Human Biomedical Research Bill

The Minister of State for Health (Dr Lam Pin Min): Mdm Speaker, first, let me thank all the Members – Assoc Prof Fatimah Lateef, Ms Ellen Lee, Dr Benedict Tan, Mrs Lina Chiam, Mr Pritam Singh and Dr Chia Shi-Lu – who have given their views and voiced their support for this Bill.

In particular, I would like to thank Ms Ellen Lee for her speech on the importance of HBR and the relevance of this Bill to society generally. Firstly, she highlighted that such research advances the standard of healthcare and is conducive to the continued development of medicine and society. Secondly, she reminded us that while we have built a solid foundation after 50 years of hard work in nation-building, our society is changing rapidly and the Government has to ensure that our legal system continues to protect the interests of every

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member of society so as to ensure social harmony.

The Members have raised various questions and made some suggestions on the Bill. Let me address the various questions and comments made by Members.

In the case of multi-centre research done locally, Assoc Prof Fatimah Lateef has correctly pointed out that the Bill provides for our local research institutions to come together and appoint a lead institution amongst themselves to coordinate the research they are collaborating on. The Bill also enables the collaborating institutions to appoint the same IRB to review their joint research, which would be more efficient than having multiple IRBs review the same research protocol. However, having such an arrangement does not mean that the lead institution will take over the responsibilities of all the other participating research institutions. Each research institution will still be accountable for ensuring that there is good governance in place for safe and ethical conduct of those parts of the research under its purview.

Assoc Prof Fatimah Lateef also asked about the impact of the Bill on international multi-centre research. For research institutions and researchers in Singapore involved in international research collaborations, this Bill will apply to them. Most of the existing international research projects that are already ongoing are not expected to face much difficulty meeting the requirements of this Bill, especially if they involve collaborations with partner institutions in developed countries. This is because the key requirements in this Bill, such as informed consent, independent ethics review and a clear framework of accountability and governance, are already the norm in developed countries. These requirements also should already be familiar to researchers in Singapore.

However, not all countries have specific laws governing human biomedical research, or impose similar, if any, regulatory and ethical requirements. In situations where the same international protocol calls for research activities to be conducted in both Singapore as well as overseas, the local research institution will, of course, be responsible for the research activities in Singapore. Additionally, the local research institution will need to ensure that its appointed IRB reviews and approves that protocol in its entirety, and not just the portion of the research activities in Singapore.

On its part, the IRB will need to be satisfied that the international protocol complies with the national laws of all the participating institutions as well as internationally-accepted ethical principles. This is to prevent research institutions from evading the requirements of the Bill by circumscribing the scope of their research activities in Singapore to only those that are lawful under this Bill while conducting research that is unethical or even prohibited or

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restricted under the Bill overseas.

An example of such a case was reported in the international media in October 1997, involving a multi-centre clinical trial conducted in the US, Africa and Thailand, to test a new treatment for HIV/AIDS. In that research protocol, test subjects in the control group in Africa were unethically given only a placebo, even though an existing HIV/AIDS treatment was available. In contrast, test subjects in the control group in the US were given the existing HIV/AIDS treatment. The differential treatment of the test subjects in different countries caused an international outcry against the unethical behaviour of the researchers. It is research like this which we should guard against and avoid participating in, if we are to safeguard Singapore's reputation as a world-class biomedical research centre.

Regarding Mrs Lina Chiam's suggestion to have a central IRB, there are three key factors MOH considered when deciding not to adopt a central IRB system.

Firstly, a central IRB will not have the same degree of knowledge and familiarity with the adequacy of the research institution's systems of oversight, compared to an IRB that is more closely connected to the research institution. This could adversely affect the central IRB's ability to effectively monitor the research institutions or to effectively assess and approve individual research protocols and ensure the safety and welfare of research subjects.

Secondly, the central IRB would detract from the focus on the research institution as the entity responsible for the HBR conducted under its auspices, which is a cornerstone of the accountability framework under the Bill.

Thirdly, the workload and responsibility of the central IRB would likely be relatively greater, which may dissuade persons from coming forward to serve as members. Centralisation of IRB reviews would also adversely affect their responsiveness. While Mrs Chiam had suggested that the members be paid a full-time salary, this may create an undesirable situation where board members no longer serve voluntarily but expect to be paid based on the volume of research protocols reviewed. This will not be conducive to conscientious and meaningful review of research protocols, unlike the current framework, where IRB members do not receive any salary or wages to review the research proposals and, at most, receive a modest honorarium.

