The Drug Development Process:

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The Drug Development Process Pharmaceutical
Industry
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Drug Development Altruistic Objective Offer the
public a therapeutic chemical compound to prevent
or alleviate disease symptoms. Commercial
Objective Cost-effectively discover and develop
a potentially therapeutic chemical compound that
generates adequate revenues to 1) Recover RD
costs of drug. 2) Sustain synthesis,
distribution and marketing activities for
drug. 3) Provide spending capital to fund new
RD activities.
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Categorical costs of drug discovery development

1. Corporate infrastructure and overhead.
2. Intellectual protection and litigation.
3. Biological research.
4. Chemical research.
5. Preclinical safety assessment (toxicology).
6. FDA relations
7. Clinical safety assessment (phase 1 clinical
   trials).
8. Clinical efficacy assessment (phase 2 clinical
   trials).
9. Large scale synthesis and formulations.
10. Distribution.
11. Marketing Sales

Discovering and bringing one new drug to the
public typically costs a pharmaceutical company
nearly 1 billion and takes an average of 10 to
12 years.
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Brand name manufacturers are given 17 years of
patent life and allowance for restoration of up
to 5 years of lost patent time due to delays in
the drug approval process.
Drug Development Timeline
Cost Recovery
Patent
RD Timeline
Expiration of patent
Date of patent application
Launch date (drug is marketed to public)
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• Critical Stages of Drug Development (in
  chronological order)
• Identification of drug target
• Screening for chemical compounds that bind to
  target
• Safety assessment (preclinical)
• Safety assessment (clinical)
• Efficacy assessment (clinical)
• Clinical monitoring (post-launch)
• Utilization of computational methods are expected
  to
• DECREASE TIME of development
• INCREASE probability of drug approval

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• Identification of drug target
• A drug target is the receptor or enzyme that the
  drug will bind to and inactivate.
• A) DNA microarray-based gene expression profiling
  in disease tissues to identify the genes
  (extrapolated to proteins) that show altered gene
  regulation in the disease state.
• B) Identification of SNPs (or mutations) that
  confer the disease state.

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• 2) Screening for chemical compounds that bind to
  target
• A) 3D characterization and modeling of the target
  enzyme or protein for the purposes of identifying
  a region or domain of the protein that a drug can
  bind to (with high affinity).
• B) Prediction of the molecular structure of a
  drug that will bind to the target. Use the
  principal components of this prediction to reduce
  the diversity (and number) of chemical compounds
  to be screened.

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• 3) Safety assessment (preclinical)
• DNA microarray focused on liver enzymes
  (metabolic enzymes) to characterize the response
  of the liver to the drug (in rats).
• DNA microarray-based expression profiling in the
  target tissue to assess the response of the
  target tissue.

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• 4) Safety assessment (clinical)
• SNP screening in normal patients to correlate
  altered drug metabolism with known SNPs in drug
  metabolism enzymes.
• Data from this represents the future of
  personalized medicine.

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5) Efficacy assessment (clinical) A)
Utilization of molecular endpoints in clinical
studies (high-content assays)
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• 6) Clinical monitoring (post-launch)
• SNPs (known new) identified in poor responders
  and toxicity issues.
• SNP screening of metabolic enzymes (in the near
  future).
• SNP screening of ALL known SNPs (in the next
  decade).

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Pfizer's Torcetrapib/Atorvastatin Significantly Raised "Good" Cholesterol While Lowering "Bad" Cholesterol 25 Nov 2005   Results presented today at the American Heart Association's annual meeting showed that torcetrapib combined with all doses of atorvastatin (Lipitor) resulted in a significant increase in "good" cholesterol (HDL-C) levels at the same time as substantially decreasing their "bad" cholesterol (LDL-C). The two Phase 2 studies involving torcetrapib/atorvastatin were designed to determine whether this combination therapy can effectively raise HDL-C while lowering LDL-C. HDL-C carries cholesterol away from cells and tissues preventing its build up and resulting deposits which contribute to heart disease. Researchers believe that raising HDL-C levels may provide further benefits in the management of cardiovascular disease (CVD) potentially reducing patients' CV risk. In a study of nearly 500 patients, those who received torcetrapib (60 mg) and atorvastatin (10, 20, 40, 80 mg) had increases in HDL-C of 44 to 66 percent. At the same time, their LDL-C dropped between 41 and 60 percent. This new approach could change the way physicians manage cholesterol and further reduce the risk of atherosclerosis in their patients. Discovered and developed by Pfizer, torcetrapib works by blocking CETP, a protein in the blood that transfers cholesterol and triglycerides between LDL-C and HDL-C. A separate study involving 40 patients showed that raising HDL-C with torcetrapib increased the transportation of cholesterol from cells - an effect seen to be functionally similar to patients with naturally occurring high levels of HDL-C. Pfizer's torcetrapib/atorvastatin development program is the largest and most comprehensive clinical trial program the company has ever undertaken. In attempting to establish the role and benefits of HDL-C in heart disease, the world's leading cause of death in adults, Pfizer is studying some 25,000 patients at hundreds of medical centers worldwide. CETP (cholesterol-ester transfer protein) is a protein that regulates cholesterol and is responsible for transferring cholesterol from its "good" HDL carrier to LDL, the "bad" carrier of cholesterol that results in plaque buildup in the arteries. Scientists believe that CETP inhibition raises HDL levels because cholesterol remains attached to HDL and is unable to be transferred or attached to LDL, where it can build up in the arteries. In addition, researchers believe that blocking CETP and raising HDL may reduce the risk of heart disease and stroke. About PfizerPfizer, with its UK business headquarters in Surrey and global headquarters in New York, is a research-based global pharmaceutical company. Pfizer discovers, develops, manufactures and markets leading prescription medicines for humans and animals, and many of the world's best-known consumer treatments. Every month, over two million patients in the UK are prescribed a Pfizer medicine. It is estimated that on any given day, 40 million people around the world are treated with a Pfizer medicine. References Torcetrapib combined with atorvastatin raises HDL-C, lowers LDL-C and is well tolerated results from a phase 2 dose-ranging clinical trial. Abstract AHA November 2005CETP inhibition in humans by torcetrapib maintains the cholesterol efflux potential of HDL. Abstract AHA November 2005Alicia SandersCommunications Manager, PfizerTel 01737 330 857Mob [phone]alicia.sanders_at_pfizer.comhttp//www.pfizer.com
                                                                                                                            


