Biotech companies -- even some pharmaceutical powerhouses -- have met with one setback after another at the FDA this year. The agency has refused to accept product applications for filing; it's told companies that their applications are lacking in important pieces of information; it's sent many back to the clinic to generate more safety and efficacy data. It's even postponed advisory committee meetings.
Everyone's frustrated. But just how slow is the product-approval process these days? And how does it compare to FDA's best years? Well, for biotech drugs, first-time approvals in 2002 have definitely lagged behind those in 1996 -- but only by six months. The real problem lies with the therapeutics that are still caught up in the FDA's gears -- one of which has been snagged for well over three years. |
Biotechnology firms and big pharma companies alike are outright alarmed at the current slow-down in new drug approvals. It's difficult enough to shepherd an experimental compound successfully through the clinic. But then the really arduous task begins -- convincing the FDA that the drug is approvable. Garnering the agency's stamp of approval has always been a demanding undertaking -- as it should be. But today, it seems, it's harder than ever.
Increasingly, the FDA has thrown one roadblock after another in the paths of drug developers anxious to bring new therapies to market. From extended review times for original applications to deficiencies within those applications -- many of which force drug sponsors to conduct an additional clinical trial -- the drug-approval delays are mounting. And everyone's displeased.
Something's wrong.
FDA critics can readily identify the ghosts in the regulatory machine. For one, the agency was leaderless for 21 months: Without a commissioner on board, key employees were loath to make critical, or controversial, drug-approval decisions, so they delayed them by asking for more data. For another, the agency is unable to keep pace with its own standards for drug-review times adopted after Congress passed the Prescription Drug User Fee Act (PDUFA) in 1992. Reviewers are overburdened trying to meet those deadlines: They're simply burning out and the attrition rate is unusually high.
Moreover, product safety has become a high profile issue. Faced with numerous drug recalls over the last decade -- products that proved distinctly un-safe in the after-market -- the agency's been harshly criticized for its failure to protect the public health. In response, it's sharpened its focus on the safety of new drugs under review, often sending companies back to the clinic to generate safety data in large numbers of individuals -- especially when the putative drug is intended treat a chronic illness.
On the other side, industry detractors point to the fact that companies are rushing things -- especially biotech firms, which are under constant pressure from investors to produce tangible results. For instance, companies sometimes submit incomplete applications to begin with -- hence the refuse-to-file letters, which the agency issues when it determines that an application contains insufficient information to permit a review, much less a judgment. Even when the FDA accepts an application for review, it will often end up asking the drug sponsor for additional information before it takes the next step. Young biotechs are simply naïve when it comes to the ways of the FDA, critics say.
These critics also blame the pharmaceutical industry, which is generating fewer applications per se because of dried-up pipelines. Fewer applications mean fewer user fees (authorized under PDUFA), therefore less money to pay reviewers…and so on.
The truth, no doubt, lies somewhere in the middle -- and now it's up to newly appointed commissioner Mark McClellan to sort it all out. He's got a head-start: In early September (before his confirmation), the FDA announced that it intends to switch the review of biotech therapeutics (but not blood products, vaccines, gene therapy or tissue transplantation) from its biologics division (CBER) to the drugs division (CDER) in an effort to speed things up. On top of that, McClellan's first official promise was to accelerate drug review. He's got his work cut out for him.
How bad is it right now? According to the Pharmaceutical Research and Manufacturers of America (PhRMA), the average approval time for new drugs in 1992 -- PDUFA's natal year -- was 29.9 months. In the following years, the FDA gradually picked up speed, hitting its peak in 1998, when the average approval time stood at 11.7 months. Since then, it's started losing ground.
The PhRMA, which now separates out drugs and biologics, said that the average approval time for new drugs in 1999 was 12.6 months, but by 2000 it had risen to 17.6 months. And for biologics, the slowdown was even worse: From an average approval time of 17.1 months in 1999 to 25.8 months in 2000.
In 2001, according to the PhRMA, the average approval time for new drugs was 16.4 months and the average approval time for new biologics was 19.6 months -- both representing an improvement over 2000.
And how about this year? Although it's too soon to know the final tally -- especially because the FDA tends to end the calendar year with a flurry of new approvals -- we do have records for the average (and median) approval times for biotech company-sponsored therapeutics (biologics and drugs) that successfully ran the regulatory gauntlet in 2002. We also have some data pertaining to the elapsed times for those product applications that are still pending.
But before we examine those numbers, let's jump in the time machine and set the clock to 1996 -- at the time, a high point in FDA's history and one that should give us a perspective on how far biotech product-approval times have fallen since then.
Overall, 1996 was a record year for the FDA, which approved 131 new drugs and eight biological products, a 63 percent increase over 1995, according to the agency. The FDA crowed about its accomplishments, but also acknowledged the critical role played by PDUFA in speeding the review and approval of new products.
According to the FDA, the median approval time for the 131 new drugs (53 of which were new molecular entities [NMEs]) was 15.4 months. (The PhRMA says the average approval time for those 53 NMEs was 17.8 months.) And (although it didn't provide the data), the agency said that the approval speed for the eight biologics -- all of which were first-time approvals -- was 15 percent faster than it had been in 1995.
Indeed, the agency approved some new drugs with incredible alacrity in 1996 -- notably various AIDS drugs, which received top priority.
The FDA had already stepped up the approval process for AIDS drugs in 1995: It approved Glaxo Wellcome plc and BioChem Pharma Inc.'s nucleoside analog Epivir for use as a combination therapy with AZT in November, a mere five months after the NDA was filed. And it approved the first protease inhibitor -- Hoffmann-La Roche Inc.'s Invirase -- in December 1995, only 97 days after the agency received the marketing application.
In 1996, the agency granted accelerated approval to Abbott Laboratories' Norvir, for treating early-stage HIV infection, in 2.3 months; at the same time, it granted full marketing approval for the product's use in treating advanced AIDS. Boehringer Ingelheim Pharmaceuticals Inc.'s Viramune was granted accelerated approval in 3.9 months; Bristol-Myers Squibb Inc.'s Zerit was granted full marketing approval (it had been approved under the accelerated review process in June 1994) and Merck & Co. Inc.'s Crixivan was granted accelerated approval in 1.4 months, according to the FDA. To top it off, Agouron Pharmaceuticals Inc.'s AIDS drug Viracept (a rationally designed HIV protease inhibitor) was approved for sale in March 1997, about three months after the company (now part of Pfizer Inc.) had filed its NDA.
