Funding

Osteoarthritis Initiative

Updated July 12, 2001

Steering Group

A public, private partnership to develop and evaluate clinical biomarkers.

The Osteoarthritis Initiative
A Public/Private Research Collaboration

Monday, February 28, 2000
Tuesday, February 29, 2000

Lister Hill Auditorium
National Institutes of Health
Bethesda, Maryland

Meeting Summary

Organized by:

The National Institute of Arthritis and Musculoskeletal
and Skin Diseases, National Institutes of Health

The Foundation for the National Institutes of Health, Inc.

Sponsored by:

The American Academy of Orthopaedic Surgeons
The Arthritis Foundation
Aventis Pharma
Bristol-Myers Squibb Pharmaceutical Research Institute
Chiron Corporation
DuPont Pharmaceuticals Company
F. Hoffman-La Roche, Ltd.
Genetics Institute
Glaxo Wellcome, Inc.
Merck Research Laboratories
Monsanto/Searle
Novartis Pharmaceuticals Corporation
Parke-Davis
Pfizer, Inc.
Procter & Gamble Pharmaceuticals
The R.W. Johnson Pharmaceutical Research Institute

Osteoarthritis Initiative Steering Group Subcommittee Chairs:

Epidemiology
Stefan L. Lohmander, M.D., Ph.D.
University of Lund
Lund, Sweden

Biochemical Markers
Thasia G. Woodworth, M.D.
Pfizer Central Research
Groton, Connecticut, U.S.A.

Imaging
Charles G. Peterfy, M.D., Ph.D.
Synarc, Inc.
San Francisco, California, U.S.A.

Administration
Stephen A. Stimpson, Ph.D.
Glaxo Wellcome, Inc.
Research Triangle Park, North Carolina, U.S.A.

Welcome

Stephen Katz, M.D., Ph.D., Director, National Institute of Arthrkers identified by currently available specimen archives and proposed longitudinal cohort studies. The subcommittee's ultimate goal is to validate surrogate biochemical markers and contribute to the regulatory guidelines for new drug development in OA.

Accordingly, the subcommittee will seek to accomplish the following:

  • Characterize the research questions and generate hypotheses regarding potential surrogates.
  • Critically examine available archives.
  • Describe the state of the art for available assays.
  • Establish assay selection criteria.
  • Establish standards for biospecimen collection, management, and quality.
  • Identify key database characteristics.
  • Identify the prospective studies that are still needed for surrogate marker validation.

Dr. Woodworth noted that the important issues this effort needs to address relate to

  • The conditions of access.
  • Confidentiality, informed consent, and anonymous databases, particularly with respect to genetic samples.
  • Proprietary and intellectual property concerns.
  • The nature and objective of the measurement, including whether it is diagnostic, characterizes status, or assesses progression.
  • The kind of markers that should be used: biochemical, molecular, or genetic markers, or some combination thereof; combinations of bone and cartilage markers; or perhaps synovial tissue markers.

Discussion (Panel Members and Meeting Participants)

Question: While there are meaningful parallels between the use of biomarkers in the study of OP and OA, there are also important differences. In general, most osteoporitic conditions are systemic, generalized processes affecting essentially the entire skeletal system. In OA, although the articular process may be somewhat generalizable, the disease within a given joint is often driven by the impact of a local biomechanical, post-traumatic, or instability-based factor. To the extent that this is true, the use of serum or urinary biochemical markers as a means to track disease may be relatively insensitive. Is joint aspiration a preferred technique for this subset of patients?

Dr. Poole responded that this is a very important point- one that is made in the Biomarkers White Paper-and that he is a strong proponent of looking at joint fluid in this type of situation, believing it to be the most accurate way to assess pathobiology and the influence of therapy. A standardized procedure to obtain joint fluid by washout has been developed, along with the ratios of markers that address the issue of variable dilution of joint effusion. Dr. Poole also noted the importance of considering joint fluid analysis in the routine assessment of how best to study biomarkers.

Dr. Heinegard pointed out that although there are fewer variables when one looks at the fluid of an individual joint, in terms of therapy, when more than one joint is involved, there may be some joints at stage one and others at stages two and three. If the therapy affects stage one only, different markers-a combination of general circulation markers and synovial fluid-are needed to assess what is going on in both the stage one and the stage two and three joints.

It was noted that a significant number of patients who have total joint replacements have mechanical malalignment of either the hip or the knee, which points to the need to consider biomechanical markers. Sophisticated techniques for defining the kinematics of the knee ex vivo have also demonstrated that many people with very early grade one disease with minimal or no malalignment have well-defined, quantifiable abnormalities of gait.

Within OA, end points that can be evaluated will likely be pain, functionality, and-potentially-hip or knee replacements. Consideration should be given to existing good and objective functional-and sometimes biochemical-markers of biomechanics, function, and pain.

There are limitations in attempting to identify biomarkers that predict therapeutic effects from the characterization of a historical or natural process database. The pathophysiologic and immunologic mechanisms involved are highly complicated, and surrogate markers are frequently not well characterized. Accordingly, consideration should be given to applying additional emphasis to the characterization of interventional studies and interventional databases in which the discernible effects of a therapeutic agent on a marker are measured and then validated against a clinical outcome measure.

It is important to obtain x-rays of many joints to ensure that the controls selected do not have an unidentified, unforeseen form of systemic cartilage degradation.

It was pointed out that even if a substance does not change with disease, markers that alter something linked to the disease process can play an important role. In addition, the biomarkers being investigated should be measured in studies that assess the clinical outcomes of a variety of interventions and demonstrate, not assume, the link between the changes in outcome and the changes in the biomarker.

Considerable data exist on the relationship between markers measured in body fluid and joint pathology. For example, osteocalcin measured in synovial fluid relates very closely to scintigraphy scan abnormalities of the knee joint and can be found in serum. The COMP measured in serum also relates quite positively to scan abnormalities of the knee.

In response to a query about how close we are to identifying usable markers, the members of the panel indicated that

  • Screening can currently be conducted, e.g., by analyzing two markers that measure the same thing and, using general patient cohorts or sample cohorts, assessing marker levels and correlations.
  • Various kinds of interventions could start to be monitored now.
  • Some of the most promising studies have resulted from efforts by groups of researchers to compare, side by side in a clinical trial, currently available biomarkers.
  • Consideration should be given to linking work on OA biomarkers to the wealth of information on disease-modifying drugs and well-defined biomarkers that exist for rheumatoid arthritis.
  • It would be particularly helpful to the overall process if the OA initiative facilitated the conduct of collaborative animal studies.

The point was made that virtually all of the published studies that have linked a biomarker to OA progression have done so on the basis of standing AP knee radiographs, for which real problems have been identified regarding the reproducibility of the technique. Relationships between biomarkers that have been established based on standing AP radiographs need to be reexamined in light of these concerns.

Dr. Poole noted that such concern exemplifies the great importance of functional studies to assess disease progression and further reinforces the need to integrate all applicable areas of research. Studies incorporating the imaging of a knee joint provide an opportunity to look-in a carefully integrated way-at biomarker changes within a specific joint, the functional aspects of the joint, pain, and imaging.

There is a great need to coordinate all available forms of data from the beginning of any study. No particular tissue or technique for determining the processes involved in OA should be excluded because, years down the road, it may turn out that a particular aspect-e.g., white blood cells-will become important in efforts to define subsets of this disease.

Imaging

Introduction

Randall Stevens, M.D., Associate Professor of Medicine, Robert Wood Johnson Medical School, Director, Clinical Science, F. Hoffman-LaRoche and session moderator welcomed the participants to the Imaging Session and introduced Drs. Hall, Buckland-Wright, and Peterfy.

Perspectives and Considerations on Imaging Techniques

Laurance Hall, Ph.D.
Professor
Herchel Smith Laboratory for Medicinal Chemistry
University of Cambridge School for Clinical Medicine

Dr. Hall indicated that his presentation would address magnetic resonance imaging (MRI) measurement of the articular joint as an intact organ in order to detect, assess the etiology of, and quantitate OA and determine the efficacy of treatment.

MRI offers a safe and noninvasive way to look at all of the soft tissues within the articular capsule, the surrounding musculature and vasculature, and bony tissue, allowing for the assessment and comparison of these different joint elements in subjects undergoing all stages of OA and normal controls. The addition of measurement science to this technique allows for the quantitation of the relative rate of progression of the different elements of OA and, in principle, the efficacy of treatment.

Dr. Hall described a study of guinea pig knees carried out by his laboratory five years ago that serves as an example of what MRI can do for the study of OA in humans. The study, which assessed with high measurement precision a small number of guinea pigs on a very regular basis, integrated the use of MRI with x-rays and histology. The technique allowed for the study of each joint as a single intact organ, the identification of the natural progression of disease etiology, and the assessment of treatment response. The images produced allowed for the detailed measurement of subchondral sclerosis; the cystic disruption of the trabecular architecture; osteophytosis; and cartilage thickness, swelling, and loss.

For the OA Initiative, perhaps the greatest value of MRI lies in its capacity to aid in the selection of patients to be admitted into clinical trials, evaluate the extent and trajectory of damage to individual joints, help choose which subgroups of patients are appropriate for specific therapeutic windows of treatment, and assess the impact of treatment. The technique utilized by Dr. Hall can efficiently generate a huge amount of data that, with computer analysis, can be further refined to produce such resources as cartilage thickness maps. An even more powerful way of integrating these data into the context of biomarkers is to create a "virtual plug biopsy" by defining and making repeated assessments of a specific region of the joint. In addition, the process of measuring the magnetic resonance parameters of water in articular cartilage holds great promise as a technique that can identify the intrinsic quality of the cartilage.

Dr. Hall noted that the type of radiological assessment and scoring of the articular joint he has described has been available for a decade. Given the importance of moving forward with the OA Initiative, he recommends that this technique be used to produce scans and place them in a databank that can then be mined for quantitative measurements.

As Dr. Charles Peterfy will discuss in the upcoming straw proposal on imaging techniques, current MRI technology is capable of supporting a global level one study that places imaging data into a database archive that is fully integrated with biomarker data. Existing methods also allow for a level two study that applies computer-based measurement science to those same data, while level three refers to a proposed mechanism that leaves the door open for the incorporation of future innovations.

Perspectives and Considerations on Imaging Techniques (continued)

Chris Buckland-Wright, Ph.D., D.Sc.
Professor, Department of Applied Clinical Anatomy
School of Biomedical Sciences
King's College London

Dr. Buckland-Wright explained that his presentation reviews the radiographic aspects of examining OA joints.

The first outcome measure of interest is joint-space width and whether or not it is a reliable representation of the articular cartilage within a joint. Dr. Buckland-Wright reviewed the results of a study that found a very tight correlation between radiographic images of joint-space width and the sum of cartilage thickness in the medial diseased compartment. In the lateral compartment, however, radiographic images of joint-space width were not found to be a reliable measure of cartilage thickness. The study also found that, within the loaded area, the width of the joint space was significantly narrower than the combined cartilage thickness of the femur and tibia, indicating that weight-bearing radiographs can be used to measure both the thickness and biomechanical status of articular cartilage.

A critical factor in the use of radiographic images to assess OA joints is the need to clearly define the radioanatomical plane of measurement, which is determined by the position of the joint during radiography and the direction of the x-ray beam as it passes between the joint's bony margins. This plane of measurement should be perpendicular to the central ray of the beam, perpendicular to the joint margins, and parallel to the film. Another important aspect is whether or not there is any degree of joint rotation. The size and appearance of osteophytes can be affected by the angle of the x-ray beam, the degree of joint rotation, the degree of joint flexion, and radiographic magnification.

Accurate radioanatomical positioning of a joint under load and in a normal functional position allows for the accurate assessment of the cartilage that a patient is actually living on. Dr. Buckland-Wright described a study that looked at three types of films, each of which produced a single view of the knee and did not use fluoroscopy for positioning. The study found that most reliable radiographic technique was that one that utilized a posteroanterior (PA), semiflexed knee position and a horizontal x-ray beam in which the front of the film is lined up with the first metatarso-phalangeal (MTP) joint. This position provided accurate radioanatomical positioning and minimal distortion of the x-ray features, allowing for reproducible measurements of joint-space width, osteophytes, cortical thickness, and cancellous bone organization. The next best technique was the PA tunnel or Schuss knee position with the x-ray beam directed 5 degrees downwards. An advantage of this view is that it can be used to measure rapid loss of articular cartilage at the posterior aspect of the tibia plateau and popliteal surface of the femoral condyles. The study found that the least reliable view was that obtained in the anteroposterior (AP) fully extended knee position with the x-ray beam horizontal.

The more expensive fluoroscopy positioning procedure ensures joint positioning that is much more reliable. Because it reduces the degree of variability, it is likely that this technique can be used when there is a need to assess changes in a smaller number of patients. Dr. Buckland-Wright expects to have data comparing the advantages of fluoroscopy positioning with those of nonfluoroscopy positioning by approximately September 2000.

With respect to the hip, a radiograph that centers the beam on the single hip joint has been shown to result in better reproducibility than the standard view of both hip joints. Other work suggests that a lateral oblique view of the hip provides an opportunity to assess both the superior and posterior aspects of the femoral head. The only limitation to this method is that it requires fluoroscopy for reliable positioning. Hand radiography is reasonably well established; a reliable method appears to be imaging the fingers held together and aligned with the axis of the forearm, with the beam centered at the third metacarpo-phalangeal (MCP) joint. Further work to develop standardized radiographic procedures for the spine, the temporal mandibular joint, and the shoulder is needed to allow for a more global assessment of the body. Dr. Buckland-Wright noted that, wherever possible, computerized methods of joint-space width measurement should be used.

In relation to the measurement of different aspects of the joint, standardized radiographic protocols are needed to quantify:

  • Changes in articular cartilage thickness measured as joint-space width within a 2-year period using standard radiography or within 1 year using microfocal radiography.
  • Changes in joint-space width due to the effect of therapeutic intervention.
  • The status of osteophytes on both the tibial spines and at the tibial and femoral margins, using devices such as digitizing tablets and computers to measure their change in number and size over time.
  • Erosions, which Dr. Buckland-Wright calls juxtarticular areas of radiolucency, that tend to fluctuate in number and size over time and may be associated with inflammatory episodes.
  • Subchondral cancellous bone organization that, with the onset of OA, takes on a ladder-like appearance in the tibia. Fractal signature analysis techniques have been developed that allow for the quantification of these changes.
  • Changes in cortical plate thickness. It is quite possible that, in the hand, changes in the vascularization of this zone lead to the advance of calcified cartilage into the joint space.
  • The mechanical alignment of a joint.
  • The remodeling and reshaping of bone in patients with advanced OA.

Dr. Buckland-Wright concluded that both standard and microfocal radiography currently have the capacity to quantify joint-space width, joint-space narrowing, osteophyte number and area, the number and size of erosion sites, cortical plate thickness, trabecular bone organization, and the mechanical axis of the joint.

Discussion

Many current populations studies and European clinical studies use standardized, fully extended, weightbearing radiographs of the knee. It has been suggested that the way to diminish the CV's of these images is not necessarily to change the extension or the flexion of the knee, but rather to take the radiograph in a highly standardized way. Can these data be used?

Dr. Buckland-Wright responded that Kenneth Brandt, M.D., Director of the Multipurpose Arthritis Diseases Center at the Indiana University School of Medicine, had just shared data with her that shows that, historically, all standing extended knee films are invalid. With respect to the argument that it does not matter what position the knee is in so long as the radiograph is taken carefully, Dr. Buckland-Wright pointed out that research he has been involved in has found that there is variation in the status of the articular cartilage in different parts of the knee. One study showed that approximately 20 percent of the population assessed tended to lose their articular cartilage very rapidly over the posterior part of the tibia and popliteal surface of the femur, more rapidly than the area that they actually moved and walked on, e.g., the middle zone of the tibia plateau. In addition, a major limitation of the standing extended knee view is that it shows a part of the cartilage that is only rarely used; the only time a person's knee is at full extension is when they are standing at attention or goose-stepping.

The point was made that, although the current focus is on measuring interbone distance or joint-space width and cartilage, epidemiologic studies have shown that the bony changes may be a much more important reflection of patient symptoms. Acccordingly, Dr. Buckland-Wright was asked to comment on the bone changes in the osteophytes in the extended standing knee.

Dr. Buckland-Wright indicated that, if the radiographs are taken in a standardized, reproducible way, standing extended knee films are a very good way to assess osteophytes. This view may cause an enlargement in the perceived size of the osteophytes, but that is not of concern as long as the effect is accounted for and the image is reproducible. However, to assess cancellus bone, Dr. Buckland-Wright encourages viewing the horizontal tibea plateau.

Asked to comment on weightbearing x-rays of the hip and on x-rays of nonweight-bearing joints such as in the hand-and the resultant impact on the assessment of joint- space width-Dr. Buckland-Wright noted that, in the hip, the weightbearing view has been found to be more reliable than the nonweightbearing view. In the hand, good stabilization can be achieved without weightbearing by applying muscle contraction across the joint in the position described earlier (fingers together and aligned with the axis of the forearm).

A participant asked whether the information Dr. Buckland-Wright presented was applicable to MRI scanners dedicated to the lower limbs, which are less expensive and easier to use. Would it be possible for longitudinal epidemiological studies to use such scanners? Dr. Buckland-Wright responded that the new generation of peripheral limb scanners used to scan an ankle, knee, or hand cost roughly one fifth as much as a whole body scanner. These scanners operate at much lower field strengths than whole body scanners; hence the signal to noise and spatial resolution of each scan is lower, decreasing the accuracy of the scans produced. However, the potential of these peripheral limb scanners has yet to be objectively explored, and this is an issue that will be addressed at the end of Dr. Peterfy's presentation.

Presentation of Straw Proposal on Imaging Techniques

Charles Peterfy, M.D., Ph.D.
Chief Scientific Officer
Executive Vice President
Synarc, Inc.

Dr. Peterfy noted that his presentation focuses on two fundamental questions:

  • Are structural features of the joint (hip, knee, or hand) and the associated tissue changes (such as joint-space narrowing and osteophyte development) reliable markers of disease and disease progression? To answer this, it is important to apply the most reliable imaging techniques and markers currently available.
  • What is the relative validity and performance of alternative imaging markers of joint structure? The capacity to characterize markers according to predetermined criteria is crucial to the rational selection and prioritization of markers for different clinical and scientific applications.

The OA Initiative Imaging Subcommittee addressed these issues at a meeting on January 11, 1999. Attendees included representatives from academia, NIH, industry, FDA, and central laboratory service providers. The participants sought to:

  • Develop a mechanism that would both answer the first question and allow for the inclusion of more experimental and specialized techniques over the course of the study.
  • Come to an agreement on performance criteria with which to compare different imaging markers.
  • Achieve consensus on a list of candidate markers and techniques to include in each tier of the study (that will support the whole organ model of OA).
  • Build an imaging protocol for the OA Initiative that will support these choices.

Before this meeting, Dr. Peterfy circulated a preprint of a manuscript (Peterfy C. Scratching the surface: articular cartilage disorders in the knee. Magnetic Resonance Imaging Clinics of North America 8:2; May 2000) that addressed the subject of imaging marker performance as it applied narrowly to MRI of articular cartilage.

In his review of what was accomplished at the January 11 meeting, a comprehensive summary of which can be found at http://www.nih.gov/niams/news/oisg/imaging.htm, Dr. Peterfy emphasized the following points:

  • Tier one of the recommended three-tiered protocol framework comprises techniques-to be applied to all subjects and sites in the core study-that are the most established in terms of their validity and performance and suitable for multicenter image acquisition. In this tier, both knees should first be imaged with a nonfluoroscopic, flexed, standing radiograph to assess joint-space width, joint-space and osteophyte scoring, and subarticular bone texture. All participants would also receive a conventional MRI using two techniques: 1) a fat-suppressed, T1-weighted, 3-D gradient echo (to visualize articular cartilage; determine cartilage score, thickness, and volume; and assess osteophytes, subarticular cysts, and bone attrition) and 2) a T2-weighted dual echo, fast spin echo, or turbo spin echo technique (to allow for whole organ scoring and the evaluation of synovial fluid volume).
  • Tier two would consist of a subset of patients and/or sites that possess special facilities, special interests, and sufficient statistical power. Tier two studies would assess less well established but highly promising markers, as well as techniques applicable to multicenter acquisition that are less available, more difficult, or less tolerable to patients. The techniques for this tier would include, in addition to the knee, imaging of the hands and hips. The radiography of the knee would be aimed at optimizing the multicenter radiographic technique, comparing different nonfluoroscopic and fluoroscopic methods, and evaluating the joints in terms of joint-space width, osteophyte and joint-space score, and-potentially- alignment. Hip imaging would use a standardized standing joint-centered radiography and evaluate joint-space width and the morphologic score. Imaging of the hand would be conducted with standardized MCP3-centered radiography of each hand and scored with the OARSI technique.
  • Tier three of the framework would be composed of experimental substudies for which the demands for statistical power would be less stringent. These substudies would investigate: 1) markers that are promising but for which there is only scant data regarding their validity or performance and 2) techniques that are not widely available, difficult to perform, and/or demanding on patients. Tier three techniques would include all of the joints assessed in tier two plus the shoulder, spine, and temporomandibular joint, with the intent of capturing all of the alternative techniques and sites that may have relevance to this study.
  • In each of the three tiers, the markers would be characterized uniformly in terms of their surrogate validity, longitudinal sensitivity, and convenience and cost.
  • The performance criteria for comparing different imaging markers should be linked to the context of their application. Clinical practice, clinical research, and clinical trials each have slightly different priorities. However, a number of performance metrics that are common to these different applications can be derived and used to compare different imaging (and biochemical) markers.
  • Critical performance metrics for markers are surrogate validity, the magnitude of the clinically relevant component of the outcome captured by the change in the surrogate outcome (dynamic range), responsiveness to disease and/or therapy, how precisely the change can be measured, convenience, and cost.
  • Candidate imaging markers for the OA Initiative are:
    • Markers of cartilage morphology (radiographic assessment of joint-space width; MRI assessment of cartilage score, thickness, and volume; optical coherence tomography (OCT) assessment of cartilage thickness and surface fraying).
    • Compositional markers in cartilage (MRI and polarized OCT assessment of collagen organization in cartilage, MRI assessment of proteoglycan content).
    • Bone markers (radiographic and MRI assessment of osteophyte score and size, technetium-MDP scintigraphy assessment of bone synthesis, radiographic and MRI assessment of trabecular measures, MRI and technetium-MDP scintigraphy assessment of marrow edema or inflammation, assessment by a variety of techniques of subarticular cysts and bone attrition).
    • Markers of effusion and synovitis (MRI assessment of effusion score, effusion volume, and synovial perfusion; Doppler ultrasound assessment of synovial perfusion).
    • Markers of other joint structures (MRI assessment of the meniscus, the cruciate and collateral ligaments, bursitis, etc.).
  • In the area of subject recruitment, the limitations of imaging relate principally to competition from the clinical cases for MRI time.
  • The total imaging cost for tier one will be $8,600 to $14,400 per subject (six visits over 4 years). For 5,000 subjects, the total cost of tier one would be $43 to $72 million. For tier two, there are a smaller number of subjects but more (nine) visits. The cost for 500 subjects over 4 years would be $12,600 to $21,600 per subject for a total of $6.3 to $10.8 million. Funding mechanisms for tier three have yet to be discussed.
  • An alternative that could help contain the imaging costs for all three tiers-and improve standardization- would be to use a small number of mobile, rather than clinical, MRI units at a cost of $1.1 million per year for each unit. To service the 15 or so centers that would be involved would take 3 mobile units. Accordingly, the total imaging costs for the entire study would be $11 million.
  • Remaining questions that need to be discussed include the determination of the type of cohort to be used; basic design, statistics, and analysis issues (e.g., whether to image one or both knees); the structure and content of the database; and issues related to imaging and analysis standardization and quality assurance (site qualification and training, image data collection and management, image analysis, and reporting).

Discussion

In response to a query on whether tier three would be supported through a Request for Applications (RFA), Dr. Peterfy responded that such a determination falls outside the role of the Imaging Subcommittee and was not discussed by the members of the group.

A participant pointed out that the verified, validated way of measuring bone blood flow noninvasively is with fluoride ion via positron emission tomography (PET). Although there are not many people representing the emission field on the Imaging Subcommittee, the OA Initiative should work to ensure that PET, ultrasound, and new contrast techniques are seriously considered for inclusion in tier three. Dr. Peterfy noted that this would be appropriate for tier three because its design is intended to include all viable imaging techniques.

In response to the question, what is the basic anatomical examination for tier 1 that everyone agrees to? Dr. Peterfy replied that the protocols for tier one were determined on the basis of methods for evaluating articular cartilage, bone, and other structures inside the knee that are the most established and lend themselves to a multicenter acquisition process. Radiographically, a nonfluoroscopic technique is considered the most applicable. With respect to which MRI technique to use, there are not many options if the existing clinical infrastructure is to be used in multiple sites, and those chosen by the members of the Subcommittee are felt to be very effective methods for identifying the morphological characteristics of the articular cartilage and quantifying its volume.

Following an attendee's query regarding where gadolinium ranks in this scenario, Dr. Peterfy noted that gadolinium would be an extra injection that would add both cost and trouble. It could be considered as an issue to study in a tier three or, potentially, tier two context. Questions related to synovial enhancement and synovitis in osteoarthritis could probably be answered outside of this study or in a tier three context.

Dr. Stevens announced that, due to time constraints, further discussion with the members of the Imaging Panel would be deferred until the evening session.

Biostatistics

Introduction

Yetunde Taiwo, section head, Late-Stage Arthritis Research, Procter & Gamble Pharmaceuticals and session moderator reviewed the concepts to be discussed during the biostatistics session and introduced Dr. Helms.

Presentation of Biostatistics White Paper

Ronald Helms, Ph.D.
Vice President, Statistics
Rho, Inc.

In his review of the Biostatistics White Paper (Statistical Issues for Establishing Relationships Among Biological Measures and Clinical End Points of Disease),
the full text of which will be posted on the OA Initiative Web site (http://www.nih.gov/niams/news/oisg/index.htm), Dr. Helms emphasized the following points:

  • The role of biostatisticians and epidemiologists in the OA Initiative is to identify appropriate statistical methods for evaluating and comparing biomarkers, select clinical trial design strategies, and perform sample size computations and cost calculations.
  • A surrogate serves as a substitute for an end point in many cases, and a study to validate surrogates must also evaluate corresponding end points. Ideally, the end points and their surrogates should be ethical; feasible; relevant to the clinical setting of the study and the stage of clinical experimentation; valid (although there is controversy regarding whether a surrogate must be valid); precise, reliable, and repeatable; sensitive and responsive to change; and comprehensible and credible to the relevant research, review, and application communities.
  • Appropriate statistical methods for evaluating surrogate markers are currently available. Mixed (random effects) general linear models can be used to assess continuous end points and surrogates; mixed effects logistics models can be applied to dichotomous end points and surrogates. Although there are some unsolved analytic problems associated with certain types of surrogate assessments, there are ways to work around them.
  • OA has multidimensional outcome end points that cannot be simultaneously summarized in one number or variable. OA outcomes can be based on clinical symptoms, pathology, histology, biomechanical factors, or biochemical changes. Accordingly, OA end points and surrogates must be restricted to one specific dimension (e.g., handicap, pain, or performance) or be represented simultaneously by multiple variables.
  • The validation of a surrogate end point is a scientific process that requires the combined effort of medical researchers, clinicians, and biostatisticians. No one discipline should dominate this process.
  • The use of surrogate end points can be dangerous; a number of studies have found that they can produce misleading or incorrect results.
  • Some statisticians are very conservative with respect to the use of surrogate variables in Phase III studies, tending to prefer that surrogate markers be used to measure biological activity in Phase II or screening trials. Although other statisticians are less conservative, those planning the OA Initiative should be aware that study review panels, including FDA panels, will include some statisticians who are very conservative with respect to the use of surrogates and will hold to a very high standard research done to validate OA surrogate end points.
  • Because so much about OA is unknown, Dr. Helms suggested that the study design have two cohorts that can be crossed with the other kinds of cohorts that have been discussed elsewhere: 1) a research development/hypothesis-generating cohort (consisting of a subset of the subjects in the study), which can be used to develop the tools that will help identify optimal biomarkers or potential surrogates, explore data, and assess possible combinations of biomarkers to serve as surrogates for specific endpoints and 2) a hypothesis-testing/evaluation cohort (made up of a different subset of subjects), which can be used to prospectively evaluate proposed surrogates, test hypotheses about proposed surrogates, and compare the surrogates to true end points.
  • The OA Initiative should plan to conduct a pilot study that tests the statistical cohorts. Prior studies and clinical trials can be used as partial pilot studies, and a run-in period pilot study should be conducted to ensure that measurements and assessments are performed consistently over multiple sites.

Discussion

A participant asked whether the two cohorts described would be designed to be equal in terms of patients and numbers. Dr. Helms indicated that the measurements applied to the cohorts would be the same and that he believed that the number of patients in each cohort would be approximately equal.

In response to a query regarding how he felt about Dr. Peterfy's ballpark estimate of 5,000 patients for 4 years, Dr. Helms noted that the biostatistics group had not worked on sample size calculations for the OA Initiative because of the need to address other issues first.

Asked to discuss how the term "clinically meaningful" should be validated, Dr. Helms responded that he felt the most important issues concerning validity related to the establishment of face validity and construct validity. Outcomes and end points that are generally accepted as measures of pain, discomfort, function, and so on are currently available. With respect to radiographic and MRI outcomes, validity has been determined subjectively by groups of experts who indicate whether a result is representative of the underlying phenomenon.

An attendee asked for an FDA representative to explain whether the FDA considers joint- space width to be a primary outcome for disease modification or a surrogate marker. If it is not considered a surrogate marker, what does FDA consider a primary outcome measure for disease modification? Kent Johnson, FDA, explained that the short answer is that the FDA has not identified a primary outcome measure for disease modification. The provisional guidance used by the agency essentially adopts the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) measures of pain, function, and patient global assessment, with consideration given to the effect of standard confounders such as analgesic use. For OA, FDA is currently entertaining the notion of utilizing an accelerated or conditional approval process such as that used for rheumatoid arthritis. In this process, conditional approval will be given to a treatment if a dramatic effect on structure is identified that, subsequent to approval, is expected to be documented as being clinically relevant. Short of that, the FDA is looking at structure as something that, instead of standing alone, should be accompanied by a clinical claim demonstrated by the results of a clinical trial. Another participant pointed out that the existing FDA guidance for OA, which is much shorter than that for rheumatoid arthritis, contains a footnote that reflects FDA's willingness to be flexible. In this guideline, following a description of how the product might improve the symptoms of, delay the structural progression of, or prevent OA, the footnote indicates that "an alternative approach may be used if such an approach satisfies the requirements of the applicable statutes, regulations or both."

The plea was made that the OA Initiative not be considered a project that has to be perfect. For example, in rheumatoid arthritis, agents that stop erosions from progressing are considered beneficial, yet there is no proof that stopping such erosion is unequivocally linked to long-term functional outcome. Similarly, a treatment that stops the progressive loss of cartilage in OA would be a good thing despite the fact that it would take a long time to prove the treatment's relationship to long-term functional outcome. The desirability of a therapy that stops the progression of osteophytes is less certain because individuals who grow large osteophytes are reported to stabilize their joints better than those who develop smaller osteophytes. These are examples of two clear-cut and unequivocal x-ray features which can be measured with precision and which may actually be completely different indicators of the long-term progression of disease.

Epidemiology

Introduction

Kenneth Brandt, M.D., Professor of Medicine, Head, Rheumatology Division, Director, Multipurpose Arthritis Diseases Center, Indiana University School of Medicine and session moderator welcomed the participants and indicated his interest in ensuring that over the course of the meeting the group discuss:

  • The differentiation between risk factors for categorical and painful OA.
  • Distinctions between risk factors for the initiation of OA in terms of pathology and disease progression.

Presentation of Epidemiology White Paper

Marc Hochberg, M.D., M.P.H.
Professor of Medicine and Epidemiology
University of Maryland School of Medicine

Dr. Hochberg explained that the role of the Epidemiology/Biostatistics/Genetics Subcommittee was to: 1) examine available clinical and laboratory data and specimens from existing OA natural history and epidemiology studies to determine their applicability to biomarker validation studies and 2) look at existing databases and determine their usefulness in meeting the needs of the OA Initiative. The information gathered on the cohorts was then included in the Epidemiology White Paper, the full text of which can be found at http://www.niams.nih.gov/Funding/Funded_Research/Osteoarthritis_Initiative/oaepip.asp

In his review of the Epidemiology White Paper, Dr. Hochberg highlighted some of the studies that are described in detail in the paper's appendices (http://www.niams.nih.gov/Funding/Funded_Research/Osteoarthritis_Initiative/oaepipappen_a.asp and http://www.niams.nih.gov/Funding/Funded_Research/Osteoarthritis_Initiative/oaepipappen_b.asp). He explained that since Dr. Nevitt would be covering hip OA later in the day, his presentation would focus on knee OA.

Population-Based Cohort Studies on the Development of Knee OA

Dr. Hochberg summarized the key characteristics of several population-based cohort studies that have assessed both the development and the progression of knee OA: the Baltimore Longitudinal Study on Aging, the Framingham Osteoarthritis Study, the Johnston County Osteoarthritis Project, the Michigan Bone Health Study, the Study of Women Across the Nation (MI site), the Chingford Study, and the Rotterdam Study. These studies, some of which comprised representative samples and some of which did not, cover the age span from the end of adolescence through the ninth and tenth decades of life. They tend to focus primarily on North American and European Caucasians, although two of the studies do offer data on African Americans.

The strengths of these studies in assessing both the development and progression of knee OA are that they are useful for either nested case-control or case-cohort designs and most offer data on covariates. The studies' major limitations in assessing the development of knee OA stem from the fact that the incidence rates of OA vary by age (causing much lower incidence rates in studies with a lower mean age), there was variability in the processing and storage of samples across studies, and no synovial fluid specimens were collected. With respect to knee OA progression, the studies are limited by the small number of cases that are available in several of the cohorts, the fact that most x-rays were taken in AP weightbearing views rather than in the Schuss or semiflexed position, and the variability that occurred in the processing and storage of samples across studies.

The risk factors associated with an increased incidence of knee OA are older age, female gender, being overweight, having hand OA, contralateral knee involvement (in persons with OA in one knee), a history of joint injury, higher levels of physical activity, quadriceps muscle weakness, greater bone mass, and lack of estrogen replacement therapy in postmenopausal women. These risk factors are considered a useful means for selecting high-risk groups in which to test OA biomarkers and interventions.

Many of the risk factors associated with the incidence of knee OA have also been found to be risk factors for progressive knee OA (increasing age, female gender, being overweight, having hand OA, having weak quadriceps muscles, and greater levels of physical activity). Other factors that have been linked to OA progression are micronutrient intake (vitamin C and D), lower bone mass, and inflammation.

Patient Cohort Studies on the Progression of Knee OA

Dr. Hochberg summarized the key characteristics of the following patient cohort studies that have assessed the progression of knee OA: the Boston OA of the Knee Study, the Indiana University Knee OA Progression Cohort, the Mechanical Factors in OA of the Knee Study, the Bristol OA 500 Cohort and more recent Bristol OA of the Knee Study, the Lund Postmeniscectomy Knee OA Cohort, the Nottingham Study, the Spenshult Knee Pain Cohort, and the Ulm OA Study.

The strengths of these studies are that data on covariates are available in most (although the degree of detail is lower than that found in population-based studies), MRI data are available in some of the cohorts, serial specimens allow for the measurement of change in markers, and several of the studies have synovial fluid specimens. They are limited in that most of the x-rays are taken in an AP weightbearing view (not in the Schuss or semiflexed position), processing and storage techniques vary across studies, and synovial fluid specimens are not available in some of the studies.

Summary and Conclusion

Dr. Hochberg concluded that existing population- and patient-based cohorts have data and specimens that are relevant to the goals of the OA Initiative. The data they can provide should be used to validate potential biomarkers for OA development and progression in the initial hypothesis-generating phase of the OA Initiative.

Discussion

Dr. Brandt asked Dr. Hochberg to comment on pain and risk factors for OA progression. Dr. Hochberg responded several studies have looked at knee pain as a risk factor for the progression of knee OA. In patient cohort and population studies in which the progression outcome was defined as having a total joint replacement, pain was clearly related to this outcome. Other studies using x-ray markers that assessed pain in the knee also found pain to be a risk factor for OA progression. Dr. Hochberg noted that pain in OA is related to changes in bone blood flow, most likely caused by inflammation, and in knee OA positive scintigraphy has been found to be a risk factor for radiographic progression. In addition, followup studies of OA patients have indicated that inflammation is probably a risk factor for OA progression in the knee.

Perspectives on the Status of Current Cohort Studies

David Felson, M.D., M.P.H.
Professor of Medicine and Public Health
Director, NIH Multipurpose and Musculoskeletal Diseases Center
Boston University School of Medicine

Dr. Felson noted that his talk would address the question of whether currently available OA population and clinical studies can provide the OA Initiative with sufficient epidemiologic data. Dr. Felson's presentation is based on studies of knee osteoarthritis and will be followed by Dr. Nevitt's presentation on studies of hip osteoarthritis.

Five general types of surrogates or biomarkers may be of interest to the OA Initiative: 1) diagnostic surrogates (a stand-in for disease) that can be obtained from a cross-sectional study, 2) surrogates for disease severity, also obtainable from cross-sectional study (neither of these first two types is of primary interest to drug development efforts), 3) predictors of response to treatment, which generally require trial data, 4) surrogates to monitor outcomes, which also usually require trial data, and 5) prognostic biomarkers that predict longitudinal outcomes.

Dr. Felson contended that for drug development and therapeutic development purposes, prognostic markers are very important. Cross-sectional or baseline prognostic markers might identify persons at high risk of OA progression who would be good candidates for studies. Longitudinal studies could help determine whether changes in disease status correlate with a biomarker or surrogate in a way that could be used to evaluate the likelihood that a drug is effective. The outcomes measured can be either incidence or progression of disease and might test whether a biomarker or a change in the biomarker correlates with a change in disease status and the strength of this correlation.

An observational study of a biomarker's validity requires a longitudinal design wherein disease assessment by a gold standard method is obtained at baseline and at followup and the biomarker is measured at baseline and followup. The outcomes of interest are cartilage loss (perhaps characterized by joint-space narrowing) and pain/disability. Dr. Felson noted that the Dougados studies showed a poor correlation between pain/disability and joint-space narrowing and pointed out that these two very different outcomes do not correlate well with each other. In addition, results emerging from the MRI field indicate that factors other than cartilage loss can narrow joints, an example being that meniscal subluxation can cause joint-space narrowing regardless of the presence of abnormal cartilage. Accordingly, structural changes in OA and OA symptoms are independent and important factors. Biomarkers may be correlated with x-ray change, worsening pain, or both, and some biomarkers may be correlated with specific structural alterations but not with global change. Biomarker studies need to include both symptom and structural data.

How many cases are needed to test a biomarker as it might relate to incident (new onset) OA? Dr. Felson's power analyses factor in errors in outcome measures (e.g., noise in joint-space narrowing measurements) and errors in biomarker measurement. To detect an odds ratio of approximately 1.75, Dr. Felson believes that about 150 incident cases are needed. More cases will be needed if the biomarker is measured with more error or if the odds ratio to be detected is lowered.

With respect to how many population study cases are available, Dr. Felson reported that of 11 U.S. population studies, only 5 have longitudinal radiographs obtained in the field (the original cohort of the Framingham Study, the Baltimore Longitudinal Study of Aging [BLSA], the Michigan Bone Health Study [MBHS], the Johnston County Study, and the Indiana University [IU] Study). Only three of these studies have serum or urine specimens (BLSA, MBHS, Johnston County); among these studies, the number of incident cases that have been published recently are BSLA: 29, MBHS: 9, Johnston County: not yet known (the study is currently in the field but this is expected to be a large number). Problems are caused by the studies' lack of consistent assessment of disease status, absence of longitudinal semiflexed films, inconsistent evaluation of pain and disability, and lack of other imaging data. The studies are also not representative of the U.S. population. There are two longitudinal European studies that would complement these studies, both of which have biomarker data from serum held for more than 10 years at -20 °C; however, it is not clear that they will produce useable data.

Because inefficiencies are caused by the absence or slow development of disease or progression in those at low risk, a population-based study of persons either at high risk of or who already have OA might be more efficient and offer a higher level of representativeness. Four clinical studies of knee OA (by Hernborg, Spector, Dieppe, and Ledingham) show some grade of progression. Although each study grades this progression differently, in general, two of the studies have higher rates of progression than those found in the Framingham Study and two do not.

Dr. Felson concluded that current population studies are not optimal for a study of prognostic biomarkers. If the results of current studies are pooled, the numbers will be driven by one large study, the one from Johnston County. A solution could be to enroll multiple current sites with followup and/or conduct a large prospective study of persons who are at high risk of or already have OA.

Within OA natural history studies, 900 subjects in 3 U.S. studies are currently enrolled and are being repeatedly followed with semiflexed films and other state-of-the-art tools. European studies are following approximately 540 subjects. Most studies are utilizing repeated standardized x-ray imaging and WOMAC assessments and have serum and urine specimen banks. In addition, other imaging data are available in some of the studies. An advantage of clinic-based natural history studies is their power to apply repeated measurements and continuously measured outcomes to the evaluation of biomarkers. Clinic-based studies also recruit persons at high risk of progression.

How many clinic-based subjects are needed to test correlation of change in biomarkers with a change in disease status? The scenario involves measuring both disease and biomarker at baseline and followup, testing to determine whether the biomarker changes when disease changes, and evaluating the correlation. The assumptions below assume 80 percent power. If the true correlation between the biomarker change and the actual disease measurement change is 0.6 and the noise of measurement (the error as proportion of population standard deviation [SD] is 0.1, and you wish to make sure the lower 95 percent confidence interval of the r between disease marker and disease change is no less than 0.3, you would need 197 subjects followed over 24 to 30 months. If the true r = 0.5, then doing a study in which the lower bound of the confidence interval for r is no less than 0.3 would require a sample of 820. If the measurement is noisier, more patients are needed. Dr. Felson recommended that a range of 800 to 1,760 patients be considered.

The existence of multiple studies with standardized assessments of knee OA makes a study of prognostic biomarkers feasible and valuable. However, such a study would be skewed to the types of patients found in clinical settings and is probably not generalizable to a larger pool of OA patients within the community, including those with earlier-stage disease. Another issue is the current and increasing belief that risk factors and possibly biomarkers may not be the same at different stages of disease; incident, early progressive, and late progressive OA may each be characterized by a different biology. If this is so, biomarker data from a clinical study would only provide an end-stage view of the processes involved.

Dr. Felson concluded that prognostic biomarkers have the most to offer the OA Initiative and recommended that information on these biomarkers be pooled from current clinical natural history studies. For population-based studies of a broader spectrum of disease, new, larger population studies of those with disease or at high risk are needed.

Perspectives on the Status of Current Cohort Studies (continued)

Michael Nevitt, Ph.D., M.P.H.
Department of Epidemiology and Biostatistics
University of California at San Francisco

Dr. Nevitt indicated that his presentation would look at some of the current longitudinal cohort data that are available for the hip in order to assess whether these studies can meet the needs of the OA Initiative. Existing studies may be most valuable for the identification of potential prognostic biomarkers, including predictors of progression and incidence, but this may also lead to potential surrogate biomarkers for use as outcomes in trials.

At least three current studies have sufficient information and numbers of cases to be potentially useful for studies of prognostic biomarkers of hip OA progression.

The ECHODIAH Study

The ECHODIAH study is a clinical study of 508 men and women with a clinical diagnosis of hip OA who were enrolled in a trial of Diacerhain. The average age of this study population is 60 years. Serum and urine were collected at baseline and at years 1, 2, 3, and 5 and stored at -20 °C. Weightbearing hip x-ray films were obtained at baseline and at years 1, 2, 3, and 5. In terms of patient outcomes, function was measured by means of the Lequesne pain index and by assessing joint-space width in each of the periodic radiographs. The occurrence of total hip replacement was also recorded.

Johnston County Study

The Johnston County Study is a population-based study in which nonweightbearing pelvis x-rays were obtained at baseline; from this assessment, approximately 675 individuals were identified as having radiographic hip OA, 50 percent of whom also had joint symptoms indicative of symptomatic OA. Serum was collected at baseline, and serum and urine are being collected in the ongoing year 5 exam; both types of specimen are stored at -80 °C. Repeat x-rays of the pelvis are being obtained in the ongoing year 5 exam. Patient outcomes were assessed through the radiographic measurement of joint-space width at baseline and at year 5, the evaluation of function by means of a health assessment questionnaire, and the measurement of pain.

Study of Osteoporotic Fractures

The Study of Osteporotic Fractures (SOF) is a population-based cohort study of elderly white women assessed with baseline nonweightbearing pelvis radiographs, the review of which identified 675 women, with a mean age of 71, who could be classified as having x-ray OA of the hip. About 40 percent of these women could also be classified as having symptomatic OA. Serum was collected at baseline and at years 2, 5, and 8; urine was collected at year 4; and both types of specimen were stored at -190 °C. Repeat pelvis radiographs were obtained at year 8. Patient outcomes were assessed through the measurement of joint-space width; the evaluation of function by means of a health assessment questionnaire; the measurement of pain at baseline and years 2, 5, and 8; and by recording the occurrence of total hip replacement.

Dr. Nevitt pointed out that it might be possible to pool the cases from these three studies to look at the progression of symptomatic hip OA. A simple power calculation can be based on the assumption that, of the individuals found to have hip pain and x-ray evidence of disease (about 1,100 individuals), 33 percent would show progression (clinical or radiographic) in anywhere from 3 to 8 years. For a continuous baseline biomarker, a pooled progression study could detect a difference between progressors and nonprogressors equal to a standardized effect size of 0.2 (marker difference between groups/SD of the marker) with a 90 percent power (alpha =0.05). In a worst-case scenario with a dichotomized biomarker having a prevalence of only 20 percent, a pooled study could detect an odds ratio of 1.7 for progression with a 90 percent power (alpha=0.05).

Although these are fairly good numbers, should a population-based sample of people from the community with radiographic OA be pooled with a clinical sample? One problem is that these two types of samples may have considerably different rates of progression. A review of the literature indicates that reductions in joint-space width of 0.2 to 0.5 millimeters per year are seen in clinical studies, whereas the annual change in the loss of joint-space width in the symptomatic hip OA cases of the population-based SOF was less than 0.1 millimeter. Additionally, 8 to 15 percent of the clinic-based samples underwent total hip replacement each year; in the SOF cohort, the annual rate was 2 to 4 percent. From a power perspective, it might make sense to combine clinic- and population-based studies of symptomatic hip OA progression; however, this raises concerns about validity. What is the appropriate target group-people in the community with OA, OA patients, or some combination of the two?

Dr. Nevitt indicated that it may be possible to use the two population-based studies (Johnston County and SOF) to look at prognostic biomarkers of hip OA incidence. Their combined samples would result in a potential incidence cohort of approximately 7,000 individuals who lack radiographic findings of hip OA at baseline and are eligible to develop incident OA. The main end point would probably be radiographic incident hip OA, although it may also be possible to look at symptomatic OA. Although the followup radiographs are not complete for the Johnston County Study, Dr. Nevitt estimates that the 2 cohorts combined will produce 290 to 300 incident cases of radiographic hip OA. For a continuous baseline biomarker, a pooled incidence study could also detect a difference between progressors and nonprogressors equal to a standardized effect size of 0.2 (marker difference between groups/SD of the marker) with a 90 percent power (alpha=0.05). For a dichotomized biomarker having a prevalence of only 20 percent, a pooled study could also detect an odds ratio of 1.7 for progression with a 90 percent power (alpha=0.05). Power will be somewhat less in a case cohort study design that measures a biomarker at baseline in all incident cases and in a sample of the controls (e.g., five controls per incident case) instead of the entire cohort.

In summary, Dr. Nevitt noted that it is clear that the individual studies themselves could identify potential prognostic biomarkers for both progression and x-ray incidence of disease. Pooling could increase the power of these analyses, although there are as yet unanswered questions regarding the appropriateness of this approach. If the value of these existing cohorts is to be realized, support will be needed for the additional analysis of stored specimens, pooled analyses, and meta-analyses. Additional funds would also be required if x-rays were to be read again to ensure standardization of reading between studies.

Although prognostic biomarkers are candidates for surrogate biomarkers, Dr. Nevitt indicated that the potential for using existing studies to validate the relationship between surrogate biomarkers and patient outcomes is very limited. The ideal study would measure multiple surrogates at various time points during the disease process, measure patient outcome data at multiple time points during the disease process, and assess biomarkers and specimens particular to a given stage or severity of disease at appropriate time points. The existing studies do not provide this information. Although the ECHODIAH study comes close to this design, the sample size is low (n=508).

Another consideration to address is whether change in radiographic joint-space narrowing is in fact a valid surrogate end point for patient outcomes, or whether it is best viewed as simply a separate outcome. This is not known at present, and changes in joint-space width over time need to be validated in terms of their relationship to patient function. One of the strengths of the ECHODIAH Study, Johnston County Study, and SOF is their potential to look at this issue in some detail.

Additional limitations of these existing cohort studies include the following:

  • The patient outcomes are not standardized, although the various instruments could potentially be cross-calibrated in retrospect.
  • The progression rate may differ in the clinical and population studies, limiting their capacity to be pooled.
  • In the two population-based studies, the outcomes are measured over a 5- or 8-year period, which may be too long a timeframe in which to assess certain disease process end points. For example, an 8-year study period could make it difficult to differentiate between risk factors for OA incidence and progression.
  • The SOF is a large study composed entirely of white women. This would tend to cause its contribution of cases to dominate the data obtained from the other studies.
  • No imaging modalities other than standard x-rays were used.
  • The measurement of markers is infrequent and variable.
  • The variety and quantity of the samples are limited.

Perhaps data from randomized controlled trials, particularly the more recent ones, can aid biomarker development efforts. Dr. Nevitt recommends that these be considered as components of the cohort studies used to generate hypotheses. In addition, are there ongoing studies that are not closed in which adding measurements could yield significant information? For example, the Health ABC Study holds the potential for serial MRIs, although additional funding would be required.

Dr. Nevitt concluded that answers to the OA Initiative's key questions on prognostic and surrogate OA biomarkers will probably require a new longitudinal study or studies. A parallel effort should seek to mine existing data for information from which to generate hypotheses about biomarkers. In designing a potential new cohort study, important issues to consider include the following:

  • Should the study target progression alone or should it include an incidence cohort? The identification of those at high risk of developing OA and the investigation of issues related to prevention will require an incidence cohort against which to evaluate markers.
  • Should the study cohort consist of a clinic-based sample, a population-based sample, or a combination of the two?
  • What definitions should be used for OA? This will depend, in large part, on the decision regarding whether to study OA in a clinic- and/or population-based sample.

Presentation of Straw Proposal on Epidemiology/Cohort Selection

Leena Sharma, M.D.
Assistant Professor of Medicine
Division of Rheumatology
Northwestern University

Dr. Sharma reported that her presentation was developed by the members of the Epidemiology Subcommittee to respond to the question of whether, in order to address needed areas of biomarker research in OA, the OA Initiative should sponsor a single study or a composite of several studies.

Several specific hypotheses fall under the umbrella of the goals of the Initiative, and a key question is what the primary hypotheses will be. Is the principal goal of the OA Initiative to identify, test, and validate: 1) a biomarker for disease initial development, presence/absence, progression, or stage; 2) a prognostic marker, i.e., a predictor of ultimate outcomes; 3) a biomarker that can identify homogeneous groups that may differ in terms of rate of progression and responsiveness to treatment; or 4) a biomarker of response to therapy, specific catabolic or anabolic processes, or side effects? The study design is driven by what the primary hypotheses are.

As in any study, validity is both an internal and external issue. Internal validity, the degree to which results are correct for the patients being studied, is determined by how well the study is carried out. External validity or generalizability is the degree to which the results of an observation hold true in other settings. A study with high internal validity may or may not be generalizable, and sampling bias occurs when conclusions based on a sample are generalized to dissimilar groups. In typical OA studies, participants are selected from a clinical setting on the basis of inclusion and exclusion criteria. Dr. Sharma noted that the results of these trials tend to be most applicable to the clinic patient group from which the subjects were recruited; they are less likely to be applicable to those from the population with symptomatic or asymptomatic OA. In addition, the emergence of new classes of disease-modifying treatment for OA will draw into the clinical trial population new sets of people with OA, e.g., persons who may not meet the usual definitions of symptomatic OA or had previously not pursued pharmacologic intervention.

Accordingly, the second key question that needs to be answered is, who is the target for emerging disease-modifying drugs: current clinical trial subjects, clinic patients, people with symptomatic OA, or all persons with OA? The cohort chosen influences the generalizability of results, and the OA Initiative needs to match the cohort choice to the ultimate target of disease-modifying OA drugs. Persons not represented in current clinical trial populations may constitute the majority of those with OA and be candidates for disease-modifying therapy. Patients not represented by current trial populations include certain ethnic groups, persons with asymptomatic OA, and those who have not sought medical attention for OA.

In this straw proposal, consideration of the following three cohorts is recommended:

  • Cohort A, a multicenter population-based cohort that would include both cases and noncases within a population. The people involved would be recruited from a population-based list and would not have to have a health care connection to be enrolled.
    • Pros. This is the most all-inclusive cohort and would include subjects both with and without OA. It would also be possible to include people at very high risk of disease. The suggested cohort would be representative of subjects in and outside of the current trial population, maximizing generalizability. The design provides opportunities to address questions beyond the primary goals of the OA Initiative, includes disease-free controls, allows examination of alternative definitions of OA, and provides an opportunity to look at both disease incidence and progression. It also provides an opportunity to look at the natural history of OA from preradiographic stages and, if large enough, would allow for the examination of disease subsets. The greatest advantage offered by Cohort A is generalizability.
    • Cons. A large number of subjects would need to be evaluated to generate a sufficient number of progressors. To ensure power, it may be necessary to perform the same evaluations in all diseased subjects. There is interest in being able to perform different sets of evaluations in different subgroups of OA, and this may be less feasible with this design. A greater cost is associated with this cohort, and the feasibility of performing long or complex x-ray and MRI protocols may be reduced. Potential ways to address these limitations include: 1) recruiting and focusing on subjects at high risk for disease, 2) focusing solely on progression and including only subjects with disease at baseline, and 3) performing a more extensive evaluation of subjects with disease at baseline. Dr. Sharma noted that the key concern with Cohort A is whether the study can be designed to ensure power.
  • Cohort B, a multicenter clinic/community cohort that, although not truly population based, would recruit patients with mainstream OA from clinics and by advertising in the community.
    • Pros. This cohort would be representative of the usual trial subjects. (Depending on point of view, this could be considered a pro or a con.) The subjects may have a more rapid rate of progression than individuals with OA in the population. This protocol would provide a more efficient means of generating sufficient numbers of progressors at lower cost, and there would be opportunities to look at disease subsets. Power is less of a worry than in Cohort A, and unique evaluations could be performed in particular groups. Dr. Sharma pointed out that the greatest advantage offered by Cohort B is power.
    • Cons. At best, this approach represents one subset and probably the minority of human OA cases-those who tend to see physicians and volunteer for studies. There are no built-in controls, and the design would provide no opportunity to examine incident disease. The focus of this approach would be narrower, with reduced potential for future applications, and there would be no opportunity to examine preradiographic OA. One way to address these disadvantages would be to recruit matched controls and follow them forward in time. A Cohort B study could be improved by being coupled with a Cohort C study. The key concern with the Cohort B design is the lack of generalizability.
  • Cohort C, a select high-risk cohort made up of patients who are almost certain to develop OA because of a specific insult, genetic predisposition, or other factor such as meniscectomy.

In selecting the cohort, consideration should be given to the fact that the scale of a larger study is not suitable for investigating:

  • Issues that require a long or complex evaluation.
  • Questions that require evaluations that are not at a stage of development suitable for inclusion in a large initiative.
  • Subgroups that may not be present, or present in sufficient numbers, in a larger study.

These components could be addressed through a subset of the larger prospective study or through cohorts established in currently existing studies.

The OA Initiative could use the cohorts of currently existing studies as future centers for the multicenter initiative. Although no current study was designed to achieve the goals of the Initiative, many existing studies offer a solid infrastructure that could be applied to a prospective study. The cohorts of currently existing studies could also be used as a means for examining questions not appropriate for inclusion in a larger study.

Dr. Sharma linked the OA Initiative goals to the above-mentioned cohorts on the basis of the recommendations of the members of the Epidemiology Subcommittee:

*For these options, there is concern regarding the applicability of the results to mainstream OA and the unpredictability of the time it takes to develop OA.

The potential goals of identifying biomarkers to quantify response to therapy or side effects of therapy are not included in the above list because of the lack of a treatment structure in the Initiative.

With respect to what definition of OA to use, Dr. Sharma indicated that none of the usual approaches (e.g., the presence of osteophytes) can identify the entire complement of individuals with OA. Consideration also needs to be given to the influence psychological factors can have on symptom and function self-reports. Accordingly, a useful byproduct of the OA Initiative could be a better definition of OA.

In conclusion, Dr. Sharma reported that the Epidemiology/Cohort Selection Subcommittee recommends the pursuit of answers to the two key questions that drive study design:

  • What are the primary hypotheses of the Initiative?
  • What groups are the targets for emerging disease-modifying OA drugs?

The answers to these questions will facilitate the selection of an optimal study design. At this point, it appears most likely that the design would involve a composite of studies. After the hypothesis is defined, one approach could be to perform studies involving Cohort B and Cohort C, generate data, refine the hypothesis, and proceed to Cohort A, with studies not appropriate for large-scale assessment conducted on a parallel track.

Administration

Introduction and Background

Gregory Downing, D.O., Ph.D.
Health Science Policy Advisor
Office of Science Policy
Office of the Director
National Institutes of Health

Dr. Downing noted that the public-private partnership model being established by the OA Initiative would create a template for the collaborative development of research resources that could be emulated by efforts targeting other disease areas. In the first half of this century, a great deal of scientific discovery was catalyzed by the collaborative efforts of the defense industry and the Federal Government. Since 1986, in the biomedical research arena, the Government has used a number of mechanisms to conduct collaborative research with nongovernment organizations such as industry. The OA Initiative represents a new iteration of this process.

Key administrative questions that need to be addressed in conjunction with the OA Initiative include the following:

  • How will the consortium be formed?
  • How will the project be managed?
  • What interactions will take place between the NIH, private sponsors, and project scientists?
  • How will access to repository samples be handled?
  • What is the true value of the OA Initiative?
  • How will intellectual property (IP) issues be handled?

To date, the management group's discussions of the Initiative's administrative aspects have considered the OA Initiative a joint international enterprise involving a variety of private- and public-sector organizations. The bridge between these sectors is the OA Initiative Public-Private Consortium. This consortium, which represents the groups underwriting the financial aspects of the Initiative, currently consists of several components of the NIH, other Federal agencies, and private sponsors. In the future, additional agencies and organizations may have liaison or ad-hoc relationships with the consortium.

The model recommended for the OA Initiative involves the NIH Foundation, a tax-exempt, nonprofit organization that has worked with numerous private sponsors to support training and other health-related research activities. OA Initiative funds would flow through the NIH Foundation to NIH institutes and centers, which-by means of the longstanding peer review system-would use these and their own resources to support the activities of a data coordinating center/repository and a series of contractors responsible for participant accrual and assessment.

Dr. Downing pointed out that a unique aspect of the OA Initiative is that the information and resources developed will be accessible to the public. The data and specimens generated by the Initiative would flow from the contractors to the data coordinating center/repository, through the NIH institutes and centers, and to the sponsors and the public through a variety of databases and mechanisms designed to appropriately control access.

Two important issues need to be worked out:

  • Who will have access to the finite specimens developed through the Initiative? Because in some cases there will not be enough specimens to satisfy the needs of everyone interested in using them, a system of prioritization needs to be developed.
  • How should the OA Initiative handle IP concerns? Resources brought in for validation may have IP attached to them, which raises a number of complex considerations. The Government is required by Bayh-Dole to give its contractors the rights to any new IP they develop using Federal funding. Although the primary OA Initiative projects (patient recruitment, core clinical and imaging data, public domain marker data, and markers that already have a filed IP) would be bound by the terms of Bayh-Dole, key independent projects-such as certain marker studies with complex IP issues-could be developed outside of the consortium. Although these independent projects would be able to apply for core resources, they would take place outside of the scope of the OA Initiative, which would allow private sponsors and collaborators to pursue licensing arrangements with the organizations involved.

Since the OA Initiative Steering Group was assembled in June 1999, the management group has interacted with the chairs of the various subcommittees to assess the state of the art in their respective fields, define key research questions, identify a broad administrative structure, and develop an overall research plan. Over the next few months, a plan for the OA Initiative Public-Private Consortium will be developed, and potential sponsors will be asked to decide whether they plan to participate. Scientific input will be coalesced, requests for proposals (RFPs) will be developed, and draft RFPs will be posted on the NIH Web site for public input from all corners of the scientific community. NIH Project Officers will be appointed to assist with the preparation and administration of the RFPs, which it is hoped will be released early in the summer, reviewed and scored in the fall, and awarded early in 2001.

Presentation of Straw Proposal on Administrative Model/Structure

Steven Stimpson, Ph.D.
Exploratory Discovery Head
Musculoskeletal Diseases
GlaxoWellcome, Inc.

Dr. Stimpson indicated that his presentation picks up at the point at which the awards for the OA Initiative have been made and project management begins in earnest. Following the appointment of a dedicated Project Officer, priority should be given to the development of the structure for the day-to-day operations of the Initiative. Key management and organizational elements include:

  • The OA Initiative Public-Private Consortium.
  • The OA Initiative Steering Committee, to be composed of the contractors and NIH staff representing the consortium (although other consortium members could attend meetings and provide input).
  • Additional committee structures charged with addressing important issues, such as resource allocation, publications and presentations, cohort recruitment, the distribution and use of samples, and IP.
  • The OA Initiative Coordinating Center, the role of which could include the development and updating of the protocol and other study materials; training clinical site staff; collecting and storing clinical data, imaging data, and biological specimens; analyzing and reporting data; establishing and maintaining central laboratories as required; and implementing quality assurance and quality control procedures.

Dr. Stimpson pointed out that the private sponsors of the OA Initiative would benefit from:

  • The creation of a valuable research resource that will facilitate future research and development activities targeting the diagnosis and treatment of OA and the utilization of new technologies.
  • The opportunity to participate in a unique collaboration involving OA experts from industry, academia, national organizations, the NIH, and the FDA.
  • The fact that funds provided to the NIH Foundation may be tax deductible.
  • Having the opportunity to provide input that could influence the direction of the research conducted through the Initiative.
  • Having potentially early access to OA Initiative data, radiographic images, and biological samples-information that could facilitate sponsors' plans for more efficient clinical programs and FDA presentations.
  • Having the potential opportunity to provide input into decisions on how the limited biological samples established by the Initiative will be used for future research.
  • Having the opportunity to gain access to core resources to pursue certain ancillary projects (such as marker studies with complex IP issues) with cross-licensing opportunities with other private sponsors.

Professional research and voluntary health organizations sponsoring the Initiative would gain from:

  • Being able to advance knowledge about OA disease pathogenesis and burden-of- illness measures.
  • Being better able to identify scientific opportunities for future research and strengthen the platforms on which clinical research and training are conducted.
  • Having potentially early access to OA Initiative data, radiographic images, and biological samples.
  • Having the potential opportunity to provide input into decisions on how the limited biological samples established by the Initiative will be used for future research.

Universities and research organizations participating as contractors would benefit from:

  • The receipt of funding for OA research.
  • Being able to develop new research cohorts.
  • The establishment of a multicenter network for OA studies.
  • Having access to data and radiographic studies and, through a defined evaluative process, the biological materials collected.
  • Being provided platforms on which to develop assays and measurement technologies.

Nonsponsoring regulatory agencies and health quality and reimbursement organizations would gain from:

  • Having access to information that facilitates science-based regulatory decision-making, including the assessment of biomarkers as surrogate end points in clinical trials, standardization of reporting, and the development of regulatory guidelines.
  • The development of an improved scientific base on which to evaluate outcomes.
  • Having access to information that facilitates health resources utilization planning.

In conclusion, Dr. Stimpson noted how impressed he has been with the collegial spirit he has observed in the broad spectrum of players involved in planning the OA Initiative.

Discussion

In response to a question about public funding of the Initiative, Dr. Katz noted that the NIH would be an equal sponsor in every respect. Because NIH cannot provide money to the NIH Foundation, Federal funds will be provided directly to the NIH components involved.

A participant pointed out that once the size of the trial has been determined, it will be important to decide what major question is to be answered and, therefore, how the trial will be powered. Will the trial be powered for clinical outcome, imaging outcome, or biochemical outcome? Vastly different implications are associated with each of these choices. Dr. Stimpson stated that a reasonable place to begin would be to consider aspects of proof of concept-proof that a hypothesis is worthwhile-in the early, Phase II components of the trial before moving on to more expensive late-stage trials.

The attendee also stressed the importance of ensuring that all OA Initiative clinical trial sites adhere to good laboratory practices (GLP), and Dr. Stimpson indicated that appropriate points of this nature could be included in the RFP description.

An attendee noted that important unresolved issues are associated with the question of IP and how it will impact panels of markers, markers coming together because of preexisting IP, or perhaps genetic markers that may also provide new disease linkages. For some of the sponsors, it will be important to know whether they will be in a position to help develop the markers toward commercial entities. Will the validation trials be conducted in a way that allows diagnostic markers to be licensed or registered? Dr. Stimpson stated that these questions reflect the need to keep the structure of the OA Initiative flexible enough to incorporate input that addresses these types of issues as the Initiative moves forward.

A participant pointed out the value of having the private sponsors of the OA Initiative incorporate marker studies in controlled clinical trials of agents they are currently testing or expect to test in the near future. This would add the double power of being able to relate markers to disease progression and to disease responsiveness to treatment, and could make very large numbers of samples available to the Initiative. Consideration should be given to how this could be facilitated without threatening companies' internal interests in terms of the agents they are testing. For example, companies might be able to immediately release access to samples from placebo groups and wait until their drugs have been registered before releasing test group samples. Pharmaceutical companies are much better at organizing clinical studies than academic institutions, and the OA Initiative should seek to utilize their expertise.

An attendee indicated that before making a commitment to sponsor the OA Initiative, his company would need to review a detailed scientific proposal and organizational structure. It would be helpful if a timeline were laid out that contained a description of the activities that need to be accomplished to reach a stage of quantitative, not just qualitative, commitment. Another participant agreed that a concrete commitment from any organization would require clarification regarding the study design, what all of the parties will get out of the study, what the cost will be, and what the timelines are. Dr. McGowan responded that the draft RFP will contain the details of what the Initiative is soliciting. Accordingly, between now and May 2000, the goal is to incorporate input from this meeting into a plan that can be presented to the management of the respective organizations. The draft RFP will solicit public comment via posting on the NIH Web site, the responses to which will be used to fine-tune its contents.

A participant noted that it was her understanding that OA Initiative funding from sponsoring private-sector organizations would not necessarily be derived from a given organization's clinical budget. Rather, as a potentially tax-deductible contribution, it could come from elsewhere in the company. Dr. Downing observed that a number of company leaders had previously indicated that this mechanism offers certain strategies that do not compromise current product development lines, e.g., by treating the funding as a charitable contribution.

In response to an attendee's query about whether sponsors would contribute equally,
Dr. Downing noted that decisions about threshold financial commitments, payment levels, and utilization of resources had not been made and were still open for debate. Such decisions should be made collaboratively by the members of the consortium.

A participant pointed out the importance of an interface with experts doing OA-related basic research outside the Initiative. Consider the existing, retrospective databases of radiographs that are now deemed to be of little use in a new prospective study. As
Dr. Poole indicated earlier, the specialists developing and extending these databases do not have the resources to test them appropriately. It is important that the members of the consortium continue to assess what is happening in the field and make every effort to keep people engaged in related research "in the loop." The strength of the consortium should be used to support the development and evaluation of new techniques and, as appropriate, promptly incorporate them into the protocol. The way the study design is currently laid out, the relevant emphasis appears to be on tiers 1 and 2, to the detriment of the important work that could come out of tier 3. In the long run, keeping the work of these other researchers right up front may help the Initiative avoid important problems and save considerable money. Perhaps a ratio could be established that would determine how the funding should be split amongst the three tiers. With respect to the difference between studies targeting optimal methods for following disease course and therapy and studies associated with the discovery of mechanisms of disease, it was noted that although the Initiative could prove very useful to studies into mechanisms, the primary purpose of the OA Initiative is to enable more efficient clinical trials through the development and validation of new markers. These will also provide new tools for basic science research.

Dr. Peterfy noted that the proposed three-tiered structure is intended to both capture the most reliable techniques known today and provide a mechanism that incorporates new knowledge as it develops. Unfortunately, the three tiers come across as being ranked, although that was not the intent. Another attendee pointed out that this perception is influenced by the fact that dollar amounts could be roughly computed for tiers 1 and 2, whereas tier 3 is so exploratory and contains so many unknown dimensions that it is difficult to attach a dollar amount to it. She pointed out that the three tiers appear to be staged not in terms of time or priority but in terms of sample size.

Dr. Stevens indicated that a primary issue for tier 1 is that it has to be robust enough for each of the sites to be able to do the methodology. Tier 2 may have a subgroup of clinical sites. Although statistical power is needed, the sites involved in these studies will have the expertise required to carry out more difficult or demanding requirements. Tier 3 studies are expected to take place in sites that are excellent in a very specific area of interest and have the research methodology and equipment required to perform the work involved.

An attendee pointed out that the Initiative represents a blend of study and repository resources that is unique in that it will probably have genetic material as well as other biological specimens and images. In some organizations, this will raise issues with institutional review control boards, particularly when one has to go back and re-consent individuals for the materials provided and address the issues associated with anonymous versus nonanonymous approvals. The members of the consortium need to think about what techniques the Initiative seeks to achieve and how to ensure it obtains the information needed in a way that will avoid future problems with confidentiality, accessibility, and so forth.

A participant commented that the consortium can make a reasonable attempt to deal with current biomarkers that show promise without necessarily engaging the whole program of research proposed. The work could be accomplished in an incremental, cost-effective fashion designed to build confidence in systems. Organizational backup and support systems could also be developed through an incremental confidence-building approach that gradually tackles the issues mentioned by the previous speaker, issues that it would be disastrous to try to address now. This participant noted that the Medical Research Council, which is the equivalent of the NIH for the United Kingdom, has just called for proposals for genetic storage for disease process assessment. However, international boundaries pose a greater ethical dilemma, and at this stage it would not appear that a consortium like the OA Initiative should seek to store genetic material. Dr. McGowan pointed out that many of the people involved in the consortium have been involved in studies that store and use genetic material and know how to write a proper consent form and ensure that all appropriate checks and balances have been addressed. Another attendee noted that the genetic materials issue does have an impact on the Initiative's ability to use data from existing clinical trials and ongoing clinical trials sponsored by the private sector.

Adjournment

The first day of the meeting was adjourned. Open forums were held during the evening to obtain feedback and invite discussion on the proposals on biochemical markers, imaging, epidemiology, and administration.

February 29, 2000

Clinical End Points

Virginia Kraus, M.D., Assistant Professor, Division of Rheumatology, Department of Medicine, Duke University and session moderator welcomed the participants to the session and introduced Drs. Freund and Bellamy.

Perspectives on Clinical End Points for Osteoarthtitis

Deborah Freund, Ph.D., M.P.H.
Vice Chancellor and Provost
Office of Academic Affairs
Professor of Public Administration
Syracuse University
(Representing the Arthritis Foundation)

Dr. Freund pointed out that although she was nominated to participate in the meeting by the Arthritis Foundation, the content of her presentation is based on her experience as principal investigator of the patient outcome research team (PORT) on knee arthritis and knee replacement at Indiana University (see Heck, D.A., R. Robinson, C.M. Partridge, R. Lubitz, and D.A. Freund, "Patient Outcomes after Knee Replacement", Clinical Orthopaedics and Related Research, Vol 356, pp. 1-18, 1998).

Her presentation's major take-home messages are that:

  • There are relatively inexpensive clinical outcome measures that can be used to obtain outcome data for whatever type of study is utilized by the OA Initiative, e.g., a single cohort study, many cohort studies, or a clinical trial with cohort studies.

  • There are methods that can be used to retrospectively attach outcome data to currently ongoing open cohort studies, providing the opportunity to answer-at least in a crude way-outstanding questions on the prognostic value of physiologic and other types of biomarkers and outcomes, particularly in clinical settings.

The goal of the PORT initiative was to determine the role and effectiveness of knee replacement in the treatment of knee OA, what the clinical indications for knee replacement were, and patient outcomes. The data was obtained primarily from clinical settings and the number of cases at any one time ranged from 40,000 to 350,000 individuals.

The population selected was all beneficiaries of Medicare, a national insurance program for persons in the United States who are 65 years of age or older. The team targeted all Medicare reimbursed knee replacements from 1985 to 1990 and endeavored to identify a comparison or control group of nonoperated patients and claims. Dr. Freund noted that this is difficult to do but can be facilitated by treating claims data obtained from billable or nonbillable services as patient encounters. Inclusion and exclusion criteria can be identified for claims data in the same way they would be in a clinical trial, enabling the population of interest to be narrowed down, albeit crudely, on the basis of clinical parameters. Claims were used as a sampling frame and permission was requested to access medical records; the positive response rate to the request for medical records was 80 percent.

General health status information was collected with the SF-36 and clinical function, pain, and other data was collected with the WOMAC. For the OA Initiative, the instrument selected should be based on the ultimate goals of the studies and the hypotheses to be tested; however, it is generally preferable to use both. The study design should also consider the inclusion of short form 8, a mechanism for tracking function over time that can be completed in approximately 30 seconds.

Dr. Freund reported that the methodology utilized by this PORT initiative can be used to:

    • Follow a cohort of patients by identifying how much they are being treated, for what, and what the burden of disease is. For a clinical trial, patient records need to be attached.

    • Use clinical outcome surveys to relate the biomarker information collected for a sample of people in an existing cohort to selected health outcomes.

    • Obtain face validity by estimating the incidence of a given procedure and comparing it to the incidence of another. For example, the PORT study compared the incidence of osteotomy to incidence data on knee replacements within a population of claims.

    • Estimate at a national level the incidence of a variety of outcomes of interest, e.g., gastrointestinal bleeds .

    • Track general health and mental health.

    • Obtain mortality data.

    • Support adjunct studies.

On the basis of the PORT's research findings, Dr. Freund indicated that is it critical that the OA Initiative adequately incorporate the outcome measures of pain and function into its study design. The data for these measures can be obtained relatively easily and attached to virtually any type of study, allowing physiologic or other types of biomarkers to be correlated with final outcomes and other intermediate outcomes such as joint-space narrowing, measurements derived from MRI or PET scans, and so forth. Once a high correlation is identified, the Initiative will have a biomarker to compare with the most important factor, the prevention of disability.

Discussion

A participant noted that his institution had conducted a small, but similar, study of the hip that found that, while many persons initially said that their primary reason for seeking the intervention was pain, post-intervention they indicated that their primary reason was to engage in a particular activity such as playing golf. Dr. Freund agreed that people's expectations can be a moving target and change over time. However, patient expectations are a very important factor that should be assessed at baseline and over the period of a study, which allows changes in expectations to be assessed, anticipated, and adjusted for.

In response to a query on whether the study data had been compared to an age-matched non-OA population, Dr. Freund noted that no such comparison had been made because the study population consisted of people with OA who had progressed to a certain point.

An attendee asked what the percentage of patients with normal joint-space width was at the time of the intervention, and Dr. Freund responded that it was 20 to 30 percent of the patients. The attendee also asked if the microscopial appearance of the cartilage in the patients had been assessed at int