Lecture 1: History of drug regulation Flashcards
What happened in 1854
1854 Cholera outbreak: Led to the establishment of ad hoc patchwork health boards in New Brunswick and Upper Canada to deal with outbreak.
- Infections spread, resorted to quarantine to avert pandemic
- Patchwork health system inadequate
- Poor sanitation – contaminated water spread
After Confederation what acts did the Parliament pass
1) Quarantine Act – to allow federal officials to inspect arriving ships for sick passengers
2) Sick Mariners Act – which provided special medical services for seaman that fall ill on Canadian waters or at Canadian ports.
WHat new legislation established the Department of Health in Canada in 1919
Responsibilities included all matters pertaining to public health:
- Medical examination of immigrants and Canadian seaman
- Health promotion within the public service
- Collection, publication, dissemination of health information and advisories.
How did the depatment of Health mandade expand in 1928
began dispensing and administering medical and convalescent care, job retraining, and pensions for returning war veterans.
- Renamed Pensions and National Health
What happened after WWII
Following WWII, repatriation of thousands of Canadian soldiers led to major government reorganizations.
In 1944 created Department of Veterans Affairs and Department of National Health and Welfare.
What was included in the Department of National Health and Welfare (1944-1993)
- Responsible for everything related to the promotion and preservation of health, social security, and welfare
- Research public health issues
- Medical examination of immigrants and seaman
- Administration of hospitals
- Supervision of public health aspects of transportation
- Health promotion within the public service
- Collection/dissemination of health information/stats
- Cooperation with provincial health authorities
Post WWII the Department of National Health and Welfare administered:
- Food and Drugs Act
- Canada Health Act
- Narcotic Control Act
- Quarantine Act
- Fitness and Amateur Sports Act
- Canada Pension Plan Act
- Old Age Security Act
- Family Allowances Act
- Vocational Rehabilitation of Disabled Persons Act
- Canada Assistance Plan Act
What was the 1993 reorganization
Welfare responsibilities transferred to the new Department of Human Resources Development
Department of National Health and Welfare was renamed the Department of Health.
Structure of the Department of Health (1993-2002):
- Health Protection branch
- Health Services Promotion branch
- Medical Services branch
- Fitness and Amateur Sports branch
- Income Security branch
- Social Service Programs branch
- Policy, Planning and Information branch
- Intergovernmental and International Affairs branch
- Communications branch
Structure of Health Canada (2002-current):
**Branches:
**
- Audit and Accountability Bureau
- Chief Financial Officer Branch
- Communications and Public Affairs Branch
- Corporate Services Branch
- Departmental Secretariat
- First Nations & Inuit Health Branch
- Health Products & Food Branch
- Healthy Environments & Consumer Safety Branch
- Legal Services
- Pest Management Regulatory Agency
- Regions and Programs Bureau
- Strategic Policy Branch
Agencies:
- Canadian Institutes of Health Research
- Patented Medicines Prices Review Board
- Public Health Agency of Canada
Act vs Regulation
**Act: **Legislation (law). A Bill requires Royal Assent to become Law.
Regulation: Subordinate legislation. Defines the application and enforcement of an Act.
Amendment to the inland revenue act (1875)
Canada’s first consumer protection law
Health Products & Food Branch
Therapeutic products directorate (TPD)
Biologics and genetic therapies directorate (BGTD)
Medical Devices Directorate (MDD)
Non-prescription and natural health products directorate (NNHPD)
Veterinary drugs directorate (VDD)
Amend the act respecting inland revenue
An Act to Impose License Duties on Compounders of Spirits and to amend the Act Respecting Inland Revenue to Prevent the Adulteration of Food, Drink and Drugs
Definition: adulterated “all articles of food with which was included any deleterious ingredients or any material of less value than is understood by the name.”
Inland Revenue Act (1875)
Four consumer protection provisions:
1) Workable terminology: Drugs were defined as “all articles used for curative or medicinal purposes”
2) Established standards through licensing
3) Imposed requirements for proper labelling and advertisement by manufacturers
4) Sanctions to allow government to train inspectors.
