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.Continue reading
HOW TO PICK THE RIGHT DRUG REGULATORY AFFAIRS PROFESSIONAL
“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.
MEETING THE CHALLENGES AHEAD
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).
WHAT CREDENTIALS MATTER
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.
WHAT TRAITS MATTER MOST
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
WHERE TO FIND QUALIFIED REGULATORY PROFESSIONALS
-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:
- CAPRA – Canadian Association of Professionals in Regulatory Affairs
- Clinical Research Canada
- Clinical Research Professionals
- Drug Regulatory Affairs
- Pharma Connection Worldwide
- Professionals in the Pharmaceutical and Biotech Industry
- RADSP – Regulatory Affairs & Drug Safety Professionals
- Total Orphan Drug
-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.
FIT: A MATCH MADE IN REGULATORY HEAVEN
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.
THE DRUG REVIEW AND APPROVAL PROCESS IN CANADA
How are drugs reviewed in Canada?
How are drugs reviewed in Canada is a question often asked. 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.
What follows is a summary of the Canadian Drug Review and Approval Process in accordance with the Food and Drugs Act (FDA), the Food and Drug Regulations (FDR), the related policies and Health Canada guidelines.
How are drugs reviewed and authorized in Canada?
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.
What is Canada’s Health Products and Food Branch?
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.
WHAT IS THE DRUG DEVELOPMENT PROCESS?
We have categorized the drug development process in 5 stages and have provided a graphic below to accompany the text.
STAGE 1: INITIAL DRUG RESEARCH
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:
STAGE 2: PRE-CLINICAL STUDIES
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.
STAGE 3: CLINICAL TRIALS
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).
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 is simple and 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.
STAGE 4: THE DRUG APPROVAL PROCESS
What is New Drug Submission (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 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.
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:
- Administrative form
- Product Monograph
- Mock-up of Inner and Outer labels
- Certified Product Information Document
- Brand Name Analysis
- Risk Management Plan
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).
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:
- What is a Priority Review? (PR): Applies to drugs that shows substantial evidence of clinical effectiveness at the end of the clinical trial phases.
- What is a Notice of Compliance with conditions? (NOC/c): Applies to drugs with promising evidence of clinical effectiveness throughout the clinical trial phases. 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.
To be considered for PR or NOC/c, the drug must meet the following standards as described by Health Canada; the drug must provide:
- effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or
- a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada
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.
STAGE 5: AFTER-APPROVAL
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.
INFOGRAPHIC & FURTHER INFORMATION
For an infographic rendering of the above drug development process, 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.
THE DRUG REVIEW & APPROVAL PROCESS IN CANADA
What follows is a graphical representation, an Infographic, of the eGuide we published titled “The Drug Review Approval Process in Canada – An eGuide“
TOP TRAITS & BENEFITS OF AN EXCELLENT DRUG REGULATORY AFFAIRS EXPERT
As someone who has often been tasked to “find solutions” to the problems that arise when a regulatory professional isn’t brought in early-on in the health product development process, I thought I’d share with you what the role of a Regulatory Affairs professional is and what traits and attributes you will want to see in the person you hire.
Studies that are not well-planned are at risk of being unacceptable from a regulatory authority perspective, and yet still get conducted. As the study proceeds, development is consequently slowed or expanded as people address requirements ad-hoc. Submissions with inappropriate or insufficient data are prepared, causing submission review delays and its associated costs. There may even be instances where there is a need to go back to the drawing board and start from scratch or close to.
If the rationale behind not bringing a regulatory professional on board early was savings, companies often discover too late that it may end up costing them more on the back end. So, the selecting of an excellent regulatory professional is key and bringing them on at the planning stage, is tantamount.
One question worth asking is: Is there a specific certification that makes someone an effective regulatory professional or is it experience that makes you an expert? Well, the RAC certification from RAPS (of which I am a proud co-author) is well reputed for expertise and is an important foundation. That being said, the patina that develops over time managing a variety of challenging regulatory dossiers makes the most effective experts, in my view.
