The clinical research industry is an ever-evolving and ever-changing enterprise. It is continuously achieving advancements that would not be possible without the many key players and stakeholders within the industry. These stakeholders range from a broad spectrum that includes the participants, research team, sponsors, regulators, monitors, government agencies, Contract Research Organizations (CROs), Site Management Organizations (SMOs), academic institutions, ethics committees or Institutional Review Boards (IRBs), and a myriad of other public and private entities whose involvements greatly effect the clinical research process. Indeed, with the added diversity of stakeholders comes added complexity in collaborative efforts and interactions (Johnson, 2005). The focus of this article is to highlight some, if not all, of the various stakeholders and elaborate on their roles and influences, as well as how they interrelate with one another within the research enterprise.
Clinical Research Stakeholders
Research sponsors are the primary stakeholders who initiate the research process. They are typically pharmaceutical or biotechnology companies in the business of making drugs, biologics, or medical devices. They may also be academic institutions or even government agencies such as the National Institutes of Health. Either way, before they can conduct their studies or introduce any drugs, biologics, or medical devices into the market, they must first gain approval by verification of their safety and efficacy. This is done by going through the clinical investigation process. However, this cannot be achieved by the sponsor alone. Hence they must rely on other stakeholders. This is where the research team, another stakeholder, is involved in performing the clinical investigation. Although the sponsor hires the research team to conduct the clinical study, the sponsor is expected to maintain their responsibilities as well. As noted in 21 CFR 312.50 (2006), some of these responsibilities include: protocol development and IND submission, selecting qualified investigators, providing all information needed to properly conduct the investigation, monitoring and ensuring that the study is conducted in accordance with the protocol, ensuring compliance with federal regulations, and informing the FDA and the participating investigators of any adverse events and risks.
The investigative site in any trial generally consists of principal investigators, sub-investigators, clinical research coordinators, site managers, laboratory personnel, technicians, analysts, pharmacists, research assistants, recruiters, and many others. This team of professionals is led by the principal investigator. This is the stakeholder hired by the sponsor to conduct their trial or clinical study. Although each member of the research team has certain duties to fulfill, it is ultimately the investigator who is responsible for all aspects of the study. Some of these responsibilities include (21 CFR 312.60):
- Ensuring that an investigation is conducted according to the regulations as well as the approved protocol and the signed investigator statement
- Obtaining the informed consent of each subject to whom the drug is administered
- Protecting the rights, safety, and welfare of subjects under the investigator's care
- Maintaining control of drugs under investigation.
- Reporting any adverse events to the sponsor and the IRB
As the research team works on the study, there is a certain level of interaction that occurs between them, the sponsor, the IRB, and the FDA. The interrelation between the research team and the sponsor is driven by the common goal of completing the study and obtaining results that may lead to an approval. The interrelation with the IRB is to ensure that the study will be conducted ethically while preserving the safety and wellbeing of subject. Thus, if the research team conducts the study successfully, the sponsor will be able to obtain the information needed to submit the necessary documents to the FDA, bringing them one step closer to gaining approval.
The FDA is the main regulatory authority stakeholder in charge of protecting the public health by assuring the safety and efficacy of drugs, biologics, and medical devices. The FDA achieves this through an extensive review process. In this process, the sponsor works with the FDA to submit an application or IND/NDA for the new product. The FDA carefully evaluates the submitted documents, which then leads to either an approval or rejection. In addition to the review process, the FDA also performs audits and inspections of any section of clinical research including sites, sponsors, or IRBs. Should the FDA discover any problems of noncompliance or regulatory issues brought on by any of the stakeholders, a warning letter may be sent in which corrective action must be taken immediately by the stakeholder responsible (Allen, 2002).
The Safety Squad:
The Institutional Review Board, or IRB, is the stakeholder that holds the role of protecting human subjects as detailed in the regulations (21 CFR 50, 21 CFR 56, and 45 CFR 46). Before a research team can begin on a study, this specially constituted review body must conduct an initial review to see if the study can be done ethically and safely. The IRB carefully analyzes the study protocol and assesses the risks and benefits, which ultimately decide whether or not the investigator can go on with conducting the study. The IRB may conduct several reviews throughout the study period. If at any point the IRB determines that subjects are exposed to any unreasonable risk, or the study is not ethically sound in any way, they may decide to require changing the protocol or halt the study altogether. No changes or deviations from the protocol can be done without prior approval from the IRB, unless it is necessary to eliminate apparent immediate hazards. Even so, the research team, or namely the investigator, must report such events to the IRB. Most of the interaction occurs between the IRB and the investigator. While the investigator is interested in conducting the study, the IRB is most interested in maintaining subject welfare. Thus, in the case of these stakeholders, the investigator who represents the research team must comply with the IRB’s requirements as well as the FDA’s requirements in order to have an approved, safe, and ethically sound study.