Adulteration Act
(AA; 1884) “An Act to Amend and to Consolidate as Amended the Several Acts Respecting the Adulteration of Food and Drugs”
Response to 1881 report
Adulteration Act (AA)
- Adhered to the four consumer protection provisions of the Inland Revenue Act (1875)
- Separate regulatory regime for Food, Drugs, and Liquor
- Updated definition of “drugs” with reference to “medicines for internal or external use”
- Aligned drug manufacturing standards in Canada with British or American Pharmacopoeia
- Further amendments were made over the years that strengthened the four principles.
Adulteration Act (AA)
AA – change to Department mandates
- 1915 Labelling standards were strengthened
- 1918 (post WWI) AA authority transferred from Department of Customs and Inland Revenue to the Department of Trade and Commerce
- 1919 AA was transferred to the new Food and Drugs Division of the new Department of Health
- 1920 AA was repealed and replaced with the Food and Drugs Act
- Modeled more heavily after the US Food and Drugs Act of 1906
1920 Food and Drugs Act
- Four consumer protection principles continue from Inland Revenue Act 1875
- Definition of drug
all medicines for internal or external use for man or animal - Standards of drug manufacture British or US Pharmacopoeia
- Label must be affixed to product with character, strength, quality and quantity
- Allowed for appointment of inspectors with powers to seize, for further analysis, food or drug products believed to be in violation of Act
- Inspectorate expanded (from 1 full time food and drug inspector pre 1920, to larger district and regional inspectorate staff by 1922) - Manufacture, advertisement, or sale of adulterated food or drug a criminal offence
1927 Act to amend the Food and Drugs Act
Revised definition of drug: All medicine for internal or external use for man or animal; and any substance or mixture of substances intended to be used for the treatment, mitigation or prevention of disease in man or animal.
- Drug definition revision requested by Department so as to expand the products covered (eg. Include antiseptics and vaccines)
Revision to structure of Act to include a schedule of drugs (Schedule B) subject to specific standards, testing, and rigorous inspection
- Schedule B drugs were biologics (strophanthus, digitalis, ergot, adrenalin) considered very potent and requested by physicians to be subject to greater control
Revision to Act: stricter drug labeling standards in line with labeling standards currently in place for food.
- Again, with the purpose to protect the public from drug adulteration and misbranding
Revision to Act: Government can hold a inspector-seized drug indefinitely
1936 Act to amend the Food and Drugs Act
Expanded the definition of drug to include cosmetics and articles used in the diagnosis, treatment, mitigation, or prevention of disease in man or animal.
- Effectively expanding the definition of drug to medical devices
Thalidomide prompts large scale changes to FDA
+ Thalidomide approved for sale in Canada in 1960 under the brand names Kevadon (William S. Merrill Company) and in 1961 under the brand name Talimol (Frank W. Horner Company)
+ Previously approved in Germany and the UK (safe?)
+ 1960 indicated as a sedative
+ Regarded as a “wonder drug”
+ Prescribed to pregnant women to treat morning sickness (anti-nausea)
+ Target of drug? Mechanism of action?
Ito et al. Science 327(5971):1345-1350, 2010.
Thalidomide prompts large scale changes to FDA
In Canada, approximately 100 deformed babies were born to mother’s prescribed thalidomide during the first trimester of pregnancy.
