Data requirements for switching medicinal ingredients from prescription to non-prescription status

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.

Guidance documents are administrative instruments that do not have force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable, provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, in order to allow the Department to adequately assess the safety, efficacy or quality of a drug product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidance documents.

1. Introduction and purpose

This guidance document provides information to help sponsors determine what evidence should be submitted to Health Canada when applying to switch a medicinal ingredient from prescription to non-prescription status.

Health Canada recognizes that there is a progression in the knowledge about a health product over its full life-cycle. This increase in knowledge reduces the uncertainty associated with the benefits and harms of a product, and can lead to improved health outcomes for Canadians.

Although Health Canada may have, at one time, decided that it was most appropriate for a medicinal ingredient to be sold by prescription only, new information on safety, efficacy and quality may permit this medicinal ingredient to be given non-prescription status and sold in non-prescription drugs or NHPs.

1.1 Policy objective

To provide guidance to sponsors on how to apply to switch a medicinal ingredient's status from prescription to non-prescription, so that it may be sold in non-prescription drugs or NHPs.

1.2 Policy statement

The evidence that can be provided for review by Health Canada to support the safety and efficacy of a medicinal ingredient in a non-prescription product that was previously sold by prescription varies, depending on:

whether the conditions of use of the medicinal ingredient will change, and the degree to which they will change;
whether there is experience in other jurisdictions with the proposed product's conditions of use, and the extent of this experience;
the knowledge gathered thus far in the product's life-cycle when sold by prescription, and whether that knowledge alters the uncertainty associated with the benefits and harms.

Conditions of use are described in Section 2.1.1.2 of this document.

1.3 Scope

This guidance document applies to applications submitted to Health Canada in support of switching a medicinal ingredient from prescription to non-prescription status (referred to as a "switch submission"). It applies to medicinal ingredients for human use only. The guidance does not apply to the following:

switch submissions for biologic or radiopharmaceutical products;
medicinal ingredients that were deemed exceptions from prescription status - e.g. influenza vaccines (for public health reasons) and nitroglycerin (for emergency use)^{Footnote 1};

The scope of this document includes two types of switch submissions:

Full switch: Asks that the medicinal ingredient and all approved conditions of use be removed from prescription status. The medicinal ingredient would be removed from the Prescription Drug List (PDL).
Partial switch: Asks that certain conditions of use be removed from prescription status. The medicinal ingredient and other conditions of use would remain on the PDL. This means that the medicinal ingredient could be sold without a prescription in certain circumstances.

Additional details on partial and full switches can be found in section 2.1.1 of this guidance document.

Note: While the majority of switches will occur as a result of a switch submission to Health Canada, the Department may initiate switches when evidence supports the safe use of a medicinal ingredient in a non-prescription product.

1.4 Background

Medicinal ingredients are given prescription status where control over the sale of a medicinal ingredient, under the specified conditions of use, is deemed the best method to protect the health and safety of Canadians. The overarching guiding principles governing prescription status are outlined in section C.01.040.3 of the Food and Drug Regulations (FDR) and described in the guidance document entitled "Determining Prescription Status for Human and Veterinary Drugs" (2013).

Medicinal ingredients that require prescription status at the federal level are listed on the PDL, which is a web-based administrative list that is not set out in regulation. Health Canada considers a medicinal ingredient to warrant prescription status when the medicinal ingredient, under the specified conditions of use, meets at least one of the PDL principles or factors.

Conversely, Health Canada recognizes non-prescription status for medicinal ingredients that, under the approved specified conditions of use, are considered safe for use by the public in a self-care environment.

In addition to federal decisions about a medicinal ingredient's prescription status, provinces and territories can further control the place of sale of drug products.

2. Guidance for implementation

When a medicinal ingredient has prescription status and a sponsor wants to sell that medicinal ingredient in a non-prescription product, a switch submission must be submitted to Health Canada. The submission must include evidence demonstrating that the medicinal ingredient no longer meets any of the PDL principles and factors, can be used safely, and is efficacious in a self-care environment.

