How to Set Up a Successful Investigative Site
Email: [email protected]
May 30, 2007
According to a recent Impact Report by Tufts Center for the Study of Drug Development, pharmaceutical companies now have an average total R&D cost of $802 million per new drug entity and $897 million, if both pre-and post approval phases are included. Pharmaceutical companies must initiate their clinical trials in an increasingly efficient manner to ensure thorough protocol development, prompt regulatory readiness, high quality, cost-effective study initiation training, accurate and efficient study supply delivery, steady enrollment, quality data collection, monitoring, reporting, timely issue resolution, data locks, and study closeout. All of these functions must be done within a set budget and timeline.
This is a difficult, multitask assignment that might become even more difficult as the medical industry braces for the aging baby boomers. Couple this with potential investigator shortfalls, stricter regulations, and tighter trial budgets as the industry tries to control drug development costs. What might be a potential option for accomplishing the challenge of developing drugs while lowering costs and decreasing development times? 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 needed to build a firm foundation for growth with quality.
The site evaluation is a critical step for both the sponsor and the site. For the site, these visits determine whether or not they will be selected to participate in the research, while for the sponsor, they are the primary method of determining the best sites to conduct their studies.
When a sponsor or contract research organization (CRO) is looking for investigative sites for a protocol, the first contact is usually by telephone. If it appears that there is a high level of interest in the protocol on the part of the potential investigator, and if the sponsor feels there is good potential for placing a study at the site, it will arrange a time to visit the site in person. This will enable the sponsor to better evaluate the investigatorâ?Ts capability to do the project. Many companies require that a signed confidentiality agreement be signed before the protocol is discussed. In this case, they will fax or mail an agreement to the site and have it signed and returned before sending the materials. When a sponsor makes an evaluation visit to a potential investigative site, he or she will be evaluating the investigatorâ?Ts experience, expertise and interest in the trial, as well as the staff, facility and potential patient population available. The sponsor may have a checklist that will guide the CRA in making an assessment. The main attributes assessed in an evaluation visit are the investigatorâ?Ts experience, expertise and interest. The sponsor will want a copy of the investigatorâ?Ts curriculum vitae (CV) in order to make a general assessment of the investigatorâ?Ts experience and expertise. The sponsor will also want to know if the investigator has conducted similar trials to the one being proposed, or has worked with similar compounds. The sponsor will also want to evaluate whether the site has sufficient staff and an appropriate facility to do the study. Many sponsors will not place a study at an investigative site that does not have a clinical research coordinator (CRC). During the visit, the CRA will want to meet with the CRC and spend some time interviewing them. Not only must there be appropriate people available for a study, but they must have sufficient time to do the necessary work. There are several factors a CRA will want to discuss during an evaluation visit. One is whether or not the site is doing or planning to do within the same time period, any competing studies. Another factor is the timing for the study. If the site has too many active studies at the same time, a study may not get the attention it needs to be done well. The CRA will also want to check on the laboratory and pharmacy, if either will be used for the study, to ensure that laboratory accreditations are current and the facilities are adequate to perform the necessary study activities. The importance of the site evaluation visit cannot be overstated. It is this visit, more than any other factor that determines whether or not the site will be selected to participate in the research. Consequently, the investigator and CRC should be well prepared for the visit and ready to show their site at its best.
Budgeting, Grants and Contracts
Protocols have become more complex, calling for more procedures, on average. This means that sites must be careful about whether or not they can actually afford to do a study, without losing money, and that they will need to be very selective about the projects they decide to take on. There are many hidden costs that the investigative site has to beware of. Investigative sites are typically taking on clinical projects that require an estimated $4,000 to 6,000 in hidden cost per study that are not being reimbursed by sponsors and CROs. Some Sponsors will determine a range or a single per subject grant figure that they will pay and will not budge from this figure. Investigators either accept it or will not be able to do the study. Other sponsors will allow more flexibility, depending on experience with an investigator or geographical location. Costs do differ in different parts of the country, so it makes sense to allow some flexibility. CRCs often help investigators when it comes to figuring a budget and determining an appropriate grant amount for a study. A good way to come up with a grant figure is to look at each study activity, attach a cost to it, add an additional amount for overhead and other required activities, and total it up. The charge for each item should also include the cost of the time of the person performing it. An example of an Uncompensated PI costs for a hypothetical study is shown below.
