Regulation of therapeutic goods

In the United States, regulation of drugs was originally a state right, as opposed to federal right. But with the increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, the need for stronger federal regulation increased.[7] In 1906 President Roosevelt signed the Federal Food and Drug Act (FFDA) which both established stricter national standards for drug manufacture and sales, and also established the Federal government as the regulating authority over the US drug industry.[7] A 1911 Supreme Court decision, United States vs. Johnson, established that misleading statements were not covered under the FFDA. This directly led to Congress passing the Sherley Amendment which established a clearer definition of 'drug marketing requirements'.[7]

More catalysts for advances in drug regulation in the US were certain catastrophes that served as calls to the US government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing.[7][4] This directly led to the passing of the Federal, Food, Drug, and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, which was originally sold in Germany (introduced into a virtually unregulated market) and eventually sold around the world, led to approximately 100,000 babies being born with various deformities.[4] In 1962 the United States Congress passed the Drug Amendments Act of 1962. The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards.[7]

The UK's Chief Medical Officer had established a group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world. The UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to the Committee on Safety of Drugs was not mandatory immediately after, the pharmaceutical industry later complied due to the thalidomide situation.

The European Economic Commission also passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug.[6] Drug legislation in both the EU and US were passed in order to assure drug safety and efficacy. Of note, increased regulations and standards for testing actually led to greater innovation in pharmaceutical research in the 1960s, despite greater preclinical and clinical standards.[6] In 1989, the International Conference of Drug Regulatory Authorities organized by the WHO, officials from around the world discussed the necessity for streamlined processes for global drug approval.[4]

Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration (TGA),[8] that was created by the Therapeutic Goods Act 1989. The availability of drugs and poisons is regulated by scheduling under individual state legislation, but is generally under the guidance of the national Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP).

Under the SUSDP, medicinal agents generally belong to one of five categories:

• Unscheduled/exempt
• Schedule 1 (S1) - Over the counter Medicines (Generally is not used)
• Schedule 2 (S2) - Pharmacy Medicines
• Schedule 3 (S3) - Pharmacist Only Medicines
• Schedule 4 (S4) - Prescription Only Medicines
• Schedule 5 (S5) - Poison
• Schedule 6 (S6) - Caution/Poison
• Schedule 7 (S7) - Dangerous/Poison
• Schedule 8 (S8) - Controlled Drug
• Schedule 9 (S9) - Prohibited Drug
• Schedule 10 (S10) - Prohibited Substance

Therapeutic goods in Brazil are regulated by the Ministry of Health of Brazil, through its Brazilian Health Regulatory Agency (Anvisa), equivalent to the US Food and Drug Administration. There are six main categories:

• Over-the-counter (OTC) medicines (medicamentos isentos de prescrição or MIPs in Portuguese): cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies.
• Red stripe medicines: sold only with medical prescription. Anti-allergenics, anti-inflammatories, and other medicines.
• Red stripe antibiotics: antibiotics are sold only with a "special control" white medical prescription with patient's copy, which is valid for 10 days. The original must be retained by the pharmacist after the sale and the patient keeps the copy.
• Red stripe psychoactive medicines: sold only with a "special control" white medical prescription with patient's copy, which is valid for 30 days. The original must be retained by the pharmacist after the sale and the patient keeps the copy. Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category.
• Black stripe medicines: sold only with the "blue B form" medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives (benzodiazepines), some anorexic inducers and other habit-inducing controlled medicines.
• "Yellow A form" prescription medicines: sold only with the "yellow A form" medical prescription - the most tightly controlled, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes amphetamines and other stimulants (such as methylphenidate), opioids (such as morphine and oxycodone) and other strong habit-forming controlled medicines.[9]

Biological medications are complex molecules of high molecular weight obtained from a biological source or biotechnological procedures and are divided by Anvisa into the following categories:[10]

• Allergens: substances from animals or plants that can induce an IgE response or a type I hypersensitivity reaction
• Monoclonal antibodies: immunoglobulins derived from the same B lymphocyte clone, propagated in continuous cell lines
• Biomedicines: obtained from biological fluids or tissues of animal origin or through biotechnological procedures
• Blood derivatives: obtained from human plasma, subjected to industrialization and standardization processes
• Probiotics: preparations containing viable microorganisms in sufficient quantity to change the microbiota
• Vaccines: immunobiological medications[11][12] that contain one or more antigenic substances capable of inducing immunity to protect against disease, reduce its severity or fight it