But what about the lower-priority new drugs and biologics? According to the FDA, its median review time for all new therapeutics in 1996 was 15.4 months. Did that hold true for the subset of biotech-related products? Well, almost.
As detailed below, the median time to approval for biotech-related products was 17 months, slightly longer but still within range. (This calculation excludes the 84-month approval time for Saizen, due to the unusual circumstances surrounding its approval.)
Although the median was 17 months, one product (Gliadel) was approved in only 7 months, while the elapsed time for CEA-Scan -- from regulatory submission to final approval -- was 63 months. Thus, the average approval time (minus Saizen) was 21.7 months. Although the comparison is rough, this is considerably slower than the average approval time of 17.8 months for the 53 NMEs cited by PhRMA.
The following biotech-developed or -related therapeutics and in vivo diagnostics received first-time approvals in 1996 (the elapsed time from NDA, PLA, or BLA submission to approval is noted in parentheses):
§ Alora. The estradiol transdermal patch developed by TheraTech Inc. (since acquired by Watson Pharmaceuticals Inc.) was approved as a hormone replacement therapy in post-menopausal women in December. (12 months)
§ Amphotec. This product, a lipid-based colloidal dispersion of amphotericin B, was developed by Sequus Pharmaceuticals Inc. (formerly known as Liposome Technology Inc.; since acquired by Alza Corp., which itself has now been acquired by Johnson & Johnson). The FDA approved Amphotec in November as a second-line therapy for invasive aspergillosis infections. (12 months)
§ Aphthasol. The FDA approved Access Pharmaceuticals Inc.'s Aphthasol (amlexanox oral paste, a 5-lipoxygenase inhibitor with anti-inflammatory properties) for treating canker sores in December. (20 months)
§ Avonex. Biogen Inc.'s product, recombinant human interferon beta-1a, was approved for treating relapsing remitting multiple sclerosis in May. (12 months)
§ CEA-Scan. Developed by Immunomedics Inc., this in vivo imaging agent consists of an anti-CEA murine monoclonal antibody fragment labeled with Technetium-99m. It was approved for determining the site and extent of colorectal cancer in July. (63 months)
§ Copaxone. Teva Pharmaceutical Industries Ltd.'s product for treating exacerbating/remitting multiple sclerosis, which is a four-amino acid peptide derived from myelin basic protein, was approved in December. (18 months)
§ DaunoXome. Developed by NeXstar Pharmaceuticals Inc. (since acquired by Gilead Sciences Inc.), this liposomal formulation of daunorubicin was approved as a first-line therapy for Kaposi's sarcoma in AIDS patients in April. (38 months)
§ Gliadel. Developed by Guilford Pharmaceuticals Inc., this product is an implantable biodegradable polyanhydride polymer wafer containing carmustine. The FDA approved its use as a second-line therapy in patients with recurrent glioblastoma multiforme in September. (7 months)
§ Humalog. Eli Lilly and Co.'s recombinant DNA-derived human insulin analog for treating diabetes was approved in June. (15 months)
§ Mentax. This product, a topical formulation of the antifungal agent butenafine HCl, was developed by Penederm Inc. (since acquired by Mylan Laboratories Inc.). It garnered FDA approval for treating athlete's foot in October. (16 months)
§ Prostascint. Cytogen Corp.'s in vivo imaging agent, an Indium-111 conjugated monoclonal antibody that targets prostate-specific membrane antigen, was approved for detecting the present and extent of prostate cancer in October. (21 months)
§ Redux. Also known as dexfenfluramine, this product was developed by Interneuron Pharmaceuticals Inc. (which changed its name to Indevus Pharmaceuticals Inc.). It was approved as an obesity treatment in April. (35 months)
§ RespiGam. MedImmune Inc.'s polyclonal antibody to respiratory syncytial virus (RSV) was approved in January for preventing RSV disease in high-risk children under the age of two. (35 months)
§ Retavase. Boehringer Mannheim GmbH developed this recombinant plasminogen activator, which was approved in October for managing acute myocardial infarcts in adults. Centocor Inc. (a Johnson & Johnson company) acquired the North American marketing rights in 1998. (16 months)
§ Saizen. Serono Laboratories Inc. filed an NDA on its recombinant human growth hormone (hGH), produced in mammalian cells, in 1989. However, the FDA put the application on hold -- along with those from fellow hGH developers Bio-Technology General Corp. and Novo Nordisk A/S -- until March 1994, when the orphan drug status on Lilly's approved product Humatrope expired. (Subsequently, all three firms amended their applications.) The agency finally approved Saizen in October for treating children with growth hormone deficiency. (84 months)
§ Serostim. Serono also submitted an NDA (this one in September 1995) for the use of its recombinant hGH for treating AIDS wasting (cachexia) in adults. The FDA approved the product in August. (11 months)
§ Taxotere. This product, a semi-synthetic taxol-related compound derived from the needles of the European yew tree, was developed by Rhone-Poluenc Rorer Inc. (now Aventis Pharma). The FDA conditionally approved its use as a second-line therapy for locally advanced or metastatic breast cancer in May. (21 months)
§ Verluma. NeoRx Corp.'s in vivo imaging agent for diagnosing small cell lung cancer consists of a monoclonal antibody labeled with Technetium-99m. It was approved for marketing in August. (29 months)
§ Vistide. Gilead Sciences' nucleotide analog was approved in June for delaying the progression of cytomegalovirus infection in AIDS patients. (8 months)
§ Vitrasert. This product, an intraocular implant that releases the drug ganciclovir over an extended period of time, was developed by Chiron Vision. It was approved for treating cytomegalovirus infection in AIDS patients in March. (8 months)
§ Zanaflex. Elan Corp. plc's subsidiary Athena Neurosciences Inc. in-licensed this product, tizanidine hydrochloride, from Sandoz Pharma Ltd. in 1991. The FDA approved it in December for treating muscle spasticity associated with multiple sclerosis and spinal cord injury. (36 months) |
All in all, 1996 was a great year for biotech: Twenty-one drugs, biologics and in vivo diagnostics received FDA's blessing. Three of those biologics -- the multiple sclerosis drugs Avonex and Copaxone as well as the RSV infection-fighting antibody RespiGam -- were truly unique therapies. And the median time to approval for these products (again, excluding Saizen) was 17 months, lagging the median for all therapeutics by about six weeks.
