7/7/2016
FOOD AND DRUG ADMINISTRATION (FDA) NEW DRUG APPROVAL PROCESS
2016 ANNUAL MEETING NEW DRUGS – PART I SCOTT KING, PHARM.D. TARA MCNULTY, CPHT, RPHT ASST. MGR, CLINICAL PHARMACY SERVICES PROJECT MANAGER DR. P. PHILLIPS HOSPITAL-ORLANDO HEALTH WELLCARE HEALTH PLANS, INC [email protected] [email protected]
2016 Annual meeting 2016 ANNUAL MEETING
DISCLOSURE FDA NEW DRUG APPROVAL PROCESS
• Scott King, Pharm.D., Every year, the FDA approves dozens of new medications, many are: • Do not have a vested interest in or affiliation with any corporate organization offering • Variations of existing products financial support or grant monies for this continuing education activity, or any affiliation • Cost saving generic formulations with an organization whose philosophy could potentially bias my presentation • New approvals (novel drugs) • Tara McNulty, CPhT, RPhT Drugs that make it to the FDA review process will undergo a rigorous evaluation • Do not have a vested interest in or affiliation with any corporate organization offering that examines everything about the drug such as: financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation • Drug design • Clinical trials side effects • Manufacturing. $359 million dollars is spent to develop a new drug (including FDA lab research to delivery to the patient)
2016 ANNUAL MEETING 2016 ANNUAL MEETING
OBJECTIVES STAGES OF DRUG DEVELOPMENT
• Discuss FDA drug approval process and recently approved drugs The stages of the FDA drug approval process can be divided into 4 major sections: • Examine the impact of the new therapy on cardiology • Pre-Clinical • Investigate the role of the pharmacy technician with the recent FDA • Clinical drug approvals • New Drug Application Review (NDA) • Post Marketing Of these 4 sections, each contain numerous steps that lead a drug to being approved by the FDA
2016 ANNUAL MEETING 2016 ANNUAL MEETING
1 7/7/2016
STAGES OF DRUG DEVELOPMENT STAGES OF DRUG DEVELOPMENT
Drug Developed Approval * Drug sponsors develop a drug compound and seek to have it approved by the FDA for sale in the United States New Drug * Application approval by FDA
Pre- Animals Tested Approval/ Phase 4 Clinical * Animal testing on a variety of animals for drug toxicity data Post * After approval, the drug is available to prescribe Marketing * Drug sponsor will provide periodic reports to FDA on any Stage IND Application side effects that occur after approval * Submission by drug sponsors an Investigational New Drug (IND) application to FDA * Data to include drugs composition and manufacturing
2016 ANNUAL MEETING 2016 ANNUAL MEETING
STAGES OF DRUG DEVELOPMENT NEW DRUG APPROVAL KEY POINTS Phase 1-Safety * Clinical trials on healthy volunteers (20-80) * Determines drugs side effects • New drug approval typically takes 12-15 years * Determines tolerated dosages * Phase process is typically 1 year • Manufacturer’s drug patents last 20 years, after which competitors Clinical Phase 2-Effectivenss may seek approval to produce a generic drug equivalent Stage- * Clinical trials on more volunteers (100-300) * Obtains preliminary data to determine effectiveness • 5 in 5,000 of all potential drugs make it to human testing New Drug * Patients are compared with similar patients receiving a different treatment or placebo • 1 in 5 of those tested are approved for human use * Short term side effects are studied Trials * Phase process is typically 2 years
