Clinical Trial Monitoring Not Ready To Go Completely Off-Site, FDA Says

Agency yields to some, denies other industry requests in final guidance that declines to lay out one prescriptive monitoring path.

As monitoring methods and technology evolve, FDA expects sponsors will decrease their use of on-site clinical trial monitoring, but the agency isn’t giving the go-ahead for 100% remote monitoring just yet.

“We expect that the pharmaceutical and device industries will, for the foreseeable future, continue to use some amount of onsite monitoring,” the agency’s Aug. 7 final guidance on a risk-based approach to monitoring clinical investigations says.

The statement may disappoint Johnson & Johnson – the company asked the agency to acknowledge cases where clinical investigations could be conducted in the absence of on-site monitoring in comments on the draft released in August 2011 (Also see "FDA Urges Centralized Clinical Trial Monitoring Over Frequent On-Site Visits - Guidance" - Pink Sheet, 6 Sep, 2011.).

For example, J&J suggested FDA might permit full remote monitoring if it incorporated proper escalation protocols as well as accessible electronic records and electronic data capture (EDC) systems.

FDA also said the approach to monitoring described in the guidance is consistent with a 1996 International Conference on Harmonisation guidance on good clinical practice for pharmaceuticals (ICH E6) and 2011 International Standards Organization clinical investigation of medical devices for human subjects – good clinical practice (ISO 14155:2011).

While these documents, which have been accepted by FDA, allow for the possibility of reduced – and even no – onsite monitoring, the agency says “they also make clear that it would be appropriate to rely entirely on centralized monitoring only in exceptional circumstances.”

Despite the agency’s hesitation to support total reliance on centralized monitoring, the thrust of the guidance is intended to “encourage” sponsors to move toward risk-based monitoring, particularly use of centralized monitoring and technological advances that make this possible, such as e-mail, webcasts and online training monitoring.

“There is a growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% data verification to ensure subject protection and overall study quality,” FDA says.

For example, FDA said that some publications suggest that certain data anomalies may be more readily detectable by centralized monitoring versus onsite monitoring. It does also acknowledge that there are limited empirical data to support one method of monitoring versus another, including data to support on-site monitoring.

FDA’s push for centralized monitoring comes as the agency looks to shift some of its compliance resources into real-time monitoring of clinical trial quality (Also see "FDA Compliance Office Wants To Find Clinical Trial Problems In Time To Correct Them" - Pink Sheet, 26 Nov, 2012.). The risk-based monitoring guidance adds that FDA is considering the need for additional guidance on a quality risk management approach to clinical trials.

Agency Yields To Many Other Requests

Despite denying J&J’s request for the potential to completely eliminate on-site monitoring, the final guidance does give industry many of the changes it requested. Per comments from the Pharmaceutical Research and Manufacturers of America, Pfizer Inc.,AstraZeneca PLC and others, FDA added about two new pages with additional descriptions of alternative monitoring techniques, particularly when such techniques could be considered in place of, or to complement, traditional monitoring.

The final guidance offers specific options for how a sponsor might handle communication with study site staff; review of site processes, procedures and records including informed consent; and source data verification and corroboration through centralized monitoring.

For example, alternatives to traditional approaches for verifying study subjects’ informed consent at the site could be an internet portal that enables the site staff to upload signed consent forms that can be accessed by designated monitors. Study sites could also electronically send signed pages through fax or email, or a monitor could perform remote comparison of dates of study procedures and documentation of informed consent on case report forms (CRFs).

FDA did acknowledge there are privacy and confidentiality concerns and legal limitations regarding monitoring informed consent and other study documents remotely – multiple members of the pharmaceutical industry asked for such an acknowledgement.

The agency’s theme however seems to be that sponsors have the ability to tailor monitoring plans to the needs and resources of the trial. It also said that while sponsors may not have remote access to electronic health records because of data privacy, security concerns and technological challenges, they should consider risk-based approaches using the format of study information available to them. FDA said many of the centralized monitoring techniques discussed in the guidance can be performed regardless of the extent to which electronic records are used in the study.

FDA will allow sponsors of drug studies to ask specific questions about a monitoring plan in a request for a formal meeting with the FDA (e.g., end of Phase II meeting), but the Center for Drug Evaluation and Research said it does not have the resources to commit to review of monitoring plans (Also see "FDA Calculates Burden Of Producing Clinical Trial Monitoring Plans" - Pink Sheet, 26 Nov, 2012.). Novartis AG and some other sponsors had wanted FDA to establish processes for formal review of monitoring plans.

Risk Assessments Addressed

FDA also included a new section on risk assessments in the final document in response to industry’s request for more specific guidance on the development and utilization of risk assessment plans, which constitute “a cornerstone of utilizing a risk-based approach” to trial monitoring, according to Pfizer.

FDA said a risk assessment should be performed after sponsors indentify the critical data and processes for a clinical trial. The risk assessment should be used to identify and understand the nature, sources and potential causes of risk that could affect the collection of critical data or the performance of critical trial processes.

For monitoring purposes, risk identification should consider the types of data to be collected, the specific activities required to collect these data and the range of potential safety and other human subject protection concerns inherent in clinical investigations, the guidance says.

Sponsors should identify, assess and prioritize risks by considering three factors:

• The likelihood of errors occurring;
• The impact of such errors on human subject protection and trial integrity; and
• The extent to which such errors would be detectable.

The guidance then directs sponsors to use the results of the risk assessment in developing their trial monitoring plan. The assessments may help sponsors determine what risks can be addressed through monitoring and the type of monitoring best suited for a particular risk. A sponsor could also determine a risk is better managed through other activities such as modifying the trial protocol, FDA said.

FDA notes that risk assessments are not a one-time activity. Sponsors are directed to periodically evaluate emerging risks and whether monitoring activities require modification to effectively oversee risks.

Despite this additional information on risk assessments, FDA declined to hold companies’ hands. The new section notes that the guidance “does not provide comprehensive detail on how to perform a risk assessment.” FDA said there are a variety of risk assessment methodologies and tools that can be used in clinical trials.

Another notable change to the final guidance, added by FDA at the request of industry, was the acknowledgement that the agency has communicated its recommendations for risk-based monitoring to staff in review, inspection and compliance functions. It also said its bioresearch monitoring compliance program guidance manual for sponsors, contract research organizations and monitors (CPGM 7348.810) as well as its manual for clinical investigators and sponsor-investigators (CPGM 7348.811) are compatible with the final guidance. These tasks were still pending when the draft was released.

Novartis had concerns about FDA’s inspection program aligning with the final guidance because it said sponsors that have already begun to employ alternative monitoring are often questioned during inspections “because these processes deviate from the ‘traditional’ approach to monitoring.”

FDA said it informs field staff that regulations do not prescribe a specific monitoring technique and while CPGM 7348.810 does not discuss centralized monitoring, “the focus is on the review of monitoring activities through documentation and whether these activities were carried out in accordance with the sponsor’s (or CRO’s) monitoring procedures.”