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New Guidance Document: Use of a Foreign-sourced Reference Product as a Canadian Reference Product

Posted: Monday December 4th, 2017

Author: Bhavesh Patel, Chartered Chemist

On November 24, 2017 Health Canada published the Guidance Document “Use of a Foreign-sourced Reference Product as a Canadian Reference Product”, for sponsors who are seeking to demonstrate pharmaceutical equivalence and bioequivalence with a Canadian Reference Drug under paragraph (c) of C.08.001.1 of the Food and Drug Regulations. The Guidance Document replaces previous guidance which had been in place since 1995. 

The objective of the Guidance Document is to provide sponsors of an Abbreviated New Drug Submission or Abbreviated Extraordinary Use New Drug Submission with guidance on how to demonstrate that the reference drug is acceptable to the Minister of Health as a Canadian reference product.

The purpose of demonstrating pharmaceutical equivalence and bioequivalence against the Canadian Reference Product (“CRP”) is to provide evidence that the safety and efficacy profiles of the subsequent-entry (generic) product will be equivalent to that of the innovative product which is marketed in Canada and for which safety and efficacy has been demonstrated clinically.  In order to determine the acceptability of this evidence, the Minister must be satisfied that a reference product proposed under paragraph (c) appears to be the same as the innovative product marketed in Canada and that any potential undocumented differences between these two products would not be therapeutically significant.

Many reference products are manufactured for other countries with the same formulations and under the same conditions as the Canadian market. On occasion, these products are manufactured in only one location for worldwide distribution. In this situation, acceptance by the Minister of a reference drug marketed in another country as a CRP can avoid repetition of comparative studies in human subjects and thereby reduce the risks for study participants and the cost to manufacturers. This is most relevant for drug submissions which involve demonstration of bioequivalence based upon bioavailability studies, pharmacodynamics studies, clinical studies, or a combination thereof.

However, detailed information regarding the formulation and manufacture of products marketed outside of Canada is not generally available to Health Canada. In respect of these products, the Guidance Document sets out a list of requirements, which, if satisfied, will render the product acceptable to the Minster for use as a Canadian Reference Product.  Some examples of the requirements include, approval and marketing abroad, reporting of undocumented differences between the foreign and domestic products, and requirements based on the dosage form of the foreign product. The complete list of all requirements can be found in Section 2 of the Guidance Document.

Health Canada will be consulting with stakeholders on potential future revisions to the Guidance Document. An additional Notice to be posted in the near future will invite stakeholders to provide comments and recommendations for future updates to the Guidance Document.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.


Health Canada guidance document: Use of a Foreign-sourced Reference Product as a Canadian Reference Product, dated 2017-11-24 https://www.canada.ca/content/dam/hc-sc/documents/services/drug-health-product-review-approval/drug-products/guidance-documents/canadian-reference-product-guidance-eng.pdf     

Toward a Strengthened Assisted Human Reproduction Act

Posted: Monday November 27th, 2017

Author: Pinky Mazumder 

The increase in infertility in Canada has seen many Canadians turn to assisted human reproductive technologies to assist with family planning. With the increase of such technologies, the Assisted Human Reproduction Act (the “Act”) was enacted to protect the safety of Canadians making use of such technologies. The Act set out a licencing scheme, prohibited activities, inspection and enforcement to protect the health and rights of Canadians using assisted human reproduction. As well, the Act created the Assisted Human Reproduction Agency. Unfortunately, the implementation of the Act has been tumultuous, including a review by the Supreme Court of Canada which held several provisions unconstitutional. In addition, many provisions have not been enforced and the regulatory framework contemplated by the Act has been largely ignored. 

On October 1st 2016, the Minister of Health announced Health Canada’s intention to strengthen the regulatory framework governing assisted human reproduction and to bring into force dormant sections of the Act. On July 11, 2017, Health Canada published a consultation document entitled “Toward a Strengthen Assisted Human Reproduction Act” which announced the start of a public consultation towards regulatory inform, the highlights include:



The 60 day consultation period, which has since closed, sought feedback from various stakeholders such as fertility clinics, researchers, as well as individualswho use assisted human reproduction procedures. Health Canada received solicited feedback in response to the consultation but also received feedback that went outside the public consultation, including  the need to reconsider the penalties for medical and scientific activities associated with assisted human reproduction, and to review some of the prohibitions in Section 5 of the Act due to the evolution of scientific technologies. Although not the concern of the present consultation, these comments will be considered in the future.

The will be another opportunity for stakeholder feedback once the proposed regulations are published in the Canada Gazette Part I. 

Thank you for reading Regulated Affairs, the CAPRA blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media. 



Guidance Document - Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs)

Posted: Monday November 20th, 2017

Author: Bhavesh Patel, C. Chem. Natco Pharma (Canada) Inc.

On October 30, 2017, Health Canada released the final version of the Guidance Document - Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions  (“NDS”) and Abbreviated Drug Submissions (“ANDS”).

The Guidance Document creates several new requirements, in particular the requirement for stability studies for three batches of product for existing drugs, as well as commercial scale batches and pilot sized batches for other products. These requirements are reflected in amendments to the Sponsor Attestation Checklist for ANDSs which request stability confirmation for stability data for three primary batches. After October 30, 2019, the regulatory project manager will issue a Screening Deficiency Notice if a submission does not contain at least six months of stability data on at least three primary batches of the drug substance and drug product. The Sponsor Attestation Checklist for ANDSs will be revised at that time to confirm that three batches have been submitted.

The Guidance Document also sets out new requirements for executed batches to be manufactured at commercial scale batch size and pilot scale for liquid products. Subsequently, the Sponsor Attestation Checklist for ANDSs will be revised to list types of products considered high risk and to request confirmation whether a commercial scale batch or a pilot scale batch meeting the criteria has been submitted. After October 30, 2019, the regulatory project manager will issue a Screening Deficiency Notice if an NDS or ANDS does not contain a commercial scale batch of the drug product identified as a high-risk of having quality issues or an appropriate pilot scale batch for liquids. The Sponsor Attestation Checklist for ANDSs will be revised to confirm that a commercial scale batch has been submitted or justification for the size of the executed batches has been provided.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.




Proposed Amendments to the Patented Medicines Regulations

Posted: Monday November 13th, 2017

Author: Pinky Mazumder

A significant portion of all healthcare-related expenditures in Canada is attributed to prescription drugs. Despite this, prescription drug costs have continued to rise, with Canada having some of the world’s highest  prices for prescription drugs. Not only does this pose financial hurdles for patients and their families, but it also limits accessibility to new and innovative drugs and treatments. In an effort to address these concerns, Health Canada has proposed amendments to the Patented Medicines Regulations in an effort to help the Patented Medicine Prices Review Board (PMPRB) better protect Canadians from excessive prices associated with patented drug products.

Significant changes in pharmaceutical therapy over the past two decades have seen an increased prevalence of high cost treatments, for example biologics and gene therapies. While many jurisdictions have responded, including Canada, in implementing measures to reduce drug prices, there has been little change to PMPRB practice.  In an effort to modernize PMPRB practice to respond more effectively to modern drug pricing issues, Health Canada has proposed five amendments to the Regulations: 

1.    New pricing factors: domestic and international price references have traditionally been used by the PMPRB to evaluate the price of drug products. Addition factors are proposed, such as long term value for money thresholds, systemic therapeutic class and price reviews, and reimbursement and clinical criteria restrictions. Also proposed are considerations of the pharmacoeconomic value of the drug, the market size of the product in Canada, and Canada’s GDP.

2.    Comparative jurisdictions: the list of countries considered for price comparison will be updated to provide a better standard for consumer protection aligned with median OECD pricing.  The criteria used to select additional countries are based on consumer protection, economic standing, and the characteristics of their pharmaceutical market. New countries proposed to be added include Australia, Japan, Belgium, and South Korea.

3.    Complaint-based system for generic patented medicines: generic products that are covered by a patent and thus subject to the jurisdiction of the PMPRB are at a lower risk of overpricing. By moving to a complaint-based system for such products, the unnecessary regulatory burden associated with self-reporting is alleviated.

4.    Modernize reporting requirements for patentee: in association with the proposed new factors to be considered by the PMPRB, the Regulations will also be amended to require additional reporting information, including: the cost utility analysis by approved indication of the medicine (where available), and the estimated uptake of the medicine by approved indication (where available).

5. Providing Information related to third party rebates: patentees are currently required to report price reductions through rebates and discounts when sold to customers (e.g., wholesalers, pharmacies). However, there is no requirement for price reduction provided to third party payers such as provincial drug plans. This will better allow the PMPRB to assess the actual prices paid in the market. 

The consultation period for the proposed-amendments has closed. CAPRA will provide further updates on the proposed amendments as they occur. For more information on the proposed amendments, please refer to the Consultation document from Health Canada in the References section below.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share out blog posts and join us on social media. 



Certificate of Supplementary Protection for Pharmaceuticals, Biologics and Veterinary Drugs.

Posted: Monday November 6th, 2017

Author: Bhavesh Patel, C. Chem. Natco Pharma (Canada) Inc.

Health Canada has released the Guidance Document - Certificate of Supplementary Protection Regulations which provides information for industry regarding the recently implemented Certificates of Supplementary for medicinal ingredients.

As part of its obligations under the Comprehensive Economic and Trade Agreement with the European Union, Canada agreed to provide innovators with a period of extended market exclusivity to compensate for the time lost due to regulatory obligations in obtaining market approval. This protection, termed a Certificate of Supplementary Protection, is a form of sui generis exclusivity for up to two years and applies to patents claiming the medicinal ingredient contained in pharmaceuticals, biologics, and veterinary drugs.

An applicant for a CSP must file an application within 120 days from the date of issuance of the Notice of Compliance. At the time of filing, an applicant is required to submit the CSP application form along with advance payment details form and the required fee. The fee for filing a CSP application is  $9,011 which is set to increase by 2% per year. The required forms are available on Health Canada’s website.

To be eligible for a CSP, the patent claims must pertain, in the case of a drug containing one medicinal ingredient, to the one medicinal ingredient, or, in the case of a drug containing two or more medicinal ingredients, to the combination of all medicinal ingredients. Please note only one CSP will be granted for a given medicinal ingredient or combination. 


Canada Gazette, Part Ⅱ, Ottawa, Registration SOR/2017-165 September 1, 2017 Patent Act, Certificate of Supplementary Protection Regulations

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.

Health Canada’s guidance on Fees for Review of Submissions

Posted: Monday October 30th, 2017

Author: Pinky Mazumder

Health Canada's guidance document on the Fees for the Review of Drug Submissions and Applications provides sponsors information concerning the fees associated with the review of submissions. The Guidance Document applies to New drug Submissions, Supplement to New Drug Submissions, Abbreviated New Drug Submissions, Supplement to Abbreviated New Drug Submissions, and Drug Identification Number (DIN) applications. It does not apply to Emergency Use New Drug Submissions, submissions for natural health products, or for submissions for veterinary drug products.

The fee associated with a particular submission is based on a several factors, including its complexity. Importantly, sponsors who have not completed their first fiscal year at the time of filing the submission are eligible for an option to defer the payment for up to two years.

For fees that are less than $10,000, payment must be submitted at the time the submission or supplement is filed. Where the submission or supplement does not progress for review, the sponsor can receive a maximum of 90% remission of the fee paid.

For fees greater than $10,000, payment is not required to be made at the time of filing. Once Health Canada screens the submission and informs the sponsor that the submission can progress for review, the sponsor is required to pay 75% of the fee. The remaining 25% is to be paid upon the completion of the review. If the submission does not move forward for review, the sponsor must only pay 10% of the required fee.  If the submission is withdrawn or cancelled before screening is finished, payment of the fee (exceeding $10,000) is not required.

Industry should also be aware of the annual fee increases, which has been set at 2 % per year since April 1st, 2012. Notices are published in Canada Gazette Part I to highlight the revised fees.

A Drug Submissions/Application Fee Form is required for every submission or supplement.  For more information on how to complete this form and information on the fees for review of submission, please refer to the guidance link in the References.



Patented Medicines (Notice of Compliance) Regulations due to Comprehensive Economic and Trade Agreement (CETA)

Posted: Monday October 23rd, 2017

Author: Bhavesh Patel, C. Chem. Natco Pharma (Canada) Inc.

Health Canada recently published the Notice - Patented Medicines Notice of Compliance Regulations as an update for the public regarding the recently implemented amendments to the Patented Medicines (Notice of Compliance) Regulations which came into effect on September 21, 2017 as part of Canada’s obligations under the Comprehensive Economic Trade Agreement with the European Union. 

The Notice advises the public that Heath Canada is in the process of updating the Guidance Document: Patented Medicines (Notice of Compliance) Regulations (“PM(NOC) Regulations”) and also provides guidance for industry on how to provide various information to Health Canada concerning procedures under the Regulations. 

How to provide litigation information

As the Minister of Health is no longer a party to proceedings under the amended Regulations, they will no longer be served with litigation documents. However, the Office of Patented Medicines and Liaison (“OPML”) must have access to relevant information to determine whether there are any barriers under the Regulations that would prohibit the issuance of a Notice of Compliance (“NOC”) for the second person’s submission. As such, the amended Regulations requires the first person to provide the TPD with certain documents as soon as feasible in the course of a proceeding. The TPD may also request any information or document required to assess whether NOC issuance is prohibited under section 7 of the Regulations. If an action is brought, requests for verification of any portion of a submission served with a Notice of Allegation or produced in the litigation can be made under section 6.05 of the Regulations.

All information related to litigation, including requests for verifications, must be submitted to the TPD electronically by email to: opml_bmbl@hc-sc.gc.ca. No duplicate copy should be sent in paper format. Information may be sent in other formats in certain circumstances, for more information please consult the Notice. 

