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The Progressive Licensing Framework

Concept Paper for Discussion

Document Objective

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This document has been created as a concept paper to introduce issues and to stimulate discussion. It offers an exploration of the core concepts that the Progressive Licensing Project has identified on a preliminary basis as fundamental to a new regulatory framework for pharmaceuticals and biologics in Canada. As such, this document is meant to support the initial stages of discussion. The Progressive Licensing Project has chosen this approach to ensure that we form a good understanding of the key values and expectations before turning to a more detailed articulation

TABLE OF CONTENTS

1 OVERVIEW

2 HOW WE ARRIVED HERE PAST AND PRESENT AS A BASELINE FOR CHANGE

2.1 The Past
2.2 The Present System

3 CHANGING CONTEXTS IN THE DRUG SYSTEM

4 THE PROGRESSIVE LICENSING MODEL

4.1 Life-cycle of product and knowledge
4.2 Evidence-Based Regulatory Cycle
4.3 Good Planning Throughout the Regulatory Cycle
4.4 Accountability

5 CONSULTATIONS, IMPLEMENTATION, AND CHANGE MANAGEMENT

6 CONCLUSION

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1 Overview

Health Canada is developing the Progressive Licensing Framework to establish a drug regulatory system for the future. This framework is intended encompass the regulation of pharmaceuticals and biologic products, including prescription and non-prescription products. The Progressive Licensing Framework is part of the Blueprint for Renewal initiative, Health Canada's plan to modernize the regulation for health products and food. Further details on the Blueprint could be found on the Health Canada website at http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen-hpfb-dgpsa/blueprint-plan/index-eng.php.

For some time in Canada the prevailing role of the federal government in regulating drugs has been to guard the public from drug tragedies, such as the thalidomide events in the 1960s¹. The harms caused by thalidomide pointed to the need for a system that could account for the fact that drugs can bear risk even when they are beneficial and in some instances the risk will outweigh the benefit of using the drug. The regulatory model of that time focussed upon generally prohibiting the sale of drugs until they were carefully tested.

We are now recognizing that, while the traditional pre-market evaluation of a drug has worked dependably as a system for many years, it does not identify all the significant information about drug benefits and risks. The scientific and regulatory ability to establish whether or not a drug works and to identify risks has become complicated to the point where it has become a field of its own, as have the instruments and methods for monitoring drugs and managing risks once the drug is marketed. While the medical and scientific community within Health Canada has kept pace and adopted many best international practices for the review of drugs over the years, the regulatory support for these practices has not been modernized. As these developments overtake the old model, numerous limitations have been emerging in the regulatory structure, many of which raise fundamental questions as to the role of Health Canada in regulating drugs.

Health Canada's role has arguably been evolving from the traditional gatekeeper role of the past to include roles such as information provider and risk manager. These roles are worth exploring, especially as patients appear to be demanding greater autonomy in making drug choices, including choosing their acceptable level of risk. The effort to define the roles for Health Canada and how they might combine, will best proceed with a harmonious understanding of the roles of other partners in the health care system. In addition to the federal regulator, the other decision-makers in the health care system include provincial and territorial governments, manufacturers, researchers, health care professionals, caregivers, patients, and consumers. Consultations about the Progressive Licensing Framework will be an opportunity to conduct this exploration in detail.

The new Progressive Licensing Framework:

• a life-cycle, evidence-based approach,
• good planning,
• accountability.

The central concept of Progressive Licensing is that, over time, there is a progression in knowledge about a drug. The emphasis of the new framework is to identify opportunities within this progression over the full life-cycle of a drug, rather than placing the focus primarily upon pre-market assessment. This represents a fundamental shift from the idea that the pre-market testing of a drug assures its safety and efficacy. The new proposed model is that a drug should be evaluated throughout its life-cycle for its benefit-risk profile.

The framework is meant to support evidence-based decision making. Not only will the key regulatory decisions throughout the drug life-cycle be justified on the basis of evidence, but so will the policy choices for all aspects of the framework, including evaluation of how the framework is achieving its objectives.

Good planning is more than regulatory foresight with respect to emerging scientific and technological developments. The suggestion is to introduce planning at every viable step of the regulatory process, which would allow for a proactive approach to managing both expected and unexpected issues. From the very beginning of the regulatory cycle, Health Canada can make best use of its science and regulatory resources, for example, inagreeing with a manufacturer as to when a regulatory filing will be made, and what data the filing will include. Early planning and assessment of clinical trial methods and protocols could reduce the number of trials that yield inconclusive or irrelevant results from a regulatory point of view. Planning for the conduct of post-market activities, including studies, effectiveness monitoring, safety surveillance, and risk management, would become a required part of the pre-market filing, so that expectations for identifying and managing drug benefits and risks are established ahead of marketing for each drug. Similarly, planning for changes in manufacturing to take advantage of a pre-approved range of parameters would cut down upon unnecessary filings while ensuring that a drug remains of high manufacturing quality over its life-cycle.

