Center For The Study Of Drug Development Research Articles

The Unbearable Cost of Drug Development

GEN BiotechnologyVol. 2, No. 2 On the MoneyFree AccessThe Unbearable Cost of Drug DevelopmentAlex PhilippidisAlex PhilippidisE-mail Address: aphilippidis@genengnews.comContributing Editor, GEN BiotechnologySearch for more papers by this authorPublished Online:18 Apr 2023https://doi.org/10.1089/genbio.2023.29089.aphAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Deloitte finds that the average cost of developing a new drug among the top 20 global biopharmas rose 15% in 2022, to ∼$2.3 billion.A pair of recently released studies shine new light on the staggering cost of developing new drugs—an expense that now exceeds $2 billion per therapy on average.In one report, the business services consultancy Deloitte details the growing research-and-development (R&D) expenses that biopharmas often cite to justify the sky-high list prices they charge for new treatments.1 Deloitte found that the average cost of developing a new drug among the top 20 global biopharmas rose 15% ($298 million) in 2022 to ∼$2.3 billion.That figure includes the average cost of developing a candidate from discovery through clinical trials to the market. Deloitte counted 278 late-stage assets last year (a slight increase on 273 in 2021), the lowest year-over-year increase since 2018—with companies ranging for 4 to 35 late-stage assets—defined as both approved and terminated assets in Phase II with breakthrough therapy designation, in Phase III or filed.R&D expenses per asset remain slightly below the ∼$2.5 billion peak reported by Deloitte in 2019, before the onset of COVID-19. The pandemic led to lower R&D per-asset costs as developers expedited an array of vaccines and drug candidates against the virus to market in just months. Total R&D spending by the top 20 biopharmas stayed relatively flat, dipping 1% from $141 billion to $139.2 billion—but still 63% above the $85.5 billion calculated in 2013.Worse for drug developers, the return on investment reaped by biopharmas for new drugs and vaccines plunged last year by 82% to just 1.2%—the lowest percentage recorded in the 13 years since Deloitte launched its annual reports on biopharma R&D—from 6.8% in 2021 and 10.1% in 2010 (the first year reported by Deloitte).Of course, drug developers have long blamed rising R&D expenses for the escalating prices of new drugs. However, a study by British researchers published recently in the British Medical Journal (BMJ) takes issue with that premise, arguing that drug prices cannot be justified as the product of rising R&D spending.2Aris Angelis, assistant professor in health economics with the department of health services research and policy at the London School of Hygiene and Tropical Medicine (LSHTM).Citing data gathered from the world's 15 largest biopharma giants from public filings between 1999 and 2018, the researchers found that the companies spent an additional 57%—$2.2 trillion—on selling, general, and administrative (SG&A) expenses, compared with $1.4 trillion on R&D.Both the Deloitte and British studies agree, however, that R&D expenses are growing and show no signs of slowing down soon.In the British report, Aris Angelis, assistant professor in health economics at the London School of Hygiene and Tropical Medicine (LSHTM), and colleagues shared one cause of rising drug prices—an industry shift away from blockbuster drugs targeting chronic diseases and sold in high volumes globally to “nichebuster” drugs targeting rare diseases or narrow indications for which higher prices can be charged.In their study, entitled “High drug prices are not justified by industry's spending on research and development,” the researchers cited a June 2022 study published in the Journal of the American Medical Association, which showed the net price of newly launched prescription drugs rocketing from a median price of ∼$1400/year in 2008 to >$150,000/year in 2021.However, in January, Reuters found an even higher median annual price of $193,900 for 17 novel drugs the FDA has approved since July 2022, paced by the $3.5 million list price of CSL's Hemgenix®, the first and only FDA-approved gene therapy for hemophilia B and the most expensive drug ever sold (to date).But Reuters acknowledged the median had fallen from $257,000 in the first half of 2022, thanks to five drugs marketed with five-figure list prices, the lowest being Spectrum Pharmaceuticals' Rolvedon™, an infection-fighting drug in adults with nonmyeloid malignancies, whose price the news agency pegged at $27,000 based on wholesaler information.Peak Sales Forecast DeclineKevin Dondarski, partner, Life Sciences Strategy with Deloitte Consulting, says the rise in Pharma R&D costs reflects increasing expenses aggravated by inflation, as well as diminishing returns as candidates advance from trials to market.According to Deloitte, the amount of money a pipeline drug is expected to generate annually (average forecast peak sales per pipeline asset) fell 22% last year to $389 million from $500 million in 2021.Deloitte said the sales forecast declines reflected several new costly or “high-value” drugs advancing from pipeline to market over the past year. The firm did not name any examples, but they would include drugs such as the controversial Biogen/Eisai Alzheimer's disease drug Aduhelm® (aducanumab), which was approved in 2021. (Aduhelm generated only $4.8 million last year; its sales were hobbled after the Centers for Medicare and Medicaid Services [CMS] limited coverage of that and other amyloid-beta targeting Alzheimer's disease therapies receiving accelerated approval to those in FDA- of NIH-approved clinical trials.)Growing competition among drugs in a relatively small number of therapeutic areas means lower sales per treatment and helps explain the drop, Dondarski said. “There's certainly more of a larger emphasis on therapeutic areas like oncology and orphan and rare diseases,” he said.Another factor is the growing number of challenges faced by drug developers in expanding access to newer drugs by pursuing reimbursements—where they clash with insurers loathe to pay for costly treatments whose benefit to patients they deem marginal at best.When COVID-19 drugs and vaccines granted emergency use approval (EUA) were excluded, the average peak sales forecasts fell 16% in 2022 to $284 million (from $340 million/year earlier). Although COVID-19 vaccines and drugs sped to market, those products took resources away from other candidates outside of those aimed at preventing or treating SARS-CoV-2.“If we had to take away a positive from how R&D was impacted during COVID, it's that it did force the adoption of some new capabilities and approaches that had been discussed in and explored throughout the industry for years—everything from remote trials to new ways of engaging patients and investigators, and so forth. That was a real positive,” Dondarski said.