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National Statement on Ethical Conduct in Human Research 2007 Human biospecimens submission

ID: 
9
Personal Details
First Name: 
Professor Nicholas
Last Name: 
Tonti-Filippini
Additional Information
Individual Background: 
Ethicist
Specific Comments
Comments: 
Introduction

The introduction indicates that the chapter will include biospecimens broadly defined. There is no distinction offered between a biospecimen and a product derived from a biospecimen. This creates an obvious difficulty in relation to the law which currently prohibits trade in human tissue but does not prohibit trade in human tissue products. This is an important distinction to maintain. The NHMRC Issues Paper "Ethics and the exchange and commercialisation of products derived from human tissue - background and issues" makes clear the importance of this distinction if we are to preserve the social capital in the existing blood bank, bone marrow bank, eye bank and practice of solid organ transplantation which are based on altruism. It is of particular concern that the current draft has dropped the statement in the existing guidelines: "There should be no trade in human tissue for research purposes" and section 3.4.4 i clearly envisages distributing profits from commercial outcomes involving biospecimens. This issue is discussed at section 3.4.4 and section 3.4.12. There is a need to distinguish between human biospecimens and products derived from human biospecimens so that trade in the products can be permitted with HREC approval but that the NHMRC maintains its existing rejecting of trade in human tissue or human biospecimens.

Suggest amending the definition of biospecimen to make the distinction between a biospecimen and a product derived from a biospecimen. The distinction between human tissue and a human tissue product was upheld in the Issues Paper and through the several rounds of consultation for that document. It was supported by the public submissions. The distinction should not be lost. The implications for the use of human tissue in clinical practice of doing so are grave. Suggest:

"The definition of 'human biospecimens" is broad: it encompasses any material taken from the human body including, but not limited to, tissue, blood, urine, sputum, gametes, embryonic or fetal tissue, and any biological material obtained from them. It does not include extraneous material such a micro-organisms that live on a person. For practical purposes, a "product derived from a human biospecimen" may be distinguished from a human biospecimen where the product has been significantly altered so that it has become attenuated such that the donor or donor's family would be likely to perceive it as no longer part of the person's body or remains. Depending on the process involved and the effects of the culture, a product derived from a human biospecimen may include cultured cell lines."

Second the introduction makes no mention of the greater risks involved in clinical research involving stem cells. The only place that the issue is raised in the document is in the glossary which contains the statement:

"Stem cells have considerable capacity to be of clinical benefit, but they may also carry significant risks in clinical use, especially if their growth and differentiation is unable to be controlled."

It is important that researchers and HRECs are made aware of the significant risks involved and that this matter is expressed in the guidelines either in the introduction or in the guidelines perhaps as an additional dot point in section 3.4.4 The consequences of experimentation in this regard in China have proved to be quite horrendous, in many instances, for people going there as medical tourists to have stem cell therapies. Thus either the introduction or preferably section 3.4.4 could have the addition:

"Where a research proposal involves a clinical intervention in a patient's body to transplant stem cells or to activate stem cells in situ, the researcher, the HREC and the recpieint should take into account that though stem cells have considerable capacity to be of clinical benefit, they may also carry significant risks in clinical use, especially if their growth and differentiation is unable to be controlled."

The draft guidelines also leave out the following important guidelines from the current current guidelines:

3.6.1 Researchers and HRECs should seek advice from the NHMRC on clinical research that proposes novel uses of stem cells.

3.6.2 Clinical trials involving the grafting, transplant or activation of human stem cells in humans should be conducted only where there is substantial evidence, from pre-clinical models, of safety and efficacy.

Given the adverse consequences that Australians have been experiencing in China as "medical tourists" receiving stem cell therapy, it is important that these guidelines are retained in the redrafting. The much greater risks involved in clinical or therapeutic research involving stem cells needs to be acknowledged and steps taken to ensure that researchers and HRECs are cautious. These sections could be added to section 3.4.4.

 

Sources of human biospecimens

The second paragraph states that stored pathology specimens will continue to be a resource for research and teaching, and that these uses may raise ethical considerations and are also covered in this chapter. However, the only paragraph that seems to bear upon this issue is paragraph 3.4.11. However, 3.4.11 refers to "identifiable human biospecimens" which were obtained without consent for research or where the research is not consistent with the original consent. There are no guidelines offered for human biospecimens that are not identifiable. However, the latter should still be subject to the same requirements in relation to needing HREC approval and waiver of consent requirements. It should not be the case that anything goes if biospecimens are not identifiable. For instance, it should not be permissible that the tissue be used in ways that would be considered controversial. It may also be the case that though the individual donor may not be identified, the use of a biospecimen may have grave implications for a family or other blood grouping. One only has to consider the sensitivities that have existed in relation to the remains of indigenous people, for instance. It would help if both this section and section 3.4.11 were amended. An amendment to section 3.4.11 is suggested to that section. An amendment to the Sources of human biospecimens section could be achieved by adding the following sentence:

"All uses of human biospecimens for research must be subject to ethical review in accordance with these guidelines whatever the source of the biospecimen."

