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Contents

Module 1: Becoming an Investigator: Considerations ................................................................... 8

Including Clinical Trials in Your Practice ..................................................................................... 8

Becoming an Investigator ........................................................................................................... 8

Investigator Benefits ................................................................................................................... 9

Patient Benefits ........................................................................................................................... 9

Patient Safeguards .................................................................................................................... 10

Changes to Your Practice .......................................................................................................... 10

Why become an investigator .................................................................................................... 12

Investigator Responsibilities ..................................................................................................... 13

What you can offer ................................................................................................................... 14

Module 1 Quiz ........................................................................................................................... 14

Module 1 Summary ................................................................................................................... 16

Module 2: Initial Site Preparation ................................................................................................. 17

Initial Considerations ................................................................................................................ 17

Ways to Participate in Trials ..................................................................................................... 18

NCI’s Clinical Trials Cooperative Groups ................................................................................... 18

NCI’s Community Clinical Oncology Program (CCOP) ............................................................... 18

NCI’s Cancer Trials Support Unit (CTSU) ................................................................................... 19

NCI’s Cancer Centers Program .................................................................................................. 19

Private Industry-sponsored Trials ............................................................................................. 19

Identifying an IRB of Record ..................................................................................................... 20

Identifying an IRB of Record ..................................................................................................... 21

The NCI CIRB ............................................................................................................................. 21

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The NCI CIRB Process ................................................................................................................ 21

The NCI CIRB Process ................................................................................................................ 21

Registering with the FDA: The 1572 Form ................................................................................ 22

1572 Form Commitments ......................................................................................................... 22

Additional Requirements .......................................................................................................... 24

Quiz ........................................................................................................................................... 25

Module 2 Summary ................................................................................................................... 26

Module 3: Choosing the Trial(s) .................................................................................................... 27

Choosing a Specific Trial............................................................................................................ 27

Factors to Consider ................................................................................................................... 27

Processes to Assist Trial Selection ............................................................................................ 28

Established Forms and Procedures ........................................................................................... 29

Funding and Reimbursement ................................................................................................... 29

Startup and Ongoing Expenses ................................................................................................. 30

Sponsor Reimbursement .......................................................................................................... 30

Insurance Reimbursement ........................................................................................................ 30

Medicare Coverage ................................................................................................................... 32

Local Institution Support ........................................................................................................... 33

Module 3 Quiz ........................................................................................................................... 33

Module 3 Summary ................................................................................................................... 35

Module 4: Building and Training the Research Team ................................................................... 35

The Core Research Team .......................................................................................................... 35

Team Roles are Varied .............................................................................................................. 36

The Principal Investigator (PI) ................................................................................................... 36

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Co-Principal Investigator ........................................................................................................... 36

Clinical Research Coordinator ................................................................................................... 37

Clinical Research Coordinator Role ........................................................................................... 37

The Data Manager .................................................................................................................... 38

Staff Nurses ............................................................................................................................... 38

Research Team Tips .................................................................................................................. 39

Research Team Networks ......................................................................................................... 39

Training the Research Team ..................................................................................................... 39

Planning a Training Program ..................................................................................................... 40

Goals of Training Program ........................................................................................................ 40

Formal Onsite Training .............................................................................................................. 41

Ongoing, Informal Training ....................................................................................................... 41

Module 4 Quiz ........................................................................................................................... 42

Module 4 Summary ................................................................................................................... 43

Module 5: Handling Site Logistics ................................................................................................. 44

The Site’s Logistical Requirements ........................................................................................... 44

Record Keeping & Reporting ..................................................................................................... 46

Source Documents .................................................................................................................... 46

Source Document Examples: Medical Reports ......................................................................... 46

Source Document Examples: Progress Notes ........................................................................... 47

Source Document Examples: Screening Log ............................................................................. 47

Source Document Examples: Other Examples ......................................................................... 47

Creating & Preserving Source Documents ................................................................................ 47

Case Report Forms (CRFs) ......................................................................................................... 48

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CRFs and Source Documents .................................................................................................... 48

Regulatory Documents ............................................................................................................. 48

Regulatory Documents ............................................................................................................. 49

Additional Documents & Records ............................................................................................. 49

Avoiding Documentation Pitfalls .............................................................................................. 50

Drug Accountability................................................................................................................... 50

Drug Accountability Tasks ......................................................................................................... 51

Quality Assurance: Good Clinical Practices ............................................................................... 51

Quality Assurance: Standard Operating Procedures ................................................................ 52

QA Helps Meet Requirements .................................................................................................. 52

Final Step: Seeking IRB Approval .............................................................................................. 52

Module 5 Quiz ........................................................................................................................... 53

Module 5 Summary ................................................................................................................... 54

Module 6: Recruiting and Enrolling Participants .......................................................................... 56

Successful Recruitment ............................................................................................................. 56

Collaborating on a Process ........................................................................................................ 56

The Recruitment Process .......................................................................................................... 57

Step 1: Identify the number of participants you will need to recruit ....................................... 57

Step 2: Strategies: Determine you recruitment strategies for the trial ................................... 57

Step 2: Identify barriers to recruitment .................................................................................... 58

Step 3: Screening Participants: Eligibility Criteria ..................................................................... 58

Step 3: Screening Participants: Informed Consent ................................................................... 59

Step 3: Screening Participants: HIPPA ...................................................................................... 61

Step 4: Enrolling Participants: Registration & randomization .................................................. 61

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Step 4: Enrolling Participants: Logistics .................................................................................... 62

Step 5: Document and evaluate your process .......................................................................... 62

Recruiting underrepresented populations: Main Challenges................................................... 63

Recruiting underrepresented populations: NIH Revitalization Act of 1993 ............................. 63

Recruiting underrepresented populations: Recruitment strategies ........................................ 64

Adherence: Retaining participants ........................................................................................... 64

Adherence Tips ......................................................................................................................... 65

Adherence & Follow-up ............................................................................................................ 65

Module 6 Quiz ........................................................................................................................... 65

Module 6 Summary ................................................................................................................... 66

Module 7: Working with Referring Clinicians ............................................................................... 68

The Referring Clinician’s Key Task ............................................................................................ 68

A Collaborative Relationship ..................................................................................................... 68

Referring Clinician’s Role .......................................................................................................... 68

The Research Team’s Role ........................................................................................................ 69

Clinical Trial Education .............................................................................................................. 69

Module 7 Quiz ........................................................................................................................... 71

Module 7 Summary ................................................................................................................... 72

Module 8: Ensuring Study Integrity .............................................................................................. 73

Tasks During the Trial ................................................................................................................ 73

Adverse Event Reporting .......................................................................................................... 73

Compliance with IRB Requirements ......................................................................................... 74

Compliance with IRB Requirements: Continuation or annual review ...................................... 74

Compliance with IRB Requirements: Protocol amendments or revisions ............................... 74

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Compliance with IRB Requirements: Adverse events .............................................................. 75

Ongoing informed consent ....................................................................................................... 75

Quality Assurance ..................................................................................................................... 75

Quality Assurance: Preparing for an audit ................................................................................ 76

Quality Assurance: Internal QA ................................................................................................. 76

Quality Assurance: The audit .................................................................................................... 77

Module 8 Quiz ........................................................................................................................... 77

Module 8 Summary ................................................................................................................... 78

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Module 1: Becoming an Investigator: Considerations

Including Clinical Trials in Your Practice

Welcome to the course “Including Clinical Trials in Your Practice: An Overview”

With this course, you’ll be able to explain the value of including NCI-sponsored clinical trials in your practice. You’ll also be able to describe the steps involved.

We’ll review:

• The benefits and responsibilities of conducting NCI-sponsored clinical trials,

• Preparing your site for trials, which involves finding a suitable research group as well as registration and credentialing,

• Choosing an appropriate trial for your practice,

• Establishing a research team,

• Recruiting and enrolling participants, and

• Ensuring data integrity.

After every module, you’ll have the opportunity to test what you’ve learned by taking a brief quiz.

Let’s begin!

Becoming an Investigator

This module will introduce practical considerations and responsibilities associated with becoming an investigator.

Upon successful completion of this module, you’ll be able to:

• List the benefits of being a clinical trials investigator,

• Identify the benefits and safeguards for participants,

• Describe how incorporating clinical trials will affect your practice,

• List the responsibilities of a clinical trials investigator, and

• Explain how to determine whether clinical trials are a good fit for your practice.

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Investigator Benefits

Becoming a clinical trials investigator offers you the following benefits:

• A greater awareness of cutting-edge therapies and the ability to access new treatments;

• A new and/or increased patient base that seeks access to state-of-the-art science and treatments only available through clinical trials;

• Continuing medical education as well as state-of-the art cancer education and research from the National Cancer Institute;

• Increased opportunity to consult with experts in the field, and the chance to be a source for a “second opinion”;

• Greater access to limited-institution trials;

• The potential to achieve additional professional and institutional credentialing as well as opportunities for a part-time faculty appointment; and,

• Ultimately, satisfaction from knowing that you are contributing to the advancement of cancer care.

Patient Benefits

Clinical trials can benefit your patients in the following ways.

• Trials within your practice allow patients additional treatment options - beyond standard care - that may be on the cutting edge.

• Through a clinical trial, patients may have access to investigational agents, devices, imaging studies , technology, equipment, or novel diagnostic techniques at no additional cost.

Clinical trials have led to significant advancements in breast cancer care. For Example the biologic agent trastuzumab, or “Herceptin,” has dramatically improved care for women with breast cancer that harbors HER2 receptor proteins, which represents about 25% of new breast cancer cases. Women participating in clinical trials were the first to receive and benefit from treatment with trastuzumab, and participants in ongoing clinical trials of this agent continue to be the first to benefit in new treatment settings.

According to a 2005 survey, only 9% of newly diagnosed cancer patients were informed about the possibility of participating in a clinical trial. A majority of those who were offered the chance agreed to participate in a trial.

Many clinical trial participants have expressed satisfaction and appreciation for the attention they received during the trial. Also cited as a benefit is the close follow-up that participants receive after treatment.

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Video Statements:

Diane, a cancer patient, discusses her participation in a clinical trial:

“For me, participating in a trial was receiving treatment but with a lot of special attention. I got a whole lot of extra attention every time, and I felt that I really benefited from that, because there were more people looking at my case than if I had just been in there in a standard treatment situation.”

Ariceli, a cancer patient, discusses her participation in a clinical trial:

“They treat you as a human being; and they care for you a lot; and it seems that you are much more important than their experiment. They give you more attention because this is experimental. And they try to make sure everything’s going well, so they have to keep a closer eye; they have to monitor my body more, my blood work more.”

Patient Safeguards

Clinical trials have associated risks. However, safeguards are built into the process to protect participants.

• Prior to accruing participants, a trial must be approved by an Institutional Review Board, or IRB.

• The research protocol must ensure consistency in study procedures and minimize potential risks for participants.

• Additional protection measures include strict adherence to the protocol as well as close monitoring and timely reporting of adverse events.

• Several federal regulations exist to protect participants involved in clinical trials.

Changes to Your Practice

Experienced researchers understand that their practice may grow as a result of clinical trial participation. One reason is that the practice may be viewed in the community as one that offers cutting-edge cancer treatment and care options.

At this point, you may be concerned about the administrative burden associated with conducting clinical trials. Will it be overwhelming? Will your time be compensated?

Dr. James Atkins, an oncologist in Goldsboro, North Carolina, describes how clinical trials have affected his practice

"Well, since the practice has grown, when I originally came to this town, I was actually told that this town could not support an oncologist, that it wasn't big enough, and now - you know we now have four medical oncologists and a radiation oncologist, and the

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radiation oncologist is extremely active in our GOG clinical trials, he's putting as many as 20 to 25 people on RTOG trials a year, so he is extremely active in clinical research in our group as well, so it has, it has been very good for our practice, for the community.” "I started off with a half time person doing data management, then we got two half time people, then full time and right now we actually have one full time data manager per doctor. Because we've put that many people on clinical trials that we need that."

You will need to consider these changes to your practice if you plan to facilitate clinical research.

• First, establish dedicated time for research. As an investigator, you have the responsibility for supervising each trial, interacting with the IRB, developing budgets, dealing with audits and inspections, and performing other duties.

• Balance your work time between conducting clinical trials and your regular and customary duties. One estimate is that after you’ve become familiar with the regulatory, scientific, and fiscal components, you can be quite successful by allocating 10 to 15% of your time to conducting trials.

• Some travel may be required, but will also be a benefit. Investigators may participate in meetings where protocols are developed and study progress is reviewed and evaluated. These are also opportunities to network with experts in the field.

