QA for the Investigative Site

If an investigative site is to grow successfully, specific functions of the clinical trials process must first be solidly in place. A common pitfall in this industry is for the owner or Director of Business Development of a young site to promote itself before it can adequately perform more studies. This happens when site management has not yet recognized the critical importance of developing the appropriate infrastructure needed to support a site aiming to grow its clinical trials business carefully and thoughtfully. There are basic elements (Figure 1) needed to build a firm foundation for growth with quality, and while a detailed discussion of each of these functions is beyond the scope of this article, a few are highlighted.

If You Need an Apple, Get an Apple

Director of Clinical Operations (DCO)

The Director of Clinical Operations (DCO) is crucial to site growth and, assuming the right person is hired, will be instrumental in moving the site to the next level. The DCO oversees all of the day-to-day clinical operations. He or she meets weekly with all study coordinators; assigns studies to the study coordinators based on their experience and current workload; participates in all study initiations, close-out meetings, monitor visits, Food and Drug Administration (FDA) and sponsor audits; meets with the quality assurance team to discuss trends and issues; acts as a liaison between the sponsor, investigator, and study coordinator to address issues relating to protocol compliance; oversees formal staff training on many topics, including HIPAA; and is involved in any clinically-related issue with regard to budgeting, contracting, and salary reviews. The DCO is the glue that holds the site together. All study coordinators, research assistants, regulatory staff, and laboratory personnel report to the DCO, who in turn, reports directly to the primary investigator and the CEO.

The ideal candidate is someone who has had site experience, is familiar with good clinical practice standards, and has a clinical background, such as a nurse who has worked in an ICU or in some other type of nursing environment with rigid, military-like rules and constraints. Hiring someone with this kind of background will increase the likelihood that the individual can function in a highly structured, regulated workplace. The DCO should also have management and leadership skills. Previous experience as a monitor is desirable, but it is strongly preferred that the DCO have site experience as a study coordinator, or as some other site-based clinical professional (see sidebar "If You Need an Apple, Get an Apple").

Figure 1. Key Elements for a Successful Site

Quality assurance

The growing site needs to establish a quality assurance (QA) department, even if that department starts with nothing more than a single full-time equivalent (FTE), or a partial FTE, depending upon workload. A number of site alliances and site management organizations (SMOs) share one quality assurance FTE who travels from site to site, to QA the charts prior to monitor visits. Sponsors, CROs, and monitors recognize and appreciate this investment in quality.

The purpose of the QA department is to develop and implement programs designed to improve the quality of studies conducted at the site,¹ starting from day one. This raises the bar for patient safety, and should enhance outcomes of monitoring visits.

Figure 2. Key Responsibilities of the Quality Assurance Department.

The QA function is a standard business practice for overseeing product quality (Figure 2). Quality Assurance, as defined by the International Organization for Standardization (ISO 9000), refers to a set of activities whose purpose is to demonstrate that an entity meets all quality requirements. QA activities are carried out to inspire the confidence of both customers and managers that all quality requirements are being met.²

Applying this definition to the clinical trials industry, QA serves to ensure that Good Clinical Practice (GCP) guidelines are adhered to, resulting in a quality product: clean, reliable data. According to FDA, GCP is a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials.³ Compliance with this standard provides public assurance that the rights, safety, and well being of trials subjects are protected, consistent with the principles originating with the Declaration of Helsinki; and that the clinical trial data are credible.⁴

Helpful Hints to Improve Site Performance and Outcome at Audits.

Because of its importance, the QA team should report to the highest level of management, and maintain independence from the operations group.⁵ In addition, the QA team should be presented to the site as a positive, cooperative force, and not as adversarial to site operations.⁶ Using this approach, the QA team can audit studies at prescribed times, such as at study-up, and once a month thereafter. Findings of each audit are to be shared with the principal investigator, sub-investigators, study coordinators, and any other personnel involved with the study. The auditing exercise can serve to prepare the site for monitoring visits, FDA audits, and sponsor audits.

Standard operating procedures (SOPs)

To facilitate the operation of a GCP-compliant site, a good Quality Assurance department works with all levels of management to develop standard operating procedures (SOPs). These procedures are designed to bring consistency to common practices conducted at the site by providing a standard format, method, authorization trail, and implementation process. The goal of SOPs is to improve quality by preventing or limiting errors and non-compliance problems at the site level. The QA Department should review the SOPs annually to keep them current, and should be diligent about their being followed.

Figure 3. Study Management SOPs.