How to provide other information 

Currently, non-litigation information related to the Regulations should be submitted in either the electronic Common Technical Document (“eCTD”) format or the non-eCTD electronic-only format. In accordance with Health Canada’s Frequently Asked Questions - Regulatory Activities in eCTD Format, regulatory transactions accepted in the eCTD format include:

·         Written correspondence related to the Regulations;

·         Notice of Allegation packages (e.g. including proof of service of the Notice of Allegation on the first person and certification of the date of filing of the submission) under the Regulations);

·         Form IVs, including updates, filed in accordance with the Regulations;

·         Form Vs, including updates, filed in accordance with the Regulations; and

·         Consent letters (under the Regulations).

·         For eCTD submissions, the regulatory transactions listed above should be submitted via the Common Electronic Submissions Gateway, as indicated in the Frequently Asked Questions - Common Electronic Submissions Gateway. For non-eCTD submissions, the above-noted information should be sent on an acceptable media format as indicated in the Guidance Document: Preparation of Drug Regulatory Activities in the 'Non-eCTD Electronic-Only' Format.

Form V update

Second persons are advised that Form V : Declaration re Patent List has been amended and that the amended version of the document must be filed beginning September 21, 2017. There is no need to re-submit a Form V that was filed before September 21, 2017.


Under section 6.05 of the Regulations, the Minister must verify, upon request of a party, that any portion of a submission or supplement required to be served with a Notice of Allegation, or that is produced as a result of an order, corresponds to the information in the submission or supplement.

The documents to be verified are now to be provided directly to the TPD. To facilitate the verification process, parties are encouraged to continue to provide good quality copies of documents that are indexed with respect to their location within the original submission or supplement. This format is similar to that requested for verifications under the former version of the Regulations.

If the productions are not formatted in a format acceptable to the TPD, they may be rejected for verification. To this effect, productions should be formatted as set out in the example in the Notice.

As of September 21, 2017, the TPD will no longer maintain a paper version of the Patent Register. The Patent Register continues to be available electronically for public inspection.

Addition of Certificates of Supplementary Protection to the Patent Register

All Certificates of Supplementary Protection will be assessed by the TPD for their eligibility for the Patent Register without requiring a separate form or request from the first person. It is possible that a Certificate of Supplementary Protection will be added to the Patent Register before publication on the Register of Certificates of Supplementary Protection and Applications.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.

FDA Regulatory Reform

Posted: Monday October 16th, 2017

Author: Pinky Mazumder

On September 8th, 2017, the Food and Drug Administration signaled the start of a major regulatory overhaul by publishing a docket in the Federal Register (the “Docket”) requesting input from interested parties regarding unnecessary regulatory burdens (1). This move by the FDA is part of the Trump Administration’s well-publicized promise to cut regulations as enshrined in two Executive Orders published earlier this year.    

The Docket requests submissions from any interested person, including those subject to the agency’s regulations (i.e., pharmaceutical, medical device manufacturers), as well as academia, researchers, consumers, healthcare institutions, and patients. The Docket requests submissions regarding regulations which are no longer appropriate or have been superseded. As well, the agency invites comments regarding regulations that are difficult to comply with and pose an unnecessary regulatory burden. Submissions may be provided electronically or in hard-copy and should be submitted on or before December 7th, 2017 (1).

In addition to the revision of existing regulations and requirements, the FDA is also considering new regulations and policies to better fulfill its mission in public health (2). With advancing technologies, the agency wishes to establish regulations that are also appropriate for modern products (2). With this the FDA is reforming their regulatory framework to reduce regulatory burden to better serve public health.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.


1. https://www.federalregister.gov/documents/2017/09/08/2017-19047/review-of-existing-general-regulatory-and-information-collection-requirements-of-the-food-and-drug

2. https://blogs.fda.gov/fdavoice/index.php/2017/09/fdas-plan-to-engage-the-public-in-the-agencys-new-effort-to-strengthen-and-modernize-fdas-regulatory-framework/

Ontario to Require Public Disclosure of Industry Payments to Health Care Professionals

Posted: Tuesday October 10th, 2017

Author: Mark Vanderveken

On September 27, 2017, the Government of Ontario tabled a bill to enact the Health Sector Payment Transparency Act, 2017, (the “Act”) which will implement reporting of transfers of value from the pharmaceutical and medical device industries to prescribed recipients. This new legislation is intended to increase the transparency of financial relationships within Ontario’s health care system to improve patients’ ability to make informed health care decisions and provide information for health system evaluation, planning, and policy analysis.

1. Who is subject to the reporting requirement?

The reporting requirement applies broadly to persons and organizations that sell or promote medical products (including drugs and medical devices, but excluding natural health products):

· Manufacturers (and persons who perform manufacturing services on behalf of manufacturers) that sell medical products;

· Wholesalers, distributors, importers, and brokers that promote or facilitate the sale of medical products;

· Marketing firms or persons who perform activities for the purpose of promoting medical products; and

· Persons who organize continuing education events for members of a health profession on behalf of a manufacturer that sells medical products.

2. When is the reporting requirement triggered?

The reporting requirement is triggered when one of the aforementioned persons or organizations provides a transfer of value, directly or indirectly, to prescribed recipients to be specified in future regulations. We expect that all regulated health professions will be prescribed recipients under the Act, as will hospitals and other health care organizations.

3. What types of transfers of value must be reported?

A transfer of value is broadly defined in the Act to include payments, benefits, gifts, advantages, and perquisites. A person or organization providing such a transfer of value is called a “payor” under the Act. A payor is not required to report a transfer of value below a prescribed threshold dollar value to be specified in future regulations. The manner and frequency of reports to the Minister will also be prescribed by future regulations.  It is expected that the types of transfers to be reported will be wide ranging, and include consulting fees, research grants, fees for speeches or participation on advisory boards, reimbursement for attendance at conferences, dinners and other forms of business entertainment.

4. What information must be reported?

A payor must report the following information to the Minister of Health and Long-Term Care:

· The names of the parties to the transaction (whether a party is a business or an individual);

· The parties’ business addresses;

· The date of the transfer of value;

· The dollar value of the transfer of value (or the approximate dollar value in the case of a non-monetary transfer of value); and

· A description of the transfer of value, including the reasons for it.

In addition, the Act empowers the Minister to request that transaction intermediaries and their affiliates, as well as payors’ affiliates, report the aforementioned information and the source of the transfer of value.

The Minister is required to comply with the notice provisions of the Freedom of Information and Protection of Privacy Act in respect of personal information indirectly collected in reports under the Act.

Records created or received in respect of the transfer of value must be retained by both payors and recipients for the prescribed length of time to be specified in future regulations.

5. Where will the reported information be disclosed?

The Minister will disclose the reported information on a website at least once per year. We expect that the website will feature a publicly searchable database of the reported information.

6. How will the Act be enforced?

The Act empowers the Minister to appoint inspectors who may, without a warrant, enter premises to examine and make copies of records relating to transfers of value that are subject to the reporting requirement. Inspectors may also question any person and audit the accounts of the parties to a transfer of value, intermediaries, and their respective affiliates. Parties subject to inspection must cooperate and provide reasonable assistance to an inspector.

An inspector can apply to a provincial judge or justice of the peace for an order compelling a person not being investigated to produce data or documents if there are grounds to believe that such materials will provide evidence respecting an offence under the Act.

The Minister or an inspector may serve a compliance order on a person who is believed to have failed to comply with the Act and regulations (however, a person may be prosecuted under the Act whether or not a compliance order has been served). A person in receipt of a compliance order may provide submissions to the Minister within 14 days showing how the person has complied. On notice to the person, the Minister may also apply to the Superior Court of Justice for a court order directing the person to comply.

The Minister will publish the names of persons to whom compliance and court orders are directed (unless the 14 day submissions period in respect of a compliance order has not yet expired, or the Minister has rescinded the compliance order) as well as a description of the non-compliance on a website.

7. What are the penalties for non-compliance?

The Act imposes monetary penalties for non-compliance that are determined based on the nature of the person in non-compliance and the number of prior offences. The Act sets out fines, up to a specified maximum, for each day or part of a day on which the offence occurs or continues, as shown below:

8. Are there any defences to a charge of non-compliance?

The Act makes available due diligence and reasonable mistake of fact defences only in respect of a charge that a payor, intermediary, or affiliate has reported false or misleading information to the Minister.

If passed by the legislature, the Act will impose significant new reporting obligations on organizations in the pharmaceutical and medical device industries. Public scrutiny of the financial relationships between industry and health care professionals will likely increase, opening the door to the politicization and further regulation of such relationships. Industry players and health care professionals alike should be prepared to account for and justify established practices that may be characterized as transfers of value under the new reporting regime. Organizations that will be classified as payors under the Act would be well advised to assess their current practices and implement policies and establish reporting infrastructure to ensure compliance with the Act once enacted, which we expect will occur in 2019.


First Nations Health Authority (FNHA) Transition to BC Pharmacare

Posted: Monday October 2nd, 2017

Author: Bhavesh Patel, C. Chem., Natco Pharma (Canada) Inc.

Beginning October 1, 2017, the FNHA will partner with BC PharmaCare to administer the FNHA PharmCare plan - a fully paid drug benefits plan for FNHA clients. Currently, drug coverage for FNHA clients is administered through Health Canada’s Non-Insured Health Benefits (“NIHB”) program. The goal of the transition, which will see the benefits plan administered at a local level, is to promote a health care system that is more responsive to the needs of the needs of the First Nations community.

Under the new FNHA PharmaCare plan, to be known as “Plan W”, eligible FNHA clients will receive full drug coverage to be paid by BC PharmaCare as the first-payer. Most FNHA clients who currently receive benefits through Health Canada’s NIHB program will be eligible for coverage of prescribed medications and services under Plan W.

Other benefits of this transition include: 

•         an increased ease of access to benefits and services;

•         a streamlined approvals process that reduces the number of steps needed for the approval of prescription coverage;

•         reduced confusion for clients who often have to navigate both federal and provincial drug coverage plans; and,

•         better outcomes for FNHA clients through a closer working partnership with PharmaCare, pharmacists, and physicians/nurse practitioners.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.

For more information please visit the FNHA website.

New Health Canada Consultation on Low-Dose Codeine Products

Posted: Monday September 25th, 2017

Author: Pinky Mazumder

On September 9th 2017, Health Canada released a notice in Canada Gazette Part I concerning the non-prescription availability of low-dose codeine products (1). Codeine is an opioid drug that is indicated for mild to moderate pain as well as cough. Like other opioids, codeine can cause psychoactive side effects and result in dependence and addiction. As a result, many codeine-containing products require a prescription. However, in a situation somewhat unique to Canada, some lower-dose codeine products have been traditionally available to patients without a prescription.

One of the issues with non-prescription low-dose codeine products is the possibility of overuse, leading to an increased risk of dependence and addiction. In fact, codeine was found to be one of the most common substances used by patients entering substance abuse treatment. Outside of Canada, countries such as France, Greece, India, and Italy mandate that all codeine containing products be available by prescription only. In early 2018, Australia will follow the trend and apply restrictions on low-dose codeine products. As many of these products also contain acetaminophen, overuse poses the risk of acetaminophen-related problems such as liver toxicity.

Health Canada proposes to amend the Narcotic Control Regulations to require all codeine products to be available by prescription only (1). It is thought that by requiring the intervention of a physician, patient outcomes will be enhanced by determining whether codeine is an appropriate treatment option in the first place, and if so, by ensuring that the patient’s treatment is adequately monitored.

The proposed amendments to the Regulations are available for consultation from September 9, 2017 to November 8, 2017. Canadians, healthcare practitioners, and those in the pharmaceutical industry have been invited to participate and provide their comments. For complete and detailed information, please refer to the sources provided in the reference section below.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.


1.       Health Canada Consultation https://www.canada.ca/en/health-canada/programs/consultation-non-prescription-low-dose-codeine.html

2.       Canada Gazette Part I http://www.gazette.gc.ca/rp-pr/p1/2017/2017-09-09/html/notice-avis-eng.php#ne3

Health Canada’s Proposed Modification for Multiphasic Modified Release Drugs

Posted: Monday September 18th, 2017

Author: Pinky

The guidance on Comparative Bioavailability Standards: Formulations Used for Systemic Effects provides sponsors with standards and parameters to consider for pharmacodynamics studies and comparative bioavailability studies against the reference product. It applies to comparative bioavailability studies for subsequent entry products, studies for line extensions or post-approval changes, bridging studies, and studies to support a Drug Identification Number Application (DINA), among others. Information from this guidance can be applied to various formulations such as oral dosage forms and non-injectable forms such as inhalers and transdermal patches for delivery into systemic circulation. However, the guidance does not include specific requirements for comparative studies of drug products with multiphasic plasma concentration vs. time profiles. It was acknowledged that the general standard for modified-release products may not be enough for such products. As a result, on July 27th 2017, Health Canada issued the Notice on Proposed Modification to Bioequivalence Standards for Multiphasic Modified-Release Drug Products. 

From the notice we learn that Health Canada proposes additional information to the guidance on Comparative Bioavailability Standards: Formulations Used for Systemic Effects to better serve drug products with multiphasic plasma concentration verses time profiles. Section of the guidance on Modified-release dosage forms will be amended to include the following information for multiphasic plasma concentration profiles:

·         “Modified-release products with multiphasic plasma concentration profiles demonstrated to be integral to their therapeutic effect will be subject to standards on the partial area under the concentration versus time curve (pAUC), defined over a restricted time interval(s) after drug administration. These standards will be applied in addition to those normally applied in the assessment of bioequivalence (i.e. AUC and Cmax).

