WHY IS IT IMPORTANT FOR SPONSORS/DRUG MANUFACTURERS TO WORK WITH SOMEONE WITH SPECIFIC EXPERTISE IN CANADIAN REGULATORY AFFAIRS?
Having a Canadian regulatory expert is important to facilitate the global Canadian submission process and all post-approval activities. It’s also important to know that Health Canada prefers speaking with individuals that understand the Canadian medical as well as regulatory environment, whether they are the sponsors or their representatives. The support of a Canadian regulatory consultant is key for the submission of clinical trial applications, New Drug Submissions, or other regulatory initiatives. But it is most important for the global product development strategy, particularly when dealing with niche products used for treating orphan or life-threatening diseases. By understanding Canadian as well as foreign regulatory environments, a Canadian consultant can provide the best strategic initiative for timely access to the Canadian market, keeping the global regulatory initiatives in mind.
The regulatory paths for market access in Canada are essentially threefold. First there is the standard regulatory new drug submission path, then there is the notice of compliance with conditions (NOC/c) path, usually applicable for oncology or other niche products, and finally there is the priority review path. The latest two have shorter review standards at Health Canada.
WHAT ARE HEALTH CANADA’S TIMELINES TO PROVIDE AUTHORIZATION FOR A DRUG TO BE SOLD ON THE CANADIAN MARKET?
The Canadian review timeline for a New Drug Submission (NDS) is competitive. A standard review consists of a maximum of 10 days eCTD validation, followed by 45 days administrative screening where it is verified that the content is acceptable and that no key information is missing. Following the screening period, a 300-day scientific review of the quality, non-clinical and clinical data packages, applies. Therefore, a total of 355 review days applies, before a sponsor obtains a final review decision.
Should the NDS qualify for an accelerated review either under a Priority Review or a Notice of Compliance with condition, the review timelines are shorter.
WHAT IS THE DIFFERENCE BETWEEN THE NOTICE OF COMPLIANCE WITH CONDITIONS AND THE PRIORITY REVIEW?
These two processes apply to drugs used to treat conditions that are serious, life-threatening or for a severely debilitating disease (such as Alzheimer’s disease, cancer, AIDS, or Parkinson’s Disease).
Priority Review (PR) applies to drugs that shows substantial evidence of clinical effectiveness at the end of the clinical trial phases, that is, once the clinical development is completed. The total review timeline is reduced from 355 days to 215 days.
On the other hand, the Notice of Compliance with condition (NOC/c) applies to drugs with promising evidence of clinical effectiveness throughout the clinical trial phases. In summary, the NOC/c can be granted with less clinical data than usually expected, that is with Phase II study results or interim reports of Phase III studies. Approval would be granted to a manufacturer to market and sell that drug in Canada with the condition that the manufacturer execute additional studies to confirm the drug’s benefit and safety. The total review timeline is reduced from 355 days to 235 days.
The condition needs to be agreed to with Health Canada. Some of the conditions of the NOC/c may include a requirement to closely monitor the drug for safety and adverse reactions and to provide HPFB with regular updates. Once the conditions are met, the designation of “with condition” is removed from the NOC.
To be considered for PR or NOC/c, the drug considered need to meet specific Health Canada criteria, that can be summarized as follows:
- Offer effective treatment, prevention or diagnosis of a disease or condition for which no drug is available in Canada; or
- Offer an improved benefit/risk profile over existing therapies, preventatives or diagnostic agents for a disease or condition, not adequately managed by a drug marketed in Canada.
Again, discussing with a Canadian regulatory expert in the early drug development stages can be an advantage for early input to establish the ideal regulatory strategy, as well as to help navigate through the requirements that are specific to Canada, while keeping in mind the global market strategy.
WHAT IS A DRUG IDENTIFICATION NUMBER? IS IT SPECIFIC TO CANADA?
A Drug Identification Number (DIN) is a unique eight-digit number assigned to each drug product considered to be compliant to the Food and Drug Act and its Regulations in Canada. It does not apply to radiopharmaceuticals. A DIN uniquely identifies the product manufacturer, product name, active ingredients, strengths, pharmaceutical form and route of administration. This number is assigned to a drug product, provided to the sponsor along with a Notice of Compliance.