GOOD, JUST ISN’T GOOD ENOUGH
Here, we look in more detail at the benefits an excellent regulatory professional brings to each stage of the regulatory process (because good just isn’t good enough when we’re talking about the time, money, and value that this industry requires).
STAGE 1: RESEARCH & DISCOVERY
An excellent regulatory professional ensures that the planned development of a health product adheres to international Regulatory Agency requirements with a clear market aim in mind; this includes planning that considers the possibility of expanding the development geographically and facilitating the process of doing – lending flexibility to a development that may need to expand or could benefit from expanding.
STAGE 2: PRE-CLINICAL RESEARCH
In this stage, a regulatory professional ensures that the pre-clinical and the quality (CMC) development programs meet both local and international requirements prior to a first in-man study. This is where the traits of the professional become particularly important. Thorough and detail oriented, a keen logistical ability and regulatory intelligence separate those who are good from those who are great.
STAGE 3: CLINICAL TRIALS AUTHORIZATION
With the aim of obtaining authorization to conduct clinical trials, at this stage the role of a regulatory professional is to ensure that both local and international requirements are met. A regulatory professional coordinates pre-submission meeting, performs efficient and strategic medical and regulatory writing, performs QA and reviews submission documents for local and global compliance, prepares submissions to Health Authorities and ensures regulatory interfacing with them during the preparation, review processes and afterwards as needed.
Considering the significant sums of money involved, it’s not enough to have someone who has done it before or knows what to do, since the attributes of the person/the team can affect outcomes.
STAGE 4: REGULATORY PROCESS AND APPROVAL FOR MARKET ACCESS
In this fourth stage, the regulatory professional provides support and knowledge during each step of the registration process. Specifically, your expert should assist you in successfully navigating submission preparation, identify potential concerns ahead of submission time and proactively find solutions. In this phase, expert should perform efficient and strategic medical and regulatory writing, QA and reviews submission documents for completeness as well as local and global compliance, interface with health authorities and makes the regulatory process more predictable until drug approval. Here also, expertise is key.
STAGE 5: COMPLEMENTARY INITIATIVES
Regulatory professionals act not only as guides through the drug development processes at the pre-clinical, clinical phases and registration for market access phases. Experts also prepare provincial reimbursement submissions and provide support in reimbursement negotiations with decision makers. They also review marketing material and advertisement initiatives for compliance with the Food and Drug Regulations and PAAB Code and liaise between PAAB decision makers and sponsor, activities that are also key in the market access profession (combination of provincial initiatives in addition to the Federal ones).
STAGE 6: ONGOING POINT OF CONTACT
When the registration process is complete, and a health product can reach the market, a regulatory professional remains the point of contact with Health Authorities, to ensure compliance behind maintaining a registration. A true regulatory expert will evaluate the reportability of pharmacovigilance activities in compliance with regulations, evaluate the type of post-approval variations and documents required, prepares and coordinates all post approval submissions to Health Authorities, and coordinates telecoms or face-to-face meetings with them as needed.
Regulatory affairs professionals are your quintessential regulatory process concierge; experts to call on the moment you first begin thinking about planning any medical device, drug or other health product development so that each stage of the process is navigated smartly and skillfully.
Considering the significant sums of money involved in the development process of a drug, medical device or other health product, it is simply not worthwhile to hire or work with someone who is not considered an excellent regulatory expert.
Myths of clinical trial and drug approval process in 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?
Myth # 1: Obtaining approval for clinical trials takes more time in Canada than elsewhere.
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.
Myth #2: The requirements for a Clinical Trial Application in Canada are more onerous than elsewhere.
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:
- Module 1 – contains administrative and clinical information about the proposed trial
- Module 2 – contains quality (chemistry and manufacturing) information about the drug
- Module 3 – contains additional supporting quality information, when needed.
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.
Myth #3: Because of its population size, recruitment and enrollment are difficult in Canada.
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.
Myth #4: All study documents must be provided in English and French.
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.
Myth #5: Health Canada’s process for approving new drugs is excessively slow.
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.
