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«11-18-2012 An Organizational Diagnosis Of A Centralized Investigational New Drug Core Within A Large Academic Health Center Kathleen M. Thomas ...»

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In 1932, the United States Public Health Service (PHS) sponsored a study at the Tuskegee Institute (and its affiliated hospitals) in southern Alabama. The goal was to investigate the stages of syphilis over the course of its lifetime. Two hundred and one healthy black males (controls) and three hundred and ninety-nine syphilitic black males were enrolled into the study. For the most part, these men were of low income and did not know the severity of the disease from which they suffered. At the time of enrollment, they were informed they were being treated for bad blood, and in actuality the doctor had no intention of treating the disease at all, due to the lack of “safe” treatment options (Center for Disease Control and Prevention).

The details of this study were revealed in 1972 leading to the National Research Act. Simultaneously the Department of Health, Education, and Welfare (DHEW) published regulations for the use of human subjects (Gordon and Prentice, 2000). These regulations -- known as 45 CFR 46 (Regulations for the Protection of Human Research Subjects) -- included the mandate of an Institutional Review Board (IRB) to oversee, review studies for safety and established criteria for Informed Consent.

These events led the United States to develop regulations for the conduct of clinical research. “It should be recognized that the system for protection of the rights of human subjects of research, which evolved painfully from the horrors of Nazi Germany, itself continues to evolve” (Gordon and Prentice, 2000, p.7). Clinical research is continuing to evolve, and the regulations will need to evolve as well.

Background The field of clinical research has been evolving over the past century and has led to the development of regulations and infrastructure to support the research. Clinical research (human subject research/clinical investigation) is defined as “any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the Food and Drug Administration under section 505(i) or 520(g) of the act, or need not meet the requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does not include experiments that must meet the provisions of part 58, regarding nonclinical laboratory studies (21 CFR 56.102).” This definition is taken directly from the Code of Federal Regulations (CFR).

AHCs have a vested interest in the conduct of clinical research protocols. Some protocols involve the use of investigational drug therapies, which in turn require the submission of an IND application to the FDA, an agency of the US Department of Health and Human Services. The FDA is responsible for overseeing the safety of all FDA regulated products and overseeing the protection of human research participants for clinical investigations. There are numerous centers under its structure with two specific to INDs: The Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research. A process for submitting an IND is clearly defined in 21 CFR 312 and is mapped out in the flowchart below (see Figure 1). The process for submitting an IND involves numerous working parts and a high level of expertise for the personnel involved.

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The process of conducting clinical research involves several stakeholders. Two of the primary stakeholders are the Investigator, an individual responsible for the conduct of the clinical research (see Table 1) and Sponsor (see Table 2). The standards for Investigators are very high, and Investigators are expected to undergo proper training before conducting a clinical research protocol (Berro, Marlene, Burnett, Bruce, Fromell, Gregg, Hartman, Karen, Rubinstein, Eric, Schuff, Kathryn, & Speicher, L. (2011).

Table 2. Responsibilities of investigators under an IND (21 CFR 312) Regulations (http://www.

accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.60) Ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation Obtain the informed consent of each human subject to whom the drug is administered Record keeping and record retention Assurance of IRB review Reporting: progress, safety and final report Investigators wishing to conduct research utilizing an investigation drug must meet regulatory requirements above those mandated for Investigators of non-drug related research. These additional regulations are set in place to ensure protection of the research participants participating in research studies involving the use of a non-FDA approved drug. “Individual investigators who initiate and conduct a clinical study, as well as being directly accountable for the administration or dispensing of the investigational drug, are designated as Sponsor-Investigator.” (Holbein, 2009, p.691) A sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization.

The sponsor does not actually conduct the investigation unless the sponsor is a sponsorinvestigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor (see Table 2).

Table 3. Responsibilities of a sponsor under an IND (21 CFR 312) Regulations (http://www.

accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.50 ) Selecting qualified investigators, training Providing them with the information they need to conduct an investigation properly Ensuring proper monitoring of the investigation(s) Ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND Maintaining an effective IND with respect to the investigations, and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug Supplying, handling and disposition of investigational products Record keeping and record retention Management of investigator non-compliance Assurance of IRB review Medical expertise, trial oversight Overview of a department within an AHC The department (which has been named Department A to protect its identity) had several Sponsor-Investigators prior to the year 2007. Several Investigators within the department had an interest in studying the safety and effectiveness of Radiopharmaceuticals. A Radio-pharmaceutical is defined as a drug (compound or material) that may be labeled or tagged with a radioisotope. These Investigators (prior to 2007) developed clinical research protocols, and submitted INDs to the FDA.

Research being conducted at an AHC entered the spotlight on September 17, 1999 due to the death of a research participant. Research restrictions and higher level oversight were implemented as a result of the event. The AHC created a centralized office – the office of Human Research (OHR) – to provide support to Investigators throughout the AHC. In addition, the AHC in collaboration with OHR reviewed all of the research being conducted and determined studies that were considered of greater than minimal risk, and needed additional oversight. Department A was considered one of the key departments with multiple high risk protocols. In order to ensure compliance, OHR developed a monitoring program, implemented in the fall of 2005, for protocols with greater than minimal risk.

