Staying abreast of drug regulatory landscapes is understandably a challenge; the environment can be challenging to master because of its complexity and the fact that it is continuously changing. Innovations in both science and data collection/reporting methods keep the landscape fluid; it takes rigor and devotion to stay current.
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In Canada, as in all countries with regulatory agencies, there are specific regulatory pathways and processes for health products to be authorized for use in clinical trials or to obtain marketing approval. This article will focus on what is called the New Drug Submission Process in Canada. If you are looking to conduct a clinical trial in Canada or submit for the marketing authorization of a new health product, it is important to be familiar with the new drug submission process in Canada and what other regulatory processes look like, including the pathways that are available to you to achieve this.
We will present the principal regulatory process for drug approval with Health Canada. The regulatory process for other health products, including Medical Devices, will be covered in subsequent articles.
Regulatory affairs in relation to clinical trials or investigational testing refers to the process of ensuring that a trial conducted with patients or healthy individuals adheres to all relevant laws and regulations during the drug, medical device, or other health product clinical development process. This includes getting necessary authorizations from regulatory agencies governing the country where the sponsors wish to launch a trial.
In Canada, that regulatory agency is Health Canada (HC). The goal of HC, its Food and Drug Regulations, and regulatory processes is to protect the health and safety of the participants in those trials and ensure the accuracy and integrity of the data collected; this includes the reporting of any serious adverse events that occur during the studies. HC is interested not only in the safety of trial participants; data accuracy and integrity are as important and are needed for the eventual market access application you will submit at the end of the clinical development process.
Most countries have their own regulating body, for example, the Food and Drug Administration (FDA) in the United States (US), European Medicines Agency (EMA) in the European Union, Therapeutic Goods Administration (TGA) in Australia and the Central Drugs Standard Control Organization (CDSCO) in India, to name a few.
What they have in common is that the approach to trials, drug development, and market access process be transparent and efficient whilst ensuring the safety, efficacy, and quality of the product for their citizens.
In Canada, Health Canada has various licensing pathways for drugs, medical devices and other health products and they continue to work towards different pathways to facilitate market access of key health products, particularly those for unmet medical needs.
The regulatory strategies and submission work are done by regulatory experts; professionals well-versed and experienced in how each regulatory body evaluates and approves New Drug Submissions (NDS), Medical Devices License Applications as well as other health product applications in Canada or their equivalent outside Canada.
Specifically, the drug approval pathways in Canada are summarized as follows:
NDS stands for “New Drug Submission” in Canada, other acronyms would apply outside Canada. It is the regulatory process required by Health Canada that pharmaceutical companies are required to go through to bring their new drugs to the market. The submission must include all relevant data and information about the drug, including non-clinical, clinical, and quality data, which address safety and efficacy as well as the overall quality (chemistry, manufacturing, and controls) of that drug. Health Canada reviews this information to determine if the drug is of good quality, safe and effective (positive benefit vs. risk ratio) for its intended use. Only then can it be approved for sale to the public.
The standard timeframe for scientific review of the NDS is 300 days, preceded by a screening period of 45 days and 10 days of technical processing, as indicated below:
A Priority Review (PR) New Drug Submission (NDS) is a type of regulatory filing submitted to Health Canada for the review of a new drug, at the end of its clinical development program, that is considered to have the potential to provide significant benefit over existing therapies (when available) for serious or life-threatening conditions. PR NDSs are prioritized over standard NDSs and are scientifically reviewed within 180 days, rather than the standard review time of 300 days. This expedited review process is intended to help bring new, innovative treatments to patients in need more quickly.
To apply for a Priority Review NDS, a sponsor must demonstrate that the drug is to be used for a serious, life-threatening, or severely debilitating condition when there is substantial evidence of clinical effectiveness that shows the following:
In summary, Priority Review New Drug Submission Process in Canada allows for drugs with a complete clinical program that address important unmet medical needs. The sponsor has to apply for a PR through an official request supported by a Clinical Assessment Package, justifying scientifically and with sufficient data why the submission should be granted PR rather than following the standard NDS process.
The Priority Review process differs from the regular NDS process as presented below:
The Notice of Compliance with Conditions (NOC/c) pathway allows a sponsor to bring a new drug to market during the clinical development process, and therefore more quickly, in exchange for accepting to complete the clinical development program agreed to with Health Canada. An approval under the NOC/c policy contains conditions that a sponsor needs to comply with after the drug approval.
Eligibility
Eligibility for advanced consideration for a NOC/c applies to NDSs and SNDSs for serious, life-threatening, or severely debilitating conditions when there is promising evidence of clinical effectiveness based on the available data that shows the following:
NOC/cs are possible for drugs with promising clinical data that addresses important unmet medical needs. The NOC/c process differs from the regular NDS process as presented below:
This refers to the use of existing scientific literature or third party published data in lieu of clinical study reports to support the safety and efficacy of a drug. Literature can be used to support a New Drug Submission (NDS) or a Supplemental New Drug Submissions (SNDS) in Canada.
