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Shared Vision

When thinking of a clinical trial in oncology – in any indication, for any type of cancer – one tends to focus on the ultimate clinical benefit to patients: prolonging overall survival. Some patients, though very few, may be cured from their cancer with a new drug; but for the majority, a new drug means a new chance to live better and hopefully longer with the persisting incurable disease.

Managing the disease and quality of life for patients is often the best goal achievable. Sponsors typically cannot afford to wait and extend a clinical oncology trial purely based on survival as an endpoint. By the time overall survival may have reached a statistical significance, other predictive surrogate endpoints are better suited to determine efficacy to either support a go/no-go decision or a licensing submission.

The term ‘surrogate endpoint’ is typically associated with blood-based biochemical, antigenic or hormonal markers such as CA-125, CA19-9 or prostate-specific antigen biomarkers. The consideration of imaging-based surrogate endpoints as biomarkers is often not obvious. These endpoints are ideal to speed up trials, underline safety and efficacy, and support clinical data for both internal decision-making or for submission to regulatory agencies.

Subtle yet decisive differences are inherent in imaging for early phase decision-making versus late phase regulatory submission, and sponsors typically do not have the necessary expertise in-house to conduct the imaging component of such trials themselves.

Definitive Biomarker

The current state of imaging in a biotech or pharmaceutical company with expertise in oncology rests on the implementable and affordable technology to deliver optimum business performance, with particular focus on the optimisation of usage of external expertise, especially imaging contract research organisations (IROs).

As Dr Peter Eggleton states: “Oncology drug development cannot do without imaging because it is an accepted and effective efficacy biomarker. Imaging supports and/or represents a decision point. As well as being the most definitive, it can also be the most cost-effective biomarker method. Imaging also generates intellectual property, provided the images are appropriately owned, and it can shorten clinical development by years” (1).

Imaging Methods

A mid-size to large pharma company usually has 25-100 studies going on simultaneously. It simply cannot afford to forego utilising approved imaging methods to evaluate efficacy. Imaging plays a vital role in oncology R&D today, encompassing a variety of technologies and applications inherent with standard imaging.

Conventional anatomic imaging in preclinical as well as clinical projects relies on computed tomography, magnetic resonance imaging (MRI), and to a lesser extent on plain X-rays. In early phase, and more so in preclinical development, specific tracer-based isotope scanning such as positron emission tomography (PET), single photon emission computed tomography (SPECT) and also functional MRI are reliable decision tools.

Innovative imaging markers are already used and reimbursed in the clinic, and more are in development. Currently, the following innovative techniques are already reimbursed:
  • Fluoro-deoxyglucose positron emission tomography (FDG-PET) in the US for lung, esophageal, colorectal, head and neck, brain, breast, thyroid, cervical, ovarian, pancreatic and testicular cancers, plus lymphoma, melanoma and soft tissue sarcomas
  • FDG-PET for all other cancer indications not previously specified
  • FDG-PET for myocardial viability, refractory seizures, dementia, neurodegenerative diseases, plus infection/inflammation
  • NaF-18 PET in the US, Canada and European Union for bone metastases imaging
Industry Expertise

Imaging in oncology plays a critical role in clinical development, supporting faster decision-making and registration. Most of its components are usually outsourced to IROs for development projects as imaging expertise is generally uncommon, disseminated and uncoordinated across organisations. Particular issues include:
  • Dedicated resources and imagingsavvy employees are extremely rare
  • Project teams often do not have a recognised internal expert team to which they can address their imaging related questions
  • Translational imaging studies are limited and highly challenging
  • A robust and validated IT infrastructure is typically not established. Imaging itself cannot be standardised, and images cannot be processed, stored or analysed in-house
  • Generally speaking, no in-house imaging development processes exist, and development projects have to be supported by IROs and academia
  • Development efficiency for both proof of efficacy and time to market will be under threat due to uncompetitive slow decision-making, and compromised by poor internal management of review processes and access to images and review data
  • Registration efficiency will be uncompetitive due to slower and costlier processes
Attempts by Big Pharma to establish large academic internal units and/or rely on major academic collaborations have met with mixed success. In any case, mid-size pharma and smaller players in the industry cannot spare resource for such functions; it is probably best allocated to identifying and establishing cross-functional teams to advise and manage outsourced projects.