Myth #6: Drug trials costs more in 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.
Myth #6.5: The Clinical Trial sponsor needs a Canadian presence.
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.
DETERMINING YOUR REGULATORY AFFAIRS NEEDS
Well-defined and appropriately supported needs increase the likelihood of successful submissions and market access. So how does one go about determining what those 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.
INVESTIGATOR DRIVEN CLINICAL TRIALS
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.
HIRE EXPERTS EARLY
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:
- Ensure the research is relevant and that it will address a medical need / allow for market access so that funds are not misspent.
- Establish a smooth relationship with Health Canada teams built on the positive reputation of the regulatory professional.
- Accelerate Health Canada’s confidence in the company developing the product because the person interfacing speaks the same language as the regulatory agency.
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.
Does Health Canada require Sponsors to have a legal representative reside in Canada?
DOES HEALTH CANADA REQUIRE SPONSORS TO HAVE A LEGAL REPRESENTATIVE RESIDE IN CANADA?
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.
With respect to having Sponsors having a legal representative residing in Canada for the Registration Process, the answer is no, Health Canada does not require Canadian residence. Nonetheless, if the sponsor is not located in Canada, a Canadian importer must be determined and their Drug Establishment License (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 and being in the same time zone as the reviewing regulatory agency.
For questions about the Canadian Drug Review & Regulatory approval process that is not covered in this section, please go ahead and contact us directly.
The Importance of working with Canadian regulatory experts.
WHY IS IT IMPORTANT TO WORK WITH EXPERTS 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.
For questions about the Canadian Drug Review & Regulatory approval process that is not covered in this section, please go ahead and contact us directly.
Canadian Drug Regulatory Glossary
What’s with all these Acronyms and Definitions?
The pharmaceutical industry is complex. The terms, expressions, abbreviations and industry vernacular are also as complex and confusing. We have attempted to put some order within this process by providing a glossary of the most common abbreviations and terms used in the industry.
All acronyms have been organized alphabetically.
ADN – Annual Drug Notification
A Notification sent to Health Canada annually, before October, by a drug sponsor/manufacturer, confirming that all information previously supplied with regard to that drug is correct, in order to comply with section C.01.014.5 of the Food and Drug Regulations. The Annual Drug Notification Form (ADNF) is available to assist manufacturers in complying with the said regulations.
ADR – Adverse Drug Reaction
A noxious and unintended response to a drug, which occurs at doses normally used or tested for the diagnosis, treatment or prevention of a disease or the modification of an organic function. It includes lack of efficacy.
AE – Adverse Event
Any adverse occurrence in the health of a clinical trial subject who is administered a drug, that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.
ANDS – Abbreviated New Drug Submission
Regulatory dossier that needs to be submitted and approved by Health Canada for a manufacturer to be granted authorizations to sell (Marketing Authorization) a generic drug on the Canadian market. This dossier typically requires a Bioequivalence study or a physico-chemical comparison (or both) against the Canadian Reference Product (innovator) plus a complete Chemistry and Manufacturing (Quality) package. Some exceptions can apply.
AR – Adverse Reaction
A noxious and unintended response to a marketed health product and includes Adverse Drug Reaction as defined in the Food and Drug Regulations and Adverse Reaction as defined in the Natural Health Products Regulations. In the later regulations, AR means a noxious and unintended response to a natural health product that occurs at any dose used or tested for the diagnosis, treatment or prevention of a disease or for modifying an organic function.
BGTD – Biologic and Genetic Therapies Directorate
Canadian regulatory authority of biological drugs (products made from living sources) and radiopharmaceuticals (drugs that have radioactivity) for human use in Canada. It is one of Health Product and Food Branch Directorates. Before giving permission to sell these therapies, the directorate must see scientific evidence of it’s safety, effectiveness, and quality, as required by the Food and Drugs Act and Regulations.
CADTH – Canadian Agency for Drugs and Technologies in Health
An independent, not-for-profit organization responsible for providing health care decision-makers with objective evidence to help make informed decisions about the optimal use of health technologies, including: drugs, diagnostic tests, medical, dental, and surgical devices and procedures. In addition to evidence, we also provide advice, recommendations, and tools.
