Drug Developments Drug Developments in 2010 in 2010 Implications for the Implications for the Pharmacy Purchaser Pharmacy Purchaser Kevin Hoehn PharmD MBA Kevin Hoehn PharmD MBA Faxton-St. Luke’s Faxton-St. Luke’s Healthcare Healthcare Utica NY Utica NY
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Drug Developments in 2010 Implications for the Pharmacy Purchaser Kevin Hoehn PharmD MBA Faxton-St. Luke’s Healthcare Utica NY.
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Drug Developments Drug Developments in 2010in 2010Implications for the Implications for the
Annual Growth in Drug Expenditures 1998-2009Diamond=total expenditures Squares=expenditures for nonfederal hospitals triangles=expenditures for clinicsAJHP Vol 67, 2010 e4 Figure 1
Total Numbers of Drug Shortages and Shortages Involving Injectable Drugs in the United States 2005-2009 NEJM June 16 2010 (ahead of print) Jensen V and Rappaport B 2010; 2010:1056
Drug Development Drug Development ProcessProcess
It takes 12 years on average for an experimental drug to travel from laboratory to medicine cabinet
Only five in 5,000 compounds that enter preclinical testing make it to human testing– One of these five tested in humans is approved
Preclinical TestingPreclinical Testing
A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evaluated for safety. These tests take approximately three and one-half years.
IND versus NDAIND versus NDA
Investigational New Drug Application (IND)– After preclinical testing, the company files an IND with
the FDA to begin to test the drug in people– Shows results of previous experiments, chemical
structure of the compound; how thought to work in the body; toxic effects found in the animal studies
– Reviewed and approved by the Institutional Review Board. Progress reports on clinical trials must be submitted at least annually to the FDA
New Drug Application (NDA)– After completing all phases of clinical trials, the
company analyzes the data and files an NDA with the FDA if the data successfully demonstrates safety and effectiveness
– Must contain all of the scientific information that the company has gathered
– Typically run 100,000 pages or more– The average NDA review time for new molecular
entities approved in 1992 was 29.9 months
IND versus NDAIND versus NDA
Clinical Trial Phase IClinical Trial Phase I
These tests take about a year and involve about 20 to 80 normal, healthy volunteers. The tests study a drug's safety profile, including the safe dosage range. The studies also determine how a drug is absorbed, distributed, metabolized and excreted, as well as the duration of its action.
Clinical Trial Phase IIClinical Trial Phase II
In this phase, controlled studies of approximately 100 to 300 volunteer patients (people with the disease) assess the drug's effectiveness and takes about two years.
Clinical Trial Phase IIIClinical Trial Phase III
This phase lasts approximately three years and usually involves 1,000 to 3,000 patients in clinics and hospitals. Physicians monitor patients closely to determine efficacy and identify adverse reactions.
ApprovalApproval
Once the FDA approves the NDA, the new medicine becomes available for physicians to prescribe.
The company must continue to submit periodic reports to the FDA, including any cases of adverse reactions and appropriate quality-control records.
For some medicines, the FDA requires additional studies (Phase IV) to evaluate long-term effects.