Concerns have been raised that the IRB may have excessively broad powers, particularly the ability to waive the appropriate consent requirements when researchers conduct their HBR. I would like to reiterate that only the IRB, as a body, and not just the chair alone, may waive the appropriate consent requirements of the Bill if it is satisfied that all the criteria in paragraph 3 (Part 2) of the Fifth Schedule are satisfied, namely, the individually-identifiable

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human biological material or health information research, as the case may be, may not practically be carried out unless there is a waiver; the use of the individually-identifiable human biological material or health information, as the case may be, involves no more than minimal risk to the research subject or donor; the waiver concerned will not otherwise adversely affect the rights and welfare of the research subject or donor; and the HBR or health information research would reasonably be considered to contribute to the greater public good.

The cumulative effect of these criteria means that such waiver will be the exception rather than the rule.

So, fundamentally, this is a regime that is prohibitive, with a comprehensive set of measures. Any exemption granted will be subject to very stringent criteria. We expect few to qualify and their operations will be constrained.

On the independent ethics review process, I would like to clarify that the effectiveness of the IRB review is based on two factors. Firstly, the rules and requirements governing the IRB itself. Secondly, the very nature of the relationship between the research institution and the IRB in the governance structure set up under the Bill.

Under this Bill, we will set the minimum requirements that must be met in terms of the composition and conduct of the IRB.

In terms of its composition, the IRB will be required to include at least one scientific member and one lay person, and these persons will not be related to the research institution. In addition, the IRB chairperson must be a registered medical practitioner, as an added measure for accountability.

The composition of the IRB helps to ensure that its deliberations and decisions are made with a full understanding of the scientific issues and consideration of the ethical values of the community. These requirements will be specified in subsidiary legislation.

In terms of the conduct of IRB members, they must declare, at every meeting, the nature and extent of any actual or potential conflicts of interest in relation to any matters under consideration by the IRB at that meeting, which emphasises the independent role of the IRB when carrying out their assessments. Such members are required to recuse themselves from the decision-making process.

While we can mandate certain requirements to help ensure the independence of the IRB, the effectiveness of an IRB in carrying out its ethics review function will also depend on

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how the research institution governs the research activities under its purview.

In this regard, the independence of the IRB should not be viewed in the context of an adversarial relationship between the IRB and the research institution. The governance structure set out in this Bill makes it imperative for a research institution to ensure that the IRB it appoints is competent and can function effectively, as the research institution is ultimately responsible for the research under its supervision and control and may be taken to task for any non-compliance.

An effective IRB, besides safeguarding the safety and welfare of research subjects by rejecting unsafe and/or unethical research proposals, also helps the research institution to manage the institutional risks by avoiding exposure to unethical research.

Conversely, a research institution that does not support the effective functioning of its IRB, or even impairs or interferes in the proper functioning of the IRB, will expose itself to greater institutional risks in the event any adverse outcome befalls a research subject.

The fact that a research proposal had been reviewed and approved by an IRB does not necessarily protect the research institution, especially if it is later found that the IRB had not performed its review function effectively.

I turn to the point raised by Assoc Prof Fatimah Lateef about the potential liabilities of IRB members, many of whom volunteer their own time to do this important work, often out of goodwill and concern for the safety and welfare of research subjects. IRB members are not paid any salary or wages to review the research protocols and, at most, receive a modest honorarium, or time-off if they are already employees of the research institution.

I wish to reassure Members that this Bill does not impose criminal sanctions on individual IRB members for the decisions they make in discharging their IRB functions. As I mentioned earlier, it is the responsibility of the research institution to ensure that the IRB it appoints functions properly and it is the research institution that will, ultimately, be accountable in the event of an adverse outcome arising from a decision made by its IRB.

Nevertheless, as IRB members may be subject to duties arising under general law in discharging their IRB functions, we also expect research institutions to indemnify their IRB members against legal liability arising from the decisions of members who have discharged their duties in good faith. Research institutions should formally assure their IRB members of these arrangements, such as in their letters of appointment.

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There have been suggestions made about the publication of rejected IRB proposals, serious adverse events and data/findings of studies. We do intend to share some of the information, such as serious adverse events, where beneficial and relevant, from time to time, and we will study how best to do this. Singapore is aligned with the rest of the international research community in this respect. However, as international best practices continue to evolve, we do not rule out the possibility of mandating the publication of relevant information in the future.

Dr Chia Shi-Lu asked if research subjects who experience adverse effects due to their involvement in the research would be compensated. The Bill itself does not mandate such compensation. However, as a matter of general law, researchers are obliged to provide compensation where their negligence has caused the subjects harm. The IRB should ensure that researchers, as well as the research institutions, do not seek to exclude or limit their responsibility to provide such compensation for injuries sustained by research subjects.