The requirements for the establishment of safety and efficacy at one point in time (the point of being licensed) through traditionally accepted studies would therefore be updated in the framework. The proposed new requirements would arguably better mirror the actual considerations for licensing a drug, i.e. that a favourable benefit-risk profile has been established on the basis of sufficient evidence, a high manufacturing quality has been demonstrated, and a sufficient life-cycle management plan has been filed by the manufacturer to allow for introduction of the drug to the market.

Accountability is associated with all aspects of the framework. The framework will reflect the ongoing requirement to justify the marketing of a drug, which is the underlying accountability of both Health Canada and drug manufacturers. The specific mechanisms for accountability in the new framework include the ability to make enforceable conditions upon issuing an initial market license, so that, for example, certain field reporting commitments or further studies are required to be completed. Health Canada will be accountable to clearly and publically state the basis of having licensed a drug for marketing, or for any subsequent significant adjustments to a license, including its removal. We could require the enhanced reporting of drug information so that, along with drug manufacturers, we can continue to evaluate a drug following initial marketing. A general accountability should be introduced in the form of well-structured mandatory periodic review of the framework itself, so that an ongoing evaluation can be conducted as to how the new system is working. This would enable the framework to remain contemporary over time.

The Progressive Licensing Framework represents the opportunity for significant change. With that in mind, this document also provides an early articulation of the methods by which we want to approach the management of change.

2 How we arrived here B past and present as a baseline for change

Establishing a drug regulatory system for the future requires an understanding of what the regulatory framework has been in the past and what it is currently.

2.1 The Past

In Canada, the history of the federal oversight of food and drugs predates Confederation. However, this role was for many years confined largely to ensuring that food and drugs were not significantly adulterated. The formulation and purity of drugs were set out in the British and later the American Pharmacopoeia. Not until the introduction of The Proprietary or Patent Medicine Act in 1909 did legislation provide for the registration of medicines, limited at the time to secret-formula, non-pharmacopoeial, packaged medicines for internal use. This early legislation did not provide control over advertising; however, it was a beginning in protecting the public against the use of many drugs that were dangerous to take without medical supervision.

Shortly following the establishment of a federal Department of Health in 1919, the Food and Drug Act was introduced in 1920. By the late 1920s, provisions were in force to allow for the licensing of certain drugs, establishing requirements such as procedures for inspection, qualifications of personnel, and methods of testing for the manufacture of licensed drugs. The issuance and continuance of a license were made conditional upon an inspection of the establishment before a licence was granted and at least once per year afterwards. The licence number of the manufacturer was to be shown on the label of all licensed drugs. The Regulations under the Act gave the Minister authority to cancel or suspend a licence for violations of the requirements.

Beginning in 1947, a significant reworking of the Food and Drug Regulations took place, resulting in the precursor of Part C (the part relating to drugs) as it is found today. Again in 1951, further significant requirements were introduced for new drugs. With the focus on safety, a new drug submission was required to be filed by a drug manufacturer prior to marketing a drug. A Notice of Compliance with the regulations was issued to the manufacturer when an acceptable submission was completed. However, it was not until 1963, in response to the thalidomide tragedy, that there was a complete revision of the regulations to strengthen the Department's regulatory authorities. Among other things, these revisions marked the first appearance of the additional requirement for manufacturers to submit evidence of efficacy in seeking a Notice of Compliance.

2.2 The Present System

The hallmark of the present Canadian system is a focus upon pre-market activities. This includes the authorization of clinical trials occurring in Canada, and the submission of information that is presented to Health Canada through a new drug submission to establish that a drug is safe, efficacious and of high manufacturing quality. There are also requirements for the licensing of manufacturing sites, and good manufacturing practices, with accompanying powers for inspection.²

The present drug development and review structure is characterized as point-in-time. A manufacturer will initially select molecules that show promise and move them through the drug development process - non-clinical studies (test-tube and animal), and finally human clinical trials. For any clinical trial occurring in Canada, a manufacturer must submit an application for approval to Health Canada.

