By Jennifer Van Brunt

Editor

'Twas the week before Christmas… and dozens of biotech and specialty pharma companies had already received the ultimate gift from the FDA – a bright, shiny new medicine that they could call their own. Given the agency's penchant for ending the calendar year with a flourish, several more firms could well find a new product approval peeking out of their stockings, too. So far, the FDA has approved 23 new biotech and biotech-derived medicines, plus an additional five medical devices (mainly dermal fillers for banishing facial wrinkles) and an in vivo diagnostic. That puts the sector roughly on par with 2003, when the agency approved 25 new drugs and biologics. If there's been a slowdown in the FDA's process – for whatever the reason – we've yet to see it reflected in the biotech space.

The FDA is in big trouble. As the nation's watchdog over the safety of medications, it appears to have failed. How else could it have allowed Merck & Co. Inc. to market the popular arthritis and pain drug Vioxx? Or Pfizer Inc. to sell its equally popular, and similar, drug Celebrex? What about Bayer AG's over the counter drug Aleve? All three painkillers have now been linked to an increased risk of heart attack and stroke – and the FDA has found itself in the hot seat.

But wait, there's more. The flu vaccine crisis this year – precipitated by Chiron Corp.'s manufacturing troubles – became a political football and the FDA was again called to account. And now it seems that AstraZeneca plc's highly touted lung cancer drug Iressa isn't all it was cracked up to be. The agency approved that product early, based on tumor response rate in Phase II trials. But when the company completed the clinical trial designed to demonstrate that Iressa provided a clinical benefit, it discovered that the drug was no better than the placebo. Now, the FDA is considering whether to pull Iressa from the market. And many are once again questioning the agency's judgment in approving the product in the first place. (The companies, of course, are not without blame here.)

Add to the mix the fact that the agency is without a permanent commissioner – again – and it's no wonder that leading skeptics and critics predict that the FDA will become extraordinarily cautious in its drug review and approval process in the months (or years) to come, even as it faces a probable overhaul brought on by angry politicians.

Lucky Number
If so, then we may look back on 2004 with a sort of wistful fondness – for the FDA did the biotech sector proud this year. As of mid-December, it had granted first-time approvals to 23 biotech and biotech-related drugs and biologics, nearly the same number of new therapies that it approved in 2003. (For a list of 2003 approvals, see the Signals article, "The New Product Parade.") As well, the agency approved five new medical devices and an in vivo diagnostic.

By New Year's Eve, the FDA may have given its stamp of approval to a few more therapies as well, meaning that each year for the past two it has approved about 25 new biotech and biotech-related products. This recent record far surpasses the previous years: In 2002, the agency approved 15 new medicines; in 2001, it approved 12; and in 2000, 16 new therapies gained marketing approval. (Editor's note: By December 31, the FDA had approved four more drugs, bringing the total to 27 new therapeutics in 2004. These four are included in the calculations for product approval times.)

Moreover, the average time it took for the FDA to approve these products – from the time the BLA or NDA was first submitted (or, in the case of rolling applications, the time the last section was submitted) to marketing approval – improved in 2004 as compared to the previous two years. In 2002, for instance, the average time to approval for all new therapies (drugs and biologics) was 27.3 months. In 2003, that time decreased to 19.9 months. And in 2004, the average approval time for all new medicines was 16 months.

As usual, the drugs were approved more rapidly than the biologics – an average of 15.7 months versus 17.2 months. But the gap in approval times between the two categories is shrinking: In 2003, for instance, it took 24.8 months, on average, for a biologic to garner FDA approval, while the average drug approval time was 17.6 months. (For more details on product approval times, and how they've changed since 2000, see the Signals article, "FDA Picks Up The Pace.")

Biotech And Biotech-Related Biologics Approved In 2004*

* Includes biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.

Priority review is granted to therapies for unmet medical needs that represent a significant advancement over available treatments. And the three biologics approved in 2004 under this classification certainly qualify. Moreover, they each represent first-in-kind therapies. For instance, Avastin, Genentech Inc.'s monoclonal antibody-based therapy for colorectal cancer, has been hailed as a breakthrough product and the first that acts by cutting off the blood supply to tumors. Amgen Inc.'s newly approved growth factor Kepivance, which targets epithelial cells lining the mouth and GI tract, will be used to treat the painful mouth sores common to blood-cancer patients undergoing high-dose chemotherapy. And Biogen Idec Inc./Elan Corp. plc's new therapy with the ungainly and unpronounceable name (Tysabri) provides yet one more medicine for treating multiple sclerosis – yet it acts by preventing immune cells from migrating into the brain, a different mechanism than that used by those already on the market.

