73.0B extreme) list price product revenues not including ancillary medical costs or cost offsets. Thus, the likely dozens of durable cell and gene therapies developed through 2030 are unlikely to threaten US health system financial sustainability.

Background The Office of Orphan Products Development (OOPD) of the United States (U.S.) Food and Drug Administration (FDA) has awarded over 700 grants to conduct clinical trials of medicals products for rare diseases since 1983, leading to over 70 marketing approvals. However, despite recent progress in rare disease product development, thousands of rare diseases still have no approved treatments. An assessment of this clinical trial grants program was undertaken to provide an in-depth analysis of the characteristics and outcomes of the program. Results of this analysis will be used to inform future goals of the program, as well as internal data collection to continue to maximize the program’s impact in supporting rare disease product development. Results Between fiscal years 2007—2011, OOPD funded 85 clinical trial grants. These grants spanned 18 therapeutic areas, included all pre-approval phases (Phases 1–3), and approximately 75% of the grants studied small molecule drugs. Nine (11%) product approvals, of seven drugs and two devices, were at least partially supported by grants funded within this 5-year timeframe. Four of the seven drugs approved were new molecular entities (NMEs). The average time from funding to approval was seven years. We also found a suggested association between collaboration with multiple types of stakeholders and the success of grants, where we defined success as either positive or negative study findings or a future marketing approval. Conclusions The clinical trials funded by OOPD provided valuable information for future product development, and there were a notable number of approvals that occurred using the support of the grants program. There was a suggested association between collaboration and successful outcomes. Efficient and innovative trial designs and collaboration among stakeholders appear vital to continue to effectively bring products to rare disease patients. Ongoing program assessments will ensure that the funding continues to be used to optimally meet the treatment needs of the rare disease community.

Background Approval of regulated medical products in the USA is based upon a rigorous review of the benefits and risks as performed by the US Food and Drug Administration (FDA) staff of scientists and is summarized in a descriptive and qualitative format called the FDA’s Benefit–Risk Framework (BRF). This present method highlights the key factors in regulatory decision-making, but does not clearly define the reason for its final approval. Method This study proposes a quantitative version of FDA’s BRF to calculate a Net-Benefit Score and a Benefit–Risk Ratio as a method to define a single-value summary of the tradeoffs between benefits and risks and allow comparisons among other products. In this retrospective review of five years of new molecular entities and new biologic (N = 185 products) regulatory decision-making, this proposed scoring system codifies and quantitates the information about a product’s benefits, risks, and risk management information in a format that may predict why regulated medical products are approved in the USA. Results Simple calculation of codified benefits, risks, and risk mitigations with numerical limits is proposed to provide a repeatable process and transparency for documenting the net-benefit of regulatory product approval. Conclusion Use of a strict process of collecting, codifying, and analyzing public information to determine a Net-Benefit score and a Benefit–Risk Ratio is possible to anticipate regulatory product approval.

April 2019 was perhaps remarkable for the amount of industry news about gene therapy, and notably the announcement by a global contract development and manufacturing organization, Catalent, that it was creating a capability in gene therapy product development and manufacturing through its acquisition of Paragon Bioservices, Inc (MD, USA). This move followed just a few weeks after another similar major contract development and manufacturing organization gene therapy acquisition. There was other encouraging gene and cell therapy news reported from AveXis (IL, USA), Ajinomoto Bio-Pharma (CA, USA), Kiadis Pharma (Amsterdam, The Netherlands), Fibrocell (PA, USA), Autolus Therapeutics plc (London, UK), ReNeuron (Surrey, England) and Kite Pharma (CA, USA). Also, there was plenty of therapeutic delivery technology innovation announced, including Calixar’s (Lyon, France) membrane protein stabilization drug discovery technology, the Eli Lilly (IN, USA)/Avidity Biosciences LLC (CA, USA) deal around antibody oligonucleotide conjugates, ViiV Healthcare’s regulatory filing for its long-acting anti-HIV-1 intramuscular injection, Marinomed Biotech’s (Vienna, Austria) solubilization technology and an EU approval filing for Novo Nordisk’s (Bagsværd, Denmark) oral delivery formulation of glucagon-like peptide-1 analog semaglutide. Diseases and treatment approaches that currently figure strongly in many biotech and big pharma pipelines and portfolios, notably nonalcoholic steatohepatitis and immuno-oncology, were as ever in the news, along with a number of rare disease therapies. As always, information sources employed to provide the materials used in compiling this update included company press releases, conference news and other news websites.