Once the manufacturer believes that it has established a body of evidence respecting the safety, efficacy and quality of a drug for a specific indication (e.g. treating, mitigating, preventing, or diagnosing a certain condition), it will file a drug submission with Health Canada. We review the information in the submission for its compliance with the Food and Drug Act and Regulations. If we find that the information complies under the proposed conditions of use, we issue a Notice of Compliance. Along with issuing the Notice of Compliance, we also approve the labelling for the drug. The labelling includes a document called a product monograph, which summarizes the scientific and medical information about a drug so that it can be used appropriately.

Once a manufacturer has received a Notice of Compliance, it is able to market a drug in Canada for a particular use (e.g. for the treatment of infection or Alzheimer's Disease). A manufacturer may also apply for listing on the different drug formularies across the country. Being listed on a drug formulary means that the drug will be covered for reimbursement, either in full or in part, by the healthcare plan (provincial, federal, or private) that manages that formulary.

Manufacturers must adhere to a number of obligations once they begin to market. Some of the obligations are: that they must inform Health Canada of any reported serious adverse drug reactions of their drug; that they must adhere to the advertising restrictions in the Act and Regulations; they must update safety information pertaining to their product(s); and that they must also maintain the quality of their drug to the appropriate standards, and apply for further authorization from Health Canada for significant changes to their product.

Health Canada has limited tools at its disposal for ensuring continued compliance with the regulations once a drug is on the market, including inspecting manufacturing compliance, and removing a drug from the market for reasons of safety.

3 Changing Contexts in the Drug System

The current drug system is under continual pressure from external forces - expectations change, relationships change, and the global landscape evolves.

Gauging any changes in public expectations. Public expectations are a crucial part of the drug regulatory context. Episodes such as drug withdrawals and challenging issues about early access to new drugs have signalled that there may be a gap between expectations and present regulatory authorities for drug review and monitoring. Population-based decisions may adversely impact individual choice. For example, removal of a drug from the market because of risks that cannot be managed in the wide population results in unavailability of the drug for an individual. Given that needs can change over time, we want to discern how expectations have been changing as to the role and effectiveness of the federal drug regulatory system.

Shifting focus of regulatory emphasis. Across the globe, the focus for drug regulatory agencies is shifting from a pre-market approval model to a more flexible, life-cycle approach. There is a greater emphasis on pharmacovigilance and risk management. In addition, regulators are increasingly recognizing that extraordinary circumstances exist and must be addressed reliably in such cases as drugs intended for serious, life-threatening diseases, drugs for rare diseases, and drugs for emergency situations.

Changes in technology and regulatory foresight. The increasingly global nature of the pharmaceutical business has impacted drug development and regulation. Drugs are being made in fewer locations, for wider international export, which highlights the need for greater international harmonization on standards. The nature of clinical trials is changing as well, becoming increasingly international. There is increasing exploration of new trial designs and techniques. A modern regulatory framework must anticipate and accommodate changing technology and methodology, such as adaptive trial design, the use of surrogate markers, and the advances of pharmacogenetics.

Changing nature of treatment of disease. Related to the changes in public expectations of the drug system are the shifts seen in the traditional patient/prescriber relationship (including a blurring between clinical research and clinical practice), the pharmacist's role in healthcare, and a greater focus on self-care treatments and natural health products. A modern drug regulatory framework should recognize and manage the current shifts, and be flexible enough to accommodate future changes in the health practitioner and patient relationship.

4 The Progressive Licensing Model

Our vision is a progressive regulatory framework based on sound science and risk management that supports:

• access to promising new pharmaceuticals and biologics, and
• the continuous monitoring and reassessment of potential safety, quality, efficacy and therapeutic effectiveness information, to allow for adequate evaluation of benefits and risks throughout the product life-cycle (i.e. both pre-market and post-market).

The central theme of Progressive Licensing is built around three elements:

1. All drugs have positive and negative effects. The positive effects, known as benefits, happen when the drug works as intended to prevent, treat, or diagnose an illness. The negative effects, called risks, happen when a drug does not work as intended or it causes an adverse effect. An adverse effect can be a self-limited event like a headache, or a serious life-threatening event such as a heart attack.
   
   
2. Drugs, like any other product, have a life-cycle. They are conceived, developed, brought to market, and eventually withdrawn from the market or replaced by other products. Knowledge and experience gained throughout the use of that drug is then used in the development of new products.
   
   
3. The knowledge about how a drug works, both positively and negatively, increases throughout this life-cycle as more and more people are exposed to the drug. For example, a new use may be discovered for a drug, and this is a potential benefit. Conversely, an interaction with another drug may be uncovered that could be a potential risk in some situations.