This guidance document provides information on how to submit a switch submission and it addresses the evidence required to support the switch of medicinal ingredients from prescription to non-prescription status. It should be read in conjunction with other applicable guidance as referenced in this document.

2.1 Applications - how to submit

The switch of a medicinal ingredient from prescription to non-prescription status will result in the medicinal ingredient being acceptable for sale either as a non-prescription drug or a NHP. Depending on which definition it meets, it will fall under one of two regulatory frameworks: the FDR or the Natural Health Products Regulations (NHPR).

A medicinal ingredient would fall under the NHPR if it meets the definition of a NHP as set out in the NHPR.

A medicinal ingredient would fall under the FDR if it meets the definition of a drug as set out in the FDR.

For questions regarding product classification, please contact the NNHPD.

In the case of drugs, applications for full switches require a Supplementary New Drug Submission (SNDS) because the prescription product, in its entirety, is being switched from prescription to non-prescription status. After the modification to the PDL, the only existing version of the product on the Canadian market would be the non-prescription product. Applications for partial switches require a New Drug Submission (NDS) because the existing prescription product is not being switched in its entirety (i.e. a new non-prescription drug is created). After the modification to the PDL, there would be two versions of the drug product on the Canadian market: one prescription, and one non-prescription.

For NHPs, applications for full and partial switches require the submission of a product licence application (PLA). The NNHPD section of the Health Canada website contains information on NHPs, such as licensing forms and templates for PLA preparation and process, in addition to information on non-prescription drugs, such as their formulation, required forms, the "Guidance Document: Preparation of Drug Regulatory Activities in the Common Technical Document (CTD) Format", additional CTD format guidance and Quality guidance.

NHPs are issued Natural Product Numbers (NPNs) pursuant to a licence application filed. Drugs are issued Drug Identification Numbers (DINs) pursuant to the filing of form 3011. The management of drug submission and cost recovery fee guidance applies only to those ingredients subject to the FDR; thus, it is not applicable to NHPs. Additional information, such as the "Guidance for Industry: Management of Drug Submissions" and the "Guidance Document - Fees for the Review of Drug Submissions and Applications", are also available on the Health Canada website.

See the "Questions and Answers - Prescription Drug List" document on the Health Canada website for information on what happens to authorized products on the market that are affected by the addition or removal of a medicinal ingredient from the PDL.

Visit our "Contact Us" page.

Sponsors are encouraged to request a pre-submission meeting to discuss their switch submission.

2.1.1 Type of submission

2.1.1.1 Full switch submission

This type of submission involves the switch of an authorized medicinal ingredient to non- prescription status without any change to the conditions of use for which the medicinal ingredient was granted market authorization as a prescription product. These conditions are specified in the Product Monograph or in the prescribing information that accompanies market authorization.

The outcome of an acceptable full switch submission is that the medicinal ingredient is removed completely from the PDL.

2.1.1.2 Partial switch submission

This type of submission involves the switch of an authorized medicinal ingredient to non-prescription status by way of changes to the conditions of use for which the medicinal ingredient was granted market authorization as a prescription product. These conditions may include a different maximum single and/or daily dose, different strength of the dosage unit, different route of administration, different dosage form, different indication, or different target population.

In most cases, the outcome of a partial switch is that the medicinal ingredient remains on the PDL, but the non-prescription conditions of use are added as exemptions in the form of qualifiers. Some examples of partial switch qualifiers are outlined below:

a new indication for the management of heartburn for famotidine: Famotidine and its salts (except when sold in concentrations of 20 mg or less per oral dosage unit and indicated for the treatment of heartburn);
a different route of administration for ketoconazole: Ketoconazole and its salts (except in preparations for topical use as a shampoo).

In some instances, the medicinal ingredient is listed on the PDL with the conditions of use that make the product a prescription product (e.g. indication for use):

specific indication: Uracil or its salts, when sold for the treatment of cancer (note: as uracil is found in all living organisms, its listing without qualifiers would result in the ingredient not being considered for use in a NHP or non-prescription drug).