March 1962 Department of National Health and Welfare pulled all thalidomide containing drugs from hospitals and pharmacies across Canada
1962 Health Minister’s recommendations
1) Review of drug approval process by College of Physicians and Surgeons
2) Changes to the F&D Act & Regulations
*Amended FDA quickly received Royal Assent (December 1962)
1963 Changes to the FDA / FDR
A. Added Section H to the FDA “Restricted drugs”
- Criminal offence to sell thalidomide (and LSD)
B. Strengthened federal government powers to restrict sale of drugs in Canada
- Health-care professionals no longer able to give drug samples
- Added additional Regulations to better control distribution and sale of drugs
C. Greater oversight of clinical trials
- Immediate reporting of serious adverse events
- Government has the power to stop a clinical trial and must approve the trial investigator
D. Stronger emphasis on the strength of the clinical data submitted and review thereof during NDS review
E. Stronger emphasis on post-market drug surveillance
F. Significant changes to the structure of the NDS
1963 FDR: Creation of
Division 8
New definition of a “new drug”
“(a) a drug that contains or consists of a substance, whether as an active or inactive ingredient, carrier, coating, excipient, menstruum or other component, that has not been sold as a drug in Canada for sufficient time and in sufficient quantity to establish in Canada the safety and effectiveness of that substance for use as a drug;”
1963 Division 8 NDS
New Drug Submission (NDS):
+Review to take 120 days versus previous 90 days
+Content of NDS to include:
- Decription of new drug, proper name, brand name
- A quantitative list of all ingredients and specifications
- Names, address of manufacturers of ingredients
- Description of manufacturing process
- Description of controls used in manufacturing
- Details of the tests performed on the drug product (to control potency, purity, stability, safety)
- Reports of above safety tests
- Evidence of clinical effectiveness
- Labels to be used, route of admin, proposed dosage, contra-indications, side effects
- Pharmaceutical form drug will be sold
1965-1968: Additional changes to Food and Drugs Directorate
- Increase in size of Directorate personnel
- Drug manufacturers / distributors need to be registered with Directorate
- Implementation of lot release program
- new Regulations to govern drug importation into Canada
1990s: New Drug Licensing Framework
- Every brand name of a drug receives a unique Drug Identification Number (DIN) (1992)
- Adverse Drug Reaction Reporting (post-market surveillence) added into the FDR (1995)
- Changes increasingly conforming to international regulations (international harmonization)
- Risk/Benefit ratio
Recent amendments
2014: Protecting Canadians from Unsafe Drugs Act (Vanessa’s Law) Amendments to the Food and Drugs Act (Bill C-17)
- First reading on December 6, 2013
+Bill brought before Parliament by MP Terrence Young
+Bill in response to the death of 15 year old Vanessa Young (2001)
++Cisapride (Prepulsid) serotonin 5-HT4 receptor agonist used to increase GI motility
++Bulemic (electrolyte imbalance)
++Young’s pharmacist was not aware of ventricular arrhythmias
+++ 80 serious (fatal) ADRs associated with Cisapride at the time in US/CAN
+++ Currently 16 ADRs for Cisapride and arrhythmias in Canada
- Royal Assent on November 11, 2014
2014 Vanessa’s Law
Enhanced post-market drug surveillance
- Mandatory adverse drug reaction reporting by healthcare institutions
Authority to recall unsafe therapeutic products;
- New penalties for unsafe products: jail, and new fines of up to $5 million per day instead of the current $5,000
- Provide the courts with discretion to impose even stronger fines if violations were caused intentionally;
Compel drug companies to revise labels to clearly reflect health risk information, including potential updates for health warnings for children
Compel drug companies to do further testing on a product, including when issues are identified with certain at-risk populations such as children.