Phase 3- Large scale study * Clinical trials on large number of volunteers (300-3,000) * Studies the drugs overall effects * Study on different populations * Testing along side other drug treatments. * Phase Process is typically 3 years
2016 ANNUAL MEETING 2016 ANNUAL MEETING
STAGES OF DRUG DEVELOPMENT DRUG DESIGNATIONS
Review Meeting * FDA will meet with drug sponsor prior to the submission of the NDA
NDA Application New Drug First- in- Class * * Formal request for approval is submitted by drug Novel Drugs Orphan Drugs Application * * Includes all testing data • New and innovative agents that • Drugs that have a different • Drugs that are approved for a (NDA) have different chemical Application Review mechanism of action of small population of patients with structures that have never been existing agents rare diseases or conditions Review * FDA has up to 60 days to file and review previously approved * Assign and evaluate research on safety and effectiveness * FDA can take up to 6 months to review application • In 2015, the FDA’s Center for Drug Evaluation and Research Drug Labeling (CDER) approved 45 novel drugs * FDA will review the labeling and communicate to health care professionals/ consumers
2016 ANNUAL MEETING 2016 ANNUAL MEETING
2 7/7/2016
RESOURCES: FDA.GOV FDA APPROVED NEW DRUG APPROVALS PER YEAR • All new drugs (and drug labeling changes) can be found on fda.gov 50 • Each new drug or change is explained (below) 45 40 • Year-end summary is provided (right) 35
30
25
20
15
10
5
0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 New Drug Approvals Linear (New Drug Approvals)
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm "U.S. Food and Drug Administration." Novel Drug Approvals for 2015. Web. 05 June 2016.
2016 ANNUAL MEETING 2016 ANNUAL MEETING
NEW FDA APPROVED DRUGS NEW DRUG SPECIFICS 2011 2015 • First in Class: 12 (40%) • First in Class: 16 (36%) • Roflumilast (Daliresp) • Palbociclib (Ibrance) • Belimumab (Benlysta) • Sugammadex (Bridion) • Icatibant (Firazyr) • Flibanserin (Addyi) • Orphan Drugs: 11 (37%) • Orphan Drugs: 21 (47%) • Ipilimumab (Yervoy) • Lumacaftor/Ivacaftor (Orkambi) • Brentuximab Vedotin (Adcetris) • Selexipag (Uptravi) • Clobazam (Onfi) • Uridine Triacetate (Xuriden)
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm285554.htm 2016 ANNUAL MEETING 2016 ANNUAL MEETING
FDA APPROVED NEW DRUG APPROVALS CHEMOTHERAPY PER YEAR
50
45
40
35
30
25
20
15
10
5
0 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 New Drug Approvals
"U.S. Food and Drug Administration." Novel Drug Approvals for 2015. Web. 05 June 2016. http://www.jewsnews.co.il/2013/10/30/what-the-cancer-industry-does-not-want-you-to-know-about-chemotherapy-and-radiation/ 2016 ANNUAL MEETING 2016 ANNUAL MEETING
3 7/7/2016
IBRANCE AXUMIN
• Generic Name: Palbociclib • Generic Name: Fluciclovine F18 • Oral kinase inhibitor given with letrozole for the treatment of • Prostate cancer is the second leading advanced breast cancer cause of death from cancer in men • Approved by FDA under accelerated • Recurrence of prostate cancer occurs approval based on progression-free in about 30% of men with survival successfully treated prostate cancer • In Paloma-1, treatment doubled • Axumin is an imaging agent used median progression-free survival in during PET imaging to detect and first line treatment localize recurrent prostate cancer • Stored at room temperature Axumin (fluciclovine F18) [prescribing information]. Oxford, UK: Blue Earth Diagnostics Ltd: May 2016. http://www.axumin.com/press.html Ibrance (palbociclib) [prescribing information]. New York, NY: Pfizer, Inc: February 2016. https://www.healthunits.com/axumin-injections-male-prostate-cancer/
