Regulations Amending the Food and Drug Regulations and the Regulations Amending the Food and Drug Regulations (DIN Requirements for Drugs Listed in Schedule C to the Food and Drugs Act that are in Dosage Form): SOR/2018-84

Canada Gazette, Part II, Volume 152, Number 9

Registration

April 23, 2018

FOOD AND DRUGS ACT

P.C. 2018-438 April 20, 2018

Her Excellency the Governor General in Council, on the recommendation of the Minister of Health, pursuant to section 30 footnotea of the Food and Drugs Act footnoteb, makes the annexed Regulations Amending the Food and Drug Regulations and the Regulations Amending the Food and Drug Regulations (DIN Requirements for Drugs Listed in Schedule C to the Food and Drugs Act that are in Dosage Form).

Regulations Amending the Food and Drug Regulations and the Regulations Amending the Food and Drug Regulations (DIN Requirements for Drugs Listed in Schedule C to the Food and Drugs Act that are in Dosage Form)

Food and Drug Regulations

1 Section C.01.014.6 of the Food and Drug Regulations footnote1 is replaced by the following:

C.01.014.6 (1) The Minister shall cancel the assignment of a drug identification number for a drug if

(2) The Minister may cancel the assignment of a drug identification number for a drug if

(3) The Minister may cancel the assignment of a drug identification number for a drug if, after he or she has, under section 21.31 of the Act, ordered the holder of a therapeutic product authorization referred to in subparagraph C.01.052(1)(b)(i) or (iii) to conduct an assessment of the drug in order to provide evidence establishing that the benefits associated with the drug outweigh the risks of injury to health,

(4) For greater certainty, the Minister’s power to cancel the assignment of a drug identification number

2 The Regulations are amended by adding the following after section C.01.049:

Information — Serious Risk of Injury to Human Health

C.01.050 (1) This section applies to a holder of one or more of the following therapeutic product authorizations:

(2) The holder of a therapeutic product authorization in respect of a drug that is part of a class of drugs set out in subsection (4) shall provide the Minister with information in respect of any serious risk of injury to human health that the holder receives or becomes aware of and that is relevant to the safety of the drug, regarding

(3) The information shall be provided to the Minister within 72 hours after the holder receives or becomes aware of it, whichever occurs first.

(4) The classes of drugs are

(5) Despite subsection (2), a holder of a therapeutic product authorization who provided information in accordance with

(6) In this section, foreign regulatory authority means a government agency or other entity outside Canada that has a legal right to control the manufacturing, use or sale of drugs within its jurisdiction and that may take enforcement action to ensure that drugs marketed within its jurisdiction comply with the applicable legal requirements.

3 The Regulations are amended by adding the following after section C.01.051:

Assessments Ordered Under Section 21.31 of the Act

C.01.052 (1) The Minister’s power to make an order under section 21.31 of the Act is subject to the following conditions:

(2) The Minister shall, after examining the results of an assessment that was ordered under section 21.31 of the Act,

Activities Ordered Under Section 21.32 of the Act

C.01.053 The Minister’s power to make an order under section 21.32 of the Act is subject to the following conditions:

4 (1) The portion of subsection C.01A.016(1) of the Regulations before paragraph (a) is replaced by the following:

C.01A.016 (1) The Minister may suspend an establishment licence in respect of any or all matters indicated in subsection C.01A.008(2) if he or she has reasonable grounds to believe that

(2) Paragraphs C.01A.016(1)(a) and (b) of the French version of the Regulations are replaced by the following:

(3) The portion of subsection C.01A.016(3) of the Regulations before paragraph (a) is replaced by the following:

(3) The Minister shall not suspend an establishment licence until

5 Subsection C.01A.017(1) of the Regulations is replaced by the following:

C.01A.017 (1) The Minister may suspend an establishment licence in respect of any or all matters indicated in subsection C.01A.008(2) without giving the licensee an opportunity to be heard if it is necessary to do so to prevent a risk to the health of consumers, by giving the licensee a notice that states the reason for the suspension.

6 Section C.01A.018 of the Regulations is replaced by the following:

C.01A.017.1 The Minister may suspend an establishment licence in respect of any or all matters indicated in subsection C.01A.008(2) if, after the Minister has, under section 21.31 of the Act, ordered the licensee to conduct an assessment in order to provide evidence establishing that the licensee’s buildings, equipment or practices and procedures, as the case may be, continue to meet the requirements referred to in paragraph C.01A.005(l), subparagraph C.01A.005(m)(ii) or (iii) or paragraph C.01A.005(o),

C.01A.018 The Minister shall reinstate an establishment licence in respect of any or all matters indicated in subsection C.01A.008(2) that are the subject of the suspension if, within 12 months after the effective date of the suspension, the licensee provides the Minister with sufficient evidence demonstrating that

7 Section C.01A.018.1 of the Regulations is replaced by the following:

C.01A.018.1 The Minister shall cancel an establishment licence if the licensee has failed to submit an application for the review of the licence in accordance with subsection C.01A.009(1).

C.01A.018.2 (1) If the Minister has suspended an establishment licence in respect of all matters indicated in subsection C.01A.008(2) and the suspension is still in effect 12 months after the effective date of the suspension, the Minister shall cancel the licence.

(2) If the Minister has suspended an establishment licence in respect of one or more of the matters indicated in subsection C.01A.008(2) and the suspension is still in effect 12 months after the effective date of the suspension, the Minister shall cancel the licence only in respect of the matters that are the subject of the suspension.

