Summary of outcomes of consultations on the regulation of human tissues and emerging biological therapies
Consultation workshops on the Discussion Paper ("The regulation of human tissues and emerging biological therapies" <http://www.tga.gov.au/docs/html/humantiss.htm>) were undertaken in every State capital and in Canberra (no workshop was held in Darwin due to a lack of response).
Approximately 135 people attended workshops, representing a wide cross-section of relevant organisations and experts in the field. Written submissions were received from 19 organisations and individuals. In general, there was a core set of issues that was discussed at each of the workshops and addressed in the written submissions. These issues are summarised below.
Proposed subject matter of the new regulation
There was very little comment during consultations about the proposed definition of human cell and tissue products (based on the US model):
articles containing or consisting of, or derived from, human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.
While there seemed to be general support for the proposed definition, the discussion predominantly focused around the proposed exemptions and whether or not they are appropriate.
Proposed exemptions from the regulatory system for human cell and tissue products
- secreted or extracted human products (eg human breast milk)
There was little comment on whether such products should or should not be regulated under the new system. One comment provided was that it would appear to be somewhat contradictory to exclude any human tissue from consideration under the regulatory framework. - reproductive tissue (sperm, eggs and embryos)
While there was little comment on this issue, it was generally recognised that it would seem inconsistent to exempt reproductive tissue from the regulatory system for human cell and tissues (recognising that many of the safety issues relevant to banked tissue are also relevant to banked sperm). On the other hand it was also recognised that there is a system of industry based oversight in place in relation to Assisted Reproductive Technology (ART) clinics and that treatment of fertility and the use of human reproductive tissue for such treatment is perceived very differently to other medical practice and the use of "therapeutic goods" developed using tissues and cells. - whole organs
The Discussion Paper proposed, consistent with regulatory systems being implemented in other countries, that whole organs not be included in the new regulatory framework. There was general support for this, but a range of different views were expressed.- Organ transplantation from cadaveric donors should be excluded from any regulatory framework - such transplants need to be performed within hours of the organ becoming available, therefore there is no opportunity to apply any GMP-like requirements on the removal, packaging, transport and handling, or transplanting. Any TGA regulation applied in this area which impacts on the time taken to obtain an organ and transplant it would affect the success rate of organ transplants, which may in turn have a negative impact on donation rates.
- Industry based national standards for organ transplantation are already applied. These standards are produced by Australasian Transplant Coordinators Association and the Transplantation Society of Australia and New Zealand. The focus of the standards is identification of risk of transmissible disease, both for viral disease and transmissible cancer.
- There may, however, be inconsistent application of these standards between jurisdictions. Some participants noted that it may be desirable to have a system of minimum standards in place that are applied by the TGA and able to be enforced. Again, it was noted by some, that it appears inconsistent to exempt whole organs while regulating the supply of other tissue and cells. Such stakeholders noted that if regulation were to be applied, it would need to be appropriate and adapted to the unique circumstances surrounding whole organ transplants.
Proposed activity that will be subject to the regulation (use of the term "manufacture")
The Discussion Paper proposed use of the term "manufacture" (as defined in the FDA's proposed regulatory framework) to describe the activity to be regulated under the new framework. The Discussion Paper notes the shortcomings of the term in relation to certain tissue types, such as the processing of corneal tissue by eye banks.
This point was raised in consultations, particularly in relation to retrieval and processing of tissues for transplantation. However, it was also acknowledged that there may not be a better term and that as long as "manufacture" was defined to capture all related activities, it should not be a problem.
Possible exemptions for certain people (including for medical practitioners in hospitals)
The Discussion Paper outlined the current position in the TG Act that provides exemptions from licensing requirements for:
- medical practitioners and health care workers, provided that the manufacture of the cell or tissue product is for a patient under his or her care; and
- biomedical engineers, radiochemists and pharmacists in public hospitals provided that the goods produced are for supply in hospitals or public institution in the same State or Territory.
The Discussion Paper questioned whether it is appropriate for these exemptions to continue under a new regulatory framework for cell and tissue therapies. This issue attracted considerable comment during the consultations and a wide variety of different views were expressed:
- Where a treatment is developed and applied entirely within a hospital setting, it is reasonable that the hospital and the treating doctor carry the full responsibility for the clinical advice and treatment.
