Public research funding and pharmaceutical prices: do Americans pay twice for drugs?

In the debate over prescription drug pricing, some pharmaceutical industry critics claim that U.S. taxpayers pay twice for costly therapies, because publicly supported research is a major contributor to drug discovery and American taxpayers are inadequately rewarded for their research investment due to high drug prices. In fact, the empirical evidence supporting these claims is weak, and the pay twice argument distracts from important efforts to ensure that impactful new drugs continue to be developed and made widely available to patients who need them.

Results of a portfolio approach to intramural research funding at an academic medical center.

In response to stagnant Federal grant funding levels and to catalyze early stage or high-risk research not currently supported by the NIH, many academic medical centers (AMCs) provide supplemental intramural funding to faculty investigators. However, it can be challenging to decide how to deploy these funds for maximum impact. We conducted a retrospective, descriptive analysis to explore trends in applications and awards associated with an institution-wide intramural funding center at a major U.S. AMC. From 2010 to 2017, the Brigham Research Institute at Brigham and Women's Hospital awarded a total of 354 grants totaling over $9 million to affiliated researchers through six distinct and complementary grant programs. The number of applicants remained essentially stable, despite expansion of the funding program portfolio. Distribution of applicants and awardees by academic rank and gender generally reflected that of medical school faculty at large. This descriptive analysis demonstrates interest in a diverse range of intramural funding programs among AMC faculty, and a lack of overt rank or gender bias in the programs' awardees. However, it highlights the institution's need to better understand the amount of residual unmet demand for intramural funding; the degree to which underrepresented constituencies can and should be actively supported; and the "return on investment" of these grants.

How to prevent the next Marathon Pharmaceuticals.

In recent years, several drug companies have exploited U.S. regulatory policies to acquire exclusive rights to cheap therapies and substantially raise their prices, and Federal agencies and state governments are exploring various ways to prevent or punish such behavior in the future. Among these cases, however, Marathon Pharmaceuticals' handling of Emflaza (deflazacort) is unique, because the drug was previously only available abroad, and was never previously sold in the U.S. before the company obtained FDA approval for it. Thus, laws and policies designed to address price hikes on already-marketed drugs are unlikely to prevent additional Marathon-like scenarios. In this article, we describe in more detail the unique features of Emflaza compared with these other recent cases of drug price increases, determine the likelihood that similar situations will arise in the future, and explore legislative and administrative options to specifically prevent such behavior.

Assessing the potential clinical impact of reciprocal drug approval legislation on access to novel therapeutics in the USA: a cohort study.

OBJECTIVE: To quantify the potential effect of reciprocal approval legislation on access to clinically impactful therapeutics in the USA. DESIGN: A cohort study. SETTING: New therapeutics approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA) and/or Health Canada between 2000 and 2010. MAIN OUTCOME MEASURES: Characteristics of new therapeutics approved by the EMA and/or Health Canada before the FDA, including mechanistic novelty, likely clinical impact, size of the affected population and FDA review outcome. RESULTS: From 2001 to 2010, 282 drugs were approved in the USA, Europe or Canada, including 172 (61%) first approved in the USA, 24 (9%) never approved in the USA, and 86 (30%) approved in the USA after Europe and/or Canada. Of the 110 new drugs approved in Europe and/or Canada before the USA, 37 (34%) had a novel mechanisms of action compared with drugs already approved by the FDA, but only 10 (9%) were for conditions lacking alternate available therapies in the USA at the time of ex-US approval-of which the majority (9/10; 90%) were indicated for rare diseases. 12 of the 37 agents with novel mechanisms of action approved first in Europe and/or Canada (32%) had their initial FDA submissions rejected for safety reasons-including 2 drugs that were ultimately withdrawn from the market in Europe due to safety concerns. CONCLUSIONS: If enacted, reciprocal approval legislation would most likely benefit only a small number of US patients receiving treatment for rare diseases, and the benefit may be somewhat mitigated by an increased exposure to harms.