8 Paragraph C.08.002(1)(c) of the French version of the Regulations is replaced by the following:

9 (1) The portion of subsection C.08.003(1) of the French version of the Regulations before paragraph (a) is replaced by the following:

C.08.003 (1) Malgré l’article C.08.002, il est interdit de vendre une drogue nouvelle à l’égard de laquelle un avis de conformité a été délivré à son fabricant et n’a pas été suspendu en vertu de l’article C.08.006 lorsqu’un des éléments visés au paragraphe (2) diffère sensiblement des renseignements ou du matériel contenus dans la présentation de drogue nouvelle, la présentation de drogue nouvelle pour usage exceptionnel, la présentation abrégée de drogue nouvelle ou la présentation abrégée de drogue nouvelle pour usage exceptionnel, à moins que les conditions ci-après ne soient réunies :

(2) Paragraph C.08.003(1)(c) of the French version of the Regulations is replaced by the following:

10 (1) Paragraph C.08.005.1(1)(a) of the Regulations is repealed.

(2) Subsection C.08.005.1(5) of the Regulations is repealed.

11 (1) Subsection C.08.006(1) of the Regulations is replaced by the following:

C.08.006 (1) For the purposes of subsection (2), evidence or new information obtained by the Minister includes any information or material filed by any person under Division 5 or section C.08.002, C.08.002.01, C.08.002.1, C.08.003, C.08.005 or C.08.005.1.

(2) The portion of subsection C.08.006(2) of the French version of the Regulations before paragraph (a) is replaced by the following:

(2) Le ministre peut suspendre, pour une période déterminée ou indéterminée, l’avis de conformité délivré à un fabricant à l’égard d’une présentation de drogue nouvelle, d’une présentation de drogue nouvelle pour usage exceptionnel, d’une présentation abrégée de drogue nouvelle, d’une présentation abrégée de drogue nouvelle pour usage exceptionnel ou d’un supplément à l’une de ces présentations, en envoyant au fabricant une notification indiquant que cette mesure est nécessaire, s’il estime :

(3) Section C.08.006 of the Regulations is amended by adding the following after subsection (2):

(3) The Minister may, by notice to a manufacturer, suspend for a definite or indefinite period a notice of compliance issued to that manufacturer in respect of a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission, an abbreviated extraordinary use new drug submission or a supplement to any of those submissions, if, after the Minister has, under section 21.31 of the Act, ordered the holder of a therapeutic product authorization referred to in subparagraph C.01.052(1)(b)(iii) to conduct an assessment of the new drug in order to provide evidence establishing that the benefits associated with the drug outweigh the risks of injury to health,

12 Paragraph C.08.008(c) of the Regulations is replaced by the following:

Regulations Amending the Food and Drug Regulations (DIN Requirements for Drugs Listed in Schedule C to the Food and Drugs Act that are in Dosage Form)

13 Section 7 of the Regulations Amending the Food and Drug Regulations (DIN Requirements for Drugs Listed in Schedule C to the Food and Drugs Act that are in Dosage Form) footnote2 is amended by replacing the section C.01.014.6 that it enacts with the following:

C.01.014.6 (1) The Minister shall cancel the assignment of a drug identification number for a drug if

(2) The Minister may cancel the assignment of a drug identification number for a drug if

(3) The Minister may cancel the assignment of a drug identification number for a drug if, after he or she has, under section 21.31 of the Act, ordered the holder of a therapeutic product authorization referred to in subparagraph C.01.052(1)(b)(i) or (iii) to conduct an assessment of the drug in order to provide evidence establishing that the benefits associated with the drug outweigh the risks of injury to health,

(4) For greater certainty, the Minister’s power to cancel the assignment of a drug identification number

Coming into Force

14 (1) These Regulations, except section 2, come into force on the day on which subsection 6(2) of the Protecting Canadians from Unsafe Drugs Act (Vanessa’s Law), chapter 24 of the Statutes of Canada, 2014, comes into force, but if they are registered after that day, they come into force on the day on which they are registered.

(2) Section 2 comes into force on the day that, in the sixth month after the month in which section 1 comes into force, has the same calendar number as the day on which section 1 comes into force, or, if that sixth month has no day with that number, the last day of that sixth month.

REGULATORY IMPACT ANALYSIS STATEMENT

(This statement is not part of the Regulations.)

Issues

Vanessa’s Law provisions that require regulations to come into force

Prior to the Protecting Canadians from Unsafe Drugs Act (Vanessa’s Law), the Food and Drugs Act (the Act) had not been substantially updated in over 50 years. Over time, it became apparent that changes to the Act were needed in order to provide Health Canada (the Department) with the legislative and regulatory tools necessary to regulate more effectively and efficiently the approval and safety of drugs for Canadians based on a life cycle approach (i.e. an approach to regulating drugs where drugs are evaluated before and after they reach the market). This approach is being adopted by regulatory agencies worldwide and is based on the recognition that important information about the safety and effectiveness of a drug can only be learned after a product is marketed and as more people use the product.

Vanessa’s Law received royal assent on November 6, 2014, and amended the Act to enable the Department to regulate a drug more efficiently and effectively throughout its life cycle, beginning with the pre-market application for an authorization to sell the drug to post-market follow-up, when the drug is made available to Canadians. The amendments provide the Minister of Health (the Minister) with a wide range of proportional regulatory tools to use and give the Governor in Council the authority to make regulations to further enhance the Minister’s ability to gain information about a drug or to mitigate risks to persons who use these drugs. For example, the Minister now has the ability to order a therapeutic authorization holder to make a label change if a safety risk has been identified once a drug is on the market, or to order the recall of a product if the Minister believes that it presents a serious risk of injury to health. Prior to these changes to the Act, the Minister had limited recourse to take timely and proportionate action when safety issues arose other than suspending or cancelling an authorization.