This approach saves time and resources for both the sponsor and HC, provided that the submission complies with the criteria established by HC. The literature must be relevant, reliable, and adequate to support the safety and efficacy of the drug in question and meet current regulations, guidelines and recommendations. The chemistry, manufacturing and controls (quality) data requirements are the same as for any other NDSs or SNDSs.
In addition to the pathways summarized above, HC does explore additional pathways to facilitate drug development to address unmet medical needs and to streamline their own processes, for example: Australia-Canada-Singapore-Switzerland (ACSS) Consortium and use of foreign reviews and decisions.
Project Orbis is another example of an international partnership HC is a part of which is designed to give cancer patients faster access to promising cancer treatments, alongside the US FDA. Products eligible for Project Orbis include oncology products that are either new active substances or new indications for previously approved drugs. Project Orbis submissions are expected to meet the criteria for “FDA Priority Review” and Health Canada PR or NOC/c criteria.
The various programs or pathways presented above can be explored with the assistance of regulatory experts, when a sponsor wishes to obtain a marketing authorization for a new drug in Canada. The various submission types have to respect specific criteria established by HC, which further underscores the need to work with regulatory experts that can orient the sponsor towards the most relevant and efficient pathway to use.
Once Health has reviewed the submission and determined that the drug is safe and effective for its population, they will issue a Notice of Compliance (NOC), which grants the sponsor permission to sell the drug in Canada.
After an NOC has been granted for a new drug in Canada, maintaining the drug on the market requires various compliance activities, including pharmacovigilance and lifecycle management to ensure that the drug continues to be compliant with the requirements of the Food and Drug Regulations. Life cycle management activities could include a Supplemental New Drug Submission with new data from clinical trials to support a new indication or other important changes to the labelling of the drug. Likewise, major changes to the manufacturing process, or adding new formulations or a new dosage form, for example, would also require a submission to HC to ensure compliance with the regulations. For major changes that require approval from HC, a new NOC will be issued once HC has reviewed the submission and supporting data and, determined that the changes are acceptable; only then these changes can be implemented.
Whichever pathway you utilize, it is imperative that the approach be one that is streamlined, transparent, and efficient, while ensuring the quality, safety, and efficacy of the product. It is the role of regulatory experts to strategize with you about which pathway to follow, and to navigate these applications through HC or their equivalent outside of Canada, to liaise with regulatory body officials, and lead the submission process.
For further information about the drug review & approval process in Canada, or about the New Drug Submission Process with Health Canada or to have a complementary discussion about your needs, please contact SPharm directly.
With a quarter of a century of consistent and successful results, SPharm has become one of the leading Drug Regulatory Advisory firms in Canada. Drug companies from around the world count on SPharm to help them navigate the drug (and other health products) review & approval process in Canada.
Avec un quart de siècle de résultats et de succès constants , SPharm est devenue une entreprise de services de référence au Canada en stratégie de développement de médicaments et affaires réglementaires. Des compagnies pharmaceutiques à travers le monde comptent sur SPharm pour faciliter le processus d’homologation de leurs médicaments (et autres produits de santé) au Canada.
Well-defined and appropriately supported regulatory needs increase the likelihood of successful submissions and market access. So how does one go about determining what those regulatory needs are or might be, especially when embarking in a health product development process at its initial stages?
Also, are there different considerations for pharma, biotech, and investigator led trials?
The short answer is yes.
It takes experience to establish a good health product development strategy and to build trust and communication channels that clearly communicate its details. Get it right, and you can reduce possible errors, save time and money, and lessen the steep learning curves that are common at the start of a mandate.
Together we will look more closely at the considerations for starting to define needs as a whole whether you are Pharma, Biotech or an Academic institution. Let’s look at the unique needs for each:
As a pharma, you have regulatory professionals on board. In instances when in-house staff does not have the expertise required in a specific situation, you will need to hire for a specific need, an expert to work in collaboration with your team. (i.e. orphan drugs, oncology, products that can be considered for priority reviews or NOC with condition, literature-based dossiers, etc.). In instances when workload is very high, or during peaks of activity, external professionals will act as an extension of your team and alleviate congestion, avoid delays and ensure timelines are respected.
For a biotech, particularly start-ups, it is unlikely to have a regulatory expert on staff. Development is costlier with biology / biotech products which means that cost efficient health product development is key. Considering the greater health product development costs for biotechnology companies, the impact of failures and errors is more significant. As a biotech, one of the most significant impact that a regulatory professional’s expertise and regulatory intelligence will have is in streamlining the regulatory process. They will increase efficiency to save you time and money.
It isn’t uncommon for investigator driven clinical trials to commence without at least an initial consultation with regulatory agencies. This typically happens when the investigators are unfamiliar with the characteristics and requirements of the regulatory process or don’t consider that the obligations apply equally to investigators as they do pharma and biotech start-ups. For some others, it’s seen as a viable cost-cutting measure until they see once in the trial that, had they had a regulatory professional to draw on in the planning stages, it would save more time, cost less money, and increase efficacy. The obligations are the same whether the sponsor is a manufacture or an investigator and it’s important that the clinical trial initiatives are developed in line with regulatory obligations and Good Clinical Practices (GCPs). A regulatory affairs professional will be able to ensure the study starts off in observance of the applicable regulations and GCPs.
