2004-2005
Module 2# 4
Drug development Plus other points worth remembering
2004-2005
Module 2 #4
• drug development
• drug regulation
• drugs in pregnancy
• drugs in children
• drugs in the elderly
• drug-drug interactions
2004-2005
drug development
patent life 20 years
preclinical clinical
phase 1phase 2
phase 3
marketing
phase 4
generic
submissionto regulatory
agency
2004-2005
drug regulation
a “drug” receives a drug identification number (DIN) - (Federal Govt. - TPD)
• it must be safe and effective for the indication
• no economic evaluation• PR drugs need a prescription• Over-the-counter (OTC) drugs are very safe (usually)
most provinces have formularies• the drug must have an advantage over
alternatives.• economic evaluation (cost/QALY)• interchangeability
2004-2005
Health Canadahttp://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_e.html
• Therapeutic Products Directorate (TPD)
• Health Canada's Therapeutic Products Directorate is the
Canadian federal authority that regulates pharmaceutical drugs
and medical devices for human use. Prior to being given
market authorization, a manufacturer must present substantive
scientific evidence of a product's safety, efficacy and quality
as required by the Food and Drugs Act and Regulations.
2004-2005
LET YOUR COMPUTER DO THE SEARCHING!• ... Need to know how to market a new drug in
Canada?• ... Want information on the drug regulatory process?• ... Need to know what the newest drugs on the
Canadian market are?• ... Want direct access to forms and policies?• ... Need to know the requirements for labeling drugs?• All this and more is available on the• Therapeutic Products Directorate / Biologics and
Genetic Therapies Directorate / Marketed Health Products Directorate Website (s)athttp://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/http://www.hc-sc.gc.ca/hpfb-dgpsa/bgtd-dpbtg/
2004-2005
ICHhttp://www.ich.org/UrlGrpServer.jser?%40_ID=276&%40_TEMPLATE=254
• The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan, the United States and Canada and experts from the pharmaceutical industry in the these regions to discuss scientific and technical aspects of product registration.
2004-2005
Clinical Trials Guidelines
• The ICH guideline: "General Considerations for Clinical Trials" has been developed by an ICH Expert Working Group ………. regulatory parties which include Canada.
• The guideline provides an overview of drug development during the clinical phases.
• The Therapeutic Products Directorate of Health Canada has adopted this international guideline.
2004-2005
Clinical trials
• Overhead
2004-2005
What is a QALY?
• quality adjusted life year
• quality of life rated by the public
• varies from 0 (dead) to 1.0 (robust health)
• cost/QALY $20,000 is good
• cost/QALY $100,000 is too expensive
• cost/QALY $20,000- $100,000 is debatable.
A quality-adjusted life year (QALY) takes into account both quantity and the quality of life generated by Healthcare interventions. It is the arithmetic product of life expectancy and a measure of the quality of the remaining life years.
2004-2005
interchangeabilitycompare Cp/time curves in >17 normal volunteers:
each receives one oral dose of both drugs 2 weeks apart
3020100
15
12
9
6
3
0
time (hr)
plas
ma
conc
. (m
g/L)
innovator copycat
AUCc = 80-125%AUCi
Tmax and Cmax(same 80-125%)
2004-2005
drugs in pregnancyUS FDA Classification
www.perinatology.com/druglist.htm ?
http://www.fda.gov/womens/registries/default.htm
• A Safe; lots of data
• B Likely safe: animals OK
• C Uncertain; risk vs. benefit
• D Likely unsafe: risk vs. benefit
• X Unsafe, do not use
•(see overhead)
2004-2005
drugs in pregnancywww.motherisk.org
www.orpheus.ucsd.edu/ctis/www.perinatology.com
ACE inhibitors renal tubular dygenesisanticholinergics meconium ileusanticancer drugs CNS malformationshypoglycemic drugs neonatal hypoglycemiaphenytoin growth retardationwarfarin skeletal and CNS defects
hypertension methyldopa, beta blockersdepression tricyclics. fluoxetinediabetes insulin, gluburide, metforminheadache acataminophennausea Diclectinthrombosis heparin
unsafe
safe
the placenta is a lipid barrier
2004-2005
Drugs in breast milk
• http://www.who.int/child-adolescent-health/New_Publications/NUTRITION/BF_Maternal_Medication.pdf
• http://www.ukmicentral.nhs.uk/drugpreg/qrg_p1.htm• It contains a summary of the significance of the excretion of
the commonly used drugs via breast milk, and their absorption by the infant.
• In the interests of clarity and easy reference this guide is limited to those drugs which are more commonly prescribed for breast-feeding mothers. It is not intended that it should include all drugs and non-inclusion does not imply safety.
2004-2005
Drugs in breast milk
These drugs are unsuitable for administration to breast-feeding mothers because;
Serious adverse effects have been described. Serious adverse effects may be anticipated on theoretical
grounds.These drugs can be administered to breast-feeding mothers only
where the mother and infant can be monitored. Minor adverse effects have been described. Insufficient information relating to breast-feeding available to
allow classification as a safe drug. These drugs may be administered to breast-feeding mothers.
They either: Are not excreted in breast milk. Are not absorbed by the infant.
Give very low levels in infant with no apparent effectssee overhead
2004-2005
drugs in children• few studies done in kids
• some changes in clearance
Changes in clearance with age: Developmental patterns of CYP1A2 isoform – caffeine as a substrate
2004-2005
• reduced gastric acidity, gi motility decreased absorption?• increased body fat increase Vd (lipid sol)• reduced GFR (0.5%/year) decreased clearance
(water sol drugs)
CCr= (140-age)*Wt(kg)/ 0.81.SeCr (for females multiply by 0.85)
• reduced hepatic blood flow decreased clearance(not phase 2)
drugs in the elderly those >65- 14% of population, 33% of prescription drugs, 25% of
DAEsaverage of 5 drugs per patient
physiologic changes
2004-2005
drug interactionswww.medletter.com
pharmacodynamic 2 drugs affecting the same system: e.g. sedatives
pharmacokinetic 1 drug changes the ADME of another
absorption tetracycline/antacids, thyroxine/Cadistribution competition for albumin by
phenylbutazone and warfarinexcretion probenecid/penicillinmetabolism CYP3A4 drugs
2004-2005
Advisories and Warnings
The Marketed Health Products Directorate (MHPD), Therapeutic Products Directorate (TPD) and the Biologic and Genetic Therapies Directorate (BGTD) posts safety alerts, public health advisories, press releases and other notices from industry as a service to health professionals, consumers, and other interested parties.
To receive the Newsletter and Advisories free by e-mail, join Health Canada's Health_Prod_Info mailing list
2004-2005
Advisories and warnings
• Important drug safety information for Paroxetine: warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm- GlaxoSmithKline Inc.
Date: 2004-06-02• Health Canada advises of potential adverse effects
of SSRIs and other anti-depressants on newbornsDate: 2004-08-09
2004-2005
summary
• the feds decide what drugs get on the market• the provinces decide which ones to pay for• drugs in pregnancy are problematic:
teratogenicity• pediatric dosing is problematic, clearance may be increased.• geriatric dosing is problematic
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