While the US Food and Drug Administration (FDA) encourages sponsors to submit imaging data as digital files rather than hard-copy films, there currently are no regulations governing what images should be incorporated into a New Drug Application (NDA) or Biologic Licensing Application (BLA), or how the images should be prepared and made available for FDA review. Each reviewing division at the FDA has the flexibility to determine the imaging content, format, and technology for a specific submission. Because there are numerous options for presenting digital images and their accompanying documentation, early dialogue with the reviewing division is absolutely vital to develop an appropriate imaging submission strategy for each NDA/BLA. Without this consultation, sponsors run the risk of delaying the review process—a result that no pharmaceutical company can afford in this era of rapidly increasing development costs and intense global competition.

Despite the challenges, sponsors can reap the benefits of electronic medical imaging submissions—while avoiding the pitfalls—by leveraging the right combination of technical and regulatory resources that allows them to respond quickly and flexibly to specific FDA requirements.

Working with the FDA

Successful utilization of medical imaging technology to support an NDA/BLA requires that sponsors work closely with the FDA during the presubmission period. The requirements for electronic medical images to support an NDA/BLA are determined by the FDA division that will review the regulatory submission: the Center for Drug Evaluation and Research (CDER), for drug products; or the Center for Biologics Evaluation and Research (CBER), for biological products. If the reviewing division decides that an imaging database should be included in a regulatory submission, it will determine the content, format, and presentation requirements for the images. It will also designate what supporting data and documentation will be required (see Figure 1).

Because the requirements for the types of images and image review systems can vary for each submission—based on the nature of therapy being developed, the targeted indication, and the type of images that were collected—the FDA makes its determination about imaging data in consultation with the sponsor. Although the Agency has invested in some imaging review technologies, much of the software tools and hardware the Agency uses to analyze medical images are supplied by the sponsor submitting the data, so the parties must agree on what approach will provide the division with the most appropriate resources to review the imaging information thoroughly, efficiently, and fairly.

To accommodate this consultative process, sponsors should begin working with Agency personnel well in advance of preparing an NDA/BLA to develop an acceptable imaging plan. A typical consultation between the Agency and the sponsor on imaging requirements would involve a teleconference that takes place at least 6 to 8 months before the sponsor anticipates submitting the NDA/BLA. With the multiple options available for electronic image submissions, this early dialogue is essential to allow adequate time for discussion, planning, and interim review of the electronic imaging review system. The 6-to-8-month time frame usually falls within the pre-NDA/BLA period following the end of the clinical trials, but might also occur while later-stage trials are still under way.

Medical imaging documentation commonly submitted with an NDA/BLA.

  • Imaging Charter
  • Investigator Site Manual
  • Imaging Acquisition Guidelines
  • Query Tool User Guide (if applicable)
  • Image Analysis Software User Guide
  • Independent Reviewer Training Manual
  • List of Missing/Unreviewed Scans

Figure 1

Often, a sponsor partners with an outside company offering specific medical imaging expertise to develop the imaging protocols and gather the imaging data for a trial. If that is the case, the sponsor should consult with that company in advance of the initial teleconference with the FDA to help prepare questions for the meeting and provide information on the imaging modalities used in the trial.

Once the framework for the imaging data submission is agreed upon, the imaging database and analysis functions are developed. The system usually includes the same image analysis software used by the independent imaging reviewers during the study. Within 3 to 4 months of the submission date, the sponsor typically arranges a demonstration for the reviewing division of the user interface that has been developed based on the preferences discussed during the initial teleconference. This advance demonstration allows Agency reviewers to provide additional feedback as necessary to fine-tune the imaging approach, and gives the sponsor time to make any required changes and perform a final validation of the imaging system.