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FDA Home Page Search FDA Site FDA
A-Z Index Contact FDA FDA Centennial   FDA
Statement FOR IMMEDIATE RELEASEStatementDecember
3, 2006 Media Inquiries Kristen
Neese, 301-827-6242Consumer Inquiries
888-INFO-FDA Pfizer Stops All Torcetrapib
Clinical Trials in Interest of Patient Safety On
December 2, 2006, FDA was notified that Pfizer
will suspend a large, Phase 3 trial evaluating
the investigational cardiovascular therapy
torceptrapib/atorvastatin (T/A) due to an
increased rate of mortality (death) in patients
receiving the combination compared to those
receiving atorvastatin alone. With the T/A
development program, as it does with all such
development programs, FDA assured that Pfizer had
the appropriate protections in place for patients
participating in the drugs development,
including informed consent, a Data Safety
Monitoring Board (DSMB) for its outcome study,
and that the development program was done in a
careful, stepwise manner. For this trial, the
DSMB was conducting a monthly analysis of
mortality data and a quarterly analysis of a
number of outcomes including stroke, heart
attack, and revascularizations (e.g., coronary
stents or bypass surgery) to ensure the ongoing
safety of patients in this trial. This
independent board notified Pfizer of the
mortality finding early the morning of December
2, 2006 and FDA was notified at 400 PM EST that
evening that Pfizer planned to halt this trial
and the development program overall. FDA fully
supports Pfizer's decision to suspend this trial.
The system of biomedical research monitoring was
effective in this case, assuring that once a
certain signal was seen, the trial was halted.
FDA will continue to work with Pfizer and other
sponsors developing molecules in this class of
drugs to ensure that appropriate protections are
in place to identify any safety signals as early
in the development process as possible. Clinical
trials are an integral part of the process for
developing new medical innovations and the
healthcare system is dependent upon this
research, and the patients willing to
participate, to advance therapies. Clinical
trials often tell us unexpected things, both
positive and negative, about new medical
products, which is why carefully designed and
conducted trials are an essential part of the
pre-market process for demonstrating that new
drugs are safe and effective before they can be
approved for marketing.
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Pfizer to cut 10,000 jobs, shut 5 plants No. 1
drugmaker unveils an additional 1 billion in
restructuring moves net income surges on sale of
consumer health care business. By Aaron Smith,
CNNMoney.com staff writer January 22 2007 406
PM EST NEW YORK (CNNMoney.com) -- Pfizer
announced Monday that it will cut 10,000 jobs and
close five plants, including three RD sites and
two factories, by the end of 2008, and said its
quarterly earnings grew but sales were little
changed. In revealing an additional 1 billion in
restructuring moves, Pfizer also said it does not
expect sales to grow in 2007 and 2008, and that
it might purchase up to 10 billion of its own
stock. "There are no sacred cows" said Jeffrey
Kindler, Pfizer's chief executive, at an
analysts' meeting in New York to unveil the
latest moves, which bring the company's total
cost-saving effort to 5 billion. The world's
biggest drug maker in terms of sales said the job
cuts represent 10 percent of its worldwide work
force. The cuts include the recently announced
termination of 2,200 sales representatives in the
U.S., meaning the number of new cuts is
7,800. The company said it plans to close three
research sites in Michigan, including two
facilities in Ann Arbor, and one in Kalamazoo.
The company also plans to close manufacturing
sites in Brooklyn, N.Y., and Omaha, Neb. The
announcement was part of Pfizer's five-year plan
to reduce its manufacturing plants from 93 to 48
by the end of 2008. Pfizer said it is also
considering the closure of research sites in
Japan and France, and it is also considering
selling a factory in Germany, but all this is yet
to be decided. The company plans to invest 3
billion of the money it saves in cost cuts in new
products and business development through the end
of 2008. "We fully understand that we cannot cost
cut our way to long-term success," Kindler
said. He said he hopes to triple the size of his
late-stage pipeline by 2009, and for the company
to generate four of its own new products per year
beginning in 2011.
The company's best hopes for growing sales took a
blow in December, when studies of the