- Application of TGA licensing (and cGMP compliance) in hospitals would have impacts throughout the hospital, including for operating theatres, wards, imaging and pathology laboratories, significantly increasing costs and therefore reducing the amount of health care that can be provided.
- Current industry based regulation, such as ACHS hospital accreditation or NATA laboratory accreditation, seem sufficient.
- A new TGA regulatory framework for cells and tissue therapies applied within hospitals will not be able to provide for the risk/benefit health care decisions made by patients in full consultation with their treating doctor. This relationship is the proper province of hospitals, State Health Authorities and physicians.
- The alternative view stated was that there should be no distinction made between a laboratory manipulating cells in a hospital under the direction of a medical practitioner and a laboratory manipulating cells off site, usually under the direction of a medical professional.
- All relevant practitioners and manufacturers should work to the requirements of the same quality system.
- A practitioner in a hospital using a treatment made by a third party (off-site) would expect standards of GMP to be applied to the product they administer to a patient.
Proposed classes of risk/regulation
The Discussion Paper outlined 3 classes of activities that would attract different levels of regulation. Although there was general consensus on this approach, it was noted that the scheme (as reflected in the Paper) may be too simplistic, as there is a wide range of factors that can influence the level of risk posed.
Many stakeholders noted that the level of regulation needs to be related to a combination of the tissue type, the tissue source, the level of manipulation and the effect of the manipulation on the end product.
A number of specific concerns were raised about where certain products would fall in the proposed scheme and in some cases, the impact that the classification may have on the ongoing viability of the use of such products.
For example:
- the need for a distinction between "banked" and "stored" tissue - banked tissues are intended for transplantation into an unknown, unrelated recipient whilst stored tissues are generally for autologous use, with no risk of transmitted viral infection or issues of consent;
- level and form of cell manipulation needs to be distinguished in the risk assessment. For example, stimulation of cells by a biological reagent, such as cytokine, can have significant safety issues, compared with selection of cells using physical methods, where there is no alteration to the cell;
- the risk classes as described in the Discussion Paper will place cadaver pancreatic islet transplantation in Class 3. It would not be possible for the hospital to meet TGA cGMP and licensing requirements with respect to retrieval and processing of the cells, therefore this procedure would be stopped by TGA regulation;
- there needs to be a distinction between cadaver tissue and surgical tissue (ie living donation). For example, cadaver bone is serologically tested once and the donor is not available for interview, whilst surgical bone is typically quarantined for 6 months, tested at the time of harvest and after 6 months and the donor is extensively interviewed;
- the description under Class 3, where cells or tissues are manipulated to change the natural properties, would capture banked bone, which is subject to freezing and irradiation (for terminal sterility) which is acknowledged to change the bone's natural properties, even though this is generally considered a low risk product.
It was also noted that:
- the legislation would need to provide for some flexibility (through exemptions) so that as the safety of products was established over time, commensurate changes could be made to the level of regulation applied. Similarly it may be beneficial to be able to draw other things into the regulatory system (for example, products that are initially proposed to be exempt) if this proves necessary over time;
- while it was agreed that the description of the classes of activity in the legislation should be general (and avoid listing particular products) the risk categories might be better understood if further examples of the different types of cell and tissue products were provided for each category in any further explanatory documents or Discussion Papers.
The Code of Good Manufacturing Practice (cGMP)
The Discussion Paper suggested that it may be necessary to produce a new cGMP specific to cell and tissue therapies. At the workshops, the Canadian model of safety standards, which includes a set of generic standards, with a number of attached standards for specific tissue types (eg perfusable organs or ocular tissue) was discussed. Comments raised in consultations were generally supportive of producing a cell and tissue specific code:
- Developing a cGMP with a general overview with specific standards attached was seen as a sensible idea. This would enable changes to be made to attachments, or the addition of new attachments, overtime.
- If such specific standards are to be produced, they should be developed in consultation with all stakeholders.
- Any new cGMP for cell and tissue products should be less prescriptive than the current cGMP for Human Blood and Tissues and should focus on principles or standards to be observed rather than detailing prescriptive means for meeting such standards.
