Submission to the Health Research Council consultation on a new research investment process

In its Consultation Document for a New Research Investment Process, the Health Research Council of New Zealand (HRC) asked for the views of all those interested in how it invests in health research. NZORD prepared a submission in response to this request. Here is a summary of what we said.

GENERAL COMMENTS ON THE PROPOSED SCHEME

The two-stage application process

NZORD strongly supports the concept of a two-stage application process, provided the early assessment of proposals is considered on a scientific merit basis only. Any assessment and prioritisation based on targets or broad health priorities should only occur later.

If a two stage application process is introduced for Small Project Grants, we believe a success rate of approximately 50 % at the full application stage is too low because it will still involve a huge amount of "dead time" by too many researchers writing grant applications that are doomed to fail. The problem and the solution to this are clearly related to low total health research funding and efforts to slice up an effectively diminishing pie. While the solution is a political one about research investment (which HRC will no doubt be strongly advocating for with government), the system used would ideally minimise the amount of unproductive time spent by researchers.

Innovation Grants

NZORD is interested to see the inclusion of Innovation Grants as a mechanism whereby high quality research on genetic and rare diseases might be funded in New Zealand at a rate much greater than in the past. We qualify this with some reservation about the inevitable trade-off between this type of research and existing programme grants, but consider this dilemma to be inevitable when total research funding is so grossly inadequate. On balance, we think the Innovation Grants will help address a significant imbalance that currently exists in the allocation of existing funds, despite the dilemmas this approach will inevitably cause.

We add further reservation below in a comment about the impact of portfolios and how these might still act as a negative impact on quality research into rare and genetic diseases.

Innovation Grants (section 2.3.3) support research projects seen as risky, but that could have significant impact on health. We agree that more support should be offered to projects that are viewed as risky as it rewards individuals or research groups for taking chances and thinking outside the box. We need more innovative thinkers and approaches to doing things. The study of rare diseases might be seen as high-risk by some funding agencies, but they can provide insight into common conditions, enhancing basic biomedical science.

An excellent example comes from Professor David Palmer and colleagues at Lincoln University, who have reported that in Batten disease (a fatal neurodegenerative disease in children affecting four out of every 100,000 births), it is not the toxic accumulation of material in cells that causes pathology, as previously thought, but instead an aberrant immune response. Anti-inflammatory agents are now being explored as treatment. In the USA, there are 150 children with Battens, nine affected children in Australia. The limited patient numbers for Battens and other rare diseases is very challenging for researchers and funding organisations, in stark contrast to conditions that are high profile and continue to attract significant research funding, such as cardiovascular disease, diabetes and cancer. Nevertheless, this type of research is critically important to affected families.

There needs to be a source for genetic and rare disease funding in New Zealand, and the HRC should play a part.

Investment Signals

It seems that the use of Investment Signals as a mechanism for communicating HRC's research priorities might be clearer and provide for more efficiency than the rather murky complexity of the previous portfolio approach.

Health Impact Targets

Without offering a detailed analysis of how the Health Impact Targets (HITs) should be determined, we comment that if the proposed system is adopted, we strongly support the inclusion of category A – high impact health research – as a catch-all for proposals that do not fit neatly into any of the other categories.

We raise concern that the HRC priorities in the draft HITs, and in the prioritisation process elsewhere, are aligned to health priorities of government for health services generally. While there can be some benefit in such an alignment, we suggest it is plausible to make a case for a reversal of priorities – i.e. that research should also go into the "hard things", rather than the "top ten" list that is likely to parallel the priority list of many health research funders worldwide. A more strategic approach is needed, and that should be based on quality of the research proposal, along with workforce retention and development, unique research opportunities in New Zealand, etc.

We comment further that researchers should provide input on investment signals and high impact targets as they are at the forefront of emerging concerns or breakthrough areas that warrant further investigation. Setting of the signals and targets should not be done away from their consideration and input.

Input from patient support groups such as NZORD should also occur as we not only are the direct beneficiaries of such research, but we try to be well-informed about the types of research taking place here and overseas, and to contribute constructively to debates on these topics.

Replacement of current prioritisation scoring

We have significant concerns about the proposed replacement of the current prioritisation (or relevance) scoring process with assessment of fit to and impact on an Investment Signal. In our view it opens up the possibility of distortions when, for example, the fit of a proposal is being assessed against health priorities that are politically determined about health services and health delivery planning, and which may have little relevance to appropriate topics for health research.

An example of this is in the chronic disease HIT where excellent proposals on rare chronic diseases might be marked down because they are not common conditions in the Ministry's priority list. The Ministry's list is health economic driven, and this different perspective should not automatically transfer into a process that should be science driven.

Criteria for outline proposals

We suggest criteria at the outline proposal level should be quality of the proposal, workforce retention and development, along with unique research opportunities for New Zealand.

Potential continued influence of portfolios

Despite the proposed assessment process for full applications apparently doing away with the portfolios system, we note with concern that they may still have an influential role.

