CDER Closes Out 2008 With 24 Novel Approvals, But Few Are First In Class

FDA's second-half surge in approvals made 2008 the agency's best year for NME approval counts since 2004, but the relatively high number is generated by a slate of products with a relatively low level of innovation.

¹ Twenty-one new molecular entities and three therapeutic biologics were approved by FDA's Center for Drug Evaluation and Research in 2008, but after a slow start. Only three were cleared in the first quarter, and 10 were approved in the final three months of the year.

The total of 24 ² novel approvals goes a long way toward eclipsing the 25-year low of 18 novel products cleared by CDER in 2007, at least numerically.

Higher Numbers, But Lower Profiles

But viewed in terms of therapeutic advances, 2008 actually pales in comparison to 2007. It is telling that 2008 was a banner year for medical imaging, with a possibly unprecedented four approvals of medical imaging agents among the NMEs.

Only about 40 percent of the 2008 approval class are first-in-class molecules, represent a significant therapeutic advance, or address a disease not previously treated with pharmaceuticals.

The most advances were seen in the usually fallow field of hematology, with Genzyme's CXCR4 chemokine antagonist Mozobil for hematopoeitic stem cell mobilization and the first two thrombopoeitin agonists for idiopathic thrombocytopenic purpura, one a drug (GlaxoSmithKline's Promacta ) and one a biologic (Amgen's Nplate ). FDA also approved the first treatments for the orphan conditions of Huntington's disease (Prestwick/Ovation's Xenazine ) and Cryopyrin-Assisted Periodic Syndromes (Regeneron's Arcalyst ).

The prior year, in contrast, saw two first-in-class HIV therapies, the first new class of topical antibiotic in 20 years, two novel classes of oncologic, a first-in-class antihypertensive, and two first treatments for rare diseases.

Looking at the proportion of NME approvals that were priority reviews, one proxy for agents that offer a significant medical advance, 2007 also topped 2008. In the past year, one-third of CDER NME/BLA approvals carried priority review designation. In 2007, half of CDER new product approvals had priority status.

Average Approval Time Returns To Average

The average time from NDA or BLA submission to approval grew to 18.3 months, after the record low of 12.3 months in 2007. The low average in 2007 was primarily attributable to the high proportion (75 percent) of first cycle approvals in that year (³ Pharmaceutical Approvals Monthly January 2008, p. 3).

In 2008 there was a similar percentage of first cycle approvals (69 percent), but fewer were priority reviews and there was an unusual number of long reviews. Some of the first-cycle reviews took longer because of the additional time needed to develop Risk Evaluation and Mitigation Strategies.

The number of very long reviews was the most significant factor putting upward pressure on the average approval time figure for 2008. Seven products were approved two years or more after submission, accounting for almost one-third of novel CDER approvals in 2008. Only one-tenth of the 2007 approval cohort posted 24-month-plus times to approval.

The title of longest review in the 2008 NME class goes to Epix's imaging agent Vasovist , for its 60-month journey from NDA submission to approval, marked by two action letters and a trip through FDA's appeals process. Adolor/GlaxoSmithKline's Entereg is a year behind with its third-cycle approval occurring 47 months after initial NDA submission.

The lengthy review group may be larger than past years, but it is not constituted much differently: the products are - mostly - standard review applications that do not break new ground, like Eisai's triazole anticonvulsant Banzel (36 months), Toviaz , a metabolite of Pfizer's Detrol (31 months), Pristiq , the active metabolite of Wyeth's Effexor (26 months) and Cimzia, the fourth anti-TNF biologic for Crohn's (almost 26 months).

The outlier of this group of outliers, then, is Prestwick's Xenazine, the lone priority application. As the first drug approved for Huntington's chorea, it is a significant medical advance, but the review took four cycles over 35 months.

Despite the high number of long reviews, the 2008 average time to approval is nonetheless within the range of average time to approval since 2000. It is lower than the 18.7 month average in 2004 and the 18.5 month 2001 average, and above the shortest averages, posted in 2007 (12.3 months) and 2005 (14.4 months).

New Frontiers On The Safety Side Of Reviews

Although the novel drugs approved in 2008 may not contribute that much in "newness," there were plenty of "new" things going on at FDA in 2008. It just came from the safety side of the review process, with the expanded safety powers under the FDA Amendments Act and a more co-equal footing for the Office of Surveillance and Epidemiology and the Office of New Drugs in drug reviews (⁴ The RPM Report, July/August 2008).