My Role in the clinical research industry:
The role I play in the clinical research industry is generally that of a consumer but also as a coordinator. As a consumer I have a limited view of the market as I take note of what new drugs are available and how drug prices are impacted. On the other hand, as a coordinator, I play a greater role from within the industry since I have a greater knowledge of the stakeholders involved and a deeper understanding of how the clinical research process works along with its complex intricacies.
The clinical research coordinator, or CRC, is an essential member of the research team, the stakeholder who conducts the study as discussed above. This member plays a critical role in organizing a site's participation in the expanding arena of clinical trials. The primary function of the CRC is to manage and coordinate the smooth, accurate progress of clinical protocols from the planning stage through study completion by acting as a liaison to other member stakeholders including the investigator, the subject, the research site, the IRB, and the sponsor. The reason why this role holds such great importance is because the CRC is at the center of the study process. The CRC assists in the development, review, and maintenance of conducting a study in accordance with appropriate SOPs, GCPs, and regulatory guidelines. This includes assisting in the review of protocols, checking for protocol feasibility, preparing documents for IRB submission, recruiting and screening study participants, obtaining informed consent from study subjects, facilitating continued participation of subjects, and tracking study progress while maintaining compliance (Woodin, 2004).
Considering this multi-faceted role and the many responsibilities that it entails, sometimes it can be a struggle to remain afloat. This individual stakeholder holds the task of maintaining efficiency and effectiveness in conducting all trial activities. Since the CRC is heavily relied on by many stakeholders, the CRC must be aware of all activities of the trial and what goes on at the site. Any slip ups may lead to problems. Since the CRC interacts with such a variety of stakeholders, it is likely that conflicts and moments of tension may arise. For instance, one common complaint from some CRCs may be due to having an investigator who leaves all the work for them to do while the investigator hardly ever shows up at the site. This may certainly build tension between the CRC and the investigator and may even lead to CRC burnout (Woodin, 2004). In the worst case scenario the research site may lose the CRC which could be devastating to the study since the CRC maintains much of the workload and streamlines the operations of the study. In another scenario, should the CRC remain at the site, the CRC may use the wrong consent form for a patient and not realize it due to being overworked. This would cause a problem for the investigator and for the subject. The subject would need to be re-consented and the investigator must report the events and actions taken to the IRB and the Sponsor.
Conflicts and Tension among Stakeholders
Regardless of the position or type of stakeholder, anyone who works in clinical research knows it is a very cooperative field. Many aspects of the clinical research process rely on much collaboration, partnerships, and forming alliances. Teamwork is an essential skill for every clinical research professional since their jobs require working with all kinds of people. This explains why the industry has so many stakeholders involved. However, in this vastly interdependent environment, it is important to remember that different stakeholders have different interests and their collaborative efforts are driven by varying motives (Johnson, 2005). Of course, each stakeholder most likely wishes to protect their interests but as a result, there are times when conflicts and tension may arise and stakeholders may not see eye to eye. The following will explore cases which demonstrate this point.
Case Study #1: Discovering and Reporting Falsified Data
A sponsor contracts with a CRO to monitor their study. During an inspection, the FDA discovers falsified records at the site. Both the sponsor and the CRO conduct their own follow-up inspections in which it is later revealed that the CRO’s records contained falsified data. However, this was not known until after the study was completed at the site. This information was then reported to the sponsor, but the sponsor denies ever receiving such information from the CRO. Thus, the falsifications were never reported to the FDA by either party (Woollen, 2000).
When analyzing any situation such as this, it is important to understand each stakeholder’s roles and responsibilities. In this case, the stakeholders involved are the FDA, the sponsor, the investigator and the CRO. Under the FDA’s Code of Federal Regulations (21 CFR 312.56) “the sponsor shall monitor the progress of all clinical investigations being conducted under its IND.” At the same time, 21 CFR 312.52 states that any or all sponsor obligations may be transferred by contract. In other words, the CRO in this case agreed by contract to take responsibility in monitoring the trial progress and all other aspects of the study. Therefore, the CRO and the sponsor would be held accountable since the CRO that assumes any obligation of a sponsor is subject to the same regulatory actions as the sponsor. Although the CRO reported its findings to the sponsor, the sponsor denies ever receiving any report. This would require further investigation as to whether or not the CRO truly did sent in a report or if the sponsor is merely blaming the CRO. Furthermore, the investigator who was involved in the study is also accountable since he is responsible for conducting the study, supervising the study, and for maintaining adequate and accurate records of the study. Thus, the investigator should have been terminated for the falsification of data and for failure to follow the responsibilities as indicated by the regulations and in FDA Form 1572. Nevertheless, the situation could have been avoided or at least minimized if the CRO also reported to the FDA in addition to reporting to the sponsor. That way, even if the sponsor denies receiving the report, the CRO would have still fulfilled its responsibility by reporting to the FDA.