2.2 Overview of data requirements

2.2.1 All switch submissions

The body of evidence for a switch submission, as with any non-prescription submission, when taken in its entirety, must show that the proposed conditions of use of the medicinal ingredient, as specified on the product label, are amenable to self-treatment and self-monitoring. In other words, the evidence must show that the prescription medicinal ingredient, under the proposed conditions of use, can be used safely and effectively by the general public in the absence of a practitioner^{Footnote 2}. In addition, as with all drugs approved by Health Canada, the benefit of use of the product must outweigh the risks.

Evidence should be used to develop the rationale to explain why the medicinal ingredient, under the proposed conditions of use, no longer meets any of the PDL principles and factors. The points that need to be considered when developing the rationale are outlined in section 2.3 below.

Consumer use studies, such as label comprehension, self-selection, and actual use, may be required for indications, directions of use, and/or warnings or contra-indications that:

have never before been marketed for sale in a self-care environment in Canada or internationally;
are considered complex for the self-care environment and therefore present a possible risk of misuse.

Consideration will be given to consumer use studies conducted in foreign countries on a case-by-case basis, in place of studies conducted in Canada.

Sponsors may choose to follow methodologies for consumer use studies suggested by other regulatory agencies. Choice of methodologies could be discussed at a pre-submission meeting.

A brief description of each of the different types of consumer use studies can be found in the Appendix.

2.2.2 Additional requirements for partial switch submissions

Additional efficacy and safety evidence must be submitted when the modifications involve a new indication, target population, route of administration, or dose/dosage regime. The types of safety and efficacy evidence that can be submitted are outlined in sections 2.4 and 2.5, respectively. Additional chemistry and manufacturing data will be required when there are changes made to the dose/dosage unit, formulation or dosage form. Information on quality requirements can be found on the Health Canada website in existing guidance documents for both NHPs and drug products.

In addition to supporting the safety of a change in indication, target population or route of administration, the safety evidence must also address, as outlined in section 2.4.2 below:

the prescription use(s) for a medicinal ingredient that are known to the general public, and the risks associated with the general public intentionally misusing the product with therapeutic intent based on knowledge of its prescription use^{Footnote 3}; and
the risk(s) to a consumer taking the non-prescription and prescription products at the same time when the indications for use of the products differ. The risk to vulnerable sub-populations, such as children and the elderly, should be included.

Depending on the severity and the likelihood of the risks mentioned above, the risks may be mitigated through cautionary labelling and/or may require additional evidence, such as consumer use studies (see Appendix), to demonstrate that such misuse/concomitant use is not likely. In addition, when products of identical composition exist as both a prescription and a non-prescription product, but have different indications, contra-indications and/or warnings, the brand name of the non-prescription product should be clearly distinguishable from the prescription product so as to avoid medication errors.

2.3 Characteristics of a non-prescription product

The rationale for why a medicinal ingredient, under the specified conditions of use, does not meet the PDL principles/factors must be included as part of the body of evidence in support of a switch submission. The guidance document "Determining Prescription Status for Human and Veterinary Drugs" describes the principles and factors that need to be addressed. If none of the principles and factors apply, then a drug will be considered a non-prescription drug.

The characteristics of a non-prescription product (described below) are intended to provide sponsors with considerations that might be included in developing the required rationale as to why the medicinal ingredient, under the proposed conditions of use, does not meet the PDL principles/factors. Where a principle/factor does not apply, "not applicable" should be stated with the reason why it is not applicable.

A non-prescription product should have the following characteristics:

The use of the product is amenable to self-diagnosis^{Footnote 4}.
It is important that the conditions or symptoms for which the product is indicated can be correctly diagnosed without practitioner supervision or can be easily recognized following initial diagnosis by a practitioner. Some symptoms common to a diverse range of underlying pathologies could be misdiagnosed by the consumer without the aid of a practitioner. The risks associated with a misdiagnosis of symptoms, and/or a delay in using the appropriate treatment or use of sub-optimal treatment should be addressed. The possibility that a chronic condition may proceed unchecked because of inappropriate self-diagnosis must also be ruled out. Furthermore, the long term effects of an inappropriately selected treatment should also be addressed (i.e. the risk of long term exposure to the product with no health benefit to the consumer).
The use of the product is amenable to self-treatment.
The consumer should readily comprehend how the product is to be taken and be able to easily self-administer the product. Exceedingly complicated dosage regimens and/or instructions for use, the need for parenteral administration, dose titration or doses that must be tailored to a patient's specific circumstances, likely will make a product unsuitable for non-prescription status. The possibility that symptomatic treatment might mask an underlying condition requiring medical attention must be addressed. If such an indirect danger might exist, the risk, its frequency, the seriousness of the consequences, and ability to label the product to mitigate the risk and serious consequences (e.g. a recommendation to seek medical advice if symptoms persist beyond a stated time period) must be determined. It may also be necessary to consider whether incorrect use might lead to a delay in seeking medical treatment, and if so, whether the consumer would suffer serious health consequences as a result. Consumers should also be able to recognize contraindications and understand essential precautions and warnings.
The use of the product is amenable to self-monitoring.
The use of the product, and the disease itself, should not require practitioner supervision. Consumers should be able to understand the natural course of the disease and the possibility and consequences of recurrence. They should be able to distinguish adverse drug reactions that can be experienced with the use of the product as well as when they should stop taking the product and seek medical advice. If the use of the product requires collateral measures for effective use, such as a diagnostic device to monitor blood glucose levels, these instruments should also be consumer friendly, useable without practitioner intervention, and have been authorized by Health Canada where required by the Medical Devices Regulations. The inclusion of information sheets for the consumer may help to address this point.
The use of the product is associated with an adequate margin of safety.
It is acknowledged that non-prescription products may be associated with certain side effects. However, there should be a reasonably wide margin between therapeutic doses and the doses at which adverse reactions appear that are medically significant because of their seriousness, severity or frequency, or for which there is no suitable preventative action, such as the exclusion of a clearly identifiable at-risk group. Consideration also should be given to potential harm arising from drug interactions with commonly used medicines (prescription and non-prescription, including NHPs) or foods, and if preventive measures can be taken to mitigate their occurrence. For a partial switch submission, when the indication for use of the non-prescription and prescription product differ, the likelihood and the severity of the risk associated with a consumer taking both products at the same time should also be considered, particularly in vulnerable sub-populations, such as children and the elderly. A product likely may not be suitable for non-prescription status if the labelling lists a high rate of drug-drug or drug-food interactions in the target population. In these instances, safety may be supported by consumer use studies (see Appendix).
The consequences of misuse of the product are minor.^{Footnote 3},^{Footnote 4}
Consideration of the consequences of misuse is an important component of the overall safety profile of the product. The margin of safety of the drug product should be sufficiently large to accommodate potential misuse. A desirable feature of a non-prescription product is a shallow dose response curve with regard to its toxic effects. This ensures that the risk to health is small if the consumer uses the product when it is not indicated, exceeds the recommended dose or recommended length of treatment, or fails to read the contraindications or warnings. The likelihood and the severity of the risks associated with the general public intentionally misusing the product with therapeutic intent based on knowledge of the product's prescription use should also be addressed. Other types of misuse that require addressing include unintentional misuse, accidental overdose, and intentional misuse related or unrelated to the knowledge of the product's prescription use (e.g. due to non-adherence to label instructions).
The use of the product does not lead to dependence.
The use of the product does not have potential for diversion, addiction or abuse, leading to harmful nonmedical uses to either the individual or the public at large.
There is adequate market experience with the product.
If there is limited market history with the prescription product for which non-prescription status is being considered, further investigation may be necessary since the number of patients exposed is relatively small, as is the case when the product has only recently been granted market authorization.
The use of the product does not present a significant risk to human, animal or public health.
For example, a product that will result in the emergence of drug resistance (such as an antimicrobial or anti-parasitic) is not appropriate for use in a self-care environment, particularly if the product represents an important treatment option for a serious disease.