At the time the NDA/BLA is submitted, the sponsor or its imaging partner delivers a tested and validated image viewing system and database to the location designated by the reviewing division. Personnel familiar with the system—from either the sponsor or the imaging partner—should be available during the installation, and throughout the review period, to provide any needed training or ongoing support that will maximize the usability of the system for the reviewing division. It may also be helpful for the sponsor to have a “mirror” system to the one supplied to the Agency, so the sponsor has immediate access to the same data and equipment being used by the reviewing division if questions should arise.

By following this process of early discussion, consensus, review, and support, a sponsor can be more confident that the needs of the Agency are clearly understood, and that the expectations of the reviewers are achieved. By the time the system is delivered, Agency personnel are familiar with the imaging approach and the equipment, which should greatly reduce delays during the submission and review process.

Understanding the Options for Imaging Submissions

At one time, the FDA preferred images submitted on CD-ROM, but parameters have changed.

While the process of consulting with the FDA to develop an imaging plan is relatively straightforward, the technical and logistical issues that must be addressed to create an effective electronic imaging submission remain challenging. In the absence of comprehensive imaging standards, sponsors must weigh a variety of options in determining how to organize and present the necessary imaging data in a way that accurately presents the results of the studies and meets the needs of the FDA reviewers.

Historically, pivotal imaging data from clinical trials was submitted to the FDA in the form of hard-copy films. In recent years, however, the FDA has clearly stated to the biopharmaceutical industry that it prefers submissions with electronic/digital images rather than film. The issues surrounding hard-copy film include both the sheer volume of the thousands of films that might be included with a typical submission, and the difficulty reviewers have in quickly accessing a particular set of films. There may be occasional circumstances where an NDA/BLA will still include hard-copy films, but electronic images are the preferred format for FDA submissions.

Although electronic images are now the norm at the FDA, there are several important variables that sponsors must consider when developing an imaging submission strategy.

Diagnostic images must be either uncompressed or in a compressed form that maintains full resolution with no data loss. The result is large files that require significant electronic storage space. At one time, the FDA preferred images submitted on CD-ROM. However, the advent of increasingly larger clinical trials produced growing volumes of data that required hundreds of CDs to accommodate the study images. High-capacity data storage drives, which allow large volumes of data storage in a small space, are increasingly common for submitting images from large pivotal trials. If such a drive is used, it must be compatible with the imaging review workstations specified for the submission by the FDA reviewing division.

For some submissions, the FDA may want to perform its own ad hoc analysis of the images. In several recent cases, for example, the FDA has contracted with academic radiologists to perform a repeat central analysis on a subset of images. If the reviewing division requests this option, the sponsor or its imaging partner must be able to provide the Agency with the same tools used during the original analysis of the images, including a licensed copy of the image analysis software. It is also important for the sponsor to provide the Agency with training on the use of the software, as well as ongoing support as required.

Hard-copy film is rarely used for submissions today, as it is difficult for reviewers to quickly access a particular set of films.

If the FDA requires only a small subset of the study images to be included in the submission, the sponsor may supply image data for a manual review by the agency. In those cases, the sponsor or imaging partner would provide electronic copies of the requested images on digital media (such as a CD, DVD, or removable drive) along with a copy of the image analysis software used during the independent medical imaging review. The Agency may also request that the electronic image files contain the measurements from the independent review. This type of electronic image submission is appropriate if the reviewing division does not require the ability to manipulate or interrogate the independent image analysis data.

A complex clinical trial may include hundreds of patient visits that require the collection of images, resulting in thousands of individual images for a single study. Sorting through such a large volume of images can be time-consuming and burdensome to Agency reviewers, which in turn may increase review times. To address this issue, the Agency has in many cases expressed a preference for an “Image Browser” interface for the imaging database—a tool that allows reviewers to select an individual subject from a list of patient identification numbers, then quickly open all of the images for that patient. Upon selecting the subject, the reviewer may easily launch all of the images for that patient. While this tool, called an Image Timepoint Patient Browser, makes it simple to launch and view images, it does not have the ability to display image analysis data. In addition, it does not allow the sorting or filtering of any image-related data (such as sites, patients, response criteria, or independent reviewers). This tool is most useful when the FDA reviewing division has requested a limited image submission.