“The big challenge for the industry now is to ensure that those types of things become, to use a cliche, the new normal and not really an exception,” he added. “Companies haven't forgotten about those things. But the speed at which they're scaling those across their holistic portfolios could probably be accelerated.”Kevin Dondarski, Partner, Life Sciences Strategy with Deloitte Consulting.11% Below HighDeloitte's study—entitled “Seize the digital momentum: Measuring the return from pharmaceutical innovation 2022”—is the latest in a series of annual reports focused on “Measuring the return from pharmaceutical innovation,” produced by the firm's Deloitte Centre for Health Solutions.The $2.28 billion in average per-asset R&D cost reported by Deloitte is 11% below the all-time reported high for drug R&D costs. A 2014 study by the Tufts Center for the Study of Drug Development (CSDD) found that the cost of developing and winning marketing approvals for a new drug had more than doubled in a decade, rocketing to a record-high $2.56 billion in 2013 ($3.32 billion in today's dollars). That figure marked a steep increase in a decade, when a 2003 Tufts study pegged the cost at $802 million ($1.32 billion in 2023 dollars). This figure was memorialized by Modern Healthcare editor emeritus Merrill Goozner in his 2005 book The $800 Million Pill.In a follow-up 2015 study, drug developers told Tufts CSDD they would cut development costs by improving R&D management and operations. By then, pharma giants had begun reducing R&D spending; a GEN report calculated the combined R&D spending by the top 20 biopharmas as growing just 4% year-over-year, from $88.64 billion in 2013 to $92.26 billion in 2014.3“It's no longer reasonable for large pharma companies to try to maintain the capabilities to bring compounds from the laboratory bench all the way to the marketplace. It's too expensive. It's too difficult to justify the upfront cost, and it's just not a formula for success,” Kenneth I Kaitin, who retired in December 2020 as director of Tufts CSDD, told GEN back in 2015.The difference between the Tufts and Deloitte figures reflects differences in methodology. Tufts studied data on clinical phase expenditures and development phase times for a randomly selected sample of drug candidates of 10 firms that participated in its survey. Deloitte's figure includes the average cost of developing a candidate from discovery through clinical trials to the market for the top 20 global biopharmas.From Blockbusters to “Nichebusters”The soaring cost of drugs drew public attention earlier this year when Vertex Pharmaceuticals slashed its annual copay assistance for cystic fibrosis drugs, which in the case of Orkambi® (lumacaftor/ivacaftor) was lowered 80%, from ∼$100,000 a year to $20,000. (Orkambi has a list price of $286,000.)Vertex is at odds with health insurers and pharmacy benefits managers, which are limiting the amount of copay assistance patients can apply through “accumulator” tools. Vertex has attacked the accumulators as predatory, while a national insurer group America's Health Insurance Plans (AHIP) has denounced copay programs as “just one more big pharma scheme to price gouge patients.”According to the BMJ study, most new drugs entering the market have provided little or no added clinical value—a conclusion they based on analyses of drug evaluation reports by health technology assessment bodies in France and Germany in the 2010s.To address these issues, Angelis and colleagues argue that governments need to press biopharmas into redeploying existing resources to generate more new and innovative treatments.“There should be no need to pass research and development costs on to patients and healthcare systems through ever higher and increasingly unaffordable prices,” the researchers assert. “This is unlikely to happen, however, without government intervention or regulation along the lifecycle of new medicines,” they write.At least one industry group also sees government intervention as an answer to rising drug prices, but in a different way. Pharmaceutical Research and Manufacturers of America (PhRMA)4 last year restated its long-standing call for policymakers to instead lower patient costs by curbing the pricing power of insurers and pharmacy benefit managers (PBMs).Through their industry group, the Pharmaceutical Care Management Association (PCMA), the PBMs in turn have long blamed drug developers for rising prices of therapies. Earlier this year, PCMA endorsed the Affordable Prescriptions for Patients Act of 2023 (S. 150), introduced on January 30 by U.S. Senators Richard Blumenthal (D-CT) and John Cornyn (R-TX). The measure would ban biopharmas from blocking generic and biosimilar versions of prescription drugs through patent law, by limiting the number of patents a manufacturer can contest to prevent “patent thickets.” The legislation would also end the right of drug developers from shifting or “hopping” patents from older to newer versions of products.Angelis and colleagues also noted the findings of a 2022 study by the U.S. House Committee on Oversight and Reform, which found that 14 of the largest pharma companies spent 11% more on stock buybacks and dividends ($577 billion) than R&D ($521 billion) between 2016 and 2020.The stock buybacks were not counted within SG&A, which includes rent and utilities, marketing and advertising, sales and accounting, and management and administrative salaries. Between 1999 and 2018, SG&A expenses for the top 15 biopharmas as a share of revenue dropped from 35% to 27%, whereas R&D spending rose from 16% to 21%.“Given the amount spent on non-R&D activities and that most new drugs add little or no therapeutic value, in theory the biopharmaceutical industry could generate more medically valuable innovation with its existing resources,” Angelis and colleagues concluded. “We need to foster the development of therapeutically superior drugs that can enhance patient outcomes. This may require a shift of more resources from [SG&A] to R&D activities and companies to prioritize disease areas with clinical unmet needs.”“Governments, policy makers, drug regulators, health technology assessment bodies, and payers need to re-think the incentives for valuable biopharmaceutical innovation, creating policy and regulatory environments that will meet public health objectives,” Angelis and colleagues added. “The world needs a truly value based health-industrial ecosystem focused on incentivizing and rewarding improvements in health outcomes and population health throughout the lifecycle of new medicines.”This story was originally published by GEN (www.genengnews.com).

