Health Canada Policy Position Paper – Autologous Cell Therapy Products

Purpose

Many emerging autologous^Footnote 1 cell therapy products may eventually prove to be safe and effective.  However, most of these products are currently at the investigational stage of development with an on-going need to gather supporting scientific evidence. In addition, there is uncertainty among some stakeholders on how these products are regulated in Canada and in particular, how the present regulatory frameworks under the Food and Drugs Act (the Act) can provide appropriate oversight of safety, efficacy and quality, while enabling patient access to potentially promising new therapies.  

This paper provides background on autologous cell therapy products, as well as the Canadian and International regulatory context. It addresses specific policy issues related to the regulation of autologous cell therapies, including:  1) The risks posed by autologous cell therapies; 2) The applicable federal product safety rules and how they can be complied with; and 3) The steps that are being taken by the regulator to assist in the development of these therapies.

Background

Autologous cell therapy involves the removal, some level of manipulation or processing, and re-introduction of a person’s own cells to treat or prevent a disease, disorder or medical condition.  This may be done in a wide variety of settings (e.g. clinical setting, a hospital setting, or a more typical drug manufacturing setting) using a wide variety of processing activities and for a myriad of uses.  Processing ranges from washing and cell separation to cell modification and expansion. Uses may vary from clinically proven application such as transplantation of minimally manipulated lymphohematopoietic stem cells to treat blood cancers within a hospital transplant centre, or Health Canada authorized investigations in clinical trials, to use of unauthorized and unproven therapies for the treatment of a myriad of disorders. However, it is the ability to use an individual’s biological material for their own therapeutic benefit that distinguishes autologous cell therapy products from allogeneic^Footnote 2 cell therapy products.

Because autologous cell therapy involves the use of a patient’s own cells, it can lead to assumptions that these therapies present minimal to no risk to recipients or that they would not be subject to the regulatory oversight given to drugs or other treatments. Some physicians may assume that autologous cell therapies are not governed by the Food and Drug Regulations – particularly when a cell therapy product involves less complicated processing steps, such as those prepared in a clinical setting using authorized medical devices.  There is further uncertainty surrounding the practical means of meeting federal product safety regulatory requirements for cell therapies that aren’t mass produced; and, for this reason, how safe and effective products can be accessed by Canadians. 

As part of its commitment to work with cell therapy stakeholders with a view to enabling these technologies to advance, Health Canada is working to address these issues from a federal regulatory perspective.

Canadian Regulatory Context:

Health Canada’s authority to regulate health products comes from the Act that has been enacted by Parliament to protect Canadians from unsafe and deceptive practices relating to therapeutic products.  Cell therapy products collected and manipulated for use in the diagnosis and treatment of disease or in restoring organic functions, meet the definition of drug in the Act.  Among other things, the Act prohibits the sale of a drug that was manufactured under conditions that might render it unsafe; and misrepresentations about a drug’s safety or effectiveness.  The Act also authorizes regulations governing the processing (manufacture), distribution, labelling, sale (including distribution and administration) and advertising of a drug.

Three different sets of regulations under the Act contain specific regulatory requirements that are relevant to cell therapies. The Food and Drug Regulations (“FDR”) contain the requirements for the clinical investigation and authorization of drugs in Canada, including the standards for quality, safety and effectiveness that must be met.  A separate set of regulations, the Safety of Human Cells, Tissues and Organs for Transplantation Regulations (“CTO Regulations”), contain similar requirements for products used in the practice of transplantation. Although the CTO Regulations exclude investigational products and autologous cell therapies from their scope, infectious disease screening and testing principles, labelling, as well as principles for quality systems contained within the Regulations are applicable to all therapies involving the use of human cells. Finally, the Medical Devices Regulations (“MDR”) are relevant as novel processing/manufacturing technologies are increasingly being used to process cells, including autologous cells, and some of these technologies have been classified as devices. 

International Regulatory Context:

Other national regulatory authorities, such as the US Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) have laws similar to Canada’s that allow them to regulate the distribution of cell therapy products in their respective jurisdictions. However, important differences exist.  In particular, the European Union (EU) has enacted regulations specifically for cell therapy products, while the US FDA, like Health Canada, applies existing drug regulatory frameworks.  Some national regulatory authorities have special exemptions for certain cell therapy products including those that are prepared at the bedside during the “same surgical procedure”, or “hospital exemptions” where all of the tissue processing and administration occurs within the same establishment. While a discussion on the regulatory challenges and benefits of these special exemptions is beyond the scope of this paper, it is important to note that no such exemptions exist in Canada.