Also, all studies conducted with a health product have the potential to be included in a registration dossier, making having a regulatory professional involved from the moment you begin to think about planning a study is a significant advantage. An expert who can help plan the health product development efficiently, including clinical development, such that no investment is lost via suboptimal planning is particularly important.
Whether you are a sponsor in pharma, a biotech, or an investigator, you will need regulatory support from inception to submission, and a good way to begin a needs assessment is with questions at the research planning stages that shape the thinking process; there are three in particular that are wise to consider at the start.
Best practices assert that the earlier a regulatory expert is brought on, the better the outcomes. A way to look at this is, bringing in a regulatory professional on for the first time at the submission stage, would be akin to hiring a boat maker after you’ve already built a boat and want help to put it in the water.
Hiring at the start to define needs and formulate a strategic regulatory plan produces three significant advantages:
Deciding whether to hire for the entire process, or part of it.
Needs change and issues can arise because both the product development and regulatory landscape evolve. New laws and regulations, requirements, and even innovations have the potential to affect health product development strategies. Regulatory professionals understand this and work it into their strategic plan, making it possible to anticipate changes and overcome challenges should they arise. The importance of being responsive to these events means that needing to find, hire and transfer knowledge (and all that this entails) would be wasteful of all resources as compared to having a team or dedicated professional involved (and informed) from the start.
Is it possible to use different professionals for different parts of the process?
Throughout every study there is a need for different skill sets and experience. A team (it can be a small one with proven experience) comprised of professionals with deep knowledge of specializations within the health product development and lifecycle management, not only will enable time to not be lost on learning about the project, but also consistency will be maintained in communications with regulatory authorities.
Still, if you opt to go the route of trying out different professionals for different parts of the process, keep in mind the importance of using a polyvalent expert to optimize information and reduce the time and money investment. It speaks directly to the costs associated to the project(s) learning phases. Subject matter expertise is a driving force in how well the development process unfolds because specialists are able to help you avoid and overcome concerns, changes, challenges or other issues along the way. Their work can help reduce overall cost, alleviate workload, and improve timelines.
To ensure that you’ve hired an excellent professional or firm, please read our post on the subject.
The more consistent the team, the lesser mistakes and errors are encountered. Adherence to regulatory requirements are best achieved with the guidance and support of a regulatory affairs professional. This has many benefits, including increasing the worth of the clinical study or development strategy by respecting regulatory paths, for future inclusion of studies/science in a registration dossier.
Hire a professional early – very early, in fact, at the planning stage so that your needs can be delineated by an experienced professional who can established a plan that will allow the drug development strategy to be responsive to changes. Regulatory needs may change depending on whether you’re in pharma, biotech, or an independent investigator, consult with a regulatory expert before you begin to ensure that nothing is missing within your health product development strategy and / or your study design, in other words, you will want to make sure that your plans will build a boat that floats.
With a quarter of a century of consistent and successful results, SPharm has become one of the leading Drug Regulatory Advisory firms in Canada. Drug companies from around the world count on SPharm to help them navigate the drug (and other health products) review & approval process in Canada.
Avec un quart de siècle de résultats et de succès constants , SPharm est devenue une entreprise de services de référence au Canada en stratégie de développement de médicaments et affaires réglementaires. Des compagnies pharmaceutiques à travers le monde comptent sur SPharm pour faciliter le processus d’homologation de leurs médicaments (et autres produits de santé) au Canada.
Press release celebrating 25 year anniversary in Regulatory Affairs. SPharm – Canada’s Drug Regulatory Experts.
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“Know thy self” is as important in life as it is in the development lifecycle of a health product – be it a drug (pharmaceutical, biologic or biotechnical), a medical device or other; particularly as you embark on finding the “perfect” fit in the regulatory employee or consultant you bring on.
In fact, the accelerated use of technologies in life sciences, such as stem cell research, gene therapy, real world evidence, mobile medical devices, and cloud computing to name a few, underscores the necessity for picking the right regulatory affairs professional.
Organizations in the Life Sciences continue to advance effective risk and compliance programs, for instance, by incorporating cyber security practices to safeguard patient data as well as corporate assets. As this new landscape emerges, regulatory affairs professionals will, more than ever, need to be agile and informed enough to meet upcoming and unexpected challenges.
Determining who that regulatory professional is depends largely on your goals. Regulatory professionals must be skilled at taking into consideration complex global dimensions – including multinational supply chains for product manufacturing, global shipping, sales, and various marketing and post-approval surveillance requirements for multiple regions.
In January 2016, the FDA released post-market guidance outlining its cyber security expectations for medical device manufactures already in the field and in the pipeline. Other similar initiatives are being either considered or implemented in various countries.
As of January 2019, agencies such as Health Canada require companies to undergo MDSAP audits. knowledge in this area is essential as companies react to the slow adoption of a global regulatory assessment process.
Because the health product/medical device development process is a complex and ever-changing one; you want to be confident and at ease with who you will have chosen to be at the helm. Here, we will look at what credentials matter, where to find Regulatory Professionals, and fit (i.e. how well the person is likely to interface with your team).