The regulatory status of vaccines, which determines their marketing and distribution, may be one of the following established by Anvisa:[13]

• Sanitary vaccine registration: definitive, for approved drugs
• Temporary emergency use authorization: similar to a US Emergency Use Authorization
• Exceptional import authorization
• COVAX Facility: temporarily lifts the requirement of registration or emergency use authorization for vaccines purchased by the Ministry of Health that are under the Emergency Use Listing of the World Health Organization[14]

Vaccines can only be administered in public health centers or authorized private vaccination services.[15]

In Canada, regulation of therapeutic goods are governed by the Food and Drug Act and associated regulations. In addition, the Controlled Drugs and Substances Act specifies additional regulatory requirements for controlled drugs and drug precursors.[16]

In Ontario, the Drug and Pharmacies Regulation Act governs "any substance that is used in the diagnosis, treatment, mitigation or prevention of a disease…in humans, animals or fowl."[17]

The regulation of drugs in China is governed by the China Food and Drug Administration.

The European Union (EU) medicines regulatory system is based on a network of around 50 regulatory authorities from the 31 EEA countries (28 EU Member States plus Iceland, Liechtenstein and Norway), the European Commission and European Medicines Agency (EMA). EMA and the Member States cooperate and share expertise in the assessment of new medicines and of new safety information. They also rely on each other for exchange of information in the regulation of medicine, for example regarding the reporting of side effects of medicines, the oversight of clinical trials, and the conduct of inspections of medicines' manufacturers and compliance with good clinical practice (GCP), good manufacturing practice (GMP), good distribution practice (GDP), and good pharmacovigilance practice (GVP). EU legislation requires that each Member State operates to the same rules and requirements regarding the authorisation and monitoring of medicines.[18]

Within the EU, EudraLex maintains the collection of rules and regulations governing medicinal products in the European Union, and the European Medicines Agency acts to regulate many of these rules and regulations. Amongst these rules and regulations are:

• Directive 65/65/EEC1, requires prior approval for marketing of proprietary medicinal products
• Directive 75/318/EEC, clarifies requirements of 65/65/EEC1 and requires member states to enforce them
• Directive 75/319/EEC, requires marketing authorization requests to be drawn up only by qualified experts
• Directive 93/41/EEC, establishes the European Agency for the Evaluation of Medicinal Products
• Directive 2001/20/EC, defines rules for the conduct of clinical trials
• Directive 2001/83/EC
• Directive 2005/28/EC, defines Good Clinical Practice for design and conduct of clinical trials

German law classifies drugs into

• Narcotics ("Betäubungsmittel")
  • Anlage I BTMG (authorized scientific use only)
  • Anlage II BTMG (authorized trade only, not prescriptible)
  • Anlage III BTMG (special prescription form required – "Betäubungsmittelrezept")
• Research chemicals ("neue psychoaktive Stoffe" – permitted only for industrial and scientific purposes)
• Prescription drugs ("verschreibungspflichtig" or "rezeptpflichtig")
• Pharmacy-only drugs ("apothekenpflichtig")
• General sales list drugs ("freiverkäuflich")
• Raw materials for synthesizing drugs
  • Kategorie 1 (authorization required)
  • Kategorie 2 (reporting required)
  • Kategorie 3 (export restrictions)

Medicines in Iceland are regulated by the Icelandic Medicines Control Agency.[19]

Medicines in India are regulated by Central Drugs Standard Control Organization (CDSCO) Under Ministry of Health and Family Welfare. Headed by Directorate General of Health Services, CDSCO regulates pharmaceutical products through Drugs Controller General of India (DCGI) at chair.