This agency was initially established in 1989 as the Canadian Coordinating Office for Health Technology Assessment (CCOHTA), CADTH adopted its new name in April 2006 to better reflect their broad activities.
CAP – Clinical Assessment Package
Document which needs to be prepared and submitted to Health Canada’ appropriate review Bureau along with a written request to obtain a Priority Review Status, in advance of the filing of New Drug Submission (NDS).
Category IV Product
Category IV Products makes reference to products that have Category IV Monographs, that are developed for drugs that have a well characterized safety and efficacy profile under specific conditions of use. A manufacturer may reference a Category IV Monograph in a drug submission when the product and its labelling are consistent with the information set out in the document. Products subject to Category IV Monographs, can obtain a DIN through a DINF application.
CBS – Canadian Blood Services
Canadian Blood Services was founded in 1998, based on recommendations from the Krever Report on the tainted blood scandal of the early 1990s. CBS is regulated as a biologics manufacturer by Health Canada and primarily funded by the provincial and territorial ministries of health. Canadian Blood Services is a not-for-profit charitable organization.
CIHI – Canadian Institute for Health Information
A Canadian health agency that collects and reports on clinical and non-clinical data.
CIOMS – Council for International Organization of Medical Sciences
The CIOMS refers essentially to the CIOMS I Form, which provides a standardised format for the reporting of suspected adverse reactions to any particular medical product, in Canada as well as worldwide. The Council plays an important role in the current pharmacovigilance practice.
Common Drug Review (CDR)
National review process for non-oncology drugs that focuses on the cost effectiveness of a drug vs. current therapies. CDR issues a recommendation to the government drug plans (except Quebec – see INESSS) as to whether or a not a drug should be publicly funded for patients who need access.
CT – Clinical Trial
An investigation with a drug for use in human subjects, intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.
CTA – Clinical Trial Application
Regulatory dossier that needs to be submitted to Health Canada and given a No Objection Letter (NOL) from Health Canada prior to the sponsor proceeding with a clinical trial with an investigational pharmaceutical, biological and radiopharmaceutical product in the Canadian population / patients. In the the context of clinical trial management activities, CTA can also mean Clinical Trial Agreement (which is the agreement between the clinical trial investigational sites/center and the sponsor, in order to conduct the aimed study).
CTA also means Clinical Trial Authorization, the equivalent to a Clinical Trial Application required in Europe (EMA). In the USA (FDA), IND (Investigational New Drug) is the equivalent of the Clinical Trial Application.
CTA-A/N – Clinical Trial Application – Amendment/Notification
CTA-A: Changes to the clinical trial protocol or quality dossier, after the original CTA submission, that will impact the safety of the subjects, will affect the analysis and the interpretation of the safety and efficacy of the drug(s) under investigation or, that may affect the quality or safety of the clinical trial drug supplies. A 30-day review period applies before these changes can be implemented.
CTA-N: Changes that do not meet the criteria for a CTA-A, which may be implemented immediately, but Health Canada must be informed in writing, within 15 calendar days of the day of the change.
CTD – Common Technical Document
Globally harmonized Submission format that is accepted by many regions, in an effort to avoid the need to compile different registration dossiers for different regulatory authorities. The CTD format was adopted by Health Canada in 2003.
CTS – Clinical Trial Site
The location where clinical trial-related activities are conducted.
CTSIF – Clinical Trial Site Information Form
Form that is required to be completed and submitted to Health Canada by the sponsor or its representative for each clinical trial site, prior to commencement of the clinical trial or implementation of a Clinical Trial Application-Amendment, at that site.
DEL – Drug Establishment License
A Licence issued to a person in Canada allowing them to conduct licensable activities in a building which has been inspected and assessed as being in compliance with the requirements of the Food and Drug Regulations. Activities covered under a DEL are: fabrication, packaging, labelling, testing, importation, distribution or wholesaling. DEL applies for active pharmaceutical ingredients, finished dosage drugs or bulk process intermediates.