2016 ANNUAL MEETING 2016 ANNUAL MEETING
CANCER TREATMENT - 2015 CHEMOTHERAPY DILUTION TABLE
Preparation Stability Notes Non-Small Cell Lung Cancer Multiple Myeloma 6 Hour (Room Temp) 1200mg (20mL) diluted in Atezolizumab 24 Hour (Ref) 250mL NS • Alectinib (Alecensa) • Daratumumab (Darzalex) (Tecentriq) Stability includes infusion (NS only) time • Osimertinib (Tagrisso) • Elotuzumab (Empliciti) May be stored for 24 hours Solution should be 1st: 1000mL total vol Colorectal Cancer • Panobinostat (Farydak) Daratumumab (Ref) colorless to pale yellow 2nd: 500mL total vol (Darzalex) Infusion must complete (do NOT use if opaque, (NS only) • Trifluridine/Tipiracil (Lonsurf) • Ixazomib (Ninlaro) within 15 hours discolored, or particles) 24 Hour (Ref) Soft Tissue Carcinoma Melanoma Reconstitute vial with SWFI Max of 8 Hour may be at Solution in vial should Elotuzumab with 18-gauge or lower Room Temp be colorless to slightly • Trabectedin (Yondelis) • Cobimetinib (Cotellic) (Empliciti) needle Stability includes infusion yellow. Dilute in 230mL NS or D5W time Tecentriq (atezolizumab) [prescribing information]. San Francisco, CA: Genentech, Inc: May 2016. Darzalex (daratumumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc: November 2015. Bolded Names are oral formulations Empliciti (elotuzumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company: November 2015. 2016 ANNUAL MEETING 2016 ANNUAL MEETING
CANCER TREATMENT - 2016 IMLYGIC
Bladder Cancer Diagnostic agent to detect recurrent • Generic Name: Talimogene • Hazardous Agent • Atezolizumab (Tecentriq) prostate cancer: laherparepvec o o • Fluciclovine F18 (Axumin) • Store intact vials at -90 C to -70 C Chronic Lymphocytic Leukemia • Genetically modified attenuated • Store in carton until use • Venetoclax (Venclexta) herpes simplex virus 1 (HSV) oncolytic virus • Thaw at room temperature until liquid • Selectively replicates in and lyses is formed (30 minutes) tumor cells • Swirly gently, do not shake • Injected directly (intralesionally) into cutaneous, subcutaneous, and/or • Once thawed, keep refrigerated for up nodal lesions that are visible, to 12 hours for 1million/mL strength palpable, or detectable by ultrasound (48 hours for 100million/mL) guidance Bolded Names are oral formulations Imlygic (talimogene laherparepvec) [prescribing information]. Thousand Oaks, CA: BioVex, Inc: October 2015. 2016 ANNUAL MEETING 2016 ANNUAL MEETING
4 7/7/2016
TALIMOGENE LAHERPAREPVEC (IMLYGIC) SUGAMMADEX (BRIDION)
• FDA approval in adults undergoing surgery for NMB reversal • MUCH more expensive than neostigmine • Available: 200mg/2mL and 500mg/5mL vials • Vials are stored at room temperature • Administered as a single bolus injection
Nature Volume:526, Pages:622–623 Date published:(29 October 2015) Merck News Release. Bridion. Dec. 17, 2015. Bridion (sugammadex) [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc: December 2015.