Most people who make the transition into the regulatory profession have relevant prior experience in related fields (e.g., research and development, quality or a clinical profession). Typically, they will hold at minimum a bachelor’s degree in science, preferably in chemistry, biochemistry, pharmacy, pharmacology, or pharmaceutical technology. However, this alone doesn’t make a good regulatory affairs professional.
There are several organizations and university departments that offer training / certifications in regulatory affairs, whether the candidate is experienced or not. Look for a professional who has the following credentials or training when hiring:
-Regulatory Affairs Certification, the RAC credential, is a well reputed, accredited, post-academic, professional credential for the regulatory professional working in the healthcare product arena, overseen by RAPS.
-RAPS (Regulatory Affairs Professionals Society) is a renowned organization that offer certification in regulatory affairs for medical devices and/or pharmaceuticals. Their numerous online courses cover essential concepts of healthcare product regulation and regulatory issues at each stage of the product lifecycle and for different regions of the world.
–D.É.S.S. en développement du médicament of the University of Montreal, offers courses specific to the global health product development.
-AAPS (Academy of Applied Pharmaceutical Sciences) This certification program provides the comprehensive background and training required of regulatory affairs professionals to address domestic and international regulatory statutes and laws. Its program includes courses on International, Health Canada, and FDA’s laws, regulations, and Guidelines, investigational and marketing applications, technical writing, negotiation skills, development of New Drug Application (NDA) submissions, labeling and drug Information, Common Technical Documents (CTD), Notice of Compliance (NOC), Good Clinical Practices (GCPs), requirements for ongoing post-marketing surveillance and post-marketing changes, communication and management skills essential for the successful regulatory affairs professional in an industry work environment.
Now, as helpful as a candidate’s background or certifications may be, there is one thing that trumps both: experience.
In an industry that is as ever-changing and complex as this one, professionals with a vast amount of experience bring to the table the most valuable skills, knowledge, insight and results.
There are attributes that are essential parts of all roles and positions. In regulatory affairs, the traits of a candidate matter as much as their experience.
We delved into the role of a regulatory affairs expert and outlined the traits necessary for an excellent professional. You can read the full article here. In the meantime, these are some of the skills and traits to look for:
TRAITS: Collaborative Leader, Logical, Analytical, Meticulous, Collaborative & Flexible, Diligent, Passionate
SKILLS: Able to perform under stress, Regulatory Intelligence, Project Management, Excellent verbal & written communication
-RAPs, AAPS, may be able to direct you to a list of graduates.
-LinkedIn is an excellent platform to find professionals who have the experience and certification you are looking for, in particular, look at the various groups within the industry such as:
-When hiring an individual to join your staff, look at the scope and length of experience directly associated to the work you need done. This is a role that a person needs to come in knowing how to do well, not a role that they can take time learning on the job. You’ll want someone seasoned and well connected; someone with the ability to adapt to such difficult circumstances. Flexibility too, is a desirable quality for working in such a complex and changeable landscape; it also happens to be one of the cornerstones of successful consultancies.
-When looking to hire an independent consultant or an outside firm like SPharm, understand that these consultants have gained a range of experiences in different markets and industries, allowing them to bring diversity of thought, experience and expertise to clients. They have also established a strong network relationships within the industry through dealing with multiple clients, colleagues and regulatory agencies. This network is an invaluable asset.
-When hiring a regulatory consultancy, much like SPharm, look at the profiles of their staff and how the team as a whole reflects the necessary broadness of skills and experience. Read any articles, posts and reports they produce because they will demonstrate depth of knowledge. If there are webinars, slide decks, whitepapers, eguides or books they have prepared or authored, watch those to also gauge their depth.
By its very nature, a regulatory consultancy must be absolutely well versed and informed on any and all regulatory specific changes, both locally and internationally. This knowledge presents an enormous advantage and opportunity for businesses seeking to hire them.
In addition to the traits above and the requisite skills and experience, you want to know that the person or company you hire has the respect and recognition of Regulatory Agencies and peers. A large and important aspect of the job is facilitating and navigating the complex regulatory landscape.
Finding the right regulatory professional has less to do with the role itself and more to do with alignment to your company culture. This is where the notion of “Know Thy Self” becomes particularly important.
When hiring an individual, look at whether their aspirations match the job. Does the candidate fit into your growth plan for your business beyond filling a need you have right now? How do they want to grow their career in next several years and do they think this job with you can help them fulfill their aspirations? Getting a sense of both aspects will help you determine whether or not there is alignment between the candidate and your company’s goals.
Next, vet them appropriately. Applicable to both candidates and consultancies, it is important to understand how they work and who they are as a co-worker/service provider. You know the experience and traits you’re looking for, now it’s a matter of matching their past performance to the desired output you want. This involves vetting their references and asking pertinent questions to get an idea of their capabilities and work ethic.
Pay attention to the questions they ask; their questions show preparedness and engagement on the part of the candidate. The best hires care about the team they’ll be on or the company they are providing services to; they care about how they can help take your company forward. Questions will demonstrate their knowledge of the industry, and how apt they are – especially service providers – to understand the unique needs and goals of your organization.
