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FDA issues statement on

ENHANCE trial p97

Multi-target kinase
inhibitor deal p98

Cardiovascular risk of
diabetes drugs p99 2008 FDA drug approvals
Specialty products continued to dominate new drug and biologic approvals in the US in a year in which
the evolving regulatory environment also featured heavily.

Bethan Hughes cautions about reading too much lacosamide (Vimpat; Schwarz) and
into slight changes year to year in the certolizumab pegol (Cimzia; UCB).
US FDA approvals in 2008 totalled number of approvals. “The fact that “Those approvals came with a pound
21 new molecular entities (NMEs) we approved a few more one year of flesh; at one point they may have
and 3 biologic licence applications than we approved in a previous year seemed in doubt but finally got
(BLAs) that were evaluated by the should not be interpreted as a trend squeezed out of the FDA’s doors.
Mark McClellan discusses Center for Drug Evaluation and or the FDA speeding up or slowing So, in no way do I think that the
challenges facing the
new US administration Research (CDER) (TABLES 1,2). down; it’s simply that those are the FDA is an easier place for companies
p102 For some, this slight increase in applications that met the standards to send their drug applications,”
approvals compared with recent years for approval,” he says. “Some were says Eric Schmidt, Biotechnology
(FIG. 1) is cause for optimism. “It still applications that went through on Equity Research Analyst, Cowen and
falls far short of the approval rate one cycle and some are applications Company, New York, USA.
seen in the 1990s, and we do need that were submitted years ago,
to see more consistency in terms of requiring multiple cycles. I think you Ongoing specialty trend
that number increasing each year, have to keep that in mind when you However, there are some situations
but overall it is encouraging,” says are looking at the data,” he adds. in which the regulatory process is
Andrew Jones, Senior Pharmaceutical Indeed, at least four of this year’s considered likely to be smoother.
Analyst, Ernst & Young, London, UK. NMEs and BLAs were delayed from “The theme is the same: if you are
New drug approved for
stem-cell mobilization John Jenkins, director of the previous years: desvenlafaxine (Pristiq; going for a rare disorder or a very
p105 FDA’s Office of New Drugs (OND), Wyeth), alvimopan (Entereg; Adolor), severe disease, such as with Treanda ▶

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60 Michael Hay, senior analyst at

BioMedTracker, Sagient Research Systems, San
53 New molecular entities
50 Biologic license applications
Diego, USA, highlights the approval of Cinryze
(which does not appear in TABLE 1 because
Number of drugs approved