While most of the amendments to the Act (e.g. the ability to recall unsafe drugs, impose tougher fines and penalties, order changes to a label or package, and seek an injunction) are already in force, some powers will be brought into force when regulations are in place to support them. These include the Minister’s power to

These statutory powers will allow the Department to gather information to resolve uncertainties that may arise respecting the benefits and harms associated with a therapeutic product. These uncertainties could be identified in new information that was not previously available to the Minister, such as a post-market safety signal obtained through a review of adverse drug reaction reports. Without additional information to resolve the uncertainties, the Minister could not reasonably be expected to decide whether there was a significant change to the safety profile of the product or its effectiveness that would constitute an elevated risk to patients and that could warrant further action to mitigate those risks.

The orders that the Minister may issue under sections 21.31 and 21.32 can be time-consuming and financially burdensome for authorization holders to comply with; therefore, regulations are necessary to specify how and when the Minister will be authorized to exercise these powers.

Notifying the Department of foreign risk communications

Currently, authorization holders do not have to inform the Department of risks associated with a drug that have been identified by foreign affiliates or regulators, or may have resulted in a recall or other regulatory action, such as the suspension or revocation of a licence, in foreign jurisdictions. Many drugs may be marketed years in advance or in a higher volume in other countries (typically the United States and members of the European Union). As a consequence, important safety signals may be detected earlier in a foreign jurisdiction. Many Canadian drug manufacturers are often aware before the Department of the actions being taken by a foreign affiliate or regulator. They are well placed to assess the risks of Canadian products and inform the Department of this. Knowing of risks communicated or actions taken to mitigate risks in foreign jurisdictions is important, as it allows the Department to assess risks to Canadians and take appropriate action to mitigate those risks when warranted.

There are few tools available in the Food and Drug Regulations (FDR) that the Department can use to compel the disclosure of this type of information, and these can only be used on a case-by-case basis and are limited in scope. For example, section C.01.013 allows the Director to request information to establish the safety and effectiveness of a drug, and sections C.01.016 to C.01.019 require authorization holders to report serious unexpected adverse drug reactions (ADRs) that occur outside of Canada and provide the Minister with the authority to require, in respect of these ADRs, annual summary reports, case reports and issue-related summary reports.

In addition, the Department maintains a number of Memoranda of Understanding (MOUs) with certain foreign regulatory agencies. Although these MOUs allow for the exchange of certain risk information between the signatories, they do not provide coverage that is sufficiently comprehensive or timely to allow the Department to rapidly assess risks (if any) to Canadian patients and take necessary actions to mitigate these risks, nor do they proactively engage the Canadian authorization holder.

Furthermore, the Department receives safety information from authorization holders through the provision of Periodic Safety Update Reports (PSURs) or Periodic Benefit-Risk Evaluation Reports (PBRERs). This type of reporting is conducted on a voluntary basis and typically only for a small subset of new drugs (i.e. drugs that have been issued a notice of compliance [NOC] pursuant to section C.08.004 of the FDR). Furthermore, these reports do not need to be submitted to the Department on an expedited basis when emergent safety issues come to light.

Clinical case reports: reducing burden

Under paragraph C.08.005.1(1)(a) of the FDR, manufacturers are required to submit a copy of all clinical case reports with a new drug submission (NDS). Clinical case reports are generated when a person who is part of a study has died, or has suffered a serious adverse reaction or an unexpected adverse reaction to a drug. These reports contain details about the event, including patient history, diagnosis and treatment. However, they represent up to half of the volume of data provided with an NDS and, therefore, represent a substantial compliance burden for manufacturers. The elimination of this requirement would not negatively impact the Department’s review of an NDS for two reasons. First, manufacturers will still be required to provide the Department with a summary of these clinical case reports [C.08.005.1(1)(c) and C.08.005.1(3)]. Second, the Minister would still be able to access these clinical case reports when necessary, using existing requirements under the FDR.

Objectives

These regulatory amendments will support the coming into force of the new powers to require assessments, tests and studies included in Vanessa’s Law by establishing the rules needed to structure the exercise of those powers. They will further support post-market drug safety by creating new foreign incident reporting rules. Finally, the regulatory amendments will reduce unnecessary requirements by removing an NDS submission obligation. Together, the provisions of the regulatory amendments will enable the Department to regulate drugs more efficiently and effectively, based on a life cycle approach.

Description

These amendments to certain provisions of Part C, Divisions 1 and 8, of the FDR will strengthen the Department’s ability to regulate drugs based on a life cycle approach. The amendments include the following:

1. Regulations to support the coming into force of new powers under Vanessa’s Law to require assessments, tests and studies

The regulatory amendments further define the scope of sections 21.31 and 21.32 of Vanessa’s Law. These amendments will come into force when these new legislative powers come into force. Together, the new amendments and legislation will create and establish the scope of the Minister’s new authorities to order drug manufacturers to conduct assessments or to conduct additional tests and studies. The amendments limit the scope of the new powers to drugs regulated under the FDR.

Assessments ordered under section 21.31 of the Act

The regulatory amendments establish the following with respect to an order made under section 21.31 of the Act:

As an example, information may become available through ADR reporting indicating that a drug may be causing a serious previously unknown injury to patients or that a known injury may be occurring at a rate much higher than what was established in clinical trials. In this case, the Minister could order the authorization holder to provide an assessment of whether the benefits of the drug continue to exceed the injury in light of the new information (and if not, whether actions would be required to mitigate the risks).

In addition, a new regulatory provision allows the Minister to cancel a DIN or suspend an NOC if, on the basis of an assessment, the risks of injury to health outweigh the benefits. In the case of an EL, the Minister could suspend the EL in relation to a licensable activity, if the results of an assessment led the Minister to believe that the licensee could no longer meet the requirements of the EL with respect to good manufacturing practices.

Tests, studies and other activities ordered under section 21.32 of the Act

The regulatory amendments establish the following with respect to an order made under section 21.32 of the Act:

If, during discussions with the manufacturer, the Minister decides that additional information is still needed to help him or her make a decision on the uncertainties related to the drug, then the Minister may use this power to order an additional test or study (for example compiling information on the number of prescriptions written or filed, conducting a randomized controlled clinical trial, or monitoring misuse of the drug). An order is meant to be used when the Minister has determined that standard product vigilance (e.g. activities related to monitoring adverse reactions or problems with reporting them) is not sufficient to obtain the additional information required for the ongoing benefit-risk assessment of the product.