A well-designed regulatory framework should support the effective collection, analysis, and communication of information about drugs (sound science) so that drugs can be used wisely (sound risk management). In designing a new regulatory framework, more than new regulations will be required; additional framework components would include guidance documents, processes and practices.

A modern regulatory structure will allow for the initial and ongoing collection, evaluation, and communication about drug information throughout the product life-cycle. The progression in our knowledge about how a drug affects the body offers the opportunity to optimize the positive effects of the drug (the drug's benefits), and minimize and manage the negative effects (the risks). As new information emerges it can be used to optimize drug use for the benefit of patients. This is the ultimate goal of the Progressive Licensing Framework.

4.1 Life-cycle of product and knowledge

Figure 1 is a diagram illustrating the critical points in the life-cycle of a drug and how a regulatory framework can connect with those milestones. A well-designed framework will recognize those critical points and connect the phases in between those points to support information collection, analysis, and communication.

The top of the diagram begins with drug development, which is carried out by the manufacturer. The early stages of drug development involve identification and initial characterization. Identification of molecules that may become beneficial drugs happens in a number of ways, and followed by non-clinical experiments to characterize structure and activities of the drug. Drugs are then tested in cells and animals to learn about how the drug affects biological systems, to begin identifying potential problems, and to explore the amount of drug needed to cause an effect. There are opportunities here to learn from manufacturers about their plans for clinical testing of the new drug in humans. This would allow Health Canada to have more foresight into what may be submitted later as a clinical trial application and ultimately a new drug submission.

Trials that are conducted in humans in Canada must be authorized through the filing of a clinical trial application with Health Canada. At this time clinical trial applications are submitted individually, and there are no requirements for a sponsor to submit a complete plan of drug development. A more complete picture of how a clinical trial fits in with the overall development of a drug would allow for a more comprehensive approach to evaluating clinical trials and an understanding of the drug when the manufacturer submits a new drug submission for review.

The new drug submission represents a significant amount of work that has been undertaken by a manufacturer to develop a drug with the intention of marketing that drug. It contains the scientific and clinical information that has been collected by the manufacturer about the drug. This collection of information results in a submission that often consists of hundreds of volumes. Health Canada reviews this information with the objective of coming to a decision about the benefit-risk profile of the drug. A drug must have a positive benefit-risk profile to be marketed; this means that for the intended use in the intended population the drug's likelihood of causing a benefit outweighs the likelihood of causing a harm. Harm can include treatment failure or an adverse event. Benefits and risks are inherently linked concepts because there are no risks that are acceptable in the absence of benefits.

Although a new drug submission contains a great deal of information, our knowledge about how the drug affects the human body is still limited at that point in time because the number of participants in clinical trials is limited. Some adverse events are often not detected during clinical trials because they happen so rarely. Interactions with other drugs may not be detected. Longer-term effects of a drug may not be apparent at the time of marketing. This makes the ongoing collection and analysis of information after the drug is marketed absolutely crucial. It is only after a drug is marketed that many more people will be exposed to the drug, and further important facts about the drug can be determined. This can be information about benefits or risks. Patients not included in the original clinical trials, such as children and the elderly, may be exposed to the drug and this may yield important information about how the drug works in those groups. Because the information about a drug increases over time, the assessment of the benefits and risks can change.

Not all drugs are developed or brought to market in exactly the same way. There are special types of drugs that fill the niche of meeting an extraordinary need. These drugs may have even more limited information available about how the drug works when a decision is needed about market authorization. Examples of such drugs are those that treat rare diseases, potential breakthrough drugs for the treatment of cancers, emergency use drugs that cannot be ethically tested in humans, and compassionate use drugs. Since the data on these drugs may be limited, the concept of evolving information is a very important factor in regulating them. A modern framework must support the collection and analysis of data obtained from the use of these products so that their benefits and risks can continue to be assessed. Doing this for extraordinary need drugs will be a challenging endeavour, but these drugs play an important role in the health care system and need to be addressed in a new framework since the principles of sound science and risk management apply to all drugs.

At the centre of Figure 1 is an arrow that represents pharmacovigilance. Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. Historically, pharmacovigilance has been planned and executed after a drug has been marketed, usually after the identification of a safety concern. Newer thinking around pharmacovigilance has been that earlier planning to detect adverse effects and better approaches to managing risks can result in better patient care and allow for continued access to needed drugs without always having to withdraw a product from the market. Planning for pharmacovigilance and risk management activities are occurring earlier in the life-cycle of drugs, indeed as early as the non-clinical testing stages. Incorporation of these elements into a regulatory framework is progressive in that, again, it supports the continuing collection and analysis of important information about a drug.