2016 ANNUAL MEETING 2016 ANNUAL MEETING
BINDERS & REVERSALS ZURAMPIC
• Generic Name: Lesinurad • Uric Acid Transporter 1 (URAT1) inhibitor • FDA approved to treats high blood uric acid levels associated with gout • MUST be used in combination with a xanthine oxidase inhibitor (e.g. allopurinol or febuxostat) • Patients MUST stay well hydrated
Zurampic (lesinurad) [prescribing information]. Wilmington, DE: AstraZeneca: January 2016. http://www.thepharmacology.com/2015/12/zurampic-to-treat-high-blood-uric-acid.html
2016 ANNUAL MEETING 2016 ANNUAL MEETING
BRIDION VELTASSA
• Generic Name: Sugammadex • Generic Name: Patiromer • Reversal of aminosteroid • Non-absorbed, cation exchange neuromuscular blockade (NMB) from polymer rocuronium and vecuronium • FDA approved to treat hyperkalemia • NOT effective in reversing other (typically associated with ESRD) neuromuscular blockers??? • Should NOT be used for emergency • Still yet to be determined treatment of hyperkalemia • Works by increasing the neurotransmitter acetylcholine at the • Available as a 8.4Gm powder – Does neuromuscular junction not dissolve • Can reverse different levels of • Store refrigerated. Use within 3 blockade including deep block months if kept at room temperature Veltassa (patiromer) [prescribing information]. Redwood City, CA: Relypsa, Inc: June 2016 Merck News Release. Bridion. Dec. 17, 2015. https://www.veltassa.com/hcp/healthcare_professional_resources/#administration
2016 ANNUAL MEETING 2016 ANNUAL MEETING
5 7/7/2016
PATIROMER (VELTASSA) IDARUCIZUMAB (PRAXBIND)
• Should be given with food • Questions left unanswered regarding drug interactions: • According to the manufacturer: • What medications? • When other oral medications are taken • Why haven’t we identified anything? at the same time as patiromer, binding of the oral drug and patiromer in the GI • Why 6 hours before and after? tract may occur • What about medications that undergo • Administer other oral medications at enterohepatic circulation? least 6 hours before or 6 hours after • What about kayexalate? patiromer • Monitor other oral medications for changes in clinical response
Veltassa (patiromer) [prescribing information]. Redwood City, CA: Relypsa, Inc: June 2016 Horn, Hansten. What to Do About Patiromer Drug Interactions. Pharmacy Times. March 17, 2016. http://www.praxbind.com/dosing-administration 2016 ANNUAL MEETING 2016 ANNUAL MEETING
DRUG INTERACTIONS: CARDIOLOGY PATIROMER (VELTASSA)
Veltassa (patiromer) [prescribing information]. Redwood City, CA: Relypsa, Inc: June 2016 Relypsa Press Release. Veltassa Drug Interactions Studies. Jan 25, 2016. http://www.pineywoodsheart.com/
2016 ANNUAL MEETING 2016 ANNUAL MEETING
PRAXBIND KENGREAL
• Generic Name: Cangrelor • Generic Name: Idarucizumab • Onset: Minutes but… • Cangrelor is an IV non-thienopyridine • Hemostasis takes around 12 hours • Idarucizumab is a humanized direct P2Y12 platelet receptor inhibitor monoclonal antibody fragment that • Duration: 24 hours • FDA approved as an antiplatelet binds specifically to dabigatran during percutaneous coronary • Available as 2.5Gm/50mL vials intervention (PCI) • FDA approved as a specific reversal • Vials should be refrigerated • Typically reserved for patients unable agent for dabigatran (Pradaxa) to take oral antiplatelets • Dosage: 5Gm (2 vials) • Given as a bolus followed by an • Second vial should be administered no infusion during PCI later than 15 minutes after first vial • Patients transitioned to oral P2Y12 antagonist after PCI
Kengreal (cangrelor) [prescribing information]. Parsippany, NJ: The Medicines Company: June 2015 Praxbind (idarucizumab) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc: October 2015 https://www.lookfordiagnosis.com/mesh_info.php?term=angioplasty,%20balloon&lang=1
2016 ANNUAL MEETING 2016 ANNUAL MEETING
6 7/7/2016
CANGRELOR (KENGREAL) ALIROCUMAB: CLINICAL TRIAL
• Vial: 50mg (powder) • 50mg vial mixed in 5mL SWFI • Further dilute in 250mL NS • May also dilute in D5W • Bolus and infusion provided by prepared bag • Stored at room temperature for 24 hours in NS (12 hours for D5W)
Kengreal (cangrelor) [prescribing information]. Parsippany, NJ: The Medicines Company: June 2015 http://www.kengreal.com/index.html Robinson JG, et al. NEJM. 2015; 372(16): 1489-1499. 2016 ANNUAL MEETING 2016 ANNUAL MEETING
PCSK9 INHIBITORS ENTRESTO
ALIROCUMAB (PRALUENT) EVOLOCUMAB (REPATHA)
• Monoclonal Antibody • Monoclonal Antibody • FDA approved: • FDA approved: • Primary heterozygous familial • Primary heterozygous familial hypercholesterolemia hypercholesterolemia • Primary hypercholesterolemia • Primary hypercholesterolemia • Familial hypercholesterolemia – homozygous (orphan drug) • Given SQ every 2 weeks • Given SQ every 2 weeks or monthly • Store refrigerated. Time outside refrigeration • Store refrigerated. Time outside should not exceed 24 hours. Keep in original refrigeration should not exceed 30 days. packaging. Keep in original packaging. Praluent (alirocumab) [prescribing information]. Tarrytown, NY. Regeneron Pharmaceuticals, Inc: October 2015. Repatha (evolocumab) [prescribing information]. Thousand Oaks, CA: Amgen Inc: August 2015. https://www.entrestohcp.com/
2016 ANNUAL MEETING 2016 ANNUAL MEETING
PCSK9 INHIBITORS WHAT IS ENTRESTO?