WHAT TYPE OF DATA PROTECTION IS APPLICABLE IN CANADA AND HOW DOES IT APPLY?
All drug products containing a new chemical entity are eligible to an eight-year period of market exclusivity. Should the drug product be aimed for a pediatric population, a further six-month extension can apply if the acceptable pediatric data are submitted within the first 5 years of the 8-year period. Health Canada will conduct a preliminary assessment while the drug is under review (NDS) and the sponsor will be notified of the outcome.
Consequently, a subsequent-entry manufacturer is not allowed to file a submission for a generic drug for the first six years of the eight-year period. For products with eligible patents, submission of patent forms within the planned NDS and SNDS is critical to avoid loss of rights and generic entries to the market earlier than the market allows.
IS IT TRUE THAT HEALTH CANADA BASES THEIR DECISIONS IN GREAT PROPORTIONS ON FOREIGN DECISIONS?
This is a major miss-conception. I have seen in many instances, new drugs or new indications approved in Canada while the approval was on hold or refused in foreign countries. Health Canada makes their own independent decisions. However, it is possible (and recommended) to submit the major Q & As issued during the foreign review, along with the Foreign Agency Reviewers Reports. If the submission includes foreign review report, it is recommended to include a completed Foreign Review Attestation Template. The extent to which Health Canada will use foreign reviews varies. The Canadian regulatory decision can be based on a critical assessment of the foreign reviews, on the Canadian review only or on a mixture of both.
WHY IS IT THAT HEALTH CANADA ASKS FOR FOREIGN REVIEWS?
The provision of foreign review reports in an NDS is not mandatory, but highly recommended. Indeed, they are usually requested at screening if not included within the original submission.
In addition, within the Screening Acceptance letter, Health Canada usually requests the sponsor to share the Questions from foreign regulatory agency reviews and the sponsor’s answers, during the review of the NDS.
In my experience and through my discussions with Health Canada, when the Canadian agency has questions that have already been addressed in a response to questions from a foreign agency, it likely reduces the number of questions to be raised to the sponsor, accordingly.
HOW HAS THE EVOLUTION OF REGULATORY AFFAIRS AFFECTED THE WAY CLINICAL TRIALS ARE CONDUCTED NOW VERSUS 10 YEARS AGO?
With regards to clinical trial applications, Health Canada’s requirements have not changed much. However, they’ve had no choice but to open up to new strategies – novel agents, personalized medicines, or orphan drugs for which there is no official designation yet – and accept novel trial designs. Health Canada is very open to hear how novel therapies can help Canadians and there’s a clear openness and opportunity for collaboration.
WHAT ADJUSTMENTS HAVE DRUG DEVELOPERS HAD TO MAKE TO RESPOND TO CHALLENGES ASSOCIATED WITH TARGETED THERAPEUTICS?
The key adjustments for drug developers have been to increase transparency with the authorities and open up to pre-submission or scientific advice meetings. These meetings become even more efficient when you bring in local experts and key opinion leaders.
The purpose of this is to discuss strategies and requirements with the authorities and to come up with agreements for the drug development activities. Meeting with Health Canada is not a requirement, but it’s highly recommended for novel therapies that would not have the same clinical data package that would usually be required or expected in Canada for market access.
With regards to submission content, contrary to common belief, Health Canada follows similar requirements to those of the FDA and EMA, therefore, usually only minor adjustments are necessary from a FDA or EMA dossier when submitting a marketing application in Canada.
WHAT ROLE DOES CANADA AND CANADIAN DATA PLAY IN THE SPONSORS’ OVERALL REGULATORY STRATEGY?
We know we can’t compete in terms of population, but Canada does have numerous strengths, making it a very attractive host for early phase clinical trials. These strengths include highly trained clinicians, the presence of key opinions leaders, world-class investigators, renowned medical care standards and a well-diversified population, all of which are desirable for testing new drugs. In addition, Canada is one of the top countries for biomedical research productivity and international reputation.
WHAT ADVICE CAN YOU OFFER DRUG DEVELOPERS ABOUT CONDUCTING THEIR CLINICAL RESEARCH IN CANADA?
