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International Clinical Trials

Compliance Conundrums

When it comes to clinical trials, the bottom line is that non-compliance can derail your entire study, resulting in expensive and sometimes insurmountable delays, huge cost overruns, and even denial of FDA approval. It is too important to ignore. The FDA’s 21 CFR Part 11 is a popular regulation that allows companies to implement computer systems that greatly increase the efficiency of individuals, as well as reducing errors through the identification of risks in the processes that use software applications, and increasing the overall productivity of the company. When the law was enacted in 1997, it aligned the world of regulation with the evolution of computers. It allows ‘paperwork’ documentation to be significantly reduced or completely eliminated. Non-compliance with this law by the imaging core lab can impair and possible inhibit the sponsor’s ability to obtain regulatory approval.


It was already established in the 1997 FDA Modernization Act that imaging-based findings was an acceptable method for making a determination about the efficacy of a drug or medical device for FDA approval. However, in March 2004, the FDA released the critical path initiative (CPI) which was a national strategy to drive innovation in the scientific processes through which medical products are developed, evaluated and manufactured (1). The goal of this initiative was to develop new scientific and technical tools that make the development process itself more efficient and effective. It was born out of necessity from a report analysing the ‘pipeline problem’ – the recent slowdown in innovative medical therapies reaching patients. There was growing concern both in the clinical trials and medical therapies world, as well as within the political arena, that many of the new basic science discoveries would not yield more effective, affordable, safe medical products in a timely fashion. This was due to the current medical product development path that was becoming ever increasingly challenging, inefficient and costly (2). As a result, there was momentum to transform, modernise and streamline the critical development pathway that leads from scientific discovery to direct patient care.

Shortly after the release of the CPI report, the FDA released guidance for study design. In their report, it was noted that in most clinical trials, onsite investigators and imaging specialists often have additional information regarding each patient that is not predefined in the trial protocol. As such, there may be subtle alteration in the investigator’s diagnostic assessment that may confound or bias the image evaluation. Since that report, there has been greater promotion and encouragement to recruit offsite image evaluations (core labs) for more clinical trials, particularly Phase III trials. Offsite evaluations are performed at sites not otherwise involved in the conduct of the study and by imaging specialists who have not had any contact with patients, investigators or other individuals involved in the trials (3). This allows for easier control of factors that may otherwise compromise the integrity of the blinded image evaluations.

Furthermore, there was motivation to use digital imaging, share centralised imaging resources, and utilise specialists. This was the major driving force of the imaging core lab. This results in faster and more efficient imaging that is both higher quality and lower cost. The timing was right in that high speed and high bandwidth internet connectivity allowed large digital images to be transmitted at low costs. Hence, the era of greater usage of imaging core labs for clinical trials was born.


The FDA has detailed specific guidance documents for software validation used in medical device and drug development for pre-market FDA submission. Not only are there published guidance principles of general software validation, but also published guidance for software contained within medical devices. The emergence of consensus standards related to software validation has helped to improve the consistency and quality of software development and documentation, particularly with respect to critical activities such as risk assessment and management (4).

Software validation means establishing objective evidence that device specifications conform with user needs and intended use. Software validation is a part of design validation of the finished device. It involves checking for proper operation of the software in its actual or simulated use environment, including integration into the final device where appropriate. Software validation is highly dependent upon comprehensive software testing and other verification tasks previously completed at each stage of the software development life cycle. Planning, verification, traceability, configuration management, and many other aspects of good software engineering are important activities that, when taken together, help to support a conclusion that software is validated (4). These high levels of validation and testing are an absolute requirement in the imaging core lab arena as well. The high levels of standards that are required of the sponsor companies are also conferred upon their agents, including the imaging core labs involved in evaluating their products and devices during clinical trials.


The Code of Federal Regulations (CFR) contains the laws for each of the government agencies. Each title of the CFR addresses a different regulated area, but every regulatory area has a Part 11 equivalent law that does the same thing. For example, electronic medical records follow 45 CFR Part 164, HIPAA security standards. Therefore, these concepts apply to all laboratory settings, not just imaging core labs. The regulations typically refer to records and approval signatures, which originally referred to paper documents and handwritten signatures. Part 11 allows any paper record to be replaced by an electronic record, and allows any handwritten signature to be replaced with an electronic signature.