However, when we consider the average time to approval (again, minus Saizen), the picture doesn't look quite so rosy -- 21.7 months versus 17.8 months for the 53 NMEs approved in 1996. Nonetheless, 14 products came in under the average time, including five of the pure biologics -- Avonex, Copaxone, Humalog, Retavase and Serostim. And except for Copaxone, they beat the median time, too. Not too bad for biologics, which are inherently more complicated to review than traditional drugs, according to CBER.
The FDA was on a roll. But was it able to maintain this relatively brisk pace going forward?
To answer that question, we examined the fate of the 14 BLAs, NDAs and PLAs submitted by biotech firms in 1996.
One of those -- Chiron Vaccines' PLA for its pediatric whooping cough vaccine -- was withdrawn for strategic reasons. A second -- Immunomedics' BLA for its in vivo diagnostic imaging agent for osteomyelitis and appendicitis -- is still pending. But the others have been approved for sale (although some may no longer be on the market).
The speediest approval -- at three months -- went to Agouron Pharmaceuticals' AIDS drug Viracept, clear evidence of the agency's continued focus on getting as many AIDS drugs into the marketplace as quickly as it could. The slowest approval time was 25 months -- shared by Cor Therapeutics Inc.'s heart drug Integrilin and Cephalon Inc.'s narcolepsy drug Provigil.
Biotech Regulatory Submissions In 1996:
Time To Approval *
|
Product
|
Company
|
Product Type
|
Indication
|
BLA/NDA/PLA Submission
(Date)
|
FDA Approval
(Date)
|
Elapsed Time
|
|
Acelluvax
|
Chiron Vaccines
|
Combined diphtheria, tetanus and acellular pertussis vaccine
|
Immunization in infants and children (especially for whooping cough)
|
PLA
(10/96)
|
Withdrawn
(2/99)
(vaccine marketed in Italy)
|
------
|
|
Actiq
|
Anesta
(Cephalon)
|
Oral transmucosal fentanyl citrate
|
Breakthrough cancer pain in patients who are already receiving and
are tolerant to opioid therapy
|
NDA
(11/96)
|
11/98
|
24 months
|
|
AmBisome
|
NeXstar Pharmaceuticals (Gilead Sciences); Fujisawa USA
|
Liposomal formulation of amphotericin B
|
Presumed fungal infections in patients with depressed immune function
and fever of unknown origin
|
NDA
(11/96)
|
8/97
|
9 months
|
|
BeneFIX
|
Genetics Institute (Wyeth)
|
Recombinant human Factor IX (blood-clotting factor)
|
Hemophilia B
|
BLA
(9/96)
|
2/97
|
5 months
|
|
Corlopam
|
Neurex
(Elan)
|
Fenoldopam mesylate (dopamine receptor agonist)
|
Severe high blood pressure; short-term hypertension
|
NDA
(6/96)
|
9/97
|
15 months
|
|
DepoCyt
|
DepoTech
(SkyePharma)
|
Sustained release formulation of chemotherapy drug cytarabine (lipid-based
drug delivery)
|
Lymphomatous meningitis
|
NDA
(11/96 - 4/97) (rolling)
|
4/99
|
24 months
|
|
Infergen
|
Amgen
|
Concensus alpha interferon (non-naturally occurring)
|
Chronic hepatitis C virus infection
|
BLA
(4/96)
|
10/97
|
18 months
|
|
Integrilin
|
Cor Therapeutics (Millennium)
|
Small molecule compound that inhibits GPIIb/IIIa receptor that mediates
platelet aggregatin
|
To reduce complications of coronary angioplasty; also for use in acute
coronary conditions
|
NDA
(4/96)
|
5/98
|
25 months
|
|
LeukoScan
|
Immunomedics
|
Antibody fragment that binds to white blood cells, labeled with Tc-99m
|
In vivo diagnostic imaging agent for osteomyelitis in diabetic patients
with foot ulcers; also for acute atypical appendicitis
|
BLA
(12/96)
|
Not yet approved in U.S.; according to IMMU's 10-K for 6/30/02, the
FDA has said the data are still not sufficient for approval (product
is on the market in European Union and Australia)
|
71 months and counting
|
|
Neumega
|
Genetics Institute (Wyeth)
|
Recombinant human IL-11 (platelet growth factor)
|
Prevention of recurrent, severe chemotherapy-induced thrombocytopenia
in cancer patients
|
BLA
(12/96)
|
11/97
|
11 months
|
|
Periostat
|
CollaGenex Pharmaceuticals
|
Orally administered drug consisting of sub-antibiotic dose of doxycycline
(inhibits production of collagenase)
|
Treatment of periodontitis (adjunct to scaling and root planing)
|
NDA
(9/96)
|
10/98
|
25 months
|
|
Provigil
|
Cephalon
|
Modafinil; synthetic compound that is thought to affect alpha-andrenergic
receptors in the brain
|
Narcolepsy
|
NDA
(12/96)
|
12/98
|
24 months
|
|
Thalomid
|
Celgene
|
Thalidomide; thought to act by modulating levels of TNF-alpha
|
Erythema nodosum leprosum (severe condition associated with leprosy)
|
NDA
(12/96)
|
7/98
|
19 months
|
|
Viracept
|
Agouron Pharmaceuticals (Pfizer [Warner-Lambert])
|
Synthetic small molecule rationally designed to inhibit HIV protease
|
HIV infection
|
NDA
(12/96)
|
3/97
|
3 months
|
* Excludes diagnostics and medical devices.
In this group, the median time to approval for the 12 products that eventually received FDA's blessing was 18.5 months -- somewhat longer than the 17-month median enjoyed by 1996's crop of biotech products.
Interestingly, the average approval time was 16.8 months for these products -- almost five months faster than it had been for the biotech products approved in 1996. Two recombinant proteins -- BeneFIX and Neumega -- beat the average and the median approval times.
Although the approval dates for these products range from early 1997 to the spring of 1999, we can get a general idea of how their approval times compare with the FDA's overall record during this interval. According to the PhRMA, the average approval time for all new medicines in 1997 was 16.2 months; in 1998 it was 11.7 months and in 1999 it was 12.6 months. It seems apparent that biotech product approvals -- at 16.8 months, on average -- were lagging behind.