39 it is purified from blood plasma and was

35 therefore approved by the Center for Biologics
30 31 Evaluation and Research, not CDER), a
30 serum-derived C1-esterase inhibitor developed
21 21 by Lev Pharmaceuticals. Cinryze is the first
20 17 18 18 product to be approved by the FDA for the
routine prophylaxis of angio-oedema attacks
10 in patients with hereditary angio-oedema.
6 7 5 7 6 5 4
3 3 2 2 2 3
Regulatory delays
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Delays in regulatory decisions were also
Figure 1 | FDA drug approvals. New molecular entities and biologic license applications approved a significant approvals-related trend in
by the US FDA’s Center for Drug Evaluation and Research by year. 2008 (Nature Rev. Drug Discov. 1, 10–11;
Nature Reviews | Drug Discovery 2009). It is no secret that in recent years
the FDA has been struggling to meet its
[bendamustine hydrochloride, developed or biotech companies, they don’t necessarily Prescription Drug User Fee Act (PDUFA)
by Cephalon for chronic lymphocytic need to generate this level of revenue, goals to achieve review of 90% of NDAs
leukaemia], you have a better shot at getting suggests Jones. “For some, the revenue and BLAs within 10 months for standard
the FDA to turn around your application potential that specialty products produce reviews and within 6 months for priority
without any delay,” says Schmidt. In this is sufficient to pursue those markets.” reviews. During the fiscal year (FY) 2008
case, the new drug application (NDA) for (from October 2007 to September 2008)
bendamustine hydrochloride, an orphan Novelty and unmet need the FDA made a management decision that
drug, was submitted in September 2007, Although the overall number of approvals they would not be able to meet all PDUFA
received priority status in December 2007 in 2008 was higher than in 2007 (FIG. 1), goals and from 1 January to 31 October
and received approval in March 2008. the number of agents given priority reviews 2008 20% (32 out of 159 NDAs and BLAs)
This perception of approvals being more (TABLES 1,2) — a reflection of their perceived were missed (
straightforward for such products may help potential to address unmet medical needs — present/fda-cms-summit2008/FDA_CMS_
explain why the majority of NME and BLA was nine in both years. From the perspective Summit_2008_120408.pdf).
approvals this year were for specialist-care of therapeutic novelty, two products that Products with delayed PDUFA dates for
indications, suggests Philip Ma, Director in the attracted attention in 2008 were romiplostim which regulatory decisions are still pending
Silicon Valley office of McKinsey & Company, (Nplate; Amgen) (TABLE 1) and eltrombopag include two potential blockbusters. For Lilly’s
USA. Other factors also attract developers to (Promacta; GlaxoSmithKline) (TABLE 2). These prasugrel hydrochloride, which has been
such products, he explains: “The unmet need drugs, both of which act as thrombopoietin developed for the secondary prevention of
tends to be relatively high and there’s generally receptor agonists, are the first two targeted thrombotic cardiovascular complications
less payer pressure than in the primary care treatments available for thrombocytopenia in patients with acute coronary syndrome
areas.” In addition, new products tend to be in patients with chronic immune (idiopathic) managed with percutaneous coronary
targeted therapies that lend themselves to thrombocytopenic purpura. In addition, intervention, the date was extended from
specialty care, and account for a lot of the R&D Regeneron’s biologic rilonacept (Arcalyst), June 2008 to February 2009. And for Takeda’s
of many of the players in this area, says Ma. an interleukin-1β blocker, became the alogliptin, a dipeptidyl peptidase 4
Overall, of the NMEs and BLAs approved first therapy to be approved for the rare inhibitor for type 2 diabetes, the PDUFA
in 2008, few are anticipated to become inflammatory cryopyrin-associated periodic date was extended from October 2008 to
blockbusters. But as many of these products syndromes, which involve excessive release June 2009. Although big pharma may be able
come from smaller specialty pharmaceutical of activated interleukin-1β. to bear the financial costs of these delays,

Table 1 | New biologics approved by the US FDA’s Center for Drug Evaluation and Research in 2008
generic name company* indication Properties Date
(Trade name) (urL of label information if available)
Rilonacept Regeneron Cryopyrin-associated periodic syndromes including familial cold interleukin-1 blocker 27 Feb (P, O)
(Arcalyst) autoinflammatory syndrome and Muckle–wells syndrome
Certolizumab UCB Crohn’s disease Tumour necrosis factor 22 Apr (S)
pegol (Cimzia) ( blocker
Romiplostim Amgen Thrombocytopenia in patients with chronic immune (idiopathic) Thrombopoietin receptor 22 Aug (P, O)
(Nplate) thrombocytopenic purpura agonist
*The company that submitted the original biologic license application to the US FDA. O, FDA orphan designation; P, FDA priority review; S, FDA standard review.