Finally, be crystal clear about expectations. They might end up wearing several hats and going above and beyond. Working in the regulatory space isn’t easy, and while it is rewarding, it’s important to make sure candidates know they are going to work in frequent shifting conditions.
Always trust your instincts. You might be in a hurry to hire but hiring right matters more than hiring now.
With a quarter of a century of consistent and successful results, SPharm has become one of the leading Drug Regulatory Advisory firms in Canada. Drug companies from around the world count on SPharm to help them navigate the drug (and other health products) review & approval process in Canada.
Avec un quart de siècle de résultats et de succès constants , SPharm est devenue une entreprise de services de référence au Canada en stratégie de développement de médicaments et affaires réglementaires. Des compagnies pharmaceutiques à travers le monde comptent sur SPharm pour faciliter le processus d’homologation de leurs médicaments (et autres produits de santé) au Canada.
How are drugs reviewed in Canada is a question often asked. What follows is a summary of the Drug Review and Approval Process in Canada – an eGuide in accordance with the Food and Drugs Act (FDA), the Food and Drug Regulations (FDR), the related policies and Health Canada guidelines.
For a drug, a biologic or a genetic therapy, a medical device, a combination product, a natural health product or other health product company seeking approval of their product for sale in Canada, it is important to understand that the approval process is subject to close scrutiny by the governing regulatory body.
However, the review process and preparing for that review process does not have to be complex, intimidating, nor frustrating. The key is to know, follow and/or clarify the process related to the health product of interest and ensure preparedness with proper data and documentation.
Most health products, including drugs to be marketed or sold in Canada are reviewed and authorized by the Health Products and Food Branch (HPFB) of Health Canada, more precisely, under the Therapeutic Product Directorate (TPD) or the Biologic and Genetic Therapies Directorate (BGTD), for drugs and biologic, respectively. Each of these Directorates have specific offices and bureaus. Drugs are authorized to reach that market only once they have successfully gone through the relevant Bureau review process, responsible for assessing their safety, efficacy and quality, and, received a favorable decision. Even after a health product receives a favorable decision and can proceed with its sale in Canada, monitoring of its effectiveness and safety continues.
Health Canada’s HPFB is the national authority that is responsible for regulating, evaluating, and monitoring the safety, efficacy, and quality of drugs, biologics, genetic therapies and other health products available for the Canadian marketplace. The HPFB’s mandate is to manage the health-related risks and benefits of health products and foods for Canadians.
We have categorized the drug development process in 5 stages and have provided a graphic below to accompany the text.
Researchers start by discovering and identifying various chemical, biological substances or other products on the way towards developing a drug. This can be done through new information regarding a disease process, many tests of molecular compounds to find possible beneficial effects, existing treatment that have unanticipated effect and new technologies. Once the researchers have identified a promising compound, they perform testing for activity, efficacy, toxicity and ultimately, gather preliminary information on its effectiveness and safety. This initial research can take a few years of experimentation. If the results are promising, researchers will proceed to the next step of development.
A representation of the Drug Development Process is presented in the graphic below:
The next step in development is where researchers administer the drug to selected species of animals (in vivo) or cells (in vitro). The drug must be shown to cause no serious harm (toxicity) at the doses required to have an effect. If results from these initial studies are promising and further tests show acceptable safety levels and clear or potential efficacy, then the next step would be to submit a Clinical Trial Application to the TPD or BGTD for authorization to allow human participation in a Canadian clinical trial.
All drugs authorized to be marketed or sold in Canada must have been studied in clinical trials. The information gathered from these trials are then included in the relevant regulatory dossiers to be reviewed for the drug to be eventually authorized for sale in Canada by the HPFB, through its relevant Directorate. The results of clinical trials conducted in humans are key components of the review process by the HPFB. The purpose of a trial is to gather clinical information about a drug’s effectiveness, safety, determine best dosing/usage in humans, evaluate any adverse drug reactions and compare results to already existing treatments for the same disease or condition or, to placebo when no treatment already exists for the aimed pathology (when ethically possible).
Clinical Development:
If clinical trials have already been done in Canada and/or in other countries, that is, at the end of the clinical development plan, the sponsor may choose to file a New Drug Submission with the HPFB in order to gain authorization to market and sell the drug in Canada (see New Drug Submission process section below).
However, when a sponsor aims to conduct a clinical trial in Canada, during the clinical development program, then a Clinical Trial Application (CTA) must be submitted to be reviewed and approved by the HPFB’s relevant Directorate in order to proceed with the trial. The results of these studies will be part of the drug approval process.
What is the Clinical Trial Application?:
The Canadian CTA dossier consists of the following documents (exceptions are possible): administrative form, protocol, protocol summary (Health Canada’s template), Informed Consent Form, Investigator’s Brochure and quality dossier summary (Health Canada’s template per study phase).
Health Canada reviews the CTA and notifies the sponsor within 30 calendar days from the date that the application is considered complete. Questions may be issued during the review, and the sponsor will have 2 calendar days to provide the response (exceptions can apply). Note that CTAs are required for phases I to III clinical trials. The authorization (No Objection Letter) is mandatory prior to initiating the trial and importing the investigational product(s) in Canada.