Given the fact that the FDA has, indeed, lost momentum over the last few years, we might predict that biotech drugs have fallen even farther behind by now.
And, if one considers the average time to approval, it's certainly true. As of late November, the FDA had granted first-time approvals to 13 biotech and biotech-related therapeutics. These products took an average of 22.3 months to make it through the approval process, six months longer than the biotech products approved in 1996.
Many of this year's products may prove to be big-sellers, too -- including Gilead Sciences' hepatitis B drug Hepsera, Amgen Inc.'s white-blood-cell stimulating product Neulasta (a longer-acting version of Neupogen), Hoffmann-La Roche's hepatitis C drug Pegasys and Idec Pharmaceuticals Corp.'s Zevalin, a radioimmunotherapy for non-Hodgkin's lymphoma.
Biotech And Biotech-Related Products Approved In 2002:
First-Time Approvals*
|
Product Name
|
Company (s)
(Developer; Marketer)
|
Product Description
|
Indication
|
Submission Type
(Date)
|
Marketing Approval
(Date)
|
Elapsed Time
|
|
Avinza
(formerly Morphelan; morphine sulfate)
|
Elan; Ligand Pharmaceuticals (U.S.and Canada)
|
Extended release formulation of morphine
|
Chronic, moderate-to-severe pain in patients who require continuous
opioid therapy (once-daily capsule)
|
NDA
(6/00)
|
3/02
|
21 months
|
|
DAPTACEL
(DTaP vaccine)
|
Aventis Pasteur
|
Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed
(contains 5 pertussis antigens)
|
Childhood immunization against diphtheria, tetanus and pertussis (first
4 consecutive doses)
|
BLA
(not available)
|
5/02
|
------
|
|
Eligard 7.5 mg
(formerly Leuprogel One-Month Depot; leuprolide acetate)
|
Atrix Laboratories; Sanofi-Synthelabo (North America); MediGene (Europe)
|
Sustained release of leuprolide (a leutinizing hormone-releasing hormone
agonist) via Atrigel Depot drug delivery system
|
Advanced prostate cancer
(subcutaneous)
|
NDA
(3/01)
|
1/02
|
10 months
|
|
Hepsera
(adefovir dipivoxil; 10 mg)
|
Gilead Sciences;
GlaxoSmithKline (Asia, Latin America, other territories)
|
Nucleotide analog (blocks HBV DNA polymerase)
|
Chronic hepatitis B virus (HBV) infection in treatment-naïve and treatment-experienced
patients (once-daily; oral)
|
NDA
(3/02)
|
9/02
|
6 months
|
|
Imagent
(formerly Imavist; perflexane lipid microspheres)
|
Alliance Pharmaceutical; Cardinal Health
|
Ultrasound imaging agent (perfluorohexane-based)
|
For use with echocardiography to assist in diagnosis of cardiac structure
and motion
|
NDA
(10/99)
|
6/02
|
32 months
|
|
INFUSE Bone Graft/LT-CAGE
|
Wyeth (Genetics Institute); Medtronic Sofamor Danek
|
Recombinant human bone morphogenetic protein (rhBMP-2), used with lumbar
tapered fusion device
|
Use in spinal fusion surgery to treat certain types of spinal degenerative
disc disease (low back pain)
|
PMA
(12/00)
|
7/02
|
19 months
|
|
MitoExtra
(Mitozytrex)
|
SuperGen
|
Version of generic drug mitomycin based on company's supergenerics
Extra platform
|
Therapy for disseminated adenocarcinoma of the stomach or pancreas
(combination therapy with other chemotherapies); also for use as a palliative
therapy when other modalities have failed
|
NDA
(12/97)
|
11/02
|
59 months
|
|
Neulasta
(pegfilgrastim)
|
Amgen
|
Long-lasting, PEGylated version of Neupogen (rG-CSF)
|
To decrease incidence of infection in cancer patients receiving chemotherapy
(injected once per chemotherapy cycle)
|
BLA
(3/01)
|
1/02
|
10 months
|
|
Pegasys
(peginterferon alfa-2a)
|
Shearwater (Inhale Therapeutic Systems); Hoffmann-La Roche
|
Recombinant interferon alfa-2a modified with PEG
|
Chronic hepatitis C virus infection in interferon alpha-naïve patients
with compensated liver disease; once-weekly injection
|
BLA
(5/00)
|
10/02
|
29 months
|
|
Procleix HIV-1/HCV Assay
|
Chiron, Gen-Probe
|
Nucleic acid amplification test to detect HIV-1 and HCV in blood and
plasma during earliest stages of infection
|
Screens donated blood for HIV and HCV
|
BLA
(1/01)
|
2/02
|
13 months
|
Remodulin
(formerly Uniprost, a.k.a., UT-15)
(treprostinil sodium) |
United Therapeutics
|
Analog of natural molecule prostacyclin
|
Pulmonary arterial hypertension (continuous subcutaneous infusion)
|
NDA
(8/00-10/00)
(rolling)
|
5/02
|
19 months
|
|
SecreFlo
|
Repligen
|
Synthetic porcine secretin
|
To stimulate pancreatic secretions to aid in diagnosing pancreatic
exocrine dysfunction and gastrinoma (injection)
|
NDA
(5/99)
|
4/02
|
35 months
|
|
Zevalin
(ibritumomab tiuxetan)
|
Idec Pharmaceuticals; Schering AG (ex-U.S.)
|
Murine monoclonal antibody that targets CD20 antigen on B cell surface,
conjugated to yttrium-90 (used in conjunction with rituximab)
|
Radioimmunotherapy for treating low grade or follicular, relapsed or
refractory, CD20-positive, B-cell non-Hodgkin's lymphoma and rituximab-refractory
follicular NHL
|
BLA
(11/00)
|
2/02
|
15 months
|
* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies, approved as of 11/20/02.
Gilead's Hepsera won the race, garnering FDA's blessing in six months. SuperGen Inc.'s version of the chemotherapy drug mitomycin -- MitoExtra -- brought up the rear at 59 months.
Interestingly, the median time to approval for 2002's products (excluding Aventis Pasteur's pertussis vaccine DAPTACEL, for which the BLA submission date is not available) is 19 months -- only two months longer than the median time in 1996.