Preclinical Phase I Phase II Phase III FDA Phase IV Testing
Assess safety Determine Evaluate Verify effectiveness Review Additional and biological safety and effectiveness, monitor adverse process / post marketing activity dosage look for side reactions from Approval testing required effects long term use by FDA 5000 1 .compds Only 5 enter trials approved evaluated
Direct Thrombin InhibitorDirect Thrombin Inhibitor•Rapid onset, lower risk of Rapid onset, lower risk of
bleeding vs. warfarinbleeding vs. warfarin•Once daily, no monitoringOnce daily, no monitoring
Factor Xa InhibitorFactor Xa Inhibitor•Currently approved for Currently approved for prevention of post surgical prevention of post surgical VTE in Canada and Britain VTE in Canada and Britain
Once daily, no monitoringOnce daily, no monitoring
•Fewer heart attacks and lower Fewer heart attacks and lower death rate than Plavix arm in death rate than Plavix arm in 18,000 patients18,000 patients•Rapid onset, reversible anti-Rapid onset, reversible anti-plateletplatelet•Does not require hepatic activationDoes not require hepatic activation•Twice dailyTwice daily oral dosage oral dosage
Biotransformation and Mode of Action of Clopidogrel, Prasugrel, and TicagrelorN Engl J Med 361:1108, September 10, 2009 Editorial
Direct Thrombin InhibitorDirect Thrombin Inhibitor•Rapid onset, lower risk of Rapid onset, lower risk of
bleeding vs. warfarinbleeding vs. warfarin•Once daily, no monitoringOnce daily, no monitoring
Factor Xa InhibitorFactor Xa Inhibitor•Currently approved for Currently approved for prevention of post surgical prevention of post surgical VTE in Canada and Britain VTE in Canada and Britain
Once daily, no monitoringOnce daily, no monitoring
•Fewer heart attacks and lower Fewer heart attacks and lower death rate than Plavix arm in death rate than Plavix arm in 18,000 patients18,000 patients•Rapid onset, reversible anti-Rapid onset, reversible anti-plateletplatelet•Does not require hepatic activationDoes not require hepatic activation•Twice dailyTwice daily oral dosage oral dosage
Review of Clotting CascadeReview of Clotting Cascade
ExtrinsicExtrinsicPathwayPathway
IntrinsicIntrinsicPathwayPathway
CommonCommonPathwayPathway
XII
XI
VII
tissuetissuefactorfactor
CaCa++++
II
XIIa
XIa
IXIXa
X
CaCa++++
(prothrombin)
CaCa++++
plateletsVa
plateletsVIIIa
fibrin
(thrombin)
ThrombusThrombus(clot)(clot)
XIII
XIIIa
HMWKHMWK
KALKAL
fibrinogen
IIa
Xa
VIIa
CardiovascularCardiovascular
PHASE III PHASE III Factor Xa InhibitorsFactor Xa Inhibitors– ApixabanApixaban
•Testing in prostate and bladder Testing in prostate and bladder cancerscancers
Phosphatidylinositol 3-Kinase Phosphatidylinositol 3-Kinase (PI3K) Inhibitor(PI3K) Inhibitor•Results in apoptotic cell deathResults in apoptotic cell death
•Testing in non-Hodgkin’s Testing in non-Hodgkin’s lymphomalymphoma
•Anti-tumor effect in Anti-tumor effect in refractory or resistant refractory or resistant
prostate cancerprostate cancer•Inhibits an enzyme Inhibits an enzyme
necessary for testosterone necessary for testosterone production anywhere in the production anywhere in the
bodybody
•Testing in triple-negative breast Testing in triple-negative breast cancercancer
Oxycodone SR (Remoxy®)Oxycodone SR (Remoxy®)– King/Pain TherapeuticsKing/Pain Therapeutics– Phase IIIPhase III
Oxycodone-IR/Niacin (Acurox®)Oxycodone-IR/Niacin (Acurox®)– King/AcuraKing/Acura– Phase IIIPhase III
Hydromorphone ER (Exalgo®)Hydromorphone ER (Exalgo®)– CominatoRx/Coridien/NeuromedCominatoRx/Coridien/Neuromed– Phase IIIPhase III
•ORADUR-basedORADUR-based•High viscosity base, when crushed High viscosity base, when crushed with water forms thick gel with water forms thick gel (cannot inject or snort) (cannot inject or snort)
•OROS osmotic pill pump OROS osmotic pill pump for controlled release for controlled release
DeterDeterDiversionDiversion
•Niacin induced side effects Niacin induced side effects when taken too oftenwhen taken too often
Pain ManagementPain Management
Duloxetine (Cymbalta®)Duloxetine (Cymbalta®)– LillyLilly– Phase IIIPhase III
Nitraproxen (Naproxcinod®)Nitraproxen (Naproxcinod®)– NicOxNicOx– Phase IIIPhase III
Naproxen-EC/Esomeprazole-IR Naproxen-EC/Esomeprazole-IR (Vimovo®)(Vimovo®)– AstraZeneca/POZENAstraZeneca/POZEN– Phase IIIPhase III
•Resubmitted for treatment of Resubmitted for treatment of chronic pain indication chronic pain indication
•For patients at risk of NSAID For patients at risk of NSAID related GI ulcers related GI ulcers