Biologicals regulatory framework changes from 1 July 2018

Including changes to regulation of autologous human cell and tissue products and classification of biologicals

2 July 2018

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Regulatory pathways for supply of autologous human cell and tissue products

The level of regulation for autologous HCT products is based on the level of risk to the public associated with the manufacturing processes and/or intended use of the autologous HCT product. The following categories apply (from lowest to highest risk):

The diagram below provides an overview of how autologous HCT will be regulated based on their level of risk.

Regulatory pathways for supply of autologous cell and tissue products

Flowchart showing regulatory pathways for supply of autologous cell and tissue products

TEXT VERSION: Regulatory pathways for supply of autologous cell and tissue products flowchart

  1. Does the product meet the eligibility criteria for 'excluded from regulation by the TGA - products used in hospitals'?
    • If YES - Excluded from TGA regulation
    • If NO - go to 2.
  2. Is it regulated as a biological
    • If YES - go to 3.
    • If NO - go to 4.
  3. Does the product meet the eligibility criteria for 'regulated with exemptions - for products used outside hospitals?
    • If YES - Regulated as a biological with exemptions
    • If NO - Regulated as a biological
  4. Is it regulated as a blood and blood component?
    • If YES - go to 8
    • If NO - Regulated as a biological
  5. Does the product meet the eligibility criteria for 'regulated with exemptions - for products used outside hospitals'?
    • If YES - Regulated as a blood and blood component with exemption
    • If NO - Regulated as a blood and blood component

For further advice on the classification of your autologous HCT please contact the TGA.

Excluded from regulation by the TGA - products used in hospitals

Where the product is subject to processing that is more than minimal manipulation, the definition of a blood component does not apply and such a product would be regulated as a biological

If a product is excluded from regulation by the TGA, it is excluded from all of our regulatory requirements, including the TGA clinical trials provisions.

Eligibility criteria

We will not regulate autologous HCT products if they meet all of the following:

  1. collected from a patient who is under the clinical care of a medical or dental practitioner registered under a law of a State or an internal Territory
  2. manufactured by that medical or dental practitioner, or by a person or persons under the professional supervision of that medical or dental practitioner in a hospital, for that patient who must be a patient of that hospital
  3. for therapeutic use in that patient by the same medical or dental practitioner, or by a person or persons under the professional supervision of the same medical or dental practitioner
  4. not advertised or promoted directly to consumers.

All of the above criteria must be met for this exclusion to apply. Where one or more of the criteria are not met, including if advertising occurs directly to consumers, a higher level of regulatory requirements will apply.

These requirements for exclusion for certain autologous human cells and tissues will be included in the legislative instrument for Therapeutic Goods (Human Cells and Tissues) Determination 2018.

Medical devices or equipment used for manufacture of these products may be regulated as medical devices.

The conditions for exclusion do not include any restrictions on:

  • the level of manufacturing (including storage and processing beyond minimal manipulation)
  • OR
  • on the treatment that can be used by practitioners within the hospital.

Further information on the regulation of the 'manufacture and use in a hospital' is provided in the definitions.

Examples of products likely to be excluded from regulation

The following include examples of clinical procedures/treatments that are likely to be excluded, when performed by medical or dental practitioners in a hospital. This list is not exhaustive, and the manufacturing and use should be carefully considered in the context of the eligibility criteria.

Skin grafts (including keratinocyte sprays)

Where healthy skin is removed from one area of the body (leg, arm, buttocks) and transplanted to an injured area (used in burns) of the same patient. In addition, some hospital burns centres are taking keratinocytes (skin cells) and culturing them before applying the cells to the injured area as part of mesh grafts or sprays. This processing is considered greater than minimal manipulation and the intended use may also involve storage of the cells and multiple treatments over the course of the treatment, but is still likely to meet the exclusion criteria.

Craniotomy and parathyroidectomy

Under specific circumstances sections of tissue may be removed and temporarily stored, to facilitate treatment of traumatic injuries and other disorders. The removed sections of tissue may be stored for a number of days and then returned to the patient when appropriate.

Vascular conduits

Blood vessels (usually veins) are used to replace injured or blocked arteries in a different area. Vascular conduits are commonly used in coronary artery bypass grafting for heart disease and in the treatment of peripheral vascular disease (poor blood flow to the lower limb/s). Autologous blood vessels may also be transplanted to facilitate heart transplants.