What's really notable, however, is the speed with which supplemental applications have gotten approved this year. It makes sense, of course, for the FDA has already approved the very same product at least once before and the groundwork has been laid. But it's not necessarily smooth sailing, because many drug sponsors are testing their approved products in other indications. (In a few cases, the supplemental applications cover additional or improved formulations.)
To date, the FDA has approved 10 supplemental BLAs and NDAs and one abbreviated NDA (used for generics). Many of these drugs have already hit the big-time -- including Enbrel, Gleevec and Remicade -- and their developers are vigorously working to expand their franchises.
One of the therapeutics on the list, while officially approved under a supplemental BLA, isn't a follow-on indication at all. Serono originally filed the BLA for its multiple sclerosis drug Rebif in 1998, but the application was put on hold due to the orphan drug exclusivity enjoyed by Biogen's competing drug Avonex. By the time Serono was ready to challenge Biogen's status, it had important new data to add to the original application, including head-to-head trial results proving Rebif's superiority.
Biotech And Biotech-Related Products Approved In 2002:
Additional Indications*
|
Product Name
|
Company (s)
(Developer; Marketer)
|
Product Description
|
Indication
|
Submission Type
(Date)
|
Marketing Approval
(Date)
|
Elapsed Time
|
|
Argatroban
(formerly Acova)
|
Texas Biotechnology; Glaxo SmithKline
|
Anticoagulant; synthetic small molecule derived from arginine; direct
thrombin inhibitor
|
For use in patients with or at risk for heparin-induced thrombocytopenia
(HIT) and who are undergoing percutaneous coronary intervention (PCI)
|
sNDA
(12/00)
|
4/02
|
28 months
|
|
Aranesp
(darbepoietin alfa)
|
Amgen; Kirin
|
Novel erythropoiesis-stimulating protein (2nd generation EPO; longer-lasting)
|
Treatment of chemotherapy-induced anemia in patients with nonmyeloid
malignancies
|
sBLA
(9/01)
|
7/02
|
10 months
|
|
Eligard 22.5 mg
(formerly Leuprogel Three-Month Depot; leuprolide acetate)
|
Atrix Laboratories; Sanofi-Synthelabo (North America); MediGene (Europe)
|
Sustained release of leuprolide (a leutinizing hormone-releasing hormone
agonist) via Atrigel Depot drug delivery system
|
Advanced prostate cancer
|
sNDA
(9/01)
|
7/02
|
10 months
|
|
Enbrel
(etanercept)
|
Amgen (Immunex); Wyeth
|
Dimeric fusion protein; recombinant soluble p75 tumor necrosis factor
receptor (TNFr) linked to Fc portion of human IgG1
|
Psoriatic arthritis (+/- methotrexate)
|
sBLA
(7/01)
|
1/02
|
6 months
|
|
Gleevec
(imatinib mesylate)
|
Novartis Pharma
|
Rational drug design; targets tyrosine kinase c-kit; signal transduction
inhibitor
|
Inoperable and/or metastatic malignant gastrointestinal stromal tumors
(GIST) (oral)
|
sNDA
(10/01)
|
2/02
|
4 months
|
|
Paclitaxel
|
NaPro BioTherapeutics; Abbott Laboratories
|
Generic paclitaxel; inhibits cell division by blocking microtubule
assembly/dis-assembly; extracted from needles and limb stock of ornamental
yew trees
|
Cancer
|
ANDA
(3/01)
|
5/02
|
14 months
|
|
Rebif
(interferon beta-1a)
|
Serono
|
Recombinant interferon beta-1a
|
Relapsing remitting multiple sclerosis
|
sBLA
(10/01)
(original BLA filed 2/98; deterred by Avonex's orphan drug status)
|
3/02
|
5 months
(49 months from original filing)
|
|
Remicade
(infliximab)
|
Centocor (J&J); Tanabe Seiyaku (Japanand Far East); Schering-Plough
(ROW)
|
Chimeric monoclonal antibody to tumor necrosis factor-alpha
|
Combination therapy with methotrexate for improving physical function
in patients with moderately to severely active rheumatoid arthritis
|
sBLA
(not available)
|
2/02
|
------
|
|
Remicade
(infliximab)
|
Centocor (J&J); Tanabe Seiyaku (Japanand Far East); Schering-Plough
(ROW)
|
Chimeric monoclonal antibody to tumor necrosis factor-alpha
|
To induce and maintain clinical remission in patients with moderate-to-severe
Crohn's disease
|
sBLA
(not available)
|
7/02
|
------
|
|
SecreFlo
|
Repligen
|
Synthetic porcine secretin
|
To aid in the location and cannulation of the minor pancreatic duct
in patients with pancreas divisum undergoing ERCP diagnosis/treatment
|
sNDA
(5/02)
|
11/02
|
6 months
|
|
Visicol
(sodium phosphate)
|
InKine Pharmaceutical
|
New formulation of sodium phosphate tablet containing less microcrystalline
cellulose
|
Bowel cleansing prior to colonoscopy
|
sNDA
(12/01)
|
3/02
|
3 months
|
* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies, approved as of 11/20/02.
The average time to approval for these supplementary applications (excluding the two for Remicade, for which submission dates are not available) was 9.6 months -- almost 13 months faster than the first-time approvals in 2002 to date. And the median time was even speedier -- six months.
So far, then, the FDA has approved 13 new biotech-and biotech-related therapeutics this year and 11 supplements. 2002 won't be a record-breaker, but it's already better than 2001, when 14 new products and five supplements garnered the agency's blessing.
However, there are another 33 product applications (including eight supplements) still pending. Sixteen of those were submitted this year. But 17 more have been enmeshed in the regulatory framework for much longer. For these 17, the median (and the average) elapsed time has already been 23 months, longer than the average time it took for the FDA to approve this year's biotech crop.