Dr. James Atkins discusses specific impacts to his practice:

"To me, it doesn't take any extra time to treat them on a clinical trial as it does off a clinical trial, so I don't see a time factor in having somebody on a clinical research trial. The administrative time is primarily going to the IRB meetings and presenting a clinical trial or answering questions that they may have. But otherwise from an administrative point of view at the community level, I don't see a lot of extra burden.” "There is some administrative burden for the clinical research professionals, the data managers - somebody obviously has to work with the protocols and get them through to the IRB and get them approved and keep up with the paperwork, so there is an administrative component that other people are also involved with, but for me as a physician, I don't see a significant administrative burden." "Your time can be compensated in many, many ways.” "The monies that we are reimbursed technically cover part of data management and technically there's nothing there to really cover physician time and effort but, my compensation comes from taking care of my patients, my compensation comes from the typical clinical oncology that we all do.”

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"Word of mouth and the fact the people know that we're involved in clinical research is an extremely important issue in maintaining your referral base."

Why become an investigator

Health professionals become investigators for many reasons. Ultimately, they want to help advance science and provide better cancer prevention and treatment to the public.

When determining whether you should participate, it may be helpful to hear from colleagues who have been there.

Dr. Atkins discuss why he became an investigator, and recommendations for new investigators

"After I got out into practice, I decided that it was very important to be involved in the clinical trial system. I knew that the most exciting advances that were going to occur in oncology were probably going to occur in the next 20 years. Here we are 18 years later, and I was right - we are at a very exciting time in oncology, and so I wanted to be in the action. I wanted to be involved in the clinical research and what was going on nationwide; I didn't want to get left behind.” "Being a part of the clinical trial system, I'm involved with new protocols, new concepts, new ways of looking at things, from the very beginning. I think there's a lot going on right now in the grassroots efforts to educate patients. We're going to see more and more patients requesting clinical trials and the doctors who are not in the system are going to lose market share." "If a new researcher wanted to...a new person wanted to get involved, then you can say okay, I'm only going to open two clinical trials. They can say I'm only going to open up two. I'm going to open one up for colon cancer; I'm going to open one for breast cancer. And I will put every single one of my new colon cancers on that clinical trial, and I will put every single one of my new breast cancers on that breast cancer trial. And just by doing that, I would expect that most clinical oncologists should be able to put 10 people anyway, if not more, on clinical trials a year.” "The bottom line is you need doctors who are interested in doing the clinical trials, who want to answer the questions, who want to be a part of the system, because it costs money to get the system - a community up and running. It will cost probably $5,000 - $10,000 and so you don't want to put $5,000 - $10,000 into developing a community and then have them not put anybody on.” "One of the things that I would recommend is that they have their own data manager. It doesn't mean the person has to be full-time. They can be half time. I think that one of the errors that people make is not taking the commitment.”

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"It has to be a philosophical commitment too. They need to make the commitment that clinical trials represent the cutting edge of medicine. I'll look at the clinical trials as the very best...that the best cancer minds in our country have put together.” "I think that they need to be willing to say I don't know which treatment is best and therefore I am going to do this clinical trial, and they have to believe that. They may have biases, okay, and I had biases. And we have to acknowledge what our biases are when we do clinical research."

Dr. Gorsch discusses why he offers patients clinical trials, and his recommendations for reducing the administrative burden:

“There have been some classic examples in oncology where we have done the wrong thing because we didn’t have the data and people were reluctant to get the data. For years in the treatment of lymphoma, it looked like newer regimens were better than the older regimens. And it made sense intuitively. When the studies looking at a comparison directly between the newer and the older regimen were finally done, we found that the older regimen was just as good and less toxic than the newer regimens. So if we’re going to do our patients a service, we need to know that what we do works. And the only way we really know is by participating in clinical trials. And I love being able to offer patients clinical trials and say to them, ‘Look, this is, to our knowledge, the state of the art—the best that we have. ‘Only by doing these studies are we really going to know what is really the best treatment. That’s the principal reason we decided to participate.”

"The single best thing they could do is to hire a good data manager. If you have a good data manager, she can support you and do the lion's share of the paperwork in terms of scheduling the appropriate tests, filling out the right forms, checking the eligibility on patients.” "Being a participant through a major university as a sponsor is helpful because then you have their resources as well as a backup. It's not very difficult to do. When you come right down to it, having - offering clinical studies, clinical trials is really not difficult, provided that you have someone helping you with the paperwork."

Investigator Responsibilities

Serving as a clinical trials investigator is rewarding in many ways, but it also requires commitment and research expertise. The investigator is ultimately responsible for overseeing the conduct of the study at his or her site. These responsibilities may include:

• Protocol management,

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• Maintenance of an adequate rate of patient accrual to studies,

• Supervision and training of research team members,

• Compliance with federal, state, and institutional regulations,

• Assurance that the highest standards of ethics and quality are met,

• Provision of informed consent to patients and compliance with all human participants protection regulations,

• Management of investigational agents,

• Assurance that there is no financial conflict of interest, and

• Participation in the auditing and quality assurance process.

For more details on investigator duties, please visit the CTEP Investigator’s Handbook on Cancer.gov.

What you can offer

There are many ways to become an investigator. While exploring options, it’s important to choose a good fit; that is, one or more trials that will best serve your practice, your patients, and your community.

Consider your practice. Is it prepared to incorporate clinical trials? You must dedicate time and staff resources to research, as well as be personally committed. Do you envision running a few studies versus a large amount? For new investigators, it’s often better to conduct one cancer study well than attempt 10 at once and run them poorly.

Also consider your patients. Is your patient population receptive to participating in a trial? Do you have

patients whom you know would benefit from a trial?

And finally, consider the impact to your community. Providing clinical trials increases the community’s

options for treatment, bringing state-of-the-art science to where patients live. But, you must consider to

what extent your community is willing to support the trials you plan to introduce. And, you’ll need to

take time to educate your patients and community.

Next, let’s test your knowledge with a short quiz on what you’ve learned in Module 1.

Module 1 Quiz

Question 1: Which statement about the benefits of clinical trials is incorrect?

a) Clinical trial investigators can provide their patients with opportunities for new treatments, even in rural clinics

b) Patients will have to split their clinic time between the clinical trial they participate in, and their regular course of treatment

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c)

d)

Costs may be reduced for patients in clinical trials for services such as investigational agents and imaging studies

Correct Answer: b Patients who participate in clinical trials do so in lieu of their regular course of treatment

Question 2: Establishing clinical trials research within your practice could affect it in what way?

Safeguards for patients include IRB review and adverse event reporting

a) b)

Reducing the time you spend on your regular practice by at least half

c) Necessitating hiring a large staff

d)

More opportunities to network with other investigators to review protocols, review and evaluate studies, and network with experts in the field, which could also take time away from your practice

Correct Answer: c Clinical trials provide you with the opportunity to network outside your practice with other investigators and experts in the field, which will also take time away from your practice

Question 3: Serving as a clinical trials investigator is rewarding in many ways, but it also requires commitment and research expertise. Responsibilities of an investigator include all of the following EXCEPT:

Diminished ability to hire staff to facilitate your existing practice

a) b)

Supervising research team members

c) Participating in the auditing/quality assurance process

d) Collecting data from each patient, on every visit

e) Implementing informed consent

Correct Answer: c Responsibilities include supervising team members, participating in the auditing process, implementing informed consent, and maintaining accrual. However, if you build the proper team, your staff should perform the data collection tasks.

Question 4: When determining whether offering clinical trials would be good for your practice, consider:

Maintaining an adequate rate of patient accrual

a) b)

Trials that would benefit your practice, your patients, and your community

c) Trials that would benefit your practice, providing a steady stream of income

d) Only those trials that would benefit at least 40% of your patient population Trials that have the potential to draw significant attention to your community

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Correct Answer: a When considering offering clinical trials, consider those that would benefit your practice, your patients, and your community

Module 1 Summary

Congratulations! You’ve now completed Module 1: Becoming an Investigator: Considerations.

You have learned about:

• The benefits of being a clinical trials investigator,

• The benefits and safeguards for participants,

• How incorporating clinical trials will affect your practice,

• Responsibilities of a clinical trials investigator, and

• Considerations for determining whether clinical trials are a good fit for your practice

In the next module, we’ll discuss the groups you can join in order to access clinical trials, as well as required credentialing.

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Module 2: Initial Site Preparation

In this module, we’ll explore how to find clinical trials and the organizations that support them, for both NCI-supported and industry-supported trials. We’ll focus on NCI-supported trials while we review membership and credentialing requirements, including how to find an Institutional Review Board, or “IRB,” of record.

Upon successful completion of this module, you’ll be able to:

• List the organizations through which investigators conduct clinical trials,

• Summarize the methods to identify an IRB of record, and

• Describe different registration and credentialing requirements.

Initial Considerations

Let’s begin by exploring how to find the types of trials that would suit you and your practice.

First, start networking by identifying existing institutional memberships and partnerships available to you and your practice. Also, talk to other investigators in the field.

Here are some questions to get you started:

• Does your local hospital have a research department or already participate in other clinical trials?

• Do you have access to a research program through a university in your region or through professional affiliations?

• Do any of your colleagues participate in cancer clinical trials? If so, what networks do they participate in?

• What type of membership affiliations are available through your professional organizations?

Next, identify the types of studies you want to participate in, such as:

• Government-sponsored or industry-sponsored trials,

• Investigator-initiated trials, or trials that you write and develop,

• Disease-specific trials,

• Phase I, II, or III trials, and

• Screening, treatment, prevention, quality-of-life, and symptom management trials.

A typical trial may include one or more of these types (for example, a Phase III breast cancer trial).

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Also, each type of study has specific membership and credentialing requirements. We’ll discuss these later in this module.

Ways to Participate in Trials

There are several ways to become a clinical trials investigator. You and/or your institution may be able to participate through:

• One of NCI’s Clinical Trials Cooperative Groups through an academic center or community hospital,

• NCI’s Community Clinical Oncology Program, or CCOP,

• NCI’s Cancer Trials Support Unit, or CTSU,

• Participation as a site or satellite site in NCI’s Cancer Centers Program, and finally,

• Clinical trials sponsored by pharmaceutical and biotech companies.

Let’s review each option in more detail.

NCI’s Clinical Trials Cooperative Groups

NCI’s Clinical Trials Cooperative Group Program is designed to promote and support clinical trials of new cancer treatments, to explore methods of cancer prevention and early detection, and to study quality-of-life issues and rehabilitation during and after treatment. This program includes translational research and lab science.

Cooperative groups are composed of academic institutions and cancer treatment centers as well as NCI’s CCOP. They differ in structure and research focus. Some groups concentrate on treatment of a single type of cancer; some study a specific type of cancer therapy; others have a broader focus.

To get involved, first contact the membership department of a group that interests you. Health professionals in the community can join cooperative groups through the sponsorship of one of the main group members, such as a university medical center. For instance, you can contact your training institution and request the sponsorship, provided that it is a main member of a cooperative group. Note that investigators can participate in one or more groups simultaneously.

For more information: See the Factsheet for NCI’s Clinical Trials Cooperative Groups program on Cancer.gov.

NCI’s Community Clinical Oncology Program (CCOP)

NCI’s CCOP helps transfer the latest research findings to the community level, so patients don’t have to leave their community to receive state-of-the-art care. It also increases the number of

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participants and physicians who can take part in clinical trials operated simultaneously in major research centers and in the community.

CCOPs are composed of community physicians who work with scientists conducting NCI-supported clinical trials.

To get involved, contact CCOP programs directly.

For more information: visit the Community Clinical Oncology Program (CCOP) Web site for procedures, forms , and applications

NCI’s Cancer Trials Support Unit (CTSU)

NCI’s Cancer Trials Support Unit, or CTSU, is designed to increase accrual to larger Phase III adult oncology trials for physicians that currently do not have access to these trials. The program provides sites with the freedom to choose trials that best suit their patient population and scientific interests without more restrictive requirements. It also provides standardized tools and support for conducting trials.

Health professionals, whether affiliated with a Cooperative Group or not, are eligible to register with the CTSU to access these standardized tools.

For more information: Visit the NCI’s Cancer Trials Support Unit (CTSU) Web site for more information and registration.

NCI’s Cancer Centers Program

NCI’s Cancer Centers Program sustains broad-based, coordinated, interdisciplinary programs in cancer research.

The program supports major academic and research institutions throughout the United States that have a strong commitment to laboratory, clinical, and population-based cancer research as well as scientifically strong research bases.

To get involved, first determine which regional cancer centers you have access to, and then determine if their specialties match your interests. Then contact the individual center.

For more information: Visit the Cancer Centers Program home page for a list of NCI sponsored cancer centers as well as policies and guidelines.

Private Industry-sponsored Trials

Pharmaceutical and biotech companies are active in new drug development in four ways:

• Initially exploring new agents for clinical activity with the NCI’s Cancer Therapy Evaluation Program, or CTEP,

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• Collaboration with NCI Cooperative Groups,

• Industry-designed studies with a selected research base of one or more institutions, and

• Support of institutional trials.

Pharmaceutical companies are now the major developers of cancer drugs. Most of their studies are done independently of NCI.

