Preclinical Outsourcing

Regulatory Shockwaves

By Steve Snyder | October 8, 2010

An FDA ruling stuns the industry

The end product of a preclinical (or nonclinical) study is the final report. The information in this document is used to support regulatory submissions and human clinical trials. The required contents of the final report are identified in the FDA's Good Laboratory Practices (GLP). The final report is the document that contains the summarization and analyses of the study data. The study director is responsible for drawing conclusions from the analyses and including them in the final report. The final report is also comprised of reports from contributing scientists. For example, if CRO A subcontracts the bioanalytical analysis portion of a preclinical study to Laboratory B, a designated scientist at Laboratory B is responsible for submitting a contributing report to the study director at CRO A. The contributing report contains many of the same elements that are required in the final report, including a summary and analysis of the data generated at Laboratory B. The conclusions of the designated scientist are also included in the Laboratory B contributing report. Some preclinical studies utilize multiple contributing scientists to generate and analyze study data. In these cases, each designated scientist (investigator) is required to submit a contributing report to the study director.

What I have described above is an oversimplification of the requirements for preclinical reporting. To better understand the recent regulatory concerns, we must first understand reporting process that has been used throughout the drug development industry.

Preclinical Reporting Process

For this example, we will assume that a Sponsor (pharma or biopharma) company has outsourced a preclinical study to CRO A. We will also assume that CRO A has subcontracted the bioanalytical analysis for the study to Laboratory B. In the real world, sometimes the Sponsor will be the impetus for subcontracting a portion of the study, due to its previous experience with that subcontractor; other times the CRO may initiate subcontracting if they don't have the appropriate scientific capabilities within their own operation. In this example, at the end of the preclinical study, the designated scientist at Laboratory B would conduct data summarization and analysis for the portion of the study protocol that it performed. This designated scientist will assemble all of the necessary report requirements into a draft contributor report that also includes the conclusions drawn from the work conducted in Laboratory B. A draft contributor report would then be submitted to the study director at CRO A for review.

Draft reports, whether they are drafts of contributor or the final report, are often used as vehicles of communication between all of the parties involved in the preclinical study. Accordingly, the study director commonly will share these draft reports with the Sponsor. Understand that draft reports are still "open," meaning that descriptions, sentence structure, and conclusions can be changed during this stage. This allows for a collaborative effort by the contributing scientist, the study director, and the Sponsor to make sure that the wording in the reports accurately reflects the study data. When these communications are completed, the contributor report or a final report is finalized when it is signed and dated by the author. Once any report is finalized, it can only be changed by an addendum. It is the responsibility of the contributing scientist, the study director, and their respective management teams to make sure that their reporting responsibilities and conclusions are not unduly influenced by another party including the Sponsor. This is essentially how the preclinical reporting process has been followed in drug development for years.

Regulatory Concerns

In the past year, the FDA has cited at least three preclinical CROs in inspection reports for using unsigned contributor reports (drafts) to prepare the final report. The FDA contends that, in using unsigned contributor reports, there was a lack of accountability and confirmation that the contributing scientists' raw data was accurate. In another statement, the FDA indicated that the practice where study directors invite Sponsors to comment on and edit contributing scientist reports and final reports would create a situation where "bias in data interpretation and reporting cannot be ruled out."

What Does the FDA Want?

Based on the regulatory findings regarding the preclinical report process, the FDA seems to be intent on eliminating the practice of sharing draft reports as vehicles of communication with study directors and Sponsors. A strict interpretation of these rulings suggests that the FDA wants contributor reports finalized before they are shared with the study director and the final report finalized before it is shared with the Sponsor. Again, the finalization of contributor reports has been cited in regulatory inspection findings at three CROs. To my knowledge, the concern raised by the FDA regarding Sponsor interaction prior to the finalization of the final report has only been raised at one CRO. From my perspective, and I am no regulatory professional, it seems like the FDA is intent on creating a documentation trail so they can track the communications between contributing scientists, study directors and Sponsors. By requiring contributor and final reports to be finalized prior to Sponsor input, the only way these reports can be changed is by an addendum, which effectively creates a documentation trail. Again, this derives from a strict interpretation of the FDA findings.

What does this mean for the drug development industry?