·         The requirement for pAUC assessment metrics for multiphasic modified-release formulations will be based on data available from various sources, including but not limited to peer-reviewed scientific literature and the approved Canadian labelling, as applicable. The time course of changes in the rate of drug delivery throughout the day should be reconciled with generally accepted and clinically relevant response data generated from a well-designed randomized clinical trial program. Specifically, standards based on the 90% confidence interval of pAUC metrics should be met. The specific pAUC time intervals to be considered will be based on clinical data showing the therapeutic relevance of the particular time interval (e.g. early onset, maintenance, dose clearance, fasted versus fed state). Selected time intervals should be justified, specified a priori and applied to all study subjects for both the test and reference products.”

Source: Health Canada’s Notice on Proposed Modification to Bioequivalence Standards for Multiphasic Modified-Release Drug Products

The notice informs the industry that this modification to the guidance is up for comments which are to be sent to the Therapeutic Products Directorate in Health Canada. The comment period will last for 60 days (Notice was issued on July 27th 2017). Detailed information is provided in the Notice listed in the reference section below.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media. 


Notice: Proposed Modification to Bioequivalence Standards for Multiphasic Modified-Release Drug Products


Guidance Document - Comparative Bioavailability Standards: Formulations Used for Systemic Effects 


Health Canada-Use of Certificates of Suitability as supporting information in Drug Submissions

Posted: Monday September 11th, 2017

Author: Pinky Mazumder

What are CEPs

Certificates of Suitability (CEPs), issued by the European Directorate of Quality of Medicines and Healthcare (EDQM), are used to support the safety and efficacy of drugs. In the Health Canada guidance on Use of Certificates of Suitability as Supporting Information in Drug Submissions, CEPs can be submitted by applicants/sponsors in place of complete manufacturing information or the restricted portion of a Type 1 Active Substance Master File (ASMF)1. However if the CEP is not considered supportive, Health Canada can request complete Active Pharmaceutical Ingredient (API) manufacturing information, and can also access the assessment reports from the EDQM if necessary. It is important to note that CEPs are not evidence of Good Manufacturing Practice (GMP) compliance for APIs. 

When does it apply

The Health Canada guidance on Use of Certificates of Suitability as Supporting Information in Drug Submissions applies to APIs in New Drug Submissions (NDS) and its supplement, Abbreviated New Drug Submissions (ANDS) and its supplement, Clinical Trial Applications (CTA), and Veterinary Drug submissions. 

What to submit

For Health Canada, CEPs and required attestations from the manufacturer are filed in Section 1.2.3 of Module 1 Administrative and Product Information. Written attestations from the manufacturer refer Health Canada to the CEP and assessment report, and attest to providing the entire EDQM dossier upon Health Canada’s request. The manufacturer is also required to provide attestations regarding the manufacture and testing of the API. Such attestations among others, include the assurance of no significant changes in the manufacturing method and controls after issuance of the CEP.

Moreover, a drug submission using a valid CEP for supporting information requires the submission of a fully completed Module 2.3 Quality Overall Summary of Module 2, however not all the sections in Module 3 Quality are required to be submitted. The Health Canada guidance document highlights specific Quality sections that are required for such a submission. Such sections include Section 3.2.S.2.2(a) where a chemical flow diagram is to be submitted, however detailed sections in Section 3.2.S.2.2 – 3.2.S.2.6 is not required. Similarly, documentation from 3.2.S.6 Container Closure System also does not need to be submitted, as long as re-test period and packaging is mentioned in the CEP. From Section 3.2.S.4 Control of Drug Substance, analytical methods and their validations reports from the manufacturer are to be submitted if they differ from the methods authorized by the EDQM. In addition for new applications, Batch Analyses for two batches should be submitted in 3.2.S.4 as well. For complete information on the eCTD section requirements when using CEPs as supporting information, please see the Health Canada guidance on Use of Certificates of Suitability as Supporting Information in Drug Submissions provided in the reference section below.

Alternatively, CEPs may also be provided as partial support for a drug submission and expedite the process. The guidance highlights specific cases where they can serve as partial support.

Thank you for reading Regulated Affairs, the CAPRA blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.


Use of Certificates of Suitability as supporting information in Drug Submissions https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/chemical-entity-products-quality/use-certificates-suitability-supporting-information-drug-submissions_08_24-eng.pdf

Changes to the Manufacturer's name and/or Product Name

Posted: Tuesday September 5th, 2017

Author: Pinky Mazumder 

The Policy on Changes in Manufacturer’s name and/or Product Name (CMPN) applies to drug submissions to Health Canada where the manufacturer's and/or product’s name is being changed due to a merger, corporate restructuring, licensing agreement, or a buy-out. According to this Health Canada Policy, a licensing agreement is defined as “an agreement between two firms whereby one firm supplies a drug product to another firm for sale under the second firm’s name”.

According to the CMPN Policy, a Drug Identification Number (DIN) Submission must be filed to Health Canada when the name of the manufacturer and/or product changes. However, a New Drug Submission (NDS) would be submitted for new drug products instead. Moreover, with a change in the product name the sponsor has to ensure that the proposed name change does not conflict with the conditions of the issued DIN, or in the case of a new drug, the issued Notice of Compliance (NOC). 

The change in the name of the manufacturer and/or product also requires all other aspects of the product to be identical to that of the approved submission, with the exception of the manufacturer's name and/or product name being filed. According to the Policy, to apply for this change manufacturers are required to submit a Certification Form to certify that the other aspects of the approved product and its labels remain unchanged. It would be understood that the product name may change in the labels and product monograph if the product name is being changed for that submission. Moreover, with the recent update of the Regulations Amending the Food and Drugs Regulations on June 13th, 2017 for Non-Prescription drug products, the CMPN policy has updated as well. For human use prescription drug products that undergo a change in the name of the manufacturer and/or product, additional certification is required to certify that the new labels are similar in size and placement of the graphics, logos, and text to that of the approved labels. Mock-ups of the new labels and packaging are required for filing this change. In addition, if the name change is due to a merger, buy-out, or a licensing agreement, there are additional requirements for filing this change. Complete and detailed information is provided in the Policy document. 

The submission of the change to the Manufacturer's and/or products name will be reviewed as per the Guidance on Management of Drug Submissions. Manufacturers must also notify Health Canada within 30 days of beginning sale of the product and inform the agency when the products marketed under the former name are no longer being sold. For more information, please refer to the Changes in Manufacturer’s Name and/or Product Name Policy from Health Canada.

Thank you for reading Regulated Affairs, the CAPRA blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.


Policy - Changes in Manufacturer’s Name and/or Product Name


Comprehensive Economic and Trade Agreement (CETA) and Canada’s Pharmaceutical Sector

Posted: Monday August 28th, 2017

Author: Bhavesh Patel, C. Chem. Natco Pharma (Canada) Inc.

On October 30th, 2016, Prime Minister Justin Trudeau, European Commission President Jean-Claude Juncker and European Council President Donald Tusk signed the Comprehensive Economic and Trade Agreement (CETA) during the European Union-Canada Leaders’ Summit in Brussels, Belgium.

Let’s have a look at CETA from a pharmaceutical point of view.

How will CETA benefit Canadian pharmaceutical companies?

·         With CETA, Canadian service providers in the pharmaceutical sector will be on an equal footing with their EU competitors and will receive better treatment than most of their non-EU competitors.

·         CETA will provide a predictable and transparent investment climate for Canadian and EU investors in the pharmaceutical sector.

·         Canadian pharmaceutical companies will also benefit from improved labour mobility provisions, expanded access to EU government procurement opportunities, and mutual recognition of compliance certification processes for pharmaceutical good manufacturing practices.

Mutual recognition of pharmaceutical Good Manufacturing Practices

·         CETA will provide a mechanism for Canada and the EU to mutually accept the results of each other’s inspections of pharmaceutical manufacturers.

·         Continued coverage under the Protocol for pharmaceutical good manufacturing practices, may reduce the number of duplicate inspection and certification requirements for Canadian pharmaceutical manufacturers.

Government procurement

·         Under CETA, Canada will gain new access at the sub-central level (regions and municipalities) to procurement by local contracting authorities and bodies governed by public law (e.g. hospitals, schools, universities).

·         CETA’s government procurement provisions cover the procurement of pharmaceutical products as well as a broad range of services that may be of interest to the pharmaceutical sector, including technical testing and analysis services.

·         CETA has been effective since July 1st, 2017. Canadian exporters of pharmaceutical products are enjoying the advantages of the agreement, when compared to their competitors in countries without a preferential trade agreement in force with the EU.


Pharmaceutical Intellectual Property (IP) and CETA. 

CETA will only affect intellectual property rights in Canada and not the EU.

CETA requires changes to the Canadian rules governing intellectual property (IP), particularly with respect to pharmaceuticals. There are two changes specifically that are consequential:

(1) patent restoration, and

(2) patent appeal

The first is concerning the period of market exclusivity granted to new drugs. Whereas the second concerns the process for allowing generic drugs to enter the market.


The changes would prolong the period of protection granted to a patent holder and this would be manifested in two ways. One is through higher prices to consumers. The other is on an external balance when royalties and dividends go to parent companies outside of Canada. This section will primarily focus on the latter of these two effects. However, the first can have important redistributive effects within Canada, and even lead to a slightly lower use than that if the price had fallen.

Canada has a well-developed capability in generic drug manufacturing. Indeed, CETA excluded exports of generics from the two years of patent restoration. Those firms compete with brand-name manufacturers, who is required to patent all the drugs that will be sold in Canada. However, even when the patent is in Canada, there are royalty payments from the Canadian company for the use of intellectual property.

Canada’s Patent Act gives 20 years of protection from the date of filing. This is similar to most of the other countries due to standardization by international agreements. However the protection afforded to intellectual property can vary significantly across countries (Park, 2008). In 2005, Canada was tied for the second-strongest intellectual property protection in a list of 122 countries (behind only the United States).

The justification for CETA to make changes to intellectual property, originates from the process of bringing a drug to the market. On the one hand, filing a patent to protect IP gives 20 years of coverage from the date that the patent is filed. On the other hand, a regulatory process must be engaged to obtain approval for trials and subsequent marketing. This can be lengthy as it requires studies to prove the drug’s efficacy and safety. Since the 20-year patent period begins to count down from the date the patent is filed, the delay in getting it to market means that market exclusivity is shorter than the patent life (by roughly 10 to 15 years). After that, the drug will sell at a price closer to its production cost since generic drugs will be able to enter the market. While 5 to 10 years is still a considerable length of time for a drug that is particularly popular, other countries tend to have longer exclusivity periods by using what is termed “patent restoration”. That is, companies can argue that the approval process was long and burdensome and a longer period is required for them to recover development costs. In the EU, United States, and Japan this period is for up to 5 years. As a result, CETA will now allow for what is called a “sui generis protection” that can provide up to 2 additional years of patent protection. The aim of patent term restoration is to compensate companies for the time lost between when the patent application is filed and when the drug is eventually approved.

In Canada, the data protection is up to 8 years of market exclusivity with an additional 6 months for companies have studied the drug in pediatric populations. Generic companies are not allowed to make use of the brand-name companies’ data in their ANDSs. During the CETA consultation, Canada has rejected the extension of data protection from 8 years to 10 years.


Another key provision includes an innovator right to appeal under the Patented Medicines (Notice of Compliance) Regulations (“PMNOC Regulations”) and a potential end to “dual litigation” in Canada under both the PMNOC Regulations and the Patent Act.

The final CETA provision regarding IPR that will put pressure on drug costs by delaying the appearance of generics is the right of appeal. A Notice of Compliance (NOC) is the term Health Canada uses when it certifies that a drug manufacturer has met their regulatory requirements for the safety, efficacy and quality of a product. In 1993, the federal government introduced the NOC linkage regulations as part of the legislation that abolished compulsory licensing to import generic drugs into Canada. Under the linkage regulations, Health Canada is prevented from issuing an authorization for market entry for a generic until the generic company can show that all of the relevant patents on the brand name product have expired. As a result, when the generic company submits its application to get a product approved, it also sends a Notice of Allegation (NOA) to the patent holder claiming that no patents are being infringed. The patent holder then has 45 days to initiate an application to the Federal Court of Canada seeking an order to prohibit Health Canada from issuing a NOC to the generic manufacturer for a period of up to 24 (originally 30) months. At that point, the matter usually proceeds to a court hearing. The stay expires either at the end of the 24 months, when the disputed patent expires or when the court case is decided, whichever comes first.

The argument put forward by the brand-name industry has been that if the generic company wins the court case and is allowed to market its product, then once a NOC has been issued any appeal filed by the patentee becomes moot. The patentee is thus left with no alternative but to start another proceeding (an action for patent infringement) once the generic has entered the market. CETA will now allow brand-name companies the right to appeal decisions made under the NOC linkage regulations. However, the generic companies have received written assurances from the Government of Canada that its implementation of the “Right of Appeal” treaty commitment will also address excessive and duplicate litigation by ending the practice of dual litigation. Dual litigation means that even if brand-name companies lose under the NOC linkage regulations, they can launch a separate case under Canada’s general patent law. It is this ability to launch a second court case that the federal government has pledged to end. Although this will work to the advantage of the generic companies there will still potentially be an additional delay to the marketing of generic drugs.

Since the EU does not use patent linkage and CETA does not require it to do so, this Right of Appeal provision applies only to Canada. Patent linkage systems automatically deliver the equivalent of an injunction without prior analysis of evidences that a patent is being infringed. In fact, the European Commission prohibits EU member countries from introducing patent linkage provisions because they delay the entry of generics. Italy was reprimanded in 2012 for trying to introduce such a system and was asked to eliminate it. It is thus ironic that under CETA, rather than Canada eliminating its patent linkage system, it will be forced to strengthen it by providing a right of appeal that will create further delays for the entry of generics. In practice, this means that under CETA there could be a further delay of 6-18 months before generics appear, as the appeal makes its way through the court system. 