To find these trials:

• Attend your own specialty meetings,

• Attend industry meetings and conferences,

• Contact a Contract Research Organization, or CRO - an independent contractor that assumes one or more of the obligations of a sponsor during a clinical trial, and

• Interface with medical science liaisons associated with the pharmaceutical industry and who work in specific diseases of interest to you.

For more information:

• Visit the website for Pharmaceutical Research and Manufacturers of America

• Visit Clinicaltrials.gov for contacts for all clinical trials

• Visit the FDA Web site for information on FDA sponsored clinical trials.

Identifying an IRB of Record

The next step in setting up clinical trials is identifying an IRB of record.

In the United States, all clinical trials are conducted under the close supervision of an IRB that has jurisdiction over the trials. Such an IRB becomes a clinical trial’s “IRB of record.”

An IRB protects the rights, safety, and welfare of human research participants and is required to comply with federal regulations.

As an investigator, you should explore options for IRBs available to your site and clarify authority and governance within your practice and care network(s).

The following resources might assist you in identifying an IRB of record and other regulatory resources: risk and compliance departments at your affiliated institutions, sponsoring research organizations, and quality assurance departments within your site’s research networks.

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Identifying an IRB of Record

When choosing an IRB of record, consider the IRB’s experience, history of successful audits, accreditation, accessibility, and user-friendliness for your site.

Options for IRB affiliation might include:

• Local or regional academic medical centers,

• Local or regional hospitals,

• Developing a site-specific IRB (although not encouraged for a site newly entering the research field),

• National IRBs, such as the NCI Central IRB, and

• Commercial IRBs, such as the Western IRB.

The principal investigator must obtain a copy of the IRB’s policies and procedures to ensure that expectations and processes are clear.

The NCI CIRB

The NCI Central IRB, or NCI CIRB, reviews Cooperative Group trials to enable local IRBs to rapidly approve these trials. Through a facilitated review process, patients and their physicians benefit from improved access.

The NCI CIRB also provides consistent, expert IRB review at the national level before the protocol is distributed to local investigators, which enhances the protection of research participants.

And finally, the NCI CIRB reduces the administrative burdens on local IRBs and investigators associated with IRB submission.

The NCI CIRB Process

The NCI CIRB doesn’t replace the local IRB; instead, it partners with local IRBs by performing full-board review of Cooperative Group clinical trials. These trials can then be accepted by local IRBs, who must ensure that the local context requirements are met.

The NCI CIRB Process

Let’s review the NCI CIRB process:

First, the NCI CIRB reviews and approves the protocols (and associated materials) for Cooperative Group

studies.

Next, it notifies the local investigator when a new study is approved through a routine group activation

announcement or through the NCI CIRB biweekly Study Activity Update e-mail.

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Then, the local investigator decides to open the study. Research or IRB staff downloads the completed

application and study documents from the NCI CIRB Web site and submit documents to the local IRB.

Next, the local IRB chair or subcommittee assesses the NCI CIRB review and decides whether or not to

accept it. If it is accepted:

• The NCI CIRB becomes the IRB of record for that study at that site,

• The NCI CIRB is responsible for full-board review of amendments, annual continuing reviews, adverse events, etc., and

• The local IRB is responsible for conducting the study within its institution, including review of adverse events occurring at their site.

More information about this process is available on the NCI CIRB Web site

Registering with the FDA: The 1572 Form

If your trial uses investigative agents, the next step in the process is to register with the FDA as an investigator.

Before a site is permitted to conduct a trial for a new drug or device, the principal investigator must complete the Statement of Investigator Form (referred to as a 1572 form) that the sponsor files with the FDA.

The 1572 form provides the FDA with the following information:

• The site name,

• The site address,

• The CV of the principal investigator,

• Information regarding sub-investigators, research sites, and clinical laboratories, and

• The IRB of record for your site.

These regulations are FDA-specific. Investigators may also need to comply with the Office for Human Research Protections, or OHRP [oh-HARP], and the Department of Health and Human Services, or DHHS, regulations. Check with the trial sponsor on which regulations to follow.

Visit the FDA web site for a copy of the 1572 form and instructions for completions and submission

1572 Form Commitments

The 1572 form is a legal contract between you and the FDA, ensuring that you will comply with all requirements outlined in the Code of Federal Regulations and other guidelines governing research involving human subjects.

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On the back of the 1572 form is a set of commitments. By signing the form, you agree to abide by these commitments. These are very important; you can be fined and jailed if you do not comply with them!

Commitment 1 I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects. Commitment 2 I agree to personally conduct or supervise the described investigation(s). Commitment 3 I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relation to obtaining informed consent in CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met. Commitment 4 I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64. Commitment 5 I have read and understand the information in the investigator's brochure, including the potential risks and side effects of the drug. Commitment 6 I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments. Commitment 7 I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68. Commitment 8 I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.

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Commitment 9 I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.

Additional Requirements

In addition to registering with the FDA, you should verify any additional requirements with your site’s sponsors and oversight authorities (for example, your site’s IRB).

Three additional required documents include:

• The site roster

o Your site must submit roster forms and other data to the sponsor to ensure ongoing

communication. Once an investigator, team, and site are registered, then other NCI

research sponsors will be able to access this data.

o After your site has submitted the data, review the database listing to ensure

accuracy and prevent gaps in site identification.

• Proof of human subjects protection training, and

o All investigators and members of the research team need to complete education in

the protection of human research subjects.

o Verify the required training programs with the sponsor and any regulatory

authorities, such as the FDA and OHRP [oh-HARP].

o The NIH online tutorial is generally accepted by most research sponsors. Be sure to

print and save a copy of the certificate for completion.

• The Federal wide Assurance, or FWA.

o The FWA is a written, binding commitment filed by the research site or responsible

institution with the Federal Government that promises compliance with applicable

regulations governing human subject research. Usually the IRB files the FWA; in

other cases, the investigator will file.

o The FWA ensures that activities related to human subject research that government

agencies fund or sponsor, will be:

Guided by the ethical principles found in the Belmont Report

Comply with HHS regulations for human research protections

Satisfy the FDA regulations relating to Good Clinical Practices, or GCPs, and

clinical trials as well as HIPAA regulations.

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This section concludes Module 2. Next there is a short quiz to review what you’ve learned.

Quiz

Question 1: Select whether the following statement is True or False:

NCI’s CTSU program allows investigators to join larger Phase III trials whether or not they are affiliated with a Cooperative Group.

a) b)

True

Correct Answer: a That’s correct! NCI’s CTSU program allows investigators to join larger Phase III trials whether or not they are affiliated with a Cooperative Group.

Question 2: The NCI CIRB:

False

a) b)

Provides a regulatory option for Phase I NCI clinical trials b. Replaces the IRB of record for the investigator’

c) s practice

d) Reduces the administrative burden on the IRB of record

Correct Answer: c That’s correct! The NCI CIRB reduces the administrative burden on the IRB of record, but does not replace it.

Question 3: Registration and Credentialing requirements for NIH investigators include the FDA’s 1572 form, a site roster, the FWA commitment, and

Allows the IRB of record to assume responsibility for full-board reviews of clinical trials

a) b)

NCI CIRB approval letter

c) Completed human subjects protection training for all research team members

d) A detailed budget

Correct Answer: b That’s correct! Registration and credentialing requirements for NIH investigators include proof of completion of human subject’s protection training for all research team members.

None; the 1572 form, a site roster, and the FWA commitment are all of the requirements

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Module 2 Summary

Congratulations! You have now completed Module 2: Initial Site Preparation. You have learned about

• The organizations through which investigators conduct clinical trials,

• Ways to identify an IRB of record, and

• Different registration and credentialing requirements.

In the next module, we’ll review how to choose the best trial for your practice.

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Module 3: Choosing the Trial(s)

In this module, we’ll discuss various aspects of specific clinical trials that will help you determine which would be best for your practice.

Upon successful completion of this module, you’ll be able to:

• List several factors to consider when choosing clinical trials,

• Describe several processes involved in evaluating trials, and

• Identify potential sources of funding and reimbursement

Choosing a Specific Trial

When building a trial menu (also referred to as a “portfolio”), carefully consider choosing trials to which you can successfully accrue participants. Keep in mind that some trials may never accrue more than a few participants, but you may choose to open those trials for the participant who presents with a rare cancer.

Factors to Consider

Factors to consider when choosing the right trials include:

• Scientific value to you: Are you interested in the science behind the study?

• Availability of the patient population, not just in your practice, but with colleagues you are affiliated with.

• The local community supporting the trial, which needs to feel that the trial is the appropriate care.

• The trial’s feasibility within your clinical care and resource networks: Do you have the resources, such as the supplies, the drugs, and the equipment to support the trial?

• The time required to initiate and maintain the credentialing and regulatory components, which continue throughout the trial.

• Your ability to support the sponsor’s expectations: Make sure you know how the sponsor will manage your site, to avoid hidden or unexpected costs, such as their monitoring or auditing requirements.

• Any other competing trials: Avoid similar trials that compete for the same population.

• The trial’s affordability: Understand your financial limits, for example, whether your site needs to make money, is able to take a loss, or can just break even.

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Here are a few examples of ways to build a good accrual network.

• If you have a strong affiliation with surgeons at a hospital, become familiar with the types of cancer they address,

• Urologists are a good source of prostate cancer patients and can direct you to eligible patients,

• Affiliate with gastroenterologists, who are performing colonoscopies, and

• If you are interested in lung cancer, affiliate with a pulmonary specialist.

Also, there may be a business opportunity for your colleagues to refer patients to your clinical trials.

Processes to Assist Trial Selection

The principal investigator will choose the trials for his or her site. Various tools and processes can help determine trials that are a good fit. These may include:

• Feasibility checklists, to guide a practical logistical review before opening a trial;

• Accrual tracking worksheets, which help your site monitor accrual and analyze your patient population;

• Investigator committee meetings and tumor boards provide an opportunity to discuss feasibility of a particular trial with colleagues;

• Research team feasibility reviews provide an opportunity for the future research team to meet and review ALL aspects of the trial in depth - for example, equipment, systems, people, and money; and

• Engaging affected departments, for example, pharmacy, lab, pathology, nuclear medicine staff, radiation oncology, physicists, and others, and ensuring that they are willing to participate in a trial.

Here is a sample feasibility issue and questions:

A researcher met with a melanoma committee composed of physicians and researchers to discuss potential melanoma trials. Before the researcher put all resources into participating in a melanoma trial, he evaluated the number of past and ongoing patients.

Evaluating trials will require considerable scrutiny of the specific trial’s requirements. Here are examples from selected studies:

• Does your pharmacy have the right security and staff, in case the trial requires a drug or reaction tracked and recorded differently from your normal procedures, for example, a double-blind?

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• Do you have access to a nuclear pharmacy? Does your budget allow for an expensive injection?

• Does the study require imaging technology? Do you have the right machines? Can the trial’s participants have access to them when they are available?

Established Forms and Procedures

Another factor in evaluating trials is whether the trial already has established forms and procedures in place. Standard forms and procedures are required for both the site and the trial - study sponsors may require that they be in place before approving a site for participation. If the study sponsor does not provide these, you’ll need to develop them.

It may be easier for new investigators to choose trials that already have forms and procedures developed. Research documentation requirements are often very specific and may require information not routinely included in standard notes and reports.

Forms and procedures must be specific for the site and accurately and succinctly reflect actual practice. It’s considered a best practice that every site invest time in developing written policies and procedures, specific to the individual site, that define all aspects of study conduct. Consistency is a critical element of research practice.

Standard Operating Procedure, or SOP guidelines, workshops, and templates can be found through professional societies or commercial vendors.

Standard of care documentation may not fully meet the needs of clinical trials - your site will still have to develop additional tools and forms.

We’ll review documentation in more depth in Module 5.

Funding and Reimbursement

Funding your research efforts is not an easy task. Funding and reimbursement may be composed of actual resources such as investigational agents, devices, imaging studies, or novel diagnostic techniques. Potential sources of funding and reimbursement include sponsors, insurance, Medicare, or local institutions.

We recommend that your site conduct a thorough assessment of the trial requirements and actual costs prior to opening a study, to ensure that you have the resources to maintain a patient population throughout the trial as well as develop a strong research program.

“Success” is determined by your site’s program goals and what you want to accomplish. Some sites may lose money up front, and some realize a profit immediately. For example, a hospital might go into the red in order to build a research practice.

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Startup and Ongoing Expenses

Participation in clinical trials requires startup capital. Investigators who have set up their regular practice will still need to put the staff and infrastructure in place to run clinical trials. Potential costs for community physicians include:

• Personnel, with roles such as a research nurse, a clinical research coordinator, a secretary, and pharmacist services, that may grow over time;

• Office expenses, such as workspace, computer access, phone, fax, and mail;

• Physician time, such as reviewing potential studies, IRB requirements, patient discussions, and monitoring and ensuring protocol compliance;

• Meeting time, with research staff, referring physicians, and possibly travel; and

• Other expenses, such as assessing insurance issues, IRB fees, audits, chart storage fees, and protocol requirements that the sponsor doesn’t cover.