1–31 December 2018, the period covered by this article, was again a very interesting period for activity under the therapeutic delivery umbrella, being a particularly solid month for business activity, notably a major acquisition by GSK to expand its oncology portfolio. This was, as it later turns out, the first of several very significant mergers and acquisitions around the turn of the year in the oncology area, more of which will appear in future articles. In that acquisition, the acquisition of Potenza Therapeutics (MA, USA) by Astellas Pharma Inc. (Tokyo, Japan), Amgen's (CA, USA) collaboration with Molecular Partners (Zurich, Switzerland), the partnership between Domain Therapeutics (Strasbourg, France) and Boehringer Ingelheim (Ingelheim am Rhein, Germany), and the deal between Argenx (Breda, The Netherlands) and Cilag GmbH International (Zug, Switzerland), all announced in the month, demonstrated the high continued interest within industry around the development of immuno-oncology therapeutics. Additionally, activity around therapeutic delivery technologies was prominent in the news, for example the Amgen/Entera Bio (Jerusalem, Israel) deal around oral delivery of large molecules, Entrada Therapeutic's (MA, USA) successful acquisition of funding to advance its work on intracellular delivery of biologics, Impel NeuroPharma's (WA, USA) securing of support continue its development of its nose-to-brain delivery pipeline, US FDA approval of inhaled levodopa from Acorda Therapeutics Inc. (NY, USA) and a sublingual delivery technology for dexmedetomidine under development by BioXcel Therapeutics (CT, USA) being advanced into clinical evaluation were just some of the items noted. As always, information sources employed to provide the materials used in compiling this update included company press releases, conference news and other news websites.

Slow uptake of biosimilars in some regions is often attributed to a lack of knowledge combined with concerns about safety and efficacy. To alleviate physician and patient apprehensions, regulatory reviews from four major regulatory authorities (RAs) (European Medicines Agency, US Food and Drug Administration, Health Canada, and Japan Pharmaceuticals and Medical Devices Authority) across a portfolio of eight biosimilars were analyzed to provide insight into RA review focus and approach. RA queries were evaluated in an unbiased and systematic manner by major classification (Chemistry, Manufacturing and Controls [CMC], nonclinical, clinical or regulatory) and then via detailed sub-classification. There was a consistent, predominant focus on CMC from all RAs. The review focus based on sub-classification of clinical and regulatory queries was influenced by molecular complexity, with significant differences between categories (monoclonal antibody or protein) in the distribution of query topics, specifically, bioanalytical (p = 0.023), comparative safety and efficacy (p = 0.023), and statutory (including the justification of extrapolation) (p = 0.00033). Each biosimilar had a distinct distribution of clinical query topics, tailored to product-specific data. This analysis elucidated areas of heightened RA interest, and validated their application of regulatory science in the evaluation of biosimilar safety and efficacy.

Gene therapy emerged as an important area of research and led to the success of multiple product approvals in the clinic. The number of clinical trials for this class of therapeutics is expected to grow over the next decade. Gene therapy products are complex and heterogeneous, employ different types of vectors and are susceptible to degradation. The product development process for commercially viable gene-based pharmaceuticals remains challenging. In this review, challenges, stability, and drug product formulation development strategies using viral or non-viral vectors, as well as accelerated regulatory approval pathways for gene therapy products are discussed.

The Orphan Drug Act (ODA) of 1983 was enacted to provide financial incentives to drug sponsors to develop therapies for rare diseases. Although this act increased the number of orphan products approved, there are still a limited number of products available for the pediatric population because orphan drug products are exempt from the Pediatric Research Equity Act. The objectives of this study were (i) to evaluate the pediatric orphan drug studies submitted to the US Food and Drug Administration (FDA) in the period of 2007-2018 and (ii) to examine whether orphan drug products were fully labeled with a pediatric indication in infants and neonates. Out of the 468 indications evaluated, 171 (37%) were FDA-labeled for use in the pediatric population. Labeling for the 12 to

Introduction: Antibody-Drug Conjugates (ADCs) have undergone a recent resurgence with 5 product approvals over the last 2 years but for those close to the field, it’s been repeated cycles of setbac...