It is not the Minister’s intent to trigger the order powers under sections 21.31 and 21.32 without providing the authorization holder with an opportunity to address the situation, which led to the Minister considering the use of these powers. As was done for other order powers available to the Minister that are already in force (for example a label change order under section 21.2 or a recall order under section 21.3), the Department has developed a process to ensure that the authorization holder has an opportunity to be heard prior to the issuance of an order.

2. Notifying the Department of foreign actions regarding serious risk communications

The amendments to the FDR require the holder of an authorization (made through the assignment of a DIN or the issuance of an NOC), for a prescription drug or a drug sold without a prescription that is to be administered only under the supervision of practitioners, to provide the Minister with information in respect of any serious injury to health the holder becomes aware of and that is relevant to the safety of the drug regarding

This information must be provided to the Minister within 72 hours of the holder receiving it, or becoming aware of it, so as to allow the Minister to follow up without delay if similar risks exist for those drugs in Canada and action would be required to mitigate those risks.

Guidance documents prepared by the Department will further specify the information that authorization holders would have to provide, which will include the brand name and manufacturer of the foreign product, the brand name of the relevant Canadian product, the name of the foreign regulator, a description of any action taken by them and the reasons for those actions. In addition, authorization holders will have to provide an explanation of how the issue that resulted in foreign actions may be relevant to the safety of the product sold in Canada and any actions proposed or taken by them in response.

The reporting requirements only apply with respect to prescription drugs or drugs sold without a prescription that are to be administered only under the supervision of practitioners, as these classes of drugs are considered to have a higher risk of injury to health in comparison to non-prescription drugs. Note that this may include some but not necessarily all drugs that are found on the Schedule II factors footnote3 that the National Association of Pharmacy Regulatory Authorities (NAPRA) considers when making a scheduling decision (i.e. drugs that are required to be sold only by a pharmacist).

Authorization holders can refer to a list, incorporated by reference in the FDR that specifies which foreign regulatory authorities’ risk communications are reportable to the Department. This list includes the United States Food and Drug Administration (FDA) as well as drug regulatory authorities in many of the nations of the European Union. The foreign authorities were chosen so as to be representative of the authorities that may have authorized the drug for sale and for use in a similar manner as Canada, and ones with which the Department has a working relationship through bilateral agreements or common membership in internationally recognized organizations. The list is attached as Appendix A to the Regulatory Impact Analysis Statement.

3. Clinical case reports — Reducing burden

The amendments repeal the requirement in paragraph C.08.005.1(1)(a) to provide clinical case reports when a new drug submission (NDS) is filed with the Minister.

This amendment is not expected to compromise the review of drug submissions since remaining provisions in section C.08.005.1 would continue to require the submission of sectional reports and comprehensive summaries in which the results of the case reports are summarized and discussed. Further to this, manufacturers would still be required to keep case reports, and the Minister would retain the authority to request those case reports during the review of a drug submission, if necessary.

“One-for-One” Rule

The requirement for the holder of a drug authorization to communicate risks identified in foreign jurisdictions is a requirement that is unique to Canada, as no other jurisdiction currently has implemented regulations that are identical to these. Authorization holders are required to notify the Department of any information they receive or become aware of (that applies to a product sold in Canada and represents a possibility of serious risk) respecting risks identified in specified foreign jurisdictions within 72 hours of the moment they become aware of it. This information includes risk communications issued, changes to label requested, recalls, reassessments, suspensions, and revocations of authorization by the regulatory authorities specified.

While stakeholders have indicated that this activity already occurs, by formalizing it in regulations, they have identified an incremental cost of between $1,050 and $1,560 with an average of $1,305 to report to the Department. This includes $600 to compile a report by working level staff and an average cost of $390 for functional review and $315 for senior management review.

Based on stakeholder input, it has been estimated by the Department that industry would have to screen approximately 729 foreign-related risk issues yearly. Using the average cost of reporting to the Department ($1,305), this new requirement creates new annual administrative burden valued at $951,345 (in 2018 dollars), or annualized costs of $818,111 in 2012 dollars.

The costs of reporting would not be borne equally. Each authorization holder would be required to report based on the information that they become aware of, and only then, when the information is relevant to products on the Canadian market. It is therefore theoretically possible that in any given year all the reporting costs would fall on only one firm, or they could be spread evenly across the entire industry. However, the latter is more likely to occur over the course of time.

“One-for-One” Rule
(Applies to Administrative Costs Only)

Current Initiative
Constitutes

“IN”
(“One-for-One” Rule)

Annualized administrative costs (constant 2012 $)

$818,111

Annualized administrative costs per business
(2012 $)

$10,100

Small business lens

The small business lens applies to regulatory proposals that have an impact on small businesses and that have nationwide cost impacts over $1 million annually. The Treasury Board Secretariat defines small businesses as any business, including its affiliates, that has fewer than 100 employees or between $30,000 and $5 million in annual gross revenues. This definition is based on commonly used definitions for what is considered a “small” business in Canada.

The prescription pharmaceutical industry in Canada does not fit the definition of small business. Further, there are no significant costs introduced by these amendments. Therefore, the small business lens does not apply.

Consultation

The Department has engaged stakeholders extensively since 2010 to understand their various positions on the provisions under Vanessa’s Law. For example, the Department hosted a series of technical discussions with stakeholders on regulatory modernization and regulating drugs and medical devices based on a life cycle approach. These discussions covered topics such as market authorization, amendments, terms and conditions, label changes, tests and studies, suspension, and revocation. Many of these components resulted in provisions found under Vanessa’s Law.