experimental cholesterol drug torcetrapib were
discontinued because of a high death rate and
heart problems among patients. The decision to
discontinue torcetrapib was "disappointing and
brought into sharper focus the need to transform
Pfizer over time to succeed in a dynamic
healthcare marketplace," said Kindler in the
statement. "We are reviewing every aspect of our
business, and I look forward to discussing our
priorities when we meet with analysts in New
York." In addition to projecting flat sales
growth for 2007 and 2008, Pfizer projected net
income of 1.45 to 1.55 a share and operating
income of 2.18 to 2.25 a share. For 2008, the
company projected net income of 1.75 to 1.93 a
share, and operating income of 2.31 to 2.45 a
share. In 2007, Pfizer plans to expand its
marketing of the inhalable insulin product
Exubera. So far, Exubera has only been made
available in very restricted quantities. But Ian
Read, head of worldwide pharmaceutical
operations, said there will be a "full-court
press" roll-out of Exubera and direct-to-consumer
advertising will begin in the second half of the
year. Behind Pfizer, Johnson Johnson is the
second largest drugmaker in the U.S., followed by
Abbott Laboratories (down 0.21 to 53.31,
Charts), Merck (down 0.27 to 45.33, Charts),
Bristol-Myers Squibb (down 0.12 to 26.51,
Charts) and Wyeth (Charts).
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Research Highlights Nature Reviews Drug Discovery
5, 722 (September 2006) doi10.1038/nrd2139 Card
iovascular disease SNP to the rescue? Charlotte
Harrison Can a common single nucleotide
polymorphism (SNP) have sufficient impact to
affect therapeutic targeting in heart disease?
This possibility has recently been raised in a
paper by Liggett and colleagues, who showed that
a polymorphism in the 1-adrenergic receptor (
1AR) altered cardiac function and response to the
adrenergic receptor antagonist bucindolol in
human heart failure. Clinical trials of 1AR
antagonists in heart failure have often revealed
substantial inter-individual variability in
outcomes, which the authors considered could be
due to differences in the 1AR gene. Indeed, the
Liggett group had previously found a common
non-synonymous SNP that results in either Arg or
Gly being encoded at amino-acid position 389 of
the 1AR. Compared with Gly- 1AR, Arg- 1AR
displayed increased stimulation of adenylyl
cyclase in transfected fibroblasts, enhanced
contractility in transgenic mouse hearts and
caused a larger increase in left ventricular
ejection fraction after 1AR antagonist
administration in human studies. The authors
therefore set out to investigate the relevance of
this SNP for 1AR antagonist therapy in heart
failure by using bucindolol, a drug that has
previously failed to show efficacy in clinical
trials. Ventricular tissue from failing and
non-failing human hearts was used to investigate
the impact of 1AR genotype on contractile
responses. In both heart types, Arg homozygotes
displayed fourfold larger agonist-promoted
contractility than Gly carriers. In transfected
fibroblasts expressing 1ARs of either genotype,
those expressing the Arg- 1AR displayed a
substantially greater degree of
noradrenaline-stimulated cAMP accumulation, and
bucindolol showed a larger absolute cAMP-lowering
effect in these cells compared with those
expressing the Gly- 1AR.
Continued Next Page
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To understand the clinical implications of the
1AR SNP, the authors undertook genotyping of the
1AR allele in patients who had taken part in a
large placebo-controlled clinical trial of
bucindolol for the treatment of moderate and
severe heart failure. Each patient cohort
consisted of gt200 subjects, grouped by treatment
and genotype. No outcome was associated with
genotype in the placebo group, indicating little
impact on the natural course of heart failure.
However, Arg homozygotes treated with bucindolol
had an age-, sex- and race-adjusted 38 reduction
in mortality and 34 reduction in mortality or
hospitalization compared with placebo. In
contrast, Gly carriers had no change in clinical
response to bucindolol compared with placebo. The
therapeutic advantage of Arg homozygotes was due
to the degree of adrenergic activity that could
be antagonized by bucindolol. Although it has
yet to be shown whether these results can be
extrapolated to other 1AR antagonists with
differing pharmacological properties to
bucindolol, this study has shown that a drug that
was not efficacious in a mixed patient population
displayed greater efficacy in patients of a
specific genotype, and so could set the stage for
genetic-based treatments in heart failure.