Pancreatic islet cells

Some patients with chronic or recurrent inflammation of the pancreas may need the pancreas surgically removed. The insulin-producing islet cells are isolated from the removed pancreas and transplanted into the liver to prevent diabetes. This procedure is considered minimal manipulation as the dissociation of the pancreas maintains the function of the islets. If a patient already has diabetes, islet cell transplantation decreases the risk of the diabetes becoming worse.

Bone grafts

Small sections of bone may be taken from healthy sites (usually the iliac crest of the hip bone) and transplanted into injured sites of the same patient to assist healing after elective orthopaedic surgery (for example knee reconstruction), and traumatic bone injuries. Osteochondral transfer (OATS, transfer of small sections of bone and attached cartilage) procedures may be used for repair of well-defined cartilage defects in joints like the knee.

HPCs for reconstitution of blood after treatment of cancer (i.e. bone marrow transplants)

Patients with a range of blood cancers often undergo powerful chemical therapies to destroy the cancerous cells. Haematopoietic cells (HPCs) are collected before the treatment and stored while the patient undergoes treatment. After the treatment the patient is re-infused with the cells to help the blood re-establish. Australian hospitals providing HPC transplants are currently subject to National Pathology Accreditation Advisory Council (NPAAC)/ National Association of Testing Authorities (NATA) accreditation.

Autologous blood to seal cerebrospinal fluid leaks

The brain and spinal cord are cushioned by a clear fluid called cerebrospinal fluid (CSF), encased in a protective membrane called the meninges. If the meninges are torn as a result of injury, surgery or sometimes spontaneously, the CSF may leak out and the patient is at risk of infection and other complications. Small tears in the meninges may be closed by applying fresh blood, which clots and seals the opening.

Autologous blood components

Some patients with rare blood types that are difficult to match may need to prepare for surgery by providing autologous donations a few weeks in advance of surgery. The blood is stored and reinfused when needed. Another approach to autologous blood replacement is the process of catching, filtering and reinfusing lost blood during surgery (cell salvage).

Autologous platelet-rich plasma is not likely to meet the criteria for exclusion, unless collected and manufactured in a hospital.

Cosmetic/reconstructive procedures (skin, bone and fat transfers)

Bone grafts and mucous membranes may be used as autologous transplant materials for patients requiring dental and maxillofacial surgery (dental implants for crowns or bridges, gum recession, facial prostheses). Adipose tissue may be collected from one area (usually stomach, thighs or waist) using a procedure termed liposuction, and reinjected into another area to increase fat content in the receiving site. This is often used for breast reconstruction after breast cancer surgery, and other cosmetic and reconstructive surgery.

Regulated with some exemptions - for products used outside hospitals

Eligibility criteria

In order to qualify for certain regulatory exemptions autologous HCT products must meet all of the following criteria:

  1. Collected from a patient who is under the clinical care of a medical or dental practitioner registered under a law of a State or an internal Territory.
  2. Manufactured by that practitioner, or by a person or persons under the professional supervision of that practitioner, for a single indication and in a single procedure on that patient by the same practitioner, or by a person or persons under the professional supervision of the same practitioner.
  3. For therapeutic application in a homologous use.
  4. Minimally manipulated.

All four criteria specified above must be met for the exemptions to apply. Where one or more of the criteria are not met, a higher level of regulatory requirements will apply. The conditions are set to limit this option to only low risk products, where there is still a high level of clinical oversight by a medical or dental practitioner. To achieve this there are restrictions on the degree of manufacturing (only minimal manipulation) allowed, and on the intended clinical use (to treatment for a single indication, in a single procedure and when the intended use is homologous).

These exemptions apply equally to autologous HCT products that would be classified as biologicals and blood and blood components (regulated as medicines).

The exemptions

Autologous HCT products that meet all of the eligibility criteria for 'regulated with some exemptions' would be exempt from the requirements for:

  • using 'unapproved' product pathways (e.g. clinical trials under CTN route, Special Access schemes):
    • however, if you choose to investigate the safety or efficacy of the product as part of a clinical trial, a human research ethics committee (HREC) should approve the trial
  • inclusion on the Australian Register for Therapeutic Goods (ARTG)
  • holding evidence that the manufacturing facility satisfies good manufacturing practice (GMP) requirements. The exemption from GMP requirements also applies to any contracted testing facilities used e.g. for sterility testing.