Assessing Biopharmaceutical Company Experience with Patient-centric Initiatives

PurposeA growing number of biopharmaceutical companies have been implementing patient-centric initiatives (PCIs). The Drug Information Association (DIA) and the Tufts Center for the Study of Drug Development (CSDD) collaborated on a study to gather data on the usage and impact of these PCIs to characterize company experience and impact. MethodsDIA and Tufts CSDD collaborated with 17 organizations to define PCIs used in clinical research and development and to quantify their use, and to define metrics in use to document impact and return on engagement (ROE) for these PCIs. The study used a mixed methods approach that consisted of an online survey, in-depth interviews, and literature review. FindingsTwenty-two unique companies responded to an on-line survey on the use of 23 PCIs identified by the study working group. PCIs most frequently implemented included patient organization landscape analysis, support of patient advocacy groups, use of patient advisory boards, and use of home nursing networks. Seven additional PCIs were found through a literature search and included in the group of PCIs for which impact measures were assessed. A total of 121 cases of use of the 30 PCIs and associated impact measures and impact data were gathered through literature review, in-depth interviews with the study companies, and in-depth interviews with organizations identified in the literature as having experience with patient engagement in clinical research as well as with patients who had participated in clinical trials. Analysis of the 121 case studies resulted in a list of 666 measures of impact (metrics) in use for 13 of the PCIs. Assessment of overall ROE for these PCIs found that PCIs such as support of patient advocacy groups and use of patient advisory boards indicated the greatest ROE, whereas costlier, more complex PCIs such as digital medicine and gaming indicated relatively low ROE. ImplicationsActivity around PCIs among the companies studied was widespread, with initiatives more frequently planned and piloted than implemented at the time of this study. Measures of impact have been identified and can be used to assess ROE, providing insights to facilitate the adoption of PCIs of highest impact for patients and biopharmaceutical research organizations.

