Guidance on switching from prescription to non-prescription status: Principles and factors

The PDL principles and factors assessment

The applicant should complete a PDL principles and factors assessment following the template provided.

In this assessment, the applicant should provide summaries of evidence and rationales demonstrating that none of the PDL principles and factors apply to the medicinal ingredient under the proposed conditions of use. In other words, the applicant demonstrates that the product does not require practitioner oversight and is therefore appropriate for self-care.

In the text that follows, Health Canada outlines points for the applicant to consider when developing the evidence and rationale. In addition, for a complete understanding of the PDL principles and factors, we advise the applicant to read:

• Determining prescription status for human and veterinary drugs

Note: The term “condition” in the text that follows refers to diseases, conditions, disorders, abnormal physical states or their symptoms.

Principle 1: Supervision by a practitioner is necessary

1. for the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in respect of which the drug is recommended for use, or
2. to monitor a disease, disorder or abnormal physical state, or its symptoms, in respect of which the drug is recommended for use, or to monitor the use of the drug

In this part of the template, the applicant should include additional information associated with this principle that the applicant has not explicitly detailed under Factors 1.1 to 1.8. Where there is no additional information to detail, the applicant should state: “All the information related to this principle is included under Factors 1.1 to 1.8”.

Factor 1.1: The drug is used in the treatment of a serious disease not easily diagnosed by the public

This factor relates to concerns associated with misdiagnosis. Products intended for the non-prescription setting should be for conditions that are amenable to self-diagnosis.

For this factor, the applicant should include:

• a description of how the condition is diagnosed
• an assessment of the ease with which a consumer would be able to self-diagnose based on available evidence and/or new evidence (for example, consumer use studies)
• an assessment of the risks associated with a misdiagnosis
• possible risk mitigation measures that would decrease the seriousness of the potential health consequences if the condition is misdiagnosed

Describing the diagnosis

The applicant should outline how the condition is typically diagnosed and in so doing, reference a reputable medical text or clinical practice guidelines.

Ease of consumer self-diagnosis

In terms of the assessment of the ease with which the consumer would be able to self-diagnose, the applicant needs to demonstrate that the consumer can accurately determine the nature of the condition based on well-recognized symptoms, as well as their severity and duration.

If the symptoms are common to a number of conditions, the applicant needs to demonstrate that the consumer can differentiate between these conditions. The applicant may need to provide consumer use studies to help demonstrate that the consumer is able to self-diagnose the condition correctly. For more information, refer to the section on Consumer use studies.

The applicant should indicate whether laboratory tests or other procedures involving a practitioner are required for diagnosis. In general, if any of these are required for diagnosis, the product would maintain its prescription status.

If effective use of the product requires additional measures, such as a monitoring device, the applicant needs to demonstrate that these measures or devices do not require practitioner involvement. For more information on medical devices, refer to the section on Switches involving medical devices.

Risks associated with misdiagnosis

The applicant’s assessment of the risks associated with a misdiagnosis of symptoms should address the:

• impact of a delay in using the appropriate treatment
• impact of the use of sub-optimal treatment
• long-term effects of an inappropriately selected treatment
  • that is, the risk of long-term exposure to the product with no health benefit to the consumer

If the applicant’s assessment identifies risks, the applicant needs to demonstrate that the measures put in place, such as labelling, mitigate these risks.

In rare cases, Health Canada may authorize a product for self-care use of a reoccurring condition where an initial diagnosis is required by a practitioner to ensure the consumer is completely familiar with the symptomatology (for example, vaginal antifungals). In these cases, the applicant should demonstrate that the consumer is able to independently conduct subsequent diagnoses and understand when they should stop treatment and consult a health care provider. The applicant also needs to address the risks of a consumer choosing not to consult a practitioner for the initial diagnosis and the resulting consequences of product use.