Canada is an attractive region for clinical trials and we clearly recommend that drug developers come to Canada early in their drug development process, for many reasons.
First of all, we have expert physicians in various therapeutic fields, key opinion leaders with internationally renowned reputations, that are clearly interested in participating in Canadian clinical trials. In addition, we have efficient regulatory experts, CROs and clinical trial start-up facilitators helping with the Canadian process efficiency.
Adding Canadian sites to a multi-centre trial is a great initiative to expose expert physicians as well as patients to novel therapies that will eventually come to market, raising interest, awareness and knowledge. The fact that the Canadian population is very similar to that of the US, makes Canada an interesting extension of the U.S. initiative for patient recruitment. This way, our Canadian population can benefit from these novel therapies, while adding to the global clinical trial recruitment initiative.
In addition, the Canadian regulatory agency provides a decision within an efficient standard review of 30 days. Also, early Canadian initiative can build the health authorities’ confidence with a sponsor and product by raising awareness, interest and knowledge. This can translate into facilitating the accelerated access to the Canadian market, should the product meet the requirements.
Should the drug be innovative and / or life-saving, we would recommend a strategic registration regulatory strategy, because of the possibility of having a faster approval granted either during the clinical trial phases or immediately upon completion. A meeting with Health Canada would be recommended to validate the strategy, secure agreements that would be part of meeting minutes, included in the upcoming registration initiative.
IS IT TRUE THAT HEALTH CANADA’S CLINICAL TRIAL APPLICATION PROCESS IS COMPLEX, SLOW AND INEFFICIENT COMPARED TO THE SUBMISSION PROCESSES IN THE US OR EU?
I’ve heard that many times before but it’s actually the opposite. When the process is properly understood and the sponsor or the representatives have established contacts with Health Canada, the clinical trial application in Canada is relatively simple and so is the review process. The actual submission structure is also simple, and the content requirements are actually less than in the US and Europe.
There are no non-clinical, nor clinical study reports needed in the clinical trial application. What is needed is the administrative documents plus key scientific documents, which are the protocol, the informed consent form and the investigators brochure. There’s two Canadian specific templates required that we need to generate: the protocol summary as well as the overall quality summary. All of these are quite easy to prepare.
The review process is also efficient. A 30-day default review period applies. If questions are raised during the dossier review a response must be provided within two calendar days (exceptions may apply). And by way of comparison, in Canada there is no clinical hold period like in the United States. The review period is always 30 days, whereas in some European countries the review period can be as long as 60 days or more, and in the US it can vary.
Due to the standard 30-day review period in Canada, I believe it does facilitate the ethics review submission planning, which speeds up clinical trial start times. Also, there are efficient clinical trials start-up experts in Canada that helps with streamlining the study start-up processes in parallel or after the clinical trials application approval.
IS HEALTH CANADA OPEN TO EARLY PHASE TRIAL DESIGNS OR PREFERS LATE PHASE STUDIES WITH COMPOUNDS CLOSE TO APPROVAL?
Health Canada is very open to all phases of clinical trials for both early and late phase. If the product is innovative or has the potential of being granted an NOC/c, we do recommend that sponsors meet with Health Canada early to ensure that the study trial design and the clinical development plan is aligned with the requirements for an accelerated access to market.
DOES HEALTH CANADA REQUIRE THAT ALL STUDY DOCUMENTS AND TOOLS BE TRANSLATED TO FRENCH?
Not at all. Both official languages in Canada, that is English and French, are accepted. That being said, the regulatory dossiers are usually submitted to Health Canada in English. French dossiers, or the supporting documents that are in French, are also acceptable, however, the review could be a little more challenging since most of the Health Canada reviewers are Anglophone. Even if it is not required to submit French documents to Health Canada, the French translation of the informed consent form must be generated and available for francophone patients. Also, there are specific language regulations to respect on Canadian labels. That being said, Health Canada has established standard target review timelines that they respect, which is not influenced by the selected submission language.
DOES HEALTH CANADA REQUIRE THAT ALL SPONSORS HAVE A LEGAL OR SCIENTIFIC REPRESENTATIVE THAT RESIDES IN CANADA FOR CLINICAL TRIAL APPLICATIONS?