Regulation requirements still applying

An autologous HCT product that meets all of the criteria would be exempt only from the requirements mentioned above. Other applicable regulatory requirements will apply, such as:

Criminal penalties may apply if the quality, safety or efficacy of the product is found to be unacceptable, the advertising requirements are breached, the product does not comply with applicable standards or the sponsor does not respond to TGA questions about the product.

Under most circumstances the TGA will not review such products with regard to compliance to applicable standards, or evidence to demonstrate safety and efficacy. However, you should hold the information and we may request information to be provided about the product concerning any of these aspects, for example, when a safety issue arises.

Medical devices or equipment used for manufacture of these products may also be regulated under the medical devices framework.

Examples of products likely to be regulated with some exemptions

The following includes examples of autologous HCT products that are likely to fall within this category of regulation and exemptions, if their use satisfies all of the outlined criteria.

Bone graft for dental procedures

A dental practitioner may take a section of bone from another area of the body, and graft it onto the jaw bone (or other orofacial region) of the same patient in a single procedure, following major dental extraction (or maxillofacial surgery). This procedure would meet the conditions as the processing of the bone is considered minimal manipulation, the use is considered to be homologous, and this procedure would usually not occur in a hospital.

Platelet-rich plasma

Platelet-rich plasma (PrP) is prepared from blood collected by a single uninterrupted venepuncture. The plasma is generally separated from the red blood cells by centrifugation, with the platelets present in the plasma. The next steps vary between protocols but are intended to discard both the red blood cells and the acellular plasma layers and to collect only the platelet rich plasma layer. Commercial kits are now available to assist in the preparation of PrP. Importantly, the preparation of PrP only separates and concentrates the cells without manipulating them.

An example of PrP that would meet the exemptions would be where a medical practitioner collects some blood from a patient outside of a hospital and manufactures the PrP using minimal manipulation. The intended use of the PrP must also be homologous.

The following points should be noted for the manufacture and use of PrP:

  • The intended clinical use of PrP under these exemptions still needs to be justified based on proven evidence of safety and efficacy.
  • PrP product would likely be considered a blood component (and regulated as a medicine), being prepared only by centrifugation, and filtration.
  • The exemptions only apply when the PrP is manufactured and administered by or under the supervision of a registered medical practitioner for a patient under their care. This exclusion does not apply to other health practitioners.
  • Where equipment (such as a commercial kit) is used in the manufacture of PrP or conditioned serum it may also be subject to regulation as a medical device.
  • Cosmetic use of injected PrP is likely to be regulated by TGA where therapeutic claims are made or inferred. Generally, injectable products fall under the Australian legal definition for therapeutic use (for example, as they are intended to cure a defect or modify the anatomy, even if it is only for 'aesthetic' purposes).

Fully regulated

Autologous HCT products will be regulated as biologicals or blood components if they do not satisfy any of the criteria for exclusion/exemption criteria specified above.

Where an autologous blood component has been subject to processing beyond minimal manipulation, it would no longer meet the definition and would be regulated as a biological. If an autologous blood component is to be used for a non-homologous use it would be regulated as a medicine.

Regulatory requirements

These autologous HCT products, which are usually more than minimally manipulated and/or for non-homologous use, and manufactured and used outside of a hospital, will be subject to all the regulatory requirements such as:

Inclusion in the ARTG

Where the autologous HCT product is required to be included in the ARTG it will be subject to the following:

  • The TGA must be satisfied (based on a dossier) as to the quality, safety, and efficacy (for their intended purpose) of the autologous HCT product to be included in the ARTG.
  • The TGA can recall goods supplied in the event that the autologous HCT product does not comply with an applicable standard or if it appeared that the quality, safety or efficacy is unacceptable. These recall procedures include requiring the supplier to make information available to the TGA and the public about the products.
  • The TGA can suspend or cancel the inclusion in the ARTG if it appeared that the quality, safety or efficacy was unacceptable, a condition of inclusion was breached, the advertising requirements were breached, the product did not comply with applicable standards or the sponsor did not respond to TGA questions about the product.

Examples of products likely to be regulated as biologicals or blood components

The following section includes examples of clinical procedures or treatments that were previously excluded from regulation but are now likely to be regulated as biologicals or blood and blood components if the processing is performed outside a hospital.

Medical devices

Medical devices or equipment used for manufacture of these products may also be regulated as medical devices.