Factor 1.2: The use of the drug may mask other diseases

This factor relates to the potential risk that use of a product could hide a serious condition. Specifically, a consumer may treat their symptoms with a product and obtain relief of those symptoms. However, in obtaining relief, the consumer may be less likely to consult a practitioner, potentially resulting in a more serious condition not being addressed in a timely manner. Products for self-care should not mask other serious conditions.

To address this factor, the applicant should include:

• information on the product’s mechanism of action, as this will help identify potential conditions which might be masked
• an assessment of whether the pharmacological effects of the product have the potential to mask underlying condition(s) requiring medical attention

If a potential risk of masking other conditions exists, the applicant should also include an assessment of the consequences resulting from each of the following situations:

• a significant worsening of the underlying condition
• a delay in diagnosis and proper treatment of the serious condition
• any other situation that could prevent a more successful therapy for the underlying condition

The applicant should provide an assessment of whether the product labelling, or other measures, could mitigate the identified consequences of masking other conditions.

Factor 1.3: Practitioner supervision is necessary for treatment and/or monitoring

This factor relates to whether the indication is suitable for the non-prescription context and the consumer’s ability to self-treat and self-monitor. In general, conditions suitable for self-care are self-limiting (that is, they will resolve on their own). Many conditions are not suitable for self-care.

The use of the product, as well as the condition itself, ought not to require practitioner supervision if the product is to obtain a non-prescription status as a non-prescription drug (NPD) or natural health product (NHP).

The applicant should include an assessment of how the use of the product and condition is amenable to self-treatment and self-monitoring. In this assessment, the applicant needs to demonstrate that consumers can correctly do the following without practitioner assistance:

• identify that they belong to the intended target population for the product on the basis of the age range and the risk statements (precautions, warnings, contraindications) included in the product labelling
• make an appropriate product selection
• understand what potential side effects may emerge and how to manage them
• identify what foods or medication to avoid while taking the product
• perform any additional measures (for example, use of an ancillary medical device)
• understand and follow the dosage regimen proposed for the product
• identify situations where treatment should be discontinued and/or medical advice sought

Consumer use studies may be necessary to substantiate an applicant’s position that the involvement of a practitioner is unnecessary. For more information, refer to the section on Consumer use studies.

Note: If effective use of the product requires additional measures, such as a monitoring device, the applicant needs to demonstrate that these measures do not require the supervision of a practitioner. For more information, refer to the section on Switches involving medical devices.

The applicant should provide a rationale for why the condition and product do not require the expertise of a practitioner for treatment and monitoring activities. The rationale should address the reasons that practitioner expertise is not needed for:

• selecting the correct product for the individual
• managing adverse reactions
• making decisions on dose adjustments and discontinuation
• developing risk mitigation strategies for the individual
• requesting or conducting any necessary testing before, during or following the use of the product
• determining whether the treatment is being effective
• adjusting the treatment and the monitoring in relation to comorbidities

Factor 1.4: The use of the drug requires complex or individualized instructions

Products for use in self-care should not require that a practitioner tailor the use of the product to an individual’s unique circumstances or explain product information. Consumers should be able to easily understand the information and how to use the product.

Therefore, the applicant should demonstrate that the product’s use does not involve any of the following:

• complex dose titration
• complex dosage regimens
• doses tailored to the individual’s specific circumstances
• complex instructions

Some examples of situations that would generally lead to the prescription status being maintained include where the:

• dose needs to be determined based on co-morbidities and/or test results
• product elicits tolerance requiring increasing doses to maintain efficacy
• product requires that a practitioner adjust the dose for the individual
• product elicits clinically significant withdrawal or discontinuation symptoms that require tapering or symptom monitoring upon product removal
• product has complex risk statements (precautions, warnings, contraindications)

With respect to the degree of complexity of directions for use, risk statements and etc., results from consumer use studies can help demonstrate the consumer’s ability to understand the instructions without assistance from a practitioner. For more information, refer to the section on Consumer use studies.