Drugs are classified under five headings. Under retail and distribution:

• Schedule X drugs - narcotics
• Schedule H and L - injectables, antibiotics, antibacterials
• Schedule C and C1 - biological products, for example serums and vaccines

Under manufacturing practice:

• Schedule N - list of the equipment for the efficient running of manufacturing wing, qualified personnel
• Schedule M

Medicines in Indonesia are regulated by National Agency of Drug and Food Control of Indonesia. Drugs in Indonesia are classified into:[20][21]

• Over-the-counter (OTC) drug (Obat bebas), drugs freely available to the public. Marked by green circle with black line.
• Limited OTC drug (Obat bebas terbatas), drugs available to the public only through pharmacy (apotek) or licensed drug stores. Marked by blue circle with black line.
• Prescription drug (Obat keras), prescription only medicine. Marked by red circle with letter "K" inside circle and black line.
• Narcotics and psychoactive drugs (Obat psikotropika dan narkotika). National Narcotics Board perform law enforcement measure at illegal drug abuse and drug trafficking.

Medicines in the Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs (CDs) are divided into five categories based on their potential for misuse and therapeutic effectiveness.

• CD1: cannabis, lysergamide, coca leaf, etc. Use is prohibited except in limited circumstances where a license has been granted.
• CD2: amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc. Prescriptions must be handwritten and are only valid for 14 days. Repeat prescriptions are not permitted. Drugs must comply with safe custody and destruction of unsold/unused medication must be witnessed. Must be registered in a Controlled Drugs register.
• CD3: temazepam, flunitrazepam, etc. As CD2, except witnessed destruction and CD register are not required.
• CD4: benzodiazepines, e.g. diazepam, nitrazepam, low dose (methyl)phenobarbitone
• CD5: low-dose codeine, etc.[22]

The regulation of drugs in Burma is governed by the Food and Drug Administration (Burma) and Food and Drug Board of Authority.

Medicines in Norway are divided into five groups:

Class A

Narcotics, sedative-hypnotics, and amphetamines in this class require a special prescription form:

• morphine and its immediate family, heroin, desomorphine, nicomorphine;
• codeine and its immediate family, dihydrocodeine, ethylmorphine, nicocodeine;
• morphine relatives: hydromorphone and oxymorphone;
• codeine relatives: hydrocodone and oxycodone;
• synthetic opioids: pethidine, methadone, fentanyl, and levorphanol;
• various sedative-hypnotics: temazepam, methaqualone, pentobarbital, and secobarbital;
• various stimulants: amphetamines and methylphenidate;
• flunitrazepam (moved from class B)

Class B

Restricted substances which easily lead to addiction like:

• co-codamol
• tramadol
• diazepam
• nitrazepam
• all other benzodiazepines (with the exception of temazepam and flunitrazepam)
• phentermine

Class C - All prescription-only substances

Class F - Substances and package-sizes not requiring a prescription

Unclassifieds - Brands and packages not actively marketed in Norway

The Food and Drug Administration regulates drugs and medical devices in the Philippines.

Prohibited. Brands and packages not actively marketed in Sri Lanka.

Medicines in Switzerland are regulated by Swissmedic. The country is not part of the European Union, and is regarded by many as one of the easiest places to conduct clinical trials on new drug compounds.

There are five categories from A to E to cover different types of delivery category:[23]

• A: Supply once with a prescription from a doctor or veterinarian
• B: Supply with a prescription from a doctor or veterinarian
• C: Supply on technical advice from medical staff
• D: Supply on technical advice
• E: Supply without technical advice

Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product.

The United Kingdom has a three-tiered classification system:

• General Sale List (GSL)
• Pharmacy medicines (P)
• Prescription Only Medicines (POM)

Within POM, certain agents with a high abuse/addiction liability are also separately scheduled under the Misuse of Drugs Act 1971 (amended with the Misuse of Drugs Regulations 2001); and are commonly known as Controlled Drugs (CD).

Therapeutic goods in the United States are regulated by the U.S. Food and Drug Administration (FDA), which makes some drugs available over the counter (OTC) at retail outlets and others by prescription only.

The prescription or possession of some substances is controlled or prohibited by the Controlled Substances Act, under the FDA and the Drug Enforcement Administration (DEA). Some US states apply more stringent limits on the prescription of certain controlled substances C-V and BTC (behind the counter) drugs such as pseudoephedrine. Three primary branches of pharmacovigilance in the U.S. include the FDA, the pharmaceutical manufacturers, and the academic/non-profit organizations (such as RADAR and Public Citizen).