For more information on these technical discussions, visit the Department’s website at http://www.hc-sc.gc.ca/ahc-asc/activit/strateg/mod/reg/tech-eng.php.

Canadian academics, clinicians and health technology assessors have been engaged at various times and expressed support for a framework that would allow for enhanced information gathering and sharing throughout the life cycle.

The Department conducted surveys concerning costs in 2014 regarding potential regulations stemming from the passing of the Vanessa’s Law. The surveys provided industry with a chance to inform the Department of the cost impacts of various provisions and how some costs could be lowered.

A notice of intent (NOI) announcing the Department’s intention to develop supporting regulations under Vanessa’s Law to bring into force the Minister’s power to order an assessment; to order the conduct of further tests, studies, and other activities; and to require authorization holders to report foreign risk communications was published on June 18, 2016. Only one stakeholder provided comments related to those provisions. Notably, the stakeholder commented that the regulatory amendments should provide a clear framework for fulfilling the foreign risk communication obligations, and that orders should be issued when companies do not voluntarily comply with requests made by the Department.

Finally, a number of information sessions were held in October 2016 with various associations representing the pharmaceutical industry in Canada. These stakeholders were provided with an overview of the Department’s policy intent with respect to these regulatory amendments. Some stakeholders expressed the need to be able to have a dialogue with the Department before an order is issued by the Minister. As with the order powers that have already come into force, the Department has developed procedures to allow an opportunity for the authorization holder to be heard prior to the issuance of an order. Some stakeholders asked which specific information each authorization holder would be required to provide the Minister under the foreign risk communication proposal. The Department realizes that there is the possibility of duplicative reporting in some instances and the guidance document will detail what information would be required and which authorization holder would be required to submit that information in order to comply with the regulatory requirements.

Prepublication in the Canada Gazette, Part I

The proposed Regulations Amending the Food and Drug Regulations (Vanessa’s Law) were prepublished in the Canada Gazette, Part I, on April 22, 2017, for comment for a 75-day period. Over the course of the consultation period the Department received more than 250 comments from 21 different respondents. Respondents included drug and cosmetic industry associations, individual drug companies, as well as academics and a private citizen. Two draft guidance documents were available, upon request, at the time of prepublication. However as there was some confusion as to their availability, the Department published them on the Government of Canada website on August 11, 2017, allowing 30 days for interested stakeholders to provide feedback.

Overall, most respondents were not opposed in principle to the proposal although concern was expressed by academics and private citizens that the Department would be losing access to valuable drug safety information by eliminating the requirement to include clinical case reports with a new drug submission. It also appears that many respondents interpreted the scope of the foreign risk communication reporting requirements to be wider than intended by the Department. These issues and other comments received are discussed in detail below. A number of comments were received that were outside of the scope of the proposal and are not considered here.

Clinical case reports

A number of respondents including drug industry associations, individual drug companies, an academic and a private citizen commented on the proposal to eliminate the existing requirement respecting case reports. It was pointed out to the Department that laws in the United States as well as the European Union, including the United Kingdom, still require the submission of information that is included in individual clinical case reports. As a result, some drug industry respondents felt the Department may have overestimated the reduction in burden by eliminating this requirement as the information still had to be provided to other jurisdictions. Others thought, however, that this did represent a substantial reduction. The academic and private citizen argued that this change represented a loss of valuable safety information that should form an important part of the Department’s drug assessment and approval process. They were concerned that patient harms could occur as a result. The Department again considered the value of the raw data in individual case reports in the assessment of the safety of a drug. As this data is used to prepare the clinical study reports and is typically presented in those reports in tabulated format (known as “line listings”) the Department determined that in most instances individual case reports would not be required. As the Minister would still retain the authority to require these to be submitted when requested, the Department is confident that proceeding with the amendment would not adversely affect its ability to conduct a comprehensive assessment of the safety of a drug.

Notifying the Department of foreign actions regarding serious risk communications

A number of drug industry associations and individual drug companies thought that the proposed 48 hours for reporting information was too short and that 72 hours would be more in line with similar reporting requirements in foreign jurisdictions. Other respondents suggested an initial notification be provided within 48 hours and additional information following that. Additionally, a number of stakeholders indicated that their existing notification processes were designed to meet the 72-hour timeline. The Department recognizes that much of the required information could be available to the Department by other means, such as through continuous scanning of publicly available information or by being directly notified by foreign regulatory authorities with whom information sharing agreements are in place. The Department is also aware that it may take some time for a market authorization holder to determine whether an occurrence in another jurisdiction could impact the safety of the drug sold in Canada. Information received through this new requirement will be evaluated to determine whether a safety issue existed and whether further action to manage risks associated with a drug would be warranted. Receiving information that is not relevant to the safety of a Canadian marketed drug would make this process inefficient and may slow the identification of real safety issues. Therefore, the Department considers that 72 hours will allow market authorization holders the time to better analyze the foreign occurrences and the potential impact on the safety of the drug in Canada and will reduce the submission of information that is not relevant. The requirement has been changed to allow 72 hours for reporting.

One industry association regarded the Department’s estimate of 226 notifications annually to be low, citing numbers published on the U.S. Food and Drug Administration’s website respecting safety related labelling changes, recalls and drug safety communications. The Department’s original estimate was based on an assessment of foreign safety information that could have relevance to the safety of the drug in Canada and, as a result, was not simply the sum of safety notifications, recalls and other safety-related actions that occurred in other jurisdictions. However, the Department has reviewed the original estimate based on stakeholder feedback and has revised it upwards to 729, this number is being used for revised cost estimates. Additionally, in order to limit the number of duplicative notifications, the regulatory text has been clarified to indicate that authorization holders do not need to notify of the same occurrence more than once. This means that if a safety issue (such as a recall, risk communication, etc.) has been identified in one jurisdiction and the authorization holder has provided the Department notification, then further notification would not have to be made if the same safety issue was identified in another jurisdiction at some later time.