Factors 1.5: Practitioner expertise is necessary to administer the drug or oversee the drug’s administration

Products with non-prescription status should be easy for consumers to self-administer. To demonstrate this, the applicant should provide:

• a description of why practitioner expertise is not needed to administer or oversee the administration of the product
• an assessment of the consequences of the product being administered improperly
• a discussion of any risk mitigation measures the applicant has put in place

Note: Health Canada considers most injectable products unsuitable for self-care use.

Factor 1.6: The drug has a narrow margin of safety

The margin of safety is the difference between the optimal effective dose and the dose at which undesirable or unmanageable side effects begin to appear. For products that have a narrow therapeutic index, the individual must receive precisely the right dose to prevent serious consequences. In contrast, products for use in self-care ideally have a wide margin of safety to ensure minimal risk to health if the consumer uses the product incorrectly.

Safety profile

The applicant’s evidence and rationale for this factor should include a summary of the product’s safety profile. The summary should reflect:

• the content of the most recent Health Canada-approved product monograph or prescribing information for the prescription drug product, if that exists
• a comprehensive overview of in vitro, pre-clinical and clinical studies
• the market experience data
  • refer to the section on Market experience
• the published literature
• the safety assessments from other major regulatory authorities and any available safety information from the World Health Organization or other national or international health organizations
• information on the dose at which unintended and intended psychotropic drug effects occur for products that contain known psychoactive substances
  • these effects can include, for example, alterations in perception, cognition, levels of arousal and mood

The applicant needs to demonstrate that there is an adequate margin between the product’s therapeutic dose(s) and the doses at which clinically significant adverse reactions occur. Adverse reactions can be clinically significant because of their seriousness, severity or frequency. They can also be clinically significant if there are no suitable preventative measures.

Assessing the consequences of inaccurate dosing and risk mitigation measures

The applicant should show that the impact of minor dose deviations would not result in significant harm. To this end, the applicant needs to:

• address the likelihood and the severity of the risks associated with inaccurate dosing
• summarize any related market experience data that are available

In terms of inaccurate dosing, the applicant should address overdosing as it pertains to the product’s margin of safety and underdosing as it pertains to a lack of efficacy. The applicant also needs to demonstrate how the directions for use could help mitigate these risks.

Additionally, the applicant should identify whether the product has a narrow margin of safety in particular sub-populations, such as pregnant and nursing individuals, children and the elderly. The applicant should include any risk mitigation measures that they have taken with respect to these sub-populations and the effectiveness of those measures.

In some cases, an NPD and a prescription drug product, or an NHP and a prescription drug product, will co-exist on the market after a successful switch. If this is the anticipated outcome of the switch, the applicant should address how the risks of a consumer taking both products at the same time are being mitigated.

Factor 1.7: At normal therapeutic dosage levels, the drug has potential or is known to cause serious adverse reactions or serious interactions with food or other drugs

This factor relates to the potential harm arising from serious adverse reactions or interactions with commonly used medications (prescription drug products, NPDs and NHPs) or foods. To be suitable for self-care use, the product should not be associated with potential or known serious adverse reactions or serious drug-drug or drug-food interactions in the target population, unless there are effective risk mitigation measures in place.

The applicant should include an assessment of the serious adverse reactions and potential serious interactions of the product with food or other drugs, at the proposed dose and regimen, with reference to:

• the safety results for all relevant clinical trials
• drug-drug and drug-food interaction studies
• available market experience data
  • refer to the section on Market experience
• any other available safety data

Other available safety data includes information from:

• in vitro studies
• absorption, distribution, metabolism and excretion (ADME) studies
• mechanism of action studies
• toxicological studies
• other relevant pharmacokinetic and pharmacodynamics studies

If applicable, the applicant is expected to describe any risk mitigation measures, including labelling, that may address the risk of serious adverse reactions or potential serious interactions. The applicant may use data from consumer use studies to help demonstrate that these measures are effective in altering consumer behaviour so that serious adverse reactions and potential serious interactions are avoided. For more information, refer to the section on Consumer use studies.