OHR monitored protocols under an IND throughout the spring of 2006. The monitoring reports documented non-compliance. The Administrative leadership of OHR and SOM met with the leadership within Department A to discuss the findings and an action plan. Leadership of Department A was charged with designing a plan to dissolve non-compliance among Sponsor-Investigators. The departmental leadership took the findings very seriously and decided the department would be named as Sponsor.

Simultaneously while these discussions were occurring, leadership was in search of a new chief for a division within the department. The selected candidate brought with him previous experience of working within a centralized IND core model. He offered his expertise of Sponsor requirements and to serve as the Sponsor's authorized-representative if hired into the chief position. Soon thereafter, this gentleman was chosen as the Sponsor's authorized-representative on behalf of the Sponsor.

My involvement I began working in the department in the fall of 2002 as a Clinical Research Coordinator (CRC) for Dr. X on a multi-modality project that lasted until June 2007.

During the five-year period, I gained extensive knowledge of clinical research conduct and advanced into a project manager position. Shortly after the completion of the project, Dr. X promoted me to a senior level project manager and requested I work with him to develop a centralized Clinical Research Coordinator core (known as RADCORE). I created training manuals, protocol file templates, regulatory organization tools, standard operating procedures, and hired several new CRCs into the group. I was proud of my accomplishments and found the core was operating smoothly. I was eager to take on more responsibilities within the department.

My involvement in the IND core began two years ago; I was a young, enthusiastic worker willing to take on extra responsibilities and sought out challenges. My role evolved early in 2010; I was promoted to Clinical Research Operations Manager. My responsibilities included developing operational processes, managing projects, and leading research staff throughout multiple cores of the research unit of the department.

Late January 2010, I received an email from my boss, Dr. X, requesting I help organize and improve the document management quality of the IND core. I had little knowledge of the current organizational structure within the IND core and was not aware of the history of the OHR audits so, I was a bit nervous about this new responsibility.

When I spoke with Dr. X he explained he needed my help organizing the regulatory files of the IND core, creating a more effective and efficient organization system, and hiring an individual to serve as the IND Manager. He briefly explained the IND core had been centralized for three years (implemented in 2007) and was still not operating effectively. The centralized model was set in place because individual investigators did not have the resources to maintain compliance with the regulations. To solve this problem, the department was named Sponsor and an individual was appointed as Sponsor's authorized-representative. In addition, an IND core manager was hired to manage the administrative activities and monitor research protocols under INDs.

Since the IND core was a newly adapted model and not one that other department were utilizing, the AHC leadership were watching carefully. OHR has been conducting audits of the IND core throughout the 2009 academic year, and the audit findings included: lack of communication with Investigators, missing documentation, lack of training, and lack of documented communication among all working parts of the core.

OHR provided recommendations for re-organizing and resolving the major audit findings. Unfortunately, the findings were not resolved and the core was at risk of being closed down. Dr. X explained a change in administrative staff was warranted, and a new individual would be hired under my supervision. Before I could go through the recruitment and hiring process, my first priority was resolving the auditing findings.

I spent the next several months going through regulatory files, creating tracking systems, and resolving most of the findings from the 2009 OHR audits. I remember feeling fairly confident in the systems I had created and felt strongly it was time to focus on recruiting and hiring an IND core manager. I met with Dr. X and Dr. Y (SponsorRepresentative at the time) to determine the responsibilities that would be associated with the position. After a few discussions with both leaders and researching IND Manager Job descriptions, I drafted the position summary and submitted it to Human Resources for approval and posting.

I interviewed several candidates who demonstrated knowledge of clinical research, FDA regulations, Good Clinical Practices, communication, organization, and initiative competencies. With buy-in from Dr. X, and Dr. Y, I made a decision on the best suited candidate for the IND Manager position. I offered the position to an internal candidate in the department, who demonstrated all of the above mentioned qualities. She accepted the offer and started her new position in June 2010.

My goals (agreed upon by IND Manager ) for the IND core included: developing a monitoring plan, Sponsor Standard Operating Procedures (SOPs), training manual for Investigators, a website, standard filing naming conversions, electronic file management, and standard file organization. In addition to all of this, I knew the daily operations had to continue. The IND Manager took the lead on filing annual reports (for each IND) protocol amendments and new protocols to the FDA. She continued maintaining the site files of protocols under each IND and defining regulatory submission processes for Investigators, a monitoring plan, and wrote out the mission of the IND core. These three tasks were quite a challenge because we did not know if our perception of the core matched the unspoken mission Dr. X and Dr. Y had intended.

Problem statement The centralized IND core was developed and implemented to resolve noncompliance issues among Sponsor-Investigators; however, non-compliance issues were still noted on audit reports after the implementation of the centralized IND core. The centralized model was not fully implemented, nor fully staffed to operate in the way it was structured.

There are several assumptions I have which led me to conduct this diagnosis.

These assumptions include: There was a lack of planning about the infrastructure for the centralized IND core, roles were not identified and the purpose of the core was not clearly defined.

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