Ongoing assessments of the new information that emerges about a drug can be used to help all decision makers in the health care system: drug manufacturers, the regulator, provincial and private funders, health care professionals, caregivers, and patients. Current and accurate assessments can be used to help answer questions of these decision makers, such as:

• Should a new use be developed for this drug?
• Does the benefit-risk profile of the drug support its marketing in Canada?
• Is this a cost-effective therapy for our healthcare plan?
• Should I prescribe this drug for my patient?
• How often should I give this drug to my child, and can I give it with a meal?
• What side effects should I be aware of, and what should I do about them?

All the decision makers in the system perform risk management activities, from deciding whether a drug meets the requirements for marketing to monitoring oneself or a loved one for an adverse effect, and such activities are enhanced when available information is current and of high quality.

Effective and timely communication of new information is an important element of a life-cycle approach to the regulation of drugs. As the regulator, Health Canada may be made aware of emerging information prior to other decision makers. Communication of this information can be challenging, particularly since our current regulatory framework provides little structure around such activities. But as a part of a modern regulatory framework built around information, it is necessary to provide the support needed to allow for effective and timely communication.

Drug information can be complex. Communication of information to users such as manufacturers, funders, health professionals, caregivers, and patients must be supported in a manner that makes the information truly accessible. If up-to-date information and assessments are to enhance decision-making, they must be provided in a useful way to those who need the information. The proposed framework will be progressive in that it will support the involvement of users, particularly around the sharing and communication of information, realizing that different users have different needs.

After a drug has been marketed for some time, the new information that develops may indicate that the drug no longer has a positive benefit-risk profile, and the drug may be withdrawn from the wide market. Another way a drug may leave the market is if a manufacturer decides to no longer sell the product. However, the information that has been generated in both of these situations can be used in developing new drugs and improving the use of other drugs. The life-cycle of the product is thus intimately linked to its own knowledge cycle as well as that of other drugs.

4.2 Evidence-Based Regulatory Cycle

There has been a generally accepted scientific standard of evidence for clinical efficacy and safety traditionally used by regulators worldwide to provide the scientific basis in the assessment of benefits and risks for drug products considered for market authorisation. This standard requires positive, validated outcomes from adequate, randomised, controlled, confirmatory studies. In these types of studies, patients, usually in large numbers, are randomly assigned to treatment groups. These patients will be exposed or unexposed to the test drug under conditions of use that reflect those intended once on market, although all patients receive the same care in the course of the trial. This trial design has been accepted in recent decades to be key in minimizing uncertainty about drug efficacy as well as for reducing uncertainty about the more common types of safety issues. These types of studies have also provided the basis for initial extrapolation of results to the general population and for communicating that information through product labelling. This trial design also reflects fundamental aspects of " scientific method " to objectively and rigorously test cause and effect - in other words, whether an effect (positive or negative) seen in a patient population can be robustly demonstrated to be caused by the test drug.

Benefit-risk is founded upon scientific evidence of safety and efficacy but also encompasses a larger scope of evidence regarding contributing circumstances, including effectiveness. The broader issues that can factor into benefit-risk evaluation and provide a more complete perspective on the potential use of a drug, beyond core safety and efficacy, can include but are not limited to:

• availability and performance of other therapies;
• domestic and international clinical practice environments (for example, clinical practice standards and realities, clinical expectations for the product, foreign regulatory status and conditions of use in those contexts);
• anticipated use patterns that may lie outside the conditions of use studied in pre-market trials including duration, real-world target population(s), indication, and dosing; and
• anticipated manageability of risks, including potential therapeutic impact of remaining uncertainties regarding the drug.

Currently, we incorporate information regarding many of these factors in assessing drugs both in the pre-market and the post-market setting. Although methodologies have been developed for benefit-risk assessment, there is no generally accepted national or international process or standard. With the current Canadian regulatory threshold set narrowly at considerations of safety and efficacy, the assessment of benefit and risk is not explicitly well supported. This arguably has contributed to public criticism of the regulator"black-box" approach to drug regulation. We also suggest that this lack of an accepted method for benefit-risk assessment affects the decision-making of others in the system, such as clinical practitioners, patients, and drug plan managers.

We are proposing that the new standard would continue to require substantial evidence for safety, efficacy and quality but that it would incorporate other kinds of evidence as well, allowing for a full benefit-risk assessment. The new standard would remain evidence-based while providing flexibility to accommodate the decision makers' overall considerations about the initial and continuing acceptability of drugs for the marketplace. Such a refocussing would serve to clarify the actual basis of decision making, so long as the principles, methods, and rationales are clearly stated and widely available. Formalising the application of benefit-risk concepts to both the pre-market and post-market licensing standard would provide for a single, stable standard, in keeping with a life-cycle approach to drug regulation.