Some respondents noted concern over whether they would have to notify the Department about labelling changes that were proposed but not final in other jurisdictions. The Department considers that the regulations are clear in this regard as C.01.050(2)(b) states “changes that have been made to the labelling.” Proposed changes would not be required to be submitted. Guidance documents have been revised to provide additional detail for clarity.

A drug manufacturer and an industry association suggested that the List of Foreign Regulatory Authorities could be reduced in size to correspond to “major authorities” only. The list was compiled so as to include the U.S., EU and a sample of non-EU jurisdictions as well as include those foreign regulatory agencies that Canada has mutual recognition agreements with. This was done so as to ensure that the Department would be notified of safety risks in a timely manner if they were first discovered in a smaller jurisdiction.

Some stakeholders also commented on the need to define “serious risk of injury to human health.” Given that each occurrence is case-specific, the Department has identified key elements that may be considered in order to determine whether a “serious risk of injury to human health” is present. These key elements can be found in Annex A of the Amendments to the Food and Drugs Act: Guide to New Authorities document.

Assessments ordered under section 21.31 of the Act

Two industry associations and a drug manufacturer asked whether the Department would remove potentially proprietary information prior to public release of any assessment summaries. The Department would not normally release any information that it considered to be confidential business information. Of note, however, is the ability the Minister has under subsection 21.1(2) of the Act to release confidential business information without consent if the product may present a serious risk of injury to health.

Tests, studies and other activities ordered under section 21.32 of the Act

One industry association and numerous drug manufacturers commented that the Department may have underestimated the cost of studies that could be conducted subject to an order under section 21.32. However the respondents did not provide any further information to substantiate this. The cost estimate by the Department represents a reasonable average anticipating that many studies may cost substantially less than the $100,000 estimate while some substantially more. As the Minister will be required to take into account the feasibility and burden associated with any study before proceeding with an order, there will be an opportunity for industry to propose less costly means of gaining the required information or provide a rationale as to why the Department should reconsider the need for the additional information.

Guidance documents

A substantial number of comments received identified the need to clarify how the proposed regulations would be implemented by the Department. These comments have been taken into consideration and the supporting guidance documents have been revised accordingly. A few comments that resulted in the revision of the guidance document related to the requirement to notify the Department of foreign actions regarding serious risk communications include the need to clarify the type of information that needs to be provided to the Department, to clarify the various triggers that would initiate a reporting requirement, or to simplify the information that needs to be reported.

Summary of changes to the Regulations following prepublication

The regulatory amendments differ from those prepublished in the Canada Gazette, Part I, in the following manner:

  1. Subsection C.01.050(2) was amended to reduce the possibility of duplicative and unnecessary information being submitted to the Department.
  2. Subsection C.01.050(3) was amended to replace “48 hours” with “72 hours” so as to provide additional time to authorization holders to compile and submit a notification.
  3. Subsection C.01.050(4)(b) was amended to replace “that are administered” with “that are to be administered” to better reflect the intent of the requirement.
  4. The coming into force date was revised to indicate that the requirements that relate to notifying the Department of foreign actions regarding serious risk communications would come into force six months after the other sections. This is in order to comply with treaty obligations under the World Trade Organization. All other sections will come into force when subsection 6(2) of Vanessa’s Law comes into force. That subsection, as well as sections 4, 10, and 11 of Vanessa’s Law will come into force on a date specified by an order in council.

Rationale

The amendments to Division 1 are necessary to specify how and when the Minister may exercise key provisions from Vanessa’s Law. In the absence of these regulatory amendments, several safety provisions such as the Minister’s power to order an assessment of a drug or for a company to conduct further tests and studies would not be able to come into force, nor would companies be required to notify the Department of foreign risk communications of which they are aware. All of the above are important tools necessary for the Department to be able to effectively monitor a drug once it is on the market and to act upon important post-market safety information.

The amendment to Division 8 reduces unnecessary burden on industry by eliminating the requirement to produce all clinical case reports when applying for an authorization.

Benefits and costs

1. Regulations to support the coming into force of new powers under Vanessa’s Law to require assessments, tests and studies

The regulatory amendments relating to assessments and to tests and studies are required to operationalize Vanessa’s Law. They set, in the FDR, the thresholds and procedures to be used with these powers. Therefore, the costs set out below stem from amendments to the Act, and not the regulatory amendments. The regulatory amendments are meant to ensure the effectiveness of the new provision of the Act and provide transparency while also introducing procedural fairness for market authorization holders.

These powers would only be used in instances when there is evidence that the benefit-harm-uncertainty profile of a drug may have changed. Currently, these activities are done voluntarily by industry, often as a result of pressure from other regulatory bodies, and it is expected that industry will continue to do so. While most of this information can be gained through discussions with manufacturers, the Minister needs the authority to compel a manufacturer that refuses to voluntarily act to resolve significant uncertainties associated with a product, and would typically be done once all regulatory tools available to the Minister are exhausted. It is anticipated that the new authorities created by Vanessa’s Law (assessments, tests and studies) would be utilized approximately three times per year, cumulatively. A survey of firms indicated that the annual incremental cost of these powers would be $300,000. Since the costs are borne by the Act, they are not used to calculate the net benefit of these regulatory amendments.

2. Clinical case reports

The removal of the requirement to automatically provide case reports should greatly reduce the compliance burden on industry. Industry provided a wide range of estimates for the annual savings of removing this requirement. Industry stated it was difficult to give a per product estimate of the savings, but numbers ranged from a low of $2,500 to a maximum of $4,000,000 per marketed product depending on certain situations that could arise.