Longer reporting timelines: Using the strict interpretation of the FDA rulings, companies that conduct preclinical testing will be required to wait for finalized contributor reports before these documents are shared with the study director and the Sponsor. If these companies embrace the same regulatory guidance for final reports, timelines could be stretched even longer. A report finalization process also requires a review by the quality assurance component from the organization where the data originates. The FDA's guidance would move these finalization steps earlier in the report process.

Safety risks for clinical trials?: The whole purpose of preclinical or nonclinical testing is to assess the toxicity of a potential new drug so that Sponsors can go forward into human clinical testing with minimal risk to the trial participants. In fact, Sponsors are required to report severe and unexpected findings in nonclinical testing to the FDA within 15 days as a part of a safety mechanism to protect clinical trial participants. If the regulatory guidance on reporting is embraced and Sponsors are not allowed to view results until report finalization, there could be a delay before Sponsors are aware of a severe and unexpected finding on a nonclinical study. A delay in this awareness could result in a delay in alerting clinical trial participants of a potential risk.

More pressure on preclinical CROs: Many Sponsors select CROs based on their proven ability to generate a final report by a designated target date. CROs that embrace the FDA's guidance will need to change some aspects of their report process. Accordingly, historic on-time reporting metrics may no longer be predictive of a CRO's ability to meet a target report date and, because there is a new report process, CROs may not know if they can meet future planned report dates or not.

More regulatory risk: To date, three preclinical CROs have been cited for using unsigned contributor reports in the preparation of the final report. One of these CROs has since received a Warning Letter from the FDA where this finding was cited again. Until some common interpretation of this regulatory guidance is agreed to by the FDA and the drug development industry, preclinical CROs must decide how they will react to this changing environment. While CROs that haven't been cited by the FDA to date may continue with business as usual, it is likely that this regulatory guidance will continue to spread across the industry. No CRO likes to get cited by the FDA so management teams at these companies will need to weigh the regulatory risk of not changing their report process based on findings elsewhere in the industry. It is also important to note that this regulatory guidance on contributor reports also applies to work that is conducted inside pharma and biopharma companies.

More staffing?: At a time when the preclinical CRO industry still has not seen a rebound in customer demand, embracing the FDA's regulatory guidance may require CROs to add more support staff to help process the increased documentation requirements, maintain the reporting throughput, and assure compliance. Ironically, this resource need could be realized when CROs are actually trying to cut costs,
so there are financial implications to CROs as well. Those CROs that added capacity in 2008 and 2009 now may need to add staff just to maintain the current diminished workload. Concerns that there is too much capacity in the industry may now be accentuated.

Selecting CROs: Don't be surprised if Sponsors start jumping to those CROs that have yet to embrace the FDA's regulatory guidance. However, as this regulatory guidance spreads across the CRO industry, Sponsors ultimately will have fewer choices to enact this strategy. In time, this could also be a risky strategy for Sponsors in that more regulatory scrutiny could be directed at final reports that were prepared using the "old" reporting process. Now Sponsors will need to assess regulatory risk when selecting a CRO. This may be an especially bad sign for CROs in emerging markets. If Sponsors are precluded from viewing draft reports, they may be more inclined to place work at CROs were potential language and data interpretation issues are less of a concern.

More preclinical testing?: In a strict interpretation of the FDA's regulatory guidance, Sponsors would be precluded from commenting on reports until the finalization process is completed. Even then, authors would need to agree to Sponsor-proposed changes and the report would need to be amended
to create a documentation trail. Following this example, it is possible that the contributing scientist or the study director could make seemingly innocent comments about the study results that could inadvertently raise new or additional safety concerns. Under the new guidance, if these concerns could not be addressed effectively by a report addendum, the Sponsor may be forced to do additional preclinical testing and, perhaps, increase the number of animals used in drug development. I know the FDA did not intend to produce this outcome, but the potential for it is very real.

So where does the industry go from here? Ideally, the FDA and industry interests should engage in conversation to arrive at a mutually acceptable solution that will satisfy the needs of both parties.The impact of this guidance on the drug development industry could be substantial. In 2007 and early 2008, the preclinical CRO industry was booming. Sponsors and CROs couldn't conduct studies fast enough. The industry was in "production mode." If the FDA continues to use regulatory inspection findings or issues additional Warning Letters to enforce its guidance on the preclinical report process, we may be witnessing a fundamental change in the industry that will never see a "production mode" again.

SteveSnyder is a consultant with more than 25 years of experience in preclinical toxicology as an outsourcing customer and provider. He can be contacted at