SACUBITRIL VALSARTAN
• Neprilysin inhibitor • Angiotensin II receptor antagonist • Neprilysin is involved in the degradation of • Inhibition of angiotensin II causes: several vasoactive substances • Vasodilation • Inhibition of neprilysin increase these • Reduces secretion of vasopressin vasoactive substances leading to decreased • Reduces production and secretion of neurohormonal activation aldosterone • Decreased vasoconstriction • Decreased sodium retention • Decreased maladaptive remodeling
Entresto (sacubitril/valsartan) [prescribing information]. East Hanover, NJ: Novartis: August 2015 Lambert G, et al. J. Lipid Res. 2012; 53: 2515-2524. http://www.entresto.com/info/how-entresto-works.jsp 2016 ANNUAL MEETING 2016 ANNUAL MEETING
7 7/7/2016
WHAT IS ENTRESTO? IS IT GROUNDBREAKING?
YES NO • 4.7% absolute risk reduction in time • Dosing to first occurrence of CV death or HF • Aggressive Entresto goal dose hospitalization (versus enalapril) • Low comparative enalapril dose • 3.2% absolute risk reduction in time • Selection Criteria to occurrence of CV death (versus enalapril) • Run-in period • 2.8% absolute risk reduction in death • Study ended early – Long term? from any cause (versus enalapril) • Side Effects: • Hypotension 18% vs. 12% https://www.entrestohcp.com/ http://www.qscience.com/do McMurray JJ, et al. NEJM. 2014; 371 (11): 993-1004. i/pdf/10.5339/gcsp.2014.34 Entresto (sacubitril/valsartan) [prescribing information]. East Hanover, NJ: Novartis: August 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING
PARADIGM-HF: SACUBITRIL / VALSARTAN (ENTRESTO) ENTRESTO
McMurray JJ, et al. NEJM. 2014; 371 (11): 993-1004. Entresto (sacubitril/valsartan) [prescribing information]. East Hanover, NJ: Novartis: August 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING
PARADIGM-HF: SACUBITRIL / VALSARTAN (ENTRESTO) ENTRESTO
McMurray JJ, et al. NEJM. 2014; 371 (11): 993-1004. Entresto (sacubitril/valsartan) [prescribing information]. East Hanover, NJ: Novartis: August 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING
8 7/7/2016
SACUBITRIL / VALSARTAN (ENTRESTO) TECHNICIAN ROLE IN NEW DRUG APPROVALS
The Pharmacy Technician has a responsibility to ensure they are familiar with new drugs • ACE inhibitors MUST be stopped for emerging into the market. Important knowledge to know: at least 36 hours before starting Sacubitril/Valsartan Indications for Use Routes of Administration Associated Precautions • During 36 hours washout, patient Storage Requirements Comparison of new agents with Medication Preparation may take an ARB like valsartan alone other products that have similar indications • Start slowly
• Titrate to a target maintenance dose • Visit FDA website http://www.centerwatch.com/drug-information/fda-approved-drugs/ to find out of 97/103mg PO twice a day about new available drugs • Learn via Continuing Education presentations
Entresto (sacubitril/valsartan) [prescribing information]. East Hanover, NJ: Novartis: August 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING
CORLANOR SUMMARY