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Table 2 | New molecular entities approved by the US FDA’s Center for Drug Evaluation and Research in 2008
generic name company* indication Properties Date
(Trade name) (urL of label information if available)
Etravirine Tibotec HiV-1 Non-nucleoside reverse 18 Jan (P)
(intelence) ( transcriptase inhibitor
Desvenlafaxine wyeth Major depressive disorder Selective serotonin and 29 Feb (S)
(Pristiq) ( noradrenaline reuptake
Bendamustine Cephalon Chronic lymphocytic leukaemia Mechlorethamine derivative 20 Mar (P, O)
hydrochloride ( with DNA-alkylating activity
Regadenoson CV Therapeutics Pharmacological stress agent for radionuclide imaging A2A adenosine receptor 10 Apr (S)
(lexiscan) ( agonist
Methylnaltrexone Progenics Opioid-induced constipation Peripherally acting μ opioid 24 Apr (S)
bromide (Relistor) receptor antagonist
Alvimopan Adolor To accelerate gastrointestinal recovery following bowel Peripherally acting μ opioid 20 May (S)
(Entereg) resection surgery receptor antagonist
Difluprednate Sirion inflammation and pain associated with ocular surgery Ocular corticosteroid 23 Jun (P)
(Durezol) ( thought to act by the
induction of phospholipase
A2 inhibitory proteins
Gadoxetate Bayer Gadolinium-based contrast agent Paramagnetic compound 3 Jul (S)
disodium (Eovist) (
Clevidipine The Medicines Peri-operative hypertension when oral therapy is not Short-acting dihydropyridine 1 Aug (S)
butyrate Company feasible or not desirable calcium channel antagonist
Tetrabenazine Prestwick Chorea associated with Huntington’s disease Monoamine-depleting agent 15 Aug (P, O)
(Xenazine) (
iobenguane GE Healthcare Radiopharmaceutical agent for the detection of primary or Taken up by the 19 Sep (P, O)
i-123 (AdreView) metastatic phaeochromocytoma or neuroblastoma noradrenaline transporter in
( adrenergic nerve terminals
Silodosin watson Benign prostatic hyperplasia α1 adrenoceptor antagonist 8 Oct (S)
(Rapaflo) (
lacosamide Schwarz Partial-onset seizures in epilepsy Selectively enhances slow 28 Oct (S)
(Vimpat) ( inactivation of voltage-gated
sodium channels and binds to
collapsin response mediator
protein 2
Fesoterodine Pfizer Overactive bladder disorder Competitive muscarinic 31 Oct (S)
fumarate (Toviaz) ( receptor antagonist
Rufinamide Eisai Seizures associated with lennox–Gastaut syndrome Sodium channel activity 14 Nov (S)
(Banzel) ( modulator
Eltrombopag GlaxoSmithKline Thrombocytopenia in patients with chronic immune Thrombopoietin receptor 20 Nov (P, O)
(Promacta) (idiopathic) thrombocytopenic purpura agonist
Tapentadol Ortho–McNeil– Moderate to severe acute pain μ opioid receptor agonist 20 Nov (S)
hydrochloride‡ Janssen and noradrenaline reuptake
Fospropofol Eisai Monitored anaesthesia care sedation Prodrug of propofol 12 Dec (S)
disodium (
Plerixafor Genzyme Autologous transplantation in patients with non-Hodgkin’s CXCR4 antagonist 15 Dec (P, O)
(Mozobil) lymphoma and multiple myeloma
Gadofosveset Epix Gadolinium-based contrast agent Paramagnetic compound 22 Dec (S)
Degarelix Ferring Advanced prostate cancer Gonadotropin-releasing 24 Dec (S)
(Firmagon) ( hormone receptor antagonist
*The company that submitted the original new drug application to the US FDA. ‡Trade name not available at the time of going to press. O, FDA orphan designation;
P, FDA priority review; S, FDA standard review.

