Oncologics Drove FDA’s 2012 Novel Approval Count To 15-Year High
Executive Summary
With 45 new molecular entities and novel biologics cleared in 2012, FDA approvals have reached a level not seen since the mid-90s, the golden age of modern medicine. The group reflects a boom in oncology; other drug development trends like orphan diseases and personalized medicine held steady. Big pharma contributed just over a third of the 2012 class, with Pfizer regaining the lead with five novel approvals.
Cancer therapies were the driving engine as FDA’s annual new molecular and biological entity approval count roared back to levels not seen since the boom years of the mid-1990s. Almost 40% of the 39 novel products approved by Center for Drug Evaluation and Research in 2012 came through the Office of Oncology Products.
The CDER class of 2012 is 30% larger than 2011’s 30 novel approvals – and 2011 was a good year, a recovery from a seven-year NME doldrums where output averaged just under 22 novel approvals per year (Also see "Innovation Pays: Priority Drugs Drove Novel 2011 Approvals To New Heights" - Pink Sheet, 1 Jan, 2012.).
The last time CDER approved 39 novel products was 1997. The only time in the PDUFA era that CDER cleared more NMEs in a single calendar year was 1996, when the total hit 56. (See chart, (Also see "CDER’s Novel Approvals In 2012" - Pink Sheet, 7 Jan, 2013.)).
Cancer drugs take a big share of the credit for the swift upward trajectory of CDER approvals. Oncology Office Director Richard Pazdur signed off on almost as many novel approvals in 2012 as were approved across the whole center during the worst of the slow years (especially when a 2012 dermatology approval for a precancerous condition is taken into consideration, which brings the 2012 cancer-related total to 16 compared to the 2006 center total of 17).
Taking out the 15 novel cancer agents approved in 2012, CDER’s non-oncology approval total is 24 – a slight gain from 22 non-oncology approvals in 2011. The growth in non-oncology NMEs is not insignificant, but also is not the order of magnitude increase seen on the oncology side.
Tracking FDA Approvals Over The Years
Novel CDER Approvals Show Upward Trajectory
New molecular and biologic entities approved by the FDA’s Center for Drug Evaluation and Research from 2008 to 2012.
Elsevier Business Intelligence; FDA
Because oncology drug approvals are rising more rapidly than novel approvals in other therapeutic areas, their share of the total has sharply increased. Pazdur signed off on almost four of every ten CDER novel approvals in 2012, a considerable jump from the office’s one-quarter share of 2011 approvals. Cancer drug approvals had dropped to under 10% of CDER novel approvals in both 2008 and 2010.
Oncology drugs consistently stood out on review metrics, from first-cycle percentage to priority review status, compared with other divisions. In this, 2012 was a continuation of recent trends. A Tufts Center for the Study of Drug Development study called oncology the “exemplary” review office (Also see "Oncology Review Division At The Head Of The Pack – But Can The Others Keep Up?" - Pink Sheet, 1 Apr, 2012.). But the number of reviews that smashed the six-month priority review mark may be the most dramatic measure (Also see "Evolution, Not Revolution, Marks Progress In Targeted Oncology Therapy – AACR" - Pink Sheet, 1 Oct, 2012.).
Four 2012 oncology approvals came in one month or more before the priority review user fee goal date; three of them are among FDA’s ten fastest oncology approvals overall (#2 Iclusig, #4 Xtandi and #10 Erivedge). The only year close to the 2012 faster-than-PDUFA approval tally is 2011, which also entered three NMEs into the ten fastest oncologics list (Zelboraf is now #7, Zytiga #8 and Xalkori #11) (Also see "Evolution, Not Revolution, Marks Progress In Targeted Oncology Therapy – AACR" - Pink Sheet, 1 Oct, 2012.).
And faster-than-PDUFA reviews were not limited to oncology. Vertex Pharmaceuticals Inc.’s Kalydeco (ivacaftor) cleared FDA in just 3.43 months for cystic fibrosis. FDA approved 12 NMEs/NBEs prior to their user fee goal in 2012 – 8 oncologics and 4 in other categories -- although some were just days short.
The increase in beat-the-clock review times comes just as FDA is switching to longer review periods under the FDA Safety and Innovation Act; the PDUFA V negotiations added a two month filing review to both standard and priority review timelines for NMEs and novel BLAs – meaning FDA now has 12 or 8 months to come to a decision. It will be interesting to see if the extended user fee goal timeframe will alter the FDA oncology office’s push for internal goals that come earlier than the PDUFA timetable for significant new oncologics (Also see "Will The New Math Of Oncology Drug Review Times Carry Over Into PDUFA V?" - Pink Sheet, 1 Nov, 2012.).