DIN – Drug Identification Number
An eight (8) digit numerical code assigned to each drug product approved under the Food and Drugs Act and Regulations (except for Schedule C drugs – radiopharmaceuticals). A DIN identifies the following product characteristics: manufacturer, brand name, medicinal ingredient(s), strength of medicinal ingredient(s), pharmaceutical form, route of administration.
DINA – Application for a DIN
When a product is not subject to Division 8 of the Food and Drug Regulations, the application is called a DIN submission.
Note: Under the provisions of section C.01.014 of the Food and Drug Regulations, no manufacturer shall sell a drug in dosage form unless a drug identification number (DIN) has been assigned for that drug and the assignment of the number has not been cancelled pursuant to section C.01.014.6. In the case of a new drug, a new drug submission filed pursuant to Division 8 of the Food and Drug Regulations is regarded as an application for a DIN.
A DINB is an Application for a DIN specific to a Biologic Product.
A DIND is an Application for a DIN specific to a Disinfectant Product.
A DINF is an Application for a DIN specific to a Category IV Product.
FDA – Food and Drug Act
An Act respecting food, drugs, cosmetics and therapeutic devices.
FDR – Food and Drug Regulations
The legislation that oversees and sets out requirements for the manufacture, packaging, labelling, storage, importation, distribution and sale of foods, and prescription and non-prescription drugs in Canada. Requirements for drug clinical trials are also set out in the regulations. Health Canada develops and enforces regulations under Government of Canada legislation. The Department consults with the Canadian public, industry and other interested parties in the development of laws that protect health and safety. They also prepare guidelines and policies in order to help interpret and clarify the legislation surrounding drugs and health products.The purpose of the legislation is to protect the health and safety of Canadians with respect to the sales of food and drug products.
GCP – Good Clinical Practice
Generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons, and the good clinical practices referred to in section C.05.010 of the Regulations.
GMP – Good Manufacturing Practices
The part of quality assurance ensuring that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization. Part of the Health Products and Food Branch Inspectorate (Inspectorate) program is to conduct inspections of establishments that are involved in activities covered by the Establishment Licensing framework.
HC – Health Canada
Federal department responsible for helping Canadians maintain and improve their health, while respecting individual choices and circumstances.
HP – Health Product
Products regulated under the Food and Drugs Regulations (drugs) and the Natural Health Products Regulations (natural health products). Drugs include both prescription and non-prescription pharmaceuticals; biotechnology products and biologically-derived products such as vaccines, serums, and blood derived products; disinfectants; and radiopharmaceuticals.
HPFB – Health Product and Food Branch
Health Canada Branch mandated to manage the health-related risks and benefits of health products and food by: 1) minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; 2) providing information to Canadians so they can make healthy, informed decisions about their health. The HPFB activities are carried out under various Directorates and Offices, including the Therapeutic Product Directorate, the Biologic and Genetic Therapies Directorate and the Marketed Health product Directorate.
HPFBI – Health Product and Food Branch Inspectorate
Part of the HPFBI program to conduct inspections of establishments that are involved in activities covered by the Establishment Licensing framework. These inspections are conducted to verify the compliance with GMP (Part C, Division 2 of the Food and Drugs Regulations) which is a requirement for the issuance of an establishment licence.
HQ – Héma Québec
Société à but non lucratif, Héma-Québec a été constituée en 1998, des longues suites du rapport final de la commission Krever, initié en raison du scandale du sang contaminé du au début des années 90. En matière de sécurité de l’approvisionnement, Héma-Québec est une organisation nationale, pour le Québec, légiféré par Santé Canada comme fabricant de produits du sang (biologique).
HTA – Health Technology Assessment
The process followed to provide an evidenced based recommendation on whether a health technology merits being publically funded.
IB – Investigator’s Brochure
In respect of a drug, a document containing the nonclinical and clinical data on the drug that are described in section C.05.005(e) of the Regulations.