Numbers provided by industry suggest that the savings from the elimination of this requirement for a medium-sized submission would be around $5,000 per year.footnote4 The Department’s records indicated that in the fiscal years 2012–2013, 2013–2014, and 2014–2015, the number of filings that were made that required the inclusion of case reports were 365, 340, and 315 respectively. This represents an average of 340 filings per year that required the submission of case reports.

This amounts to $1.7 million dollars per year of burden to satisfy a Canadian-specific requirement.

$5,000 × 340 filings per year = $1,700,000 per year

Over 10 years, the total benefit to industry would be $17 million. Adjusted for present value using a 7% discount rate, the savings would be $11.9 million over that period. Since these savings are not administrative in nature, they are also not captured in the “One-for-One” Rule.

Taking into consideration the costs associated with the foreign risks reporting requirements and the savings of the clinical case reports requirements, the annualized net benefit of the proposal would be $748,655, or a net present value benefit estimated to be $5,258,239 over 10 years.

Implementation, enforcement and service standards

These amendments will not alter existing compliance and enforcement mechanisms under the provisions of the Act and the FDR.

Implementation activities, such as the training of staff, standard operating procedures as well as updating internal databases and the Department’s website, are needed to support these amendments. The guidance documents entitled Guidance Document for Notifying Health Canada of Foreign Risk and Amendments to the Food and Drugs Act - Guide to New Authorities will be made available on the Government of Canada website to aid regulated parties in coming into compliance.

Coming into force

The regulatory amendments regarding the ordering of assessments under section 21.31 of the Act, the ordering of tests, studies and other activities under section 21.32 of the Act, and the elimination of the requirement to submit clinical case reports come into force once subsection 6(2) of Vanessa’s Law comes into force. An order in council will bring into force this subsection and sections 4, 10 and 11 of Vanessa’s Law on a date specified by the Governor in Council. The provisions relating to Notifying the Department of foreign risk communications will come into force six months following that date. This six-month period will provide time for industry to plan for and adjust to the new regulatory requirements, and provide the Department time to update its processes and train staff.

Contact

Bruno Rodrigue
Office of Legislative and Regulatory Modernization
Policy, Planning and International Affairs Directorate
Health Products and Food Branch
Health Canada
Holland Cross, Suite 14
11 Holland Avenue
Ottawa, Ontario
K1A 0K9
Address Locator:
3000A
Email:
LRM_MLR_consultations@hc-sc.gc.ca

Appendix A — List of Foreign Regulatory Authorities for the Purposes of Section C.01.050 of the Food and Drug Regulations

Part A

Regulatory authority

Country

The United States Food and Drug Administration

United States of America

The European Medicines Agency

European Commission

The Australian Therapeutic Goods Administration

Australia

Australian Pesticides and Veterinary Medicines Authority

Australia

Ministry of Primary Industries

New Zealand

Swiss Agency for Therapeutic Products

Switzerland

Health Sciences Authority

Singapore

Bundesamt für Sicherheit im Gesundheitswesen (Federal Office for Safety in Health Care, BASG)

Austria

Federal Agency for Medicines and Health Products

Belgium

Pharmaceutical Services, Ministry of Health

Cyprus

Státní Ústav pro Kontrolu Léčiv (SÚKL) — State Institute for Drug Control — Institut national de contrôle des médicaments

Czech Republic

Laegemiddelsstyrelsen (Danish Health and Medicines Authority)

Denmark

State Agency of Medicines, Estonia (SAM)

Estonia

Lääkealan turvallisuus- ja kehittämiskeskus, Finnish Medicines Agency, Fimea

Finland

Agence nationale de sécurité du médicament et des produits de santé (ANSM)

France

Agence nationale du médicament vétérinaire

France

Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten

Germany

Bundesministerium für Gesundheit

Germany

Bundesamt für Verbraucherschutz und Lebensmittelsicherheit

Germany

National Organization for Medicines

Greece

Gyógyszerészeti és Egészségügyi Minőség - és Szervezetfejlesztési Intézet Országos Gyógyszerészeti Intézet Főigazgatósága (Short name: GYEMSZI-OGYI) National Institute for Quality and Organizational Development in Healthcare and Medicines (Institut national de pharmacie) [INP]

Hungary

State Agency of Medicines

Latvia

State Medicines Control Agency

Lithuania

Inspectie voor de Gezondheidszorg (IGZ) Health Care Inspectorate

Netherlands

Health Products Regulatory Authority (HPRA)

Ireland

Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

Poland

Main Pharmaceutical Inspectorate

Poland

Autoridade Nacional do Medicamento e Produtos de Saúde (INFARMED) — National Authority of Medicines and Health
Products I.P. — Autorité nationale des médicaments et des produits de santé

Portugal

Italian Medicines Agency (AIFA)

Italy

Medicines Authority

Malta

National Medicines Agency

Romania

SIDC/State Institute For Drug Control

Slovak Republic

Agencija za zdravila in medicinske pripomočke — Agency for Medicinal Products and Medical Devices of the Republic of Slovenia

Slovenia

Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) — Spanish Agency of Medicines and Health Products — Agence Espagnole des Médicaments et des Produits de Santé

Spain

Medical Products Agency

Sweden

Medicines and Healthcare products Regulatory Agency (MHRA)

United Kingdom

Veterinary Medicines Directorate

United Kingdom

Lyfjastofnun/Icelandic Medicines Agency (IMA)

Iceland

Amt für Gesundheit (AG)

Liechtenstein

Norwegian Medicines Agency (NoMA)

Norway

Ministry of Agriculture, Forestry and Fisheries

Japan

Part B

Regulatory authority

Country

The United States Food and Drug Administration

United States of America

The European Medicines Agency

European Commission

The Australian Therapeutic Goods Administration

Australia

Australian Pesticides and Veterinary Medicines Authority

Australia

Ministry of Primary Industries

New Zealand

Swiss Agency for Therapeutic Products

Switzerland

Health Sciences Authority

Singapore

Bundesamt für Sicherheit im Gesundheitswesen (Federal Office for Safety in Health Care, BASG)