If the HPFB provides authorization, the study can be underway with human subjects that are informed and have given their consent to be administered the drug for their participation. Note that a Canadian Ethic Committee must also approve the study material (protocol, Investigator’s Brochure and Informed Consent Form). Tests are conducted in a controlled environment where drug administration procedures and results are closely tracked, monitored and analyzed.
What are the Clinical Trial Phases?
There are, in summary, four (4) phases in the clinical trials process. Each clinical trial phase for drugs has a different purpose.
Phase 1 – The Safety phase
This phase usually tests an investigational drug on a small group of healthy individuals for the first time (except when not ethically acceptable to do so). The purpose is to determine the pharmacokinetics/pharmacological action of the drugs, find a safe dosage range and identify adverse drug reactions.
Phase 2 – The Effectiveness phase
In this phase, the drug is given to a larger group of individuals with the pathology to be treated (usually several hundred). The purpose is to obtain data on the effectiveness of the drug, to further assess the drug’s safety and to determine the best dose.
Phase 3 – The Confirmation Phase
If the results from Phase 2 look promising, the drug manufacturer would proceed into Phase 3 trials. In this phase, the drug is given to even larger groups of patients (usually in the thousands). The purpose of this phase is to confirm the drug’s effectiveness, monitor side effects, compare the drug to other commonly used treatments and to collect further information that will allow the drug to be used and marketed safely.
Phase 4 – The Monitoring phase
Phase 4 trials are done after the drug is already approved and sold on the market. The purpose of this phase is to gather more information on the best ways to use a drug, and the long-term benefits and risks to the population. Unless agreed to with Health Canada, these studies do not need to be submitted under a Clinical Trial Application, when used according to the terms of the market approval.
If the drug is to be used outside the terms of the market approval (that is in a different population, for a different indication, using a different dose, etc.), the study will not be considered a phase IV. Consequently, in these cases, a CTA will need to be submitted to Health Canada in order to obtain a No Objection Letter.
What is New Drug Submission Health Canada (NDS)?
If results of all the preclinical studies and the clinical trials show that a drug’s potential therapeutic benefit outweighs its risks (side effects, toxicity, etc.), and the chemistry and manufacturing dossier is complete, then the sponsor may decide to file an NDS with the appropriate HPFB Directorate in order to be granted authorization to sell the drug in Canada. A sponsor can submit an NDS whether the clinical trials were done in Canada or in other countries. The NDS must include the results of the quality (Chemistry and manufacturing), preclinical and clinical studies, whether done in Canada or in other countries.
The drug’s efficacy and safety data is evaluated and the Risk/Benefit analysis is performed, before reaching a decision.
The information requested by Health Canada as part of an NDS application must be detailed enough that Health Canada can make an assessment on the safety and effectiveness of the new drug. All submissions must be provided to Health Canada in an electronic Common Technical Document (eCTD) format.
For a more complete look at NDS, please review our article on the New Drug Submission Health Canada Process.
What is a Common Technical Document?
The CTD format originates from the International Conference on Harmonization (ICH) initiatives, in their effort to harmonize efficacy, safety and quality (chemistry and manufacturing) requirements globally for the registration of drugs (pharmaceuticals, biologicals, genetic therapies, …) for human use. This initiative includes standard information organization for new drug registration applications. The CTD format is divided into five modules: Module 1 contains region-specific information and Modules 2–5 contain common clinical, nonclinical and quality information with some regional variations.
The CTD format is presented below.
The Module 1 (regional) includes the following, amongst other information:
What is an Abbreviated New Drug Submission (ANDS)?
The ANDS regulation was created to make the approval process for generic drugs simpler and more cost effective. Under an ANDS, the manufacturer of a drug has to prove that its product is pharmaceutically equivalent and/and bioequivalent with the innovator’s drug. For the purpose of an ANDS the sponsor may need to perform a bioequivalence study or a physico-chemical comparison (parenteral drugs or drugs for which it is not ethical to conduct the study on healthy volunteer).
Review Process
The HPFB reviews the NDS and all the information about the drug captured during the development process (quality, preclinical and clinical) and evaluates the risks of the drug versus its benefits to the Canadian population. More specifically, HPFB reviews information regarding the drug’s manufacturing, packaging and labelling, as well as, information about the drug’s therapeutic claims and side effects. What Doctors and patients will be told about the drug will also be reviewed, through the drug’s monographs and information sheets. All drugs allowed to be sold in Canada are reviewed to ensure that they meet the requirements of the Food and Drugs Act and its Regulations. Once these requirements are met, the sponsor (usually the Marketing Authorization Holder) would receive a Notice of Compliance, confirming the dossier’s compliance with the Food and Drugs Act and its Regulations.
How long does the Health Canada drug review process take?
The target review timeline ranging from 7 months (accelerated review and ANDS) to 1 year (standard NDS). The exact time for Health Canada to review drug safety and efficacy information from an NDS depends on the type of drug, the quality of the dossier, the amount of questions that Health Canada raises during the review process, the answers provided by the sponsor and if the targeted timelines for the responses are respected. Once the review is complete, the Regulatory Agency decides to approve (or reject) the use of a new medication. In some instances, it can take longer than the targeted review timelines. HPFB review timelines are based on internationally competitive performance targets that are usually respected. By experience, the review can take anywhere from 6 months to 2 years, rarely more. The average time of the full drug development and approval process from initial research, preclinical studies, through the 3 phases of clinical trials to drug approval is 12 years (between 8 & 15 years).
