Harpa - Glossary

Understanding the Regulatory Review of Drug Therapies

GLOSSARY OF TERMS

Drug research and regulatory systems are complex. This is reflected in a large number of terms and abbreviations used by stakeholders in government, academia, industry, and healthcare sectors. This glossary aims to increase understanding of these terms and related policies for limiting risk of harm to Canadians from new drugs or new applications of existing drugs. Public health leaders may find this glossary useful to support communication with stakeholders—including the general public—about public health and safety related to new drug treatments and pharmaceutical products in development. Shared understanding of terms in this subject area may affect public confidence in these products, whether in ‘peace time’ or pandemic circumstances. NCCID engages public health and other stakeholders in conversations about evidence-informed interventions. This glossary is also a starting point for further conversations focused on proven and investigational drug therapies, with consideration of public health ethics and equity.

Why this glossary?

The glossary terms are arranged in alphabetical order, with some exceptions for closely related terms that are grouped under one entry. All definitions are quoted verbatim from the original source. Click the document icon to find a link to the source document. More than one definition is given when needed for clarity. Some annotations are included to cross-reference related terms, or to provide a common synonym. The list is not comprehensive. However, the glossary will be managed as a ‘living document’, with periodic updates as our work on the topic expands.

Tips for readers

Use the arrow at the right to view the glossary terms in alphabetical order, or click on a tile to find terms beginning with that letter

Index

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Serious Unexpected Drug Reaction

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See also: Adverse Event

In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase ‘responses to a medicinal product’ means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility; that is, the relationship cannot be ruled out.

Any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.

Adverse Drug Reaction (ADR)

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Serious Unexpected Drug Reaction

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See also: Adverse Drug Reaction

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Any adverse occurrence in the health of a clinical trial subject who is administered a drug that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.

Adverse Event (AE)

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As defined in the UK. Also referred to as ‘licensed product’

A medicinal product, marketed by a specified company, for which there is in force: (a) a marketing authorization; (b) a certificate of registration as a homeopathic medicinal product; (c) a traditional herbal registration.

Authorized Medicinal Product (Licensed Product)

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See also: Phase I clinical trial, Phase II clinical trial, Phase III clinical trial, Phase IV clinical trial

Clinical Trial

An investigation with a drug for use in human subjects, intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.

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Phase IV clinical trial

All studies performed within the approved indication after the drug has been approved by the regulator for the market. These studies are often important for optimizing the drug's use. They may be of any type but must have valid scientific objectives. Commonly conducted studies include safety studies and studies designed to support use under the approved indication, for example mortality and morbidity studies, or epidemiological studies. These trials do not usually require regulatory approval by Health Canada.

Phase III clinical trial

Controlled or uncontrolled trials conducted after preliminary evidence suggesting efficacy of the drug has been demonstrated. These are intended to gather the additional and confirmatory information about the clinical efficacy and safety under the proposed conditions of use for the drug.

Phase II clinical trial

Clinical trials to evaluate the efficacy of the drug in patients with medical conditions to be treated, diagnosed or prevented and to determine the side effects and risks associated with the drug. If a new indication for a marketed drug is to be investigated, then those clinical trials may generally be considered Phase II trials. These trials provide preliminary information on the safety and efficacy of the drug in patients.

Phase I clinical trial

Clinical trials designed mainly to determine the pharmacological actions of the drug and the safety (side effects) associated with increasing doses. Pharmacokinetic studies (evaluating drug levels in tissues such as blood) as well as drug interaction studies are usually considered as Phase I trials, regardless of when they are conducted during drug development. Phase I trials are generally conducted in healthy volunteers, but may be conducted in patients when administration of the drug to healthy volunteers is not ethical.

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Regulatory dossier that needs to be submitted to Health Canada and given a No Objection Letter (NOL) from Health Canada prior to the sponsor proceeding with a clinical trial with an investigational pharmaceutical, biological and radiopharmaceutical product in the Canadian population / patients.

CTAs are required for human clinical trials using drugs not authorized for sale in Canada, including clinical trials in Phases I through III of drug development and comparative bioavailability studies, as well as trials involving marketed drugs, where the proposed use of the drug is outside the parameters of the NOC (Notice of Compliance) or DIN (Drug Identification Number).