A Study on the Application and Use of Artificial Intelligence to Support Drug Development

PurposeThe Tufts Center for the Study of Drug Development (CSDD) and the Drug Information Association (DIA) in collaboration with 8 pharmaceutical and biotechnology companies conducted a study examining the adoption and effect of artificial intelligence (AI), such as machine learning, on drug development. The study was conducted to clarify and understand AI adoption across the industry and to gather detailed insights into the spectrum of activities included in the definition of AI. The study investigated and identified analytical platforms and innovations across pharmaceutical and biotechnology companies currently being used or planned for in the future. MethodsA 2-part method was used that comprised in-depth interviews with AI industry experts and a global survey conducted across pharmaceutical and biotechnology organizations. Eleven in-depth interviews focused on use and implementation of AI across drug development. The survey assessed use of AI and included perceptions about current and future use. The survey also examined technology definitions, assessment of organizational and personal AI expertise, and use of partnerships. A total of 402 responses, including data from 217 unique organizations, were analyzed. FindingsAlthough 7 in 10 respondents reported using AI in some capacity, a wide range of use was reported by AI type. Patient selection and recruitment for clinical studies was the most commonly reported AI activity, with 34 respondents currently using AI for this activity. In addition, identification of medicinal products data gathering was the top activity being piloted or in the planning stages, reported by 49 respondents. The study also revealed that the most significant challenges to AI implementation included staff skills (55%), data structure (52%), and budgets (49%). Nearly 60% of respondents noted planned increases in staff within 1–2 years to support AI use or implementation. ImplicationsDespite the challenges to AI implementation, the survey revealed that most organizations use AI in some capacity and that it is important to the success of an organization's workforce. Many organizations reported expectations for increasing staff as implementation of AI expands. Further research should examine the changing development landscape as the role of AI evolves.

The Use of Real-World Evidence and Data in Clinical Research and Postapproval Safety Studies.

The adoption and use of real-world evidence (RWE) is becoming increasingly important to drug development and patient safety. The Tufts Center for the Study of Drug Development (CSDD) conducted a benchmark survey of pharmaceutical and biotechnology companies and contract research organizations in a number of areas that support real-world data (RWD) and evidence, including operations and performance areas. Data were gathered on organizational functions, staff, roles and responsibilities, and skill sets required. Also, current and future allocation of budgets and spending were examined as well as return on investment measures. A total of 30 unique companies responded to the survey. Nearly all respondents (29/30 companies) reported that their organizations had an RWE function and most companies indicated that their RWE functions were increasing in size (21 companies). From a postapproval regulatory and labeling perspective, there were two primary areas for company use of RWD to generate evidence: one for postapproval safety studies, including decreasing the severity of a label warning or to support risk evaluation and mitigation strategies (REMS) (12/22 companies; 55%), which allows for real-world patient population data to inform safety decisions; and the other for postmarketing studies (13/23 companies; 57%). Developing greater insight into therapeutic area needs, gaining market access, and greater understanding of drug effectiveness were the top measures identified for return on investment for use of RWE. Expanding the use of RWE in regulatory decision making and increasing uses of real-world data by sponsors will fill the gaps that are critically needed for drug development and safety.

Assessing Study Start-up Practices, Performance, and Perceptions Among Sponsors and Contract Research Organizations.

Site identification, site selection, and study start-up have become the focus of improvement by organizations conducting clinical trials. To examine and measure the process from site identification through site activation, Tufts Center for the Study of Drug Development (CSDD) conducted a comprehensive survey among pharmaceutical organizations, biotech companies, and contract research organizations (CROs). Responses from over 400 unique companies were gathered and analyzed. The results indicate that the start-up process is on average 5 to 6 months in total duration, and cycle times across all activities, including site identification, site selection, and study start-up, are faster for repeat sites than for new sites. Comparisons between sponsor and CROs indicate that CROs completed all site-related activities 6 to 11 weeks faster than sponsors. Other areas impacting cycle times were examined, including centralized versus decentralized functions, investment in technology, and organizational strategies that improve cycle time efficiency and performance. Tufts CSDD will explore this area in future research to gather additional insights into other factors that may be associated with speed and efficiency.

