Accelerating Drug Development with Today’s Innovation in Imaging
Imaging biomarkers play an important role in early and late-phase clinical trials. The importance of imaging endpoints in clinical trials is reflected by specific FDA guidance to industry published April 2018.
Generally, biomarkers are used in trials to support the rationale of therapeutic intervention and to enable objective decisions in the drug development process.
For specific indications, imaging techniques such as MRI, CT, PET provide specific biomarkers for to support patient stratification, to inform trial protocol and trial design, to provide information for modelling of pharmacokinetics and pharmacodynamics and to predict drug response early.
Most importantly, as we often deal with drug combinations and advanced therapies, the imaging allows reliably and non-invasively monitor short-, mid- and long-term therapeutic outcomes.
Which imaging biomarker to use in your trial will depend on which question needs to be answered. Read more about particular therapeutic areas and the relevant biomarkers.
In early drug development phases, imaging is needed to answer specific questions around whether the new drug candidate reaches the target and, if so, in sufficient quantity or whether the expected mechanism of action can be observed.
When a research project is at the pre-clinical stage, there is a number of tools which can be used to address these questions, assess biological processes and take greater safety risks, including novel tracers for PET/SPECT, invasive techniques and others.
Imaging plays a critical role when it comes to translating pre-clinical biomarkers into clinical procedures.
A number of innovative methodologies, including those based on AI and Machine Learning have been used in trial. Finding the right imaging biomarker will allow for much faster assessment of therapeutic efficacy of a new treatment and making early go / no go decisions.
As it on average takes 15 years to take a drug from the lab to approval, more information on the efficacy, safety and mechanism of action should be sought from early-stage clinical trials to minimize late-stage attrition. The use of imaging biomarkers allows making objective decisions on the new drug safety and efficacy sooner, thus reducing overall R&D timelines and costs through effective early phase trials.
The use of imaging biomarkers and surrogate endpoints can facilitate small group sizes, quick results and good statistical power, when assessing new drug efficacy. Imaging can reveal small, subtle changes indicative of incremental progression or regression that might be missed with traditional approaches.
Imaging can also help to detect early disease and define stratified study groups. Imaging can be used to separate -as early as possible responders from non-responders in patients undergoing therapeutic intervention. Imaging biomarkers are more objective and faster to measure.
When planning a trial, one must make critical choices on whether to use imaging as a surrogate endpoint and how to link imaging based and clinical outcomes.
Selected Published Examples of Strategic Use of Imaging in Clinical Studies
At relatively small additional cost, imaging can offer the sensitivity required to monitor drug distribution and pharmacokinetics (PK) and to image specific molecular endpoints. PET has been applied to a wide number of drugs to demonstrate activity in vivo, from standard chemotherapy to combination therapies addressing tumour angiogenesis and antivascularity.
An example of the development of 18F-labeled antifungal agent fluconazole (Diflucan, Pfizer) was monitored by PET to establish the concentration of the drug in different organs, particularly at the site of infection. The imaging study found that the observed concentrations compared favorably to the concentrations required to inhibit in vitro pathogen growth.
MRI can also be used to evaluate dosing regimens in conditions such as multiple sclerosis (MS), infliximab (Remicade, Centocor) for psoriatic arthritis, and PTK787 for colorectal cancer.
Yi-Xiang Wang and Min Deng, Medical imaging in new drug clinical development, J Thorac Dis. 2010 Dec; 2(4): 245–252
Pien HH, Fischman AJ, Thrall JH, Sorensen AG. Using imaging biomarkers to accelerate drug development and clinical trials. Drug Discov Today. 2005;10:259–66.
Alpert NM, Babich JW, Rubin RH. The role of positron emission tomography in pharmacokinetic analysis. Drug Metab Rev. 1997;29:923–56.
Aboagye EO, Price P. Use of positron emission tomography in anticancer drug development. Invest New Drugs. 2003;21:169–81.
Mamo D, Sedman E, Tillner J, Sellers EM, Romach MK, Kapur S. EMD 281014, a specific and potent 5HT2 antagonist in humans: a dose-finding PET study. Psychopharmacology (Berl) 2004;175:382–8.