ICF – Informed Consent Form
A document that describes: The risks and anticipated benefits to his or her health arising from participation in the clinical trial; and all other aspects of the clinical trial that are necessary for that person to make the decision to participate in the clinical trial.
ICH – International Conference on Harmonization
International initiative 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 include standard information organization for new drug registration applications.
INESSS – Institut national d’excellence en santé et en services sociaux
Quebec’s review process to evaluate therapeutic value and cost-effectiveness of oncology and non-oncology drugs. INESSS issues a recommendation to Quebec’s Minister of Health and Social Services as to whether or not a drug should be publicly funded for patients who need access
ITA – Investigational Testing Application
The equivalent of a CTA but for a Medical Device.
MAH – Marketing Authorization Holder
The entity that holds the Notice of Compliance, the Drug Identification Number (DIN), the Natural Product Number (NPN), the Homeopathic Medicine Number (DIN-HM), or the product licence.
MDLA – Medical device License Application
Equivalent of a CTA but for Investigating the efficacy and safety of a Medical Device.
MF – Master File
Formerly known as Drug Master File. Reference that provides information about specific processes or components used in the manufacturing, processing, or packaging of a drug. The MF is a useful vehicle for providing information to Health Canada, where that information is of a proprietary nature [i.e., confidential business information] and is not available to the manufacturer of the dosage form or to the sponsors of a drug submission or clinical trial application (also referred to as the applicants).
NAS – New Active Substance
- Chemical or biological substance not previously authorized for sale in Canada as a drug;
- Isomer, derivative or salt of a chemical substance previously authorized for sale as a drug in Canada, but differing in properties with regard to safety and efficacy;
- Biological substance previously authorized for sale in Canada as a drug, but differing in molecular structure, nature of the source material or manufacturing process.
NC – Notifiable Change
Notifiable changes are Level II Changes and are classified either as:
Moderate Quality Changes (chemistry and manufacturing) which have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. This level of change does not apply to Human Pharmaceuticals.
Risk Management Change (clinical) defined as a change to the label that has the potential to improve the management of risk to the population currently indicated for use of, or in any other way exposed to the drug. These changes are classified as either 90-day review changes (more urgent changes) or 120-day review changes.
NDS – New Drug Submission
Regulatory dossier that needs to be submitted and approved by Health Canada for a manufacturer to be granted authorizations to sell a new drug (i.e. pharmaceutical, biologic, vaccine, biotechnology product). This dossier typically requires complete Pre-clinical, Clinical and Chemistry and Manufacturing (Quality) package. Specific requirements may differ depending on the drug type, the pathology treated, the aimed patient population, amongst other elements.
NHP – Natural Health Product
A substance set out in Schedule 1 of the Natural Health Products Regulations or a combination of substances in which all the medicinal ingredients are substances set out in Schedule 1 of the Natural Health Products Regulations, a homeopathic medicine or a traditional medicine.
NOC – Notice of Compliance
Notification issued by Health Canada indicating that a manufacturer has complied with the requirements of the Food and Drug Regulations at the end of the review of an NDS, ANDS, S/NDS or S/ANDS.
NOC/c-QN – Notice of Compliance with Conditions Qualifying Notice
Notification issued by the Director of the responsible reviewing Bureau/Centre upon completion of a review, should a submission be determined to qualify for further consideration under the NOC/c policy. The NOC/c – QN will indicate that the submission qualifies for a NOC, under the NOC/c policy, as well as outline the additional clinical evidence to be provided in confirmatory studies, post-market surveillance responsibilities and any requirements related to advertising, labeling, or distribution. Submission review will cease upon issuance of the Qualifying Notice.
This applies to products that has promising evidence of clinical effectiveness with acceptable safety profile intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating disease or condition for which there is no existing therapy available in Canada which possesses a similar therapeutic profile or for which the new drug submission demonstrates a significant improvement in the benefit/risk profile over the available alternative product.
NOD – Notice of Deficiency
If deficiencies and/or significant omissions that preclude continuing the review are identified during the review of a submission, a NOD will be issued.
