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