What is the Notice of Compliance from Health Canada?: Once the review is complete, if the conclusion is that the benefits of the drug outweigh the risks, that the risks can be managed and confirming the dossier’s compliance with the Food and Drugs Act and its Regulations, then the sponsor in Canada receives a Notice of Compliance (NOC), as well as a Drug Identification Number (DIN), which is specific to a drug product to be sold on the Canadian market.
What is a Notice of Non-Compliance from Health Canada? Upon the completion of the review process, if the HPFB finds that there is insufficient evidence to support the safety, efficacy or quality claims of the drug, HPFB will not grant a marketing authorization for that drug. At this point, the sponsor typically has 3 options: to supply additional information to the HPFB, to re-submit a submission at a later date with additional supporting data (without prejudice), or to ask that HPFB to reconsider its decision.
What is an Accelerated Review Process from Health Canada?
For health conditions that are serious, life-threatening or for a severely debilitating disease (such as Alzheimer’s disease, cancer, AIDS, or Parkinson’s Disease), the HPFB can provide faster authorization of a drug as follows:
To be considered for PR or NOC/c, the drug must meet the following standards as described by Health Canada; the drug must provide:
Related to the NOC/c, some of the conditions of the Notice of Compliance include a requirement to closely monitor the drug for safety and to provide HPFB with regular updates. Once the conditions are met, the designation of “with condition” is removed from the NOC.
Getting a Notice of Compliance from Health Canada isn’t the last step in the process of selling and marketing the drug in Canada. Once a health product is approved and, on the market, the HPFB requires a sponsor to ensure that the use of its drug is done under the terms of its market authorization. In addition, Life Cycle Management activities (post approval submissions to Health Canada, for new indications, new dosage forms, new strengths, manufacturing changes, etc.) are required to ensure the maintenance of the product License with its related improvements. In summary, sponsors need to ensure its continued compliance with the Food and Drug Regulations, while their products are on the market.
On the other hand, Health Canada monitors drug information & adverse drug reactions reporting, conducts market surveillance, investigates complaints and manages recalls if necessary, amongst other things.
There are also more processes and regulations to follow and consider, either before, during or after the review process, and before that drug is officially marketed, distributed and sold in Canada. Topics such as licensing, warehousing, wholesale distribution rules and the Drug Establishment Licence (DEL), regulations around distribution to consumers, regulations around the marketing and advertising activities, provincial requirements, health insurance funding rules, among others.
All of these topics are worthy of their own article and are beyond the scope of this one.
Health Canada is the federal body that regulates the drug approval process under the Food and Drugs Act (FDA) and its regulations (FDR), its related policies and guidance. Before a drug can be distributed and sold in Canada, its manufacturer must receive a Notice of Compliance (NOC) from Health Canada, and the drug must be assigned a Drug Identification Number (DIN), uniquely identifying all drug products sold in a dosage form in Canada. New drugs must also go through extensive testing before being granted an NOC.
It can take anywhere from 6 months to 2 years for Health Canada to review drug safety and efficacy information before providing a decision on whether an NOC is to be granted. Once granted, it represents that the drug meets the required standards under the Food and Drugs Act and its regulations, for use in humans. The monitoring for drug safety continues even once the drug finally makes it to consumers.
The process of marketing and selling any new drug in Canada can certainly seem complex or intimidating. However, for drug companies seeking approval of their new drug in Canada, a number of strategies are recommended to make the process more effective. Focusing on preparedness, having proper data and documentation from research & trials and following proper guidelines are valuable recommendations to follow.
Another recommendation is for drug companies or sponsors to work in collaboration with Canadian regulatory experts so as to optimize the registration process to ensure the best strategic registration initiatives, to anticipate the health authority’s potential concerns and to help in finding proactive solutions prior to submitting to Health Canada. Working with regulatory experts or consultants can help avoid unwanted review complications and delays and therefore, reduce cost consequences of potential market entry delays.
Following the above recommendations will help turn a seemingly complex or intimidating Drug approval process into a more manageable and predictable one.
For a more complete look at NDS, please review our article on the New Drug Submission Process.
For an infographic rendering of the above drug review and approval process in Canada, please click on the image below to have the option of downloading it in either PDF or JPEG version.
For further information about the drug review & approval process in Canada, please contact Spharm directly.
With a quarter of a century of consistent and successful results, SPharm has become one of the leading Drug Regulatory Advisory firms in Canada. Drug companies from around the world count on SPharm to help them navigate the drug (and other health products) review & approval process in Canada.
Avec un quart de siècle de résultats et de succès constants , SPharm est devenue une entreprise de services de référence au Canada en stratégie de développement de médicaments et affaires réglementaires. Des compagnies pharmaceutiques à travers le monde comptent sur SPharm pour faciliter le processus d’homologation de leurs médicaments (et autres produits de santé) au Canada.