Bergström M, Grahnén A, Långström B. Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development. Eur J Clin Pharmacol. 2003;59:357–66.
- Fischman AJ, Alpert NM, Livni E, Ray S, Sinclair I, Callahan RJ, et al. Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography. Antimicrob. Agents Chemother. 1993;37:1270–7.
Drug Efficacy Studies
The application of imaging in efficacy trials involves the assessment of the structural disease related manifestations that can be visualized and quantified with a selected imaging modality; these should ideally correlate to patient symptoms and long term outcomes.
An example cited in the recent review (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256476/) is the development of Etanercept (Amgen) for the treatment of rheumatoid arthritis. When examining the potential for etanercept as a first-line treatment, early trials used two sets of criteria: (i) American College of Rheumatology (ACR) scores, which use a combination of subjective pain and function assessments, in addition to serum C-reactive protein levels; and (ii) conventional radiography images of joint-space narrowing and erosion. Whereas clinical scoring showed no significant difference between etanercept and methotrexate (the standard therapy at the time), the imaging-based erosion score showed statistically significant differences.
On the basis of these data, the FDA granted Immunex marketing approval with the condition that additional supporting data be collected. A subsequent study showed etanercept achieved sustained improvements over methotrexate in terms of both clinical and imaging scores.
In another therapeutic areas, the Alzheimer’s disease, the current gold standard comprises behavioural or cognitive measures, but these suffer from poor reliability. MRI measurement of whole brain or hippocampal atrophy rate can be used to support clinical outcome measures in therapeutic trials for Alzheimer’s disease, and functional brain activity can be objectively quantified by measuring regional glucose metabolism with PET. With clinical trials for MS, there has been great reliance on imaging data, especially using T2-MRI lesion burdens, and the number of contrast-enhancing lesions. These imaging biomarkers can serve as primary outcome measure in Phase I and Phase II trials, and also can serve as secondary outcome in Phase III trials. Other examples of early bioactivity assessment include MRI and CT for examining ischemic stroke and imaging assessment of cardiovascular disease, referenced below.
- Yi-Xiang Wang and Min Deng, Medical imaging in new drug clinical development, J Thorac Dis. 2010 Dec; 2(4): 245–252
- Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586–93.
- Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443–50.
- Jack CR Jr, Slomkowski M, Gracon S, Hoover TM, Felmlee JP, Stewart K, et al. MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. 2003;60:253–60.
- Matthews B, Siemers ER, Mozley PD. Imaging-based measures of disease progression in clinical trials of diseasemodifying drugs for Alzheimer disease. Am J Geriatr Psychiatry. 2003;11:146–59.
- Cummings JL. Alzheimer’s disease. N Engl J Med. 2004;351:56–67.
- McFarland HF, Barkhof F, Antel J, Miller DH. The role of MRI as a surrogate outcome measure in multiple sclerosis. Mult Scler. 2002;8:40–51.
- Frank JA, Richert N, Bash C, Stone L, Calabresi PA, Lewis B, et al. Interferon-beta-1b slows progression of atrophy in RRMS: Three-year follow-up in NAb- and NAb+ patients. 2004;62:719–25.
- Rao AB, Richert N, Howard T, Lewis BK, Bash CN, McFarland HF, et al. Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFNbeta-1b. 2002;59:688–94.
- Provenzale JM, Jahan R, Naidich TP, Fox AJ. Assessment of the patient with hyperacute stroke: imaging and therapy. 2003;229:347–59.
- Wu O, Koroshetz WJ, Ostergaard L, Buonanno FS, Copen WA, Gonzalez RG, et al. Predicting tissue outcome in acute human cerebral ischemia using combined diffusion-and perfusion-weighted MR imaging. 2001;32:933–42.
About IAG, Image Analysis Group
At IAG, we leverage 10 years of expertise in advanced image analysis, global footprint and many imaging methodologies, which have been used in ph I/II-III trials to accelerate and to support drug development, to de-risk trial execution and to ensure integrity and scientific credibility of your data. Our study teams, led by experienced project managers and equipped with DYNAMIKA’s single-view reporting of the information will closely work with biotech management on the execution of the trial.