As a matter of ethics, there is an ethical obligation for researchers to offer compensation where subjects suffer significant injury as a result of their participation in the research, regardless of the fault of the researcher. For example, this is practised for Phase 1, or first-in-human, clinical trials, where the pharmaceutical company sponsoring the trial usually underwrites all the medical costs resulting from injuries sustained by the research subjects.

As the significance and frequency of risks due to HBR are varied and wide-ranging, research institutions should work in consultation with their IRBs to develop policies on when such no-fault compensation should be provided, and the mechanism for doing so. For example, the research institution could take up appropriate insurance coverage for such research.

In any case, research subjects should be informed at the outset during the consent-taking process, whether there are any provisions for compensation for injuries arising from their participation in the research, as well as whether there are any insurance or indemnity arrangements made for the research.

There are also questions from Dr Benedict Tan and Assoc Prof Fatimah Lateef concerning the definition of "human tissue". In general, any biological material obtained from the human body that consists of, or includes, human cells, would be considered as "human tissue". However, some biological material, such as hair, nails and natural body secretions and excretion, such as saliva and urine, have been excluded as there is very little risk to the human donor in the collection of such material. There is no need to regulate them under the human tissue framework, the objectives of which are to protect the safety and

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welfare of tissue donors and prevent commercial trading of human tissue.

It should be noted that even though some biological materials are excluded from the definition of "human tissue", if a researcher conducts research using a person's biological material, for example, saliva, in such a way that the person is individually-identifiable, that research would be regulated as human biomedical research. The researcher would need to get that person's informed consent to be a research subject.

In the case of biological materials, such as human skin grafts or human bone chips to be transplanted into another person, they will, indeed, be regulated as "human tissue". The consent of the tissue donor is required before such tissue can be removed from the donor's body and collected for use.

Such tissues should be obtained through altruistic donations and cannot be commercially traded. However, we also recognise that certain tissues may be unavailable or in short supply in Singapore but are, nevertheless, needed for use in medical therapy and/or essential research. Under the Bill, the Minister may grant exemptions for such tissue and, to this end, may convene an expert committee to advise on the circumstances under which such exemptions may be granted. These circumstances include the therapeutic indications, prevailing forms of therapy, available alternatives and whether the tissue can be practically obtained from any other non-commercial source.

Dr Benedict Tan spoke of using residual biological specimens, which had originally been collected as part of a patient's clinical treatment, for research purposes. With the new human tissue framework under this Bill, it is possible to use such excess or leftover tissue for research provided that:

(a) the doctor responsible for the treatment of the patient has confirmed that all the necessary treatment and diagnostic procedures have been completed, and that the remaining tissue is no longer needed; and

(b) appropriate consent has been obtained for the use of the leftover tissue for research purposes.

It should be noted here that the consent to use the leftover tissue for research is separate from, and in addition to, the consent to collect the tissue for clinical treatment and diagnosis. The consent for use in research can be taken at the same time as the consent for treatment or diagnosis, or it can be taken later on a separate occasion.

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This may involve some extra effort on the part of the doctor or the researcher, but, as a matter of principle, it should not be assumed that once a patient consents to having his tissue taken for treatment or diagnosis, he has no say in the use of any leftover tissue for other purposes, such as for use in research. Going forward, with the new regulatory framework for human tissue, getting consent for the use of tissue for research purposes should be the norm and the standard practice for all.

As to Dr Benedict Tan's question regarding the waiver of appropriate consent for certain types of HBR under certain circumstances as described in the Fifth Schedule of the Bill, an IRB may waive the requirement to obtain appropriate consent if the IRB is satisfied that all four of the criteria (a), (b), (c) and (d) in paragraph 3, Part 2 of the Fifth Schedule are met.

Dr Chia Shi-Lu also asked whether tissue donors, whose tissue samples were used in research that subsequently results in commercially successful new products or treatments, are entitled to any remuneration or a share of the profits from commercialisation.

Let me clarify and reiterate this point. The principle adopted in this Bill is that all tissue donations must be made voluntarily and altruistically. Among the information that must be provided upfront to a tissue donor during the consent-taking process, under clause 12(2)(e), is that the donor would be renouncing his rights to the donated tissue and any intellectual property derived from the tissue. Therefore, the donor cannot rely on the fact that the donated tissue came from him to assert a right to any financial benefits that may result from successful commercialisation of the research using the donated tissue.