NOL – No Objection Letter
Letter emitted by Health Canada after the review of a Clinical Trial Application or a Notifiable Change, if the application is deemed acceptable to them. It confirms that a sponsor can proceed with its Clinical Trial in Canada or can implement the changes presented in the Notifiable Change.
NON – Notice of Non Compliance
Notice issued after the comprehensive review of a submission is complete, if the submission is deficient or incomplete in complying with the requirements outlined in the Food and Drugs Act and Regulations.
NSN – Not Satisfactory Notice
A notice issued by the Director of the responsible reviewing Bureau/Centre if deficiencies are identified during the review of a Clinical Trial Application, Clinical Trial Application-Amendment or Notifiable Change. The deficiencies will be specified and review of the submission will stop on the date of the Not Satisfactory Notice.
PAAB – Pharmaceutical Advertising Advisory Board
An independent and not-for-profit organization funded on a fee-for-service basis. It is the only regulator whose preclearance service is recognized by Health Canada for advertising directed to healthcare professionals. PAAB works to protect Canadians by ensuring that healthcare product advertising meets the regulatory, scientific, therapeutic, and ethical standards outlined in the Code of Advertising Acceptance. All PAAB approved materials bear the PAAB logo.
PBRER – Periodic Benefit Risk Evaluation Report
A pharmacovigilance document intended to provide a comprehensive, concise, and critical analysis of new or emerging information on the risks of the health product, and on its benefit in approved indications, to enable an appraisal of the product’s overall benefit-risk profile. The current ICH guidance ensures that PSURs for marketed drugs have the role of being periodic benefit-risk evaluation reports by covering: Safety evaluation, evaluation of all relevant available information accessible to sponsors/MAHs and benefit-risk evaluation.
pCPA – pan-Canadian Pharmaceutical Alliance
National mechanism designed to achieve greater value for government drug plans. pCPA negotiates with a drug company to determine both the cost and criteria under which governments will pay for a medication, concluding with a Letter of Intent to fund the drug.
PMPRB – Patented Medicine Price Review Board
A board that protects and informs Canadian consumers by ensuring that the prices of patented medicines sold in Canada are not excessive, and by reporting on pharmaceutical trends.
PR – Priority Review
A status granted by Health Canada to an NDS or an SNDS for a serious, life-threatening or severely debilitating disease of condition for which there is substantial evidence of clinical effectiveness that the drug provides: 1) effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or 2) a significant increase in efficacy and/or a significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.
PSEAT-CTA – Protocol Safety and Efficacy Assessment Template – Clinical Trial Application
A protocol summary to be prepared and submitted within the CTA. The summary is expected to contain: protocol identification, background and rationale, trial objectives, study design and duration, total number of sites (including number of Canadian sites), investigators, sample size, patient population, inclusion & exclusion criteria, drug formulation, dosage regimen, washout period, screening & baseline evaluation, treatment & assessment visits, concomitant & rescue medication, risk management, withdrawal/discontinuation criteria, efficacy & safety variables and analysis, statistical analysis.
PSUR – Periodic Safety Update Report
Mechanism for summarizing interval safety data, and for conducting an overall safety evaluation. It is a tool for sponsors to conduct systematic analyses of safety data on a regular basis. In addition to covering ongoing safety issues, the PSUR should also include updates on emerging and/or urgent safety issues, and major signal detection and evaluation that are addressed in other documents.
QHCP – Qualified Health Care Professional
A person who is a member in good standing of a professional medical, nursing, pharmacists’ or other health care practitioner association and entitled to provide health care under the laws of the jurisdiction in which the person is located, and other individuals retained by the Marketing Authorization Holder who have the appropriate health care education and therapeutic expertise.
QI – Qualified Investigator
The person responsible to the sponsor for the conduct of the clinical trial at the clinical trial site, who is entitled to provide health care under the laws of the province where that clinical trial site is located.
QIU – Qualified Investigator Undertaking
The undertaking that must be completed by the qualified investigator responsible for the conduct of the clinical trial at the clinical site and retained by the clinical trial sponsor for a period of 25 years. This undertaking should not be submitted to Health Canada unless requested.