The HRC has stated in its new investment model that while the previous portfolios would no longer be in use, they will “… [continue] to use the taxonomy process to classify funded proposals according to the current research portfolio descriptions.” (Consultation document, pgs 6, 9). The portfolios would be used as a “monitoring and evaluation tool” (Consultation document, pg. 6). We are wary that using the previous portfolios as reference documents would quash any real changes.

None of the previous HRC portfolios mentioned rare disease as a research topic. This was not surprising to us, but has made us steadfast in raising awareness of rare disease amongst policy makers. We feel it is important to change the misconceptions about genetic and rare disease studies. Without explicit support, there is little incentive for researchers to work in this area.

SPECIFIC SUGGESTIONS RELATED TO GENETIC AND RARE DISEASE RESEARCH

More support for genetic and rare disorders research

We are asking the HRC to show support for individuals with genetic and rare disease, and to support research opportunities in these areas.

Genetic and rare diseases were not prioritised in the previous HRC research portfolios, even though a 2003 report from the National Health Committee cited concerns regarding New Zealand’s existing genetics services.

We would like the HRC to provide more support for researchers to focus on genetic and rare disorders. Enhanced capability in this area would significantly improve the health and well-being of affected families, and contribute to the HRC objective of training and retention of the health research workforce, as stated in the consultation document.

We recognise that there are excellent examples of HRC funded work incorporating genetic studies, for example progress made in inflammatory bowel disease (HRC Research Highlights 2007-8), progress in identifying defective genes associated with heart attack (HRC Research News, Oct 2008), identification of genes associated with inherited stomach cancer (Dr Parry Guilford), genes involved in congenital malformation (Prof. Steve Robertson), Huntington’s disease (Prof. Richard Faull and Ms Melanie Cheung) and more.

It leads us to question that given the excellent research New Zealand is capable of, what more could be achieved if the HRC makes a stronger commitment towards rare disorders?

Genetic and rare diseases within Investment Signals and HITS

We suggest that “genetic and rare disease” be included as an Investment Signal, and as a High Impact Target area, or alternatively that special reference be made to these diseases as explicit examples of research topics that would fit within HIT categories B, C, and D – i.e. categories in which they should naturally occur, in addition to proposals that might fit under the “catch-all” category A.

Removal of dismissive wording

NZORD would like dismissive wording regarding genetic disease studies to be removed from reference documents.

We were particularly concerned with wording in the Non-Communicable Disease Portfolio. This states that that genetic disease studies are of benefit to only a few, and best dealt with in New Zealand’s developing biotechnology sector. Specifically, it states that studying single gene disorders benefits “specific individuals” (NCD, “Other Non-communicable diseases” pg 8); that single gene disorders “account for a very low proportion of overall burden of disease” (NCD, pg 8); and that “ … a number of innovative biotechnology companies have been launched … providing great potential for support …” (NCD, pg 8).

FACTS TO CONSIDER REGARDING GENETIC AND RARE DISEASE

We ask the HRC to consider the following regarding genetic and rare disease:

Significant collective impact of rare disease

A rare disorder is defined as affecting 1 in 2,000 (EU definition). A single rare disorder may be individually rare, but as there are approximately 6000-8000 rare disorders, their collective impact on a population is significant.

  • The European Organisation for Rare Disorders (EURORDIS) estimates that 8% of a given population could be affected by a rare disorder.  In a NZ population of 4 million, this could potentially amount to 320,000 affected individuals.
  • The impact of rare disease on health providers has caused the EU, USA and other nations to examine the impact of rare disease on public health services and create rare disease policy.

For every person affected by a rare disease, approximately two other people in the household are also affected, often profoundly so, given the severity of the disease. For inherited conditions, more than one child in the household may be affected, and for parents, roles fall outside the “norm”, with extensive medical, behavioural, and physical demands in caring for their children.

Rare disorders are often life-long and severe. They align significantly with chronic diseases, which are recognised as another significant burden on health systems, yet the connections are often not made by policy makers.

Rare disorders are often multi-symptom chronic conditions and require a wide range of services across the health, disability and social services sectors.

We think the HRC has not well appreciated the burden of genetic and rare diseases in the past.

Rare diseases poorly understood by medical professionals

Rare disorders and how to treat them are not readily understood by most medical professionals. This leaves the burden of care (and research into modes of treatment) with family caregivers. The HRC needs to recognise the heavily disproportionate impact of rare and/or single gene disorders on affected families. Parents of children with rare disorders describe a “diagnostic odyssey”, the endless shuttle between specialists to obtain a diagnosis. Rare disorders are often misdiagnosed, leading to inappropriate surgeries, clinical care, and medications. Some families – if they are able – go overseas for treatment. Many of our specialist professionals – in search of better funding opportunities – also leave. We need to support research in this area. This is in stark contrast to conditions that are at times well understood yet continue to attract significant research funding, such as heart disease, diabetes, and cancer. In some instances, these conditions can be prevented with better lifestyle choices; a rare disorder/genetic disease is generally not preventable.

Majority of biotechnology sector not health related

In the NCD portfolio, gene studies were referred to the biotechnology sector, but a majority of New Zealand biotechnology is focused on improvements in agriculture, animal health, and forestry. Human health applications account for 17 % of New Zealand biotech, only a small proportion of which is dedicated towards understanding genetic disease.

Increasing recognition of importance of genetics in medicine

80% of rare disorders have identified genetic origins. Genetics is strongly indicated as the cause of a significant majority of those whose origin or cause is not yet clearly defined.

There is increasing recognition of the importance of genetics and genetic screens in medicine. In New Zealand, genetic factors for Maori and Pacific populations have not yet been adequately addressed, though Maori and Pacific people would directly benefit from such health research. For example:

  • Dr Parry Guilford of Otago University has identified a gene involved in inherited stomach cancers and was able to do so by working closely with Maori families affected by this form of cancer.
  • Ms Melanie Cheung (Ngati Rangitihi) a doctoral student from the University of Auckland was recently profiled in the international journal Science (9 Nov ’07) for her work on Huntington’s Disease in Maori families.

Rare disorders research contributes to basic biomedical science

Research into rare disorders can provide a glimpse into the “normal” pathways of growth and development – enhancing basic biomedical science. For example:

  • Fibrodysplasia ossificans progressiva (FOP) a rare condition of excessive extra-skeletal bone growth has provided insight into bone development.
  • Fanconi anemia has given insight into pathways of DNA repair and cancer treatment.

FOLLOWING THE MINISTRY OF HEALTH’S LEAD

New Zealand’s Ministry of Health has given their commitment to improve New Zealand’s genetics services and rare disease policy.  We ask the HRC to follow their lead.

In March 2008, then Health Minister David Cunliffe agreed to support work into improving genetics services within New Zealand.  This follows a rather negative report published in 2003 by the National Health Committee about the state of genetics services, but which had languished for want of official action to implement it.

The EU and USA have developed strong policies that will significantly improve the management and treatment of rare disorders in these jurisdictions. In New Zealand, the Health Minister committed to providing centralised responsibility for dealing with rare disorders, and with urging from NZORD and with the support of the minister, the Ministry has now allocated a policy responsibility for rare disorders within its Population Health directorate.

REFERENCES

European Commission, Health & Consumer Protection Directorate-General, Directorate C – Public Health and Risk Assessment, C2 – Health Information, “Rare Diseases: Europe’s Challenges,” Public Consultation document, 2007

Helm, N. “Breaking the Bio-barrier.” e.nz magazine, Jan-Feb, 2008.

Jacquemont, C. and Taniguchi, T. (2007) “The Fanconi anemia pathway and ubiquitin.” BMC Biochemistry, vol 8 (Suppl 1): S10.

Jolly RD, Thompson KG, Murphy CE, Manktelow BW, Bruere AN, Winchester BG. (1976)  “Enzyme replacement therapy--an experiment of nature in a chimeric mannosidosis calf.”  Pediatr Res. 10(4):219-24.

Kaplan, F.S.  “The key to the closet is the key to the kingdom: a common lesson of rare diseases.”  July 2006,  a column contributed to the National Organization for Rare Disorders (NORD), USA.

National Advisory Committee on Health and Disability (National Health Committee). “Molecular Genetic Testing in New Zealand” Wellington, New Zealand, Oct 2003.

National Advisory Committee on Health and Disability, “Meeting the needs of people with chronic conditions.” Wellington, Feb 2007.

Oswald MJ, Kay GW, Palmer DN. (2001) “Changes in GABAergic neuron distribution in situ and in neuron cultures in ovine (OCL6) Batten disease.” Eur J Paediatr Neurol. 5 Suppl A:135-42.

Palmer, D.N., Kay, G.W., Frugier, T., Hughes, S.M., and Cooper, J.D.  “Studies towards anti-inflammatory and gene therapy in ovine Batten disease.” 11th International Congress on Neuronal Ceroid Lipofuscinosis (Batten Disease). Rochester, NY, USA, July 14-17, 2007.

Rochester University Press Release

Shore, E.M. and Kaplan, F.S. (1997) “Fibrodysplasia ossificans progressiva (FOP): the value of studying a rare disorder.” Drug Information Journal, vol. 31, pp. 273-277.

The New Zealand Biotechnology Industry Growth Report 2006, commissioned by NZBio, New Zealand Trade & Enterprise, Ministry of Research Science & Technology (MORST).

Walkley, S.U., Thrall, M.A., Dobrenis, K., Huang, M., March, P.A., Siegel, D.A., and Wurzelmann, S. (1994) “Bone marrow transplantation corrects the enzymatic defect in neurons of the central nervous system in a lysosomal storage disease.” Proc. Natl. Acad. Sci., USA, vol. 91, pp. 2970-2974.