Mandatory clinical trial registration
New regulation making powers
Current Structure of the FDA
Part 1 FOODS, DRUGS, COSMETICS AND DEVICES
- Sale and importation, powers to require information*
Part 2 ADMINISTRATION AND ENFORCEMENT
- Marketing authorization and inspections, punishments
Part 3 and 4 SCHEDULES
Schedule A
- List of diseases, disorders, or abnormal states for which advertisement is prohibited for drugs
Schedule B
- List of standards (eight)
Schedule C
- Radiopharmaceuticals
Schedule D
- Biologics
Food and Drug Regulations
Part A – Administration
Part B – Foods
Part C – Drugs
Part D – Vitamins, Minerals, and Amino Acids
Part E – Cyclamate and Saccharin Sweeteners
Part G – Controlled Drugs
Part J – Restricted Drugs
Part C – Drugs
Division 1 – All drugs, general information and definitions
Division 1A – Establishment Licences
Division 2 – Good manufacturing practices
Division 3 – Schedule C drugs (Radiopharmaceuticals)
Division 4 – Schedule D drugs (Biologics)
Division 5 – Drugs for human Clinical Trials
Division 6 – Canadian Standard Drugs
Division 7 – Programs for access to low cost patented medicines
Division 8 – New drugs (modern definition of drug)
Division 9 – Non-prescription drug regulations
Division 4 Schedule D drugs (biologics)
Allergenic substances used for the treatment or diagnosis of allergic or immunological diseases
Anterior pituitary extracts
Aprotinin
Cholecystokinin
Drugs obtained by recombinant DNA procedures
Drugs, other than antibiotics, prepared from micro-organisms
Drugs that are or are made from blood
Glucagon
Gonadotrophins
Immunizing agents
Insulin
Interferon
Monoclonal antibodies, their conjugates and derivatives
Secretin
Snake Venom
Urokinase
General - C.04.001 to .049
- Segregation of work with spore formers and infectious agents
- Submission of protocols and samples
- Animal use
Bacterial Vaccines - C.04.050 to .085
- General, Typhoid, Pertussis, BCG
Viral Vaccines - C.04.100 to .136
- General, Rickettsial, Small pox, Polio
Toxins, Toxoids, Antisera - C.04.140 to .229
- Diphtheria, Tetanus
Human Plasma Collected by Plasmapheresis - C.04.400 to .428
Insulin Preparations - C.04.550 to .656
Anterior Pituitary Extracts - C.04.675
Complexity of therapeutic products
Acetaminophen
Insulin
Cell Product
Definitions
Therapeutic product: means a drug or device or any combination of drugs and devices, but does not include a natural health product within the meaning of the Natural Health Products Regulations;
Drug: includes any substance or mixture of substances manufactured, sold or represented for use in
(a) the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in human beings or animals,
(b) restoring, correcting or modifying organic functions in human beings or animals, or
(c) disinfection in premises in which food is manufactured, prepared or kept;
Device: Health or medical instrument used in the treatment, mitigation, diagnosis or prevention of a disease or abnormal physical condition. (abbrev.)
Biologic: A drug product derived from a living organism (animal, plant or microbe)
- Blood, blood products, cells, tissues, organs, including xenografts (living cells, tissues and organs from animal sources), gene therapies, viral and bacterial vaccines, therapeutic products produced through biotechnology, and radiopharmaceuticals
Natural Health Product: A finished health product derived from nature (biologic or food) (adapted)
- Vitamins and minerals, herbal remedies, homeopathic medicines, traditional medicines such as traditional Chinese medicines, probiotics, amino acids, and essential fatty acids (all non-prescription; have their own regulations)
Biologics versus Conventional Pharmaceuticals 1/4
Raw materials used for biologics are variable in nature
- Eg. serum derivatives, enzymes, cell substrates
Manufacturing processes are biological in nature and variable
- Eg. prokaryotic or eukaryotic cell systems
Biologics are highly susceptible to microbial growth (biologic: mixture of protein or polysaccharides)
- Microbial contamination must be considered at every step during the manufacture of a biologic.
Biologics versus Conventional Pharmaceuticals 2/4
Heat sensitive (heat labile); most are stored continuously at 2 to 8 0C, some are not only stored cold or frozen but are shipped in a frozen state e.g. live polio vaccine.
- manufacturing process may require temperatures below 10 0C depending on the nature of the product being manufactured and the length of time required to complete the manufacturing process.
Biologics versus Conventional Pharmaceuticals 3/4
The stages of manufacture are often carried out under conditions that cannot meet the same standards as conventional pharmaceuticals
- no terminal sterilization
- aseptic processing
Test methods needed to characterize batches of the product are variable in nature
- potency, purity and safety of most biologics can not be adequately tested by chemical or physical means alone
- bioassays have a high degree of variability/invalidity
Biologics versus Conventional Pharmaceuticals 4/4
Complex structure of final product
-molecular weight and structure undefined
-composition undefined (vaccines)
A system of in-process controls required for biologic production
Quality can not be established entirely by tests on the final product
- “Quality is built into a product and not just tested into a finished product.”
+Consistency in
+ production/product
Absence of Contamination
