02 April 2007
Key Points:
ANZTPA - Consultation paper on regulation of clinical trials released.
A consultation paper released on the ANZTPA website on 21 February 2007 outlining the proposed approach to regulation of clinical trials under ANZTPA is likely to significantly impact the conduct of clinical trials in Australia.
The proposal sets out the arrangements for a risk managed scheme, to allow lawful supply of therapeutic products for use in clinical trials. The Medicines and Medical Devices Rules ("the Rules") propose two routes of approval for clinical trials: the Clinical Trial Assessment ("CTA") scheme for studies that pose a higher risk to the participant and which require review by ANZTPA, and the Clinical Trials Certification ("CTC") scheme for all other clinical trials for therapeutic products. On the face of it, these schemes appear to be similar to the current CTX and CTN routes of approval for clinical trials, however, there are significant differences that sponsors should be aware of.
The proposed CTA scheme is intended to govern all clinical trials in Australia and New Zealand involving the first administration in humans of a new substance or a new medical device, that is, Phase 1 clinical trials. Currently, a significant majority of Phase 1 clinical trials are conducted under the CTN scheme, and the requirement for all future Phase 1 studies to be submitted under the CTA scheme will be more costly and time consuming for sponsors. If trials that were previously conducted under the CTN scheme are now forced to proceed under the CTA scheme, it may be less appealing for overseas companies to conduct clinical trials in Australia. This is because there will be less return on investment and, therefore, less incentive to select Australia as a destination.
The proposed CTC scheme requires that sponsors of clinical trials in Australia or New Zealand involving the first use of a therapeutic product in a new patient group, or for a new indication, or via a substantially different route of administration must submit more documentation than is currently required under the CTN scheme. This includes basic trial documentation such as the investigator's brochure, protocol, and the patient information and consent documents, in addition to self-certification of compliance with ethical and scientific guidelines. Sponsors are faced with an additional regulatory burden in achieving approval to conduct a clinical trial in Australia. Although the time frame for approval under the proposed CTC scheme, (where all the documentation is correctly provided) will be five working days, the fact that the sponsor will be required to submit more regulatory documentation than is currently required will potentially cause delays in the submission of clinical trial applications, and the conduct of clinical trials in Australia.
It has been suggested in the consultation paper that the proposed approach balances the need to protect public health with an intention to foster clinical research, and ANZTPA's intent to provide timely access to therapeutic products that are considered of sufficient quality, safety, and efficacy by international standards, in both countries. However, it would seem that timely access is a factor that is adversely affected by the proposed scheme.
The proposed CTA and CTC schemes will continue to require all clinical trials conducted in either country to adhere to relevant ethical standards, as well as meet international standards of good clinical practice. Notably, the ICH Note for Guidance on Good Clinical Practice CPMP/ICH/135/95, and for medical devices the ISO standard 14155:2003 Clinical investigation of medical devices for human subjects - part 1 and 2.
The closing date for written submissions on the consultation paper is 18 April 2007. As the proposed changes are likely to significantly impact investment in clinical trials in Australia, it is expected that there will be some heated debate over the proposed changes to the current schemes.
Proposed amendments to the Therapeutic Goods Advertising Code
In February the Australian Government made its intention clear to amend the Therapeutic Goods Advertising Code ("the Code") to impose a ban on healthcare professionals endorsing therapeutic products in advertisements direct to consumers.
The Code's intention is to ensure that marketing and advertising of therapeutic goods to consumers is conducted in a manner that promotes the quality use of therapeutic goods, is socially responsible and does not mislead or deceive the consumer[1]. The prohibition will be given statutory footing pursuant to the Therapeutic Goods Act 1989 (Cth) and Therapeutic Goods Regulations 1990 (Cth). Products covered by the Code include complementary medicines, over-the-counter products and medical devices.
This action revokes controversial changes made to the Code in August 2005, allowing advertisements to contain or imply an endorsement by an individual, or individual groups of, healthcare professionals (see our September 2005 edition). At the time, the change was made on the basis of findings from the Interim Advertising Council, established to develop the trans Tasman advertising scheme under the Government's proposed Australia New Zealand Therapeutic Products Authority ("ANZTPA"). According to the Chair of the Therapeutic Products Advertising Code Committee, it was felt that "consumers could benefit from recommendations by health care professionals".[2]
The Code is set to be amended "as soon as possible"[3], returning the relevant section of the Code to its 2003 form, prohibiting medical professionals from endorsing non-prescription medicines and medical devices[4]. This decision has been based on consultation with, (among other bodies), the Therapeutic Goods Advertising Code Council, which comprises the Therapeutic Goods Administration and twelve other organisations (including the ACCC), which believe the current form of the Code presents, among other problems, conflict of interest issues. Presently medical endorsement gives one product apparent superiority over others, inappropriately influencing consumers.
The recent developments create another issue in the life of the long-awaited Australia New Zealand Therapeutic Products Authority. At present it is unclear as to whether or not the changes to the Australian Code will be reflected in an updated version of the ANZTPA Therapeutic Products Advertising Code. In the past, amendments to the Code have been linked to changes in the draft ANZTPA Code (see Jocelyn Kellam's article in our December edition). Drafts of the ANZTPA Code are largely reflective of the Australian Code, thus it is assumed that the most recent proposed amendments will soon be adopted in the trans Tasman Code. Andrew Morrison further examines the issues relating to the Code under the joint regulatory scheme in this edition of Life Sciences Insights.