Cancer drugs are disproportionately represented in the ranks of the new drugs that FDA considers to represent significant therapeutic advances. Of the 16 NME/NBEs approved with priority review status in 2012, more than half were oncologics (nine). The next largest group of priority agents is composed of just two infectious disease therapies, both for orphan uses. But while other review divisions are not as widely represented, they did produce some of the year’s most notable priority approvals. Bristol-Myers Squibb Co./Pfizer Inc.’s anticoagulant Eliquis (apixaban) has the biggest commercial potential of any priority approval in 2012, while Kalydeco is one of the most pioneering, as the first drug to address one of the genetic defects underlying cystic fibrosis rather than treating symptoms.
Highlights of the oncology class of 2012 range from first-in-class therapeutic mechanisms like Genentech Inc./Curis Inc.’s pioneering Hedgehog pathway inhibitor Erivedge (vismodegib), the first FDA-approved treatment for advanced forms of basal cell carcinoma, the most common form of skin cancer, to the biggest overall survival benefit seen yet in castration-resistant prostate cancer with Medivation Inc.’s Xtandi (enzalutamide).
FDA Demonstrates Mastery Of PDUFA Timetables, Just In Time For FDASIA
Overall, FDA patted itself on the back for its recent innovative drug approval performance, calling its approvals “notable for their efficiency and timeliness” in its FY 2012 Innovative Drug Approvals report, released Dec. 5, 2012 (Also see "FDA Wants To Help You Develop Drugs" - Pink Sheet, 5 Dec, 2012.).
FDA appears to have found the formula for meeting user fee goal deadlines. Only one NME review in the 2012 cohort ran past its PDUFA target, and it was the last NME of the year. Salix Pharmaceuticals Ltd.’s Fulyzag (crofelemer) was approved New Year’s Eve for antiretroviral-associated non-infectious diarrhea in HIV/AIDS patients. Despite an extension of the goal date, the review carried on for close to four months after the target date as FDA grappled with production and control of the active botanical ingredient. As only the second botanical drug approved by FDA under its botanical drugs guidance (and the first oral botanical drug), crofelemer posed an unusual challenge, and the outcome – a first-cycle approval in just under 13 months of review time – is probably better for the sponsor (and patients) than an on-time “complete response” letter kicking off another period of sponsor work time and another review cycle.
FDA has now surpassed the Prescription Drug User Fee Act’s prescribed goal for on-time performance for two years in a row. The legislation calls for FDA to review and act on 90% of NMEs by their target dates. CDER met goal dates for 97.4% of NME and novel BLA approvals in 2012 and 96.7% in 2011.
The new, longer review timeframes for incoming NMEs and original BLAs under FDASIA kicked off Oct. 1, 2012. What FDA called the “program” for NMEs and NBEs also seeks greater communication between sponsor and agency, ranging from a recommended pre-submission meeting to a letter from FDA 74 days after submission that outlines a planned review timeline and points out deficiencies and areas where more information is needed, followed by a mid-cycle communication and a late-cycle meeting.
Office of New Drugs Director John Jenkins predicted that implementation of the “program” will be able to capitalize on the progress made under the agency’s 21st Century Review initiative and produce less upheaval in the review process than the previous round of PDUFA reauthorization. “We’ve now fully implemented … the 21st century review model across all application types, across all divisions, so everyone is following the same model as far as how they’re approaching the application review, the team based approach, and now we’re doing the same for the ‘program,’” he told Elsevier Business Intelligence’s FDA/CMS Summit Dec. 10. “We’re committed to implementing the ‘program.’” (See sidebar.)
Moving Closer To The First-Cycle Approval Ideal
FDA has long held approval after a single review cycle as an internal review ideal; it is an explicit goal of PDUFA V. The consistently high number of approvals reaching that goal – which requires not only efficient work by FDA but complete and well-constructed applications from industry – indicates that FDA’s efforts have paid off. “Average first-cycle approval rates for NME applications in PDUFA IV are at the highest levels since the start of PDUFA,” Jenkins reported, and 2012 was no exception: 31 of 39 novel approvals occurred on the first review cycle, or 79.5% – just topping the 2010 high of 76.2%.
Jenkins credited both FDA and industry with his possible reasons for the high first-cycle approval rate. He points out the agency’s growing experience with the review tools provided by the FDA Amendments Act, especially new authority to direct safety evaluation with Risk Evaluation and Mitigation Strategies and post-marketing required studies. He also highlighted improvements in the quality of applications arriving at the agency, as well as a “fall in ‘me-too’ submissions for chronic symptomatic diseases where benefit/risk ratio is often less favorable.”