A scientific or medical officer residing in Canada that represents the sponsor and who’s responsible for providing an attestation with respect to the clinical trial application or the amendment that is being filed, is required. There is no additional information available in the regulations or guidance related to the Canadian officer. Therefore, any Canadian scientific personnel that are authorized by the sponsor to submit the application on their behalf and to be the representative can be the signatory. Normally the regulatory agent or the CRO can sign the clinical trial application on behalf of the sponsor.
DOES HEALTH CANADA REQUIRE THAT ALL SPONSORS HAVE A LEGAL OR SCIENTIFIC REPRESENTATIVE THAT RESIDES IN CANADA FOR THEIR REGISTRATION DOSSIERS?
No, Health Canada does not. Nonetheless, if the sponsor is not located in Canada, a Canadian importer must be determined and their Drug Establishment Licence (DEL) submitted or amended at least 3 months prior to the submission of the marketing authorization submission (NDS or ANDS) in Canada. This is one of the Good Manufacturing Practice requirements.
That being said, having a Canadian regulatory point of contact in Canada is an advantage for the Canadian regulatory language with Health Canada as well as for dealing rapidly with questions, being in the same time zone as the reviewing regulatory agency.
IS IT TRUE THAT UNLIKE THE UNITED STATES FDA WHERE THE IND SUBMISSION MAY COVER ALL PROTOCOLS FOR A SINGLE COMPOUND, HEALTH CANADA REQUIRES THAT A NEW CLINICAL TRIAL APPLICATION SUBMISSION BE DONE FOR EACH AND EVERY PROTOCOL WITHOUT EXCEPTION?
This is partly false. Presently, drug developers may submit more than one protocol into one single clinical trial application (CTA), when the Application is submitted to the Therapeutic Drug Directorate (TPD). Each protocol would then be considered a different dossier with a different control number per protocol; an approval per protocol would apply. When the CTA is submitted to the Biologic and Genetic Therapies Directorate (BGTD), one protocol only can be submitted per CTA. The upcoming electronic submission requirements for the CTA will likely impose the submission of one protocol per CTA for both Directorates.
Even with these differences, globally the process is quite similar in the US and Canada, however, the terminology used is different and this can cause some confusion.
In the U.S., we see one IND per product under clinical development, which is open to adding new protocol amendments etc… Clinical holds can apply to these INDs and the duration of the holds may vary. In Canada, there is a clinical trial application process, whereby one or more protocols can be submitted at once. New protocols are submitted as new CTAs. There are amendments and notifications that can be brought to clinical trial applications that are approved.
An amendment is considered a major change to an approved protocol or quality dossier, and therefore requires the same 30-day default review period. Minor changes are submitted as notifications within 15 days of the implementation of the change and no review period applies. Now, as mentioned, a new protocol must be submitted via a new clinical trial application. However, cross-referencing to an approved clinical trial application already on file for sections that are not changed, is possible. For example, cross-referencing to an approved investigator’s brochure or to an approved quality dossier. Therefore, it reduces the submission requirement and content. The process is simple and very similar to an IND amendment in the U.S., even if it’s classified as a clinical trial application in Canada.
WILL HEALTH CANADA APPROVE CLINICAL TRIALS DESIGNED WITH MORE THAN ONE INVESTIGATIONAL PRODUCT?
Yes, definitely. With the appropriate quality information for both investigational products, Health Canada will review the dossier and approve it if it meets the Canadian requirements, and that will be under the same 30-day default review period.
ARE HEALTH CANADA’S SAFETY FOLLOW-UP POLICIES AND GUIDELINES MORE STRINGENT THAN THOSE IMPOSED BY THE FDA?
No. The requirements are similar in Canada and in the U.S. for clinical trial applications as well as for post-approval initiatives.
DO WE NEED TO PROVIDE HEALTH CANADA WITH THE LABELS OF CLINICAL TRIAL DRUG PRODUCTS?
No, clinical trial drug products labels do not need to be submitted at the time of the Clinical Trial Application. Labels must conform with section C.05.011 of the Food and Drug Regulations, in both official language, and should be provided to Health Canada upon request.