Experienced community investigators recommend that you hire a dedicated nurse or coordinator to keep your site’s study coordination and data management at peak performance. These team members play a key role in the success of implementing trials in your practice. We’ll review these roles in more detail in Module 4.

Sponsor Reimbursement

Sponsors, such as NCI or private industry, may reimburse sites to cover the research costs of clinical trials. Amounts can vary. For example, if a research site participates in an NCI or private industry-sponsored clinical trial, the sponsor may pay a defined amount per participant registration.

The sponsors determine the amount of startup funds and when they are available to your site. For example, one sponsor may pay a percentage of the total budget as an upfront payment, while another may not pay anything until the first participant is enrolled.

Clarify your site’s funding availability and negotiate your site’s needs before opening a trial.

In many community investigators’ experiences, the financial reimbursement from sponsors may be used to pay research team expenses. Sponsors also may be able to identify additional sources for support if the investigator encounters funding problems.

Insurance Reimbursement

To understand how insurance companies reimburse expenses associated with a trial, let’s consider how insurance companies categorize them.

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First, there are patient care costs. Usual care costs include items such as doctor visits, hospital stays, clinical laboratory tests, and x-rays, which occur whether the patient is participating in a trial or receiving standard treatment. These costs have usually been covered by a third-party health plan, such as Medicare or private insurance.

Extra care costs are associated with clinical trial participation, such as additional tests required to evaluate the study interventions. These may or may not be fully covered by the clinical trial sponsor or research institution. In some cases, the sponsor and the participant’s health plan should resolve coverage.

Second, there are research costs associated with conducting the trial, such as data collection and management, research physician and nurse time, and data analysis. Such costs are usually covered by the sponsoring organization, such as NCI or a pharmaceutical company.

Some insurance will not cover any clinical trials. Many states have laws related to coverage for government-funded research. Visit NCI’s Web site for information on states’ insurance coverage of clinical trials.

Health insurance companies and managed care companies decide which health care services they may

pay for by developing a coverage policy regarding the specific services.

In general, the most important factor determining coverage is a health plan’s judgment as to whether

the service is established or investigational.

Health plans usually designate a service as established if there is a certain amount of scientific data to

show that it’s safe and effective. If the health plan doesn’t think that such data exist in sufficient

quantity, the plan may label the service as investigational.

For some health plans, clinical trial participation may result in a denial of coverage. However, some health insurance plans make case-by-case decisions about clinical trials, and some health insurers, such as Medicare, now cover the usual patient-care costs.

A health plan may also define specific criteria that a trial must meet before extending coverage, such as:

• Lack of standard therapy: Some plans may limit coverage of trials to situations where no standard therapy is available.

• Sponsorship: Some plans may only cover costs of trials sponsored by organizations whose review and oversight of the trial they consider to be careful and scientifically rigorous.

• Medical necessity, trial type, and trial phase: Some plans may cover patient care costs only for the clinical trials they judge to be “medically necessary” on a case-by-case basis

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The type of trial may also affect coverage: it may be more difficult to get coverage for the care costs associated with prevention and screening trials.

Additionally, while a plan may be willing to cover costs associated with Phase III trials, which include treatments that have already been successful with a certain number of people, the plan may require some documentation of effectiveness before covering a Phase I or II trial.

• Cost “neutrality”: Some health plans may limit coverage to trials they consider cost-neutral - that is, not significantly more expensive than treatments considered standard.

• Facility and personnel qualifications: A health plan may require that the facility and medical staff meet specific qualifications to conduct a trial involving unique services, especially intensive therapy such as a bone marrow transplant (for example, high-dose chemotherapy with bone marrow/stem cell rescue): A health plan may require that the facility and medical staff meet specific qualifications to conduct a trial involving unique services, especially intensive therapy such as a bone marrow transplant (for example, high-dose chemotherapy with bone marrow/stem cell rescue).

Some health plans, especially smaller ones, will not cover any costs associated with a clinical trial. Policies vary widely, but in most cases the investigator should consider initiating discussions with the health plan, before the participant is enrolled in the trial. You may have to advocate for the participant and obtain preapproval, if necessary.

Medicare Coverage

In general, Medicare covers cancer treatment and diagnosis trials if:

• They are funded by NCI, NCI-designated Cancer Centers, NCI-Sponsored Clinical Trials Cooperative Groups, and other federal agencies that fund cancer research. Other trials may be eligible for coverage and the investigator can ask Medicare to pay the participant’s costs.

• The purpose or subject of the trial is within a Medicare benefit category. For example, cancer diagnosis and treatment are Medicare benefits, so these trials are typically covered.

• View the NCI fact sheet for Medicare beneficiaries and visit the Centers for Medicare and Medicaid Services.

Costs not covered by Medicare include:

• Investigational items or services being tested in a trial; in this situation, sponsors of clinical trials often provide the new drug for free,

• Items or services used solely for the data collection needs of the trial,

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• Anything that the sponsor provides for free, and

• Cancer prevention trials.

For a participant, Medicare may pay the following:

• Anything normally covered is still covered when it’s part of a clinical trial, even if it’s a service or item associated with the trial’s treatment. This includes tests, procedures, and doctor visits that are ordinarily covered. For example, while the sponsor pays for the new chemotherapy drug being tested in a trial, Medicare may pay for the intravenous administration of the drug, including any therapy to prevent side effects.

• Anything normally covered even if it resulted from participation in the clinical trial.

For example, Medicare may pay for a test or hospitalization resulting from a side effect of the new treatment that it would ordinarily cover.

Local Institution Support

To supplement external funding sources, your local institution or practice may need to provide additional support, especially in the start-up phase of your program. This support may include office space, staff support, computers, supplies, IRB services, human resources, benefits management and even financial support.

Work with senior level management at your local institution, so they understand the value of your research program and what it brings to your community. Your institution can gain prestige by sponsoring a clinical trials research program and providing state-of-the-art cancer care.

Module 3 Quiz

Question 1: Which statement is INCORRECT regarding factors to consider when choosing clinical trials?

a)

b)

A trial that already has established forms and procedures will be easier for a new investigator to select

c)

The patient population you have to choose from, must derive from your own practice

d)

A new investigator should perform some research to determine whether there are any competing trials similar to the one he/she is considering

Correct Answer: b That’s correct! Patient populations can derive from your own practice or from colleagues and affiliations.

A new investigator should consider the time required to maintain certain components of a trial

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Question 2: Potential processes and tools to help you determine the best trials for your site include:

a) b)

Feasibility reviews with your practice

c) Meeting with any affected departments in your practice, such as pharmacy

d) Meeting with colleagues

e) Checklists and worksheets found online

Correct Answer: e That’s correct! Potential processes include feasibility reviews with your research team as well as affected departments, meetings with colleagues, and checklists and tools that you can find online.

Question 3: Select whether this statement is True or False: Sponsors will cover all costs related to research team expenses for each trial; additional expenses may vary.

All of the above

a) True b) False

Correct Answer: b That’s correct! Sponsors will not necessarily cover all expenses for a site’s participation in a clinical trial. Investigators should verify with sponsors as to what they will reimburse.

Question 4: Which statement concerning insurance reimbursement is correct?

a)

b)

Health insurance companies cannot restrict potential reimbursement on the basis of the sponsor or facility qualifications The investigator will not need to contact the patients’

c)

insurance companies; that is the responsibility of the individual patient or the sponsor

d)

Most health insurance coverage of clinical trial participation is conditional: some may deny coverage, some make case-by-case decisions, and some may cover costs for treatment that is not significantly different than standard care

Correct Answer: c

Most insurance companies will consider cancer prevention trials

That’s correct! Health insurance coverage of trials is conditional. Coverage will depend on the individual insurance company or organization.

Question 5: For a participant, Medicare will pay for:

a) Items that the sponsor will not provide

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b) c)

Anything normally covered

d) Prevention trials

Correct Answer: b

That’s correct! Medicare will cover anything normally covered by insurance, such as tests, procedures, and doctor visits, as well as services or items associated with a trial’s treatment.

Data collection time for that participant

Module 3 Summary

Congratulations! You have now completed Module 3: Choosing the Trials. You have learned about

• Several factors to consider when choosing clinical trials,

• Several processes for evaluating trials, and

• Potential sources of funding and reimbursement.

In the next module, we’ll introduce the key members of your research team and methods for training them in research practices.

Module 4: Building and Training the Research Team

In module 4, we’ll discuss staffing and training your site’s research team.

Upon successful completion of this module, you’ll be able to:

• Identify the key members of a research team and define their responsibilities,

• List tips for building a solid research team network, and

• List strategies for training staff involved in a clinical trial.

The Core Research Team

Clinical trials require an onsite collaborative team that possesses a wide range of expertise.

Ultimately, each staff member has a role to play in the research process. For many community researchers, the research team will include the entire office staff, from the front-desk receptionist, to the insurance claim specialist, to the oncologist.

Successful investigators recommend separating the duties of clinical trials personnel from those of existing staff. At a minimum, make sure that each employee involved with the trial dedicates

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time for completing research work. The amount of time and resources for research activities will depend on the size and needs of the research program.

Each team may be set up differently, depending on the staffing and resources of the site. Many research teams will include an oncologist’s office staff with the addition of dedicated clinical trials staff.

Team Roles are Varied

The roles and responsibilities of research team members will vary by site.

For example, a site may choose one team member to fill the roles of both the clinical research coordinator and the data manager, and have the staff nurses responsible for drug dispensing and inventory.

Every team member should receive training and clarification on their roles and responsibilities to empower them to fully comply with research and regulatory expectations.

The Principal Investigator (PI)

The principal investigator, or PI, is a physician who serves as the leader for the research team. The PI understands the science of the protocol and has the clinical expertise to manage the potential side effects and possible adverse events that may arise.

The PI is accountable for maintaining the scientific integrity of the protocol as well as regulatory and reporting compliance. The PI is recognized by the IRB of record and oversees all aspects of the clinical trial. The PI is also responsible for Good Clinical Practices and GCP guidelines.

Specifically, the PI oversees:

• Protocol submission for local IRB approval,

• Participant recruitment,

• Informed consent,

• Protocol adherence,

• Data collection and analysis, and

• Ongoing interaction with the IRB.

Co-Principal Investigator

Along with the principal investigator, a co-principal investigator acts as a designee to make decisions on major issues. For larger sites, the co-PI assists the PI and performs the same tasks.

Even if your site is small, designate a co-PI role for the time when your program grows, to ensure your program’s future success.

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Other names for the co-principal investigator role may be “associate investigator,” “sub-investigator,” or “co-investigator.”

The co-PI should have a medical or related advanced degree, appropriate for the responsibilities of the role, and have a 1572 form on file, as required by the sponsor, if he or she makes any decisions regarding protocol interventions.

Clinical Research Coordinator

Research team members are often referred to globally as data managers or clinical research coordinators. In reality, the coordinator performs more tasks than managing data - it’s a complex and varied area of practice.

This role may be composed of one person or a team that focuses on research coordination.

The clinical research coordinator plays a key role in implementing and managing the protocol.

Main duties can include:

• Serving as a resource to investigators, staff, and participants, including working with referring physicians,

• Assisting in screening participants or directing the details of recruitment as well as facilitating the informed consent process,

• Ensuring that test procedures are scheduled,

• Organizing the collection of specimens,

• Receiving reports and other paperwork, and meeting IRB requirements,

• Monitoring test results and working with investigators for necessary treatment adjustment,

• Educating research staff and patients,

• Alerting the PI to significant trends in the data as well as assessing for and reporting adverse events,

• Ensuring proper chart documentation of response and side effects, and

• Managing data, including developing data collection tools, maintaining study files, and providing a quality assurance plan for data checks.

Clinical Research Coordinator Role

When establishing a clinical trials program, many sites initially select a nurse to serve as the coordinator. Research nurses can incorporate clinical care components, such as managing toxicities, adjusting doses, and educating staff and participants, as allowed within the scope of practice in the state where they are licensed.

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However, the coordinator may also need to provide overall management of trials as well as perform database development, data tracking, and specimen management tasks.

A research nurse can perform both roles. However, a coordinator who is not a nurse can only perform non-clinical duties.

Successful sites often team a research nurse and a coordinator together to co-manage a participant caseload and maximize efficiency.

Staff nurses may also partner with research team members to assume some coordinator responsibilities.

For your team, pay careful attention to developing clear job descriptions for the various tasks.

For more information on roles, training and credentialing research team members, see the Resources section of this course

The Data Manager

The term “data manager” is often applied globally to multiple members of the research team. Although research nurses and clinical research coordinators may incorporate data management into their responsibilities, it is important to clearly delineate the role of data manager.