Adipose-derived cell extract (including stromal vascular fraction)

There are a wide range of methods used to collect and process adipose tissues to isolate cells prior to re-injection in the patient. We would consider almost all of them to fall outside of the eligibility criteria for exclusion or the exemptions from regulation.

The methods used to prepare adipose-derived cell extracts are generally considered to be more than minimal manipulation.

The intended clinical use of adipose-derived cell extracts would result in a product being fully regulated as a biological when the clinical uses are non-homologous and subject to greater safety concerns (e.g. intrathecal or intravenous injection), or the cell preparation is used in more than a single procedure, for example, if extra cells left over from the initial treatment cycle are stored for a later procedure.

More information on the classification of cells extracted from adipose tissue (including stromal vascular fraction (SVF)) is provided in the explanation of key terms.

Conditioned serum

Autologous conditioned serum is the term used for products made from a blood collection, where the serum is cultured for several hours to induce the white blood cells to secrete anti-inflammatory compounds into the serum. This product does not contain platelets and should not be confused with platelet-rich plasma (PrP).

The processing of the blood component, in this case, is considered more than minimal manipulation; and thus conditioned serum products will be fully regulated as a biological.

Access to 'unapproved' autologous HCT products

For autologous HCT products that will become regulated, the provisions to access unapproved therapeutic goods will still be available to patients and their treating doctors via access to 'unapproved' autologous HCT product, subject to fulfilment of specific requirements.

Clinical trials

Importation into and/or supply in Australia of 'unapproved' therapeutic goods for use in a clinical trial may fall under either the Clinical Trial Notification (CTN) scheme or the Clinical Trial Exemption (CTX) scheme.

The CTX scheme is mandatory for a trial of any Class 4 biological unless (a) use of the biological is supported by evidence from previous clinical use; or (b) the use of the biological in a clinical trial has been approved for an equivalent indication from a national regulatory body with comparable regulatory requirements. For more information about the Clinical Trials schemes see the guidance.

GMP licensing or certification of manufacturing sites is required, unless the persons or goods are exempt e.g. first-in-human trials.

Special Access Scheme (SAS)

The Special Access Scheme (SAS) applies to all regulated therapeutic goods and refers to arrangements that provide for the import and/or supply of an 'unapproved' therapeutic good for a single patient, on a case-by-case basis.

  • Category A is a notification pathway which can be accessed by a prescribing medical practitioner or a health practitioner on behalf of a prescribing medical practitioner for patients who are seriously ill with a condition from which death is reasonably likely to occur within a matter of months, or from which premature death is reasonably likely to occur in the absence of early treatment.
  • Category B is an application pathway that can be accessed by health practitioners for patients that do not fit the Category A definition. Category B applications must be reviewed and approved by TGA before the unapproved product may be accessed. Category B applications must be completed in full and include the patient diagnosis and indication for which the product is sought. The application also requires a thorough clinical justification for the use of the product, which includes the seriousness of the condition, details of previous treatment and reasons why a therapeutic good currently included on the ARTG cannot be used for the treatment of the individual patient in the particular circumstance. The application must also include sufficient safety and efficacy data to support the proposed use of the product. This may include references to clinical trial results and published peer-reviewed data, or evidence that the product has been approved for an equivalent indication by a national regulatory body with comparable regulatory requirements. The request should include details of intended monitoring for adverse events and patient response to treatment. The SAS Category B pathway is intended for exceptional circumstances and not for routine use of an unapproved product. In addition, the applicant has responsibilities when seeking to use unapproved therapeutic goods that include adherence to relevant standards of good medical practice. For further information about the SAS, see the guidance.

    The product to be accessed via the SAS B pathway must be manufactured in accordance with appropriate good manufacturing practice (GMP).

  • Category C is a notification pathway that allows health practitioners to supply goods that are deemed to have an established history of use. Most autologous HCT products that do not satisfy the criteria for exclusion from regulation by the TGA, or the criteria for exemption from some parts of the Therapeutic Goods Act 1989, will not be considered appropriate for inclusion in the pathway.

Authorised prescribers

In some circumstances a medical practitioner may be granted authority to become an authorised prescriber of a specified 'unapproved' therapeutic good (or class of unapproved therapeutic goods) to specific patients (or a class of patients) in their immediate care with a particular medical condition. The authorised prescriber must obtain approval from a Human Research Ethics Committee (HREC) or endorsement from a specialist college.

GMP certification of manufacturing sites is required when accessing unapproved therapeutic goods under the authorised prescriber scheme.

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