What follows is a graphical representation, an Infographic, of the eGuide we published titled “The Drug Review Approval Process in Canada – An eGuide“
DOWNLOAD JPEG VERSION HERE
DOWNLOAD PDF VERSION HERE
For further information about the drug review & approval process in Canada, please visit our FAQ section or contact SPharm directly.
With a quarter of a century of consistent and successful results, SPharm has become one of the leading Drug Regulatory Advisory firms in Canada. Drug companies from around the world count on SPharm to help them navigate the drug (and other health products) review & approval process in Canada.
Avec un quart de siècle de résultats et de succès constants , SPharm est devenue une entreprise de services de référence au Canada en stratégie de développement de médicaments et affaires réglementaires. Des compagnies pharmaceutiques à travers le monde comptent sur SPharm pour faciliter le processus d’homologation de leurs médicaments (et autres produits de santé) au Canada.
Canada has become an increasingly popular destination for clinical trials and drug approvals. Despite that, misconceptions persist about everything from approval time to the language used in the approval process. We have identified six of the more common myths about clinical trial applications and drug approval in Canada. Which ones have you believed?
Reality: You’ll receive your approval (No Objection Letter) — or rejection — in 30 days. Once a Clinical Trial Application (CTA) has been submitted, questions can be raised by Health Canada to which an answer (with or without commitment) needs to be provided within 2 days. Once the CTA review is complete, Health Canada notifies the sponsor if the application is found to be acceptable or not. If the CTA is acceptable, Health Canada issues a No Objection Letter (NOL) within the standard 30-day review period; this NOL needs to be received before moving forward with the trial and will be needed for investigational drug importation purpose.
Compare that to the U.S., where the FDA has 30 days to determine whether a clinical hold is necessary or if the clinical trial can start. There is no specific duration for a clinical hold in the U.S.. There is no such hold in Canada.
In most european countries in Europe the target review timeline is 60 days but it often takes more than that to obtain a decision at the national level. EMA is looking into applying a centralized procedure that will have a longer review period than 60 days.
Reality: The content requirements are actually less onerous than in the U.S. and in the EU. No non-clinical or clinical study reports are required to be submitted within the CTA in Canada. What is needed are the administrative documents plus key scientific documents on which Health Canada bases their review on: the protocol, the informed consent form and the investigator’s brochure, in addition to the standard chemistry and manufacturing data. The Clinical Trial Application is composed of three modules:
There can be delays in initiating Clinical Trials in Canada, as in other jurisdictions. For instance, there may be delays in obtaining Research Ethics Board reviews and approvals (a decision independent from Health Canada). Also, sponsors and CROs in North America can prioritize the U.S. sites ahead of Canadian sites for many reasons including patient population (see myth no. 3). Typically, for global studies it can take a few months to get a site up and running in Canada.
It is to note that 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.
Reality: Enrollment — recruitment and retention — is no more of a challenge in Canada than elsewhere. In fact, the average time from trial set up to first patient visit is three months, with 98 percent of subjects enrolled within the planned study period, according to the Canadian Clinical Trials Coordinating Centre (CCTCC). One reason for this success is that Canada’s universal healthcare system means coordinated access to patients and better patient data.
Moreover, Canadians are highly educated and interested in research: More than 70 percent of the population has expressed interest in participating in clinical research, according to the CCTCC.
Finally, as one of the most diverse nations in the world, Canada provides researchers to a broad pool of potential subjects.
Reality: Either language is accepted; for regulatory submissions, English is used more often. There are two exceptions: Labels and informed consent forms must be in both languages. Of course, all patient materials for trials in Quebec must be translated into French.
Reality: Health Canada have established submission review targets that are respected. Submissions to Health Canada are often delayed, but it has very little to do with the Health Canada process.
Research published in the Canadian Medical Association Journal in 2015, found that the submission of new drugs to Health Canada for approval is systematically delayed compared with submissions to regulatory agencies in the United States and the European Union. Over the years, it has been my experience also. Differences across jurisdictions in approval-processing times play a small role in the delays; differences in the timing of drug submissions are clearly an important factor.
Accessibility to new drugs in Canada is delayed primarily because of delays in submission to Health Canada by pharmaceutical companies and not because of a longer nor more complex approval-processing time at Health Canada.
Reality: Canada has the second lowest cost among G7 nations in the management, design and coordination of clinical trials. Only France is cheaper, according to the Canadian Clinical Trials Coordinating Centre. Canada has one of the most attractive tax environments for research and development compared to the U.S. and other G7 countries.
Reality: The CTA must be signed by a scientific or medical officer residing in Canada. Generally, the regulatory agent or the CRO can sign on behalf of the sponsor.
With a quarter of a century of consistent and successful results, SPharm has become one of the leading Drug Regulatory Advisory firms in Canada. Drug companies from around the world count on SPharm to help them navigate the drug (and other health products) review & approval process in Canada.
Avec un quart de siècle de résultats et de succès constants , SPharm est devenue une entreprise de services de référence au Canada en stratégie de développement de médicaments et affaires réglementaires. Des compagnies pharmaceutiques à travers le monde comptent sur SPharm pour faciliter le processus d’homologation de leurs médicaments (et autres produits de santé) au Canada.