QOS – Quality Overall Summary
Summary template that follows the scope and the outline of the Quality Body of Data (of CTD Module 3.2). Specific QOS templates exists for Clinical Trial Applications Phases I, II & III; for Bioavailability studies and for DIN applications. The QOS for new chemical entities is presented below.
QOS-CE – Quality Overall Summary – Chemical Entities (CTA)
Summary template that follows the scope and the outline of the Quality Body of Data (of CTD Module 3.2). This template can be used by sponsors to summarize the Quality information for New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs) containing drug substances and their corresponding products of synthetic or semi-synthetic origin that are filed with Health Canada pursuant to Part C, Division 8 of the Food and Drug Regulations.
This would exclude submissions for Biotechnological/Biological (Schedule D) and Radiopharmaceutical (Schedule C) drugs. Nonetheless in reality, the referenced QOS-CE is used to summarize the Quality information for Schedule D New Drug Submissions (NDSs); sections of the template are then bonified with the requirements of the Schedule D NDS guidance. A Quality Information Summary (QIS) is available for radiopharmaceuticals, upon request from Health Canada.
REB – Research Ethics Board
A body that is not affiliated with the sponsor, mandated to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being. The body needs at least five members, that are in majority Canadian citizens or permanent residents under the Immigration Act, and composed of both men and women. Additional criterias apply.
RMA – Risk Minimization Activity
Risk minimization activities are interventions intended to prevent or reduce the occurrence of adverse reactions associated with the exposure to a medicine, or to reduce their severity or impact on the patient should adverse reactions occur. These measures may include warnings in the label or minimization activities beyond routine, such as health care provider educational material.
RMP – Risk Management Plan
A document that describes a set of pharmacovigilance activities and interventions designed to identify, characterize, prevent or minimize risks related to drug products, and the assessment of the effectiveness of those interventions (adopted from the European Medicines Agency definition of a Risk Management System).
S/ANDS – Supplemental Abbreviated New Drug Submission
Same as for a S/NDS presented below but for generic products.
S/NDS – Supplemental New Drug Application
Submission required for Level I Quality or Safety & Efficacy (Clinical) Changes that have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product or a change to the label of a drug that has the potential to increase the exposure levels of the drug, either by expanding the population that is exposed, or by increasing individual exposure.
SAP – Special Access Programme
Programme that allows access to nonmarketed drugs for practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or unavailable. The SAP authorizes a manufacturer to sell a drug that cannot otherwise be sold or distributed in Canada. Drugs considered for release by the SAP include pharmaceutical, biologic, and radio-pharmaceutical products not approved for sale in Canada.
SADR – Serious Adverse Drug Reaction
An adverse drug reaction that requires in-patient hospitalization or prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life threatening or that results in death.
SAR – Serious Adverse Reaction
A noxious and unintended response to a natural health product that occurs at any dose and that requires in-patient hospitalization or a prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life threatening or that results in death.
SEO – Senior Executive Officer
The most senior person with policy and operational decision making authority within the sponsor, or is an official who has this delegated authority in respect of a clinical trial. The SEO is responsible for providing an attestation with respect to the Clinical Trial Application/Amendment at the time of filing the CTA to Health Canada.
SUADR – Serious Unexpected Adverse Drug Reaction
A serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out in the investigator’s brochure or on the label of the drug.
TPD – Therapeutic Products Directorate is Canada’s regulator of prescription drugs and medical devices for human use. Before giving permission to sell a product, the directorate must see scientific evidence of the product’s safety, effectiveness, and quality, as required by the Food and Drugs Act and Regulations.
YBPR – Yearly Biologic Product Report
A report that must be submitted annually by manufacturers of all Schedule D (Biologic) drugs in accordance with Guidance for Sponsors: Lot Release Program for Schedule D (Biologics) Drugs. The report contains production information on both drug substance and drug product lots, including test methods and results, reasons for any recalls and corrective action taken, as well as other pertinent post-market information.