SOPs address a wide range of clinical and administrative topics, ranging from obtaining informed consent to randomization procedures to collecting data to handling a code on a patient (Figure 3). Most procedural errors occur with the first three or four patients enrolled in a study, so it is a good idea to develop an SOP instructing the QA Department to review and approve all charts and source documents for the first four patients in all studies. Once enrollment extends beyond the first few patients, it is suggested to have all paperwork completed by the study coordinator, research assistant, or data entry staff within 24 hours of each patient visit. This process limits the number of missed procedures. For example, the study coordinator may have taken a blood pressure reading during the patient visit, and may have quickly jotted it down on a piece of paper instead of recording it in the case report form. Implementing this simple procedure can improve the quality of the paperwork completed at the site.

Whether sites create their own SOPs, or customize templated SOPs, they include various elements such as title and objective (Figure 4). As company SOPs are generally considered to be confidential documents, it is recommended that anyone at the site who is given the SOP binder fill out a sign-out sign-in sheet to document this transaction. If SOPs appear on the company's intranet, they should be password-protected. Further information about SOPs can be found in How to Grow Your Investigative Site.⁷

Figure 4. Sample Format for Standard Operating Procedures (SOPs).

Regulatory affairs

Growth at the site level is accompanied by a tremendous increase in regulatory paperwork generated in support of clinical studies. This workload becomes particularly noticeable once the site reaches a milestone of some seven to nine ongoing trials. As long as the site participates in a smaller number of trials, it is usually possible for regulatory responsibilities to be assumed by an administrative type or by the study coordinator. Once this milestone is reached, however, the site will probably need to hire a regulatory affairs person.

Initially, this individual may assume other administrative duties if he or she is not fully consumed with regulatory paperwork, but eventually the position will expand into a full time job. Some of the responsibilities of the regulatory affairs person (or, eventually, the regulatory affairs director) include corresponding with local, central, and in-hospital Institutional Review Boards (IRBs); keeping abreast of HIPAA issues; maintaining all paperwork for the regulatory binder; and properly reporting adverse events (AEs) and serious adverse events (SAEs) (Figure 5).

Figure 5. Some of the Tasks Assumed by Regulatory Affairs.

Dedicating an FTE to regulatory activities will accomplish two major goals: it will free up the study coordinator to perform other study-related tasks; and it will improve the site's turnaround time for submitting paperwork needed for study startup. Offering good turnaround times is an important marketing tool for the site. It shows efficiency, and complements the skill, knowledge and experience that a site can offer to sponsors.

The regulatory binder

The regulatory binder is the record of study documentation. Because all clinical studies tend to have many of the same components, the regulatory affairs department, with input from the site, should consider developing a format for the binder that standardizes needed documents for all studies. Although various sponsors and CROs may provide study binders, it is preferable that the site uses its own standard binder. This will regiment the site, and enhance quality by organizing paperwork needed for proper study conduct and for visits from monitors, FDA and sponsors.

The binder includes:

• IRB-approved signed informed consent forms

• Serious Adverse Event (SAE) reports

• FDA Statement of Investigator Form 1572

• Continuing and final review reports (CVs and medical licenses of the principal investigator(s) and sub-investigator(s))

• Letters of indemnification and confidentiality

• 21 CFR (Code of Federal Regulations) 54 Financial Disclosure by Clinical Investigators

• Clinical supplies: Proof of receipt of CRFs, lab kits, diaries, etc.

• Protocols, protocol amendments and signature pages

• Investigator brochures

• Drug accountability records

• Telephone logs

• IRB-approved materials, IRB correspondence and Continuing Review Reports

• Advertisements and approvals

• General correspondence with the CRO and/or sponsor (includes newsletters)

• Reorder forms

• Site signature and delegation logs (stating who is responsible for which study activity. The logs are signed and initialed).

• Follow-up forms

• Monitoring logs and reports

• Shipment records

• Screening logs (documenting who was screened for enrollment)

• Laboratory certificates and values

• Equipment logs

• IND safety reports

FDA audit

The real test of a site's preparedness is how it fares during an audit by FDA. It's not a question of if an FDA audit will happen, but when. According to the Center for Drug Evaluation and Research (CDER), a division of FDA, there are approximately 300 onsite inspections annually of U.S. clinical investigators (Figure 6). Inspections can last anywhere from several days for routine inspections to a few weeks if serious problems are uncovered.

Figure 6. Number of inspections of U.S. clinical investigators.