Overall, it may be concluded is that the provisions in CETA regarding drug prices and the pharmaceutical industry, will lead to increased costs for Canadians and for governments without any compensating benefits.


Government of Canada (http://www.international.gc.ca/trade-commerce)

Office of the Parliamentary Budget Officer. Government of Canada

Statistics Canada, Government of Canada

1 CETA and Pharmaceuticals: impact of the trade agreement between Europe and Canada on the costs of prescription drugs, House of Commons, Government of Canada.

Changes to the Annual Drug Notification Form (ADNF)

Posted: Monday August 21st, 2017

Author: Bhavesh Patel, C. Chem. Natco Pharma (Canada) Inc.

Editor: Madhur Jadawala, B.Sc. Pharm. Quality & Compliance Services Inc.

On March 14, 2017, Health Canada published a notice outlining upcoming changes to the Annual Drug Notification Form.

The intent of Annual Drug Notification Form (ADNF) is to help manufacturers in complying with section C.01.014.5 of the Food and Drug Regulations that mandates every manufacturer of a drug to confirm annually (before October) that all information previously provided related to that drug is correct.

The upcoming changes are, in part, due to the Regulations Amending the Food and Drug Regulations (Shortages of Drugs and Discontinuation of Sale of Drugs) which were published in the Canada Gazette, Part II on June 29, 2016 and have been enforced as of March 14, 2017. Other changes have also been made to the ADNF in an effort to streamline the process. Health Canada believes implementation of these changes will increase the accuracy of the information presented in the Drug Product Database Online Query (DPD).

Here is the list of significant changes pertaining to the information included in the ADNF:

1. Drug products which have been assigned a Drug Identification Number (DIN), but have not been marketed (Approved Products), will now be included as a separate list in the ADNF, in an effort to encourage manufacturers to cancel the DINs they do not intend to market in Canada. This will allow the Department to ensure that the drug information provided on the Department's website is accurate and up to date. It will also be beneficial for manufacturers as they will have a complete list of all their DINs in one report on an annual basis. With the implementation of this change, the biennial DIN Assigned Project, which had manufacturers clarify the status of their "Approved Products" in a separate report, will be eliminated.

2. In accordance with section C.01.014.7 of the Food and Drug Regulations, for drug products that were marketed but now are noted as being discontinued on the ADNF, manufacturers will be required to provide the discontinuation date, the lot number and the expiry date of the last lot sold by the manufacturer. This information will be recorded on a separate form that will be provided with the Annual Drug Notification Form.

3. Drug products which are marketed but have not had sales for 12 consecutive months (Dormant Products) will be included as a separate list in the ADNF. Additionally, in accordance with section C.01.014.12 (1) of the Food and Drug Regulations, there will be an option for manufacturers to note if a marketed product has become a dormant product1.

These changes have been incorporated in the ADNF sent to manufacturers in June of 2017.


1. The requirement to report the Dormant Products as per section C.01.014.12 (1) of the Regulations only applies to the following drugs for human use:

a. drugs included in Schedules I, II, III, IV or V to the Controlled Drugs and Substances Act

b. prescription drugs;

c. drugs listed in Schedules D and C to the Act

d. drugs that may be sold without a prescription, but are administered only under a practitioner's supervision




Planning to File Your 505(b)(2) Product in Canada?

Posted: Tuesday August 15th, 2017

Author: Dr. Jan Sedgeworth Vice President, Regulatory Affairs at Intrinsik Corp.

Canada may not be top of the list of countries that companies target for first registration of their product (although it may be for orphan drugs – however, that’s a subject for another day!), but it’s usually in the next tier after USA and Europe, since typically Canada represents about 10% of the market size of the USA. In the last decade, there has been a surge of interest in the 505(b)(2) regulatory pathway in the US – this allows for registration of a new formulation/route of administration/indication for a known chemical entity based on an abbreviated development program, and in many cases offers at least some degree of market exclusivity. But since there is no equivalent 505(b)(2) pathway in Canada, how can that 505(b)(2) NDA form the basis of a marketing application submission in Canada? It’s a question we are frequently asked, and based on our experience there are a number of key points to consider, some of which are described below.

Reference Product – if the 505(b)(2) NDA relies primarily on bioequivalence (BE) to a US Reference Listed Drug (RLD) to establish safety and efficacy, then this can be a stumbling block for registration of the new product in Canada, which has its own requirements for a reference product – the Canadian Reference Product, or CRP. If it can be established that the RLD and CRP are identical, BE data generated using the RLD can be used to bridge to the CRP. However, establishing that the CRP and RLD are identical can be difficult without the co-operation of the manufacturer of the RLD and CRP. There are other ways to address this issue, for example through comparative physicochemical testing of the RLD and CRP, but this must be done using samples of the RLD lot that was used in the BE study and the CRP that is currently marketed in Canada. Sounds simple, but not if the BE study was conducted long before the sponsor decides to pursue registration in Canada, and the retained samples of RLD have since expired!

NDS vs ANDS – In Canada, there is no equivalent to the 505(b)(2) pathway, a new drug must be filed as either a New Drug Submission (NDS) or an Abbreviated New Drug Submission (ANDS, or generic submission). In some cases where the 505(b)(2) NDA relied only on BE, it has been possible to file the submission in Canada as an ANDS rather than as an NDS, but this is not a common situation, as in most cases the 505(b)(2) product is sufficiently different from the reference product that an NDS is warranted. Of note, the new product and the CRP must be considered pharmaceutically equivalent in order to qualify for filing as an ANDS. In Canada, products that are pharmaceutically equivalent contain “identical amounts of the identical medicinal ingredients, in comparable dosage forms” but not necessarily the same non-medicinal ingredients. Health Canada’s Identical Medicinal Ingredient (IMI) policy is not always straightforward and has been both challenged and revised based on recent case law, so this is also something that deserves careful consideration.

Exclusivity – in Canada, innovative new drugs are eligible for 8 years of market exclusivity (with an extra six months if there are pediatric data), however, since most 505(b)(2) submissions do not involve a New Active Substance (NAS), an NDS based on a 505(b)(2) is unlikely to garner innovative drug status. Unlike other jurisdictions, changes to a previously approved medicinal ingredient such as a new dosage form/delivery system, or a new indication will not qualify for market exclusivity, even if the changes required new clinical data as the basis for approval. Thus, a 505(b)(2) product must rely instead on patent protection for any form of data protection or exclusivity in Canada. A literature-based 505(b)(2), which would correspond to a Submission Relying on Third Party Data (SRTD) NDS in Canada would not be eligible for innovative drug status either, even if the medicinal ingredient has never been approved before in Canada. This is because Health Canada interprets the regulations granting innovative drug status as requiring an investment of time and effort (research) in exchange for market exclusivity, and using third party data to support registration does not “count” in their view.

505(b)(2) NDAs with clinical and nonclinical data – for submissions that include clinical and/or nonclinical data generated with the new product, the question becomes how much of the data generated for the reference product can be relied on, and how much new data must be generated? There can also be issues on how to “bridge” to the existing data for the reference product (specifically a Canadian Reference Product), particularly when there has been a significant change in the dosage form and route of administration (e.g., an oral drug reformulated to be administered topically). In some cases, the RLD may have never been approved or marketed in Canada and there is no CRP to which to bridge. For clinical data, the choice of active comparator, and the inclusion or exclusion of a placebo arm in the pivotal studies can be an issue when repurposing a clinical data package for the Canadian NDS, not to mention that there may be different expectations from Health Canada in terms of study outcomes, although this is less common nowadays.

Of course, the devil is in the details, so it’s very important to have an experienced pair of eyes review the data package and identify the critical issues to be addressed prior to filing an NDS for a 505(b)(2) product in Canada. Furthermore, there are other issues that apply to all NDSs, not just those based on 505(b)(2)s, such as the need to address Drug Establishment Licence requirements well in advance of NDS filing.

Summary on Recent Intellectual Property Hold for Notifiable Change Submissions

Posted: Monday August 7th, 2017

Author: Pinky Mazumder

On April 7th, 2017, Health Canada released the Intellectual Property Hold for Notifiable Change Submissions notice. This notice is geared towards subsequent entry manufacturers and sponsors as per the Patented Medicines (Notice of Compliance) Regulations and the Food and Drug Regulations.

When filing submissions for subsequent entry products, the subsequent manufacturer and/or sponsor includes the patent of the innovative product from the Patents Register. If the subsequent entry product submission is placed on an Intellectual Property (IP) Hold, any notifiable changes related to that submission will also be placed on an IP Hold upon completion of the notifiable change review. Previously, when notifiable change submissions were placed on an IP Hold, the Office of Submission and Intellectual Property (OSIP) of Health Canada, would notify sponsors with a letter indicating that their notifiable change has been placed on an IP hold.

However according to the notice, as of May 1st, 2017, OSIP is no longer sending out IP Hold letters for notifiable changes. The notice also aims to inform subsequent entry manufacturers and sponsors that while they will no longer receive IP Hold letters for notifiable change submissions, they should check the status of their submissions in the Drug Submission Tracking System - Industry Access. If the notifiable change in placed on an IP Hold, the status of the submission will state “IP Hold” to notify sponsors when the review is complete. For more information on the notice on Intellectual Property Hold for Notifiable Change Submissions, please refer to: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/announce-annonce/ip-nc-hold-notice-avis-pm-pi-suspens-eng.php. For more information on subsequent entry manufacturers, please refer to the Patented Medicines (Notice of Compliance) Regulations from Health Canada.

Thank you for reading Regulated Affairs, the CAPRA blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.





An Update on the Regulatory Progress of Biosimilars in Canada, the EU and the U.S.

Posted: Monday July 31st, 2017

Author: Oxana Iliach, PhD[1] , Raymond Huml MS, DVM, RAC1

In the last 10 years, biosimilar regulatory guidelines have evolved significantly in Canada, the European Union (EU) and the United States of America (U.S.). Anchored on the patent expiration date, there is a wave of biosimilars development in Western countries as well as other countries – all demanding cheaper versions of biologic medicines for their citizens.  Notable examples include India and China in the Asia Pacific region. Since the first biosimilar was approved in Europe in 2006, sponsors of biosimilars have accumulated varied expertise with regards to the development of biosimilars: biologic versions of expensive medicines that are similar in terms of quality, safety and efficacy to an already licensed reference product.  Doctors and patients are increasingly being educated about biosimilars and about the potential for substantial cost savings. Health Authorities in multiple jurisdictions have established regulatory requirements to ensure that biosimilars are safe, efficient and of high quality.  Despite progress over the last decade, the uptake of biosimilars is still slower than patient demand.  The reasons for this is complex and involves strategies by the innovators to protect their lucrative franchises, the complexity of successfully manufacturing a copy of a biologic product, the net present value analysis of a sponsor’s product in relationship to the pipeline, the capital required to run the clinical studies required for registration and an ever-evolving regulatory affairs landscape.  This paper will focus on the regulatory requirements that have resulted in the current biosimilars landscape and discuss how this pipeline was impacted by regulatory requirements in Canada, EU and the U.S.

Current Biosimilar Landscape and Biosimilars Development
As of December 2016, there were six biosimilar approvals in Canada, twenty-three biosimilars approved in the EU, and four approved in U.S., though only one of these products was launched (Zarxio™).  These numbers are disappointing considering a timespan of drug development surpassing a decade. As a comparison, consider that since 1999, the FDA approved 1,002 generic drugs[i]. This translates into roughly 589 approvals in 10 years.  We know that biosimilars are more complex – and require much bigger analytical and clinical comparative studies when compared with small molecule generic drugs, but many patients and doctors would still like to see faster access to these alternative and affordable treatments.

Looking at the history of biosimilars approvals, it was anticipated that the first cohort of biosimilars were the simplest biological drugs, such as somatropin, epoetin and filgrastim. Following by the development and approval of more complex biosimilars, like monoclonal antibodies, such as infliximab, etanercept and adalimumab, see Table 1 below with the summaries of biosimilars approval in Canada. EU and USA.  Due to the significant advances in biotechnological manufacturing processes – some techniques are even more accurate or sensitive than the analytic methodology used for approval of the originator, the complexity of biologic manufacturing is becoming less of a hurdle to registration. Companies like Sandoz, Amgen and Celltrion all now have extensive expertise and proven that they can successfully overcome the manufacturing challenges of biosimilars development as demonstrated by their latest approvals, including of biosimilars of etanercept, adalimumab and infliximab. There are also several other companies that have successfully manufactured biosimilars such as Coherus Biosciences and Zydus Cadila, to mentioned a few[ii]

Table 1: Summary of approved biosimilars


Current Uncertainties in Regulatory Requirements
There has been significant progress in defining the regulatory framework over the last 10 years.  Canada and Europe led the way, with the U.S. still trying to catch up. The EU was the first jurisdiction that introduced an abbreviated licensure pathway for biosimilars under Article 6 Regulation (EC) 726/2004 and Article 10(4) of Directive 2001/83/EC which led the first biosimilar approval in 2006. It was followed by the U.S., where section 351(k) of the Public Health Service Act (PHS) Act as amended by “Biological Price Competition and Innovation Act of 2009” (BPCIA) established an abbreviated pathway for biosimilars, but their first biosimilar approval did not occur until March 2015[i] with the launch delayed until September 2015[ii]. In Canada, interesting to note and contrary to both the EU and the U.S., biosimilars and new drugs are approved under the same Food and Drugs Act and Food and Drug Regulations Part C, Divisions 1, 1A, 2, 4, 5 and 8.