Example of Top Uncompensated PI Costs 18 week, 10 subject trial
Investigator Meeting Attendance
Case Report Form
Initiation Visit Attendance
Adverse Event Management
CRA Meetings and Interactions
An example of a grant worksheet for a hypothetical study is shown below.
Number of Visits
Treadmill stress test
Subtotal for Procedures
Grand Total per completed subject
In the example shown there are three visits that are more labor-intensive, the three that involve physical exams and stress testing. To determine the prorating dollar amount, each of these visits should count as two and the other five visits should be counted as one, for a total of eleven. If the cumulative amount of $5,152 is divided by 11, the cost per visit is $468.36. Based on this, the three more intensive visits should be prorated at $937, and the other five at $468 (with the extra dollar added to the cost of the last visit). Note that if a subject drops out after visit 3, the investigator would be paid $1,837. For a subject dropping out at Week 7, the payment would be $4,214, and so forth. This is a simple way of calculating grants and prorating visit cost, but it is quite effective if the initial amounts for each procedure and activity are realistic. It is easy to explain and should help the investigator and the CRC in negotiating a grant amount that is fair to both the sponsor and the site. If the CRC is involved in grants, he or she must have a good understanding of both the process and the specifics for each protocol in order to be able to discuss the grant with the investigator and the sponsor, and to track the figures to ensure that all sums are paid as appropriate. A contract between the Sponsor and the investigator will be signed before the trial starts at a site. This document usually contains the responsibilities of the investigator, including the number of subjects the site is expecting to enroll, timelines for enrollment, grant amounts and the regulatory requirements for the investigator. It also contains the responsibilities of the sponsor, including when and how the grants will be paid, monitoring of the study and sponsor regulatory requirements. The investigator should always request for an indemnification clause from the sponsor. It will be signed by the appropriate company representatives, and by the investigator. ( Note that in larger institutions contracts may be signed by someone in the contract office, rather than by the investigator.) Contracts are rarely written, negotiated or signed by the CRC, although he or she may have input into the contract when working on it with the investigator.
Study Initiation meetings
The study initiation visit, sometimes known as the start up visit, is held at the investigatorâ?Ts site just before the study begins. The CRA, and sometimes additional sponsor personnel, will meet with the investigator and the supporting staff. The purpose of the meeting is to review the study protocol, processes and procedures to ensure that all site personnel understand what is necessary to perform the study.
The study initiation should be held at the point when all regulatory paperwork is complete for the site and the study drug and other supplies have been shipped, but before any subjects have been enrolled. Many sponsors will not allow the site to begin enrollment until after this meeting is held. A good meeting may take half a day, or even longer for a very complicated study, so you may have to work with your sponsor to find a time when all your relevant staff is available for a meeting.
The CRA is almost always in charge of the initiation meeting, although the sponsor medical monitor and/or an in house associate monitor may also be present. It is important that all site personnel who will be involved in the study attend the meeting. The initiation meeting provides an opportunity for everyone at the site to become familiar with the study and to understand everyoneâ?Ts study role.
After the meeting, the CRA will complete a visit report detailing what was discussed and completed during the visit. Many companies have a special visit report for this meeting. ICH Guidelines call for a trial initiation monitoring report that documents the trial procedures were covered with the investigator and his or her staff; this report is to be kept in both the sponsor and investigator study files. The same purpose can be accomplished by the CRA sending the investigator a letter listing what was covered during the meeting. This meeting can go a long way in helping to ensure a successful study. It deserves the full attention of the CRC, the investigator and other involved staff.
