Bethan HughesThe US FDA approved 17 new molecular entities (NMEs) and2 biologic license applications (BLAs) in 2007 (TABLE 1; FIG. 1), the lowest number recorded since 1983.Unsurprisingly, one factor to which the scarcity of approvals has been attributed by some is an increased level of regulatory caution in the wake of high-profile safety issues, such as those for Avandia (rosiglitazone; GlaxoSmithKline) last year. It does appear that the agencyis changing how it assesses benefits and risks when it approves new products. It is extremely concerning to us if the outcome of this effortis a slow down in drug approvals,says Sara Radcliffe, Vice President for Science and Regulatory Affairs at the Biotechnology Industry Organization. But it is statistically difficult to identify a trend, she adds.Alternatively, as the FDA has reportedly countered, it could be that their expectations have not increased, but rather that they have simply become better at identifying potential risks, and that not only have the number of applications decreased, they are also not good enough.Unless you go through piece by piece to compare packages, which is not easy to do, it is hard to see who is correct. It appears that the bar is being raised a bit, and maybe that is necessary, says Christopher-Paul Milne, Associate Director of the Tufts Center for the Study of Drug Development, USA. From a public health standpoint, the FDA is leaning towards asking for more information rather than allowing the product on the market and dealing with any problems as they arise.Specialty trend continuesAccording to Milne, another reason why the FDA wants to see more information is often because less scientific and medical literature is available for novel drugs. In newer fields the FDA wants to see more [data] because their familiarity is less. It makes the FDA cautious about what they are willing to approve.However, a new drug that addresses an unmet medical need may tip the riskbenefit balance towards approval, suggests Milne. When you are dealing with[an indication] for which there are very few, or no, treatmentsyou can perhaps accept that more risk can be borne than you would have in any other situation because the benefits are greater.Nine out of the 17 NMEs and 2 BLAs approved in 2007 received priority review status, a designation given to drugs that are considered to offer major advances in treatment, or provide a treatment for which no adequate therapy exists (TABLE 1).This reflects an ongoing trend, says Senior Research Analyst Eric Schmidt of Cowen and Company, USA. Drugs that meet unmet medical needs such as Soliris for PNH [paroxysmal nocturnal haemoglobinuria] and Kuvan for PKU [phenylketonuria] are the ones getting through. Michael Hay Senior Analyst and Project Manager of BioMedTracker, Sagient Research, USA also observes that more infectious disease and oncology therapies are being approved because from the riskbenefit profile, you can tolerate more risk. Indeed, 2007 saw the approval of the first new types of oral anti-HIV drugs in a decade: the CCR5 antagonist Selzentry (maraviroc; Pfizer) and the HIV-1 integrase inhibitor Isentress (raltegravir; Merck), for the treatment of HIV-1. Also, 4 out of the 17 NMEs in 2007 were indicated for the treatment of cancer, one of which was designated as an orphan drug, Torisel (temsirolimus; Wyeth), for the treatment of advanced renal cell carcinoma.Regulatory setbacksLast year also saw a number of high-profile regulatory delays. Perhaps the most prominent was Provenge (Sipuleucel-T; Dendreon), a pioneering prostate cancer vaccine. In May 2007, the FDA asked for more data about the effectiveness, chemistry and manufacturing of the vaccine, even though an FDA advisory committee had voted in favour of its efficacy and safety in March. Analysts expect more data in 2008, but while they are waiting, it seems likely that the US Congress will investigate why the FDA chose not to follow the advisory committees recommendations to approve Provenge (Nature Biotech. 1, 1; 2008).Two major drugs that analysts had previously expected to be launched in 2007, Acomplia (rimonabant; SanofiAventis) for obesity and Galvus (vildagliptin; Novartis) for type 2 diabetes, also remain unapproved by the FDA. Innovative Medicines Initiative formally adopted p110AstraZeneca sues over generic Crestor p112Stephen Friend discusses Mercks approach to anticancer R&D p114Strategies for anti-angiogenesis drugs p115First integrase inhibitor approved for treating HIV p1172007 FDA drug approvals: a year of fluxSpecialty products dominate innovative drug approvals a trend that looks set to continue.Its a period of flux in getting from A to B.NATURE REVIEWS | DRUGDISCOVERYVOLUME7|FEBRUARY2008|107NEWS & ANALYSIS 2008 Nature Publishing Group Nature Reviews | Drug DiscoveryNumber of drugs approved6050403010201996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 200705336 7303935273 252417 17213118 182425 6 7New Molecular EntitiesBiologic License ApplicationsFollowing a negative FDA advisory committee vote in June that raised concerns about central nervous system side effects, SanofiAventis decided to withdraw its rimonabant new drug application (NDA) and plans to resubmit the file to the FDA in the future. The vildagliptin NDA remains filed, but at the approvable stage, after the FDA requested more clinical trial data to demonstrate safety and efficacy in specific patient groups with renal impairment. Both drugs were approved in the EU last year.Apart from safety concerns, changes to FDA internal processes may have also affected approvables this year as recent draft guidelines for developing antibacterials were cited as a reason for the antibiotic dalbavancin (Pfizer) receiving an approvable letter in December 2007. This may also have affected Theravances telavancin. The FDA is at a crossroads as per the advice from some of its panels, with them moving the goal posts on the companies for indication-specific guideline changes, says Schmidt.Another reason thought to influence whether a drug is considered approvable rather than granted approval is the increased FDA workload. We looked at the report to Congress from fiscal year 2006, released in August 2007, and every metric of workload the FDAs review staff has responsibility for is up considerably, says Hay (http://www.fda.gov/ope/pdufa/report2006/PDUFA2006perf.pdf). These findings are mirrored in a recent FDA subcommittee report that found that demands on the FDA have increased dramatically without resources increasing proportionally (http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_00_index.html).Delays and failuresWhatever the reasons are for delaying approvals, according to Sagient Research the number of approvable letters as a percentage of all FDA decisions made has increased from 20% in 2006 to 28% in 2007 (FDA Approval Study, 2008. BioMedTracker, Sagient Research Systems). Hay thinks that this increase also reflects insufficient communication between the FDA and companies, which could result in poor application packages. The issues being raised by some of the approvable letters should have been addressed during the first review process, he says.Most of the 3-month delays occurred in biotech, says Stefan Ryser, Founding Partner of Bear Stearns Health Innoventures, USA.By looking at approvals and regulatory setbacks over the past 2 calendar years, Elizabeth Czerepak and Stefan Ryser have observed that three-quarters of the products with 3-month delays were from biotech companies (Nature Rev. Drug Discov.; in the press). Interestingly, over the same time period, they also identified that products originating from the biotech industry accounted for approximately two-thirds of all approved new drug applications, but also for more than 90% of Phase III failures.In keeping with this second observation is the fact that pharma achieved more NME and BLA approvals than biotech in 2007 (TABLE 1). So, combining biotechs talent for innovation with pharmas experience of the drug approval process through development alliances may help increase the number of approvals over time. Its the best of both worlds, says Ryser.Meanwhile, to mitigate the risk and high R&D costs of developing novel agents, both pharmaceutical and biotech companies are reformulating, generating line extensions and looking for new indications for existing products. Forecasted revenues for these strategies help to explain why this makes good business sense. For example, Novartis Exforge (amlodipine and valsartan) is forecast to have revenues above US$600 million in the seven major markets (France, Germany, Italy, Spain, UK, Japan and US) by 2012 according to Alistair Sinclair and Tijana Ignjatovic, Senior Analysts at Datamonitor Europe, headquartered in the UK.Financial timesAmong the NMEs or BLAs anticipated to be the most commercially successful of those approved in 2007 are Letairis (ambrisentan; Gilead), for the treatment of pulmonary arterial hypertension, and Isentress for the treatment of HIV-1. Letairis has sales forecast above $400 million in the seven major markets by 2012 according to Datamonitor, and Isentress has sales forecast above $500 million by 2010, with the possibility of sales rising to $1 billion if the drug achieves first-line approval (see page 117). Of the drugs currently in late-stage development, analysts will be closely watching Amgens denosumab for the treatment of osteoporosis and metastatic bone disease, for which key clinical data is due out in the second half of this year. It is make or break for Amgen because of the problems with their EPO [erythropoietin] franchise, says Hay.In terms of market share in 2008, Datamonitor expects oncology, immunology/inflammation and infectious diseases to increase the most, whereas cardiovascular, gastroenterology and respiratory are predicted to decrease owing to major patent expiries.By dividing agents into four categories small molecules, therapeutic proteins, monoclonal antibodies (mAbs) and vaccines Datamonitor has predicted that mAbsand vaccines will see a 25% rise in revenuesin 2008 compared with 2007, from$29.5 billion to $36.8 billion (across the top50 companies in the seven major markets).In particular, Datamonitor identify Roche/Genentechs Avastin, Herceptin and Rituxan as the products that will drive an increase of revenues derived from mAbs from a 