All three agencies: Health Canada, EMA, and FDA issued guidance documents to help biosimilar sponsors meet statutory requirements. Interestingly, the number of guidance documents issued by any Health Authority is not always proportional to the number of approved biosimilars in the country; however, all sponsors of biosimilars agree that there is less regulatory risk in countries that provide more detailed regulatory guidance when compared with countries that have not issued detailed regulatory guidance. A summary of regulatory guidances is presented in Table 2.

Those regions, like the EU, that have promulgated detailed guidance will encourage sponsors to seek marketing authorisation in their jurisdiction.  Other critical considerations for the selection of region choice include market size, competition, patent expiration, access to the originator product, and reimbursement strategies, to mention a few.

Table 2: Biosimilars Guidance Documents


Even though regulatory expectations for biosimilar development have been increasingly clarified, there are still significant areas of uncertainty when it comes to meeting regulatory expectations which include:

-          Requirements for selection of Reference Product

-          Acceptance of switching or interchangeability of biosimilar and reference product

-          Requirements for post-approval changes in biosimilars

Health Canada is the only agency that accepts use of a reference product from another jurisdiction for the full biosimilar program development, including analytical similarity, non-clinical and clinical studies, as long as sponsor sources the reference product from a jurisdiction that formally adopts ICH guidelines and demonstrates that the reference product is comparable with the Canadian-approved reference biologic. Both EMA and FDA have demonstrated flexibility in their acceptance of clinical data that are generated with a reference product approved in other ICH jurisdictions, but they still expect the comprehensive analytical similarity evaluation to be performed with the reference product that was approved and is licensed in the EU and US, respectively. To fulfill this requirement, sponsors spend a significant amount of time and capital to procure multiple lots of reference products from different jurisdictions, following by side-by-side comparative testing of multiple reference products and biosimilars. It is unclear if this multiple comparative testing of EU and US-sourced reference products is resulting in a scientific evidence of similarity or if this exercise is promulgated to fulfill statutory requirements.  Hopefully, there will be sufficient evidence in the future to convince EMA and FDA to re-evaluate their position and to allow sponsors to simplify the reference product sourcing part of their biosimilar development program.

Despite multiple independent studies that demonstrate that switching, including multiple switching, between biosimilar and reference product is safe and has no adverse effects, interchangeability remains unclear when it comes to the substitution and marketing of biosimilars.[i]

EMA doesn’t provide recommendations on interchangeability, leaving this decision to the Health Authorities of individual member states. This approach resulted in a wide spectrum of interchangeability approaches: from full substitution such as in Finland[ii] to not allowing substitution such as Spain[iii], [iv], with all possible approaches in between. Some countries, such as Italy[v], are relaxing biosimilar switching rules in order to address the needs of patients desiring affordable biologics and to reduce their health care expenses.

FDA postponed the issuance of guidance on interchangeability until 2017, despite earlier promises to issue guidance.  Therefore, the only way to get insight into this topic is to meet with the FDA on a case-by-case basis.  Therefore, it is – as yet – unclear how Paragraph 6 of Section 351 (k) of BPCIA will be interpreted and implement for the first biosimilar in the U.S. which obtains interchangeability status[vi]. 

In line with the EMA approach, Health Canada does not declare interchangeability. It’s up to the individual province to decide. This creates a regulatory obstacle for sponsors during biosimilars registration in provincial formularies.

When it comes to the post-marketing requirements, both EMA and Health Canada declare that after approval, the biosimilar is not linked to the reference product and any change to the product has to be evaluated in accordance with the post-approval guidance documents. This approach sets clear expectations for the sponsors. It also encourages sponsors to apply a “quality-by-design” approach to the development of biosimilar products to ensure compliance with post-approval guidance requirements and reducing post-approval changes.[vii]

The FDA, on the other hand, is working on post-approval guidance for biosimilar products and it is uncertain what these post-approval requirements will be.  This lack of clarity could dissuade sponsors from pursuing biosimilar marketing in the U.S. or even postpone the submission of biosimilar applications to FDA until further clarification on regulatory requirements is available.

These uncertainties in regulatory requirements are reflected in the number of approved biosimilars. EU has the most advanced regulatory framework and as a result it has twenty three approved products. The U.S., despite being the biggest market, still has only four approved biosimilars – with only one launch. Canada, even though its market is much smaller in comparison to EU and USA, has already six approved biosimilars. This advancement in bringing biosimilars to Canadian market is thought to be linked to the Health Canada policy of setting favorable conditions of acceptance of a dossier for a globally developed biosimilar, as outlined in the latest revision of Health Canada guidance document[viii].

The last ten years of biosimilar drug development has resulted in over 30 regulatory approvals in ICH countries, including Canada, EU and the U.S.  The EU is leading the way with the largest number of approvals and the most extensive regulatory guidance, followed by Canada and, lastly, the U.S.  Delays that could have led to more approvals in these regions are a result of multiple factors, including the capital required to conduct biosimilar trials, innovative strategies to delay the acceptance of biosimilars, litigation (especially in the U.S.), and lack of regulatory guidance around substitution.  Another key factor that needs greater clarity includes the acceptance of reference products from different jurisdictions and harmonization of the approach on interchangeability.


FDA Listing of Authorized Generics as of September 30, 2016, last accessed on December 14, 2016: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM183605.pdf

Biosimilars of adalimumab. GaBi on line, March 10, 2014, last accessed December 16, 2016: http://www.gabionline.net/Biosimilars/General/Biosimilars-of-adalimumab

‘NOR-SWITCH” Paper explores impact of biosimilar switching research. Biosimilar Development, Sep 23, 2016. Last accessed December 16, 2016: http://www.biosimilardevelopment.com/doc/nor-switch-paper-explores-impact-of-biosimilar-switching-research-0001

Finnish drug regulator recommends interchangeability of biosimilars. GaBi online, May 29, 2015, last accessed December 16, 2016: http://www.gabionline.net/Policies-Legislation/Finnish-drug-regulator-recommends-interchangeability-of-biosimilars

Spanish Society of Rheumatology issues position statement on biosimilars. GaBi online, June 12, 2015, last accessed December 16, 2016: http://www.gabionline.net/Biosimilars/General/Spanish-Society-of-Rheumatology-issues-position-statement-on-biosimilars

Biosimilar policies in Spain. GaBi online, November 16, 2012, last accessed December 16, 2016: http://gabionline.net/Reports/Biosimilar-policies-in-Spain

Ian Schofield, Italy To Relax Biosimilar Switching Rules In Cost-Savings Effort, Pink Sheet, December 14, 2016, last accessed December 14, 2016: https://pink.pharmamedtechbi.com/PS119675/Italy-To-Relax-Biosimilar-Switching-Rules-In-CostSavings-Effort

Biologics Price Competition and Innovation Act, Section 7002, Paragraph 6.

ICH Guideline Q8(R2) 'Pharmaceutical Development'. August 2009.

Health Canada: Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs, revised date 2016/11/14. Last accessed December 16, 2016: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/brgtherap/applic-demande/guides/seb-pbu/seb-pbu-2016-eng.pdf



Plain Language Labelling Summary

Posted: Monday July 24th, 2017

Author: Pinky Madhur

A few years ago on June 13th, 2015, the Plain Language Labelling Regulations became effective for prescription drugs in Canada. This new regulation affected pharmaceutical drugs, biologic drugs, and radiopharmaceutical drugs, but it did not apply to medical devices, veterinary drugs, or natural health products. This year on June 13th, 2017, the Plain Language Labelling Regulations became effective for non-prescription drugs as well.

As stated in the Questions and Answers: Plain Language Labelling Regulations guidance, the purpose of the Plain Language Labelling Regulations is to improve the understanding of information provided on drug labels and packages, by making them easier to read and understand. This would help prevent confusion on how to use drug products and enhance the safe use of drugs in Canada. To carry out its purpose, the Plain Language Labelling Regulations introduced multiple new requirements for drug product submissions received on or after their respective effective dates. Some of these requirements include:

·         Ensuring that the information provided on the drug product label is expressed in “plain language” and prominently displayed. This requirement applies to both prescription and non-prescription drug products, to help patient/consumer/target audience comprehension of labels for safe drug use. This also requires labels and packages to be formatted and presented in a manner that does not prevent understanding of the information.

·         Assessing the brand name of the drug product against similar drug products to prevent confusion and reduce patient risk. Health Canada is concerned with Look-alike sound-alike names of drug products and enforces this requirement to prevent errors due to similar drug names when self-selecting, prescribing, transcribing, etc., medication for patient use. Errors in these activities could result in patient harm and even be fatal. A brand name assessment of the drug product would help towards patient safety.

·         Providing contact information for adverse events on the inner and outer labels of drug products. This will allow patients/consumers to contact the appropriate contact person if there is an adverse event (e.g. adverse reaction, medication error, etc.) or if they have a question about the drug product. The contact information could be provided as a toll-free number, email, or website, as these are the recommended methods of contact. The contact person is required to be located in Canada, but their name does not have to be listed.

·         The submission of mock-ups of labels and packages for Health Canada to review. The review will consider the font size, type, colour, and placement of the information on the label to check if they prevent legibility or understanding of the information. The Questions and Answers: Plain Language Labelling Regulations guidance suggests that labels be submitted for review as unlocked PDF files, to allow reviewers to check the font type and size of the information on the labels.

It is important to note that some of the Plain Language Labelling requirements differ for different drug product types. Please refer directly to the Health Canada guidance and regulations for complete and original information on these regulatory requirements for compliance. A link to the guidance can be found in the reference below.


Questions and Answers: Plain Language Labelling Regulations


Thank you for reading Regulated Affairs, the CAPRA blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.

Health Canada Begins Consultations on Mandatory Reporting by Health Care Institutions

Posted: Monday July 17th, 2017

Author: Mark Vanderveken and Alanna Tevel

Health Canada has commenced consultations on proposed changes to the Food and Drug Regulations and Medical Devices Regulations that would require mandatory reporting of serious adverse drug reactions and medical device incidents by health care institutions. The changes are pursuant to amendments to the Food and Drugs Act contained in the Protecting Canadians from Unsafe Drugs Act, which was enacted in November 2014. Health Canada published a Notice of Intent to amend the regulations in June 2016.

The proposed changes are intended to enhance post-market surveillance of drugs and medical devices to improve identification of emerging patient safety issues.

Health Canada is seeking input on five elements of the proposed changes to the regulations:


Comments on non-regulatory approaches to improve reporting of serious adverse drug reactions and medical device incidents, including outreach, education, and feedback for reporting institutions, are also being solicited.

More information on the proposed changes can be found on Health Canada’s consultation webpage and in the accompanying Consultation Paper. The online consultation period ends on August 11, 2017. Health Canada expects that the proposed changes will be implemented, at the earliest, in 2019.

Patients and Philanderers: Why the Ashley Madison Report has Something Important to Say about Cybersecurity Standards for Patient Data

Posted: Monday July 10th, 2017

Author: John Beardwood

A) Introduction

Privacy legislation in Canada, the U.S. and elsewhere, while imposing detailed requirements on issues such as consent, often reverts to high level principles in outlining privacy safeguards or security obligations.  One concern of the legislators has been that by providing more detail, the laws could make the mistake of making a “technology pick,” which – given the pace of evolving technology – could very well be out of date in a few years.  Another concern is that what constitutes appropriate security measures can be very contextual.  Nevertheless, however well-founded those concerns, the result is that organizations seeking direction from the law as to how these safeguard requirements translate into actual security measures are left with little to no clear guidance on the issue.  

For example, the Personal Health Information Protection  Act (“PHIPA”) provides guidance as to what constitutes appropriate security safeguards for personal health information in Ontario.  However, PHIPA simply states that a health information custodian shall take steps that are reasonable in the circumstances to ensure that personal health information in the custodian’s custody or control is protected against theft, loss and unauthorized use or disclosure and to ensure that the records containing the information are protected against unauthorized copying, modification or disposal. Unfortunately, this principles-based approach loses in clarity what it gains in flexibility.

On August 22, 2016, however, the Office of the Privacy Commissioner of Canada (the “OPC”) and the Australian Privacy Commissioner (together with the OPC, the “Commissioners”) provided some additional clarity as to privacy safeguard requirements in their published report (the “Report”) on their joint investigation of Avid Life Media Inc. (“Avid”).[1] 

The Report is significant, in that organizations collecting, using and disclosing highly sensitive personal information – like personal health information -have now been provided with reasonably detailed guidance as to what the cybersecurity standards are under the law:  that is, what measures are expected to be implemented by an organization in order to substantiate that the organization has implemented an appropriate and reasonable security standard to protect highly sensitive personal information.  While these cybersecurity standards have been proposed by the federal Privacy Commissioner, and not by the provincial privacy commissioners primarily charged with regulating the use of personal health information, given the relationship between the federal and provincial privacy commissioners we expect that the standards expressed in the Report will be very influential in shaping the cybersecurity expectations of those commissioners.

A. Key Privacy Security Insights

1. The Report:  Security Safeguards Due Diligence

In the Report, the OPC provides guidance on the level of diligence expected of an organization when determining adequate security safeguards under Principle 4.7 of PIPEDA, namely that: 

· Sensitivity of Data: an organization needs to understand the sensitivity of the personal information that they collect, use and disclose, and the corresponding required level of safeguards under PIPEDA;

· Security Risk Policy: an organization should adopt clear and appropriate processes, procedures and systems to handle information security risks, supported by adequate expertise, whether such expertise is internal or external;

· Safeguard Assessment: an organization should conduct a meaningful assessment (i.e. one that doesn’t just focus solely on the risk of financial loss to individuals due to fraud or identity theft, but also on their physical and social well-being) of the required level of safeguards for any given personal information; and

· Risk Balance: safeguards should be adopted by an organization with due consideration of the risks faced.