Major functions of a data manager can include:

• Abstracting data into paper or electronic CRFs,

• Assisting in preparing data to be provided to monitoring agencies, and

• Collaborating with the principal investigator and research coordinator on how participant data will be tracked, which includes:

o determining where to find the data,

o determining the tools needed to collect the data,

o deciding how to record the data, and

o educating physicians about data collection.

Staff Nurses

Both inpatient and outpatient oncology staff nurses often work with research team members. They play

an integral part in the implementation of a protocol. Staff nurses may:

• Administer the intervention to participants as specified in the protocol (with proper education and training and according to human subjects protection regulations);

• Assess and record toxicity, drug tolerance, and adverse events;

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• Collaborate with the principal investigator and research coordinator in observing and reporting clinical trends; and

• Provide clinical management and participant education.

Research Team Tips

The following are practical tips from experienced investigators:

• Existing office staff can take on new responsibilities if properly trained and supported. Make sure that their roles and responsibilities are clearly defined to avoid confusion.

o For example, a chemotherapy nurse may also do data management, with proper

training.

• Set aside dedicated time to allow for staff members to complete research-related work. As a program grows, additional staff may be necessary.

• Nurse practitioners and oncologists can complement each other in their work with protocol patients. Nurse practitioners make patient education a high priority, and they can spend time with patients and their families to answer questions regarding a clinical trial.

• Your insurance claim specialists can check that a participant’s insurance company will pay for the drugs and procedures required by the protocol.

• Discussing available clinical trials increases awareness and builds shared investment and network development.

o For example, investigators and team members can be active in section meetings and

Tumor boards.

Research Team Networks

Multiple care providers - both the core research team and the participant’s other care providers - compose the extended research team that provides care for the participant.

Clinical trials incorporate data from this research team network. Depending on the protocol’s requirements and a site’s policies and resources, the extended team may also include the following specialties: pharmacy, pathology, radiology, radiation oncology, surgery, primary care, oncology nursing, administration, nutritional services, social work, bioethics, and biostatistics, as well as study participants and advisors, clinical trial recruitment specialists, and chaplains.

Training the Research Team

The key to conducting a successful clinical trial is a well-trained clinical research team.

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A successful training program requires detailed planning, a trainer knowledgeable in the research requirements, and effective training tools. For most clinical trial sites, the PI and coordinator serve as trainers.

Training ensures that your staff understands the importance of clinical research in advancing cancer care. It also provides them with the knowledge and skills in implementing the protocol in compliance with regulations and quality assurance measures - especially human subjects protection.

Example of Benefits Training: Front-desk staff who understand the importance of strictly following the protocol treatment schedule will make sure that appointments are given to protocol participants at the right time and for the right purpose. They can also more effectively triage calls from research participants.

Additional information training clinical trials teams is located in the Resources section of this course.

Planning a Training Program

Effective planning of a training program requires that the trainers have a thorough knowledge of the clinical trials process as well as how it will work at their site. This knowledge helps assess the responsibility of the research team members in the trial.

The trainers need to identify:

• Guidelines for the responsibilities of each investigator and staff member,

• Equipment necessary to implement clinical trials,

• Any new skills that are required, or any gaps in knowledge for protocol implementation and compliance, and

• Regulations regarding roles and responsibilities.

Goals of Training Program

A staff training program needs to achieve the following goals:

• Motivate staff to actively and responsibly participate in the research effort,

• Explain the conduct and requirements of the protocol - including ensuring that subjects are eligible and that data integrity is maintained,

• Explain relevant regulations and guidelines,

• Provide the skills necessary to implement the protocol,

• Provide tools to assist job performance, and

• Provide continuous support to staff in updating their knowledge and skills.

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Your site can employ both formal and informal training to achieve these goals.

Formal Onsite Training

Formal onsite training sessions are used to help staff develop or improve required research skills. Such sessions can include:

• Explaining the importance of clinical research,

• Instructing on how to comply with research ethics standards,

• Presenting the protocol, scientific rationale, and objectives,

• Describing the doses and administration of treatments,

• Explaining most likely and less likely toxicities and procedures for managing and reporting adverse events,

• Monitoring and managing side effects, and

• Instructing on how to use specialized equipment necessary for implementing the study.

Formal training also involves reviewing the following items:

• Tests required by a study,

• Instructions on processing ancillary tests (such as pharmacokinetics),

• Questionnaires to be completed by the research participants,

• Names and telephone numbers of the clinical trial staff,

• Order forms that may be used for a protocol, and

• Any forms that will require completion by staff.

The sponsor may provide some of this training via an initiation visit, especially with industry trials.

Ongoing, Informal Training

Informal training reinforces research skills through ongoing education and program development. Examples include:

• Regularly scheduled staff meetings, which provide time to solve problems,

• Sharing frequent updates on new findings and trends, especially with staff providing direct care, and

• Observing the PI conducting an informed consent session.

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The investigator should continue informal training efforts after the protocol opens to ensure protocol compliance and participant safety.

Additional training tips include the following:

• Keep a copy of the protocol in every department and unit involved in the trial,

• Identify and correct any deficiencies while implementing the study, and

• Address any areas of concern.

Module 4 Quiz

Question 1: Which statement is INCORRECT?

a)

b) T

The research team at any site comprises both existing office staff as well as dedicated research staff

c)

he principal investigator is ultimately responsible all aspects of a clinical trial, including participant recruitment

d)

The principal investigator is the only member of the research team that has the authority to stop therapy

Correct Answer: c That’s correct! The only member of the research team that has the authority to stop therapy is the principal investigator. Of course, the participant has a right to withdraw at any time.

Question 2: A research team network can strengthen your site’s research program by:

The clinical research coordinator may also be responsible for data management tasks

a)

b)

Establishing a solid research team for one site, since all other sites within the same program must follow that team setup

c)

Allowing existing office staff to extend their skill sets, with the proper training and support

Correct Answer: c That’s correct! Existing office staff can take on new responsibilities as long as they are properly trained and supported.

Question 3: Trainers must have a thorough understanding of ___________________.

Ensuring that only data that the core research team provides - not the extended team - is recorded

a) Their site’s clinical research coordinator’b)

s responsibilities Their site’s research program

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c) d)

Team roles and responsibilities Their site’

e) s research protocol

Correct Answer: e That’s correct! In order to effectively plan training for their site’s staff, trainers must have a thorough knowledge of the coordinator’s responsibilities, their site's research program, team roles and responsibilities, as well as their site’s research protocol.

All of the above

Question 4: Select whether this statement is True or False:

Both the clinical research coordinator and research nurse will often manage patients together

a) True b) False

Correct Answer: a That’s correct! Both the clinical research coordinator and the research nurse will manage patient caseloads, but the coordinator is ultimately responsible for overall management

Module 4 Summary

Congratulations! You have now completed Module 4: Building and Training the Research Team. You have learned about:

• The key members of a research team and their responsibilities,

• Tips for building a solid research team network, and

• Strategies for training staff involved in a clinical trial.

In the next module, we’ll cover preparing your site for a trial, including logistics, recordkeeping and reporting, drug handling, and initial QA and regulatory needs.

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Module 5: Handling Site Logistics

In this module, we’ll discuss the logistics involved in running clinical research activities at your site, to prepare for enrolling participants.

Upon successful completion of this module, you will be able to:

• Identify your site’s logistical requirements,

• Identify recordkeeping and reporting requirements for conducting clinical trials,

• List typical tasks involved in handling research study drugs,

• List required quality assurance procedures, and

• List the steps involved in seeking IRB approval.

The Site’s Logistical Requirements

Your practice will need all the necessary components in place for conducting clinical trials, before you can enroll participants. These components include:

• Locked drug storage:

o Federal regulations require that a clinical investigator have a secure, lockable

storage area for trial drugs.

o Issues critical for the safe implementation of a trial include providing a safe mixing

area for agents and complying with FDA standards.

o Drugs may require refrigeration or freezers.

o Some research sites have built-in storage rooms for study drugs that are guarded by

alarm systems. Regardless, make sure to separate the site’s drugs from trial drugs,

and include trial documentation related to all trial drugs.

• Access to medical records: Research team members must be able to access data in a timely manner and review it in light of protocol requirements and deadlines. Many practices need a process or system to:

o Access key data for analysis,

o Flag research participant records for other care providers, to increase awareness

and compliance,

o Screen for toxicities, and

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o Easily capture protocol-required data.

For example, if a study participant shows signs of infection, the site needs a timely process to be able to retrieve data on white cell counts across participants.

• Dedicated space for research work:

o Your site should establish a research space, such as a dedicated research work

station, for data management. This work station should include a computer, printer,

phone, fax, and sufficient storage for research data and study supplies - for

example, locked file storage for Case Report Forms.

o Additionally, each research core team member will need his or her own dedicated

computer resources, because research bases use online protocol tools such as Web-

based forms for electronic data submission and updates.

• A monitor work area and/or conference room:

o Monitors conduct regular visits to your site and need an uninterrupted, private work

space. Their job is to ensure that the conduct of the study is in compliance with the

protocol and all applicable regulations.

o Depending on the number of participants enrolled in the study and the complexity

of the protocol, they may spend a significant amount of time reviewing case report

forms, the drug inventory, and source documents. A comfortable work area enables

them to work efficiently.

o If your site has the space for a conference room, rest assured that it will get

frequent use at study initiation visits, study close-outs, and sponsor audits. It will

also provide an area for research team meetings.

o Your site may need an alternate, private room if two monitors visit your site at the

same time.

• Record storage: Once a trial is completed, the records can be moved to storage in order to allow room for ongoing and new trials. Documents from closed trials can be stored in a remote storage facility. Remember that these documents should be retrievable within a few days notice in case of an audit, or if questions should arise about how the research was conducted. Records should not be discarded without clarifying long-term follow-up requirements with the sponsor.

• Specimen storage: And finally, as with drug storage, specimen storage may include refrigerators and freezers - another cost and space consideration.

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Record Keeping & Reporting

In addition to establishing your site’s logistical requirements, your site must have proper documentation in place, most of which the sponsor will provide. Complete and meticulous record keeping is vital to the success of a clinical trial.

The research team needs to complete and maintain source documents, case report forms, regulatory documents and other study-specific forms and records for every patient.

We’ll discuss each of these documents in detail.

Source Documents

Source documents include all observations or notations of clinical activities as well as all reports and records necessary for the evaluation and reconstruction of the clinical research study.

Source documentation is the foundation of all clinical studies. It provides a paper (or electronic) trail of any observation made or data generated about a study participant during his or her participation in a trial. Source documents:

• Comprise accurate, complete, and appropriate clinical research documentation,

• Include written informed consent by all participants prior to the implementation of any study-related procedures,

• Verify the completeness and accuracy of data collected on the CRFs,

• Show evidence that the study was conducted in compliance with the protocol, Good Clinical Practices (GCPs), and relevant regulations, and

• Permit the data to be recovered in case the CRF is lost.

If it’s not documented, it didn’t happen!

Source Document Examples: Medical Reports

Examples of source document include the different types of medical reports generated while a participant is enrolled in a study. Typically, the final report is the source document; it will include the institution, date, and appropriate signature. A copy of any final reports should be added to the research file.

Reports may include:

• Laboratory reports,

• ECG reports,

• X-ray and scan reports,

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• Radiology reports,

• Pathology reports, and

• Admission and discharge summaries.

A transcription of test results onto a flow sheet is not generally acceptable as a source document.

Source Document Examples: Progress Notes

Progress notes record the participant’s visit as part of a clinical trial. They should list completed study procedures, treatments that the participant received, and any adverse experiences, illnesses, or problems that the participant reported.

Source Document Examples: Screening Log

Besides tracking participants who are screened and enrolled into a study, research team members must also document those who are screened but don’t meet the eligibility criteria, or who simply decide not to participate.

Source Document Examples: Other Examples

Additional examples of source documents may include:

• Medical history, including demographic data and documentation of inclusion or exclusion eligibility,

• Physical examination results,

• Current and past medications,

• The original, signed, and dated informed consent form,

• Screening and intake forms,

• Telephone logs and appointment books,

• Study-specific flow sheets and checklists,

• Adverse event reports, and

• Participant diaries.

Creating & Preserving Source Documents

Anyone involved in the clinical care of participants can create source documents. For example:

• The staff nurse,

• A pharmacist who records the dispensing of the study drug, and

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• The research participant who completes study-specific diaries.

Source documents should not be discarded during the trial or for a specified period after the trial has ended. Source documents are routinely compared to CRFs at audits to make sure that what your site documented did in fact happen. This is an important measure to prevent fraud. The Compliance Program Guidance Manual used by the FDA to audit an investigative site is an excellent resource for source documentation.

Case Report Forms (CRFs)

Case report forms, or CRFs, enable the transfer of data regarding efficacy, safety, medication use, and other aspects of the study to the trial sponsor. The principal investigator, the research coordinator, or members of the research team complete CRFs for each participant, based on data collected in source documents. The trial sponsor will design and provide the CRFs.

Keep in mind that CRFs don’t replace source documents! Source documents must still be filed in the research charts.