Working with CRAs
For actual study conduct the study coordinator or CRC is the most important person at the site and the CRA is the most important sponsor representative. Since they will be spending a lot of time working on the study together, the CRC and the CRA must establish a good working relationship. Monitoring can be relatively easy and enjoyable or it can be a nightmare; the difference is often dependant upon the relationship between the CRC and the CRA. It takes time to develop a rapport with the CRA and to develop a monitoring visit routine that works well for both of you. Each person needs to understand how the other works. The CRA should determine the best times and methods for routine communications with the CRC and let the CRC know the sponsor expectations. Some CRCs, and some CRAs, simply have better interpersonal relationship skills than others do. Itâ?Ts amazing what a smile and good manners will do. Taking the CRA to lunch occasionally is a nice gesture. Remember, however, to always maintain a professional relationship. Itâ?Ts easy to develop a friendship over the course of a long study, but you still need to remember that it is a business relationship.
Some sponsors will hire a contract research organization (CRO) to do the study monitoring for a project. The dynamics of the working relationships among the CRC, the CRA, the sponsor and the CRO can be complex. If not clearly defined during the investigator meeting, the study initiation meeting is a good time to clarify the communication channels for the study. The CRC may be required to communicate regularly with the CRO for some things, such as enrollment updates, and the sponsor for other things, such as serious adverse event reporting. Whatever the situation, being clear on the correct reporting and communication procedures will help the study progress smoothly.
A good relationship with the sponsor throughout the study is one of the major factors in obtaining more studies from the same sponsor. Being able to maintain a good relationship with the CRA, whether a sponsor or CRO person and timely and correct communications about other issues is not only a good for the study, but is good public relations for your site.
Shipping of Biological Samples
The packaging and shipping of biological samples is often the responsibility of the CRC. These activities are highly regulated, and there are significant fines for not complying with the regulations. All North American airlines and FedEx, the largest shipper of infectious materials, use the IATA regulation as their standard. Meeting the conditions of this standard will ensure meeting the provisions of the other US regulations. Many sponsor companies require evidence of training in this area when it is relevant for their trial.
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, starting from day one. This raises the bar for patient safety, and should enhance outcomes of monitoring visits. 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. 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. 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. 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. 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. 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.
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). 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
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), divisions of FDA, there are approximately 300 onsite inspections annually of U.S. clinical investigators. Inspections can last anywhere from several days for routine inspections to a few weeks if serious problems are uncovered. Through its Bioresearch Monitoring (BIMO) Program, the FDA carries out three types of clinical investigator audits:
* Study-oriented Inspection
* Investigator-oriented Inspection
* Bioequivalence Study Inspection
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.
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 and you are sure to have a successful clinical trial that will run smoothly and cost efficient for all parties involved.
1.Tufts Center for the Study of Drug Development, “Impact Report: Post-Approval R&D Raises Total Drug Development Costs to $897 Million,” 5 (3) May/June 2003.
2.J. Carpenter, “21 CFR 11 Compliance at Investigator Sites,” Applied Clinical Trials, 12
(7) 35 (July 2003).
3. 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).
4. Definition of Quality Assurance, praxiom.com/ accessed September 25, 2003.
5. Food and Drug Administration, www.fda.gov/oc/gcp/default.htm accessed September 25, 2003.
6. “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.
7. 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).
8. Ibid., The Monitor, p. 30.
9. B.M. Miskin and A. Neuer, How to Grow Your Investigative Site (Boston, MA, CenterWatch, 2002), www.centerwatch.com/bookstore/pubs_profs_grwinv.html.
10. FDA Information Sheets, Guidance for Institutional Review Boards and Clinical Investigators, www.fda.gov/oc/ohrt/irbs/operations.html#inspections. accessed September 25, 2003.
11. Ibid., FDA Information Sheets, accessed September 25, 2003.
12. www.fda.gov/oc/ohrt/irbs/operations.html#inspections. accessed September 25, 2003.
13. The CRCâ?Ts Guide to Coordinating Clinical Research by Karen E. Woodin, PH.D.
14. Thomson Centerwatch
15. Clinical Trials.gov
16. Guide to Monitoring Clinical Research by Karen Woodin & John Schneider
17. Department of Health and Human Services
19. Government Clinical Trial Website