For projects with a large number of patient visits, some FDA reviewers have expressed a preference for a more powerful software tool that provides the ability to sort, filter, and interrogate the data associated with the images—ie, the analysis results—as a way to facilitate the imaging review process. Examples of typical functionality provided by such an Image Data Query Tool would be the ability to sort patients by response criteria, by independent reviewer, or by patients showing the most change over time, as well as the ability to display the electronic case report forms (eCRFs) completed by the independent imaging reviewers. For maximum functionality and ease of use, the Image Data Query Tool should be integrated with the Image Patient Timepoint Browser.

Getting Technical

During the pre-NDA/BLA consultation between the sponsor and the FDA about the imaging data requirements, several key imaging technology questions that have a significant impact on the complexity of the submission must be answered. One of the first issues to be addressed is whether the reviewing division has a particular set of guidelines for the imaging data that it wants to apply to the submission. Although the existing guidelines are not definitive, the FDA has published specifications for the image review technologies in which they have invested, and may request that the sponsor provide the imaging data in a compatible format.

Another major question concerns the scope of the imaging data to be included in the submission—whether the reviewing division wants to receive the complete image database, a specific subset of the images (such as responders), or imaging datasets provided on an “as requested” basis. If a transfer of a complete image set is requested, an Image Data Query Tool is usually developed and included with the submission to allow for image querying based on a variety of criteria that can be defined by the reviewer. The query tool can also support the launching of associated analysis data, as well as provide auto launching of images with or without independent reviewer assessments. For submissions requiring a subset image database or an “as requested” capability, an Image Timepoint Patient Browser is usually sufficient to support the division’s image review. The discussions will also pinpoint the specific criteria to be used to define the subset of data to be submitted, and address issues such as whether the Agency wants to view the images with or without the independent reviewer measurements.

A third important issue that must be resolved is the type of review imaging hardware that the division would prefer—for example, whether it will be a freestanding system supplied by the sponsor, or a system that will be used in conjunction with an existing Agency workstation. A system capable of supporting high-resolution (1280 x 1024) monitors is usually recommended to provide the required level of detail and ease of viewing. Workstations with the same capabilities as those used by the independent imaging reviewers are preferable. In addition, a sponsor typically offers to provide the same analysis software used by the independent reviewers on the system to be used by the Agency. A demonstration of a beta version image review system, such as the Image Data Query Tool, is another way to ensure that the system being supplied to the Agency will meet its requirements.

Other questions that are typically addressed during the technical discussions include:

  • Where and when will the review system be installed and removed?
  • What level of training for the reviewers will be required, and when will it take place?
  • Who within the reviewing division’s information technology group and the Agency’s Office of Information Management will be the liaisons for the sponsor or the imaging partner to coordinate the installation of the review system and ensure a smooth transition of the data?
  • When will the imaging data actually be submitted and available to the Agency?

Meeting the Imaging Challenge

Despite the technological and logistical challenges, the incorporation of digital imaging into NDAs and BLAs provides tremendous benefits for both the FDA and the biopharmaceutical industry, allowing vital trial data to be reviewed much more quickly and accurately than is possible with hard-copy films. For sponsors—who are constantly under pressure to speed up the drug development process—the key to maximizing the benefits of electronic imaging for regulatory submissions is to assemble the right technical and regulatory team. With those resources, the sponsor can deliver a flexible, easy-to-use imaging review system that meets the Agency’s needs and helps the division review the imaging data efficiently, while avoiding unnecessary delays. With that kind of support, imaging technology has the potential to revolutionize the regulatory review process in the same way it has revolutionized the practice of medicine and the development of new drugs.

Edward J. Hogan, Jr, vice president, operations, Medical Imaging; Nicholas R. Enus, senior project manager; George Q. Mills, MD, vice president, medical imaging consulting; and Gaurav Sawhney, director, business development, work with Perceptive Informatics, a PAREXEL Company.