The applicant also needs to identify any special considerations for vulnerable sub-populations, such as pregnant and nursing individuals, children and the elderly.

Factor 1.8: The drug has dependence and/or addiction potential

Products for use in self-care should not have the potential to cause dependence and/or addiction (that is, substance use disorder).

Some products have the potential to induce psychoactive effects. These effects can be primary (desired) (for example, sedatives), or secondary (unintended or undesired). These effects include symptoms such as dizziness, anxiety, cognitive impairment or irritability. They also include symptoms that can be experienced as reinforcing, such as euphoria, changes in consciousness, perception and/or mood.

Psychoactive ingredients that cause these types of reinforcing effects are of particular concern because they may carry a heightened risk for dependence and/or addiction (refer also to Factor 3.2).

Some products have the potential to induce symptoms related to discontinuing or reducing the dose, including withdrawal and rebound effects. These types of adverse reactions can make it very difficult for a consumer to stop using the product.

For example, a consumer who no longer needs to use a product may continue to do so because an attempt to discontinue use had resulted in worsening symptoms. Oversight by a practitioner in this situation may be necessary to determine if the symptoms are solely rebound in nature or if the underlying condition still exists.

In addition, some products may require dose tapering or secondary medications to manage the withdrawal symptoms and thus require practitioner oversight (refer to Factor 1.4). Note: Discontinuation symptoms are not confined solely to psychoactive ingredients.

The applicant should demonstrate that the use of the product does not cause:

• clinically significant psychoactivity requiring practitioner oversight or
• symptoms upon discontinuation or rapid dose reduction that require practitioner oversight

The applicant may demonstrate this by providing data from clinical trials that include adverse event profiles and outcomes from specific validated scales or questionnaires, as well as post-market data or literature. A mechanism of action rationale may also be sufficient to address this factor.

Note: Health Canada expects the product to have clinically significant effects when its indication is based on a psychoactive effect (for example, sedatives). Nonetheless, the applicant still needs to provide evidence to characterize these effects and demonstrate that these effects are manageable in a non-prescription context without practitioner involvement.

In some cases, secondary psychoactive effects may be sufficient to necessitate maintaining prescription status. In other cases, the effects may be effectively mitigated (for example, through labelling) such that practitioner involvement is not required. For instance, slight drowsiness may be addressed through label warnings for a product used to treat the symptoms of allergies and may not necessitate practitioner intervention.

The applicant should include information on any mitigation measures they have instituted in relation to secondary psychoactive effects and the effectiveness of these measures.

Principle 2: The level of uncertainty respecting the drug, its use or its effects justifies supervision by a practitioner

This principle relates to the possibility that some uncertainties may remain about the product, such as:

• a lack of market experience
  • for example, new product, new use, small target population or a lack of adequate post-market data
• a lack of full characterization of its pharmacological effects or
• unknown consequences of its long-term use

Where significant uncertainties exist, the product would generally maintain its prescription status.

Ideally, a product for self-care is well characterized. That is, in addition to its safety and efficacy profile, the pharmacodynamics, pharmacokinetics and toxicological profile of the product are known and well documented.

The applicant needs to provide any information relevant to this principle not mentioned under Factor 2.1.

The applicant should demonstrate that the proposed NPD or NHP has limited uncertainties that do not warrant oversight by a practitioner. The applicant needs to summarize where uncertainties and gaps in the information exist, including analysis on the:

• uncertainties and gaps in the data regarding the toxicology and safety of the product
• uncertainties and gaps in the body of evidence supporting the product’s safety and efficacy related to its proposed use in the non-prescription context and under the proposed conditions of use

The applicant needs to substantiate that there is only a minimal level of uncertainty and minimal gaps in the evidence. The applicant should also explain the reason(s) any remaining uncertainties and gaps would not justify the need for practitioner oversight.

Factor 2.1: There is limited market experience with the use of the drug

Products for which there is limited market experience typically maintain their prescription status. Market experience may be limited with respect to years of sales or volume of sales (population exposure).