[Editor’s note: For more analysis of the 2012 class of novel approvals and FDA performance metrics, see the January issue of Pharmaceutical Approvals Monthly. To sign up for a free trial, please click here
or contact customer care at 1-800-332-2181.]
Good Trials Make Good Reviews
The rise of targeted therapy has also been a significant contributor to FDA’s ability to reach decisions swiftly and efficiently. The genomics revolution has matured from excited speculation to a drug development tool that radically streamlines drug targeting, and is thus enabling much more efficient clinical development in the patients most likely to benefit from the drug candidate. Such trials are more likely to produce what Jenkins called a “large effect size,” clearly establishing efficacy. Good trials make good reviews.
The past year saw the continued emergence of personalized medicine, with the approval of Kalydeco and Genentech Inc.’s Perjeta (pertuzumab) for patients with specific molecular signatures. Other approvals drew on knowledge of molecular pathways without requiring genetic screening of patients. Ariad Pharmaceuticals Inc.’s Iclusig (ponatinib) offers efficacy for chronic myeloid leukemia patients with a genetic profile associated with resistance to currently approved tyrosine kinase inhibitors. Teva Pharmaceutical Industries Ltd.’s Synribo (omacetaxine) started out as a personalized medicine candidate for CML with a 2009 NDA, but retrenched after a “complete response” letter and submitted a new NDA for a non-personalized claim for patients resistant to two or more TKIs.
Balancing benefit and risk of new drugs often requires the dexterity of a tightrope walker, but unmet medical needs can provide a steadying clarity. A review that doesn’t have tricky balance issues can move more quickly. Jenkins pointed out the “increased focus on rare diseases, which improves benefit/risk ratio.”
The percentage of NMEs for rare diseases has held steady in the range of one-third of total NMEs for close to a decade. The 2012 cohort came in toward the low end of that range, with about 30% of CDER novel approvals addressing a rare disease.
Average Review Time Hits Five-Year Low, Approaches One-Year Mark
The past year’s high ratio of priority to standard review targets, near-perfect user fee goal compliance and the record high number of first-cycle approvals combined to push average review times to a historically low level. The effect is especially striking if you remove the outlier five-cycle, seven-plus year review of Windtree Therapeutics Inc.’s pulmonary surfactant Surfaxin (lucinactant).
The average time from submission to approval for all 39 CDER novel approvals in 2012 was 13.3 months, the shortest since the 12.3 month average in 2007, which came as the agency also reached a contemporary nadir of only 18 novel CDER approvals. The 2007 total was recently revised down to 17, with the reclassification of Torisel as not an NME (Also see "What's "New" at FDA?" - Pink Sheet, 16 Nov, 2012.). Review times had been inching downward, averaging 15.1 months in 2010 for 21 CDER approvals and 15 months in 2011 when the approval count jumped to 30 (Also see "Innovation Pays: Priority Drugs Drove Novel 2011 Approvals To New Heights" - Pink Sheet, 1 Jan, 2012.).
Without the outlier Surfaxin, the average time to approval for all CDER NMEs/NBEs in 2012 drops to 11.3 months. The NME cohort, without Surfaxin, averages just 10.3 months. As is usual, therapeutic biologics reviewed by CDER take longer to reach approval. In 2012, the average CDER BLA took 16.0 months. [Editor’s note: This article has been updated to correct the average time to approval for all novel CDER approvals and for novel CDER biologics. FDA uses median times to track performance instead, to blunt the impact of outliers; for 2012, the median time to approval was 10 months for NMEs, 6 months for NBEs and 9.95 months for all novel CDER approvals combined.]
Compared with the much larger 2012 NME cohort of 32 drugs, the seven CDER therapeutic biologic approvals were more likely to receive a “complete response” letter. Four BLAs and five NMEs required multiple-cycle reviews. That translates to 43% of BLAs but only 16% of NMEs. The BLA class was, nonetheless, more heavily weighted to priority applications: 71% of the CDER BLAs had priority review compared with 34% of the NMEs.
The Center for Biologics Evaluation and Research, which still holds review responsibility for certain biologics, like vaccines, added another six approvals to FDA’s total (see sidebar).
