STEM CELL FEATURE PART 2: Tangled up in red?

For the second of our two-part series examining Australia's new laws on embryonic stem cell research and human cloning, Pete Young asked medical researchers, IVF clinics and companies developing stem cell-related products for their views on the impact of the legislation.

A tide of red tape will rise in the wake of the Prohibition of Human Cloning Act and Research Involving Human Embryos Act, which are now law after a noisy passage through Parliament late last year.

But not high enough to drown either medical researchers working with products derived from human embryos or in vitro fertilisation clinics supplying the embryos. That is one consensus emerging from a survey of organisations most affected by the new legislation.

For many, the most pressing question is the actual size and number of forms they will have to complete in order to comply with licensing requirements. Commercial developers of stem cell-related products are unhappy with a clause that limits the embryos they can access to those frozen before April 5, 2002.

The identity and views of the individuals who will make up the all-powerful licensing committee being created by the National Health and Medical Research Council (NHMRC) is another blank space that workers in the field would like to see filled in as soon as possible. And there are suggestions that the Commonwealth legislation may restrict some aspects of IVF practice in Queensland and NSW, where no state-based rules apply.

Teething problems

One medical research centre heavily involved in stem cell research is the Diabetes Transplant Unit of the University of New South Wales (UNSW). Part of the National Biotechnology Centre of Excellence for Stem Cell and Tissue Repair, the DTU is the first unit in NSW to grow human embryonic stem cells and has been developing multiple approaches to turn adult and embryonic stem cells into beta cells using cell culture and genetic tools.

DTU head Prof Bernie Tuch says he is sure the new licensing procedures "will produce some teething problems" but doesn't expect to be snarled in fresh layers of red tape.

For one thing, the DTU works with existing cell lines derived from overseas sources, a scenario which will not require its researchers to seek licences under the Research Involving Human Embryos Act. However, the legislation opens the door for creation of new stem cell lines in Australia and the transplant unit "will be happy to work with the people creating them," says Tuch. Applying to work with new sources will necessarily create more paperwork, he concedes.

The new legislation also reinforces guidelines governing the approval by ethics committees of the use of stem cells derived from embryos. It requires researchers to lay out a paper trail of documentation demonstrating the cells came from spare fertilised eggs made available with donor consent.

For IVF clinics who generate the excess embryos on which researchers rely, the devil will lie in the detail. Of key concern will be the final shape of forms and information requirements that licensing authorities will impose in the areas of donor consent and embryo provenance.

"There will be intense interest in the notification forms specified by the NHMRC to show that relevant people have given their consent and that embryos were created before April 5, 2002," says Prof Rob Jansen, the medical and managing director of Sydney IVF.

"How this will be approached is the greatest unknown from our perspective and is where the most inappropriately excessive bureaucratic requirements might reside."

Already tough

Sydney IVF believes its current policies regarding the use of surplus embryos for stem cell research actually exceed the requirements of the new act." Being tougher, they provide additional safeguards for patients who are giving embryos for stem cell research," says Jansen.

The question is the degree of bureaucratic overburden which will be generated by the need to translate that underlying reality into a form acceptable to licensing authorities. "We are satisfied that we have consent in an appropriate form now, but the requirements for communicating that consent to the licensing committee ahead of any experimentation have not been spelled out and could be potentially onerous for us," says Jansen.

A standard notification form has been foreshadowed in preliminary discussions with the NHMRC, but whether that will be something as simple as a single signed slip of paper is yet to emerge. Jansen says it is in the best interests of licensing authorities to keep forms and procedures as uncomplicated as possible, because "if the paperwork requirements drives [clinics] crazy, it will drive them crazy too."

The Sydney IVF is privately owned, like most IVF units. Unlike most, which carry out minimal research themselves, Sydney IVF has an active embryo research program conducted along NHMRC guidelines and "very well-organised documentation procedures" which it does not expect to be dramatically impacted by the incoming licensing procedures for researchers.

In research terms, the use of most embryos at Sydney IVF is channelled into culture medium research. Its culture medium is proprietary and marketed worldwide under licence. It currently is being exported to 40 countries and was approved in January 2002 for the US market. That medium was developed as a result of experimentation involving human embryos in NSW, and Sydney IVF will be seeking a licence to continue that research, Jansen says.

"We always knew we would require licensing once the legislation was passed, but we are not new to it because we have had our embryo research protocol approved under NHMRC in the past," says Jansen.

Although members of the NHMRC Licensing Committee have not yet been identified, Jansen is not overly concerned that individual appointments could skew the direction of the committee in ways unacceptable to the IVF community. "The legislation specifies the credentials that members of the licensing committee must have and says both the committee member with experience in regulating ART (Assisted Reproductive Technology) and the chairman must have the approval of the majority of the states," he says. "That should protect against any sort of radical appointment to the positions."