To demonstrate that there is adequate market experience supporting the safety of the product, the applicant should address all the elements outlined in the section on Market experience.

Principle 3: Use of the drug can cause harm to human or animal health or a risk to public health and the harm or the risk can be mitigated by a practitioner’s supervision

To be granted non-prescription status, products should not pose a danger to the health and safety of individuals, animals or the general public. If the applicant has identified ways to mitigate potential dangers, they should demonstrate that the mitigation measures are effective.

If the applicant has additional information relevant to this principle that is not covered in the sections on Factors 3.1 and 3.2, they should include it in this part of the template. If the applicant does not have additional information, they should indicate in this section of the template that all the information related to this principle is included under Factors 3.1 and 3.2.

Factor 3.1: There is potential for harm to public health

To be suitable for self-care use, the widespread or improper use of a product should not have the potential to cause public health issues.

Examples of public health issues are the development of drug resistance in strains of microorganisms (bacteria, viruses or fungi) and parasites emerging as opportunistic pathogens. A product whose use in the non-prescription setting could contribute to the development of drug resistance will generally maintain its prescription status.

For this factor, the applicant should include an assessment of whether there is potential for harm to public health and, if applicable, any risk mitigation measures taken.

Factor 3.2: There is potential for abuse or diversion leading to harmful non-medical use

A product for use in the non-prescription setting should not have the potential to lead to abuse or diversion.

Products that have the potential to lead to abuse typically have reinforcing or rewarding properties (refer to Factor 1.8). These properties can be associated with alterations in perception, cognition, mood and/or levels of arousal and, therefore, could lead to harmful patterns of use. The potential for diversion of these products also exists.

In general, in these cases, the medicinal ingredient will be regulated as a controlled substance under the Controlled Drugs and Substances Act (CDSA)and its regulations, including being restricted to prescription-only status. This is in addition to being regulated under the Food and Drug Regulations (FDR).

For non-CDSA substances, in order for the product to be switched to non-prescription status, the applicant should demonstrate that the product has a low likelihood for abuse.

For guidance on assessing the abuse potential of substances, consult the following notice, which outlines Health Canada’s expectations:

• Guidance on the clinical assessment of abuse liability for drugs with central nervous system activity

The applicant may need to provide some or all of the following:

• an examination of whether the structure of the medicinal ingredient in question is similar to other known substances associated with abuse
• receptor binding studies to determine the affinity of the medicinal ingredient and its metabolites to cellular targets known to be common to drugs associated with abuse
• functional assays to determine the nature of neurotransmitter activity
• non-clinical and clinical studies designed to assess whether the ingredient or its metabolites contain reinforcing or rewarding properties and whether there is an increased likelihood that the product will be used for these reinforcing properties
• an assessment of whether the product elicits withdrawal symptoms upon discontinuation
• dose-response studies to characterize the psychoactivity as well as the total content of the medicinal ingredient available in each dose/container/package
• a summary of market experience listing adverse events associated with abuse or abuse potential
• a review of available information to determine if abuse or diversion has been reported with the ingredient

The review of available information should include an extensive survey of various sources of information. This includes published peer-reviewed literature, grey literature (such as reports from international health organizations and media reports) and so on. The applicant should also provide a list of all known street names of the product or its active ingredient(s) and include these terms in their search. The applicant’s search strategy should be included in the submission.

The applicant should be clear on what effects are observed under normal conditions of use (the conditions for which the switch and market authorization are being sought) versus those seen under other conditions of use, such as at higher doses. The applicant should also address whether the product could be tampered with in order to accentuate the reinforcing psychoactive properties.

For a product to be granted non-prescription status, the applicant needs to demonstrate that these types of concerns do not exist or can be successfully mitigated without practitioner involvement. In all situations, the applicant should address whether there are any special concerns for particular sub-populations, such as those with a history of addiction (substance use disorder).