Traditionally, CRFs are preprinted forms. The use of electronic CRFs is becoming more and more common since it speeds data collection and is more streamlined for auditing purposes. With electronic CRFs, data can be submitted to the sponsor throughout the study.

For all CRFs, follow the guidelines provided by each sponsor for every trial; expectations can vary between studies and groups.

CRFs and Source Documents

The data on the CRFs must be consistent with the source documents.

In a clinical trial, all information entered on a CRF must be supported by, and consistent with, information found on a source document. The site will be required to produce source documents for review at an audit. Collecting and organizing the data in real-time as the participant proceeds through the study ensures that a site is always prepared for an audit.

It’s good practice to set up a research chart to store the CRFs and study-specific documentation. Other documentation may be necessary, such as quality-of-life forms, additional interviews, and dietary assessment forms. The amount of documentation can be large and may be difficult to store in the participant’s clinical record.

Regulatory Documents

Every clinical trial site is required to compile and continuously update all of the regulatory documents for each of the trials it conducts.

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These documents must be kept on file for every protocol. Creating a study binder dedicated to storing regulatory documents will increase efficiency and accuracy.

Regulatory Documents

Several regulatory documents will compose the study binder. Be sure to verify your sponsor’s expectations for any additional documents for each trial. Regulatory documents in the binder will include:

• A copy of the protocol and all amendments,

• The original 1572 form and any revisions,

• Updated copies of signed and dated CVs for the investigator and associate investigators,

• Laboratory certification, which must be updated every 1 to 2 years and the laboratory normal ranges list, which must be updated each time calibration tests are completed,

• A copy of the investigator’s brochure,

• The IRB approval letter,

• The original IRB-approved informed consent form and any IRB-approved revisions,

• IRB-approved advertisements used in the study,

• Serious adverse event reports, and

• Correspondence with the sponsor and the IRB.

Additional Documents & Records

In addition to source documents, CRFs, and regulatory documents, the research team must complete, compile, and maintain other study-specific forms and records.

• Drug Accountability Record: For example, the Drug Accountability Record records the receipt, storage, dispensing, return, and/or disposal of the investigative agents used in the trial. We’ll review drug accountability later in this module.

• Adverse Events Form: The Adverse Events form records events that the investigator considers adverse experiences; these may include previously unreported complaints. The PI decides whether to record incidents as adverse events. Reporting adverse events also includes any additional forms that the sponsor or IRB requires. We’ll discuss ongoing adverse event reporting in Module 8.

• Specimen Handling and Submission Forms: Specimen Handling and Submission Forms cover the collection and shipment of biologic specimens to a reference-testing laboratory. Trial sponsors provide instructions for collecting, storing, and

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shipping specimens, as well as the submission forms for the site to complete at the time of shipment.

• Participant Enrollment form : The Participant Enrollment form documents that the participant meets the eligibility criteria for the trial.

• Delegation of Authority Log: The Delegation of Authority Log documents the study-specific tasks that the PI delegates.

A sample guide for PI delegation of responsibilities is available in the Resources section of the guide

Avoiding Documentation Pitfalls

To avoid any problems with documentation, follow these guidelines:

• Always sign and date source documents.

• Never complete a CRF until the data exist in a source document to back up the entry on the form.

• Never alter the data on a source document. Changes can only be made by the individual or institution that generated the original document.

• For corrections, note with a single line through the change, then date and initial.

• Never do write-overs; never obliterate data; and never use White-Out!

Never, ever falsify data!

You need to avoid audit citations - your site could lose funding or your program could be closed.

Drug Accountability

In addition to logistics and documentation, drug accountability is a large component of preparing your site for clinical trials.

The PI or his or her designee is accountable for dispensing and returning investigative agents and documenting these tasks on the Drug Accountability Record, or DAR, or an equivalent form that the trial sponsor provides.

The investigator, research team members, and any affiliated pharmacy personnel must know and comply with Investigational Drug Management guidelines in addition to Pharmacy GCP guidelines. The trial sponsor should provide these guidelines.

At NCI the Pharmaceutical Management Branch oversees investigational drugs for NCI trials. Also, for policies, procedures, forms, and additional information, see CTEP’s Requisition and Management of Agents site.

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Drug Accountability Tasks

Typical tasks involved in handling research study drugs include:

• Receiving study drugs, which requires the PI or designee to:

o Verify the study drug against the protocol,

o Review and file the drug receipt,

o Record the drug shipment on the DAR, and

o Label and securely store the drugs.

• Storing study drugs, which requires:

o Storing the drugs in a locked place with limited access,

o Storing drugs for different protocols separately, and

o Keeping a daily temperature log for drug storage in the refrigerator and freezer.

• Dispensing study drugs, including:

o Recording the preparation and dispensing of the drugs on the DAR and

o Labeling the drug as “Investigational Drugs.”

• And, finally, returning or disposing of study drugs, which requires the PI to:

o Return or dispose of the drugs as required by the protocol,

o Fill out and file the Return Drug List or an equivalent form supplied by the trial

sponsor, and

o Record the return or disposal on the DAR.

Quality Assurance: Good Clinical Practices

Preparing your site for clinical trials includes ensuring that procedures are in place for quality assurance, or “QA.”

Solid QA procedures incorporate Good Clinical Practices, or GCPs, which are based on Federal regulations. GCPs define the responsibility of:

• The sponsor and its employees,

• The IRB of record, and

• The PI and other research team members who work at the site.

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Quality Assurance: Standard Operating Procedures

During the treatment phase of a clinical trial, all of the guidelines and procedures specified in the protocol should be strictly followed and precisely documented. The medical record should be monitored regularly to ensure that compliance with the protocol is documented accurately. Moreover, the site should maintain clear documentation of response to the investigational therapy.

Standard Operating Procedures, also known as SOPs, along with GCPs, standardize the way typical research processes, such as obtaining participant consent, drug dispensation, and IRB interaction, are conducted at a research site. The research team should establish SOPs, train team members in their use, and keep them at the site to provide reference and guidelines.

QA Helps Meet Requirements

Quality assurance helps ensure that sites and investigators meet requirements regarding:

• Obtaining informed consent from every participant,

• Maintaining accurate documentation, including case histories, drug dispensation and disposition, and treatment and response assessment,

• Notifying the IRB of all amendments to the study protocol,

• Reporting all adverse events to the sponsor and IRB, and

• Maintaining a record of accreditation for all laboratories used during the study.

We’ll discuss ongoing QA tasks in Module 8.

Final Step: Seeking IRB Approval

The last step before participant recruitment and enrollment can begin is for the IRB to review and approve several documents. The IRB is concerned about a broad range of issues ranging from scientific validity of the research question to the risks and benefits for study participants.

The IRB must review and approve:

• The protocol, for both science and safety issues and

• The informed consent form, to ensure that it includes all required elements.

o Use caution if you modify the model consent form provided by the sponsor: if

changes are needed, you should maintain a written record of communications with

the IRB. Any changes in risk, alternatives, and tissue banking language should also

be verified and approved by both the sponsor and the IRB.

The IRB will also review and approve:

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• The HIPAA authorization, which must name all agencies or entities. This authorization may be incorporated into the informed consent document or may be a separate document. Consult your institutional privacy board.

• Recruitment materials/advertisements, and investigator brochures, if applicable.

Module 5 Quiz

Question 1: Select whether this statement is True or False:

Each research team member will need his/her own dedicated computer resources, to facilitate tasks such as electronic data submission.

a) b)

True

Correct Answer: a That’s correct! Each research team member will need dedicated computer resources, not only for electronic data submission but also additional protocol-related online resources and communications

Question 2: Source documentation includes all of the following EXCEPT:

False

a) b)

Pathology reports

c) Progress notes

d) Radiology reports

Correct Answer: d That’s correct! All information listed in a case report form must be consistent with information found in source documents

Question 3: Which research team member is accountable for overseeing investigational drug management for the clinical trial?

Case report forms

a) b)

The principal investigator

c) The co-PI

d) The research coordinator A

Correct Answer: a That’s correct! The principal investigator is ultimately accountable for dispensing drugs in a clinical trial.

ny research team member who can dispense drugs to participants

Question 4: Quality assurance procedures ensure that all the following tasks will be documented EXCEPT:

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a) b)

Notifying the IRB of record when a participant leaves the trial

c) Recording which drugs were received and dispensed

d) Reporting adverse events to the sponsor

Correct Answer: a That’s correct! QA procedures ensure that drug receipt and dispensation, adverse events, and informed consent are all gathered and reported

Question 5: Sites can begin to enroll participants in their trials ONLY after:

Gathering informed consent from each participant

a) T

b)

he site has received a CRF form from the sponsor and can therefore sufficiently record participant data

c)

The PI has established QA procedures and documentation for the site and reviewed them with the team T

d) he site has conducted training on the protocol and finalized site logistics

The IRB has issued written approval to the site’

Correct Answer: d That’s correct! Sites can begin to enroll participants when they have received written approval from their IRB of record

Question 6: Select whether this statement is True or False:

It is acceptable to alter a source document if the individual who created or signed the source document is no longer available.

s PI

a) True b) False

Correct Answer: b That's correct!. It is never acceptable to alter a source document; changes can only be made by the individual or institution that generated the original

Module 5 Summary

Congratulations! You have now completed Module 5: Handling Site Logistics. You have learned:

• How to identify your site’s logistical requirements,

• The recordkeeping and reporting requirements for conducting clinical trials,

• Typical tasks involved in handling research study drugs,

• Required quality assurance procedures, and

• The steps involved in seeking IRB approval.

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In the next module, we’ll discuss the processes involved in recruiting and enrolling participants once the IRB has approved the protocol for your site.

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Module 6: Recruiting and Enrolling Participants

Confidence in the findings of clinical research relies directly on the quality of the data. Therefore, sites must rigorously adhere to sound data management practices, which includes successfully retaining the participants that sites enroll.

In this module, we’ll introduce a 5-step recruiting plan to help the trial at your site reach its enrollment goals, as well as tips to resolve recruitment challenges you may face.

Upon successful completion of this module, you will be able to:

• List the steps to successfully recruit and enroll participants,

• Explain why informed consent is critical to the success of a trial,

• Explain practical methods for retaining participants in a trial, and

• Describe challenges to participant recruitment, as well as solutions.

Successful Recruitment

At this point, your site should have already developed a menu of trials that are a good fit for its patient population or that of the site’s network of care providers.

The trial must enroll enough participants to ensure that results will not only be statistically valid but also generalizable. The sooner a trial can reach its enrollment goal, the faster the data can be collected, analyzed, and shared in the medical community.

Many sponsors will provide a recruitment plan for a trial that will be conducted at several sites; however, your research team will need to develop its own process specific to your site.

Recruiting participants for each trial at your site is a unique effort: what works at one site may not work at other sites, or even different studies at the same site.

Collaborating on a Process

The secret to successfully recruiting participants is a well-designed process that maps out tasks, methods, and team member responsibilities for the recruitment efforts. Your site should develop this process before beginning the clinical trial.

Participant recruitment requires a concerted effort from everyone on the research team, so each team member must be actively involved in developing a sound process as well as recruitment strategies and methods for the trial.

Engaging community members, local experts, and previous clinical trial participants from the beginning can strengthen the development of a strong recruitment process and program

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infrastructure. Some communities develop research advocacy networks and local advisory committees based on principles of community-based participatory research, or CBPR.

The Recruitment Process

For most clinical trial sites, participant recruitment for each trial follows this process:

• Step 1: Identify the number of participants you’ll need to recruit for the trial,

• Step 2: Determine your site’s strategies for recruiting participants for this trial,

• Step 3: Screen potential participants,

• Step 4: Enroll eligible participants, and

• Step 5: Continually evaluate recruitment for all trials at your site.

Let’s review each of these steps in further detail.

Step 1: Identify the number of participants you will need to recruit

The first step requires an estimate of the number of participants in the recruitment area who would qualify for enrollment. Note that the number of participants to be screened may be larger than the number you need to enroll. Not all participants screened will meet eligibility criteria.

Recruitment is tough and can be overwhelming at times.

It may help to break your total recruitment goal into small, attainable segments so that your site can reach intermediate milestones. For example, a site hoping to enroll 12 participants per year could set an enrollment goal of one to two per month.

Step 2: Strategies: Determine you recruitment strategies for the trial

Recruitment strategies include highlighting the open clinical trials at your site and encouraging referrals, based on the phase and type of trial. Some examples include:

• Meeting regularly with potential referring physicians and care providers to update them on new trials,

• Speaking at local and state medical societies,

• Sharing at tumor conferences and Grand Rounds,

• Posting notices on bulletin boards or in key waiting areas,

• Presenting to patient support groups or high-risk patients, and

• Displaying study-specific informational brochures and flyers.

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• Of course, referrals also come from your existing patient base as well as family and friends of current participants.