FDAAA authority to require post-marketing studies and REMS only came into effect in March of last year, but the 2008 experience suggests that REMS prolong review times by three to nine months (⁵ , p. 14).

As the agency works to adjust its review processes to incorporate the new safety authorities, FDA is rolling out its new review process, the Good Review Management Principles, designed to carve out room for REMS and labeling negotiations in the final months before the user fee deadline (⁶ The RPM Report, December 2008).

Missing User Fees

In considering the world of FDA's drug review process in 2008, one of the clearest headline stories is the increasing rate of missed user fees - a step OND Director John Jenkins allowed to reflect the workload and difficulty of implementing FDAAA (⁷ The RPM Report, September 2008).

A full reckoning of the impact of FDA's move away from emphasizing user fee goals must await the maturing of the 2008 review cohort. As 2009 starts, at least seven NMEs or significant NDAs with 2008 user fees are pending, including high-profile products like Lilly/Daiichi's antiplatelet agent prasugrel, Takeda's antidiabetic alogliptin, and Theravance's antibiotic televancin.

However, it is still instructive to look at the 2008 approval cohort. A clear majority - 70 percent - of CDER's NME and new BLA approvals in 2008 met their final user fee goal (see chart: ⁸ 'As The Review Cycles Turn' ). A difference in average review time is only to be expected between applications that did and did not meet user fee goals, but the difference in the 2008 cohort is not excessively large: 16.3 months for products that met user fee goals versus 21.8 months for the missed user fee goal group.

The 2008 data suggest that priority review status does not protect against missed user fee goals. Almost 30 percent of the missed user fee group had priority review status, a difference of just over 10 percent from the priority review percentage in the group of approvals where the user fee goal was met (41 percent).

Of the reviews that failed to meet the user fee goal, only about 40 percent required multiple review cycles. Others, like Amgen's Nplate, missed user fee goals as the agency applied its fledgling REMS authority.

Division Of The Year?

The past year is notable for the outsized contribution of the Division of Medical Imaging and Hematology to the approval total. With seven NME and novel therapeutic biologic approvals in 2008, that one division produced more novel approvals than the total approvals of the entire Office of Oncology Drug Products (which includes DMIHP plus the typically busy oncology divisions for drug and biologic products) in any recent year.

In fact, OODP was the most productive office at FDA in terms of new molecule approvals in 2007 with five approvals - fewer than DMIHP alone in 2008.

DMIHP faced boom years for both imaging agents (four approvals) and hematology products (three approvals, all for first-in-class or new therapeutic advance products: Mozobil, Promacta and Nplate).

The novelty level of the imaging agent portfolio is low, featuring the fifth gadolinium-based contrast agent ( Eovist ); another gadolinium-based agent, Vasovist , for a new use (magnetic resonance angiography); a modified form of adenosine (CV Therapeutics/Astellas' Lexiscan ); and AdreView , a GE product in the established class of diagnostic radiolabeled iobenguane agents that was already widely compounded.

Anti-cancer therapeutics were actually down slightly, with only two 2008 NMEs (Cephalon's Treanda and Ferring's degarelix) compared with the steady rate of three or four new oncologics cleared in recent years (when fewer NMEs were approved overall).

Anti-infectives may have provided the biggest surprise of 2008: no NME antibiotics were approved during the year, despite a full slate of NDAs under review ( ⁹ (Also see "The Antibiotic Drought Of 2008: Plenty Of Action But No NME Approvals" - Pink Sheet, 26 Jan, 2009.) ).

Similarly, the central nervous system drug review divisions in ODE I had busier years than their NME totals would suggest. In addition to approving three new drugs (the anticonvulsants Banzel and Vimpat and Pristiq , the active metabolite of Wyeth's antidepressant Effexor ), ODE I did not approve a number of drugs, including Vanda's "not approvable" antipsychotic iloperidone and Schering-Plough's antipsychotic Saphris (asenapine). Schering-Plough recently announced a "complete response" letter for Saphris for schizophrenia and bipolar mania indications, months after Saphris' June user fee goal.

ODE I did not meet user fee goals for a third NME anti-epileptic with 2008 user fee goals, Ovation's long-pending Sabril - but the drug's 2009 prospects are looking up after a recent advisory panel recommendation.