Bet the bank
While the FDA approved only five new biologics in 2004, it gave its stamp of approval to 18 new drugs – and several of them also represent real breakthroughs in targeted therapy. For instance, Eyetech Pharmaceuticals Inc./Pfizer's Macugen is the first drug approved for treating all forms of wet age-related macular degeneration. (For more information on AMD drugs, see the Signals article, "The Eyes Have It.") Like Genentech's Avastin, Macugen targets vascular endothelial growth factor.

Biotech And Biotech-Related Drugs And Devices Approved In 2004*

* Includes drugs, devices and imaging agents developed by biotechnology and specialty pharmaceutical companies as well as relevant drugs developed by big pharma.

And Tarceva, the lung cancer therapy developed by OSI Pharmaceuticals Inc., Genentech and Roche, targets the epidermal growth factor receptor (EGFR) – the same target at which ImClone Systems Inc.'s colorectal cancer therapy Erbitux is aimed and, interestingly, the same as that targeted by AstraZeneca's troubled lung cancer drug Iressa. In fact, analysts now predict a very bright future for Tarceva – because, unlike Iressa, Tarceva has actually been shown to prolong life.

Biotech And Biotech-Related Drugs And Devices Approved In 2004*

* Includes drugs, devices and imaging agents developed by biotechnology and specialty pharmaceutical companies as well as relevant drugs developed by big pharma.

Companies continue to devise new drugs for treating HIV infection, too, as well as formulations that require less frequent dosing. Indeed, gone are the days when AIDS patients had to swallow 25-30 pills daily in a difficult-to-follow regimen. Now, thanks to two new combination drugs – GlaxoSmithKline plc's Epizcom and Gilead Sciences Inc.'s Truvada -- that dosing is down to one pill a day.

Luck of the Irish
Once a drug or biologic has been approved for its first indication, most sponsoring companies will continue to try it in other disease settings, thus expanding both the label and the patient population – not to mention the revenue. Plenty of products garnered further approvals in 2004, including the following :

