Print Friendly Page

Funding

Photo of two institute staff members in a meeting

Osteoarthritis Initiative

Updated April 16, 1999

Summary Of The Exploratory Meeting On Biomarkers For Osteoarthritis

Dr. Richard Hodes welcomed the participants to this "potentially historic event" having government and pharmaceutical representatives in the same room together. The goal of this meeting was to explore opportunities for collaboration that have never been explored before. He noted the areas of common interest that both groups share:

the conviction that osteoarthritis is a public health problem.
the conviction that there are challenges in addressing this problem.

At best, this meeting is a very first step. One outcome could be a standing working group with membership from the NIH, FDA, and industry. Dr. Hodes suggested that each group respond in the next 30 days whether they are interested in participating in such a working group.

Dr. Susana Serrate-Sztein provided a brief summary of the September 1997 roundtable discussion on arthritis biomarkers. She stated that three years ago, Dr. Katz became Director of the NIAMS and expressed a commitment to outstanding science, training, and interest in cooperative arrangements with for-profit and not-for-profit groups. In September 1997, industry, academia, and government representatives met and identified opportunities. It was clear at that time that each group had an interest in pursuing these opportunities. One area that was identified as being especially ripe was biomarkers for osteoarthritis, in which numerous trials were possible. Dr. Sztein stated that collaborative arrangements are not new to the NIH. Following the September 1997 meeting, the NIAMS embarked on a number of collaborative arrangements, including one with the Arthritis Foundation seeking genes for susceptibility and severity of rheumatoid arthritis, an arrangement that works very well for the NIH. NIH and industry must establish a dialog so that industry understands NIH issues like review and administration.

Dr. Hodes then reinforced the commitment of the NIH to pursuing collaborations with industry. He acknowledged that there are issues like conflict of interest, but the constraints can be discussed openly – the NIH can work and has worked with them.

Dr. Evan Hadley stated that the topic of biomarkers for osteoarthritis is of interest to several NIH institutes, and there may be others that join in these discussions later.

Dr. Joan McGowan emphasized that the NIH participants had enthusiasm for this potential collaboration and, while there were problems, they were not as difficult as might be thought. If a working group is formed, members can work on issues that exist. She explained briefly how the NIH works: always starting with scientific expertise, the NIH taps into the science with workshops and meetings, and there is no reason industry could not be involved in these meetings. Next NIH writes a solicitation and there is no reason industry could not be involved in developing the research questions and the solicitation. There are lots of opportunities. There are also lots of questions, including what is the project to be undertaken, who manages it, what about the data that are generated. All of these questions can not be answered at today’s meeting, but all of them can ultimately be answered.

Dr. Janet Woodcock said that the FDA is very enthusiastic about moving forward with this initiative and will support it any way they can. There is currently no effective therapy for osteoarthritis, treatments address symptoms only, and drug toxicity is a serious issue. Osteoarthritis is a public health problem and clinical trials in this area are the most primitive of any field. The "good news" is that this is a virgin slate and there is a window of opportunity to proceed with natural history studies. The FDA is eager to find measurements that can be used for osteoarthritis. There are some drugs in development for long-term treatment that address more than just symptoms in osteoarthritis, but such studies are very long term and issues include which populations to use and proof of generalizability. In addition, safety and risk are major issues in studies of prevention vs. pain and symptom studies. Dr. Woodcock referred to the one page document distributed by the FDA, and noted the importance of standardization of imaging measure definitions and methodology, and the importance of adequate epidemiologic studies to define osteoarthritis risk factors. In addition, robust population-based outcome studies on "traditional therapy" are needed to enhance confidence in future trial design. For example, the use of joint replacement surgery as an outcome is very variable and may not represent a common place in disease course. Efforts over the last seven years have helped the FDA in evaluating drugs for rheumatoid arthritis and useful drugs are now available to these patients.

Bayer Corporation (Dr. Richard Leff)

Key points made include:

This company is in the process of testing for an agent of disease progression.
Their assessment of the current state is that there is a lack of data in osteoarthritis. The change in x-rays over time, especially in knees, is somewhat known, but there is no standard method to assess x-rays.
Clinical measures in NSAIDS have limited data beyond 3 to 6 months.
Cartilage is typically studied in one joint and there is a need to correlate structure in one joint to how the whole patient is doing. There is a dichotomy to measuring in the population overall — the challenge is to measure in the population and have a clinical correlation.

Bristol-Myers Squibb (Dr. Michael Stewart)

Key points made include:

There is nothing in long-term trials at the moment, but they do have experience with long-term challenges.
They are enthusiastic about participating in this partnership.. They are very interested in getting involved in studies of early disease, especially identifying early susceptibility markers – a major emphasis for them scientifically. Such studies are necessary before product development. The "devil is in the details" in any large organization.

Dr. Hodes commented that he hopes this partnership will also define basic biologic mechanisms, not just superficial markers.

Glaxo-Wellcome (Dr. John Didsbury)

Key points made include:

4 private sector goals include (1) better understanding of disease; (2) clinical trial efficiency including reducing the time, increasing the confidence, and patient stratification; (3) improved internal decision making; and (4) the long-term goal of expediting regulatory review.
Tier review includes (1) linking radiographic imaging with MRI (there is a need for biochemical and biophysical studies); (2) identify the chemicals in bodily fluids (company could have two years of exclusivity); and (3) appropriate validation.
Other issues include cost sharing; the usefulness of a short initial study; and mechanisms for sharing data as well as many tactical issues.

Hoffman LaRoche (Dr. Randall Stevens)

Key points made include:

Agrees with points made by the other companies
The issue is having the scientific community, industry, and regulatory groups working together to assess biochemical markers so all agree, and not to validate each other.
Biochemical markers need to be linked to imaging modalities and ultimately to patient outcome, including stage of therapy and whether the therapy is effective for the patient.
The goal is not a single biochemical marker, and there is a need to link to other biochemical markers.
Suggested that diagnostics be combined with therapeutics – to develop drugs and identify how to administer them.

Dr. Hodes commented that there is a difference whether a product is proprietary or not.

Pfizer, Inc (Dr. Thasia Woodworth)

Key points made include:

For three years she has led a team to design methodology trials. She is very enthusiastic about this partnership also.
The ultimate goal of this collaboration is to enhance the feasibility of conditional clinical trials to develop new agents for osteoarthritis. The challenge is to convince industry management that clinical trials are do-able.
There is a need to support biochemical markers, genetic linkage, imaging, validation, radiographic joint space measurements.
There is a need to validate the usefulness of biochemical markers on longitudinal studies – requiring the commitment of resources.
There is a need to integrate databases and archive specimens.
There is a need to standardize methodologies so that they are recognized across the scientific community, FDA, NIH, and industry, and to enhance the ability to stimulate this research further.

Proctor & Gamble (Dr. Yetunde Taiwo)

Key points made include:

Also agrees with much that has been said at this meeting.
There is a need to be inclusive at the start and to exclude later on.
There is a need to challenge our paradigms and use new methodologies for long-term progressions. In industry, there is a recognition that you have to start somewhere. Their company has a great investment in cartilage, but the partnership needs to take a broad approach at the beginning.
There is a lot of excitement in the area of biomarkers for osteoarthritis, the scientific opportunity is great.
If an individual company spends a lot of resources and identifies a marker, it can be challenged. But if all work together, that will not be the case.
The conclusion from the one pager from their company is not that the partnership should not be pursued, it just suggest the structure to do it right, and asks what do we really need to learn.
For this company, the interest is not just in finding a marker, but also finding progression points – an area of big opportunities. Also, an important goal is to identify patients earlier and treat them earlier.

SmithKline Beecham (Dr. Michael Lark)

Key points made include:

Agrees with all that have spoken this morning. They are also very enthusiastic about collaborative projects such as this. This would allow the identification of markers of progression, earlier markers of disease.
The "con" is related to the design: what design? What patients? What standardization? What sharing? One concern is that the study could be so large that it would be hard to control and get useful information.
They are very excited to be involved.

Dr. Woodworth commented that it would be useful if a central patient-centered group could be identified as part of this project.

Dr. Hodes delineated the issues that stand between making the decision to move forward:

a lot has been spent in the last decade trying to identify markers, so there is already some proprietary knowledge. How do we deal with that? This may be a good issue for the next meeting – for both sides to do research and include technical experts in this area at the next meeting. He stated that no issues are prohibitive for moving forward.
how the whole structure of the study would be developed and financed.
an important consideration is what kind of dollars would be involved for such studies and how the funds would come in to a consortium. Companies have Profits & Losses, so funding is an issue. Companies would want people with financial expertise to develop the character and financing of the study. One goal of the next meeting could be to develop order of magnitude estimates.

Another discussion point was whether the data generated by the consortium is public and what is proprietary. The goal is openness; legal and technology transfer issues need to be addressed.

The question was raised how the companies were selected for this meeting, why other companies were not included, and what the selection process was. Dr. Downing responded that it was not scientific and was not by solicitation. Participants were identified by the people involved in the meeting. Dr. Hodes noted the need for fairness and openness and suggested that perhaps the next meeting should be open and participants invited. Between now and the next meeting the group can consider how to open the participation up. The down side is that this could involve many, many participants and require a large room, but should still be pursued. It was also suggested that the group be international and not just involve U.S. companies. The inclusion of other government agencies like the Veterans Administration and the CDC can also be explored. Dr. McGowan noted that the relevant agencies participate in a federal working group. In response to the question if there were any other major players that were not participating at this meeting, suggestions were made for the Arthritis Foundation and for the CDC to be involved in light of their National Arthritis Action Plan. Dr. Sztein suggested that this could be discussed at an AMDICC meeting and with the National Arthritis Data Group. It was also suggested that the International Osteoarthritis Research Society be included. This involves some 6000 to 7000 patients and 40 to 50 trials. The President of the Society was present and stated that they had been working on this issue for years, trying to gather data and work out criteria for ostearthritis. They are also considering forming a group to develop guidelines for imaging ostearthritis. The Society would be more than pleased to interact with the consortium.

Dr. Cummings asked if there were any precedent in another disease area that would be helpful, such as cancer or heart disease. It was noted that Canada is doing a similar model in arthritis. It was further suggested that AIDS provides a good example for joint sharing of clinical data. Dr. Hodes suggested that technology transfer discussions at the next meeting would include such expertise and precedents.

This meeting may include an under-representation of people who work on markers. Dr. Sharma suggested that there is a real possibility that no marker will ever be identified – we may learn a lot, but develop no marker. Longitudinal studies may be needed any way. The technologies are not that hard to do. Dr. Hodes suggested that it may be easier to be optimistic that markers would be developed some day and to archive samples for future study. He suggested that we will not know unless we try. The efforts to date have been piece meal and not coordinated. What are we seeking markers for? All different aspects of markers need to be evaluated ultimately.

It is important for the companies to identify what they want to get out of a partnership – diagnostic, prognostic, therapeutic. Companies will have multiple new agents being developed, but no single marker or entity.

It is pragmatic to ensure that something useful emerges from the partnership – for example, shore up imaging for solid characterization of joints, then bodily fluids can be collected.

The President of the OARS suggested that the bottleneck is not the technology itself, it is access to good, clinically well characterized groups with bodily samples. This partnership has the potential to really make a difference. He suggested that having access to material in a central biobank which each company could access separately.

Dr. Hodes observed that there was consensus and enthusiasm for moving ahead. He stated that a summary of this meeting would be prepared and circulated to all participants, also inviting additional comments.

The academic sector should have input. It was noted that some representatives were present at this meeting. As the consortium moved to develop a grant or contract solicitation, they would need to exclude those who participate from applying.

Dr. Hodes suggested a separation of the various issues involved in pursuing a partnership, including technology transfer, funding, clinical accrual, and bioassays. He suggested that the next meeting of the group should still have broad representation and perhaps include others. First, we would need to do a solicitation to identify other groups. He welcomed suggestions for widening participation, including a mailing to all pharmaceutical and biotechnology companies.

Dr. Tamara Harris identified three sets of issues: identifying markers, leveraging studies, and determining mechanisms, and she proposed that the group focus on these. Dr. Hodes suggested that all the requisite groups were not yet at the table so it was premature to focus in this way at this time.

Dr. Brandt endorsed the value of looking at existing data bases, determining how satisfactory they are, and distributing that analysis before the next meeting. It was suggested that the next meeting could be over two days with smaller break-out groups with various expertise and then a large meeting with all participants.

The process issues include funding, confidentiality, and proprietary information. What is the nature of the project to be pursued? What is the goal of such a project? There is a need to balance patient availability with epidemiology advice on design. The sooner we look at this globally, the better. The question was raised what the break out groups would actually tackle. Dr. Hodes responded that we will need to exclude scientific experts at some point so that they would not be prevented from applying for research grants or contracts in this area. He suggested that perhaps the experts could participate on the first day in a large meeting and then be excluded from subsequent parts of the next meeting. He proposed that perhaps a small group could meet to talk about the overall strategic aims, and then have a two day meeting to put "meat on the bones." A scientific meeting would be very useful and could have multiple objectives. There are many issues to be addressed including predictivity of patient selection – often projects begin with a small subset of patients and such studies can be very valuable. The ultimate vision is to enhance the feasibility of clinical development studies. The group could develop a list of opportunities and use that to sort out break out groups. The focus could first be on the strategic objectives and a smaller group could articulate that and then broaden the participants for discussion. Strategic scenarios could be developed and they would be useful in informing other scenarios. Dr. Cummings suggested that it would be useful to have a draft developed by a small subgroup for the next meeting to react to.

Dr. Hodes proposed that the next meeting include one representative per entity, that NIH would organize this next meeting, and that comments from this meeting would be distributed within one month. NIH would plan the next meeting and send out broad invitations. This group will also help to identify issues for a scientific symposia. The vision is quite broad, so we need to flesh out the issues.

Dr. Woodcock stated that the group may want to flesh out all issues and then decide how to address each one. For example, there could be a listing of the range of all issues of concern to this group with an accompanying list of options for addressing each issue.

It was suggested that the group should plan on having subsequent meetings and the dates for a large meeting in the fall would need to be set now. It was agreed that options for the larger meeting would be sent out with the minutes from this meeting.

Dr. Cummings asked a question related to companies – product development in a company can take 3 to 5 years, but does company interest decrease if it takes longer than 1 to 2 years to develop. The Bayer representative responded that 3 to 5 years was his minimum guess. When actual studies are initiated, it can involve even longer times, but companies expect 5 years of time. Dr. Woodcock stated that a minimum of 3 to 5 years was recognized by companies. The Bayer representative stated that global participation and a framework will be very important in this partnership.

Dr. Hoth observed that, while the reality of this project is impressive, all the participants are seeing a slightly different reality. He suggested that the group focus on what this project can do that is unique, so they do not get bogged down. It was also suggested that the cost of involvement may set the threshold for the groups that can be involved.

Dr. Hodes concluded the meeting by stating that within one month materials would be sent to all participants, including a summary of this meeting and a strategy for communicating broadly as well as time lines.