New Formulations, New Challenges

One of the hottest sectors of CNS drug reviews came not from NMEs but novel formulations of pain drugs. Analgesics are under the purview of ODE II, in the Division of Anesthesia, Analgesia and Rheumatology Products. The division wrestled with (and issued action letters for) a slew of new, but not NME, products, notably once-daily tramadol and abuse-resistant opiate formulations.

FDA has granted priority review status to abuse-resistant opiate products in response to a pressing public health need. The drugs are also excellent candidates for REMS; indeed, the November advisory committee reviewing Alpharma's abuse-resistant morphine Embeda and Pain Therapeutics/King's abuse-resistant oxycodone Remoxy strongly urged a class-wide REMS for opioids (¹⁰ , p. 7).

FDA is considering a blanket REMS for all opioids, a process that undoubtedly is prolonging the reviews of Embeda (no action as the Dec. 30 user fee passed) and Remoxy ("complete response" letter issued Dec. 11). Another candidate came onto the scene as 2009 opened, with Acura's Jan. 2 announcement of an NDA submission for its abuse-resistant oxycodone Acurox .

DAARP's labyrinthine review of once-daily tramadol products bore fruit as 2008 came to a close, with the approval of Labopharm/Purdue's Ryzolt . Sponsors of pending ER analgesics are hoping to follow a smoother path: Ryzolt's Dec. 30 clearance followed two "approvable" letters and a denied dispute resolution appeal. An unsuccessful appeal of an "approvable" letter also preceded Cipher's revised NDA filing for its tramadol candidate, CIP-tramadol ER; DAARP's review continues after missing the October user fee goal.

Big Boost From CBER

One section of FDA that performed quite well by 2008's numbers was the Center for Biologics Evaluation and Research, which has responsibility for BLAs that are not considered therapeutic biologics, including blood products and vaccines.

CBER approved seven new BLAs in 2008 (see chart: ¹¹ Biologic Approvals In 2008 ). The average time to approval at CBER, 15.3 months, was lower than at CDER, and CBER met all user fee goals for the new BLAs approved in 2008. Adding in the three therapeutic biologics approved by CDER, the average time to approval for all biologics is virtually unchanged: 15.2 months.

The novelty level of the 2008 CBER cohort is reduced by the new BLAs for new combination vaccines that do not include any new active components, including GSK's Kinrix and Sanofi Pasteur's Pentacel . GSK's Rotarix is new to the market, but is the second rotavirus vaccine to come through CBER. Baxter's fibrin sealant Artiss and ZymoGenetics' recombinant thrombin Recothrom join other products in their class in the surgical market. The biggest splash first-in-class CBER biologic in 2008 came from the small firm Lev, in partnership with Viropharma, for the orphan drug Cinryze .

Adding the novel, non-surgical CBER approvals to the 24 NMEs and therapeutic biologics approved by CDER brings the 2008 tally of novel products cleared by FDA to 27 (without counting combination vaccines or surgical products, only Cinryze, Xyntha and Rotarix).

Small Showing For Big Pharma

Only six of the major pharma and biotech firms appear on the list of 2008 approvals, and that comes with a significant assist from CBER. The contribution from big pharma gets whittled down when the origins of the molecules are taken into account (see sidebar: ¹² 'Where Do NMEs Come From?' ).

Johnson & Johnson has two NME approvals, Intelence and tapentadol. Wyeth has one internal NME (the Effexor follow-on Pristiq) and will market one NME (Progenics' Relistor ). Wyeth also received a biologic approval from CBER for Xyntha , a recombinant Factor VIII product for hemophilia A. GSK also received an NME approval for Promacta and will market Adolor's Entereg , and received two vaccine approvals from CBER: Rotarix and Kinrix. Sanofi Aventis received one new approval, the combination vaccine Pentacel, through CBER.

Amgen was the only major biotech to receive an NME approval in 2008, with Nplate. The mid-sized Genzyme and small firm Regeneron rounded out pure-play biotech's presence on the NME/BLA approval list for 2008 with Mozobil and Arcalyst, respectively.

Mid-scale biopharma firms had an excellent 2008, with UCB and Eisai each receiving two NME/new BLA approvals. Watson, GE, Cephalon, Baxter and Ferring also made it on the board.

Ten NME NDAs and BLAs from small firms received approval in 2008. Three of the products are biologics: Regeneron's Arcalyst, Zymogenetics' Recothrom, and Lev/Viropharma's Cinryze.

- Bridget Silverman ([email protected])