Xenotransplantation
The Discussion Paper outlined the current process being undertaken by the NHMRC in relation to xenotransplantation. It also noted that other countries undertaking regulation of cell and tissue products are separating xenotransplantation from the regulatory schemes for human cell and tissue products.
Workshop participants generally agreed that the regulation of xenotransplantation should be kept separate from that of human cells and tissues. In that way, when the community and Parliament has debated the ethical arguments surrounding this issue, the TG Act would have the necessary regulatory force if required, or the relevant section could be easily removed, if not required. It was agreed that consideration of the ethical issues is outside the scope of the TG Act.
A related issue that was raised, is how inactive animal products (such as porcine heart valves) would be regulated and whether porcine heart valves would continue to be regulated as a device or fall under any xenotransplantation regulation. It was noted that the TGA anticipates that sterile, non-viable animal products would continue to be regulated as devices or medicines and would not be caught in any new regulatory system for xenotransplantation.
Gene therapy
Many of the issues raised about xenotransplantation were also raised for gene therapy. It was noted that, in relation to current clinical trials using gene therapy, the GMP requirements for Phase II and Phase III trials are not entirely clear as the current Codes of GMP for both medicines and blood and tissues do not contain specific requirements for gene therapy. It was noted that any new Code for cell and tissues (with appendices dealing with xenotransplantation and gene therapy) should also be able to be applied to clinical trials. This point will also be raised with the consultants currently undertaking the TGA review of clinical trials.
Whole blood and blood components
The regulatory framework for whole blood and blood components was approved by AHMAC in 1999 with TGA as the designated regulator.
Operation of the framework formally commenced with implementation of a requirement to comply with the Australian Code of Good Manufacturing Practice - Human Blood and Tissues and with gazettal of Therapeutic Goods Order No.66 in August 2000. By this order, blood components include red cells, white cell, stem cells, platelets and plasma (other than plasma for fractionation), and must meet the requirements of the Council of Europe "Guide to the preparation, use and quality assurance of blood components" 8th Edition (TGO 66A). Blood components, such as the progenitor cells in cord blood and PBSC are subject to this Order.
Therefore the proposed new regulatory system for human cells and tissues will not cover blood and blood products.
TGA fees
Concerns were raised about the impost of full cost recovery for any new regulatory framework, particularly for public hospitals and non-profit organisations such as tissue banks. Some urged consideration of fees being met by Commonwealth and State governments. The significant internal costs of compliance with GMP requirements were also noted by many stakeholders.
Implementation timeframes
In all of the workshops, stakeholders emphasised that there will need to be sufficient lead times for organisations to comply with any new regulatory requirements. It was also noted that it will be important for guidance documents (and TGA application forms) to be clear and for there to be sufficient resources within the TGA to support the transition to the new system of regulation.
Timeframes for further consultation
During consultations, two possible options were put for further consultation on the proposed regulatory system: circulation of another Discussion Paper describing the proposed regulatory system; or circulation of a draft legislative framework with accompanying explanatory materials. In general there was most support for the second proposition as many people thought it would be more valuable if they could start seeing some definitions and draft clauses in "black and white" to provide comment on. However, there was also strong criticism of this approach from some, as it was thought that some fundamental issues were still open for discussion and that consultation on any form of draft legislation would pre-empt this further discussion.
Proposed means for effecting the changes in the TG Act
During the consultations, it was proposed that a separate part of the TG Act be developed to address "biological therapies". It was proposed that this new Part include separate sections to regulate human cell and tissue products; blood and blood products; xenotransplantation (if required); and gene therapy.
There was general support for this approach, rather than trying to "weave" the new regulatory requirements into the existing Act.
Initial notification to TGA of activity relating to cell and tissue therapies
In outlining the approach being taken by other countries to the regulation of cell and tissue products, the Discussion Paper mentioned the registration process undertaken by the Center for Biologics Evaluation and Research (within the US Food and Drug Administration) in order for them to keep records of activities in this area.
This concept was discussed at the consultations and there was strong support for the TGA to undertake a similar process, at least to initially scope the level and type of activity currently carried out, with a view to possibly making it an annual registration of such activities. The TGA therefore proposes to shortly send organisations a letter with an accompanying form and explanatory material to enable the TGA to collect information about activities currently being undertaken utilising human tissues and cells.