In introducing such changes, we plan to retain the demonstration of efficacy, safety and quality for the proposed conditions of use (e.g. authorised indication, target population, dosing regimen, duration of use) as the baseline requirement for initial market authorisation. This is a known and valid approach. It will be important, however, to articulate that safety evidence at time of initial market authorisation would be limited to identifying the most commonly occurring adverse drug reactions. Overlaying these core elements could be a broader requirement for an evidence-based, favourable benefit-risk profile for the drug. If the profile of a drug is unclear in the sense that the benefit does not clearly outweigh the risk, a further evidence-based determination regarding the impact of market authorisation could take into account larger public health, societal, and ethical considerations.

The benefit-risk elements and evidence that would underpin the standard for initial authorisation are therefore anticipated to fall into two categories:

1. information on benefit-risk considerations regarding the product that contextualises the safety, efficacy and quality evidence, already outlined above, and
2. information regarding other, important contextual benefit-risk considerations. These could include:
   • considerations relating to public health and/or individual health, as identified by regulatory and other potential decision-makers;
   • risk acceptance.

In essence, the standard for initial authorisation would require an evidence-based favourable benefit-risk profile for the drug's use under the proposed conditions.

In keeping with the proposed life-cycle approach, maintenance of market authorisation could require a continuing favourable benefit-risk profile for the authorised conditions of use throughout the product's lifespan. The favourable benefit-risk profile would be based on the same elements required for initial market authorisation with some possible additions, i.e., substantial evidence of efficacy, safety, and quality; substantial evidence for a favourable overall benefit-risk profile regarding the product and evidence of other important benefit-risk considerations relating to the impact of market authorisation on external decision-makers.

When a manufacturer is considering departing from the baseline requirement for substantial evidence of efficacy and safety for initial market authorisation, a more flexible approach regarding the underlying efficacy and safety evidence is envisaged when there is a compelling reason. While the regulatory requirement for a favourable benefit-risk profile for the drug's use under the proposed conditions would remain, initial requirements for substantial evidence of efficacy and safety may be counterbalanced against other, important evidence concerning contextual benefit-risk considerations. For example, the potential benefits of bringing the drug to market are deemed to outweigh the relatively increased uncertainty regarding the safety and efficacy.

There must be a reliable and transparent process for such a departure, with strong emphasis upon ensuring that the remaining uncertainties regarding the core efficacy and safety evidence be resolved through the collection of further evidence once the product is on the market. It is important to note that the requirement for substantial evidence of manufacturing quality at time of initial market authorisation would remain intact for products considered for a "flexible departure", or deviation from the normal standards of evidence, since products of poor manufacturing quality can provide no assurance of efficacy and safety.

Good planning, preferably involving a broader cross-section of key decision-makers than is currently the norm, would be crucial to the successful use of this flexible departure route. Such an evidence-based process will help ensure that the standards for market authorization are not lessened over time.

The flexible departure route would address the issue of emerging techniques and strategies in target disease identification, drug development (including the use of surrogate markers as study end-points) and data collection and analysis (e.g., adaptive trial design). These methodologies are rapidly evolving and hold promise, but still remain to be validated. The intention is to allow for enough flexibility in achieving the accepted standard for evidence of safety and efficacy for drugs with exceptional benefit-risk drivers so that:

• the best, proven methods and techniques for gathering this evidence can be adopted across the life-cycle and as drug development technologies mature;
• the global nature of drug development and regulation can be taken into account, and
• critical Canadian decision makers can exert real influence over the process.

There have been wide-spread calls for greater involvement of decision makers beyond the federal regulator and the industry in the drug regulatory process. The inclusion in the licensing standard of benefit and risk concepts, which are broader in perspective than the core efficacy and safety concepts, would provide a legitimate forum for the participation of a spectrum of key decision-makers in the planning and decision-making processes for drugs seeking flexible departure. This kind of broader involvement also would address the need for greater transparency in drug regulation.

4.3 Good Planning Throughout the Regulatory Cycle

Good planning is a well-structured, strategic approach to the generation and exchange of information throughout the entire regulatory life-cycle. It could:

• enhance timely access to beneficial drugs for Canadians as a result of better streamlined drug development and regulatory strategies;
• ensure the systematic collection of useful data throughout the life-cycle,
• increase efficiencies in drug development strategy for the industry;
• optimize resource management; and
• reduce the conduct of inadequately designed clinical trials, thereby reducing difficulties in scientific interpretation of outcomes at time of submission.