Clinical Trial Application (CTA)

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See also: Sponsor

Form that is required to be completed and submitted to Health Canada by the sponsor or its representative for each clinical trial site, prior to commencement of the clinical trial or implementation of a Clinical Trial Application-Amendment, at that site.

Clinical Trial Site Information Form (CTSIF)

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A trial in which subjects receive a sequence of different treatments.

Crossover Trial

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‘Drugs’ include both prescription and nonprescription pharmaceuticals; biologically-derived products such as vaccines, blood derived products, and products produced through biotechnology; tissues and organs; disinfectants; and radiopharmaceuticals. According to the Food and Drugs Act, "a drug includes any substance or mixture of substances manufactured, sold or represented for use in: the diagnosis, treatment, mitigation or prevention of a disease, disorder, abnormal physical state, or its symptoms, in human beings or animals; restoring, correcting or modifying organic functions in human beings or animals; or disinfection in premises in which food is manufactured, prepared or kept".

Drug / Drug Product

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A Drug Identification Number (DIN) is a computer-generated eight digit number assigned by Health Canada to a drug product prior to being marketed in Canada. It uniquely identifies all drug products sold in a dosage form in Canada and is located on the label of prescription and over-the-counter drug products that have been evaluated and authorized for sale in Canada.

Drug Identification Number (DIN)

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A (drug) trial designed to determine if a treatment is able to treat or prevent a given medical condition.

Efficacy Trial

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In some circumstances, patients can access medical treatments before they have been subject to rigorous testing and approved by medical regulators, which are often referred to as ‘experimental treatments’. ...We use the term experimental treatments, but terms used elsewhere include innovative, novel, unproven, unvalidated, non-standard, and unlicensed treatments. There is a spectrum of treatments that might be considered to be experimental, from those which have never been used in humans, to those which are used routinely but are not licensed for the condition in question. Experimental treatments include medicines, surgery, the use of medical devices and implants, stem cell and gene therapies, and fertility treatments.

Experimental treatment is the use of an unproven therapy or modality that has not yet been shown to be effective in the human subject. Normally, experimental treatment is offered to patients for whom all standard treatment has been ineffective. Experimental treatment is in need of further study via clinical trials to establish efficacy and safety.

Experimental Treatment

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Early trials that usually involve a limited group of healthy volunteers or patients. These trials are designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a drug.

Human Pharmacology Trial

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The Product Monograph can be consulted to determine the approved indication(s) for the reference product.

See also: Product Monograph

An indication for a drug is the reason the drug is used, usually to treat an illness or disease.

Indication

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See also: Sponsor

A clinical trial that is initiated and conducted by an institution or an individual investigator. For such trials, the institution or investigator is considered to be the sponsor of the trial and must fulfill all the regulatory obligations of the sponsor as outlined in the Regulations.

Institution / Investigator-initiated Clinical Trial

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A trial in which the treatment assigned to the trial subject is predefined by the trial protocol.

Interventional Trial

Investigational Treatment

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See also: Investigational Product

A medication approved by the Health Protection Branch (Health Canada) for limited clinical use in Canada by approved investigators. This includes a new drug or a novel use of a commercially available drug being investigated according to a prescribed protocol for administration and evaluation.

Investigational Drug

Investigational Treatment

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See also: Investigational Drug

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use".

Investigational Product

Investigational Product

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See also: Investigational Drug

Investigational treatment is a therapy that has preliminary data (laboratory or similar) and is approved by Health Canada for testing in humans. (…) An investigational treatment may be approved for use in one disease condition but still considered investigational in other diseases or conditions.

Investigational Treatment

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When a drug is authorized for sale in Canada, Health Canada authorizes specific indications, doses, safety profiles, and directions for use. This information is then included in the labels affixed to the container or packaging (i.e., inner/outer labels) of the drug and in any separate Health Canada-authorized documents, such as the official prescribing information, product monographs, package inserts, etc., that are collectively referred to as the “label” for that drug.

Label

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Health Canada reviews scientific evidence of a drug or vaccine, including results from clinical trials, to assess the product’s safety, efficacy and quality before it can be sold in Canada.

Market Authorization

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A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.

Multi-centre Trial

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A notice issued under section C.08.004 or C.08.004.01 of the Food and Drug Regulations to a manufacturer following the satisfactory review of a drug submission for a New Drug.