Position Statements

1. The risks associated with autologous cell therapies:

With the exception of donor-derived infections and anti-donor immune responses, autologous cell therapy products present the same risks to patients as their allogeneic counterparts, including:

• the potential introduction of bacteria or viruses;
• between-patient cross contamination, for example if equipment is not properly sterilized;
• risks resulting from processing activities and exposure to processing reagents; and
• the stimulation of unwanted immune reactions, ectopic tissue and/or tumour formation.

From a clinical perspective, cell therapy products have unique absorption, distribution, metabolism, and elimination characteristics compared to other drugs, and have the potential to persist in recipients for a prolonged period of time.  This prolonged exposure, relative to the duration of exposure to most drugs, carries the potential for both long-term benefits and long-term risks. Indeed, a number of serious adverse events have been associated with use of autologous cell therapies and strategies to mitigate these risks are needed.

The potential for harms associated with the use of cell therapies for which effectiveness has not been established, are also concerning. Therapeutic interventions pursued on the basis of anecdotal evidence that are ultimately proven ineffective or harmful when studied in well-controlled trials are common.  The “new drug” sections c.08.002(1) and c.08.002(2)(g) of the FDR, together prohibit selling and advertising a drug where effectiveness has not been established. Claims that cell therapies are safe and effective must be based on evidence from well-controlled clinical studies. These requirements help prevent the use of unsafe or ineffective therapies, while permitting access to therapies with a favorable risk–benefit balance.

2. Accessing autologous cell therapy products:

All cell therapies are “drugs” as defined in the Act and as such are subject to the specific provisions for drugs under the Act.  If an autologous cell therapy is made under conditions that could render it unsafe, or potentially harmful because it is ineffective, anyone who processes it, or then distributes (administers) it, will have contravened the Act. 

Autologous cell therapies, except lymphohematopoietic cells which have been minimally manipulated and are intended for homologous use^Footnote 3 in transplantation, are subject to Part C, Division 5 (Clinical Trials) and Division 8 (New Drugs) of the FDR.    As manufactured new drugs, these “advanced” autologous cell therapy products must be licensed for sale and advertising through the market authorization process except when they are for use in clinical research. A "New Drug Submission" must be filed containing information and data about the drug's safety, effectiveness and quality. It includes the results of preclinical and clinical trial studies, whether done in Canada or elsewhere, details regarding the production of the drug, and information regarding therapeutic claims and side effects and proposed risk management measures.

Authorization to sell (administer) investigational drugs, when there is insufficient evidence of safety and efficacy to support market authorization by Health Canada, is accomplished through the Health Canada Clinical Trial Application process described in Division 5 of Part C of the FDR.  Clinical trials authorized by Health Canada are the mechanism through which patients can access investigational drug products where much remains to be known about safety and efficacy.  These investigations in humans ensure that the best interests of patients are protected and that the product is administered in accordance with national and international ethical, medical and scientific standards.  A manufacturer or other sponsor (e.g. a physician or treatment centre) can submit a Clinical Trial Application to Health Canada at any time. A trial can be large in nature or for a single patient, and once a submission is received by Health Canada it is reviewed under short timelines of 30 days or less. Once they have sufficient evidence to support the drug’s quality, safety and efficacy any drug sponsor is able to file a New Drug Submission. Health Canada is willing to work with drug sponsors to help guide them through the CTA or NDS process.

It is important to highlight that medical device licences have been issued to equipment used in the preparation of some autologous cell therapy products.  A medical device licence does not mean that Health Canada has already reviewed and approved the safety, quality, and efficacy of the cell therapy output of the device. While a Health Canada authorized device may present certain advantages in respect to a product’s quality, unless a device has received Health Canada approval for specific therapeutic indications related to the cell therapy output, the FDR requirements apply to the cell therapy manufacturer.

3. Meeting regulatory requirements for individualised products

The individualised nature of autologous cell therapy products, like many precision medicines, may present challenges with meeting regulatory requirements because of their inherent variability, cost to manufacture and to store/test samples, transportation, and manufacturing setting (occasionally involving a decentralised model using multiple manufacturing sites).  Many biologic drugs are subject to complex manufacturing processes which must be characterized and standardized in order to achieve a high quality, and consistent final authorized drug product. In that regard, ‘the process is the product’ and Health Canada has a demonstrated track record in the ability to regulate highly variable products. While each recipient may, in-effect, be treated with a different batch or lot of the same product, manufacturing products with proper process controls increases the probability that products will be consistent in strength, quality and purity.   