2.4 Safety evidence requirements

2.4.1 All switch submissions

At a minimum, the following safety evidence should be submitted for all switch submissions:

The most recent Health Canada approved Product Monograph for the prescription product;
Clinical trial evidence not already captured by the Product Monograph mentioned above, with emphasis on the reported adverse reactions, and taking into consideration the comparability of the product tested in the clinical trial to that of the switch submission;
Post marketing surveillance information for the prescription product in Canada;
Where available, a tabulated summary of the Periodic Safety Update Reports and Periodic Benefit-Risk Evaluation Reports that have been routinely submitted to Health Canada;
Regulatory status of the product in Australia, France, Germany, Switzerland, United Kingdom, the United States of America, and other countries, where applicable. The date in which non-prescription status was granted should be included. The non-prescription label text should also be submitted, where available. An accurate translation must be added if the label text is in a language other than English or French.
Post marketing surveillance information outside of Canada as a prescription and/or non-prescription product, taking into account the following considerations:
- Similarity between the foreign product and the non-prescription product to be marketed in Canada (e.g. uses, recommended single and maximum daily dose, contraindications, warnings, target population, etc.);
- Similarity in current labelling of the product from other regulatory jurisdictions;
- The length of time the product has been available in the foreign country;
- The regulatory requirements and procedures by which adverse reactions are collected in the foreign country;
- For products with non-prescription status outside of Canada, the level of consumer access (i.e. pharmacist assisted or self-selection) and the comparability of the legislation (at all levels of government) that oversees the sale of the non-prescription product in the foreign country to that of Canada.

Additional safety evidence can include:

Safety evaluations from a regulatory body with standards similar to those of Canada (e.g. the United States Food and Drug Administration, Australia's Therapeutic Goods Administration, the European Union's European Medicines Agency, or the U.K. Medicines and Healthcare Products Regulatory Agency), including any available safety information from the World Health Organization or other international health organization;
Any available information about accidental overdose and/or misuse/abuse of the product;
Published literature containing safety information.

Consumer use studies, such as label comprehension, self-selection, and actual use, may be required for indications, directions of use, and/or warnings or contra-indications that:

have never before been marketed for sale in a self-care environment;
are considered complex for the self-care environment and therefore present a possible risk of misuse.

In cases where the conditions of use are complex or new to the self-care environment, if the associated risks can be adequately mitigated through cautionary labelling, consumer use studies will not be required. Information on labelling requirements can be found in section 2.6 below. A scientific/clinical justification must be submitted in instances where these potential risks do not warrant consumer use studies or cautionary labelling.

2.4.2 Additional requirements for partial switch submissions

Consumer use studies may be required, depending on the severity and likelihood of the risks identified below:

The risk associated with the general public intentionally misusing the product with therapeutic intent, based on knowledge of its prescription use; and
The risk of a consumer taking both the prescription and non-prescription products at the same time, particularly in vulnerable sub-populations, such as children and the elderly.

Up-to-date prescribing information in Canada, as described in section 2.4.1 above, will be required to fully understand these risks.

2.5 Efficacy evidence requirements

2.5.1 Full switch submissions

For full switches, the conditions under which the product was approved by Health Canada as a prescription drug (i.e. indication, route of administration, formulation, directions of use and target population) remain identical to the proposed switch (non-prescription) product. The efficacy evidence requirement for full switches, therefore, relies primarily on the prescription Product Monograph, as well as more recent published clinical trials (i.e. phase IV) investigating the product under the same conditions of use.

Efficacy data may be required if the data in support of the prescription drug was generated by investigations not meeting present day standards for safety and efficacy evaluations.

2.5.2 Partial switch submissions

For partial switches, the conditions of use of the proposed (non-prescription) product differ from those approved by Health Canada for the prescription product. In this case, additional efficacy data, outside the prescription Product Monograph, will need to be submitted. Efficacy evidence can include the following:

Clinical trials;
Bioequivalence studies, where applicable;
Efficacy evaluations from other regulatory bodies with standards similar to those of Canada (see section 2.4.1), where available;
Cross-referencing the authorized prescription drug indications, where applicable.

Guidance documents on efficacy evidence requirements and bioequivalence, pertaining to non-prescription drugs and NHPs, are available on the Health Canada website.