Biotech And Biotech-Related Products Under FDA Review 2002*
|
Product Name
|
Company (s)
(Developer; Marketer)
|
Product Description
|
Indication (Sought)
|
Submission Type
(Date)
|
Review History; Details
|
Elapsed Time (as of 11/20/02)
|
|
Aldurazyme
(laronidase)
|
BioMarin Pharmaceutical, Genzyme General
|
Recombinant human alpha-L-iduronidase
|
Enzyme replacement therapy for patients with Hurler syndrome (mucopolysaccharidosis;
MPS I)
|
Rolling BLA
(4/02 - 7/02)
|
Advisory committee will meet 1/15/03
|
4 months
|
|
Amevive
(alefacept)
|
Biogen
|
Fusion protein; human LFA-3 IgG1 fusion protein (a.k.a., LFA3TIP)
|
Moderate-to-severe chronic plaque psoriasis (IV or IM)
|
BLA
(8/01)
|
FDA's Dermatologic and Ophthalmic Advisory Committee recommended approval
(5/02);
FDA sent complete response letter, requesting clarification and information
on already-submitted data (6/02);
after Biogen submitted this information, FDA said it will complete its
review within 6 months, putting approval back to 2003 (9/02)
|
15 months
|
|
Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method
(rAHF-PFM)
|
Baxter Healthcare
|
Recombinant factor VIII
|
Hemophilia A
|
BLA
(6/02)
|
-----
|
5 months
|
|
Bexxar
(tositumomab, iodine I 131)
|
Corixa (Coulter Pharmaceutical); GlaxoSmithKline
|
Murine monoclonal antibody against CD20 antigen on B cells, conjugated
to I-131
|
Patients with relapsed or refractory low-grade or transformed low-grade
B-cell non-Hodgkin's lymphoma
|
BLA
(7/99);
FDA requested reorganization of BLA (8/99);
BLA resubmission (9/00)
|
Assigned 6-month priority review status (10/00);
in complete review letter, FDA requested additional clinical and manufacturing
information (3/01), which company submitted (8/01 and 9/01);
in 2nd complete review letter, FDA requested additional clinical studies
on safety and efficacy (3/02);
company provided information and met with FDA; agency still thinks new
trials necessary (5/02);
company filed request for formal dispute resolution (5/02);
FDA granted the appeal and product will go before an ODAC panel on 12/17/02
|
40 months
|
|
Campath
(alemtuzumab)
|
Ilex Oncology; Berlex Laboratories (Schering AG)
|
Humanized monoclonal antibody against CD52 antigen on T and B cells
|
To incorporate long-term efficacy and safety data in label on approved
product
|
sBLA
(5/02)
|
------
|
6 months
|
|
Cialis
(tadalafil)
|
Lilly ICOS LLC (Icos; Lilly JV)
|
PDE5 (phosphodiesterase) inhibitor
|
Erectile dysfunction
|
NDA
(6/01)
|
FDA issued approvable letter; companies must conduct additional clinical
pharmacology studies (4/02)
(US launch projected in 2003)
|
17 months
|
|
Coviracil
(emtricitabine)
|
Triangle Pharmaceuticals
|
Nucleoside reverse transcriptase inhibitor
|
Treatment of HIV disease
(once-daily)
|
NDA
(9/02)
|
------
|
2 months
|
|
D2E7
(adalimumab)
|
Cambridge Antibody Technology, Abbott Laboratories (Knoll/BASF)
|
Fully human monoclonal antibody to tumor necrosis factor-alpha
|
Moderate-to-severe rheumatoid arthritis in adults who had inadequate
responses to DMARDS (subcutaneous)
|
BLA
(4/02)
|
------
|
7 months
|
|
Dynepo
(gene-activated EPO)
|
Transkaryotic Therapies; Aventis Pharma
|
Human erythropoietin produced via gene activation (inserts DNA sequences
into human cells, thus activating the endogenous human gene to stimulate
EPO production)
|
Anemia in patients with chronic renal failure (both dialysis and non-dialysis
patients)
|
BLA
(8/00)
|
FDA did not accept BLA for filing; it requested data on additional
manufacturing runs of Dynepo (due to change in manufacturing process);
amount of new data means this information will be submitted as part
of a new BLA, expected to occur in 6 months
(11/00);
As per TKTX's 10-Q for 9/30/02, Aventis is still gathering these data
and has not yet submitted new BLA
|
27 months
|
|
Eligard 30 mg
(four-month depot)
|
Atrix Laboratories, Sanofi-Synthelabo (North America); MediGene (Europe)
|
Sustained release of leuprolide (a leutinizing hormone-releasing hormone
agonist) via Atrigel Depot drug delivery system
|
Advanced prostate cancer
(subcutaneous)
|
sNDA
(4/02)
|
------
|
7 months
|
|
Enbrel
(etanercept)
|
Amgen (Immunex), Wyeth
|
Dimeric fusion protein; recombinant soluble p75 tumor necrosis factor
receptor (TNFr) linked to Fc portion of human IgG1
|
To inhibit the progression of structural damage in patients with psoriatic
arthritis
|
sBLA
(10/02)
|
------
|
1 month
|
* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.
As detailed in these tables, the wait has been painful for many. The FDA has requested additional information from one company after another. Sometimes, the agency asks for clarification of already-submitted data, other times it wants more information on certain aspects of manufacturing or quality controls; but much too often, it seems, the agency tells the drug sponsor to go back to the clinic.
A few companies have even withdrawn their applications while they conduct another Phase III trial --- including Cellegy Pharmaceuticals Inc. (Cellegesic), Forest Laboratories Inc./Neurobiological Technologies Inc. (Memantine) and Praecis Pharmaceuticals Inc. (Plenaxis).