Based on the foregoing diligence, the Report provides specific insight into what Canadian privacy commissioners would likely require as adequate safeguards where an organization collects, uses or discloses highly sensitive personal information like patient information. 

[1] PIPEDA Case Summary #2016-005 - Joint investigation of Ashley Madison by the Privacy Commissioner of Canada and the Australian Privacy Commissioner/Acting Australian Information Commissioner.

ICH “Good Clinical Practice Renovation”

Posted: Wednesday July 5th, 2017

By: Pinky Mazumder

On January 2017, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) released a reflection paper titled Good Clinical Practice Renovation: Modernization of ICH E8 and Subsequent Renovation of ICH E6. The reflection paper discusses current issues with the ICH guidelines regarding clinical trial design and conduct, and the need to update the guidelines to reflect current concerns. This article will recap some of the key highlights from the reflection paper and why the renovation was proposed.

ICH E6 Guideline for Good Clinical Practice:

The ICH E6 guideline, Guideline for Good Clinical Practice, is a procedural document for conducting clinical research trials. ICH E6 focuses on areas such as clinical trials with regulatory intent, data quality, and the assurance of human subject protection, among others. However, since the development of ICH E6 in the mid 1990s, Good Clinical Practice (GCP) has evolved and expanded over the years to accommodate the growing field of science and healthcare. For instance, clinical research trials were initially conducted in a few clinical sites, however today these trials can take place in multiple sites and even across multiple nations worldwide. This increases the complexity of clinical trials and makes it difficult to apply the GCP guidelines from ICH E6, which mainly addresses traditional clinical trial designs. The proposed renovation intends to updates the GCP guidelines with additional flexibility to reflect the growing diversity of study designs.

ICH E6 also addresses human subject protection and data integrity, and although the renovation will maintain these principles, some flexibility may be incorporated into the guidelines to address the different types of clinical trials and in different context. For example, observational studies of approved products may not require the same level of informed consent and documentation as randomized clinical trials with investigational products. Such differences should be addressed in the GCP guidelines and will be considered for the renovation.

The GCP renovation also intends to prevent the duplication of patient/subject data by better integrating clinical studies into regular healthcare delivery. This would help connect electronic case report forms of subjects with their electronic medical records, to prevent duplication of patient/subject data. These are some of the main concerns leadings to the renovation of GCP guidelines. Although the ICH E6 was supplemented with ICH E6(R2) in 2014 to better ensure data quality and human subject protection, additional updates are required to reflect current concerns.

ICH E8 General Considerations for Clinical Trials:

In addition to updating ICH E6, the renovation also proposes to modernize ICH E8 General Considerations for Clinical Trials, to reflect and focus on the current and critical aspects of clinical research and study/data quality. The ICH E8, which was released in 1997, does not seem to approach data quality with the current notion of “quality by design”. While the guideline does include studies for regulatory submissions, it does not include study design and planning to ensure quality of the data. This is one of the key areas of change in the proposed renovation as it is currently and widely believed that the quality of the study determines the quality of the data it generates. This has become a fundamental notion, however it is not reflected in the current ICH E8. As a result, the ICH renovation intends to modernize E8 by including:

1.       Identification of Critical-To-Quality (CTQ) factors or aspects of the trial that are critical to generating reliable data.

2.       Ways to effectively and efficiently support quality in these critical areas of the studies. The updated guideline could also provide examples of general CTQ factors and how to determine critical factors.

Overall, the ICH reflection paper on GCP renovation intends to update guidelines E8 and E6 to reflect current GCP concerns and areas of focus. These guidelines have served a primary role in GCP compliance and clinical trial success for investigational drugs for many years, however due to the evolution of clinical research, they may need to be updated. ICH E8 would be modernized to highlight the importance of study design and planning for data quality and reliability. In addition, ICH E6 will also be updated to address the diversity of data sources and trial designs, while still including traditional interventional trials. For more information on the proposed ICH renovation on GCP guidelines, please refer to the original ICH Reflection Paper in the Reference section below.


ICH Reflection on “GCP Renovation”: Modernization of ICH E8 and Subsequent Renovation of ICH E6 http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/GCP_Renovation/ICH_Reflection_paper_GCP_Renovation_Jan_2017_Final.pdf

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing professional development opportunities in Regulatory Affairs. Feel free to share our blog posts and join us on social media.


Canadian Drug Establishment Licences: GMP Requirements for API foreign building

Posted: Monday June 26th, 2017

Author: Madhur Jadawala

Canada's Food and Drug Regulations (FDR) were amended to extend the requirements of Division 1A - Establishment Licensing and Division 2 - Good Manufacturing Practices (GMP) to active ingredients used in pharmaceutical drugs for human use only. The amended Regulations came into force on November 08, 2013. This API program was implemented for 3 years and it came into full effect on November 08, 2016. On July 31, 2016, Health Canada did publish a “Notice to Stakeholders - Updates to drug establishment licence applications and good manufacturing practice evidence requirements for active pharmaceutical ingredients” and it can be found here:



·         All the Canadian establishments (persons) conducting API related activities for APIs used in the manufacture of drugs listed on the Prescription Drug List, Scheduled under the Controlled Drugs and Substances Act (Schedules I, II, III, IV, or V inclusively), or defined as a “narcotic” under the Narcotic Control Regulations:

o   API importers

o   Finished dosage form (FDF) fabricators who import APIs for use in manufacturing

o   FDF importers


·         As per section C.02.003.3 of the Food and Drug Regulations (FDR), no person shall use an active ingredient in the fabrication of a drug unless it is fabricated, packaged/labelled, tested and stored in accordance with GMP requirements.

·         Effective November 08, 2016, importers are required to update their API Table-A with Health Canada and ensure to keep it comprehensive and consolidated with all the API foreign sites.

·         Importers, along with their most recent API Table-A must also submit section 5.1 attestation of FORM-0033 attesting to maintain API foreign sites Good Manufacturing Practices (GMP) compliance evidence based on inspections by Health Canada or by one of the following recognised regulatory authorities / organizations:

o   Regulatory partners with whom Health Canada has established equivalence under Mutual Recognition Agreements (MRA);

o   Regulatory partners whose inspection system has been assessed and found comparable under the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (PIC/s);

o   Organizations such as the European Directorate for the Quality of Medicines and Healthcare (EDQM) and the World Health Organization (WHO), which inspect against ICH Q7 guidelines.

·         Consultant or corporate audits, and other GMP evidence should not be used to demonstrate the API foreign site’s compliance with GMP for the drugs listed on the Prescription Drug List, Scheduled under the Controlled Drugs and Substances Act (Schedules I, II, III, IV, or V inclusively), or defined as a “narcotic” under the Narcotic Control Regulations.

·         The GMP evidence must be readily available with the importer and must be supplied to Health Canada when requested.

·         Health Canada will continue to seek clarification with respect to Table A, as applicable, and assess the GMP compliance evidence of foreign buildings during the inspection of an importer, during the off-site paper assessment, or during the foreign on-site inspection.

List of GMP evidence documents:

v  Foreign buildings inspected by the above-noted recognised regulatory authorities and organizations

1.       most recent, available, signed inspection report issued by Health Canada or by a recognised regulatory authority;

2.       copy of the GMP certificate issued by the recognised regulatory authority, stating the outcome of the inspection above (if available);

3.       corrective actions taken, signed by the foreign building’s responsible official (if applicable);

4.       copy of the Site Master File, or a similar document (such as a quality manual); and

5.       copy of the quality/written agreement between the foreign building’s responsible official and the Canadian establishment

v  Foreign buildings which have not been inspected by the above-noted recognised regulatory authorities and organizations

1.       most recent (within last 3 years) corporate or consultant audit, signed and dated by the lead auditor;

2.       justification for using a consultant/corporate audit report (e.g. only available GMP evidence);

3.       qualifications and experience of the auditor(s);

4.       scope of the inspection (including activities being performed, drugs/APIs covered, and specific building address);

5.       evidence that the consultant or corporate audit was conducted against all applicable sections of Part C, Division 2 of the Food and Drug Regulations;

6.       corrective actions taken, signed by the foreign building’s responsible official and assessed by the auditor for adequacy (if applicable);

7.       copy of the Site Master File, or a similar document (such as a quality manual); and

8.       copy of the quality/written agreement between the foreign building’s responsible official and the Canadian establishment

·         If the foreign buildings’ GMP evidence is not based on inspections by recognised regulatory authorities or organizations, in order to meet the required GMP evidence by November 8, 2016, importer should:

1.       Source APIs from an alternate supplier that has the required GMP evidence. It is the importer’s responsibility to advise the DIN holder of any change in suppliers, so that the DIN holder may obtain Health Canada approval, as applicable;

2.       Arrange for a corporate or consultant audit to be conducted as noted in the “Next phase – Beginning November 8, 2016” section of the July 2015 Notice; or

3.       Request a Health Canada inspection using Good Manufacturing Practices − Request for Inspection of a Foreign Site Form (FRM-0213).

Health Canada takes a risk-based approach to inspections. An inspection should be requested as soon as possible for API foreign buildings involved in activities related to prescription and controlled drugs that the importer would deem medically necessary and/or for which there are no alternate suppliers.


1.       “Notice to Stakeholders - Updates to drug establishment licence applications and good manufacturing practice evidence requirements for active pharmaceutical ingredients”:


2.       Health Canada issued DEL Bulletin #2 dated August 04, 2016.

A Recap on Vanessa’s Law

Posted: Monday June 19th, 2017

Author: Pinkiy Mazumder

With the evolution of healthcare products and its regulations, today we will recap one of the most significant recent changes in Canadian regulations; Vanessa’s Law. 

Vanessa’s Law, also known as the Protecting Canadians from Unsafe Drugs Act, was launched with the purpose of strengthening the safety of therapeutic products and its regulation (1). Following the death of 15 year old Vanessa Young from a prescription drug in 2000, Bill C-17 Protecting Canadians from Unsafe Drugs Act, was initiated to propose the first amendment to the Food and Drugs Act in 50 years (1,2). With its introduction in December 6th 2013 by the Federal government, Bill C-17 Protecting Canadians from Unsafe Drugs Act received Royal Assent the following year on November 6th 2014 (3).

The Protecting Canadians from Unsafe Drugs Act applies to therapeutic products including prescription drugs, over-the-counter (OTC) drugs, vaccines, medical devices (including combination drug-devices), gene therapies, cells, tissues, organs, however it does not apply to Natural Health Products (1).

The Act brings multiple new changes to the regulation of therapeutic products, to protect patients and the public from unsafe products. For instance, the Act allows the government to mandate the reporting of adverse drug reactions and medical device incidents by healthcare institutions, and recall therapeutic products that are considered unsafe (1). In addition, for enhanced transparency, the amendment allows the Minister of Health to collect additional product information from the sponsor, require new tests/studies, and monitor patient experience for product assessment (4). Moreover, the Minister of Health also has the authority to demand a re-labelling of drug products or a change in drug packaging for safety concerns, and even reveal confidential business information for product safety (4). These changes, among others, form the basis of Vanessa’s Law. For more information on the Protecting Canadians from Unsafe Drugs Act (Vanessa’s Law), please refer to Health Canada’s Overview of Vanessa’s Law, Amendments to the Food and Drugs Act, and Protecting Canadians from Unsafe Drugs Act Questions/Answers.

Thank you for reading Regulated Affairs, the CAPRA Blog. CAPRA is a non-profit organization dedicated to providing networking and professional development opportunities in Regulatory Affairs.


1.    Protecting Canadians from Unsafe Drugs Act Questions/Answers: http://www.hc-sc.gc.ca/dhp-mps/legislation/unsafedrugs-droguesdangereuses-faq-eng.php

2.    Vanessa Young’s Legislative Legacy: http://www.macleans.ca/news/canada/vanessa-youngs-legislative-legacy/

3.    Protecting Canadians from Unsafe Drugs Act Amendments to the Food and Drugs Act (Bill C-17): http://www.hc-sc.gc.ca/dhp-mps/legislation/unsafedrugs-droguesdangereuses-eng.php

4.    Overview of Vanessa’s Law: http://www.hc-sc.gc.ca/dhp-mps/legislation/unsafedrugs-droguesdangereuses-overview-ensemble-eng.php

Changes to the Annual Renewal Process of Canadian Drug Establishment Licences

Posted: Monday June 12th, 2017

Author: Author Madhur Jadawala


Effective 2017 Annual Licence Renewal (ALR) of Drug Establishment Licences (DEL), Health Canada has added an extra step to the ALR submission process by DEL holders. This change constitutes of an addition of a MS Excel sheet known as “Product List” and it has been provided to all the DEL holders along with the 2017 ALRs packages.



·         All the Canadian Drug Establishment Licence (DEL) holders who wish to renew their importation DEL and maintain its active status. Although the name of this new sheet is “Product List”, not only it covers the list of drug products (DINs) imported by the importer DEL holder but also the foreign sites and their activities corresponding to these DINs.



·         An accurately completed “Product List” Excel sheet must now be submitted along with the ALR package to Health Canada every year by March 31. Health Canada may issue Screening Deficiencies in case where “Product List” is not provided or is not completed appropriately.

Refer to Figure 1 below for the snapshot of the “Product List” issued by Health Canada:

·         As it is evident from Figure 1 below, Health Canada has already pre-filled the “Product List” with the information they have on their records, and yes, it may not be completely comprehensive. One may find some activities or foreign sites that are actively listed on their DEL but are missing from this “Product List”. This is fine, for Health Canada has provided us with this sheet so that we can add more details and submit the most accurate and comprehensive sheet along with the renewal before March 31st.