Objective Under the circumstances that several oncology drugs have been approved under expedited programs in the US, this study aimed to analyze the relationship between the expedited programs and characteristics of approvals in the recent decade, and the attitude of the Food and Drug Administration (FDA) toward the development and review of oncology drugs. Results Of the 162 approvals that were analyzed, the proportion of orphan drug (OD) designation was higher in accelerated approval (AA) than regular approval (RA). In contrast, no difference was observed in the proportions of priority review (PR) in AA versus RA or in ODs versus non-ODs. In the development time, no difference was observed in any of the expedited programs. Regarding review time, a significant difference was observed in PR versus standard review (SR). In the characteristics of the pivotal study, such as randomization, number of patients, and endpoints, differences were observed in AA versus RA and in ODs versus non-ODs. Conversely, no significant difference was noted in PR versus SR. Conclusion The overall results of this research validated the attitude of the FDA toward applying each expedited program to facilitate an earlier delivery of innovative oncology drug products to patients with cancer.

Background The Orphan Drug Act was enacted in 1983 to encourage the development of drugs for rare diseases. Previous research has attempted to examine the impact of the Act by assessing either the number of orphan designations that have been granted or the number of new orphan drugs approved for marketing. This study provides a more in-depth understanding of the effect of the Orphan Drug Act by investigating all types of drug approvals with an orphan designation, along with multiple characteristics of the drugs, over the entire 35 years of the Act. These orphan approvals include: new molecular entities (new drugs approved first for a rare disease), secondary indications (an expansion from the first approved indication), and new formulations. Results The results show that the number of approvals for orphan indications has been increasing over time, and the upward trend is especially large in the most recent years. Much of this increase has been driven by the increase in secondary indications being approved for previously approved drugs, although there have also been increases in the number of approved new drugs. We also find that while oncology indications have been increasing significantly, there has also been an increase in other therapeutic areas. Additionally, we find that the proportion of biologic drugs being approved has increased over time. Lastly, while other parts of this drug landscape have dramatically altered over time, the proportion of orphan approvals receiving priority review has not changed. Conclusions Our data suggest that the Orphan Drug Act appears to have stimulated significant drug development for rare diseases. Additionally, approvals of orphan indications have been increasing over time. This increasing effect has not targeted a single area of the rare disease space, rather, gains in approvals have been seen across: therapeutic areas, approval types (both new drugs and secondary indications), and for both biologics and small molecule drugs. Electronic supplementary material The online version of this article (10.1186/s13023-018-0930-3) contains supplementary material, which is available to authorized users.

The long path from initial research on oligonucleotide therapies to approval of antisense products is not unfamiliar. This lag resembles those encountered with monoclonal antibodies, gene therapies, and many biological targets and is consistent with studies of innovation showing that technology maturation is a critical determinant of product success. We previously described an analytical model for the maturation of biomedical research, demonstrating that the efficiency of targeted and biological development is connected to metrics of technology growth. The present work applies this model to characterize the advance of oligonucleotide therapeutics. We show that recent oligonucleotide product approvals incorporate technologies and targets that are past the established point of technology growth, as do most of the oligonucleotide products currently in phase 3. Less mature oligonucleotide technologies, such as miRNAs and some novel gene targets, have not passed the established point and have not yielded products. This analysis shows that oligonucleotide product development has followed largely predictable patterns of innovation. While technology maturation alone does not ensure success, these data show that many oligonucleotide technologies are sufficiently mature to be considered part of the arsenal for therapeutic development. These results demonstrate the importance of technology assessment in strategic management of biomedical technologies.

In recent decades, extensive emphasis has been given on developing nanopharmaceutical products for improving the therapeutic performance of drugs, resulting in an increasing number of product approvals by drug regulatory agencies. Although nanopharmaceuticals are subjected to the same regulatory pathways as conventional pharmaceutical products, their biopharmaceutical characteristics at the nanoscale make them vulnerable to high variability in quality. Positive effects on drug quality assurance have resulted from adopting systematic quality-by-design (QbD) principles, boosting pharmaceutical manufacturing with improvements in the quality, safety, and efficacy of drugs.