Recruitment Tips:

• Strategies that have worked in prevention trials that may also help in treatment trials include featuring stories or ads in radio or television spots, Internet sites, and mailings to targeted zip codes.

• Use multiple participant sources in cancer prevention or screening trials, since participants eligible for these trials generally do not have a diagnosis of cancer. Primary care physicians and family physicians are important referral sources, since they have direct access to this participant population.

Step 2: Identify barriers to recruitment The site may face several challenges to recruitment:

• Participants may completely lack or have insufficient health insurance, which limits access to primary health care and to clinical research studies that require third-party payment.

• Participants may not be able to afford to take time off work or incur out-of-pocket expenses.

• Participants need language that is clear to people who don’t work in medical fields. The use of medical jargon further excludes people with low literacy.

The solution is to provide resources to reduce or eliminate these barriers that, in turn, can help both your recruitment and retention efforts. Such resources may include transportation, child care, financial assistance, education, or other logistical support

Incorporate strategies such as those available at the Federal Government’s Plain Language Web site in to oral discussions and written materials to help alleviate some of these issues

Step 3: Screening Participants: Eligibility Criteria

The next step in the participant recruitment process involves:

• Screening participants according to eligibility criteria determined by the protocol, as well as

• Addressing informed consent.

At this point, the team should create any necessary study tools, such as forms for tracking their participant screening efforts.

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The study protocol will clearly state the eligibility criteria for the trial, including inclusion and exclusion criteria. These criteria will establish the parameters and guidelines that define the appropriate participant population.

Basic components of eligibility criteria include:

• Evidence of a specific cancer or hematologic diagnosis,

• Level of overall health of the patient,

• Performance status,

• Age limits and projected lifespan,

• Major organ system functioning,

• Prior medical history, especially related to other malignancies

• Prior treatments for cancer,

• Establishment of a baseline disease state from which to measure disease response,

• Stipulation regarding exclusion of certain concomitant illnesses or medications,

• Protection for offspring of patients of childbearing age, and

• Establishment of a psychological or mental status that presumes compliance with the study.

Dr. Gorsch his routine for presenting clinical trials:

“In terms of actually presenting the study to the patient, I have a sort of fixed routine. One of the concerns that patients have is whether they’re in fact a guinea pig when they’re being offered the study. And I tell them that there are several reasons why they might want to be on a clinical trial. The first reason is that it’s a way of getting a national second opinion. It’s not what Dr. Gorsch thought of; it’s what the best colon cancer doctors in the country or the best breast cancer doctors in the country sat down, hammered this out, and they said ‘How are we going to advance the treatment?’ This is the national second opinion; they say ‘This is the best we have.’ Another reason is it’s quality assurance. I can tell patients that, ‘If you’re on this clinical trial, everything I do is reviewed: your x-rays, your blood work, the doses of chemotherapy. You know that what I’m doing is being done the right way,’ and that’s something that is, I think reassuring to patients. And then ultimately, of course, there’s the altruistic motivation of providing information that will be useful for future patients.”

Step 3: Screening Participants: Informed Consent

Informed consent is more than a document; it’s an ongoing dialogue between the research team and the participant that fosters strong communication.

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The investigator must obtain informed consent from participants before they take part in any activities related to the study - and even before confirming their eligibility. To enhance the quality and efficiency of the communication, most providers encourage a potential study participant to bring a friend or family member along for support and provide written information for reference.

Some investigators tape their conversations with participants to allow them time to consider the study and its implications and further discuss it with family members.

When presenting a study to a participant for the first time, it’s imperative to give every consideration possible to ensure that he or she has adequate time to process the information and ask questions.

During this initial encounter, consider the following questions:

• Can the participant explain the treatment options, and what they will offer him or her?

• Can the participant understand the terminology being used? The language in which the information is being presented?

• Is the participant capable of following the instructions necessary to comply with all aspects of the study? Some studies have very detailed scheduling and follow-up requirements and can be overwhelming.

• Can the participant fully understand the dangers or risks involved with the study?

• Will the participant be responsible in reporting symptoms and warning signs to the appropriate medical personnel?

• Is the participant aware that participation is voluntary, and that he or she can stop study participation at any time?

As governed by the Code of Federal Regulations, it is not ethical to put a participant on a study if he or she isn’t able to comprehend what’s involved.

To ensure understanding, the research team member can ask participants to repeat back their understanding of what they need to do, what the potential risks are, and so on. The investigator and the research team should work closely with the IRB of record to take the proper steps and provide the correct tools to ensure that the participant has every opportunity to make an informed choice to participate in the trial.

Remember... the participant assumes a significant responsibility during the trial!

In addition to discussions with the participant:

• The participant must review and complete the formal consent document.

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• He or she must sign and date the consent form. Other required signatures include the investigator’s and that of the person obtaining consent. The IRB of record may require additional signatures and/or initials.

• File the original, signed copy of the form with the participant’s source documents in the research chart.

• Give a copy of the form to the participant.

• Document your activities in obtaining consent in the participant’s medical record in a note that the investigator signs and dates.

See NCI's guidelines for information on the process of informed consent and the required elements of success.

Step 3: Screening Participants: HIPPA

A quick note about HIPAA.

According to HIPAA, the research team can discuss the option of enrolling in a clinical trial without having participants sign a privacy waiver or an IRB or Privacy Board waiver of participant authorization.

However, if you need to disclose an individual’s information to a third party for purposes of recruitment in a research study, you must first obtain either authorization from that individual or a waiver of authorization, as permitted at Sec. 164.512(i) of the Privacy Rule.

See NIH’s Web site on HIPAA rules for useful information on HIPAA and conducting clinical trials.

Step 4: Enrolling Participants: Registration & randomization

To avoid delays when enrolling a participant, there are several things that can be done. Keep in mind that eligibility criteria can be strict and time-sensitive. It is important to review the participant registration instructions in the protocol before the planned registration date to ensure that all required prestudy steps have been completed and are within the allowable timeframes.

Required prestudy exams, sample collections, tests, and other requirements, are sometimes outlined throughout the protocol.

Prior to beginning a study, a research team member is responsible for registering the participant and for obtaining the randomization arm assignment. The treatment assignment is documented as part of the participant’s source documents.

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Participants are usually registered with the study sponsor. If the clinical trial is a randomized study, participants are randomized into a specific treatment arm to keep participant, physician, or researcher bias at a minimum and maintain the scientific integrity of study results. Such randomization is often computerized and done by an institution independent of those providing the treatment.

Step 4: Enrolling Participants: Logistics

Taking part in a clinical trial should be as participant-friendly as possible. For example, your site should make every effort to:

• Streamline and coordinate visits, tests, and appointments;

• Remove logistical barriers (such as parking and location) whenever possible;

• Provide a clear, understandable study calendar to each participant;

• Identify key contacts, to provide continuity in the front-line research team; and

• Provide necessary resources, such as a brochure describing clinical trials and study-specific instructions.

Helping participants take an active role in their therapy can enhance their compliance. Ultimately, retaining the same participants throughout the study can reduce the time it takes your site to complete recruitment.

Step 5: Document and evaluate your process

Finally, documenting your recruitment plan and tracking outcomes makes it possible to determine what works at your site and what can be improved. This information allows the team to review and discuss strategies and methods both before the trial starts and throughout the trial.

So that your recruitment plan is efficient, your site should define its criteria for success before the plan is actually implemented.

For example, one criterion might be the number of participants that your site is required to enroll by the sponsor or the research base with which you are affiliated.

If recruitment falls short of your site’s evaluation criteria, then the team should identify problems, evaluate strategies, and plan any additional actions to improve recruitment.

Maintaining a screening log - which identifies why participants didn’t go on a study or why they were ineligible - is an invaluable tool for identifying recruitment needs and strategies. For example, the protocol eligibility criteria may be too strict, or it may require too many office visits for the participants.

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Recruiting underrepresented populations: Main Challenges

People are more likely to choose to take part in clinical trials if they think the benefits associated with participation outweigh the burdens. Women and ethnic minorities traditionally face more financial and logistical burdens, and they often are unaware of the benefits of participating.

Women and ethnic minorities are more likely to live in poverty than men or Caucasian populations.

For ethnic minorities who speak a language other than English, understanding informed consent and compliance with protocol requirements may pose major problems.

And finally, the different cultural values that ethnic minorities hold may prevent them from participating in clinical trials.

For example, many people think that disease and death are natural occurrences and not something to fight against. Others think that the soul lives in every part of the body, and that it should remain whole instead of taking out organs or other specimens.

Other challenges to recruitment of women and minorities include:

Failure of researchers to adequately consider recruitment of a diverse population, and

Alienation and failure to collaborate with minority scientists and healthcare professionals.

Recruiting underrepresented populations: NIH Revitalization Act of 1993

In order to improve gender and ethnic diversity in health intervention research, the NIH Revitalization Act of 1993, Public Law 103-43, requires recruitment of women and minorities in all clinical research studies, especially clinical trials. Guidelines include:

• Ensuring that women and members of minority groups are included in all human subject research;

• For phase III clinical trials, ensuring that women and minorities are included so that valid analyses of differences in intervention effects can be accomplished;

• Not allowing cost as an acceptable reason for excluding these groups; and

• Developing outreach programs to recruit these groups into clinical studies.

Next, we’ll review recruitment challenges for these populations.

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Recruiting underrepresented populations: Recruitment strategies

To successfully recruit women and ethnic minorities into cancer clinical trials, the research team needs to be culturally responsive. This may require additional training in cultural competency, and in connecting to a diverse set of groups in your community.

Low-income persons are least likely to participate in research and most likely to drop out. In addition to strategies discussed previously in this module, the use of culturally targeted mass mailing and media presentations are very effective recruitment strategies.

Other recruitment tips for underrepresented populations include:

• Actively involving minority members in the research from the outset of the project to instill a sense of project ownership;

• Inviting previous participants to serve as advisors to the research team and as potential resources for other participants;

• Considering establishment of a Community Advisory Board, or CAB, or engaging a CAB that may already exist in your community;

• Sending follow-up letters acknowledging the participant’s time and effort;

• Obtaining support from local community leaders; and

• If possible, recruiting people in their communities and conducting interviews in their homes.

Adherence: Retaining participants

Enrolling participants is only part of successfully completing a trial. The research team also needs to pay special attention to retaining them. Participants must adhere to the protocol’s treatment, in order for their participation to be successful.

Participants always have the right to drop out of the study at any time. However, if a participant chooses to drop out or fails to show up for follow-up visits, some of the data collected may be unusable. This is one reason why retaining participants throughout the study is just as important as enrolling them.

The health care team and the research team, as well as the participant, all play important roles in the completion of a clinical trial. The research team should emphasize the participants’ responsibilities to them. These include adherence to clinic appointment schedules, laboratory and radiology requirements, dosage and timing of at-home oral chemotherapy, and reporting of side effects to the research nurse.

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Adherence Tips

There are many ways that a site can encourage its participants to remain in the trial. Here are a few practical tips:

• Show the participant they are respected and valued for their commitment throughout the study and the follow-up. Some sites send a thank-you letter to participants after they have signed an informed consent. It can be helpful to set up a template for your research team to use.

• Be flexible, within the limits of the protocol requirements or study calendar, when scheduling visits and testing.

• Keep participants informed of study progress and results. Be sure they have the information and tools that they need.

• Include the participants’ caregivers in your communications plan. They have great influence over long-term decisions made by the participant or on their behalf.

• Serve as a resource for information and support for the participant and their family beyond the scope of the trial.

• Keep referring clinicians informed of participants’ treatment, progress, and adverse events, so they can help provide support to participants and answer questions.

• Make reminder phone calls or send written reminders regarding upcoming appointments or follow-up visits.

Adherence & Follow-up

Participants often feel let down after their initial treatment is over, so keeping communication going assures them that you care and that you will work with them.

Again, it’s important to thank people once they have finished their treatment. This is also an opportunity to remind them of the importance of follow-up procedures.

Newly diagnosed patients often talk to several survivors. If these survivors had a positive experience in a clinical trial, they’re likely to mention it to someone who may be eligible for your next trial.

Module 6 Quiz

Question 1: A solid recruitment process for your site will:

a) b)

Recruit for the exact number of participants your trial requires

c) Include only one source for participant recruitment Include materials for the participants, such as brochures and trial-specific instructions

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d)

Correct Answer: c That’s correct! A solid recruitment process will include materials to assist the participants’ education, such as brochures on the trial and trial-specific instructions.

Question 2: Informed consent is MOST critical to the success of a clinical trial because:

Follow the same procedures as previous trials at your site

a) b)

Paperwork needs to be complete before any trial treatment begins

c)

The participant should understand that he/she is participating in research and associated potential risks and that he/she can leave the trial at any time

d) The participant needs to communicate with his or her referring clinician

Correct Answer: b That’s correct! It is critical that the participant understand that he or she is participating in research and associated potential risks and that he/she can leave the trial at any time.