Biotech And Biotech-Related Products Under FDA Review 2002*
|
Product Name
|
Company (s)
(Developer; Marketer)
|
Product Description
|
Indication (Sought)
|
Submission Type
(Date)
|
Review History; Details
|
Elapsed Time (as of 11/20/02)
|
|
Enbrel
(etanercept)
|
Amgen (Immunex), Wyeth
|
Dimeric fusion protein; recombinant soluble p75 tumor necrosis factor
receptor (TNFr) linked to Fc portion of human IgG1
|
To improve physical function in patients with rheumatoid arthritis
|
sBLA
(10/02)
|
------
|
1 month
|
|
Estrasorb
(17-beta-estradiol)
|
Novavax, King Pharmaceuticals
|
Uses micellar nanoparticles to deliver natural hormone 17-beta-estradiol
through the skin
(cream)
|
Topical estrogen replacement therapy for short-term use in reducing
vasomotor symptoms in menopausal women
|
NDA
(6/01)
|
FDA completed review of NDA and requested additional information regarding
the chemistry, manufacturing and controls section; Novavax withdrew
the NDA (4/02);
company prepared that information and resubmitted NDA (9/02):
FDA accepted NDA for review (11/02)
|
17 months
|
|
Fabrazyme
(agalsidase beta)
|
Genzyme
|
Recombinant human alpha-galactosidase A
|
Enzyme replacement therapy for patients with Fabry disease
|
BLA
(6/00)
|
FDA said advisory committee review not necessary (11/00);
FDA requested clarification and additional data (12/00);
FDA sent complete response letter, requesting more information (10/01);
FDA postponed Endocrinologic and Metabolic Drugs Advisory Committee
meeting (scheduled for 9/26/02) midst concerns about the composition
of the committee (9/02);
advisory committee meeting now scheduled for 1/13/03
|
29 months
|
|
FluMist
(Influenza Virus Vaccine Live, Intranasal)
|
MedImmune (Aviron); Wyeth-Lederle Vaccines
|
Attenuated, cold-adapted live virus vaccine (intranasal)
|
To prevent influenza in children and adults
|
BLA
(10/00)
|
Delayed BLA submission due to manufacturing issues (11/99);
Vaccines and Related Biological Products Advisory Committee said product
is efficacious but not convinced of safety, needs more data (7/01);
FDA sent complete response letter (8/01);
company sent reply which included the requested additional information
and clarification on clinical and manufacturing data (1/02);
FDA sent complete response letter; requests clarification and additional
information related to data (7/02);
company responded (8/02);
advisory committee scheduled for 12/17/02
|
25 months
|
|
Fuzeon
(enfuvirtide; formerly T-20)
|
Trimeris; Hoffmann-La Roche
|
HIV fusion inhibitor; blocks virus from entering cells; 36-amino acid
peptide (binds to HIV surface protein gp41)
|
HIV-1 infection (combination therapy with other antiretroviral agents)
(subcutaneous injection, twice daily)
|
NDA
(9/02)
|
------
|
2 months
|
|
Gleevec
(imatinib mesylate)
|
Novartis Pharma
|
Rational drug design; blocks function of Bcr-Abl protein (which causes
uncontrolled proliferation of WBC); signal transduction inhibitor
|
First-line therapy for patients with newly diagnosed chronic myeloid
leukemia (oral)
|
sNDA
(7/02)
|
------
|
4 months
|
|
Gliadel Wafer
(polifeprosan 20 with carmustine implant)
|
Guilford Pharmaceuticals
|
Biodegradable polyanhydride wafer containing carmustine (implant)
|
First-line therapy for patients with newly diagnosed glioma
|
sNDA
(4/01)
|
Oncologic Drugs Advisory Committee voted 8-5 that product provides
clinical benefit with acceptable safety (12/01);
FDA sent company non-approvable letter (3/02);
company submitted amendment to sNDA with data on long-term survival
(11/02)
|
19 months
|
|
Hemopure
(hemoglobin glutamer -250 [bovine])
|
Biopure
|
Chemically stabilized bovine hemoglobin formulated in balanced salt
solution
|
Treatment of signs and symptoms of acute anemia in adult patients undergoing
orthopedic surgery; to eliminate, delay or reduce the need for red blood
cells in these patients
|
BLA
(7/02)
|
------
|
4 months
|
|
Iressa
(gefitinib)
|
AstraZeneca Pharmaceuticals
|
EGFr inhibitor; epidermal growth factor receptor-tyrosine kinase inhibitor
(blocks signaling pathways that play major role in solid-tumor growth)
|
Advanced non-small cell lung cancer in patients who have failed at
least two chemotherapy agents (3rd-line therapy) (once-daily oral tablet)
|
NDA
(~7/01 - 8/02) (rolling)
|
FDA's Oncology Drugs Advisory Committee voted 11-3 to recommend accelerated
approval (9/02)
|
3 months
|
|
Istalol
(timolol)
|
ISTA Pharmaceuticals, Senju Pharmaceutical Co.
|
New formulation of timolol (non-selective beta adrenergic receptor
blocking agent, a.k.a. beta blocker)
|
Glaucoma (once-daily topical formulation)
|
NDA
(9/02)
|
------
|
2 months
|
|
Kineret
(anakinra)
(formerly Antril, Synergen)
|
Amgen
|
Recombinant interleukin-1 receptor antagonist
|
To inhibit the progression of structural damage in adult patients with
moderately to severely active rheumatoid arthritis
|
sBLA
(10/02)
|
------
|
1 month
|
* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.
The longest-suffering of them all has to be Corixa Corp., though, whose BLA for Bexxar, a radioimmunotherapy for non-Hodgkin's lymphoma, has been in the agency's hands for 40 months. The company disagrees with the agency's assessment that a new clinical trial will be necessary to prove the product's safety and efficacy -- so it filed a request for a formal dispute resolution. And, on December 17, Bexxar will finally get its day in court as it goes before an Oncologic Drugs Advisory Committee.
December 17 will also be a big day for FluMist, MedImmune's attenutated, live virus vaccine for the flu. On that day, the company will present its case -- for the second time -- to the Vaccines and Related Biological Products Advisory Committee. The BLA has been pending for 25 months.