Assoc Prof Fatimah Lateef also asked about having a directory or database of institutions that conduct HBR. As mentioned earlier, any organisation that wants to be a research institution under this Bill must formally notify MOH and periodically submit declarations of its compliance as long as it continues to conduct HBR. This requirement applies to all such research institutions, regardless of whether they are medical institutions or not, or whether they are from the public or private sector. Although these notifications and declarations do not amount to a licence or regulatory approval from MOH, MOH will, nonetheless, have a list of such research institutions in Singapore, and this information can be made available to the public.

Assoc Prof Fatimah Lateef had requested that paperwork be kept to the minimum. We will certainly keep this in mind. Documentation is important, but, wherever possible, we will use electronic or other innovative solutions to streamline processes and avoid unnecessary paperwork.

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Assoc Prof Fatimah Lateef also had some good suggestions on how to smoothen the implementation of the new regulatory framework. We do not intend to rush into bringing the new regulatory requirements into operation. After this Bill is passed, there will be a "sunrise period" before it is brought into force, to allow the affected parties to make preparations, including seeking clarifications, to be compliant with the regulatory requirements under the Bill. During this period, MOH will organise forums and dialogue sessions with the biomedical research community to address any implementation issues that they may have.

MOH is also preparing a guidance document to help the research community better understand and navigate the new regulatory framework. After the Bill is brought into operation, MOH will continue to monitor the situation and work with stakeholders to ensure smooth and successful implementation.

Dr Chia Shi-Lu asked how MOH plans to audit the research institutions to ensure that they comply with the regulatory requirements and wanted to know who will be the regulator.

In short, MOH will be the principal regulator responsible for administering and enforcing the regulatory requirements under this Bill. The Bill provides for the appointment by MOH of public officers and officers of Statutory Boards as "authorised officers" to carry out regulatory functions, such as inspecting and auditing research institutions and tissue banks, and, where necessary, investigating into possible offences under the Bill. The Bill also allows for the appointment of other persons, for example, scientific experts, to assist these "authorised officers" in carrying out their regulatory functions.

After the Bill comes into force, MOH will take a risk-based approach to regulation. The focus will be on those research institutions and tissue banks that are assessed to be of higher risk. This may be based on various factors, such as the types of research or tissue they handle, their organisational profile and, over time, their track record.

With regard to Dr Chia's query about the suspension of research or tissue banking activities, MOH will have the power to order researchers, research institutions and tissue banks to stop any such activities, and to take necessary remedial action, if MOH has reason to believe that their activities are detrimental to the safety and welfare of research subjects or tissue donors. Such actions will be taken first as a precautionary measure to protect the human subjects and donors.

MOH also has powers to conduct such investigations as may be required and, once investigations are completed, will review whether or not the suspension order should remain

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in force based on the findings.

To Mrs Lina Chiam's question on the use of great apes in HBR involving human neural stem cells, MOH had consulted various ethicists and researchers in this area. It is recognised that the greater the possibility of "humanisation" of the animal, the greater the need for restrictions. This is in line with the practices of many countries. We will continue to monitor developments in medicine and science, both locally and overseas.

Mrs Lina Chiam had also asked why the Bill is silent on human genome editing, germline modification, nanotechnology and synthetic biotechnology. To clarify, human genome editing and germline modification research, which involve the use of human biological material, will be regulated under this Bill. If they involve the use of human eggs or embryos, they will be subjected to tighter controls as "restricted research" under the Fourth Schedule.

This additional control is required for all restricted research and is in addition to the individual research institution's IRB review. Restricted research involving human animal combinations will be subject to approvals from MOH, and which will be subject to appropriate conditions being met during the conduct of the research. To this end, a national advisory committee of experts will deliberate upon the ethical and scientific rationale of such research and recommend to the Minister whether or not to approve such protocols.

For research on nanotechnology and biosynthetic technology, where the research involves subjecting an individual to any intervention, or where there is use of individually-identifiable biological material or health information, as described in clause 3(2), it will also be regulated under this Bill. This means that the research will be subject to review by an IRB to ensure that the research is conducted ethically and that there is accountability for the safety and welfare of the research subjects.

Mr Pritam Singh had shared his reservations on the powers of the Minister under this Bill to amend the Schedules in this Bill and to grant exemptions. The fundamental principle of this Bill is to regulate to ensure the safety and welfare of research subjects whilst not stifling sound, ethical research. The Minister needs to be able to calibrate the regulations of certain types of research or biological material, if they are shown to pose low risk to the safety and welfare of research subjects and tissue donors. By the same token, the Minister also needs to be able to impose additional requirements for certain types of research that are more sensitive and controversial. This will ensure timely and adequate protection for the affected individuals and appropriate controls over the regulated activities.