Through its Bioresearch Monitoring (BIMO) Program, the FDA carries out three types of clinical investigator audits⁸:

• Study-oriented Inspection

• Investigator-oriented Inspection

• Bioequivalence Study Inspection

The first two types; study-oriented, and investigator-oriented, comprise the majority of inspections at the investigative site. A study-oriented inspection occurs almost exclusively to review trials that are important to new drug applications (NDAs) or product license applications (PLA) pending before the agency. The investigator-oriented inspection may occur because an investigator conducted a pivotal study that merits in-depth examination due to its importance in product approval or its effect on medical practice.⁹ This type of inspection may also be initiated for cause. For example, representatives of the sponsor have reported to FDA that it is having difficulty getting case report forms from the investigator, or there is some other concern with the investigator's work (Figure 7).

Figure 7. Additional Reasons for an Investigator-oriented Inspection.

A few comments about FDA audits

Within the first five minutes of visiting a site, the FDA inspector usually develops a good sense as to whether a problem exists. If staff acts nervous and worried, the inspector will suspect that something is awry and will find deficiencies. If, however, the clinical staff is secure about the quality of the data, SOPs are properly followed, and the regulatory binder is carefully kept, this, too, will be obvious to the inspector.

The auditor's job is to ensure that regulations designed to protect the rights and safety of human subjects are being followed along with aspects of good clinical practice leading to ethical development of investigational compounds and devices. With this in mind, it is best to go through the audit in the spirit in which it is intended.

On the final day of the FDA audit, the inspector will conduct an exit interview. During this interview, the FDA inspector will discuss findings. For this reason, it is helpful if the site's top management can sit in at this meeting. It is preferable if the CEO, DCO, principal investigator, and QA director are present. A site manager may have to request permission from the inspector to include these members of the management team. Sometimes, the inspector will not permit all of these people to be present, allowing only the primary investigator and the QA director.

Following the inspection, FDA generally issues one of three types of letters to the investigator¹⁰:

1) A notice that no significant deviations from the regulations were observed. This letter does not require any response.

2) An informational letter identifying deviations from regulations and good investigational practice. This letter may or may not require a response from the clinical investigator. If a response is requested, the letter will describe what is necessary for follow-up.

3) A Warning Letter identifying serious deviations from regulations requiring prompt correction by the clinical investigator. FDA may inform both the study sponsor and the IRB of the deficiencies. The agency may also inform the sponsor if the investigator's procedural deficiencies indicate ineffective monitoring by the sponsor.

The Quality Assurance and regulatory affairs departments can seek to limit deficiencies by paying particular attention to the most commonly found deficiencies in FDA audits, including protocol non-compliance and record keeping deficiencies (Figure 8).

Figure 8. Top Five Deficiencies Found in FDA Site Audits in 2002.

Summary

There are necessary ingredients for growing a site into a larger, highly professional operation. This includes the creation of an infrastructure for the purpose of improving the quality of clinical trials conduct, leading to cleaner data, greater patient safety, and improved outcomes of visits from monitors, and auditors. To achieve this, there needs to be new staff positions, such as a Director of Clinical Operations, and head of Quality Assurance; SOPs have to be developed, and the regulatory binder has to be maintained. Using this type of professional approach, the site will grow in an organized, regulatory-compliant manner.

References

1. R.A. Koshore Nadkarni, S. Antel, and K. Sargent, "The Value of Site-Based Quality Assurance Systems for Clinical Testing Sites,"

The Monitor

, 14 (4), 29 (Winter 2000).

2. Definition of Quality Assurance, praxiom.com accessed September 25, 2003.

3. Food and Drug Administration, www.fda.gov/oc/gcp/default.htm accessed September 25, 2003.

4. "Guidance for Industry Good Clinical Practice: Consolidated Guidance," Center for Drug Evaluation and Research, April 1996, p. 1, www.fda.gov/cder/guidance/959fnl.pdf accessed September 25, 2003.

5. R.A. Koshore Nadkarni, S. Antel, and K. Sargent, "The Value of Site-Based Quality Assurance Systems for Clinical Testing Sites," The Monitor, 14 (4) 30 (Winter 2000).

6. Ibid., The Monitor, p. 30.

7. B.M. Miskin and A. Neuer, How to Grow Your Investigative Site (Boston, MA, CenterWatch, 2002), www.centerwatch.com/bookstore/pubs_profs_grwinv.html.

8. FDA Information Sheets, Guidance for Institutional Review Boards and Clinical Investigators, www.fda.gov/oc/ohrt/irbs/operations.html#inspections. accessed September 25, 2003.

9. Ibid., FDA Information Sheets, accessed September 25, 2003.

10. www.fda.gov/oc/ohrt/irbs/operations.html#inspections. accessed September 25, 2003.