Difficulties with individualized products can be overcome, and Health Canada has released a guidance document intended to help clinical trial sponsors navigate Division 5 of the FDR for the use of cell therapy products in humans.^Footnote 4  Indeed, clinical trials can and have been approved by Health Canada to gather further evidence to support safe and effective autologous cell therapy uses. 

Autologous cell therapy product sponsors may also be challenged to follow established drug commercialization pathways, a feature they share in common with certain other types of precision medicines. Health Canada is aware that cell therapy sponsors need a clear indication that the department will be able to review autologous cell therapy products when they are ready for broad distribution in Canada.

Health Canada possesses the scientific and regulatory expertise to address the challenges posed by these individualized products. In particular autologous cell therapy sponsors may struggle to manufacture consistent products from a wide variety of patients in different laboratories or in hospital settings. Challenges in establishing consistency in manufacturing (e.g., validity and reliability of study data), meeting Good Manufacturing Practices (GMP) requirements under Division 2 of the FDR, and Establishment Licencing rules under Division 1A of the FDR for market authorization requests can be discussed with Health Canada in the context of product development. 

4. Ongoing Support for Patient Access to Safe and Effective Therapies

Health Canada’s regulatory mandate is to minimize the risks of health products while maximizing their benefits, and helping Canadians to make healthy choices. It is not unusual that a lack of regulatory awareness by developers surrounds emerging cell therapy products; this is the case for many innovative technologies during early development stages.  Regulations are intended to ensure proper benefit-risk balance for health products, and patient access to safe and effective new therapies is of paramount importance. However, Canadians may not be able to access the most appropriate products if the sponsors of these products are assuming they are unable, or are unwilling, to navigate the Canadian regulatory framework.   

Health Canada is also aware that certain sections of the FDR may prove to be challenging for certain products, particularly those prepared at the bedside. Health Canada has experience with similar situations where products are manufactured onsite, and is prepared to provide guidance for sponsors to navigate the regulatory requirements. The Department is monitoring developments in the field of autologous cell therapies closely, and is ready to work with sponsors to navigate regulatory requirements.  Should a product be demonstrated to be safe and effective through authorized clinical trials, Health Canada will take steps where needed to support access for patients in Canada. Stakeholders can be confident that Health Canada will address challenges presented by certain Divisions under the FDR, such as establishment licencing, GMP, labeling etc., should they require adaptation to support therapies that have been demonstrated to be safe and effective.  

Work will be undertaken in collaboration between cell therapy sponsors, medical specialists, provincial governments, and Health Canada to support research on these kinds of products in order to facilitate the development of safe and effective innovative products. It remains a priority for Health Canada to work with the Canadian and international cell therapy community to develop strategies that enable cell therapy researchers and support cell therapy regulatory submissions.

Consolidated Policy Statements

As a result of the clarifying information provided above, Health Canada’s policy approach to autologous cell therapy products is described in the following five statements:

Statement 1:  Autologous cell therapy products meet the definition of “drug” and persons who prepare (manufacture) and administer (distribute) them must comply with sections 8 and 11 of the Food and Drugs Act.

Statement 2: Autologous cell therapy products, except lymphohematopoietic cells which have been minimally manipulated and are intended for homologous use in transplantation, like other new drugs, are regulated under the Food and Drug Regulations and must be authorized by Health Canada.  As new drugs, they are subject to Division 8 of Part C of the Food and Drug Regulations, and as investigational drugs they are subject to clinical trial requirements under Division 5 of the Food and Drug Regulations. Clinical trials authorized by Health Canada are the mechanism through which patients can have access to investigational products where much remains to be known about safety and efficacy.

Statement 3:  Health Canada considers that there is the potential for life threatening or life altering risks from treatments with autologous cell therapies that have not been developed and studied in accordance with the Food and Drugs Act and the Food and Drug Regulations.

Statement 4:  There exists confusion regarding the regulatory status of autologous cell therapy products that are processed using equipment that has an authorized medical device licence. Clarity is needed and Health Canada plans to develop separate criteria to address this issue.  Regardless, a medical device licence for a piece of manufacturing equipment does not by default constitute authorization for cell therapy products that are processed using an authorized medical device. Unless a device has received Health Canada authorization for specific therapeutic indications for the cell therapy output, the pertinent Food and Drug Regulations requirements apply to the cell therapy manufacturer. 

Statement 5:  Health Canada is working to identify and overcome challenges specific to meeting regulatory requirements for the manufacturing and sale of autologous cell therapy products, including those prepared at the bedside.  Policy interpretations of existing regulations will be pursued until regulatory amendments are clearly required, and it can be expected that cell therapy products will be authorised when evidence is presented to Health Canada that demonstrates a product is safe, of good quality, and efficacious.