Regulators from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) do not always agree on interpretation of data for a drug's safety and efficacy.The authors compared all new molecular entities approved or rejected in a 5-year period from 2007 to 2011, identified where FDA and EMA reviews resulted in different regulatory decisions, and explored potential mechanisms for the discrepancies. Thirteen entities were associated with different regulatory decisions, and 2 drugs were withdrawn from their respective markets in 2010: one from the US (Mylotarg; gemtuzumab ozogamicin) and the other in Europe (Thelin; sitaxentan sodium).There are relatively few cases where FDA and EMA substantively differ with regard to product approvals and market withdrawals. It is likely that the scientific and cultural differences between FDA and EMA will continue to diminish over time, because these two agencies increasingly work together as pharmaceutical product development increasingly becomes a global endeavor.

The baculovirus expression vector system (BEVS) platform has become an established manufacturing platform for the production of viral vaccines and gene therapy vectors. Nine BEVS‐derived products have been approved – four for human use (Cervarix®, Provenge®, Glybera® and Flublok®) and five for veterinary use (Porcilis® Pesti, BAYOVAC CSF E2®, Circumvent® PCV, Ingelvac CircoFLEX® and Porcilis® PCV). The BEVS platform offers many advantages, including manufacturing speed, flexible product design, inherent safety and scalability. This combination of features and product approvals has previously attracted interest from academic researchers, and more recently from industry leaders, to utilize BEVS to develop next generation vaccines, vectors for gene therapy, and other biopharmaceutical complex proteins. In this review, we explore the BEVS platform, detailing how it works, platform features and limitations and important considerations for manufacturing and regulatory approval. To underscore the growth in opportunities for BEVS‐derived products, we discuss the latest product developments in the gene therapy and influenza vaccine fields that follow in the wake of the recent product approvals of Glybera® and Flublok®, respectively. We anticipate that the utility of the platform will expand even further as new BEVS‐derived products attain licensure. Finally, we touch on some of the areas where new BEVS‐derived products are likely to emerge., The baculovirus expression vector system (BEVS) has become an established commercial manufacturing platform. The authors review this technology, which enables fast, flexible and scalable protein production and is increasingly being used for the production of viral vaccines and gene therapy vectors. Nine BEVS‐derived products have been licensed by global regulatory authorities, paving the way for new products that are in development. WILEY‐VCH

This chapter situates contemporary debates over regenerative medicine governance within a broader framework, taking intersections with economic, political, and other kinds of technological zones into account. With the inherent complexities of regenerative medicine products, the advent of techniques such as gene editing and tissue organoids, and pragmatic problems of scaling-up cell manufacturing, conventional ways of thinking about and producing evidence are challenged. At the same time, the push to speed product approvals endures, but now in political and economic environments that include differing attitudes toward risk and patients’ roles in decision-making. The chapter highlights how crossing technological and political zones, data-driven approaches plus a return to observational data in particular are being incorporated into US regulatory law and product review.

The twin forces of payors seeking fair pricing and the rising costs of developing new medicines has driven a closer relationship between pharmaceutical companies and diagnostics companies, because stratified medicines, guided by companion diagnostics, offer better commercial, as well as clinical, outcomes. Stratified medicines have created clinical success and provided rapid product approvals, particularly in oncology, and indeed have changed the dynamic between drug and diagnostic developers. The commercial payback for such partnerships offered by stratified medicines has been less well articulated, but this has shifted as the benefits in risk management, pricing and value creation for all stakeholders become clearer. In this larger healthcare setting, stratified medicine provides both physicians and patients with greater insight on the disease and provides rationale for providers to understand cost-effectiveness of treatment. This article considers how the economic value of stratified medicine relationships can be recognized and translated into better outcomes for all healthcare stakeholders.