Drug R&D Costs Take Big Leap

A New Report published by the Tufts Center for the Study of Drug Development (CSDD) pegs the cost of developing a prescription drug that gains market approval at $2.6 billion, a 145% increase, correcting for inflation, over the estimate the center made in 2003. CSDD’s finding, a bellwether figure in the drug industry, is based on an average out-of-pocket cost of $1.4 billion and an estimate of $1.2 billion in returns that investors forgo on that money during the 10-plus years a drug candidate spends in development. The center’s analysis drew from information provided by 10 pharmaceutical companies on 106 randomly selected drugs first tested in humans between 1995 and 2007. The study concludes that another $312 million is spent on postapproval development—studies to test new indications, formulations, and dosage strengths—for a life-cycle cost of $2.9 billion. The steep rise in costs comes despite an intense effort in recent years ...

Innovating by Developing New Uses of Already-Approved Drugs: Trends in the Marketing Approval of Supplemental Indications

BackgroundMuch of the literature on trends and factors affecting biopharmaceutical innovation has focused overwhelmingly on the development and approval of never-before approved drugs and biologics. Little attention has been paid to new uses for already-approved compounds, which can be an important form of innovation. ObjectiveThis paper aimed to determine and analyze recent trends in the number and type of new or modified US indication approvals for drugs and biologics. We also examine regulatory approval-phase times for new-use efficacy supplements and compare them to approval-phase times for original-use approvals over the same period. MethodsWe developed a data set of efficacy supplements approved by the US Food and Drug Administration (FDA) from 1998 to 2011 that includes information on the type, approval-phase time (time from submission to the FDA of an application for marketing approval to approval of the application), and FDA therapeutic-significance rating for the approved application, which we obtained from an FDA Web site. This data set was merged with a Tufts Center for the Study of Drug Development (CSDD) data set of US new drug and biologics approvals. We developed descriptive statistics on trends in the number and type of new-use efficacy supplements, on US regulatory approval-phase times for the supplements, and on original new drug and biologics approvals over the study period and for the time from original- to new-use approval. ResultsThe total number of new-use efficacy-supplement approvals did not exhibit a marked trend, but the number of new pediatric-indication approvals increased substantially. Approval-phase times for new-use supplements varied by therapeutic class and FDA therapeutic-significance rating. Mean approval-phase times were highest for central nervous system compounds (13.8 months) and lowest for antineoplastics (8.9 months). The mean time from original to supplement approval was substantially longer for new pediatric indications than for other new uses. Mean approval-phase time during the study period for applications that received a standard review rating from the FDA was substantially shorter for supplements compared to original uses, but the differences for applications that received a priority review rating from the FDA were negligible. ConclusionsDevelopment of and regulatory approval for new uses of already-approved drugs and biologics is an important source of innovation by biopharmaceutical firms. Despite rising development costs, the output of new-use approvals has remained stable in recent years, driven largely by the pursuit of new pediatric indications. FDA approval-phase times have generally declined substantially for all types of applications since the mid-1990s following legislation that provided a new source of income for the agency. However, while the resources needed to review supplemental applications are likely lower in general than for original-use approvals, the approval-phase times for important new uses are no lower than for important original-use applications.