6% market share in 2007 to 11% in 2012. These forecasts also reflect mergers and acquisitions, in-licensing and alliances activity last year with pharma investing heavily in both ready-made biologics and platform technologies.A time of changeThroughout 2008, analysts expect to see a continuation of pharmabiotech deals to help expand pipelines, particularly in the biologics arena. Some analysts say that figures already suggest that there will be more NDAs in 2008; however, as it is election year in the USA and with drug developers unsure as to how the recently passed FDA Amendments Act 2007 will affect FDA requirements, it is too early to predict.Figure 1 | FDA drug approvals. New molecular entities and biologic license applications approved by the US FDA by year.NEWS&ANALYSI S108 |FEBRUARY2008|VOLUME7www.nature.com/reviews/drugdisc 2008 Nature Publishing Group Table 1 | New molecular entities and biologics approved by the US FDA in 2007Generic name(Trade name)Company* IndicationMode of action DateNew molecular entitiesLisdexamfetamine dimesylate (Vyvanse)New River Attentiondeficit/hyperactivity disorderhttp://www.fda.gov/cder/foi/label/2007/021977s002lbl.pdfProdrug of dextroamphetamine with CNS stimulant activity23 Feb (S)Aliskiren (Tekturna) Novartis Hypertensionhttp://www.fda.gov/cder/foi/label/2007/021985lbl.pdfDirect renin inhibitor 5 Mar (S)Lapatinib (Tykerb)GlaxoSmithKline Advanced or metastatic breast cancerhttp://www.fda.gov/cder/foi/label/2007/022059s002lbl.pdfKinase inhibitor with targets including HER2 (also known as ERBB2)13 Mar (P)Retapamulin (Altabax)GlaxoSmithKline Impetigohttp://www.fda.gov/cder/foi/label/2007/022055lbl.pdf Bacterial protein-synthesis inhibitor12 Apr (S)Rotigotine (Neupro) Schwarz BioSciencesEarly stage idiopathic Parkinsons diseasehttp://www.fda.gov/cder/foi/label/2007/021829lbl.pdf Dopamine receptor agonist 9 May (S)Temsirolimus (Torisel) Wyeth Advanced renal cell carcinomahttp://www.fda.gov/cder/foi/label/2007/022088lbl.pdf Mammalian target of rapamycin (mTOR) inhibitor30 May (P, O)Ambrisentan (Letairis) Gilead Sciences Pulmonary arterial hypertensionhttp://www.fda.gov/cder/foi/label/2007/022081s000_lbl.pdfEndothelin receptor antagonist15 Jun (P, O)Maraviroc (Selzentry) Pfizer CCR5-tropic HIV-1http://www.fda.gov/cder/foi/label/2007/022128lbl.pdfCCR5 co-receptor antagonist6 Aug (P)Ammonia (Ammonia N13)Feinstein Radioactive agent for positron emission tomography diagnosis of coronary artery disease 23 Aug (S)Lanreotide(Somatuline Depot)Biomeasure Acromegalyhttp://www.fda.gov/cder/foi/label/2007/022074lbl.pdf Somatostatin analogue 30 Aug (S, O)Doripenem(Doribax)Johnson & JohnsonUrinary tract infectionshttp://www.fda.gov/cder/foi/label/2007/022106lbl.pdfSynthetic broad-spectrum carbapenem antibiotic12 Oct (S)Raltegravir potassium (Isentress)Merck HIV-1http://www.fda.gov/cder/foi/label/2007/022145lbl.pdf HIV integrase strand transfer inhibitor12 Oct (P)Ixabepilone (Ixempra) BristolMyers SquibbAdvanced or metastatic breast cancerhttp://www.fda.gov/cder/foi/label/2007/022065lbl.pdfMicrotubule inhibitor 16 Oct (P)Nilotinib (Tasigna) Novartis Chronic myelogenous leukaemiahttp://www.fda.gov/cder/foi/label/2007/022068lbl.pdf BCRABL kinase inhibitor 29 Oct(S, O)Sapropterin dihydrochloride (Kuvan)BioMarin Hyperphenylalaninaemiahttp://www.fda.gov/cder/foi/label/2007/022181lbl.pdf Synthetic tetrahydro-biopterin, cofactor forthe enzyme phenylalaninehydroxylase13 Dec (P, O)Nebivolol (Bystolic) Mylan Bertek Hypertension-adrenoceptor antagonist17 Dec (S)Hydroxyethyl starch(Voluven)Fresenius Kabi Serious blood volume lossBlood volume expander 27 Dec||BiologicsEculizumab (Soliris) Alexion Paroxysmal nocturnal haemogobinuriahttp://www.fda.gov/cder/foi/label/2007/125166lbl.pdfRecombinanthumanized monoclonalimmunoglobulin G2/ 4 antibody that binds to complement protein C516 Mar (P, O)Methoxy polyethylene glycol-epoetin beta (Mircera)HoffmanLa-RocheAnaemia associated with chronic renal failurehttp://www.fda.gov/cder/foi/label/2007/125164lbl.pdf Erythropoietin receptor activator14 Nov (P)*The company that submitted the original new drug application or biologic license application to the US FDA. See full labelling information online. Label not available at time of going to press. ||Information not available at time of going to press. O, FDA Orphan designation; P, FDA Priority Review; S, FDA Standard Review.As part of the Act, Congress also established the ReaganUdall Foundation to identify and address unmet scientific needs in the development, manufacture and evaluation of FDA-regulated products, although the level of funding is currently uncertain. And across the Atlantic, the EU has just officially launched the Innovative Medicines Initiative, with 2 billion euros in funding from the EU and the pharmaceutical industry, to find solutions to overcome research bottlenecks in the drug development process. With such efforts to improve drug development processes, there is much to be hopeful for in the coming years, but there is no overnight remedy. Milne concludes: Its a period of flux in getting from A to B.NEWS&ANALYSI SNATURE REVIEWS | DRUGDISCOVERYVOLUME7|FEBRUARY2008|109 2008 Nature Publishing Group