Potential for identification

The statement on markers replaces the statement in the current guidelines that human tissue remains in principle reidentifiable. The statement about markers being unique to individual donors is misleading because too narrow in its application. The practical reality is that there are markers that may identify families or other blood related groupings so that it only requires a blood relative to be on an identified data base for it to be possible to identify the family or group. The agencies that trace parentage have been able to do that to identify paternity on the basis that once the family grouping has been identified, it is then possible to identify who within the family or other blood related grouping is likely to have been in likely circumstances at the time when sperm donation occurred, such as a medical student. The second sentence, which plays down the likelihood of identification as not being realistic if the identification is not required or not worth the cost, is also misleading, given the rapid and extensive development for research purposes of genetic databases linked to medical records and genealogical records, and the relative ease of comparing data about markers via data linkage and data mining techniques, and in that way to identify the family or group. The cost of tracing paternity for sperm donors has not proven to be prohibitive or too difficult in many instances. Further, many of the ethical issues relate not just to the individual but the group to which they belong, such as a group identified by a particular disease trait. The Fragile X scandal in Tasmania is a good example of the latter.

It is important that biospecimen donors know that it might not always be possible to reidentify a biospecimen once the identifers have been removed, but it is also important that people be informed that there can be no guarantee that a biospecimen that has had the identifiers removed will not be linked to them or their family or other grouping.

Suggest reworking this paragraph to amend the first sentence to include the broader category than individuals, and to replace the second sentence with a statement that provides more accurate information to the community, research participants, researchers and HRECs. Thus the paragraph might read:

"Human biospecimens that include all or part of a human genome contain markers that may be unique to the individual donor or to the family or other blood related grouping. If data or tissue from an individual, or a member of their family or other blood-related grouping is recorded on a genetic tissue or genetic data base, then it may be possible to identify the family or group and through identifying the family or group, to identify the individual donor, given their differing social and demographic circumstances within the group. That may raise ethical issues to do with the potential for discrimination, invasion of privacy and the possibility of being contacted about relevant health information. Human biospecimens that contain genomic information remain in principle, reidentifiable. It is important that specimen donors and their families know that it might not always be practically possible to re-identify a biospecimen, once the identifiers have been removed, but it is also important that they are aware that there can be no guarantee that a biospecimen that has had the identifiers removed will not later be linked to them or their family or other blood related grouping."

Prospective collection of human biospecimens for research – paragraphs 3.4.1 – 3.4.4

Section 3.4.1 e states "Those proposing to collect human biospecimens prospectively for research should:

e. have an understanding of the ethical issues."

The researchers need to have more than "an understanding". The latter could be interpreted entirely individualistically and in conflict with or disregard for the National Statement and HREC requirements. The community needs the reassurance that the researchers will comply with the National Statement and any additional requirements thought necessary by the HREC. Suggest revising (e) to read;

"e. have an understanding of the ethical issues and comply with the National Statement and any additional requirements identified by the relevant HREC."

A problem with 3.4.2 is that it is so vague about processes. One of the problems identified in obtaining consent is the coercive nature of linking consent to using tissue for research to consent to a clinical treatmentr or diagnostic procedure, especially if the same form is used. Using the same form or process implies that the patient may be denied treatment or diagnosis if they do not also agree to research uses of their biospecimens. Suggest amending 3.4.2 to read:

"3.4.3 There should be ethical review and approval of the proposed collection and consent process and that review must ensure that the consent is free, materially informed and competent, including ensuring that consent to obtaining or using human biospecimens for research is a separate process and on a separate form and not linked to the decision to consent to a treatment or diagnostic procedure. The decision to donate biospecimens for research should not be connected, in any way, to the decision to consent to treatment or diagnostic procedures. Any such link would be potentially coercive.”

Section 3.4.4 subsections (h) and (i) deal with "cost recovery" and "commercial outcomes" of research involving human biospecimens. This section has dropped the NHMRC's prohibition on trade in human tissue. That is a significant change and not one I support. As indicated earlier, it poses a grave danger to the existing social capital in our blood bank, bone marrow bank, eye bank and solid organ transplantation all of which are based on altruistic donation. There are also several other harmful consequences of trade in human tissue including the creation of perverse incentives, loss of equity in access to treatments using the tissues, loss of community benefit, and offence to sensitivities of those who consider such trade to lack respect for the human body and the remains of those who have died. Dropping the prohibition on trade in human tissue would do great harm to the Australian community.