Notice of Compliance (NOC)

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Off-label use means that the medicine is being used in a way that is different to that described in the license. Some examples of “off-label” uses are:

• Using a medicine for a different illness to that stated in the license. Doctors may have found that the medicine works very well for this illness or condition. This use may be supported by expert groups, but the drug manufacturer has not extended the license.
• Using a medicine in an age group outside the licensed range (usually children or the elderly).
• Using a medicine at a higher dose than stated in the license.

The use of an approved drug beyond the criteria set out in the product’s approval is referred to as “off-label” use of drugs. The manufacturers cannot promote off-label use of their products “because the terms of such authorization have not been established and the proposed indication(s) for use have not been verified.”

The term off-label describes the use or intended uses of a drug for indications other than those that have received regulatory authorization. A clinician may use his or her discretion in prescribing a drug off-label, but this common practice should be informed by evidence, need, a sound clinical rationale and an assessment of the potential risks and benefits of a particular drug for a particular patient. It is important to understand the authorized indications versus off-label use for antivirals and to make sure that patients understand the risks and benefits, and that they consent to taking the prescribed drug.

Off-label

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A status granted by Health Canada to an New Drug Submission or a Supplement to a New Drug Submission for a serious, life-threatening or severely debilitating disease or condition for which there is substantial evidence of clinical effectiveness that the drug provides: 1) effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or 2) a significant increase in efficacy and/or a significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.

Priority Review (PR)

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A product monograph is a factual, scientific document on the drug product that, devoid of promotional material, describes the properties, claims, indications, and conditions of use for the drug, and that contains any other information that may be required for optimal, safe, and effective use of the drug. A product monograph should include appropriate information respecting the name of the drug, its therapeutic or pharmacologic classification, its actions and/or clinical pharmacology, and its indications and clinical uses. The monograph should also include contraindications, warnings, precautions, adverse reactions, drug interactions and effects on laboratory tests, symptoms and treatment of over dosage, dosage and administration, storage and stability, pharmaceutical information, dosage forms, pharmacology, toxicology, microbiology, special handling instructions, information on clinical trials, information for the patient, references, and the dates of the initial printing and current revision.

Product Monograph

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A protocol summary to be prepared and submitted within the CTA. The summary is expected to contain: protocol identification, background and rationale, trial objectives, study design and duration, total number of sites (including number of Canadian sites), investigators, sample size, patient population, inclusion and exclusion criteria, drug formulation, dosage regimen, washout period, screening and baseline evaluation, treatment and assessment visits, concomitant and rescue medication, risk management, withdrawal/discontinuation criteria, efficacy and safety variables and analysis, statistical analysis.

Protocol Safety and Efficacy Assessment Template – Clinical Trial Application (PSEAT-CTA)

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The person responsible to the sponsor for the conduct of the clinical trial at the clinical trial site, who is entitled to provide health care under the laws of the province where that clinical trial site is located.

Qualified Investigator (QI)

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A trial that gathers information on the adverse effects of a drug. Usually all clinical trials of drugs in development will collect information on adverse events.

Safety Trial

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Adverse Event

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See also: Adverse Drug Reaction

A serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out in the investigator's brochure or on the label of the drug.

Serious Unexpected Adverse Drug Reaction

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A Health Canada program that provides access to non-marketed drugs for practitioners who are treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or are unavailable. The SAP authorizes the manufacturer to sell a drug that cannot otherwise be sold or distributed in Canada. Drugs considered for release by the SAP include pharmaceutical, biologic, and radiopharmaceutical products not approved for sale in Canada.

Special Access Programme (SAP)

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An individual, corporate body, institution or organization that conducts a clinical trial.The sponsor is ultimately responsible for all regulatory requirements regarding the conduct of the trial in Canada. Where a third party, such as a contract research organization (CRO) or a site management office (SMO), has been delegated by written contract to carry out some or all of the sponsor's responsibilities, they must also demonstrate adherence to the applicable regulatory requirements. If a physician is identified on the clinical trial application (CTA) as the sponsor, he/she must assume the responsibilities of both the sponsor and the Qualified Investigator. This would include ensuring that all of the sponsor's obligations under section C.05.010 of Part C, Division 5 are met at all sites at which the trial is being conducted, as well as all other applicable sections of Part C, Division 5.

