Correspondence Address:
Kunal Shah
Associate Manager, Clinical Operations, Eisai Clinical Research Singapore Pte Ltd., Mumbai
India

Full Text

In recent years, US Food and Drug administration (FDA) has been ramping up its enforcement efforts by increasing the number of inspections within and outside the United States. The FDA has also been collaborating with different regulatory authorities to conduct these inspections. Along with this, these recent warning letters also show some trends in inspection findings, which suggest a change in the inspection focus of FDA and probably hint at major reforms that may happen in regulatory policies for inspection. [1],[2]

Total number of warning letters issued by Division of Scientific Investigations (DSI), the division within the FDA's Center for Drug Evaluation and Research (CDER) responsible for ensuring compliance with GCP regulations and verifying the quality of data submitted in support of drug approvals, has increased from 2 in 2002 to 20 in 2009. In 2002, both the letters were issued to investigators. In contrast, 2009 letters cover all stakeholders:13 to investigators, 5 to IRB/IEC, 1 to sponsor company and 1 to contract research organization (CRO).

The numbers above may look small at first instance; however, these are the letters issued by the headquarters only and do not include letters issued by district offices. If we were to look at all the warning letters from DSI (including the ones from district offices), they issued just 13 warning letters from 2005 to 2006; however, number increased significantly to 52 warning letters between 2007 and 2009.

Not only the number of letters is on the rise, but there is also an increasing focus on big pharma players. In 2007, a warning letter was issued to a leading pharma company for misconduct in clinical trials. This resulted in chain of hearings followed by a Congressional report. This event marked an important shift in the DSI's approach to enforcement. Before this, the agency has been usually sending warning letters to clinical research sites or investigators. This letter was distinctive as a large pharmaceutical company was cited for study misconduct. As the study was outsourced to a CRO, the letter also mentions the CRO and the designated monitor. However, no warning letter was issued to CRO. In fact, the FDA made it very clear that it was the responsibility of the sponsor to ensure and monitor that the trial was conducted as per GCP.

Following this, in August 2009 DSI issued a warning letter to another big pharma sponsor. In this letter, the DSI charged monitors for failure to identify that drug infusions were given at the identical time to multiple subjects.

Both these warning letters issued to pharma companies cited the sponsors for activities most likely contracted to CROs. Though there is a provision in the GCP that allows for a transfer of obligations from sponsor to CRO, it is not clear which party is responsible for specific regulatory obligations. The FDA has reinforced the golden GCP recommendation, i.e., "A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor." This raised significant concerns for sponsors about the extent and scope of responsibility for oversight in outsourced clinical trials.

Three months later, a leading CRO, which monitored the trial, received a similar letter. This was the first time that FDA cited a CRO for clinical trial responsibilities delegated from a sponsor. This letter to CRO indicated that if the FDA detects problem, it will try to explore the role of the sponsor and the CRO in the study conduct and oversight. This warning letter to the CRO suggested a significant shift in the agency's supervision of clinical research activities. Before that, it was always assumed that the sponsor is ultimately responsible for ensuring study conduct as per GCP.

In April 2010, DSI issued a warning letter to another leading pharma company charging the monitors for failure to recognize or report that 13 subjects received an overdose of the study drug.

FDA has realized that there is an increasing strategic partnership of sponsor with CRO to conduct clinical research activities to reduce the operational cost. The outsourcing partnerships are getting more and more complex with changing industry requirements. The FDA is facing immense pressure from government authorities and politicians, media and research critics, patient and public advocacy groups, etc to provide better and stringent oversight of clinical studies, sponsors and CROs. The sponsors and CROs can expect more scrutiny of their outsourcing relationships and so will need to critically review delegation of responsibilities and legal wordings in the outsourcing contracts.

It is obvious that authorities can find out more by inspecting a sponsor or a CRO then by inspecting a single investigational site. Hence, the industry can expect increasing sponsor and CRO inspections in future. Another important stakeholder is site management organizations (SMOs) whose inspections can give more information about the entire site. We will need to wait and watch if they will come on radar for inspection by regulatory authorities. The increasing regulatory scrutiny for CROs definitely makes them more accountable not only from repeat business perspective from a sponsor but also from regulatory perspective. At the same time, sponsors are worried with ambiguity in how much oversight should they be providing to CROs as that is likely to increasing their operational and development costs.

If we were to look at the warning letters to see the other trends, the most common findings are:



failure to ensure that informed consent was obtained in accordance with 21 CFR Part 50failure to maintain accurate, complete, and current records of each subject's casefailure to follow protocol

These three findings cover most issues identified in the inspections. These issues may have come up due to involvement of multiple stake holders - the investigator, the study coordinator, site staff, and the monitor.

In a recent analysis of all warning letters issued from 2006 to 2009, Centerwatch reported that almost 40% of the findings were related to monitoring violations. This is a matter of concern as during that period the trend was to do extensive and 100% monitoring, which we all know has been adding huge cost to drug development. Although cost saving alternatives to 100 % SDV, e.g., selective monitoring are being discussed, such an approach may be unwarranted in light of the FDA's current findings. It appears that till the new monitoring approaches become acceptable, it would be critical to train the monitors to be extra vigilant to find out issues from sample of data, look back for trends, mitigate them, avoid them, and report them in a timely manner. This vigilance will not only ensure their continued contribution of ensuring data quality but also contribute to reduction in drug development cost in the long term by providing convincing data to regulatory authority.

The current FDA focus on increasing inspections, targeting both sponsors and CROs, and citing monitoring violations, will pose significant challenges for the industry in meeting FDA's expectations of GCP and regulatory compliance. It is time the pharma industry and CROs make concerted efforts to ensure that the conduct of clinical trials complies with stringent scientific and ethical standards.

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