The Digest/The Wire

Human Gene TherapyVol. 21, No. 2 Free AccessThe Digest/The WirePublished Online:17 Feb 2010https://doi.org/10.1089/hum.2010.2021AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Chaperoning β-thalassemiapage: 149In adult humans, hemoglobin is found as a tetramer consisting of two α and two β subunits that are noncovalently bound. Hemoglobin chain imbalance leads to hemoglobinopathies such as β-thalassemia, wherein deficient or altered synthesis of β-globin causes the intracellular precipitation of excess α-globin chains and ineffective erythropoiesis. There is presently no curative therapy for the most severe form (called β-thalassemia major) other than allogeneic hematopoietic stem cell transplantation. Genetic correction of autologous hematopoietic stem cells has been examined as an attractive alternative to bone marrow transplantation. This approach relieves the need for a compatible donor and eliminates the risks of graft-versus-host disease and graft rejection associated with allogeneic bone marrow transfer. Several groups have shown that transplantation of autologous bone marrow cells transduced with lentiviral vector carrying wild-type β-globin gene results in elevated hemoglobin production and correction of anemia in animal models of β-thalassemia major; this approach is currently undergoing clinical testing in France with another trial soon planned for the United States.1 In this issue of Human Gene Therapy, Wang and colleagues in the laboratory of Dr. Jingzhi Zhang at the Shanghai Institute of Medical Genetics explore an alternative to gene replacement therapy. The authors reason that because β-thalassemia major results from excess α-globin, transfer of a gene encoding a chaperone protein called α-hemoglobin stabilizing protein (AHSP) should neutralize excess α-globin subunits and help to relieve symptoms of β-thalassemia. Using a transgenic approach, Wang and colleagues demonstrate that expression of AHSP partially relieves some of the pathology in affected β-thalassemic mice, including splenomegaly. Although the strategy appears to be less efficient than β-globin gene replacement therapy, this study confirms the importance of AHSP in α-globin synthesis and the development of β-thalassemia. (sk)An Eye for Sendaipage: 199The aspirational goal of in vivo gene therapy is high efficiency and specificity of target cell transduction. One approach to accomplish this is to provide extended residence time for the vector in close proximity to the cell type of interest. The situation is no different for gene therapy approaches in the eye, as was shown in the recent clinical success in the treatment of an inherited blindness named Leber's congenital amaurosis (LCA). In this application, vector is delivered to the subretinal space. The vector solution is deposited between the retinal epithelial layer (RPE) and the neuronal retina by interrupting their interconnectivity and creating a subretinal space. This elevation of the retina created by the procedure dissipates gradually in the first 24 hours after injection. The two flanking cell types of the subretinal space, the RPE and the photoreceptors, are both relevant targets for gene therapy.In this issue of Human Gene Therapy, Murakami and colleagues tackle the concern that prolonged subretinal detachment due to the presence of the vector volume delivered by subretinal injection may be harmful. Indeed, there has been some indication that retinal thinning occurs after this procedure, but overall the procedure is deemed safe. The concern remains, however, that the procedure leads to the neuronal retina being deprived of trophic and metabolic factors provided by the RPE and choroid. The authors, however, acknowledge the necessity to bring vector and target into close proximity in order to achieve high-level functional transduction. With this as their main objective, they evaluate pseudotypes of lentivirus-based vectors in in vitro and in vivo models of RPE transduction.The data indicate that the Sendai pseudotype achieves similar levels of transduction when vector is removed shortly after inoculation versus when it is left on the cells. Their interesting approach in vivo allows, with residence time of only 5 minutes, the achievement of functionally significant levels of transduction, after which vector is aspirated and the subretinal space is collapsed. The authors demonstrate the efficacy of this optimized procedure in a laser-induced choroidal neovascularization murine model for age-related macular degeneration by gene transfer of the antiangiogenic factors soluble Fms-like tyrosine kinase-1 (sFlt-1) and human pigment epithelium-derived factor. (lhv)141Regulatory wireOrphan Drug Designations SoarA new study conducted by the Tufts Center for the Study of Drug Development (CSDD) reports that the number of orphan product designations in the United States has more than doubled during the last decade, reflecting growing interest by pharmaceutical and biotech companies in developing products to treat orphan diseases.1The U.S. Orphan Drug Act of 1983 was passed with the objective of encouraging pharmaceutical companies to develop drugs for diseases that have a small market. Officially, the Act defines an orphan disease as one with a prevalence rate of fewer than 200,000 individuals in the United States (see inset). The National Institutes of Health estimates that there are more than 7000 orphan diseases affecting approximately 25 million people in the United States. Under the law, companies that develop an orphan drug may sell it without competition for 7 years, and may get clinical trial tax incentives among other benefits. Market exclusivity under the Act, however, differs from that of a traditional product or process patent in several ways. Coverage is narrower than with a patent; it applies only to orphan drug use for the rare disease for which it was approved. During the 7-year-period of market exclusivity, a second sponsor could apply for, and receive, market approval for the exact same drug for any other use (i.e., use other than treatment of the initially approved rare disease), including the treatment of a different rare disease. Furthermore, unlike a patent, the “exclusivity” granted a manufacturer is limited by the Act if the original sponsor is unable to meet the demand for the drug, decides to cease drug production, or consents to “shared exclusivity” with another supplier. In these circumstances, the Secretary of the Department of Health and Human Services may permit a second company to market the nonpatented orphan drug to ensure a continuous, adequate supply of necessary medications.2According to the CSDD report, since 1983 more than 2000 products in development have been designated as orphan drugs, with the U.S. Food and Drug Administration (FDA) granting market approval to 350 drugs and biologics. Before 1983 fewer than 10 such orphan drug products were on the market. Over the last decade, orphan products comprised 