New drug and biologic product marketing applications submitted to FDA's Center for Drug Evaluation and Research (CDER) between 2006 and 2010 were analyzed to identify rare disease application characteristics associated with higher approval rates. The results show that approval rates were similar for rare and common disease applications. Larger company size, prior regulatory experience and priority review designation were associated with higher approval rates. The study findings show that rare disease product development is feasible, and increased interactions between product developers and FDA in early investigational phases can facilitate product development.

In 2006, the US Food and Drug Administration (FDA) published draft guidance to provide recommendations for development, validation, implementation, and interpretation of patient-reported outcome (PRO) measures that can support treatment benefit claims in product labeling. Here, we summarize and discuss FDA approvals of anticancer products in the context of the draft guidance. We identified anticancer product approvals having efficacy claim(s) based at least in part on a PRO. In addition, we collated limitations of PRO instruments commonly submitted for regulatory review over the period from October 1, 2004 to September 30, 2006. From 1995 onward, nine indications were approved for seven anticancer products based at least in part on a PRO. In eight of nine approvals, PRO data supplemented other evidence of clinical benefit. In seven approvals, the PRO measured a single symptom or functional domain that was directly attributable to the treatment benefit observed in the disease. The FDA's draft PRO guidance describes principles that have been used in anticancer product approvals for more than a decade. PRO end points typically support treatment benefit claims that refer to a patient's symptoms or ability to function. Single-item PROs may be acceptable. PRO data should be both internally consistent and aligned with other evidence of clinical benefit. The FDA encourages sponsors to consult with the FDA early in the process of PRO development.

Biotechnology firms face new challenges as biologics account for an increasing share of product approvals and pipelines and their high costs are under scrutiny by regulators, employers, and consumers. Although the first generation of biologics often targeted niche markets with little impact on payers' total costs, the current product wave addresses larger populations. To meet the needs of all stakeholders, manufacturers must adopt an evidence-based approach including three principles: demonstration of clinical and economic value, price evolution according to market conditions (from orphan diseases to large areas such as diabetes), and an early timetable integrating clinical and economic endpoints.

Hypoglycemia complicating diabetes therapy is well recognized to be an ever-present threat to patients, their families, providers, payers, and regulators. Despite this being widely acknowledged, the regulatory stance on hypoglycemia as an endpoint in clinical trials to support new product registration has not evolved in any meaningful way since the publication of a position paper by an American Diabetes Association (ADA) Workgroup in 2005. As the impact of hypoglycemia on persons affected by diabetes is of major importance when assessing new treatments, the historical position of regulatory agencies on hypoglycemia is reviewed with respect to product approvals. The purpose of this article is to present proposals for facilitating development of therapies that reduce hypoglycemia risk through (1) development of composite measures of benefit for regulatory endpoints and (2) facilitation of the fulfillment of an unmet clinical need for reducing hypoglycemia. In view of greater comprehension of the effects of hypoglycemia, coupled with improved methodology to assess its frequency, the authors recommend: (1) a numerical cut point of

This article has outlined only a small example of product safety standards, but the message is that product approvals are complicated and exist for a good reason. Believing they are quick and simple has all too often proved be short-sighted and expensive, so it is worth having or hiring an experienced set of eyes to review the project before it is completed ideally at the start of a project, or before the product is submitted for approvals testing. Approvals bring kudos and demonstrate a level of competence, plus diligence on the part of the business.

Background Millions of patients are treated with opioid analgesics (OpAs) to relieve pain. Unfortunately, these medications are subject to abuse and/or unintended misuse. Abuse deterrent formulations (ADFs) represent an intervention strategy to decrease abuse/misuse without affecting patient access. The Food and Drug Administration (FDA) has issued Draft Guidance “Abuse deterrent opioids, Evaluation and Labeling” and is currently actively pursuing scientific input on this issue. Methods The development of ADF technologies was reviewed using peer reviewed journals describing OpA post marketing studies, web sites containing FDA announcements on product approvals and manufacturer product use profiles. Results Reviewed is the FDA recent approval of a product label describing the abuse deterrent characteristics of OxyContin ® (physical barrier formulation), and the FDA determination that studies were insufficient for an Opana ® (physical barrier) ADF label. Additional reviewed marketed OpAs with ADF technologies include: Suboxone ® and Embeda ® (opioid agonist/antagonist combinations), Oxecta ® (aversion technology), and Nucynta ® (physical barrier). Reviewed ADF technologies currently in development include: new physical barrier and aversion technologies, an innovative extended release formulation as well as novel polymer–opioid conjugates. As ADF technologies are part of a comprehensive intervention strategy to promote safe OpA use, additional components including governmental, community, and educational initiatives are reviewed. Conclusions The outcomes of the recent ADF labeling applications for OxyContin ® (Tier 3 approval) and Opana ® (non-approval) suggest that the threshold for ADF labeling will be appropriately high. The presented findings indicate that ADF technologies can be a critical component of a comprehensive strategy to promote the safe and effective use of OpAs.