While Part 11 and all the similar laws are essential and very successful, there has been much controversy and misunderstanding about the requirements for compliance. The Part 11 final rule from the FDA is less than three pages long and doesn’t give much detail about electronic records and signatures. This allows for a significant level of confusion and misinterpretation of the existing law. Adding to the confusion is the rapid evolution of computer technology that has made Part 11 compliance a moving target.

Computers have made people much more productive, so it is natural to use electronic records in place of paper records. Every company has electronic records, and most companies are so unsure about electronic signatures that they print out copies of electronic records and sign the paper. Increasingly, the trend is to replace paper medical records with electronic medical records. This translates into another area for competition in the global marketplace as remote access and remote care is more feasible, thus lowering the barriers to entry into any marketplace.

While regulatory and accrediting agencies are inspecting companies for compliance, computer systems in general are changing and therefore what needs to be inspected is changing as well. The law hasn’t been altered to provide any meaningful details, so companies and auditors are continually trying to understand the specifics of compliance and predict what changes may be forthcoming. This problem occurs for all industries under regulation, including imaging core labs and sponsors involved in clinical trials.

In July 2010, the FDA announced it would be begin conducting a series of focused inspections to evaluate the industry’s compliance with and understanding of regulations in 21 CFR Part 11. Under this plan, inspectors would ‘tag along’ on select inspections specifically to examine electronic recordkeeping systems and determine what changes, if any, need to be made to regulations in this area (5). The FDA intends to use these inspections to assess how to best proceed with possible modification of Part 11, and to take appropriate action to enforce Part 11 requirements for issues raised during the inspections. Since the FDA announcement, there will be more focus on Part 11 in all regulated areas, including imaging core labs.


Technology changes rapidly, and regulatory agencies have great difficulty keeping up with changes. As a result, there is often very little leadership and guidance for companies dealing with new and updated technologies that enhance speed and throughput for their clinical trials. Regulated companies, including imaging core labs, get little insight and guidance on the published regulations, and their IT departments are not experts on regulations, nor on all the software components used in a single organisation. There is often inconsistency between users in a single working environment, and quality assurance staff do not possess the knowledge, computer expertise or experience required to ensure that all components are running smoothly. Software vendors are not regulated and often do not understand what users truly require. Finally, the end users are focused on doing their jobs, and don’t fully comprehend the requirements that Part 11 places upon them. As a result of all of these issues, there is trepidation in the marketplace for true Part 11 compliance.

The FDA and Health and Human Services have not, and legally cannot, provide specifics for compliance. The industry has developed standards, but sharing between companies that compete with each other is at best difficult. Also, there are few resources available that cover all of the pieces of Part 11 compliance, and these can provide the leadership needed to coordinate all the players involved and ensure true compliance.


The imaging core lab can use Part 11 to greatly increase efficiency, lower costs for sponsors, improve security, and return high quality results in significantly shorter timeframes. Today, the imaging core lab has blended the skills of the imager and imaging technology with information technology to provide a service that is superior to the services that most organisations provide on their own. This blending of Part 11 and the imaging core labs allows for more reliable, secure and efficient return of data to the sponsor, which ultimately leads to more timely regulatory submission.

  1. FDA Critical Path Initiative: ScienceResearch/SpecialTopics/CriticalPathInitiative/ ucm076689.htm, accessed 1st December 2010
  2. Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, US Department of Health and Human Services, FDA, March 2004
  3. Guidance for Industry, Developing Medical Imaging Drug and Biological Products, Part 3: Design, Analysis, and Interpretation of Clinical Studies US Department of Health and Human Services, FDA, June 2004
  4. Guidance for Industry and FDA Staff, Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, US, Department of Health and Human Services, FDA, May 2005
  5. FDA news, The Food and Drug Letter, 19th November, 2010, article?articleId =132025&issueId=14230, accessed 1st December 2010

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Christian Teague is the Chief Core Lab Administrator for RadCore Labs, LLC. He has oversight of all clinical trials, and has 12 years of experience in the industry. He has been involved in numerous international imaging trials while at UCLA and Loma Linda Medical University. He is a member of ARRT and NMTCB with a sub-specialisation in molecular imaging.

David Nettleton is an industry leader, author and teacher for 21 CFR Part 11, Annex 11, HIPAA, software validation and computer system validation. He is involved with the development, purchase, installation, operation and maintenance of computerised systems used in FDA compliant applications. He has also completed more than 200 mission critical laboratory, clinical and manufacturing software implementation projects.
Christian Teague
David Nettleton
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