Austria

Federal Agency for Medicines and Health Products

Belgium

Pharmaceutical Services, Ministry of Health

Cyprus

Státní Ústav pro Kontrolu Léčiv (SÚKL) — State Institute for Drug Control — Institut national de contrôle des médicaments

Czech Republic

Laegemiddelsstyrelsen (Danish Health and Medicines Authority)

Denmark

State Agency of Medicines, Estonia (SAM)

Estonia

Lääkealan turvallisuus- ja kehittämiskeskus, Finnish Medicines Agency, Fimea

Finland

Agence nationale de sécurité du médicament et des produits de santé (ANSM)

France

Agence nationale du médicament vétérinaire

France

Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten

Germany

Bundesministerium für Gesundheit

Germany

Bundesamt für Verbraucherschutz und Lebensmittelsicherheit

Germany

National Organization for Medicines

Greece

Gyógyszerészeti és Egészségügyi Minőség - és Szervezetfejlesztési Intézet Országos Gyógyszerészeti Intézet Főigazgatósága (Short name: GYEMSZI-OGYI) National Institute for Quality and Organizational Development in Healthcare and Medicines (Institut national de pharmacie) [INP]

Hungary

State Agency of Medicines

Latvia

State Medicines Control Agency

Lithuania

Inspectie voor de Gezondheidszorg (IGZ) Health Care Inspectorate

Netherlands

Health Products Regulatory Authority (HPRA)

Ireland

Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

Poland

Main Pharmaceutical Inspectorate

Poland

Autoridade Nacional do Medicamento e Produtos de Saúde (INFARMED) — National Authority of Medicines and Health
Products I.P. — Autorité nationale des médicaments et des produits de santé

Portugal

Italian Medicines Agency (AIFA)

Italy

Medicines Authority

Malta

National Medicines Agency

Romania

SIDC/State Institute For Drug Control

Slovak Republic

Agencija za zdravila in medicinske pripomočke — Agency for Medicinal Products and Medical Devices of the Republic of Slovenia

Slovenia

Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) — Spanish Agency of Medicines and Health Products — Agence Espagnole des Médicaments et des Produits de Santé

Spain

Medical Products Agency

Sweden

Medicines and Healthcare products Regulatory Agency (MHRA)

United Kingdom

Veterinary Medicines Directorate

United Kingdom

Lyfjastofnun/Icelandic Medicines Agency (IMA)

Iceland

Amt für Gesundheit (AG)

Liechtenstein

Norwegian Medicines Agency (NoMA)

Norway

Ministry of Agriculture, Forestry and Fisheries

Japan

Part C

Regulatory authority

Country

The United States Food and Drug Administration

United States of America

The European Medicines Agency

European Commission

The Australian Therapeutic Goods Administration

Australia

Australian Pesticides and Veterinary Medicines Authority

Australia

Ministry of Primary Industries

New Zealand

Swiss Agency for Therapeutic Products

Switzerland

Health Sciences Authority

Singapore

Bundesamt für Sicherheit im Gesundheitswesen (Federal Office for Safety in Health Care, BASG)

Austria

Federal Agency for Medicines and Health Products

Belgium

Pharmaceutical Services, Ministry of Health

Cyprus

Státní Ústav pro Kontrolu Léčiv (SÚKL) — State Institute for Drug Control — Institut national de contrôle des médicaments

Czech Republic

Laegemiddelsstyrelsen (Danish Health and Medicines Authority)

Denmark

State Agency of Medicines, Estonia (SAM)

Estonia

Lääkealan turvallisuus- ja kehittämiskeskus, Finnish Medicines Agency, Fimea

Finland

Agence nationale de sécurité du médicament et des produits de santé (ANSM)

France

Agence nationale du médicament vétérinaire

France

Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten

Germany

Bundesministerium für Gesundheit

Germany

Bundesamt für Verbraucherschutz und Lebensmittelsicherheit

Germany

National Organization for Medicines

Greece

Gyógyszerészeti és Egészségügyi Minőség - és Szervezetfejlesztési Intézet Országos Gyógyszerészeti Intézet Főigazgatósága (Short name: GYEMSZI-OGYI) National Institute for Quality and Organizational Development in Healthcare and Medicines (Institut national de pharmacie) [INP]

Hungary

State Agency of Medicines

Latvia

State Medicines Control Agency

Lithuania

Inspectie voor de Gezondheidszorg (IGZ) Health Care Inspectorate

Netherlands

Health Products Regulatory Authority (HPRA)

Ireland

Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

Poland

Main Pharmaceutical Inspectorate

Poland

Autoridade Nacional do Medicamento e Produtos de Saúde (INFARMED) — National Authority of Medicines and Health
Products I.P. — Autorité nationale des médicaments et des produits de santé

Portugal

Italian Medicines Agency (AIFA)

Italy

Medicines Authority

Malta

National Medicines Agency

Romania

SIDC/State Institute For Drug Control

Slovak Republic

Agencija za zdravila in medicinske pripomočke — Agency for Medicinal Products and Medical Devices of the Republic of Slovenia

Slovenia

Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) — Spanish Agency of Medicines and Health Products — Agence Espagnole des Médicaments et des Produits de Santé

Spain

Medical Products Agency

Sweden

Medicines and Healthcare products Regulatory Agency (MHRA)

United Kingdom

Veterinary Medicines Directorate

United Kingdom

Lyfjastofnun/Icelandic Medicines Agency (IMA)

Iceland

Amt für Gesundheit (AG)

Liechtenstein

Norwegian Medicines Agency (NoMA)

Norway

Ministry of Agriculture, Forestry and Fisheries

Japan