Major reliance will need to remain on IROs to manage imaging in clinical studies, and management resource focused on IROs as informed sponsors. IROs have the expertise, the necessary staff and the IT-infrastructure to manage the added complexity, and they have well-established processes to manage huge volumes of image data and facilitate a truly independent review.

Main Functions

In oncology Phases 1 and 2, the main function of imaging is to support internal decision-making, which in turn is based on imaging endpoints. In oncology regulatory Phase 3, imaging is used both for primary endpoints and critical secondary endpoints.

The purposes of imaging in early phase are two-fold:
  • Exploratory: its use is to develop imaging biomarkers and then subsequently validate these as eligibility and efficacy surrogates. These have a high power and reduce the numbers of studies to replace clinical outcomes; they help increase sponsors’ efficiency by saving money to discontinue compounds early during development
  • Safety: the use of imaging outcomes as safety measures may give additional certainty to detect intervention-induced pathology, that otherwise may remain covered until more patients in a wider study are exposed
Phase Differences

Although similar, there are pivotal differences when comparing imaging in early and late phases. A few early phase sites, and multiple, mostly international, late phase sites pose a variety of complexities.

While in an early phase, the study team has close contact with academia in both clinical development and radiology expertise. The team is able to rely on this contact with all players to achieve the best imaging outcome; this is not possible in a late phase. Here, one needs to embed the study requirements into daily clinical and radiology routines, lacking any direct contact with the investigators and certainly to the radiologists, yet at the same time demanding equal, standardised, comparable imaging from all sites for all patients.

Risks and Benefits

Imaging in oncology will support faster decision-making and faster registration, although the return on investment cannot be guaranteed. There will be cancers that do not show the expected signal on images, and cancers in which imaging plays a subordinate role, such as cancers with a fast and high mortality.

There is a low risk that the desired imaging data is not always supportive for decision-making. There is a medium yet manageable risk that the imaging endpoint preferred may not always be accepted by regulatory authorities.

However, to not use imaging is a risk in itself – it means that sponsors are in a process of non-competitive drug development, proof of efficacy and time to market, and potentially unable to match what others can deliver. There could be lost opportunities with missing biomarkers, and the adverse impact of loss of quality and investments.

The risk involved in relying on sites’ imaging results alone is difficult to quantify. Of course, each investigator will claim that the assessments made on images and the outcomes are unbiased, that the assessment criteria are followed accurately, and that all deviations and rules are adhered to. Side-effects or typical treatment reactions often help circumvent the blinding to treatment arm. Independent central review results can only be accurate and unbiased. Site-central discordance rates are a fact and are always present.

Established Processes

Imaging provides extra levels of quality and security – and shows reliable and reproducible results. Its benefits are reflected in the fact that today imaging-based biomarkers are no longer exotic but well-established. Expertise resides not within pharma and biotech companies but within IROs, where companies are able to engage their experts early on during study and protocol development. Imaging does add complexity, yet IROs have well-established processes and the expertise to take that burden away from sponsors.

Prolonged overall survival is the ultimate endpoint in any oncology study, but survival after completion of treatment is dependent on many different factors. Patients may enter other studies, or receive supportive treatments or alternative therapies that may or may not impact the duration of living with the cancer. As such, the pure endpoint – overall survival – in itself is not so pure; it is tainted with whatever addon treatment each patient might receive after ending treatment on your study.

Reference
1. Eggleton S, Analysis of problems experienced by pharmaceutical companies handling oncology imaging, Imaging in Cancer Drug Development, March 2012



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Dr Oliver Bohnsack is Senior Director of Medical Affairs for Perceptive Informatics, a technology subsidiary of PAREXEL International Corporation, and Head of Oncology and Medical Relations in Europe. Throughout his career with Perceptive, he has led and managed the imaging component of more than 200 clinical trials. A Board Certified Radiologist, Oliver gained an MBA in Healthcare Management from the University of California, Irvine and has a PhD in Radiology, Radiation Modulation and Reduction from the University of Munich.
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