• Generic Name: Ivabradine • FDA indicated to reduce the risk of • Many new drugs shown in this presentation were approved for various cancers, hospitalization for worsening heart heart failure, high cholesterol, and first approved reversal agent for a commonly • Selective inhibitor of the failure in patients with stable, used blood thinner. hyperpolarization-actived cyclic symptomatic chronic heart failure with nucleotide-gated channels in the SA LVEF ≤ 35% who have a sinus • 2015 New Drug Innovation was a remarkable year with the most productive year node of cardiac tissue resulting in: rhythm with resting heart rate ≥ 70 for the pharmaceutical industry since 1996 with 51 new approvals, 45 which were • Prolonged diastolic depolarization BPM and either are on maximally Novel drugs tolerated doses of beta-blockers or • Slowed firing in the SA node have a contraindication to a beta- • With the quantity of new drugs emerging into the market, the need for Pharmacy • Reduced heart rate blocker technician education of these new drug approvals is paramount. • Manufacturer slogan: “More Home. Less Hospital.”
Corlanor (ivabradine) [prescribing information]. Thousand Oaks, CA: Amgen: April 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING
TECHNICIAN ROLE IN NEW DRUG QUESTIONS? APPROVALS
2016 ANNUAL MEETING 2016 ANNUAL MEETING
9 7/7/2016
REFERENCES
• "U.S. Food and Drug Administration." Novel Drug Approvals for 2015. U.S Food and Drug Administration, n.d. Web. 05 June 2016.
2016 ANNUAL MEETING 2016 Annual meeting
REFERENCES
• Ibrance (palbociclib) [prescribing information]. New York, NY: Pfizer, Inc: February 2016.
• Axumin (fluciclovine F18) [prescribing information]. Oxford, UK: Blue Earth Diagnostics Ltd: May 2016.
• Tecentriq (atezolizumab) [prescribing information]. San Francisco, CA: Genentech, Inc: May 2016.
• Darzalex (daratumumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc: November 2015.
• Empliciti (elotuzumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company: November 2015.
• Imlygic (talimogene laherparepvec) [prescribing information]. Thousand Oaks, CA: BioVex, Inc: October 2015.
• Bridion (sugammadex) [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc: December 2015.
• Zurampic (lesinurad) [prescribing information]. Wilmington, DE: AstraZeneca: January 2016.
• Veltassa (patiromer) [prescribing information]. Redwood City, CA: Relypsa, Inc: June 2016
• Praxbind (idarucizumab) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc: October 2015
2016 ANNUAL MEETING
REFERENCES
• Kengreal (cangrelor) [prescribing information]. Parsippany, NJ: The Medicines Company: June 2015
• Praluent (alirocumab) [prescribing information]. Tarrytown, NY. Regeneron Pharmaceuticals, Inc: October 2015.
• Repatha (evolocumab) [prescribing information]. Thousand Oaks, CA: Amgen Inc: August 2015.
• Entresto (sacubitril/valsartan) [prescribing information]. East Hanover, NJ: Novartis: August 2015
• Corlanor (ivabradine) [prescribing information]. Thousand Oaks, CA: Amgen: April 2015
• Nature Volume:526, Pages:622–623 Date published:(29 October 2015)
• Lambert G, et al. J. Lipid Res. 2012; 53: 2515-2524.
• Robinson JG, et al. NEJM. 2015; 372(16): 1489-1499.
• McMurray JJ, et al. NEJM. 2014; 371 (11): 993-1004.
2016 ANNUAL MEETING
10