·         The Excel sheet may seem to be fairly simple at first sight but there is a lot of fact finding and information search involved behind before one can completely fill this sheet with high accuracy. There are clear instructions in cell “H1” for listing only 1 DIN per cell, and this is where it becomes a bit tricky.


·         Health Canada wants us to use each row to list each foreign site carrying out each activity for each DIN. As an example, if a foreign site “Foreign Site 1” is involved in Fabrication, Packaging and Labelling of DIN 01234XXX, this needs to be listed in 3 separate rows for each activity as illustrated in Figure 2 below.


·         Many times, a single foreign site is involved in carrying out licensable activities for more than 1 DIN product. As an example, “Foreign Site 2” is involved in Fabrication and Packaging of 2 DIN products – 01234XXX and 01234XXY. In this case, both the DINs need to be entered separately in separate rows corresponding to Fabrication and Packaging by “Foreign Site 2” as illustrated in Figure 2 below.


·         Health Canada has limited gathering of this information to activities of “Fabrication, Packaging and Labelling” only. Foreign sites involved in “Testing” only need not be listed on this “Product List”.

Figure 1: “Product List issued by Health Canada”



Figure 2: “Product List issued completed by DEL holder”



*Different Colours for DINs 01234XXX and 01234XXY have been used to demonstrate that these are two separate unique DINs.

FDA’s eCTD Mandate: Are You Ready?

Posted: Monday June 5th, 2017

Author: Anisah Bipatnath, M.Sc. Project Manager, Regulatory Operations

When FDA posted their eCTD mandate last year, it was more of a whisper than a bang.  It certainly did not wreak havoc in the industry; after all, we were all warned that the time would come sooner rather than later.

The deadlines are quite clear:

After May 5, 2017

The following submission types must be filed in eCTD format:

·         NDAs

·         ANDAs

·         BLAs

·         MFs

After May 5, 2018

The following submission types must be filed in eCTA format:

·         Commercial INDs

Source: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm

*Submissions not filed in eCTD format will not be filed or received.

Statistics show that the majority of incoming submissions are already in eCTD format:


Source: Electronic Submissions Update presentation at RAPS2016: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/

Roughly 90 percent of the industry is already filing in eCTD format (DMF filings at least are on the rise) to FDA.  For those of you still holding out, FDA’s eCTD mandate is now forcing your hand to make the switch.  If you’re currently filing paper submissions for IND, you have a year to consider the following:

1. To host or not to host?

eCTD software is expensive.  There exist different cost structures, depending on your decision to host the software in-house or access the software via a remote host.  Hosting eCTD software in-house entails a battery of qualification and validation steps, and can be practical if you already have an IT group with relevant expertise, or can enlist one to manage the installation.  If you’re not in possession of a Computer Science degree, the amount of work and length of time (and the terminology) might be daunting.  Increasingly, eCTD software providers are making cloud based solutions available, which allow you to access the eCTD software remotely.  Your eCTD software vendor can then perform most of the installation and qualification steps, with minimal qualification steps required by you as the end user.

2. Submission compilation – keep in-house or outsource?

This is another key point for consideration.  What would be the utility of having (expensive) eCTD software if you don’t know how to use it to maximize the potential, or compile a submission that meets FDA’s requirements?  Like it or not, FDA has specifications for your PDF files, metadata for submission types that need to be entered correctly or else you run the risk of your submission being rejected.  There are also PDF tools that can facilitate PDF processing at the click of a mouse.  All of these activities require trained professionals and standard operating procedures in order to ensure a consistent and high quality product.

3. Electronic Submissions Gateway (ESG) or Courier?

eCTD and ESG go hand in hand.  Submissions under 10GB should be filed through the Gateway.  Any submissions exceeding 10GB can also be uploaded to the ESG or can be submitted on appropriate physical media and sent by courier to FDA.  You can dispatch your eCTD immediately through ESG once your submission has your internal stamp of approval (no printing, and no more paper cuts!).  Using the ESG also provides an electronic receipt and acknowledgement files, reducing post-filing anxiety (did the courier arrive at FDA? In one piece?), and enabling quicker notification to your submission team that FDA has your submission for review.  However, in order to use the ESG, you must first be qualified by FDA and undergo a sample submission review process and electronic certificate exchange.

4. Health Canada and the Common Electronic Submissions Gateway (CESG)

Health Canada also implemented an eCTD mandate, in order to stay aligned with FDA and the European Medicines Agency (EMA).

Effective January 1, 2018, the following regulatory activity types (as well as all additional information/subsequent regulatory activities) must be filed in eCTD format:

•             New Drug Submission (NDS);

•             Supplement to a New Drug Submission (SNDS);

•             Abbreviated New Drug Submission (ANDS); and,

•             Supplement to an Abbreviated New Drug Submission (SANDS).

Source: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/announce-annonce/ectd-mandatory-notice-avis-obligatoire-eng.php

eCTD filing format for Master Files, Clinical Trial Applications (CTAs), Drug Identification Number (DIN) applications and Post-Authorization Division 1 changes (PDC) is recommended, but not yet mandatory. Medical devices and veterinary drug submissions are currently considered to be out of scope and must follow the non-eCTD electronic only filing format (for details on this guidance, click here: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ctd/gd_prep_non_ectd_ld-eng.php

Effective January 1, 2017, all eCTD transactions under 10GB in size must be transmitted through the CESG, and sponsors are advised to obtain CESG accounts as soon as possible.

Source: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/announce-annonce/cesg-mand-notice-avis-oblig-pcde-eng.php

Information on the new Access to Cannabis for Medical Purposes Regulations

Posted: Monday May 29th, 2017

Author: Rachelle D’Souza

On August 11, 2016, Health Canada announced the new Access to Cannabis for Medical Purposes Regulations (ACMPR) which came into force on August 24, 2016. These new regulations were intended to replace the Marihuana for Medical Purposes Regulations (MMPR) as of August 24, 2016, and be implemented as a result of the Federal Court ruling in the case of Allard v. Canada. The ACMPR allows for reasonable access to cannabis for medical purposes for Canadians who have been authorized to use cannabis for medical purposes by their healthcare practitioner.

Under the ACMPR, Canadians who have been authorized by their healthcare practitioner to access cannabis for medical purposes, will continue to have the option of purchasing safe and  quality-controlled cannabis from one of the producers licensed by Health Canada. Canadians will also be able to produce a limited amount of cannabis for their own medical purposes, or designate someone to produce it for them.Individuals who have the support of a licensed health care practitioner may consult Accessing Cannabis for Medical Purposes for further information on how to access cannabis for medical purposes under the ACMPR.

Please refer to the statement released by Health Canada and supporting Fact Sheet for additional information.

For more information on the content of the new regulations, please see our guide: Understanding the New Access to Cannabis for Medical Purposes Regulations.

The following information bulletin is also available: Safety and security when producing cannabis for your own medical purposes.

The full text of the new regulations was published in the Canada Gazette, Part II, on August 24, 2016.

Regulations no longer in effect
The Marijuana for Medical Purposes Regulations (MMPR) were repealed on August 24, 2016. The MMPR created conditions for a commercial industry that would be responsible for the production and distribution of marihuana for medical purposes. They also made sure that Canadians with a medical need, could access quality-controlled marihuana grown under secure and sanitary conditions.

In addition, on March 31, 2014, the Marihuana Medical Access Regulations (MMAR) were repealed. However, as a result of a Federal Court Order granted on March 21, 2014, individuals who were previously authorized to possess and/or produce marihuana under the former MMAR and who meet the terms of the Federal Court injunction order may continue to do so until the Court orders otherwise. Individuals covered by the injunction who wish to change the terms of their license, such as a change in address or designated producer, will be able to do so by registering with Health Canada under the new ACMPR.



Annual Drug Notification Form

Posted: Tuesday May 23rd, 2017

Article by: Rachelle D’Souza, Regulatory Heights Inc.

The Annual Drug Notification Form (ADNF) is intended to assist manufacturers in complying with section C.01.014.5 of the Food and Drug Regulations which requires that every manufacturer of a drug confirms annually before October that all information previously supplied with regard to that drug is correct.

Health Canada would like to inform manufacturers of changes to the information that is included in the Annual Drug Notification Form (ADNF). These changes are, in part, due to the Regulations Amending the Food and Drug Regulations (Shortages of Drugs and Discontinuation of Sale of Drugs) (the Regulations). These regulations were published in the Canada Gazette, Part II on June 29, 2016 and will come into force on March 14, 2017. Other changes have also been made to the ADNF in an effort to streamline the process.

The significant changes to the information included in the ADNF, and how it will affect manufacturers, are summarized below. These changes will be incorporated in the upcoming ADNF, which will be sent to manufacturers in June of 2017.

The inclusion of these changes to the ADNF will bring the annual notification process into compliance with the Regulations. Furthermore, it will increase the accuracy of the information presented in the Drug Product Database Online Query (DPD).

1.     Drug products which have been assigned a Drug Identification Number (DIN), but have not been marketed (Approved Products), will now be included as a separate list in the ADNF, in an effort to encourage manufacturers to cancel the DINs they do not intend to market in Canada. This will allow the Department to ensure that the drug information provided on the Department's website is accurate and up to date. It will also be beneficial for manufacturers as they will have a complete list of all their DINs in one report on an annual basis. With the implementation of this change, the biennial DIN Assigned Project, which had manufacturers clarify the status of their "Approved Products" in a separate report, will be eliminated.

2.     In accordance with section C.01.014.7 of the Regulations, for drug products that were marketed but are noted as being discontinued on the ADNF, manufacturers will be required to provide the discontinuation date, the lot number and the expiry date of the last lot sold by the manufacturer. This information will be recorded on a separate form that will be provided with the Annual Drug Notification Form.

3.     Drug products which are marketed but have not had sales for 12 consecutive months (Dormant Products) will be included as a separate list in the ADNF. Additionally, in accordance with section C.01.014.12 (1) of the Regulations, there will be an option for manufacturers to note if a marketed product has become a dormant product.

If you have any questions regarding this notice, please contact OSIP, TPD, Email: sipdannual_annuelledppr@hc-sc.gc.ca, Telephone: 613-946-1151, Facsimile: 613-954-3067


Regulatory Highlights

Updated: GD207: Guidance on the Content of ISO 13485 Quality Management System Certificates Issued by Health Canada Recognized Registrars

Future Regulatory Initiative for Opioids

Posted: Monday May 15th, 2017

Article by: Pinky Mazumder

If you have been tuning in to recent Canadian news, you will have noticed various critiques and discussions around the use of opioids. In case you are not familiar, opioids are narcotic pain relieving medications and are commonly prescribed in North America for acute and chronic pain1. However, in addition to its therapeutic effects, opioids carry various side effects including increasing tolerance and the potential for dependence and overdose, which can be fatal2. In fact in the year of 2015, there were approximately 2000 deaths in relation to opioid use in Canada1. With such alarming rates of overdoses and deaths across the nation, the need for a change could not be overlooked.

To respond to the opioid crisis, on May 8th, 2017, the Canadian Medical Association Journal published a clinical practice guideline with suggested recommendations on prescribing opioids. The guideline is primarily directed to physicians and relevant policy makers, and includes 10 recommendations for prescribing opioids for cases of chronic pain (non-cancer related)1. For more information, please read the guideline by clicking on this link. In addition to such clinical changes, Health Canada has also released a proposed regulatory initiative for opioid drugs3.

For the Forward Regulatory Plan of 2017-2019, Health Canada proposed a regulatory initiative titled: Amendments to the Food and Drugs Regulations – Labelling and Risk Management Plans for Opioid Drugs. These amendments may bring additional regulatory requirements for opioid drugs such as affixed warning stickers and mandatory risk management plans3. Complete and detailed information on the Forward Regulatory Plan by Health Canada, can be found here. The proposed changes are expected to be released in Canada Gazette Part I in 2017, to allow for public comments and consultations on the matter3. A link to the Canada Gazette Part I: Notices and Proposed Regulations can be found here.

Thank you for reading the CAPRA Blog. If such information is relevant to you, your organization/company, or to someone you know, please feel free to share this blog post with the Share buttons provided. Tune in next time for information on regulatory changes/updates for the industry. However, for implementation of any mentioned regulatory information and other regulatory information, please refer to the information directly released from the appropriate regulatory authorities. CAPRA is not a regulatory authority, nor a regulatory affairs consultation service. Thank you.




Changes to Submission Filing Requirements - Good Manufacturing Practices (GMP)/Drug Establishment Licences (DEL)

Posted: Monday May 8th, 2017

Article by: Madhur Jadawala, Lead Consultant, Quality & Compliance Services Inc.

Health Canada on February 10, 2017 has issued a notice outlining changes to the submission filing requirements pertaining to Good Manufacturing Practices (GMP)/ Drug Establishment Licences (DEL). These changes are effective immediately for drug submissions filed after the date of this notice (February 10, 2017).


Pursuant to Sections C.08.002(2)(e ), C.08.002.01(2)(b), C.08.002.1(2)(a) and C.08.003(2)(e) of the Food and Drug Regulations a new drug submission (NDS), an extraordinary use new drug submission (EUNDS), an abbreviated new drug submission (ANDS), an abbreviated extraordinary use new drug submission (AEUNDS), or a supplement to any of these submissions, shall contain “details of the method of manufacture and the controls to be used in the manufacture, preparation and packaging of the new drug ”. The “controls” include those which ensure GMP, and which are required in order to be in compliance with Division 1A (Establishment Licences) and Division 2 to 4 (Good Manufacturing Practices) of the Regulations.