The NHMRC Working Committee that I chaired on commercialization of human tissue and human tissue products supported the existing prohibition on trade in human tissue but made some recommendations in relation to commercial uses of tissue products in research. These were reflected in the earlier consultation draft, but are now missing from this draft. The Committee concluded that the concept of attenuation was significant in differentiating human tissue products from human tissue.

The Working Committee document Ethics and the exchange and commercialisation of products derived from human tissue - background and issues, (2011) which the NHMRC has adopted held that in some circumstances human tissue products that had become sufficiently attenuated could be traded without offending community sensitivities or harming the existing practices based on altruistic donation of human tissue. For instance there does not seem to be much concern about trading an acellular, non-genomic human tissue product such as collagen. However, if such trade is to be permitted for research purposes then some ethical restrictions are needed to preserve the concept of custodianship of human biospecimens necessary to protect the interests of donors. Suggest restoring the effect of the earlier draft in this respect so as to protect the altruistic basis of biospecimen donation and the ethical concept of custodianship of donated human biospecimens for research purposes. The reasons for so doing are explained in the Background and Issues Paper referred to above.

Thus the segment could be amended such that (h) and (i) read:

"Before people consent to donation of their biospecimens, they should be given information about:

h. any cost recovery arrangements that may apply to the collection, retrieval, handling, storage and distribution of their biospecimens (see paragraph 3.4.12) and the reassurance that no profit will be drawn from the practice beyond recovery of reasonable costs of the service.

i. any foreseeable commercial research use involving products developed from their biospecimens, how these will be managed and to whom the benefits, if any, will be distributed, and the reassurance that:

  • the value of the biospecimen or its use is not to be derived from a unique property substantially derived from the donor's tissue rather than being later added by processing, and
  • processing of the biospecimen to form a product will attenuate the product so that it has lost connectedness to the donor (such as might not be the case if the commercial use immediately followed death or donation of the biospecimen or the product retained the human genome or parts of the human genome of the donor), and
  • the trade will not create perverse incentives whereby donors, researcher or others act in ways that they would not normally act to their detriment or to the detriment of others or the community, such as, for instance withholding information that might affect the recipients of a biospecimen or biospecimen product; and
  • the trade will not affect pricing of the biospecimen product such as to make access to the biospecimen product for therapeutic on non-therapeutic research purposes less equitable or based on ability to pay rather then on medical factors such as need, urgency and outcome, and
  • the biospecimen itself will not be bought or sold for a profit.

As mentioned in relation to the introduction, the warning about stem cells and their greater risks in therapeutic research was removed from the current guidelines and only included in the glossary. There is need to give greater prominence to this statement because of the danger of stem cells and the greater need for scrutiny and care. Suggest adding an additional point (j) to section 3.4.4:

"(j) Where a research proposal involves a clinical intervention in a patient's body to transplant stem cells or to activate stem cells in situ, the researcher, the HREC and the recipient should take into account that though stem cells have considerable capacity to be of clinical benefit, they may also carry significant risks in clinical use, especially if their growth and differentiation is unable to be controlled."

Also as suggested in the introduction, 3.4.4 should also contain the current guidelines to the effect:

Researchers and HRECs should seek advice from the NHMRC on clinical research that proposes novel uses of stem cells.

Clinical trials involving the grafting, transplant or activation of human stem cells in humans should be conducted only where there is substantial evidence, from pre-clinical models, of safety and efficacy.

Ethical review before human biospecimens are used in research – paragraphs 3.4.6 – 3.4.11

In section 3.4.7, given the inclusion of a distinction between human biospecimens and products derived from human biospecimens it would be important to include a reference to the latter. Suggest adding after "use",

"and whether products will be derived from the human biospecimens in the course of the research."

In section 3.4.9, it would be consistent to include a clause such as the clause contained in the National Statement 2.3.6 e. The use of human biospecimens would be greatly undermined if people thought that their specimens could be used for controversial procedures without their consent. Suggest adding:

"e. there is no known or likely reason for thinking that participants would not have consented if they had been asked."

3.4.10 e. states "the potential for sampling or coding errors and, in the case of research using human biospecimens and data, how certain the researchers will be that the human biospecimens and/or data came from a particular donor;" and is problematic. The issue is not whether the data came from a particular donor, but whether the information that has been derived from a biospecimen is materially relevant to the particular donor, members of the donor's family or other blood related grouping.

Suggest (e) be revised to reflect by amending the wording to read:

"3.4.10 e. the potential for sampling or coding errors and, in the case of research using human biospecimens and data, how certain the researchers will be that the information obtained will be materially relevant to the particular donor, members of the donor's family or other blood related grouping."