The provisions of this Bill draw on the feedback received during our various consultations in view of the nature of the field of biomedical science, which is complex,

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highly technical and rapidly evolving. The intent is to continue to consult domain experts where appropriate, to give scientific, technical and ethical advice to the Minister in the exercise of his powers under the Bill. In addition, the First, Second and Fifth Schedules only envisage exemptions or waivers to the general requirements of the Bill where these requirements would be disproportionate to the minimal risks to the safety, welfare and interests of the subjects and will seriously impede valuable HBR or tissue banking activity.

It is worth noting that the Minister's power under clause 62 to amend the Schedules, as well as the Minister's power to exempt under clause 57, only function to circumscribe what is regulated under the Bill. Even for the research identified in the Third and Fourth Schedules, where the Minister has the power to impose more and tighter controls, this is research that already comes under the scope of the "human biomedical research" as defined in clause 3 of the Bill. The Minister will not have the discretion, using these powers, to expand the scope of what is regulated under the Bill, which can only be done by Parliament, and rightly so. I would highlight the fact that such powers are not unusual and can be found in many pieces of legislation in Singapore.

On Dr Benedict Tan's query about the appointment of advisory committees, in selecting the members of these committees, what is important is that the person is suitably qualified, well-experienced and has a good understanding of the biomedical research field and is able to give sound and unbiased advice on the issues at hand.

Mr Pritam Singh has raised concerns about the consultation process. MOH has, in fact, consulted widely with stakeholders, particularly the research community in both healthcare and academic institutions, over the past few years at various stages in developing these regulatory frameworks.

Prior to the introduction of the Bill, we conducted a series of stakeholder consultations in August and September 2014, involving leaders and key personnel of institutions engaged in HBR and tissue banking.

Subsequently, a draft version of the Bill was put up for public consultation in November 2014. The consultation period was extended to January 2015 for a total period of 10 weeks at the request of the stakeholders for more time to consider the Bill and provide their feedback. The feedback was generally favourable and supportive of having a Bill that would protect the safety and welfare of research subjects and tissue donors and which would provide clarity to the roles and responsibilities of those engaged in HBR and tissue banking.

The Bill before this House has been refined to incorporate relevant feedback received during the public consultation. For example, the definitions for "human tissue" and "tissue

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bank" were adjusted and a clause was added to protect the identity of informers who provide information on contraventions under this Bill.

We have conducted extensive consultations on this Bill with both stakeholders and the public. This has provided an avenue for scrutiny of the Bill and further refinement, and all relevant inputs and feedback have been considered and incorporated into the Bill. After the Bill is passed, we will also continue to engage stakeholders and the public on the implementation of the Bill. As such, there is no compelling need to refer the Bill to a Select Committee.

Mdm Speaker, let me conclude. This Bill will put in place regulatory frameworks to protect research subjects and tissue donors. These frameworks set out controls and requirements that will help to ensure HBR and dealings in human tissue are conducted in an ethical and responsible manner. They will also provide clarity and certainty as to the rights as well as the duties and obligations of the various parties, whether public or private, involved in HBR and tissue banking.

However, beyond the matters of law, ethics and science, we should also remember the human element in this, namely, the human research subjects and tissue donors, without whom HBR would not be possible, as well as all the future patients who will benefit from the advancements in health and medicines that can be brought about by HBR. As Ms Ellen Lee put it so aptly, the goal of HBR is, ultimately, to help all of us achieve healthier and happier lives.

I call on Members of the House to give their support to the Human Biomedical Research Bill. Mdm Speaker, I beg to move.

Thank you, Mdm Speaker. I would just like to confirm with the Minister of State the question I asked on clause 63 with regard to the penalty threshold of the $20,000 fine and a two-year imprisonment term. How was this derived in view of the number of regulations in the sub-sections that are covered in clause 63?

I would like to thank the Member for the question. The penalties for HBR vary, depending on the severity of the offence, and this is consistent with other Singapore laws, for example, the Human Cloning and Other Prohibited Practices Act and the

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Human Organ Transplant Act.

In fact, if you look at the penalty regime, there are basically four tiers to it, the highest being what we call the type 1A kind of offence which warrants a penalty of $100,000 and/or 10 years of imprisonment. With regard to what Mr Pritam Singh has queried – which is with reference to clause 63 – the penalty prescribed is a maximum of $20,000 and/or two years of imprisonment. This is actually quite consistent if you compare it to other equivalent provisions in other Acts. In fact, if you look at some of the other Acts, the penalty imposed in HBR is a little bit more stringent rather than more lax, as mentioned by Mr Pritam Singh.