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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.

Footnotes:

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

References:

https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/announcements/upcoming-changes-annual-drug-notification-form.html

 




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

Introduction
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

graph

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

graph2

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].

Conclusion
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.

References:

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.

Reference:

Questions and Answers: Plain Language Labelling Regulations

https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/pll_qa_fin_qr_elc-eng.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.




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:

chart

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.

Reference:

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:

https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/notice-stakeholders-updates-drug-establishment-licence-applications-good-manufacturing-practice-evidence-requirements-active-pharmaceutical.html

WHO DOES THIS APPLY TO?

·         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

WHAT’S NEW

·         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.

References:

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

https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/notice-stakeholders-updates-drug-establishment-licence-applications-good-manufacturing-practice-evidence-requirements-active-pharmaceutical.html

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.

References

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

OVERVIEW

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.

 

WHO DOES THIS APPLY TO?

·         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.

 

WHAT’S NEW

·         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”

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

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*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:

[Untitled]

Source: Electronic Submissions Update presentation at RAPS2016: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/
FormsSubmissionRequirements/ElectronicSubmissions/UCM522105.pdf

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.

Reference:

http://www.hc-sc.gc.ca/dhp-mps/marihuana/about-apropos-eng.php




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.

References
1.http://www.cmaj.ca/content/189/18/E659

2.https://www.canada.ca/en/health-canada/services/substance-abuse/prescription-drug-abuse/opioids/about.html

3.http://www.hc-sc.gc.ca/ahc-asc/legislation/acts-reg-lois/frp-ppr/2016-2018/opioid-opiode-eng.php




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).

Regulations

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.

Background

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.

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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

OVERVIEW

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.

 

WHO DOES THIS APPLY TO?

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

 

WHAT’S NEW

·       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.

 

KEY POINTS

·       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).

 

References:

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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