Clause 3.4.11 states, "Where identifiable human biospecimens were obtained without consent for research (e.g. in a clinical investigation), or where the proposed research is not consistent with the original consent, the human biospecimens may be used only if an HREC is satisfied that the conditions for waiver of consent are met (see Chapter 2.3: Qualifying or waiving conditions for consent). If the proposed research using human biospecimens may reveal information of potential importance to the future health of the donor(s), their blood relatives or community, researchers should prepare an ethically defensible plan to disclose or withhold that information (see paragraph 3.5.1, page [to be inserted in final layout])."

There is no paragraph numbered 3.5.1.  I presume that the requirements of the ethically defensible plan were meant to be those that are stated in section 3.4.10 discussed above. If not then it raises a whole new set of issues that would need to be discussed in subsequent public consultation.

Second, this paragraph was discussed earlier in relation to the introduction and the problem of the guidelines not providing ethical guidelines for biospecimens that are not identifiable, such as pathology samples obtained for diagnostic purposes or for autopsy that have lost their identifiers and where there is no consent for their use in research. The implication would seem to be that no ethical review is needed if the pathology samples are not identifiable. However, it is still important that those specimens be subject to ethical review and meet the requirements of the National Statement, particularly if, as is likely, the need to obtain consent were to be waived. I mentioned earlier there may be concerns such as the sensitivities that have been expressed by indigenous people in relation to tissue from relatives who have died or concerns about discrimination in relation to the outcome of research that affects a particular group, such as happened in Tasmania in relation to research involving people who were affected by Fragile X. Suggest adding:

" Where human biospecimens have been gathered, such as by a pathology service, but the specimens are now not identified, they may be used for research purposes if an HREC waives the need to obtain consent in accordance with the conditions set out in section 2.3 in the National Statement. No human biospecimens and no products derived from human specimens may be used for research without a process of ethical review in accordance with the National Statement. Where the information gained has relevance to a particular family or other blood related grouping, even though the individual donor may not have been identified, then the requirements for an ethically defensible plan as described in section 3.4.10 apply."

 

Cost recovery for human biospecimens – paragraph 3.4.12

It is strange that section 3.4.12 requires HREC review of cost recovery for use of biospecimens but does not require it for trade, yet currently section 3.4.4 i clearly envisages the distribution of the commercial outcome of research involving biospecimens, in other words, profit from trade. The issue of trade in human biospecimens must be addressed as was discussed above in relation to section 3.4.4 h and i.

As discussed in the NHMRC document Ethics and the exchange and commercialisation of products derived from human tissue - background and issues (2011) suggest reaffirming the current prohibition on trade in human tissue but making the exception for an HREC to approve trade in human products derived from human biospecimens. Thus 3.4.12 would have a new section:

"3.4.12 b. There should be no trade in human biospecimens for research purposes. However, subject to the approval of an HREC, products derived from human tissue may be trade provided that the HREC is satisfied that

(i) the value of the biospecimen or its use is not to be derived from a unique property substantially derived from the donor's tissue, rather than being later added by processing, and

(ii) the use and processing of the biospecimen to form a product will have attenuated the product so that it is likely to have lost connectedness to the body of the donor in the view of the donor, donor's family, or other grouping (such as might not be the case if the commercial use immediately followed death or donation of the biospecimen or the product retained the human genome or parts of the human genome of the donor), and

(iii) the trade will not create perverse incentives whereby donors, researcher or others act in ways that they would not normally act to their detriment or to the detriment of others or the community, such as, for instance withholding information that might affect the recipients of a biospecimen or biospecimen product; and

(iv) the trade will not affect pricing of the biospecimen product such as to make access to the biospecimen product for therapeutic or non-therapeutic research purposes less equitable or based on ability to pay, rather then on medical factors such as need, urgency and outcome, and

(v) the biospecimen itself will not be bought or sold for a profit."

 

General Comments
Comments: 

I have a major concern that the proposed new section has abandoned the NHMRC's prohibition of trade in human tissue. This is the most controversial element in the proposed redrafting.

In doing so the drafting has dropped the previous inclusion of proposals formulated in the NHMRC document: Ethics and the exchange and commercialisation of products derived from human tissue - background and issues (2011) that recommended that the prohibition on human tissue be maintained but that in some circumstances trade in products derived from human tissue for research purposes could be permitted provided that an HREC approved of the trade in accordance with ethical guidelines. It is important to reinstate the distinction between trading in human tissue and trading in a human tissue product. As is explained in the submission, not to do so endangers the existing clinical uses of human tissue including the blood bank, the bone marrow bank, the eye bank and the use of solid organs for transplantation. It will also bring the use of human biospecimens into disrepute by permitting the distribution of profits from the commercial use of biospecimens in research, in other words, trade in human tissue as is envisaged at section 3.4.4 i.

 

Page reviewed: 3 June, 2013