In the past, a planned approach was missing in the initial stages of the regulatory cycle, sometimes resulting in years of study being found to be unsatisfactory very late in the process. As well, there has been only limited planning of risk management activities.

Good planning will be essential in establishing the way forward for all new drugs. We want to enable planning at the earliest stages of drug development, so that we can reduce uncertainties about what must be filed with Health Canada to seek and maintain market authorization.

Planning in this early period will be of crucial importance for manufacturers who apply to depart from the usual initial standards of safety and efficacy evidence to establish the benefit-risk profile. Such departures must be well justified through a reliable, transparent process that will incorporate an appropriate level of scrutiny.

This area requires a high degree of scrutiny since it really amounts to planning how to demonstrate that a drug has an acceptable benefit-risk profile with methods that are new and generally not validated to the same extent as traditional methods. Some of the benefits of these new approaches can include earlier market access, or surmounting the problem of not being able to demonstrate the safety and efficacy of a drug (e.g., when there is a very small patient population). However, the challenges that arise are also considerable. One of the principle concerns is that initial licensing on the basis of a more limited or non-traditional data set increases uncertainty about safety. Providing more certainty about safety after marketing is a challenging task.

While it may appear straightforward to continue gathering reliable data after a drug is marketed, this is an area that is just being pioneered. The ethics and logistics around patient enrolment for studies needed to confirm efficacy and study safety in the post-market setting, for example, present very real challenges. Why should patients enrol in a controlled trial for a drug that has already been authorized for marketing when they stand a chance of not receiving the drug? Is it ethical to suggest that patients (in many cases very ill) should enrol in placebo-controlled trials when the drug is marketed? Why should patients be subject to experimental conditions if licensing suggests that uncertainty around the benefits and risks has been resolved?

Additional challenges exist as to the true status of a market approval when there is still much to confirm about the benefit-risk profile. Do provincial payers pay for the drug at this early stage? What sort of grounds do they need to be able to justify paying?

The proposed approach to manage the choices about flexible departures from the accepted demonstration of safety and efficacy is to involve key experts and decision makers in the planning process. This would be accomplished through the establishment of a pre-submission body the mandate of which would be to ascertain:

• whether a drug or class of drug is suitable for the flexible approach;
• the specific types of studies that would be acceptable to meet quantity and quality of evidence standards for initial market authorization; and
• the plans that would ensure the reliable accrual of efficacy, effectiveness, and safety information necessary for a meaningful evaluation of benefit-risk throughout the life-cycle.

Such a body would represent a wide breadth of expertise and perspectives in addition to Health Canada, such as clinical practice experts, scientists, patient group representatives, industry representatives, health care system experts, drug plan managers, and ethicists. The determinations made by this body would be only for drugs for which a flexible approach is being considered. They would be made early on in the process, ideally before the manufacturer conducts studies. This approach would allow for an evidence based flexibility over time as drug development science matures.

Significant planning will take place, therefore, both in instances where a drug company is performing traditional studies, and where they are departing from the norm at the very beginning of the process. Planning will also be a measure involved in the full life-cycle of the drug.

For all drugs, there will be a requirement to file a life-cycle management plan. Such plans could include:

• any intended further studies, including controlled clinical trials, effectiveness studies,
• any foreseen new indications;
• a paediatric investigation plan;
• a comprehensive risk management strategy, incorporating pharmacovigilance planning, risk mitigation, safety reporting, and risk communications; and
• a full life-cycle quality management strategy, including pre-approving ranges of parameters within which a manufacturer could make changes to the product without filing a submission.

These plans would be filed and reviewed prior to the drug receiving market authorization. They could be subject to updating where appropriate as knowledge about the drug progresses.

4.4 Accountability

In a progressive licensing framework accountability will be defined as the ongoing requirement to justify decisions concerning drugs that are made by Health Canada and the industry. This includes decisions regarding clinical trials, marketing authorizations, labelling, and post-market activities. This is the underlying accountability of both Health Canada and drug manufacturers.

Specific mechanisms to ensure accountability will range throughout the life-cycle. At the early stages of the cycle, the proposed pre-submission body for determining which drugs would qualify for a departure from traditional standards, would be required to render a clear justification for acceptance or denial. Similarly, it would be required to justify any decisions about the quantity and quality of the evidence required for initial market authorization. This would be in keeping with a general requirement upon Health Canada to clearly state the basis of any regulatory decision in the life-cycle, including any conditions set upon market authorization.