Sponsor

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TPD is part of the Health Products and Food Branch of Health Canada

Health Canada's Health Products and Food Branch is the national authority that regulates, evaluates and monitors the safety, efficacy, and quality of therapeutic and diagnostic products available to Canadians. These products include drugs, medical devices, disinfectants and sanitizers with disinfectant claims.

The Therapeutic Products Directorate is Canada’s regulator of prescription drugs and medical devices for human use. Before giving (manufacturers) permission to sell a product, the directorate must see scientific evidence of the product’s safety, effectiveness, and quality, as required by the Food and Drugs Act and Regulations.

Therapeutic Products Directorate (TPD)

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A "pending" status means Health Canada is pending the receipt of information from the sponsor indicating that the trial started. An "ongoing" status means Health Canada has received information from the sponsor indicating the proposed study start date, and an "ended" status means Health Canada has received information from the sponsor indicating that the clinical trial has ended.

Trial Status

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Also referred to as an unlicensed product

A medicinal product for human use in respect of which no marketing authorization has been granted by a relevant licensing authority.

Unauthorized Product

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As defined in the UK

These are often medicines used for treating rare illnesses. The manufacturer may have decided that it was too expensive to carry out the clinical trials or it would be difficult to find enough patients for the clinical trials needed to get a license.

Unlicensed Medications

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Also referred to as an unlicensed product

Unproven medications are those for which supporting data proving safety and efficacy have not been submitted to the Food and Drug Administration, according to the rigorous standards of the scientific method. Thus, for the purpose of this Statement, the term unproven medications includes dietary supplements, herbal medicines, and homeopathic medications, but excludes legitimate pharmaceuticals under active investigation (e.g., investigational medications). By extension, unproven therapies encompasses (sic) medical therapies outside the realm of evidence-based medicine, such as pseudomedical devices, therapeutic touch, reflexology, iridology, naturopathy, traditional Chinese medicine, etc.

Unproven Medications / Therapies

• Standing Senate Committee on Social Affairs, Science and Technology. Prescription Pharmaceuticals in Canada-Off-label Use. January 2014.

• SPharm. Canadian Drug Regulatory Glossary. 2020.

• Pray, SW. Nonprescription Medications and Self-Care; Ethical, Scientific, and Educational Concerns With Unproven Medications. American Journal of Pharmaceutical Education, 2006; 70 (6) Article 141.

• Oxford University Hospital. NHS Foundation. Unlicensed and “Off-label” Medicines Information for patients, parents and carers. Published: April 2019.

• Nuffield Council on Bioethics. Patient Access to Experiment Treatments. Bioethics Briefing Note. Publication date: November 20, 2018.

• Health Canada. How Drugs are Reviewed in Canada. Date modified: February 12, 2015.

• Health Canada. Guidance for Industry, Good Clinical Practice: Consolidated Guidelines. Published 1997.

• Health Canada. Guidance Document: The Management of Drug Submissions and Applications. Publication date: July 2019.

• Health Canada. Guidance Document: Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving Human Subjects” Date modified: August 20, 2019.

• Health Canada. Guidance Document, Administrative Processing of Submissions and Applications Involving Human or Disinfectant Drugs. Publication date: March 2020.

• Health Canada. Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications. Date modified: June 29, 2016.

• Health Canada. Drug Products, Guidance Document-Product Monograph. Published 2014.

• Health Canada. Drug Product Database-Terminology. Date modified: June 18, 2015.

• Health Canada. Clinical Trials Database, Glossary. Date modified: May 29, 2013.

• Health Canada, Guidance Document – Health Canada and Advertising Preclearance Agencies’ Roles Related to Health Product Advertising, 2010.

• Government of Canada. Canadian Pandemic Influenza Preparedness: Planning Guidance for the Health Sector. Antiviral Annex. Date modified: September 24, 2019.

• College of Physicians and Surgeons of Saskatchewan. Standard, Unproven and Unconventional Treatment. June, 2016

• Canadian Society of Hospital Pharmacists. Glossary.

• CADTH. Off Label Use of Drugs. CADTH Tool. July 2017.

• Aronson, JK and Ferner, RE. Unlicensed and off-label uses of medicines: definitions and clarification of terminology. British Journal of Clinical Pharmacology (2017) 83 2615–2625.

References

email: nccid@umanitoba.ca