Pfizer Roars Back
The weak productivity in terms of NME and novel biologics of the world’s biggest pharmaceutical company, Pfizer, has been a consistently recurring theme in recent years. The company, facing a steep patent cliff drop-off, received just five novel agent approvals from FDA (both CDER and CBER) between 2006 and 2011. It matched that total in just the 12 months of 2012, with the clearance of expected blockbuster anticoagulant Eliquis (with Bristol); the first JAK inhibitor for rheumatoid arthritis, Xeljanz (tofacitinib); two standard review oncologics (the second-generation VEGF inhibitor Inlyta for second-line treatment of renal cell carcinoma and a kinase inhibitor from the Wyeth acquisition, Bosulif, for a non-orphan CML population); and a new enzyme replacement therapy for the orphan condition Gaucher disease with a novel plant-cell-based production method, Elelyso (taliglucerase), with Protalix BioTherapeutics Inc.
Big pharma overall posted a second strong year in a row, although Pfizer was the only company to receive more than two approvals. Specialty pharma had dominated the annual NME/NBE count storyline for a few years (Also see "For NMEs, The Song Remains The Same: Specialty Markets Eye Further Growth For 2010, While Traditional Big Pharma, Primary Care NDAs Are Few" - Pink Sheet, 1 Feb, 2010.), but big pharma roared back in 2011 with 14 novel approvals – nearly half of all novel agents approved in the year (after an anemic showing of five approvals, or less than 20% of NME/NBEs, in 2010). FDA matched the 2011 number in 2012, but with more approvals from smaller firms; big pharma’s share declined to a still-respectable 35.9% of novel FDA approvals.
The big pharma presence in 2012 approvals, aside from Pfizer, was evenly spread. Five big pharma companies reached two approvals. Sanofi posted Aubagio (teriflunomide) for MS and, through a deal with Regeneron Pharmaceuticals Inc., the colorectal cancer biologic Zaltrap (ziv-aflibercept). Roche’s Genentech business contributed both of its approvals, the oncologics Erivedge (vismodegib, with Curis Inc.) and Perjeta. Novartis AG and GlaxoSmithKline PLC each received an orphan approval from CDER – Novartis’ Signifor (pasireotide) for Cushing’s disease and GSK’s anti-anthrax biologic raxibacumab (via Human Genome Sciences Inc.) – and a new vaccine approval from CBER (Novartis’ cell culture flu vaccine Flucelvax and GSK’s pediatric meningococcal/Hib preventative MenHibrix). Johnson & Johnson joined the ranks by looking outside of CDER; in addition to MDR-TB therapy Sirturo, J&J’s biosurgery business Ethicon Inc. received approval from CBER for its fibrin sealant patch Evarrest (considered both a biologic and a device) to assist in control of soft tissue bleeding during surgery.
Some of the most consistently-performing specialty firms filled out the ranks of multiple-approval recipients. Forest Laboratories Inc. received clearance for its entry into the busy COPD market, Tudorza (aclidinium), as well as GI agent Linzess. Astellas Pharma Inc. shared one of the year’s headline approvals with Medivation for the prostate cancer treatment Xtandi, as well as a first-in-class entry into the established overactive bladder segment, Myrbetriq (mirabegron). Eisai Co. Ltd. shepherded Fycompa to approval and will market Arena Pharmaceuticals Inc.’s Belviq in the U.S. Teva’s corporate acquisitions brought the Isreali firm two 2012 approvals: Synribo from Ivax Corp. and a novel version of the leukocyte growth factor filgrastim, tbo-filgrastim, from Sicor Inc.
With so many approvals in 2012, there was plenty of sponsor credit to go around. “The new drug research and development paradigm is shifting rapidly from traditional big pharma to venture capital-backed small companies,” Jenkins told the FDA/CMS Summit.
Sixteen sponsors received their first novel drug or biologic approval from CDER in 2012. Half of those agents will be marketed with the help of a larger, more experienced company; three of the sponsors had been acquired by larger companies at the time of approval (Avid/Lilly, Sicor/Teva, and Ivax/Teva). Alliances remain common for emerging sponsors with drugs targeting large or diffuse markets, like prostate cancer (Medivation’s Xtandi, with Astellas), obesity (Arena’s Belviq, with Eisai), and chronic kidney disease-associated anemia (Affymax Inc.’s Omontys, with Takeda Pharmaceutical Co. Ltd.).
The record CDER novel approval performance in 2012 required significant contributions from all sectors of the industry: resurgent productivity from big pharma, a specialty sector in continuing good health, and a rapidly emerging class of small firms and emerging sponsors. After years of concern over lagging productivity and anemic pipelines, two years in a row of historically high CDER approvals appears to show that with that new mix, industry, as well as FDA, is back to operating at the top of its game.