Licensing committee fears

Repromed -- Adelaide University's Reproductive Medicine Unit -- is another IVF facility with a large research component. Dr Jeremy Thompson, head of clinical and research embryology at the university, is comfortable with the levels of documentation which will be required from researchers and in vitro fertilisations units under the new rules.

"The paper trail holds no terrors for us," Thompson says. That's because South Australia, like Victoria and Western Australia, has in vitro fertilisation legislation in place, already requiring Repromed to deal with documentation issues similar to those being ushered in by the new Commonwealth acts.

But there is one large unanswered question looming over the licensing committee being formed under the auspices of the NHMRC which concerns Thompson. The question is rooted in what Thompson calls a widespread misconception that stem cells are the centre of attraction for researchers using products derived from embryos.

While most media and official attention is concentrated on the use of embryos for stem cell research, in actuality, most embryos deemed excess to requirements are used for research aimed at questions involving fertility and embryology, he says.

The vested interest of most IVF units with frozen embryos "is not in the development of stem cells but in fundamental questions about embryos such as what causes them to grow," says Thompson.

"So it is a misconception to say that those researching the field of embryology will just be interested in stem cells."

The unanswered question relates to how the NHMRC licensing committee will view this subject, Thompson says. "Nobody knows what they will think about whether embryos should be primarily used for stem cell production or for the greater development of human embryology per se."

The issue is important because the committee's licensing powers basically give it control over the future direction of research. "The committee may take it on itself that some kinds of research are not acceptable, even though it may fall within the scope of the act," Thompson says. "I have seen drafts of how the licensing process will work but they offer no insights into what the committee will judge as high-quality research.

"I can imagine a committee saying it doesn't want to use any embryos for research into human infertility and will only allow use for stem cell activity." Thompson says he has no indications such will be the case, "but I hope the committee will be broad-minded and non-restrictive.

Restrictions removed

"We are mostly delighted with the Act," says Thompson.

One reason is its removal of restrictions in areas such as diagnostic research which had been imposed by South Australia's Reproductive Technologies Act. "It prevented us from doing any research that in any way did harm [to an embryo], so we could not do any kind of diagnostic investigation on a whole embryo," Thompson says.

Less happy might be Queensland and NSW in vitro fertilisation companies, which until now have had no legislation governing human embryos. Some IVF sources suggested certain training and quality management practices by IVFs in those states will have to be scrapped or modified under the new rules.

To Sydney IVF, at least, that is not a significant worry, according to Rob Jansen: "We don't regard these new requirements as being inconsistent with our present practice."

In terms of the use of embryos for training purposes, the new rules "are not particularly onerous for an IVF program that has good documentation of its procedures and its embryo availability."

Commercial impact

Besides research labs and IVF facilities, the new legislation impacts on companies with commercial stem cell interests such as BresaGen.

Chris Juttner, BresaGen's vice-president of clinical development and executive director, believes the new regulations will add to red tape levels but says his company has "no issues" with that.

"Frankly, we would rather operate under the highest level of regulation because it gives us the greatest commercial level of safety," he says. "It is a form of risk management." It will also happily meet any licensing requirements because the new laws give BresaGen the opportunity to derive new cell lines in Australia where research costs are lower and IVF units maintain higher standards and a wider ethnic mix of embryos than the US.

However, BresaGen has deep reservations about the legislation's ban on any derivation of stem cell lines from embryos frozen after April 5, 2002. In BresaGen's view, embryos frozen before that date "may be fine for research but they are doubtful for current Good Manufacturing Practices (cGMP)," says Juttner. To be licensed for use in the all-important US market, it will be vital for stem cell therapies to be based on cGMP embryos.

Any successful organ transplantation therapies derived from stem cells will have to address the compatibility issues which determine transplant rejection, Juttner says.

The company believes the best method of achieving that is to establish banks of stem cell lines -- about 600 to 1000 lines will be necessary, in BresaGen's view, although others have suggested much higher numbers -- derived in the context of cGMP.

The new legislation has a sunset clause which scraps the April 2002 barrier in April 2005. However that lag translates into a crippling handicap in the fast-moving field of stem cell therapy, BresaGen argues. "The position of ourselves and other companies in this field is that we will want to produce cGMP embryos before then because of the pace at which science is moving," Juttner says.

BresaGen has an operation in the US but Juttner says BresaGen would prefer to derive new cGMP compatible lines in Australia for several reasons. One is because IVF standards are higher in Australia than the US, where the industry is essentially unregulated. Another is that the developers of any successful therapy will want it made available to the broadest possible racial mix of patients. Australia's IVF program possesses a broader ethnic mix of embryos than the US -- a major plus considering transplant compatibility determinants are based partly on race.

"Because of the nature of our health system, a much wider cross-section of racial and ethnic groups has access to IVF here than in the US," says Juttner. Finally, BresaGen is looking forward to conducting its research in Australia because of the country's twin tradition of advanced cellular biology and lower research costs.