2.6 Labelling

The safety evidence will assist in developing the label cautionary statements, in addition to supporting the safe use of the product in a self-care environment. Label components include inner and outer label, and package inserts. For non-prescription drugs, a Product Monograph is also required as part of the label component.

Information on labelling requirements can be found in sections 3, 9 and 10 of the FDA, as well as in guidance documents specific to NHPs, such as ("Labelling of Natural Health Products guidance document" and "Labelling Requirements Checklist"), and non-prescription drugs ("Guidance Document Labelling of Pharmaceutical Drugs for Human Use").

Health Canada has amended the Natural Health Products Regulations. For more information and to access the supporting Labelling of Natural Health Products guidance document, visit What's new: Natural and non-prescription health products.

2.6.1 Section 3 of the FDA

Section 3(2) of the FDA prohibits the sale of drugs, including non-prescription drugs and NHPs, that are labelled or advertised to the general public, for the treatment, prevention or cure of the diseases, disorders, or abnormal physical states listed on Schedule A.

On June 1, 2008, a regulatory amendment to the FDR and NHPR came into force to remove the prohibition on the labelling and advertising of Schedule A preventative health claims for NHPs and non-prescription drugs. Schedule A and Section 3 of the FDA guidance is found on the Health Canada website.

2.6.2 Section 9 of the FDA

Section 9 of the FDA prohibits the labelling of drugs in a manner that is false, misleading or deceptive, or is likely to create an erroneous impression regarding its character, value, quantity, composition, merit or safety.

2.6.3 Section 10 of the FDA

Section 10 of the FDA sets out labelling requirements with respect to standards that have been prescribed for drugs.

3. References

PDL:

FDA:

NHPs:

Non-prescription drugs:

Literature based references:

Brass, E.P., Lofstedt, R. and Renn, O. (2011) Improving the decision-making process for nonprescription drugs: A framework for benefit-risk assessment. Clin Pharmacol Ther 90 (6), 791-803.
Brass, E. P. (2001) Changing the Status of Drugs from Prescription to Over-the-Counter Availability N Eng J Med 345 (11), 810-816.

Other:

4. Appendix - Consumer Use Studies

Consumer use studies are valuable in substantiating that the product can safely be used in the non-prescription setting. There are three main types of consumer use studies:

Label comprehension studies
Self-selection studies
Actual use studies

International examples of information on consumer uses studies include:

Consumer use studies can be conducted in English or French if the text of the other language on the product label is a faithful translation of the tested label.

Label Comprehension Studies:

A label comprehension study assesses consumer understanding of the communication elements of a label based on language, layout and graphics. Label comprehension studies are conducted to create a non-prescription product label that will communicate all the necessary information to the consumer for them to use the product effectively and safely. (E.g. "US FDA Guidance for Industry: Label Comprehension Studies for Nonprescription Drug Products" (August 2010))

Self-Selection Studies:

Self-selection studies test whether consumers can apply the label information to their personal medical situations and make correct decisions to use or not use the product (self-selection decision). The key questions to be addressed are: Can consumers identify the purpose for the product and, based on their health conditions, can they demonstrate good judgment about whether the product is right for them? Self-selection studies therefore evaluate the ability of consumers to determine whether a potential non-prescription product is appropriate for their use based on the recommended use(s) of the product, the precautions/warnings specified on the proposed product label and their personal health history. (E.g. "US FDA Guidance for Industry: Self-Selection Studies for Nonprescription Drug Products" (April 2013) druginfo@fda.hhs.gov)

Actual Use Studies:

An actual use study incorporates elements of both a self-selection study and a label comprehension study, but also provides information about consumer compliance with the recommended dosing and dosing regimen, and provides insight on potential misuse of the product. An actual use study determines the safety and effectiveness of the product under the proposed non-prescription conditions of use, based on consumer compliance with respect to warning(s), dosage instructions, and other advice that constitutes non-prescription labelling. These studies are intended to demonstrate the way consumers will use the product in everyday life.

Language selection

Search