Case Study #2: A Fifteen-Foot Span of Misconduct
In another study, subjects were asked to read an eye chart from a distance of fifteen feet as indicated in the trial’s approved protocol. The subjects stood at the marking point instructed to read the chart and did so during every visit. Upon the time of monitoring, the CRA that arrived at the site decided to measure the distance and discovered it to be only thirteen feet. It was then revealed that the investigator was aware of the discrepancy but he figured it was not that significant. As a result, he did not think it was important to mention and continued to use the shorter distance (Woodin, 2003).
Based on the information in this case, the stakeholders involved are primarily the CRA and the investigator. The investigator clearly failed to conduct the trial in accordance with the approved protocol, failed to follow the agreements in FDA Form 1572, and deliberately continued to use a measurement fully knowing that it was incorrect. Consequently, the data was rendered completely useless which in turn was a waste of time, effort, and resources for those involved in the study. The CRA was vigilant to measure the distance since it may not have been discovered at all. As part of the CRA’s responsibility, he would have to make a report of this situation and inform the sponsor and CRO. The sponsor would then determine what corrective action would be required including the investigator’s termination from the study and make a report to the FDA as well. Unfortunately, this case could have been easily avoided simply by using the correct distance measurement from the beginning. If the CRA had measured the distance before the subjects were enrolled it would have made a great difference in saving the study from being wasted.
Case Study #3: What’s in the flu vaccine?
On June 30, 2006, the FDA issued a warning letter to Sanofi Pasteur Inc., after performing an inspection of one of the company’s facilities in Swiftwater, PA. Inspectors observed several objectionable conditions and discovered issues of sterility failure and general failures of good manufacturing practices in the production of the Fluzone® vaccine and other licensed biological products (Holland-Moritz, 2006). According to the warning letter Sanofi was reported to have significant deviations from current good manufacturing practices including, but not limited to (FDA, 2006):
Failure to keep equipment and supplies used in, work on, or otherwise exposed to any potentially pathogenic agent separated from other equipment and supplies to prevent cross-contamination.
Failure to establish a system for maintaining equipment to control aseptic conditions
Failure to follow appropriate written procedures designed to prevent microbial contamination of drug products purporting to be sterile.
Failure to establish the accuracy, sensitivity, specificity, and reproducibility of test methods established by the firm.
Failure to report any event and relevant information associated with the manufacturing of a licensed biological product that represents a deviation from current good manufacturing practice.
Failure to inform FDA about a change to a licensed product stability testing program.
Among the violations, one of the most serious pertains to the manufacturing of monovalent concentrate, an intermediate derived from one of the three influenza strains used to produce Sanofi’s Fluzone® vaccine. As many as eleven batches of the monovalent concentrate were discarded when they failed the sterility test as a result of bacterial contamination (FDA, 2006). These concerns raised speculation as to how this would impact the production and distribution of the influenza vaccine during the 2006-07 flu season.
Of course, the stakeholders here are Sanofi and the FDA. This is an example of what happens when a stakeholder fails to follow the regulations; a warning letter is typically issued. The reason for the warning letter in this case is due to deficiencies and reasons of noncompliance. When such a letter is received, it should be taken seriously as it indicates the risk of further regulatory action by the FDA. For this reason it is advisable to provide a timely response and take immediate corrective action to rectify the deficiencies or non-compliance described in the warning letter. In this case, Sanofi was fortunate since both the company and the FDA confirmed that the contamination did not reach the finished vaccine and so no recall was required (In-PharmaTechnologist, 2006). Nevertheless, Sanofi was required to take sufficient remedial action in order to avoid license suspension, revocation, seizure, or injunction from the FDA.
The clinical research industry is made up of many stakeholders and each hold varying interests. However, there is a common goal that leads these stakeholders to form alliances and work together to overcome tensions that may arise along the way. Sponsors continue to compete for innovation and to be at the cutting edge of new advancements in medicine. Regulatory agencies are expanding their efforts in ensuring the safety and efficacy of new drugs, biologics, and devices. All the while, patients and consumers watch the changes in market as prices increase and new drugs are introduced. In an industry where many stakeholders are involved and even more are affected, there are many expectations and increased pressures to meet the needs of many sides. Some wish to make a significant discovery, some wish to make a profit, and others merely wish for a cure. Perhaps no other industry can influence so many parties and affect so many lives as remarkably as the clinical research industry.
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