• Campath. Ilex Oncology Inc.'s humanized monoclonal antibody was originally approved in May 2001 for treating B cell chronic lymphocytic leukemia. In October 2004, the FDA approved a new single-use vial which will offer greater convenience to healthcare providers.
• Captique and Hylaform Plus. Genzyme Corp. and Inamed Corp.'s newest dermal filler Captique is made from hylauronic acid derived from non-animal sources. It was approved in December for the correction of moderate to severe facial wrinkles. The companies' wrinkle filler Hylaform, which is derived from rooster combs, was first approved in April (see the first-time approvals table) and in October, a large particle-size version, Hylaform Plus, received the agency's blessing.
• Eligard 45 mg. Originally developed by Atrix Laboratories Inc., which has since been acquired by QLT Inc., this six-month sustained release formulation of leuprolide (a leutinizing hormone-releasing hormone agonist) was approved in December for treating advanced prostate cancer. The four-month sustained-release version was approved in February 2003. The product was first approved in January 2002 in a one-month sustained-release formulation and then in a three-month formulation in July 2002.
• Enbrel. The market for Amgen's breakthrough product, originally approved for treating rheumatoid arthritis (RA), keeps on expanding. In April 2004, it was approved for treating moderate-to-sever plaque psoriasis. And in September, the therapy received two further approvals: It's now offered in a once-weekly prefilled syringe for convenience and ease of use. Importantly, the agency also granted a label change that claims Enbrel's ability to induce a major clinical change in patients with RA, representing a significantly high level of symptom control over an extended period of time. Previously, Enbrel was approved for treating psoriatic arthritis and ankylosing spondylitis (as well as RA).
• Fuzeon. Trimeris Inc.'s novel AIDS drug, which works by blocking HIV's entry into cells, garnered accelerated approval in March 2003. The FDA granted it traditional approval in October 2004.
• Gonal-F Pen Serono S.A.'s recombinant human follicle stimulating hormone for use in infertility treatment is now available in a prefilled device, which was granted marketing approval in May.
• Humira. In August, the FDA approved this fully human monoclonal antibody to tumor necrosis factor alpha, which was developed by Cambridge Antibody TechnologyGroup plc and AbbottLaboratories, for improving physical function in patients with moderately to severely active RA. The product received its first approval in December 2002, as an RA therapy in patients who had inadequate responses to DMARDS.
• Norditropin and Nordiflex. Novo Nordisk A/S's recombinant human growth hormone Norditropin has been marketed in the U.S. since 1997, when it was approved for use in children with growth failure due to growth hormone deficiency. In October 2004, the FDA approved a premixed, prefilled disposable pen (Norditropin Nordiflex) for use in children; and in November, the agency approved the therapy for treating adults with growth hormone deficiency, as well.
• Pegasys. Roche's recombinant pegylated alpha 2a-interferon is also now available in a prefilled syringe, which was approved for sale in January 2004. The drug received its first approval in October 2002 for treating chronic HCV infection as a monotherapy; in December that year, it was also approved for use in combination with the antiviral drug Copegus (ribavirin).
• Provigil. Cephalon Inc.'s marketed drug Provigil was approved in January 2004 for improving wakefulness in patients with sleep apnea and shift work sleep disorder. Its first approval, for treating narcolepsy, came in December 1998.
• Rebif. Serono's multiple sclerosis drug Rebif is now available in a dosage form specifically for first-time users. The product, recombinant interferon beta-1a, was first approved in the U.S. in March 2002. The new formulation, Rebif Titration Pack, garnered the FDA's blessing in December 2004.
• Remicade. This monoclonal antibody to tumor necrosis factor-alpha, developed by Centocor (a Johnson & Johnson company), racked up two more approvals in 2004. In December, the product was approved for treating ankylosing spondylitis – adding to a host of other approved indications, including multiple aspects of Crohn's disease and rheumatoid arthritis. In September, the FDA approved Remicade for use as a first-line therapy in RA, when used in combination with methotrexate. The FDA initially approved the product in August 1998 for treating Crohn's disease.
• Remodulin. United Therapeutics Corp.'s prostacyclin analog was approved in November 2004 for intravenous administration in the treatment of pulmonary arterial hypertension. The drug was originally approved in May 2002 for administration via subcutaneous infusion.
• Synagis. A new liquid formulation of MedImmune Inc.'s humanized monoclonal antibody to respiratory syncytial virus received approval in July 2004 for preventing serious RSV disease in high-risk pediatric patients. The freeze-dried formulation of the product was initially approved in June 1998.
• Taxotere. Aventis' anticancer drug Taxotere, a semi-synthetic taxol-related compound, was approved in August 2004 for the post-surgical treatment of early-stage breast cancer. It's also been approved for use in advanced, metastatic breast cancer and non-small cell lung cancer.
• Vitrase. The FDA approved ISTA Pharmaceuticals Inc.'s hylauronidase solution (in a multi-use vial) for use as a spreading agent in May 2004 (see first-time approvals table); in December, the agency also approved a single-use vial.

Wheel of Fortune
Thus, the FDA granted approvals to 29 supplemental applications (including new formulations and formats) as well as the five new biologics, 18 new drugs, five medical devices and one in vivo imaging agent. Not bad. But it's still faced with a backload of pending applications: 55 NDAs (including supplemental NDAs), 15 BLAs (including supplemental BLAs), one PMA and an ANDA. The tables that follow highlight the current review status of these applications.

Biotech And Biotech-Related Products Under FDA Review 2004*

* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.

Biotech And Biotech-Related Products Under FDA Review 2004*

* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.

Biotech And Biotech-Related Products Under FDA Review 2004*

* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.

Biotech And Biotech-Related Products Under FDA Review 2004*

* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.

Biotech And Biotech-Related Products Under FDA Review 2004*

* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.

Biotech And Biotech-Related Products Under FDA Review 2004*

* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.

Which of the pending applications will be approved before New Year's? Well, one of them already has been: Santarus Inc.'s 40 milligram dose of the gastric ulcer drug Zegerid received the FDA's imprimatur on December 22. And if the agency upholds its own holiday tradition, a few more will follow suit.

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