22% of all new molecular entities (NMEs) and 31% of all significant biologics (SBs) receiving U.S. marketing approval. The CSDD report notes that orphan drug developers had a higher rate of clinical approval compared with mainstream drug makers, with 22 and 16% success rates, respectively. Among the orphan products that have been developed since 1983 are drugs for glioma, multiple myeloma, cystic fibrosis, and phenylketonuria. Dr. Christopher-Paul Milne, Associate Director of the CSDD, commented in a press release that “the Orphan Drug Act, without question, can be considered a success. It has been emulated throughout the world, and today Japan and Europe have similar programs, while Singapore and Australia give special allowance for the importation and marketing approval of orphan products approved in the U.S.”Yet, some critics have questioned whether orphan drug legislation was the real cause of the increase in orphan disease treatments (claiming that many of the new drugs were for disorders that were already being researched anyway, and would have had drugs developed regardless of the legislation), and whether the Orphan Drug Act has really stimulated the production of truly nonprofitable drugs. The Act has also received some criticism for allowing some pharmaceutical companies to make a large profit off drugs that have a small market but still sell for a high price.3,4Regardless of these criticisms, the global orphan drug market continues to grow and is expected to reach $81.8 billion by 2011. Biologics account for more than 60% of the orphan drug market and are expected to reach annual sales of $53.4 billion by 2011.5 (sk)What Is an Orphan Disease?There is no universal definition for what constitutes an orphan disease. The term has been used to describe diseases that are neglected by doctors (e.g., Fabry's disease, alveolar echinococcosis, etc.) or, more commonly, the term orphan disease is used to designate diseases that affect only small numbers of individuals (health orphans).In the United States, an orphan disease is officially defined as one with a prevalence of fewer than 200,000 individuals, but in Japan the number is 50,000 and in Australia it is 2000. In the European Union (EU), an orphan disease is one that affects fewer than 5 people per 10,000 and includes some neglected tropical diseases that are found primarily in developing nations. The EU legislation, administered by the Committee for Orphan Medicinal Products of the European Medicines Agency (EMEA), grants 10 years of market exclusivity. In an effort to reduce the burden on manufacturers applying for orphan drug status, the FDA and EMEA agreed in late 2007 to use a common application process for both agencies. However, the two agencies continue to maintain separate approval processes. There are also lists of diseases, mostly genetic disorders, that are regarded as rare. As a group they have nothing in common apart from their rarity, but the lists vary strikingly in length; for example, that published by the U.S. National Organization for Rare Disorders contains about 1200 items, whereas the Office of Rare Diseases of the NIH publishes a list of more than 6000, and the EMEA list includes 1127 conditions ranging from Aagenaes syndrome to zygomycosis. (sk)142Science wireDeep Exome Sequences Pin Down Mendelian DisorderIn a proof-of-concept tour de force, a team from the University of Washington in Seattle, Washington was the first to identify the previously unidentified genetic basis for an inherited disorder through whole-exome sequencing.1 The interesting aspect of the study was the design of the approach. They focused sequencing on the coding regions that make up a mere 1% of the whole genome. The execution of the approach to identify genes underlying mendelian disorders, however, required a sophisticated analysis of sequential steps to filter variants and identify which is responsible for the disease phenotype.Four DNA samples from individuals with the rare Miller syndrome were sequenced. Postaxial acrofacial dysostosis, by which the malformation syndrome is also known, manifests itself in anomalies that include severe micrognathia, cleft lip and/or palate, and absent digits among others. It is hoped that this team's finding and the innovative technique used will not only improve diagnosis, but also lead to the faster identification of the genetic signatures of other disorders and conditions and open the door for novel disease targets for gene therapy. (lhv)Industry wireArk Therapeutics, the United Kingdom-based biotech firm with a focus on gene therapies, received a regulatory setback in the approval process for Cerepro, a human adenovirus serotype 5 (hAd5) vector expressing herpes simplex virus thymidine kinase (HSV TK), for the treatment of malignant glioma. In a notice from the European Medicines Agency (EMEA), a rejection from the Committee for Medicinal Products for Human Use (CHMP) stated concerns about the integrity of the Cerepro clinical trial, which in turn brought into doubt the efficacy of the drug relative to existing therapies. Ark Therapeutics has filed an appeal of the decision with the EMEA and is providing additional data about the phase III study in question.Crucell, the Dutch vaccine company, entered a research agreement with the Southwest Foundation for Biomedical Research in San Antonio, Texas. The goal of the collaborative agreement is to test and develop multivalent vaccines against Ebola and Marburg virus in high-level biocontainment animal facilities. The vaccine effort by Crucell is funded by a $30 million dollar grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.Genetix Pharmaceuticals, located in Cambridge, Massachusetts, announced its intent to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration, as well as to expand its European trial on lentiviral gene therapy for the treatment of adrenoleukodystrophy, following the promising human trial results from their French collaborators Drs. Patrick Aubourg and Nathalie Cartier of INSERM.GenVec and Novartis signed a licensing deal in which GenVec received a $5 million dollar up-front payment in anticipation of potential future milestone payments. The collaboration explores novel treatments for hearing loss and balance disorders with the GenVec adenoviral platform. Novartis also purchased approximately $2 million dollars' worth of GenVec common stock.Oxford BioMedica has received a designation for orphan drug status for its gene therapy treatment in development for Stargardt disease, resulting in 10 years of marketing exclusivity and reduced regulatory fees. StarGen's clinical development is announced to start in 2010, in collaboration with Sanofi-Aventis. (lhv)FiguresReferencesRelatedDetails Volume 21Issue 2Feb 2010 InformationCopyright 2010, Mary Ann Liebert, Inc.To cite this article:The Digest/The Wire.Human Gene Therapy.Feb 2010.140-142.http://doi.org/10.1089/hum.2010.2021Published in Volume: 21 Issue 2: February 17, 2010PDF download