Surgeons under increased scrutiny by the ACCC
The ACCC last month commenced proceedings in the Federal Court for alleged anti-competitive conduct on the part of two cardiothoracic surgeons.
Proceedings in the Federal Court, Adelaide, have been commenced by the ACCC against two cardiothoracic surgeons for alleged breaches of the Competition Code of South Australia.[5]
The ACCC alleges that the surgeons engaged in anti-competitive conduct in respect of two other cardiothoracic surgeons also operating in Adelaide. Allegations include that the surgeons took actions to hinder or prevent rival surgeons from obtaining accreditation and appointments at various hospitals in Adelaide as well as attempting to induce rivals to enter into non-compete agreements.
It remains to be seen whether this action will lead to similar actions being brought in the future by the ACCC against medical professionals in other fields, and other States, pursuant to the National Competition Policy.
Update on the TGN 1412 Trial: European Medicine Agency to introduce new guidelines
In the December edition of Life Sciences Insights we examined the UK Expert Scientific Group's (ESG) report on the lessons learnt from the Tegenero TGN 1412 Trial. The controversy resulting from the TGN 1412 Trial and the consequential recommendations made in the ESG report have led the European Medicines Agency (EMEA) to take a positive step towards changing the existing guideline on Phase 1 Clinical Trials.
Following the experience with TGN 1412, the ESG report found that the preclinical development studies performed with TGN 1412 did not predict a safe dose in humans, even though current formal regulatory requirements were met. It also made 22 recommendations for a future approach to Phase 1 studies with new types of medicines, including a microdosing approach and the use of patients, rather than healthy, volunteers in some cases.
Since the release of the ESG report, it has been widely accepted that additional guidance may be required in relation to first-in-man studies, particularly those involving species-specific substances with novel mechanisms of action. Consequently, the Committee for Medicinal Products for Human Use (CHMP), a branch of the EMEA, decided in its meeting in January 2007 to act upon the general public concern and the findings of the ESG report by developing a new draft guideline on Phase 1 Clinical Trials with high-risk medicinal products.
On 22 March 2007 the EMEA published the draft guideline for public consultation[6]. The guideline is intended to assist sponsors in the transition from non-clinical to early clinical development and it provides criteria to classify new investigational medicinal products as potential high-risk medicinal products. It also gives guidance on quality aspects, non-clinical testing strategies and designs for first-in-man clinical trials for high-risk medicinal products, including the calculation of the initial dose to be used in humans, the subsequent dose escalation and the management of risk. In producing the new guideline, the CHMP drew upon the recommendations made by the ESG in relation to the conduct and review of Phase 1 trials, and also considered proposals and related suggestions from other parties, such as the regulatory agencies of France and Germany.
The EMEA is planning an accelerated consultation process on this matter as there is wide public interest in seeing the guideline adopted rapidly. Therefore, the EMEA has invited comments from healthcare professionals and the public before 23 May 2007. At the end of the consultation period, the EMEA will convene a meeting of healthcare professionals, regulators, patient representatives, academics and the industry to consider feedback and finalise the guideline for publication.
We will provide a comprehensive report on the guideline in the next edition of Insights. We will also report on any developments in first-in-man clinical trials generally as international bodies react to the recommendations of the ESG report.
New merged regulatory authority for tissue and embryos in the UK
The UK Government proposed to create a new authority which is the only body responsible for all matters relating to the whole range of human tissue - cells, tissues, organs, gametes and embryos. This is part of a wider programme to improve efficiency and reduce the burden on the frontline. The Regulatory Authority for Tissue and Embryos (RATE) will combine the current functions of the UK's Human Tissue Authority ("HTA") and Human Fertilisation and Embryology Authority ("HFEA"). Its role will be to licence, inspect and regulate specific activities including the creation and use of embryos in vitro for treatment and research; human tissue banking, post mortem practice, anatomical examination and public display. It will also advise Ministers on developments in society, science or medicine that might significantly affect the practice of regulated activities and provide to the public and to persons carrying on activities within its remit, information and advice about the nature and purpose of such activities. In addition, RATE will take over the responsibility for the regulation of the donation, procurement and supply of blood and blood products from the Medicines and Healthcare Products Regulatory Agency.
RATE will be an independent statutory body consisting of a smaller board that has a more strategic role. Around it a broader range of experts will be assembled through a formal and transparent advisory structure.
Bringing all matters concerning human tissue, gametes and embryos under a single framework, RATE will increase safety and quality of tissues and cells. It ensures continuity at the interface between related areas and the risk of overlap between related areas is minimised. It would not only be the sole regulatory body responsible for the regulation and inspection of all functions relating to the use of human bodily material but also become the single competent authority under the EU Blood and Tissue and Cells Directives. As such its powers and responsibilities are:
On 14 December 2006 the Department of Health published a white paper proposing the establishment of RATE. HTA and HFEA both welcomed it. After a bill is being drawn up in the 2007/2008 parliamentary session, RATE prospectively will be established in 2009. Meanwhile HTA, HFEA and the Department of Health concentrate on joint working to support establishing RATE.
With thanks to Zoë Kimberley, Claire Naughton, Tyson Smith and Emma Pirvics. Quick Dose edited by Amanda Turnill.
[1] Sect 1(1), Therapeutic Goods Advertising Code 2006
[6] http://www.emea.eu.int/pdfs/human/swp/2836707en.pdf