Biotech And Biotech-Related Products Under FDA Review 2002*
|
Product Name
|
Company (s)
(Developer; Marketer)
|
Product Description
|
Indication (Sought)
|
Submission Type
(Date)
|
Review History; Details
|
Elapsed Time (as of 11/20/02)
|
|
LeuTech
|
Palatin Technologies, Mallinckrodt
|
Radiolabeled monoclonal antibody that binds specifically to white blood
cells; for in vivo imaging of infection sites
|
Diagnosis of appendicitis in patients with equivocal signs and symptoms
|
BLA
(11/99)
|
Medical Imaging Drugs Advisory Committee voted to recommend approval
(7/00);
FDA asked for more manufacturing data (9/00);
company will file BLA amendment in 2H:02 or 1Q:03 (10/01; 9/02)
|
36 months
|
|
Olux
(clobetasol proprionate)
|
Connetics
|
Stabilized foam formulation of clobetasol proprionate 0.05% (super
high potency corticosteroid)
|
Expanded label claims to include treatment of non-scalp areas in psoriasis
|
sNDA
(12/01)
|
FDA sent approvable letter (10/02)
|
11 months
|
|
Pegasys/Copegus combination
(peginterferon alfa-2a plus ribavirin)
|
Shearwater (Inhale Therapeutic Systems); Hoffmann-La Roche
|
Recombinant interferon alfa-2a modified with PEG plus anti-viral drug
ribavirin
|
Chronic hepatitis C virus infection
|
BLA/NDA combination filing
(6/02)
|
Anti-Viral Drugs Advisory Committee recommended approval (unanimous)
(11/02)
|
5 months
|
|
PolyHeme
|
NorthfieldLaboratories
|
Chemically modified hemoglobin derived from outdated donor blood
|
Oxygen-carrying blood substitute for trauma situations
|
BLA
(8/01)
|
FDA issued a refusal-to-file letter (seeks additional information)
(11/01);
per NFLD's 10-Q for 8/31/02, the company and the FDA are still in discussions
on how to proceed
|
15 months
|
|
Prestara
(formerly Aslera; GL701)
(prasterone)
|
Genelabs Technologies; Watson Pharmaceuticals
|
Adrenal hormone (dehydroepiandrosterone [DHEA])
|
To limit bone loss in women with mild to moderate systemic lupus erythematosus
who are taking low-dose glucocorticoids
|
NDA
(5/00-9/00) (rolling)
|
Designated for priority review (10/00);
Arthritis Advisory Committee split on drug benefits (4/01);
FDA issued non- approvable letter (6/01);
FDA asked for additional clinical data and analyses (1/02), which company
submitted in 2/02;
FDA issued approvable letter, with approval contingent on completion
of additional clinical trial (8/02);
company submitted Phase III protocol to FDA (11/02)
|
26 months
|
|
Replagal
(agalsidase alfa)
|
Transkaryotic Therapies; Sumitomo Pharmaceuticals
|
Recombinant human alpha galactosidase A
|
Enzyme replacement therapy for Fabry disease
|
BLA
(6/00)
|
FDA sent complete review letter, requesting clarification and additional
data (1/01);
FDA postponed Endocrinologic and Metabolic Drugs Advisory Committee
meeting (scheduled for 9/27/02) midst concerns about the composition
of the committee (9/02);
FDA said clinical data with regard to pain are uninterpretable, so TKTX
decided to seek approval on basis of renal and cardiac data (10/02);
advisory committee meeting now scheduled for 1/14/03
|
29 months
|
|
Risperdal Consta
(risperidone; long-acting injection)
|
Alkermes, Janssen Pharmaceutica Products (Johnson & Johnson)
|
Long-acting formulation of Risperdal that uses Alkermes' Medisorb drug-delivery
technology
|
Management of schizophrenia (twice-monthly injection)
|
NDA
(7/01)
|
FDA sent J&J a not-approvable letter; agency had questions about
pre-clinical data (7/02);
per ALKS 10-Q for 9/30/02, J&J has met with the FDA and is working
to answer its questions
|
16 months
|
|
Symlin
(pramlintide acetate)
|
Amylin Pharmaceuticals
|
Synthetic version of human hormone amylin
|
Adjunctive therapy to insulin for treating people with Type I or II
diabetes who use insulin
|
NDA
(12/00)
|
Endocrinologic and Metabolic Drugs Advisory Committee voted not to
recommend approval, based on safety concerns (7/01);
despite that, FDA issued approvable letter, but called for additional
clinical work prior to approval (10/01)
|
23 months
|
|
Vitrase
|
ISTA Pharmaceuticals
|
Highly purified hyaluronidase
|
Severe vitreous hemorrhage
|
NDA
(1/4/02 -- 1Q03E) (rolling)
|
------
|
NDA submission in progress
|
|
Xolair
(a.k.a. Anti-IgE, rhuMAb-E25; omalizumab)
|
Genentech, Tanox, Novartis
|
Recombinant humanized anti-IgE monoclonal antibody
|
Allergic asthma and seasonal allergic rhinitis
|
BLA
(6/00)
|
FDA issued complete response letter, requesting more data (7/01);
companies plan to submit amendment to BLA for the allergic asthma indication
in adults and adolescents in 4Q:02
|
29 months
|
|
Zavesca
(OGT 918; miglustat)
|
Oxford GlycoSciences
|
Small molecule inhibitor of glycosyltrans-ferase (inhibits glycolipid
formation)
|
Type I Gaucher disease (oral administration)
|
NDA
(3/01 - 8/01) (rolling)
|
FDA sent non-approvable letter, citing insufficient safety and efficacy
data and requiring additional clinical studies (6/02);
company met with FDA and received follow-up letter; company now plans
to submit amendment to NDA in early 2003 (11/02)
|
15 months
|
* Includes drugs and biologics developed by biotechnology companies as well as biotech-derived products developed by pharmaceutical companies.
Competitors Genzyme Corp. and Transkaryotic Therapies Inc. (TKT) have also been stymied in their efforts to present their data to an advisory committee. Both firms have developed an enzyme replacement therapy for patients with the rare genetic lysosomal storage disorder, Fabry disease. Both products -- Genzyme's Fabrazyme and TKT's Replagal -- are already approved for use in 25 countries. Both BLAs have been in the FDA's hands for 29 months, and the agency has requested clarification and additional information on each. In late September, the agency postponed its scheduled Endocrinologic and Metabolic Drugs Advisory Committee meeting -- which was set to review both applications -- after TKT objected to the composition of the panel. The advisory committee is currently scheduled to convene January 13-14 to consider the applications -- once and for all, we hope.
Meanwhile, everybody waits. We wait for the FDA to put its stamp of approval on Biogen's psoriasis drug Amevive. We wait for the agency to rule on Cialis, the Lilly ICOS LLC product for treating erectile dysfunction. And we wait for the results of additional clinical trials requested by the FDA on Genelabs Technologies Inc.'s lupus drug Prestara, Amylin Pharmaceuticals Inc.'s diabetes drug Symlin -- among many others.
But, more than anything else, we wait for the agency to kick back into high gear. It's got a new commissioner, access to $1.2 billion in user fees over the next five years under PDUFA III (money that could go to hire up to 450 additional staff members) and a plan to move the review of biotech therapeutics from the biologics division to the drugs division.
Hopefully, these factors will serve to exorcise the ghosts in the regulatory machine. |