Nucleic acid therapeutics are attracting renewed interest due to recent clinical advances and product approvals. Most leading programs use chemical conjugates, or viral vectors in the case of gene therapy, while several use no delivery system at all. Polymer systems, which have been at the periphery of this renaissance, often involve greater molecular complexity than competing approaches, which must be justified by their advantages. Advanced analytical methods, along with biological tools for characterizing biotransformation and intracellular trafficking, are increasingly being applied to nucleic acid delivery systems including those based on polymers. These frontiers of investigation create the opportunity for an era where highly defined polymer compositions are optimized based on mechanistic insights in a way that has not been previously possible, offering the prospect of greater differentiation from alternatives. This will require integrated collaboration between polymer scientists and those from other disciplines.

The drug discovery industry may find that the way to succeed in today's competitive environment is to cooperate in strategic alliances with complementary organizations, such as contract research organizations, in the creation of virtual drug development corporations (VDDCs). VDDCs do business across traditional company boundaries through strategic alliances. When the strategic alliance is thoroughly defined and complementary core competencies are identified, a VDDC can achieve quicker product approvals and greater profits than are possible when a company attempts to manage the development process alone.

The premise of this paper is a concern over the dismal record of approvals for biotechnology products despite the enormous resources poured into their development. The authors have described a number of issues which may help to explain the dearth of biotechnology product approvals. Included among those issues are suggestions for improving the development process by ensuring the presence of several key resources which may be overlooked by emerging biotechnology companies. Particularly, the authors advocate creative approaches to development rather than relying too strongly on approaches used in the past. As well, the authors suggest that applicants should intelligently use the resources of the Food and Drug Administration (FDA) for guidance and input into the development process. Finally, the authors suggest that when both applicants and FDA work smarter and faster, there will be many more approvals of biotechnology products.

Starting with properly collected, processed, annotated, and stored human specimens is critical for successful research using unsupervised, high-throughput technologies for discovery, validation, and translation from such samples. Samples that are not reproducibly collected and managed undermine data generated in platforms, such as mass spectroscopy–based proteomic technologies. The key factors that determine quality of human biosamples are use of consistent methodologies for collection, handling, processing, and storing specimens; understanding the potential sources of bias; and thoroughly annotating the life-cycle of the specimen. These factors apply when a new biospecimen resource is being created or when previously collected or banked samples are being used. Standard operating procedures permit control of bias and ensure that high-quality biosamples result in reproducible data. Compliance with increasingly complex human subject protection regulations governing the collection, management, storage, sharing, and use of human biosamples is essential to ensure that data will be published in high-quality journals, that intellectual property is protected, and that data generated using biosamples can be used as part of submissions to governmental regulatory bodies for product approvals.

 A total of 96 antidiabetic products were retrieved: 53 approved by the EMA (Table 1) and 43 by the FDA (Table 2). Generics were excluded.  Only two products with a PRO labeling claim were found in Europe (i.e., insulin glulisine and exenatide), and none in the USA. PROs identified in both claims were self-monitored blood glucose (SMBG) profiles and were used as secondary endpoints. See Tables 3 and 4.  Although insulin glulisine and exenatide were also approved by the FDA (on the same studies used in Europe) their US label did not mention any results based on SMBG profiles. Reasons for not including them in the label were not given in the corresponding medical reviews.  However, the analysis of other products’ reviews, such as insulin aspart or liraglutide (see Table 5), showed a reluctance from reviewers to include results based on SMBG profiles in the labels. Reviewers questioned the validity of the glucose profiles based on self-collected readings because of compliance issues and of a lower degree of accuracy of values obtained from glucometers vs. lab measures in a clinic.  Although measured in some cases, other PROs, such as quality of life or treatment satisfaction, were never considered for inclusion in labeling with any reasons given. This was consistent for both agencies. RESULTS Table 1. EMA Products Table 2. FDA Products