Abilities to set conditions upon a market authorization would enable a variety of accountabilities to be enforceable. For example, a condition that a post-market study be conducted and reviewed within a specified time period would ensure that continued justification for marketing of the drug would take place.

Accountability on a much different level would also be desirable in terms of ensuring that the framework itself remains contemporary and justified. A periodic review of the framework could be required, so that an ongoing evaluation can be conducted as to how the new system is working.

5 Consultations, Implementation, and Change Management

The development of the Progressive Licensing Framework offers Health Canada a unique opportunity to take advantage of the present knowledge and experience of those who make decisions about drugs. These decision makers bring their own sets of values, needs, perspectives, and knowledge that they use when making decisions about drugs, and Health Canada recognizes that all decision makers have valuable contributions to make to the creation of the framework. These decision makers include Health Canada, manufacturers, provinces and territories, health care professionals, caregivers, and patients.

For example, when Health Canada reviews a drug submission to reach a decision about whether a drug should be marketed, we conduct a benefit-risk assessment from a population-based perspective. We use the information in the drug submission to answer the question, AWill the benefits outweigh the risks of this drug for many people? "Prescribing health professionals ask a different question when conducting their benefit-risk assessment for an individual patient, AWill this drug benefit this particular patient, given this patient's specific needs?"

Health Canada's approach to the development of the new framework has included a deliberate, early engagement with other decision makers, informing them of the initiative and seeking their input. The intention is to consult in an ongoing fashion, with many opportunities for input. We believe that this will help build a truly modern and progressive system of drug regulation that will meet the needs of Canadians.

The implementation of the Progressive Licensing Framework would necessitate extensive planning and coordination as it could involve significant changes about how Health Canada receives, assesses, and responds to information regarding drugs throughout the product life-cycle. The new framework could continue to provide regulatory support for many of the activities we do now, but it might also increase our range of responsibilities. To effectively implement such a wide-ranging change, careful analysis of the impacts on all decision makers would be necessary.

We are also proposing the early creation of an implementation plan, which includes a change management strategy. The goals of the implementation plan and change management strategy are to provide a plan with milestones for the application of the new regulations and processes. Creation of this plan will require a thorough analysis of the resource impacts on Health Canada, the industry, and other affected decision makers. This resource impact analysis could be used in the generation of options for a phased and considered approach to implementation.

A thorough impact analysis could involve identifying where new processes and guidance will be necessary. The consultations and development of these new processes and guidance will require a detailed assessment of the resource implications.

The implementation of a life-cycle approach to the regulation of drugs could also require the enhancement of the scientific and medical expertise within Health Canada. Potential changes of a new regulatory framework such as earlier consultation with industry prior to drug submissions, review of pharmacovigilance and risk management plans, and re-evaluation of drug information after a period of initial marketing could require a significant investment of human resources. This could ensure that a critical mass of expertise will be established and that it will remain sustainable. This could also enable Health Canada to recruit and retain highly skilled technical experts.

A critical aspect of the implementation plan is a systematic approach to dealing with change, known as change management. The purpose of a change management strategy is to outline a phased plan that would allow Health Canada, industry, funders, health care professionals, caregivers, and patients to positively adopt changes resulting from the new framework.

Early involvement of decision makers is crucial to successful change management, including those internal and external to Health Canada. This creates opportunities for ongoing discussions with informed and engaged stakeholders and their input will contribute to the creation of a strong framework. Implementation of an entirely new regulatory framework would require extensive training programs for internal staff, and also for external parties such as industry.

6 Conclusion

The Progressive Licensing Project is intended to give Canadians a regulatory system that supports access to the drugs that will help them maintain and improve their health. We propose to achieve this through an evidence based, life-cycle approach that will involve good planning and promote accountability, so that decision makers throughout the health care system can make the most informed drug choices possible.

A progressive, life-cycle approach to the regulation of drugs is meant to recognize that valuable information continues to grow over time, and that this information should be captured and incorporated into decision making in a well-planned and transparent manner.

A true benefit-risk approach to drug regulation is a more accurate representation of the reality of the processes and considerations that influence decisions about drug management and use. Benefits and risks cannot be assessed in isolation from each other, but assessed together to provide an overall picture of the drug.

The introduction of life-cycle management plans could integrate the planning elements necessary for the sound management of drugs across a spectrum of evidence.

Canadians now have an opportunity to work with us in developing this new framework.

¹ For a more complete explanation of the federal drug review system, see the Health Products and Food Branch publication: Access to Therapeutic Products: The Regulatory Process in Canada .

² For a more complete explanation of the federal drug review system, see the Health Products and Food Branch publication: Access to Therapeutic Products: The Regulatory Process in Canada