Historically, the Therapeutic Products Directorate (TPD) of the Health Products and Food Branch (HPFB) of Health Canada has required that buildings performing licensable activities to be GMP compliant. If this requirement was not fulfilled, deficiency letters were issued to the sponsors. As a result, sponsors of drug submissions had to plan strategically when it came to the anticipated drug submission filing date because the DEL Unit’s service standard for processing DEL applications/amendments is 250 calendar days. In the worst-case scenario, the sponsor received a deficiency letter from TPD and had limited time (anywhere between 7 – 45 days) to respond to this deficiency for providing the evidence of GMP compliance. Now as mentioned above, the DEL unit takes about 250 days to process an application or amendment and hence the sponsor, by no means, can respond to this deficiency satisfactorily in the limited time provided by the TPD. Therefore, having appropriate DELs in place prior to submitting the drug submission was imperative and almost a pre-requisite activity.

Revised requirements

Therapeutic Products Directorate (TPD) of the Health Products and Food Branch (HPFB) of Health Canada is revising the process related to the requirements for evidence of Good Manufacturing Practices (GMP) for drug submissions. The goal of this revision is to better align the drug submission screening and review process with the Drug Establishment Licence (DEL) process. This should allow sponsors to make timely drug submissions while still providing adequate assurance of an establishment’s commitment to quality.

As of the date of this Notice (February 10, 2017), and as detailed below, TPD will also accept submissions where a complete application to amend the DEL pursuant to C.01A.006 of the FDR for new buildings and activities not currently listed on the drug submission sponsor’s DEL has been filed with the Minister at least 90 days prior to the time of filing a drug submission.

This requirement will be applicable to all NDS, EUNDS, ANDS, AEUNDS, Supplements, and DIN applications, thereto, submitted to the TPD for review. Eligible submissions are those where

(1) all required buildings and activities are listed on the current DEL,

(2) a site has a GMP compliance rating in Canada for the required activities and dosage form(s), and/or

(3) a complete DEL application has been filed with the Minister for any new buildings and activities.

Please note this notice is applicable ONLY to the drug submissions to TPD referred in this notice, and these are NOT applicable to drug submissions to the BGTD or any other directorate at Health Canada.

Where a DEL application was needed, the sponsor may file the drug submission 90 days after the Acknowledgment of Application Acceptance for the DEL application is issued by the Minister. Drug submissions which do not meet the requirements listed above will be issued a screening rejection letter.

In addition, where any site listed in a drug submission is considered by Health Canada to be non-compliant for GMP, a screening rejection letter will be issued.

The original complete notice published by Health Canada can be found at http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/notice_gmp_el_avis_bpf_le-eng.php

Please refer to the table below that provides a summary of activities that require documentation of a valid DEL and/or DEL application.


The Journey towards Safe Food for Canadians

Posted: Monday May 1st, 2017

Article by: Carol T Culhane, PHEc, MBA, President, International Food Focus Ltd.

With alarming food safety recalls across the nation, in January 21st 2017, the long-awaited proposed regulations under the Safe Food for Canadians Act (SFCA), which received Royal Assent on November 22nd, 2012, was published in Canada Gazette I. The proposed Safe Food for Canadians Regulations reflects a significant change in the way that the Canadian Food Inspection Agency (CFIA) approaches the regulatory oversight of food safety in Canada.

Pan-Canadian outbreaks of listeriosis and E. coli and Salmonella contaminated food remain in common memory. In 2008, a listeriosis outbreak spanned across five provinces, cost the Canadian economy $242 million, sickened 57 Canadians, and claimed the lives of 23 individuals. Several years later, a nationwide 2012 E.coli contamination of ground beef involved the disposal of 5.5 million kg of product, and revealed that “the CFIA did not possess the power to compel regulated parties to provide adequate documentation in the event of a significant food safety incident.” Moreover in 2014, imported Salmonella-contaminated chia seeds which was incorporated into 24 products sold in Canada and prepared by nine separate Canadian manufacturers. Due to the imported nature of the chia seeds, there was a significant degree of complexity in the recall procedure that needed to be addressed.

Consequent to acceptance of their portion of the responsibility, the CFIA embarked detailed scrutiny, critical analysis, and a comprehensive makeover of their entire operation. The current scope of CFIA inspections are limited to federally-regulated commodities, such as meat and dairy products, while commodities such as spices, snack foods, bakery products, fats and oils, as well infant formula, are not subject to the same scrutinous regulatory requirements. There is also limited oversight on products distributed interprovincially, thus posing possible food safety concerns for Canadians. Moreover, such limiting domestic factors render the containment of food contamination between countries to be increasingly difficult, especially with the ever-growing global scale of food trade.

As a result, the proposed 17 part SFCR is an amalgamation of the Canada Agricultural Products Act, Meat Inspection Act, Fish Inspection Act, Consumer Packaging and Labelling Act, along with food-commodity based Regulations, which will be repealed with the ratification of the SFCR. Therefore, there will be two Acts with enabling regulations pertinent to food sold in Canada – the Food and Drugs Act and the Safe Food for Canadians Act. In addition, the SFCR also uses the legislative instrument, “Incorporated by Reference” (IbR), to include specificities such as Grades and Standards of Identity of food and food commodities. In the view of the CFIA, the SFCA has been designed to “encourage innovation [….], and contains explicit authority to incorporate any document into its regulations, regardless of its source”. An IbR is efficient and practical for all stakeholders by allowing prompt regulatory responses to scientific and innovative improvements without the need for formal and often lengthy regulatory amendments. The Food and Drugs Regulation, administered by Health Canada, carries a provision for IbR since 2012.

With a focus on licensing, trade, Preventive Control Plan (PCP), and traceability, the SFCR introduces new and updated fundamental changes to food safety and requires regulatory compliance by all stakeholders. Food manufacturing, preparing, processing, storing, labelling, importing, exporting, and interprovincial trade among others, would require licensure and a fixed place of business in Canada. With a proposed fee of $250, the license would be valid for a two-year period and would be based on the activity of the establishment. Meat licensure may be subject to additional requirements.

In addition, license applicants would be required to create a PCP to identify the biological, chemical and physical hazards to which the food being prepared is subject to, and, evidence-based, verified procedures specifically designed to control or eliminate these risks. For example, fruit and vegetable producers and processors need to be cognizant of possible contamination by E.coli and Salmonella, and accordingly require documented evidence-based procedures which are proven to be effective in operation and in control of contaminants. Similarly, fish importers and exporters need be aware of histamine levels in fresh fish and have documented procedures to reduce chemicals levels exceeding acceptance. The Regulations further outline the scope of the PCP to include lot numbers on all food products, recall plans, sanitation controls, pest controls, and non-food agents,  conveyances and equipment, conditions respecting establishments, unloading, loading and storing, staff competency, personnel hygiene, communicable diseases and procedures for investigation, and notifications and complaints. The proposed SFCR does however include exemptions for some parties such as businesses with $30,000 or less in annual gross revenue, however such operators will still require preventive control procedures in place.

In addition, the SFCR will also adopt the Codex Alimentarius template of “one step forward, one step back” for every link in the supply chain for enhanced traceability. In the event of a food safety recall, electronic or paper records must be accessible in Canada within 24 hours, which should identify the partner in an immediate forward transaction (e.g. a retailer or another food business), and the immediate backward supplier.  Retailers would not be required to trace forward their sales to consumers.

With such critical initiatives in licensing, PCP, and traceability among others, the SFCR addresses  current concerns and hazards in the food and food-commodity industry. The proposed SFCR in Canada Gazette I, is available HERE and additional information can be found HERE

Natural Health Product Research Society (NHPRS) of Canada hosts 14th annual conference, Beyond Tradition

Posted: Tuesday April 25th, 2017

The Natural Health Product Research Society (NHPRS) of Canada is pleased to host its 14th annual conference, Beyond Tradition, May 8-11, 2017, at the Pinnacle Hotel Waterfront in Vancouver, British Columbia.  With over 250 expected participants, this 4-day event will provide a great opportunity to learn from leaders in the Natural Health Product (NHP) sector, as they discuss key regulatory and quality assurance updates, as well as next innovations in NHP research.  Join the NHPRS as they host speakers from Health Canada, UNPA, USP, AHP, USDA, Chinese Pharmacopoeia, Academia, and key members of the North American health products industry, presenting on current topics in key NHP fields. 

This years’ event will feature focused sessions on Botanical Authentication; Regulatory and Government Affairs; Personalized Nutrition; Industrial Innovations and Emerging Technologies; Ethnobotany, Pharmacology & Traditional Medicine; Modernization of Pharmacopoeial Standards; Gut Health and the Intestinal Microbiome; and Cannabis.  Enjoy a pre-conference workshop, “Frontiers in NHP Research”; participate in the One-to-One Partnering program, and enjoy great social events in Vancouver, including a local Brewery/Distillery Tour and Conference Gala dinner.

Visit the NHPRS website to learn more about this exciting upcoming Canadian NHP industry event! 

Confidential Business Information Disclosure Update

Posted: Monday April 17th, 2017

The Health Minister can disclose confidential business information (CBI) to protect or promote health or safety. A draft guidance document on the disclosure of CBI was published on Mar 10, 2016 and Health Canada underwent a consultation period. Comments received by May 24, 2016 have been incorporated into the revised guidance. A summary of comments received is available on request by email to rmod_stakeholders-intervenants_dgro@hc-sc.gc.ca. This document is intended for health researchers and professionals, patient groups, and pharma and medical device industries. The document includes information on the following.

  • paragraph 21.1(3)(c) of the Food and Drugs Act
  • principals and considerations for Health Canada's exercise of the authority under paragraph 21.1(3)(c) of the Food and Drugs Act
  • protection of personal information and respecting participant's informed consent
  • protection against commercial use
  • maintaining confidentiality of disclosed information
  • process to review requests for disclosure
  • requirements for persons requesting disclosure of confidential business information under paragraph 21.1(3)(c)
  • findings generated from disclosed information
  • forms and additional information:
    • review process flow chart
    • tools for finding regulatory information

Completed CBI disclosure requests under s21.1(3)(c) of the Food and Drugs Act can be found here.

Changes to the Foreign Site Expiry dates on Canadian Drug Establishment Licences

Posted: Monday April 10th, 2017


Effective July 21, 2016, Health Canada has changed the expiry date for foreign building GMP renewal evidence to a NERBY (New Evidence Required By) date.



·       Those who import or are seeking to import drugs from a foreign site listed on the DEL Foreign Annex, including API release testing sites.



·       GMP renewal evidence must now be submitted on or before a NERBY date assigned by Health Canada.

·       Health Canada reviews the submitted GMP renewal evidence, which includes an inspection report. Based on their review, Health Canada calculates a new NERBY date of three to four years from the start date of inspection.

·       Previously GMP renewal evidence had to be submitted 250 calendar days before the expiry date, requiring DEL holders to calculate and track their foreign building expiry dates.

·       Health Canada will not assign a NERBY date for the following (i.e., they must continue to submit GMP evidence 250 calendar days before the expiry date):

o   DELs for API foreign buildings listed on API Annex

o   MRA foreign buildings.



·       The foreign building expiry date is now a "new evidence required by" (NERBY) date.

·       Health Canada determines the NERBY date using a risk-based approach that takes into account factors such as the drug category and/or a building’s compliance history.

·       If Health Canada receives the application along with complete and updated GMP renewal evidence by the NERBY date, the foreign building will continue to be considered GMP compliant and remain on the DEL Foreign Building Annex during the Health Canada review period.

·       If you do not submit your application package to Health Canada by the NERBY date, the foreign building may be removed from the DEL.

·       If Health Canada deems the renewal evidence unacceptable or incomplete at any time during the assessment process, the foreign building may be removed from the DEL. 

·       You can request an extension 90 or more calendar days prior to the NERBY date or expiry date listed on the DEL.

·       Extension requests must be specific to each foreign building, and must be accompanied by an application form (section 5 of FRM-0033 for each foreign building).



1.     Quality & Compliance Services Inc. QuickNote on “Changes to DEL Application Process (NERBY Date) dated January 2017 http://www.qualitycompliance.ca/sites/default/files/QuickNotes/QuickNote_Changes%20to%20DEL%20Application%20Process%20(NERBY)%202017-01-11.pdf

2.     Health Canada DEL Bulletin No. 1 dated July 21, 2016.

3.     Health Canada Guidance on Drug Establishment Licences and Drug Establishment Licensing Fees (GUI-0002) - http://www.hc-sc.gc.ca/dhp-mps/compli-conform/licences/directives/gui-0002-eng.php

Welcome To Regulated Affairs

Posted: Monday April 3rd, 2017

We are excited to be launching a blog for The Canadian Association of Professionals in Regulatory Affairs (CAPRA)!  Your source for timely information on news, events and updates in regulatory affairs in Canada.

CAPRA is the largest and only industry association devoted to individuals working in regulatory affairs in Canada.  We hope that sharing this blog and providing you with updates on Facebook, LinkedIn and Twitter will allow our members to stay connected to the each other and with the various regulators to help build a strong regulatory industry. 

Whether you work in pharmaceuticals, biologics, medical devices, natural health products, food, cosmetics and any other regulated health products, the CAPRA blog will help strengthen your regulatory knowledge and expertise. We will be providing you with informative updates on labelling regulations, Drug Establishment Licensing, the upcoming Safe Food for Canadian’s Regulations, and various other topics to help you keep up with the latest information in the field. Tune in regularly and feel free to share our blog with your colleagues.

We look forward to receiving your feedback  and comments and hope this will be an engaging platform where we can share ideas.

Let's get started!

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