Government regulations are an increasingly important component of the environment in which firms operate. Regulations may subject firms to large costs and possibly regulatory-induced risks, both of which may have effects on stockholders' wealth. In this paper we investigate the valuation effects of Food and Drug Administration (FDA) product approvals, rejections and disciplinary decisions on the firms that operate in the food and drug industries. We find that FDA decisions have very large wealth effects. The large price changes associated with approval and rejection decisions suggest that a significant amount of uncertainty about FDA decisions is present almost up to the announcement day. These results are somewhat surprising given the lengthy period of time involved in developing and reviewing drugs and the continuous flow of information received by the market about their potential. We also find some evidence of information leaks preceding FDA announcements. With respect to disciplinary decisions, the evidence from the data suggests that stockholders experience large losses associated with FDA actions. Since these losses represent lost stream of future illegal income, it appears that ignoring FDA rules may be quite profitable for firms that are not caught.

Drugs remain a key element in the effective containment of health care costs. In 1993, 29 new drugs were approved for marketing by the US Food and Drug Administration (FDA). These entities, according to a 1993 Office of Technology Assessment study, each took on average 12 years and $359 million each to discover and develop. The FDA reported that the average review time for these entities was 26.5 months, some 3 months less than reported in 1992. Under the prescription Drug User Fee Act of 1992, which will generate an additional $327 million over the period 1993–1997, the FDA will hire an additional 600 review staff.

Regulatory and financial challenges conspire to stall the development and market approval of breakthrough medical products. Inconsistent parameters are used to assess the safety and efficacy of drugs, biologics, and devices; this glitch in the system introduces uncertainty, slows or blocks product approvals, and increases the costs of product development. Here, we consider how to balance the benefits and risks to the public in the assessment of innovative medical products. We also discuss the Institute of Medicine's recent report on the medical device approval process.