From innovation to market adoption in the operating room: The "CFO as customer".

Dr Egeland is senior director of business development and licensing in the Early Technologies business unit of the Minimally Invasive Therapies Group at Medtronic. Mr Rapp is an associate consultant at Pharmagellan, a biotech consultancy. Dr David is the founder and managing director of Pharmagellan.

Regulation of kidney development by Shp2: an unbiased stereological analysis.

Genes that regulate renal branching morphogenesis are likely to indirectly regulate nephron endowment, but few have been validated to do so in vivo. PTPN11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, acts downstream of receptor tyrosine kinases to modulate the Ras-MAPK pathway and has been implicated in branching morphogenesis in vitro and in invertebrates, and is therefore a candidate in vivo regulator of nephron number. In this work, heterozygous null mutant Shp2(+/-) mice at postnatal days 30-35 were compared with their wild-type (WT) littermates using unbiased stereology to determine if, indeed, the former had decreased nephron number due to their 50% decrease in gene/protein dosage. Although there was a trend toward decreases in total glomerular (nephron) number and kidney volume in Shp2(+/-) mice compared with WT, neither difference was statistically significant (11310 vs. 12198 glomeruli, P = 0.22; 62.8 mm(3) vs. 66.0 mm(3) renal volume; P = 0.40). We conclude that loss of 50% gene/protein dosage of PTPN11/Shp2 is insufficient to affect glomerular (and thereby nephron) number in mouse kidneys in vivo.

Authors' Submission Toolkit: a practical guide to getting your research published.

Biomedical journals and the pharmaceutical industry share the goals of enhancing transparency and expanding access to peer-reviewed research; both industries have recently instituted new policies and guidelines to effect this change. However, while increasing transparency may elevate standards and bring benefits to readers, it will drive a significant increase in manuscript volume, posing challenges to both the journals and industry sponsors. As a result, there is a need to: (1) increase efficiency in the submission process to accommodate the rising manuscript volume and reduce the resource demands on journals, peer reviewers, and authors; and (2) identify suitable venues to publish this research. These shared goals can only be accomplished through close collaboration among stakeholders in the process.In an effort to foster mutual collaboration, members of the pharmaceutical industry and the International Society for Medical Publication Professionals founded a unique collaborative venture in 2008 - the Medical Publishing Insights and Practices initiative (MPIP). At an MPIP roundtable meeting in September 2009,journal editors, publishers and industry representatives identified and prioritized opportunities to streamline the submission process and requirements, and to support prompt publication and dissemination of clinical trial results in the face of increasing manuscript volume. Journal and sponsor participants agreed that more author education on manuscript preparation and submission was needed to increase efficiency and enhance quality and transparency in the publication of industry-sponsored research. They suggested an authors'guide to help bridge the gap between author practices and editor expectations.To address this unmet educational need, MPIP supported development of an Authors' Submission Toolkit to compile best practices in the preparation and submission of manuscripts describing sponsored research.The Toolkit represents a unique collaboration between the pharmaceutical industry and biomedical journals,and reflects both groups' perspectives on how authors can help raise standards and increase efficiency in publishing industry-sponsored studies. The information provided in the toolkit can be useful to help authors navigate the manuscript

Displacement of the {beta} cytoplasmic domain recovers focal adhesion formation, cytoskeletal organization and motility in swapped integrin chimeras.

Integrin-mediated ;outside-in' signaling requires the transmission of a conformational change from the extracellular domains to the cytoplasmic domains. Although one component of this conformational change is the separation of the alpha and beta cytoplasmic domains, it is not clear how this separation could result in the initiation of downstream signals necessary for focal adhesion (FA) formation. To address this question, we used a swapped integrin heterodimer, in which the extracellular domains of the alpha and beta chains were attached to their opposing transmembrane and cytoplasmic domains. This receptor was able to bind ligand normally, but could not promote FA formation. We then displaced the beta cytoplasmic domain with either a duplication of its membrane-proximal region or an unrelated alpha-helical spacer. This displacement partially restored FA formation in these swapped receptors and rescued other aspects of integrin-mediated signaling, including cytoskeletal organization, motility and several tyrosine-phosphorylation-dependent signals. We suggest that separation of the cytoplasmic domains leads to alteration of the secondary structure of the distal beta tail, which initiates downstream signals leading to cytoskeletal reorganization.

PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.

Multiple lentigines/LEOPARD syndrome (LS) is a rare, autosomal dominant disorder characterized by Lentigines, Electrocardiogram abnormalities, Ocular hypertelorism, Pulmonic valvular stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. Like the more common Noonan syndrome (NS), LS is caused by germ line missense mutations in PTPN11, encoding the protein-tyrosine phosphatase Shp2. Enzymologic, structural, cell biological, and mouse genetic studies indicate that NS is caused by gain-of-function PTPN11 mutations. Because NS and LS share several features, LS has been viewed as an NS variant. We examined a panel of LS mutants, including the two most common alleles. Surprisingly, we found that in marked contrast to NS, LS mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-mitogen-activated protein kinase-mediated signaling. Molecular modeling and biochemical studies suggest that LS mutations contort the Shp2 catalytic domain and result in open, inactive forms of Shp2. Our results establish that the pathogenesis of LS and NS is distinct and suggest that these disorders should be distinguished by mutational analysis rather than clinical presentation.

Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes.

Mutations in the Src homology 2 (SH2)-containing protein-tyrosine phosphatase Shp2 (PTPN11) underlie half of the cases of the autosomal dominant genetic disorder Noonan syndrome, and somatic Shp2 mutations are found in several hematologic and solid malignancies. Earlier studies of small numbers of mutants suggested that disease-associated mutations cause constitutive (SH2 binding-independent) activation and that cancer-associated mutants are more active than those associated with Noonan syndrome. We have characterized a larger panel of Shp2 mutants and find that this "activity-centric" model cannot explain the behaviors of all pathogenic Shp2 mutations. Instead, enzymatic, structural, and mathematical modeling analyses show that these mutants can affect basal activation, SH2 domain-phosphopeptide affinity, and/or substrate specificity to varying degrees. Furthermore, there is no absolute correlation between the mutants' extents of basal activation and the diseases they induce. We propose that activated mutants of Shp2 modulate signaling from specific stimuli to a subset of effectors and provide a theoretical framework for understanding the complex relationship between Shp2 activation, intracellular signaling, and pathology.

Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia.

The SH2 domain-containing protein-tyrosine phosphatase PTPN11 (Shp2) is required for normal development and is an essential component of signaling pathways initiated by growth factors, cytokines, and extracellular matrix. In many of these pathways, Shp2 acts upstream of Ras. About 50% of patients with Noonan syndrome have germ-line PTPN11 gain of function mutations. Associations between Noonan syndrome and an increased risk of some malignancies, notably leukemia and neuroblastoma, have been reported, and recent data indicate that somatic PTPN11 mutations occur in children with sporadic juvenile myelomonocytic leukemia, myelodysplasic syndrome, B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia (AML). Juvenile myelomonocytic leukemia patients without PTPN11 mutations have either homozygotic NF-1 deletion or activating RAS mutations. Given the role of Shp2 in Ras activation and the frequent mutation of RAS in human tumors, these data raise the possibility that PTPN11 mutations play a broader role in cancer. We asked whether PTPN11 mutations occur in other malignancies in which activating RAS mutations occur at low but significant frequency. Sequencing of PTPN11 from 13 different human neoplasms including breast, lung, gastric, and neuroblastoma tumors and adult AML and acute lymphoblastic leukemia revealed 11 missense mutations. Five are known mutations predicted to result in an activated form of Shp2, whereas six are new mutations. Biochemical analysis confirmed that several of the new mutations result in increased Shp2 activity. Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy.