The use of surrogate markers to accelerate development time-lines

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1 The use of surrogate markers to accelerate development time-lines Four case studies reflect the importance of technique, precision and interpretation when choosing and applying surrogate markers in clinical drug development. Dr Kenneth Faulkner and Dr Charles Peterfy, Synarc Figure 1. Successful pharmaceutical research requires both a rich product pipeline and an efficient development process. This applies to both preclinical and clinical development. During the preclinical phase, it is essential to rapidly identify those products that have the greatest promise for future development. During the clinical development phase, efficient procedures are required to show both safety and efficacy, allowing rapid decisions to be made as to whether to discontinue or pursue regulatory approval. Surrogate validity - use of a surrogate end-point assumes that the designated biomarker lies directly along the disease pathway to the true outcome of interest. To be useful in therapeutic trials, the surrogate must also lie on the intervention pathway. Alternative mechanisms of disease or therapy that bypass this biomarker undermine its validity as a surrogate end-point. Efficient drug development is often hampered by a lack of easily measured outcomes. For example, in diseases such as osteoporosis and arthritis, the primary clinical outcomes of bone loss, fractures and joint degradation are slowly-progressing and difficult to measure. Research targeted at directly assessing these end-points requires studies of many years duration. From the preclinical perspective, suitable cellular or animal models are often inadequate at predicting clinical outcomes. Ultimately, it is in the best interests of both patient care and drug development that more efficient methods for assessing drug efficacy are developed. For many situations where direct clinical outcomes are difficult to measure, surrogate markers of clinical response are used. Examples of surrogate end-points include blood and urine tests, radiological imaging results and patho-histological findings related to a disease process. These morphological, compositional or process-related markers act as substitutes for the ultimate clinical outcomes, which measure directly how a patient feels, functions, or survives. Implicit in this model is the assumption that changes in the marker are related to the true clinical outcome of interest. Furthermore, it is assumed that any observed change in surrogate marker associated with therapy will lead to a commensurate change in the desired clinical outcome. This model is valid only if there are no alternate pathways for disease progression or therapeutic mechanisms that bypass the surrogate end-point being measured (Figure 1). This is not 130 Innovations in Pharmaceutical Technology

2 Efficient drug development is often hampered by a lack of easily measured outcomes Figure 2. Multiple disease pathways in osteoarthritis call for a whole-organ view of joint integrity. The structural determinants of pain and mechanical dysfunction in osteoarthritis are not well understood, but probably involve a multitude of interactive pathways. Accordingly, osteoarthritis is best modeled as a disease of organ failure. The current practice of monitoring only a few of these features (usually joint-space narrowing and osteophytes) therefore provides only a key-hole view of the disease process and limits the surrogate validity of such assessments. A broader panel of imaging markers - that is, a whole-organ evaluation - may be needed to properly appraise structural integrity in osteoarthritis. always the case, and numerous counter-examples (for example, the Cardiac Arrhythmia Suppression Trials) have recently been reported in which the surrogate end-point failed to register either adverse or beneficial effects on the clinical outcome. In contrast to the simple scheme shown in Figure 1, the reality for most diseases is much more complex. Consider the example of osteoarthritis with multiple interactive pathways leading to pain and joint dysfunction (Figure 2). Currently the evaluation of osteoarthritis focuses on only a few of the features of the disease, such as osteophyte formation and radiographic joint space narrowing. Despite awareness of the many alternative mechanisms at play in this complex disease, the commonly accepted and available technologies limit assessment to those features of the disease visible with standard radiography. The situation is analogous to a person searching for a lost set of keys at night under a street lamp. A passer-by approaches and asks if they can help in the search. The person searching answers, Yes, I lost a set of keys just outside my house. The passer-by responds, If you lost them by your house, why are you looking here? to which the person replies Well, the light is much better here. Many times in pharmaceutical development, it is necessary to look at those areas where the light is good, and not necessarily at the place where the effect is greatest. Many clinical outcomes are subjective in nature. For example, arthritis studies often use pain as a primary measure of efficacy. While relieving pain is clearly desirable, it is essential that the pathological process initiating the pain be corrected as well. Taking analgesics for a tumour will relieve the symptoms for a time, but it will not alter the the underlying neoplasia. The majority of osteoarthritis therapies target only the pain associated with the joint degradation, and do little if anything to modify disease progression. The search for disease-modifying compounds for the treatment of osteoarthritis represents an active area of research. Surrogate markers show the greatest clinical utility when they are objectively assessed and not subject to individual patient or physician interpretation. For example, blood tests and x-ray images can provide objective end-points which can greatly reduce (and often eliminate) observational bias. However, it is essential that the method used to measure the markers is technically valid and properly applied. Thus, biochemical markers need to be assayed with proper techniques and adequate quality control. Likewise, radiographic images need to be acquired using proper positioning and radiographic techniques, and evaluated by readers with adequate experience and training, and appropriate image analysis tools. In addition to technical and clinical validity, the amount of time necessary for a marker to show change in response to disease or therapy is an important metric of performance (Table 1). Marker responsiveness will determine the minimum Surrogate markers show the greatest clinical utility when they are objectively assessed and not subject to individual patient or physician interpretation Innovations in Pharmaceutical Technology 131

3 Through the use of appropriate surrogate markers of response and safety, development time-lines can be greatly accelerated... for a drug with $400 million per year of patent-life sales, each day of development time saved corresponds to $1 million in additional revenue Validity markers must also be (technical/clinical) precise. Measurement precision determines Responsiveness to Disease / Therapy the magnitude of change that can be Measurement Precision (sensitivity to change) resolved with confidence. Precision error can be viewed as the noise in Biological Variation Image Acquisition Process Measurement Process the signal-to-noise ratio. A surrogate marker Central Reading/Analysis may deliver a superior signal (that is, responsiveness), but may have Convenience a very high noise level Cost (that is, precision error). The combination of responsiveness and Table 1. Metrics of performance for surrogate markers. precision ultimately determines the utility of any surrogate marker. Sources of precision error include individual variation, instability of methods used to acquire the marker (such as radiographic technique or serum collection and storage procedures) and errors stemming from the application of the measurement method. In order to maximise precision in multi-centre clinical trials, it is essential to standardise acquisition methods, and provide centralised data management and analysis methods. This includes the use of trained readers and automated processing tools. While this type of centralised analysis is often not feasible in clinical practice, it is necessary for interventional and observational studies, where increased precision can reduce both the study duration and sample size required to test a hypothesis. Minimal investment in centralised analysis techniques during drug development can greatly reduce development costs and increase study power. Reduced costs - combined with shortened development times - can have a significant impact on the development budget and the time required to bring a drug to the market. Presented below are four individual case studies which reflect the importance of technique, precision and interpretation when choosing and applying surrogate markers. follow-up time needed for demonstrating either disease progression or treatment efficacy. Take as an example the field of osteoporosis research. The current clinically accepted end-points for osteoporosis studies are changes in bone density and prevention of fracture. Fracture studies are difficult and expensive to perform, requiring many thousands of patients to demonstrate significant effects. Whenever possible, bone mineral density is used as a surrogate of bone strength and therapeutic response. However, even bone density measurements require at least a year - and often several years - to show significant effects, even in large groups of patients. Recent advances in biochemical markers of bone turnover have enabled detection of therapeutic response in months rather than years. Highly responsive surrogate markers are not only important in clinical development but also in clinical practice. They can be used to identify patients who are failing therapy and may require dosage adjustments or a change to a different - hopefully more effective - treatment. Yet, long before surrogate markers are incorporated into clinical practice, they are typically proven during the early clinical testing of new drugs. Through the use of appropriate surrogate markers of response and safety, development time-lines can be greatly accelerated. There is an enormous financial incentive to use surrogate markers to accelerate drug development. For slowly-progressing diseases, such as osteoarthritis and osteoporosis, the formal clinical testing regulatory process can consume as much as half of the 17-year patent life of a compound. After patent expiry, generic equivalents typically capture 80 per cent of the market. Thus, for a drug with $400 million per year of patent-life sales, each day of development timesaved corresponds to $1 million in additional revenue. In addition to responsiveness, useful surrogate Case study 1: Assessing joint damage in rheumatoid arthritis - the importance of using proper technology This study, taken from the field of rheumatoid arthritis (Figure 3), illustrates the importance of proper technique when using surrogate markers. In this case, the surrogate end-point is bone erosion. This is typically monitored using conventional radiography. However, in the example provided, radiography fails to demonstrate a large erosion in the scaphoid bone of the wrist of a patient with long-standing rheumatoid arthritis. By contrast, 132 Innovations in Pharmaceutical Technology

4 A Figure 3. A Figure 4. B Imaging bone erosions in rheumatoid arthritis. a) Conventional radiograph of the wrist of a patient with rheumatoid arthritis shows no clear evidence of erosion in the scaphoid bone. b) Conventional MRI (coronal, T1-weighted spin-echo) image of the same wrist sharply delineates a large erosion in the distal pole of the scaphoid. conventional MRI clearly delineates the erosion in this same bone. The enhanced sensitivity of MRI in this example is attributable to its tomographic viewing perspective. Radiography is a projectional technique that casts a two-dimensional shadow of a three-dimensional anatomy onto flat sheets of film. This results in the superimposition of overlying structures that can obscure even large morphological abnormalities. B Imaging cartilage thickness in osteoarthritis with radiography. a) Conventional radiograph of the knee shows a wide lateral joint space consistent with ample femoro-tibial articular cartilage. b) Repeat radiograph of the same knee following slight flexion shows obliteration of the lateral joint space indicative of an absence of articular cartilage. This illustrates the importance of reproducible position in serial radiography of the knee for monitoring joint-space width as a measure of cartilage thickness. By contrast, MRI takes serial cross-sectional images through the anatomy, thereby obviating superimposition and making it easier to detect small structural irregularities. Greater sensitivity for bone erosions can be leveraged in clinical trials to reduce the number of patients and clinical sites required to test efficacy. More importantly, greater sensitivity to change can reduce study-duration and facilitate decision-making by providing an early read-out on progression of erosive disease. Case study 2: Assessing cartilage thickness in osteoarthritis - the importance of using a proper imaging technique This study, taken from the field of osteoarthritis (Figure 4), illustrates the importance of proper positioning of the knee in evaluating cartilage thickness in patients with osteoarthritis using radiography. Because conventional radiography cannot directly visualise the hyaline cartilage, the distance between the articular corteces of the femur and tibia is taken as an indirect measure of cartilage thickness in the knee. This approach, however, only samples the small region where the two cartilage plates are in direct contact and perfectly tangent to the x-ray beam. The degree of flexion of the knee determines which region of femur articulates with the tibia, and therefore the portion of cartilage included in the joint space. Since cartilage loss in osteoarthritis tends to be uneven across articular surfaces, knee flexion can have a profound influence on joint-space width. In the example provided, the initial radiograph shows ample joint space in the lateral femoro-tibial compartment. However, a second radiograph acquired only minutes later with slightly greater flexion shows complete obliteration of the lateral joint space and bone-on-bone contact. This illustrates how acquisition-sensitive radiography of the knee truly is, and underscores the importance of standardising and meticulously controlling serial imaging of the knee in clinical trials of osteoarthritis. Case study 3: Evaluating bone density changes - the importance of precision error and measurement signal This case study is borrowed from the field of osteoporosis. Typically, osteoporosis trials employ either fracture or bone mineral density as the clinical end-points of efficacy and safety. However, to produce significant differences between treatment and control groups in bone density or fracture rate requires many years of observation. By contrast, biochemical markers of bone turnover can detect meaningful changes as a result of therapy within several months. Figure 5 shows the typical time-course of bone density and biochemical 134 Innovations in Pharmaceutical Technology

5 Figure 5. Relative effects of different doses of a bone anti-resorptive compound on bone resorption and bone mineral density (BMD). The resorption marker, though less precise than BMD, shows a significant treatment effect in a few months as a result of the large signal. markers of bone turnover in a controlled interventional trial of an anti-resorptive treatment of osteoporosis. It can be seen that at least a year is required in order to demonstrate significant bone density differences between the treatment and control groups, even though the bone density measurements are extremely precise. The enhanced precision of the measurement is negated to some degree by the minimal changes in bone density, which are only a few per cent per year. Biochemical markers of bone turnover respond much more rapidly to anti-resorptive therapy than bone density measurements. The observed change in turnover markers is relatively large (50-70 per cent), representing 2-3 times the precision error of the measurement. Thus, despite the larger precision error of the biochemical marker measurement, the ability to detect change (or the signal-to-noise ratio) allows the biochemical markers of bone turnover to provide significant results within a few months. It should be noted, however, that these levels of precision and response require strict quality control and appropriate centralised analysis methods. Without proper control procedures, the "precision error" of the "biochemical error" can increase significantly. Case study 4: Bone densitometry - the importance of centralised evaluation and instrument quality control This study is taken from a multi-centre trial in osteoporosis with a bone density end-point. Bone density measurements were attained at various clinical sites involved in the study. Measurements were first analysed locally and then re-analysed centrally by expert readers. Prior to the centralised analysis, the data obtained by the highly variable centres were producing conflicting and statistically deviant results. Both inconsistent analysis techniques and machine performance drifts can cause these variations. To obtain meaningful results, it is essential to have well-defined analysis procedures performed by experienced and trained personnel, particularly in the case where the expected changes are of the same order as the precision error of the technique (as is usually the case for bone density in osteoporosis). Figure 6 shows a set of bone density measurements from the same patient acquired 3 1 /2 years apart. Based on the local analysis of these images, there was a significant variation in the placement of the various regions of interest. Using centralised analysis by an expert reviewer, the region placement was more carefully replicated, such that any observed change could be attributed to the intervention, and not to variability in the analysis technique. Conclusion The use of surrogate markers is essential to efficient drug development. However, it is vital that Innovations in Pharmaceutical Technology 135

6 Biochemical markers of bone turnover respond much more rapidly to anti-resorptive therapy than bone density measurements Baseline: Dec 23, 1992 Follow-up: April 15, 1996 Figure 6. Baseline and follow-up bone mineral density (BMD) measurements of the proximal femur using DXA. Variations in region of interest placement, as well as sclerotic changes in the femoral neck, prevent accurate and precise assessments of BMD.... it is vital that surrogate markers be properly chosen for their ability to predict relevant clinical outcomes in a timely and precise fashion surrogate markers be properly chosen for their ability to predict relevant clinical outcomes in a timely and precise fashion. Surrogate markers must, therefore, be properly validated and appropriately applied in order to ensure that they deliver optimum signal with minimum precision error. Through the choice of proper surrogate markers, clinical and preclinical development timelines can be significantly reduced, resulting in more rapid development decisions and streamlined review by regulatory agencies. Dr Kenneth Faulkner received his PhD from the University of California, Berkeley and San Francisco. He was a faculty member of the Department of Radiology at the University of California, San Francisco, for several years before relocating to Portland, Oregon, in He worked at the Oregon Osteoporosis Center for six years, where he directed the bone densitometry central laboratory. In 1998, the Oregon Osteoporosis Center central laboratory joined with four other research units in San Francisco, Denmark, France, and Germany to create Synarc, an organisation supporting pharmaceutical research in osteoporosis, arthritis and other diseases. Dr Faulkner currently directs the osteoporosis research for Synarc, and oversees the development of pharmaceutical research for the North American region. Dr Charles Peterfy is a founding member of Synarc Inc, and currently serves as the company s Chief Science Officer and Executive Vice President. He is a board-certified radiologist, a biochemical pharmacologist and a faculty member in the Department of Radiology at the University of California, San Francisco. For seven years, he served as a clinical radiologist and Director of Arthritis Research for the Osteoporosis and Arthritis Research Group. Dr Peterfy received both his MD and a PhD in pharmacology and therapeutics from McGill University, Montreal, Canada. He is an internationally-recognised researcher in the field of musculoskeletal imaging, and has developed many of the imaging techniques and surrogate end-points that are currently used by the pharmaceutical, biotechnology and medical devices industries in Phase II and Phase III clinical trials. He has published more than 50 articles and 20 book chapters, has edited two books and serves as a reviewer for 11 scientific journals in rheumatology and radiology. 136 Innovations in Pharmaceutical Technology