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smaller companies may not have the finances the potential to slow an approval, if a REMS of assembling advisory panels is thought
to ensure that a sales force is ready for launch had to be put in place, it should have been to have contributed to the delay for
of a product when it finally achieves approval, something that the agency discussed with alogliptin.
suggests Hay. the sponsor early on and should not have Another reason for the postponement
The reasons that the FDA has given had a major impact on delaying approvals,” of the alogliptin PDUFA date could be
for not meeting PDUFA goals include says Lawrence Liberti, Vice President, related to the FDA’s recent announcement
increased workload, in part related to the CMR International Institute for Regulatory that manufacturers developing new drugs
FDA Amendments Act (FDAAA) 2007, Science, London, UK. and biologics for type 2 diabetes will have
which introduced new authorities to require Nevertheless, some still consider that to provide evidence that the therapy will
post-market studies, safety labelling changes, REMS might have slowed some approvals. not increase the risk of cardiovascular
and risk evaluation and mitigation strategies Of the currently approved REMS (last events such as a heart attack (see page 99).
(REMS). To help ease the strain on the FDA’s updated 23 October 2008 (http://www. Some insight into how such guidance could
workload — which was well acknowledged be applied might come from an advisory
before the FDAAA added to it (Nature Rev. htm)), two are NMEs and two are BLAs panel meeting in March 2009 to discuss
Drug Discov. 7, 107–109; 2008) — the FDA that were approved in 2008: alvimopan Novo Nordisk’s diabetes drug liraglutide,
has been actively recruiting new employees, (Entereg; Adolor), tetrabenazine (Xenazine; a glucagon-like peptide 1 analogue.
and CDER achieved a net gain of 396 staff Prestwick), certolizumab pegol (Cimzia; “The meeting will be interesting because the
in FY 2008 with 121 specifically working in UCB) and romiplostim (Nplate; Amgen). cardiovascular guidance was not available at
the OND. Three of these products experienced the time liraglutide’s Phase III studies were
“It’s very good news that we have been able regulatory delays that have been attributed conducted and this will be the first panel
to bring up our staffing levels dramatically. in part to the sponsor having to meet the for a diabetes drug since the new guidelines
Over time, that will start paying dividends requirement for adequate REMS. came out,” says Hay.
regarding our ability to get back on track From an investor perspective, REMS have
with meeting not only our PDUFA goals an additional negative impact on commercial
but also the new provisions under the prospects. “I think that the commercial
FDAAA legislation and new paediatric drug marketplace for a drug can be constrained Risk management should
development legislation. So it’s not just the by a REMS programme. Nplate from Amgen
user fee goals that the new staffing will help us is an example of a very stringent REMS
be incorporated into drug
with,” says Jenkins. He also adds an important programme that could make it more difficult development programmes
caveat: “It can take 2–3 years for a new for prescribing,” says Schmidt. as early as possible.
reviewer to be fully trained and productive For sponsors developing products,
enough to carry a full workload because of Jenkins thinks that risk management should
the complexity of the work that we do.” be incorporated into drug development Upcoming regulatory decisions
programmes as early as possible. “Some In addition to the pending decisions for
of the REMS are very complicated to put delayed products such as alogliptin and
together, and by that I mean something prasugrel, analysts are interested in Amgen’s
For some, the revenue that has elements to assure safe use and has denosumab, a potential blockbuster for
restricted distribution. It can take months osteoporosis. There are also a few NDAs
potential that specialty
to develop a programme and interface with and resubmissions that are eagerly awaited.
products produce is sufficient us to reach an agreement. So, if you wait The first is Dendreon’s sipuleucel-T
to pursue those markets. until the end for an application that is going (Provenge), for advanced prostate cancer,
to need that type of REMS then you are for which final results of the additional
setting the whole process back by several efficacy data required by the FDA’s
Impact of REMS months at least.” Early consideration of risk approvable letter in May 2007 should be
There has also been considerable debate management may also help sponsors find available by mid 2009. “You could see that as
regarding the potential impact on approvals ways to identify patients at risk of side effects a PDUFA by the end of this year,” says Hay.
of the FDA’s authority to require REMS that could be incorporated into the clinical Another NDA of broad interest that
(Nature Rev. Drug Discov. 7, 963; 2008). development programme, he adds. is anticipated to be filed early in 2009 is
“Some people have questioned whether our for Mannkind’s inhaled insulin. “Most
ability to require REMS for drugs might lead Advisory panels and guidance companies dropped their inhaled insulin
us to approve drugs that maybe in the past Given another FDAAA 2007 requirement programmes following the withdrawal of
we would not have been willing to approve,” that all new chemical entities are referred Exubera [Pfizer],” says Hay. “Mannkind’s
says Jenkins. “I think that is a very difficult to an advisory committee unless the FDA data look good but no-one knows what to
question to answer because, before REMS, determines otherwise, both Hay and do with the lung cancer data that came up
we had the ability to work with companies to Schmidt expect to see a continued increase with Exubera, so it will be very interesting
develop RiskMAPS [risk minimization action in the number of advisory panels. to see how the FDA addresses that issue.”
plans, which have been available since 2005].” “That also could have contributed to some Such issues are among the many that will be
Indeed, earlier discussions about safety delays,” says Hay, “particularly as the conflict faced by the new FDA Commissioner, who,
issues in view of such tools might have of interest rules about who can be on the although not yet appointed at the time of
helped companies to reduce the possibility advisory panels can make it complicated to going to press, is hoped by many to take up
of REMS-related delay. “While REMS have get through a review process.” The difficulty the role as early as possible in 2009.

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