In their Policy Forum “Uncapping conflict of interest?” (7 June, p. [1172][1]), S. F. Wood and J. K. Mador argue for caps on the Food and Drug Adminstration (FDA) waivers of conflicts of interest (COIs) among members of advisory committees, but they do not identify substantial weaknesses in their arguments. A systematic study by an FDA contractor tested and rejected the hypothesis that advisers with waived and disclosed COIs vote in favor of those interests more frequently than advisers with no such conflicts ([ 1 ][2]). Golec et al. independently report similar results ([ 2 ][3]). If advisers with disclosed COIs vote like advisers with no such conflicts on questions such as product approvals and blackbox warnings, it is not clear how limiting the number of committee members with COIs would improve committee recommendations. Wood and Mador claim that many able and willing experts lack conflicts, but do not mention descriptions of unsuccessful searches for COI-free advisers typically found in the FDA's COI waivers [e.g., ([ 3 ][4], [ 4 ][5])]. Granting more COI waivers may increase the FDA's access to expertise, because advisers with waived COIs have more expertise than other advisers ([ 5 ][6]). The FDA, however, does not report (and may not collect) sufficient data to confirm whether the reduction in waivers has affected its access to expertise. The authors critique FDA's focus on financial ties less than 12 months old, implying that grants and contracts that ended shortly before the 1-year window still constitute COIs. In fact, federal rules define a COI in terms of whether the particular matter—e.g., the drug approval—will have a direct and predictable effect on the adviser's financial interest ([ 6 ][7]), regardless of the time frame. Wood and Mador also fail to acknowledge the FDA's impartiality determinations ([ 7 ][8], [ 8 ][9]), which cover noncurrent financial ties. Caps would have value if the system were otherwise flawed, but the FDA's processes are more robust than Wood and Mador acknowledge. Finally, the authors do not address possible indirect effects of the COI waiver cap. The FDA's division directors, who identify most advisory committee experts, might prefer that each meeting avoid surpassing the COI waiver cap. If risk-averse, they might find such a strategy sensible because FDA leadership has stated that it would be better to have no COIs—even though forgoing expert advisers with COIs might leave the FDA with less access to expertise overall ([ 5 ][6]). 1. [↵][10]1. N. Ackerley 2. et al ., Financial Conflict-of-Interest Disclosure and Voting Patterns at FDA Advisory Committee Meetings (Eastern Research Group, Arlington, VA, 2009). 2. [↵][11]1. J. H. Golec, 2. J. C. Cooper, 3. R. Choi , “FDA advisory committees: An empirical examination of conflicts of interest” (Searle Civil Justice Institute, George Mason University, Fairfax, VA, 2013); [www.masonlec.org/research/lec-research][12]. 3. [↵][13]Arthritis Advisory Committee meeting—Dr. Gabriel ([www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM301427.pdf][14]). 4. [↵][15]Endocrinologic and Metabolic Drugs Advisory Committee meeting—Dr. Stanley ([www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM325470.pdf][16]). 5. [↵][17]1. N. Ackerley 2. et al ., “Measuring Conflict of Interest and Expertise on FDA Advisory Committees” (Eastern Research Group, Lexington, MA, 2007); [www.fda.gov/oc/advisory/ergcoireport.pdf][18]. 6. [↵][19]5 CFR § 2640.103 ([www.gpo.gov/fdsys/pkg/CFR-2010-title5-vol3/pdf/CFR-2010-title5-vol3-sec2640-103.pdf][20]). 7. [↵][21]5 CFR § 2635.502 ([www.gpo.gov/fdsys/pkg/CFR-2003-title5-vol3/pdf/CFR-2003-title5-vol3-sec2635-502.pdf][22]). 8. [↵][23]FDA, “Guidance for the public, FDA advisory committee members, and FDA staff on procedures for determining conflict of interest and eligibility for participation in FDA advisory committees” (2008); [www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/LawsRegulationsGuidance/default.htm][24]. [1]: pending:yes [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: #ref-4 [6]: #ref-5 [7]: #ref-6 [8]: #ref-7 [9]: #ref-8 [10]: #xref-ref-1-1 "View reference 1 in text" [11]: #xref-ref-2-1 "View reference 2 in text" [12]: http://www.masonlec.org/research/lec-research [13]: #xref-ref-3-1 "View reference 3 in text" [14]: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM301427.pdf [15]: #xref-ref-4-1 "View reference 4 in text" [16]: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM325470.pdf [17]: #xref-ref-5-1 "View reference 5 in text" [18]: http://www.fda.gov/oc/advisory/ergcoireport.pdf [19]: #xref-ref-6-1 "View reference 6 in text" [20]: http://www.gpo.gov/fdsys/pkg/CFR-2010-title5-vol3/pdf/CFR-2010-title5-vol3-sec2640-103.pdf [21]: #xref-ref-7-1 "View reference 7 in text" [22]: http://www.gpo.gov/fdsys/pkg/CFR-2003-title5-vol3/pdf/CFR-2003-title5-vol3-sec2635-502.pdf [23]: #xref-ref-8-1 "View reference 8 in text" [24]: http://www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/LawsRegulationsGuidance/default.htm

The legislative history of the United States Orphan Drug Act began with rare, unanimous approval by the United States Congress. The Act, mid consequently the Regulations, have evolved since then. The two-stage process of Orphan Drug designation and approval is outlined, as well as the incentives that are offered to commercial companies for their implementation. Orphan Drugs are likely to be over-represented among drugs used under "Treatment" INDs. For patent- and "drug-difference" reasons, the benefits under the Orphan Drug Act are especially valuable to those who develop biologics. By any measure, this legislation, which requires only voluntary participation, has been a success; because the human genome is likely to lead to more biologicals than orthodox drugs, this success is likely to continue into the future. But even so, the 18-year experience with Orphan Drugs in the United States has led to some 225 Orphan Product approvals that benefit many millions of patients.

FDA in 2008 approved the marketing of an assortment of 34 unique new molecular entities, vaccines, imaging agents, and blood products—5 more than the previous year’s total. A brief synopsis of several product approvals is provided below. A full listing of products approved in 2008 and their