Policy Punctuations and Regulatory Drug Review

The FDA has dramatically decreased the regulatory review time for new drugs since the early 1990s. For example, according to the Tufts University Center for the Study of Drug Development (CSDD), which conducts triennial analyses of new drug approvals in the United States, the average FDA review time for approved New Chemical Entities (NCEs) decreased from 35.6 months in 1984–86 to 16.8 months in 1996–98. Thus, in a little more than a decade, the FDA has essentially cut its average review time in half. In addition to the declining review times, the agency's workload, as measured in terms of the number of drugs approved each year, also rose considerably in the 1990s. Specifically, the agency approved a total of 232 NCEs between 1993 and 1999, compared to just 163 approvals during the previous seven-year span—a 42 percent increase. Figures 1 and 2 illustrate the agency's decreased review times and increased workload, respectively. Thus, over the past decade the FDA has approved more drugs and done so in less time than at any other period in history. Simply stated, this change in regulatory performance, especially the declining review times, has been absolutely stunning.

The New Drug Approvals of 1996, 1997, and 1998: Drug Development Trends in the User Fee Era

This is the fifth in a series of triennial reports by the Tufts Center for the Study of Drug Development (CSDD) examining various aspects of recent new drug approvals in the United States. In 1996, 1997, and 1998 the United States Food and Drug Administration (FDA) approved 122 new drugs, 110 of which met Tufts CSDD’s definition of a new chemical entity (NCE). Of the 110, 38 (35%) received priority review, while 72 (65%) had standard review. The mean length of the clinical phase (investigational new drug application [IND] filing to new drug application [NDA] submission) was 70.3 months (ie, 5.9 years), and the approval phase (NDA submission to approval) was 16.8 months (1.4 years). Both the clinical and approval phases represent decreases from those values for the previous three-year period (19% and 31%, respectively). The decrease in the clinical phase for the 1996 to 1998 NCEs represents the first such decline since the mid-1980s. The mean approval phase for priority NCEs (11.8 months) was 38% shorter than that for standard NCEs (19.5 months). Of the 107 NCEs for which foreign marketing data were available, 49% were first approved for marketing in the United States, while 26% were available in foreign markets one or more years prior to United States approval, with a mean of 5.7 years of prior foreign marketing. The percent of products first available in the United States represents a considerable increase over that number for previous years.

A New Look At United States Drug Development and Approval Times.

Clinical development and regulatory approval times for new chemical entities (NCEs) approved in the United States through 1995 were analyzed by both year of new drug application (NDA) approval and year of NDA submission. Results and conclusions from a recent General Accounting Office (GAO) report on US new drug approval times by year of NDA submission for NDAs submitted during 1987 to 1992 were examined and the analysis was extended using data collected by the Tufts Center for the Study of Drug Development (CSDD). The hypothesis that approval times declined by year of NDA submission for 1987 to 1992 submissions, independent of such factors as the therapeutic type and significance of the drugs reviewed, is not supported by the evidence. Mean times from first testing in humans, investigational new drug application (IND) filing, and initiation of Phase III testing to NDA submission increased over time for NCEs by period of NDA submission. When analyzed by year of approval, mean approval times for the 1994 and 1995 NCE approvals were markedly lower than mean approval times for previous years (1.7 y for 1994--1995 compared to 2.7 years for 1990--1993). Mean time from IND filing to NDA submission, however, was notably longer for the 1994 and 1995 approvals than for approvals in earlier years (7.2 y for 1994--1995 compared to 5.5 y for 1990--1993).