Question 3: Select whether this statement is True or False:

If a participant drops out of a trial, the resulting data from that participant may not be usable.

The research team has to report compliance back to its IRB of record

a) True b) False

Correct Answer: a That’s correct! If a participant drops out of a trial, then his/her data may not be usable.

Question 4: Some solutions to the challenges of recruiting women and minorities to clinical trials may be resolved by all of the following EXCEPT:

a) Explaining informed consent and protocol requirements in the participant’

b)

s native language T

c) alking to potential participants in their homes

d) Paying the participants directly for their involvement

Correct Answer: c That’s correct! NCI does not advocate paying participants for their involvement.

Provide counseling to seek financial assistance for participants

Module 6 Summary

Congratulations! You have now completed Module 6: Recruiting & Enrolling Participants. You have learned about:

• A recruitment process to successfully recruit and enroll participants,

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• Reasons why informed consent is critical to the success of a trial,

• Practical methods to retain participants in a trial, and

• Challenges to participant recruitment and solutions.

In the next module, we’ll discuss how best to work with referring clinicians, now that the trial is underway.

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Module 7: Working with Referring Clinicians

In this module, we’ll detail how and why referring clinicians maintain ongoing relationships with their patients, and what research teams can do to help.

Upon successful completion of this module, you’ll be able to:

• Explain why a collaborative relationship between the participant’s referring clinician and the trial’s research team is essential, and

• List methods for educating referring clinicians as well as updating them on participant and trial progress

The Referring Clinician’s Key Task

In addition to the treatment and medical procedures required by the protocol, a research participant also receives study follow-up, ongoing health and symptom assessment, and care for any side effects that may arise from the protocol intervention during the trial. The PI often oversees and directs care if the participant lives in a nearby area and can travel to the research site easily.

For participants who live far away, however, referring clinicians play an extremely important role in managing their clinical care and communicating with the research team regularly regarding their condition. This is especially true in rural areas where there is limited access to cancer clinical researchers.

A Collaborative Relationship

A strong collaborative working relationship between the referring clinicians and the research team is essential.

Over time, participants commonly return to their primary care settings for ongoing monitoring and overall health care needs. For participants in clinical treatment trials, long-term follow-up data are often collected for life. Treatment trial interventions, such as oral hormones, for example, may continue for several years beyond the acute treatment phase.

Referring Clinician’s Role

The referring clinician performs several tasks during the participant’s initial participation in a clinical trial. For example:

• Discusses clinical trials as an option with potential participants.

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• Establishes initial contact with the clinical research team. This is preferable to direct communication by the participant, who may not have sufficient information on their medical conditions and prior treatment to determine eligibility.

• Shares appropriate clinical data and other information with the research team.

Once the participant is accepted into a trial, the referring clinician:

• Continues to provide clinical care for the participant,

• Supplies information to the research team,

• Assesses for potential side effects,

• Sends copies of the clinical records to the research team,

• Provides emotional support to the participant, and

• Helps answer questions.

Dr. James Atkins, an accomplished cancer clinical investigator, sums up the importance of good communication:

“Communicating with the family or referring doctors is extremely important whenever you’re dealing with a medical practice that’s based on referrals. It’s very important that referral physicians keep their referring doctors informed. It’s amazing, because I sort of think that when I talk with my patients that I answer all their questions and they’re satisfied when they leave. Then they go to their family doctor and may ask questions again. That is a real scenario. They do talk with their family doctors and so their doctors do need to be in the loop. We need to talk to the referring doctors about clinical trials so that they can be knowledgeable when their patients ask questions.”

The Research Team’s Role

The research team in turn:

• Provides care for the participant in compliance with the study protocol,

• Updates the referring clinician regularly regarding study progress, protocol changes, the prescribed intervention, expected symptoms, and suggested management of unexpected symptoms, and

• Seeks input from the referring clinician on standards of care, future protocol development, and any methods to promote trial efficiency and participant safety and well-being.

Clinical Trial Education

The research team can help educate and update potential referring clinicians about clinical trials. In this way, the team can directly affect referrals and speed participant accrual. Referring

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clinicians are more satisfied with their efforts in assisting in trials when they’re provided with educational information.

This effort includes:

• Presenting at meetings and hospital rounds,

• Sharing written articles or newsletters,

• Utilizing CME venues to address issues related to trial referrals and participation, and

• Hosting educational seminars featuring protocol authors and research base collaborators for additional dialogue and input.

Research has shown that referring clinicians are more satisfied and feel more involved when the research team provides them with educational information.

During the trial, to make referring clinicians comfortable with taking part in the care of the participant, it’s essential to provide them with adequate information regarding:

• Prescribed treatment and expected side effects,

• Any treatments or medications that are contraindicated or disallowed by the study protocol,

• Suggested management of any adverse events as well as any unexpected symptoms that participants experience,

• Progress the participant is making, and

• A report of each encounter between the research team and the participant.

Additional study-related communications enable referring clinicians to answer participants’ questions, which in turn facilitates retention. These include:

• Updates regarding overall study progress, revisions, and follow-up;

• Publications related to the study;

• Participant-initiated updates; and

• Invitations to participant celebrations and professional educational forums.

Unlike in a traditional consultation-referral process, the research team needs to go one step further to ensure that the referring clinician has a good understanding of clinical research.

• Help referring clinicians understand the basics of clinical trials and the importance of research in advancing cancer care. After the initial conversation with a research team member, participants often return to their referring clinicians and ask for advice. The referring clinicians need to understand the science behind the specific

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trial being considered to be able to assist the patient in this decision. They play a key role in helping participants see clinical trials as one way to get state-of-the-art treatment.

• Send a copy of the informed consent document. Patients often want to review this document with their referring clinicians before making a decision.

• Emphasize the importance of documentation and adverse event reporting. Referring clinicians must understand the importance of recording and prompt reporting of adverse events to the research team. They should also inform the team of any changes they may have initiated in the care of the participants.

• Offer to share local research participation highlights in conjunction with other professional discussions, such as tumor boards, grand rounds, and lectures.

After the trial, provide referring clinicians with a research team contact person so they can communicate information such as long-term side effects or death of participants. If appropriate, provide referring clinicians with information regarding how to manage the participant after the trial.

For more information on educating referring clinicians see NCI’s Clinical Trial Education series resources.

Module 7 Quiz

Question 1: Select whether the following statement is True or False:

The referring clinician may need to evaluate their patients’ care (e.g., side effects) if their patients live far from the research site.

a) True b) False

Correct Answer: a That’s correct! The referring clinician may take on a larger role in the trial tasks if their patients live far from the research team.

Question 2: Select whether this statement is True or False:

Methods to educate and support referring clinicians include providing them with instructions on how to manage adverse effects.

a) True b) False

Correct Answer: a

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That’s correct! Methods to educate and support referring clinicians include providing them instructions on how to manage adverse effects.

Module 7 Summary

Congratulations! You have now completed Module 7: Working with Referring Clinicians. You have learned

• Why a collaborative relationship between the participant’s referring clinician and the trial’s research team is essential, and

• Methods for educating referring clinicians as well as updating them on participant and trial progress.

In the next and final module, we’ll review the ongoing clinical trial tasks you’ll need to conduct throughout the trial, in order to ensure data integrity.

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Module 8: Ensuring Study Integrity

In this module, we’ll review ongoing tasks that the research team must conduct after the trial is underway, to ensure that the trial produces quality data.

Confidence in the findings of clinical research is directly related to the quality of the data. It’s essential that clinical sites rigorously adhere to quality data management practices.

Upon successful completion of this module, you’ll be able to:

• Describe expectations for reporting adverse events,

• List the regulatory procedures required for the site to continue the study,

• List two conditions under which the informed consent form may need to be revised, and

• Explain how to prepare your site for an audit.

Tasks During the Trial

When participants volunteer for clinical trials, they place their trust in the research team to properly report and interpret data gleaned from experiences and events that occur throughout the trial. Your site’s careful attention to data collection and reporting ensure that you can collect the highest quality research data.

This module reviews several ongoing tasks your site will be involved in throughout the trial. These tasks include:

• Adverse event reporting,

• Compliance with IRB review requirements,

• Ongoing informed consent, and

• Quality assurance, which includes monitoring and auditing.

Government-sponsored clinical trials are regulated by both the FDA and the Office for Human Research Protections, or OHRP [OH-harp].

Visit the FDA and OHRP sites for more information on these regulations

Adverse Event Reporting

An adverse event is an unexpected medical problem that may or may not be attributed to the study drug. During the study, the investigator must report all adverse experiences to the sponsor and IRB as required, as well as follow the guidelines and requirements listed in each protocol for that specific study.

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Adverse event reporting is an essential component of any clinical trial. Strict timeframes exist for reporting, depending on the severity of the event, FDA or OHRP [OH-harp] regulations, and IRB requirements.

The research team must follow the expectations defined by the research sponsor as well as the IRB. Additionally, the sponsor should provide comprehensive training on adverse event reporting to your site’s research team.

For more information on adverse event reporting, see CTEP’s Clinical Trials Monitoring Branch Web site.

Compliance with IRB Requirements

Once the IRB has approved the protocol for your site, you’ll have several different ongoing reviews and approvals throughout the course of the trial. You should familiarize yourself with your IRB’s standard operating procedures and guidelines.

Besides conducting the initial review of the protocol, the IRB also conducts the following reviews:

• Continuation or annual review,

• Protocol amendments and revisions, and

• Adverse events, as required by the trial sponsor, FDA regulations, and the IRB.

Compliance with IRB Requirements: Continuation or annual review

The study will undergo periodic IRB review and approval for as long as the trial continues.

The study MUST be approved every 12 months. Your study may be shut down if it’s not approved on time!

NCI recommends an 11-month renewal cycle to avoid any gaps in continuing approval and to prevent delays. More frequent, continuing review may be required depending on the level of risk involved in the study.

If you have a lapse in approval - even for just one day - you cannot enroll participants in a study.

As always, work closely with your IRB and the sponsor to ensure that your site maintains the appropriate study approvals.

Compliance with IRB Requirements: Protocol amendments or revisions

When new information becomes available, changes to the protocol, its informed consent form, and other study-related documents and study tools may need to be made. Changes may

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include a new telephone number, new drug dosing, changes to labs, or increased risk to the participant.

IRB review and approval may be necessary. Amendments and revisions must be submitted and approved within 90 days of the protocol change or according to the IRB requirements.

You must also list all changes separately from the original protocol and submit them to the IRB of record.

Ultimately, pay careful attention to any changes, and work with your IRB to identify the process required for updating the participant.

Compliance with IRB Requirements: Adverse events

The IRB also reviews reports of adverse reactions and unexpected events involving risks to study participants. The events may be specific to the study site or may have occurred at other sites also participating in the trial.

Work closely with your IRB and study sponsor to verify their adverse event reporting processes and expectations.

Ongoing informed consent

When new information about the investigational agent becomes available, or if changes that affect participant care are made to the protocol, the participants will need to be informed. Ongoing informed consent may require verbal notification, an update memo, or full re-consent. Work with your IRB to verify how the new information should be shared with your participants as part of the ongoing informed consent process.

The informed consent form may need to be revised accordingly and submitted to the IRB for approval. In this case the new, approved form must be shared with the participant just as the first consent form was presented. The form must be signed and dated, and filed along with the previous consent form.

A participant has the right to withdraw from a trial at any point. If the participant withdraws consent, include the proper, detailed documentation in the medical record concerning this withdrawal; maintain contact data for future contact if necessary; and notify the referring clinician, the sponsor, and the IRB.

Quality Assurance

As discussed previously in Module 5, both internal and external parties will conduct quality assurance tasks to assess protocol compliance, which will help to ensure study integrity.

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Let’s first define the term “quality assurance.” In this context, quality assurance is composed of an audit or monitoring visit in order to:

• Document the accuracy of the data submitted,

• Verify investigator compliance with protocol and regulatory requirements, and

• Provide an opportunity for the audit team to share information concerning data quality, data management, and other aspects of quality assurance with the study team.

Essentially, “monitoring” refers to internal QA tasks, and “auditing” refers to external QA tasks.

For NCI clinical trials, ongoing QA tasks include:

• Preparing your site for an audit, by conducting QA monitoring by both the research team and the trial sponsor, and

• The audits themselves.

Additionally, the sponsor may monitor and review data remotely.

For more information on monitoring and auditing see NCI’s Clinical Trials Monitoring Branch Web site.

Quality Assurance: Preparing for an audit

To prepare for any type of audit, your site should prepare the following documents:

• All source documents, such as physicians’ office records, hospital records, laboratory test results, participant medical history, participant follow-up data, and the appointment calendar;

• All case report forms;

• All regulatory documents; and

• All drug accountability records.

Quality Assurance: Internal QA

Each site should develop an internal QA program to help ensure data integrity. As a result, your site will be ready for an audit at any time.

This program may include:

• Verification that the participant meets all eligibility criteria by a second team member prior to registration,

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• Review of all data forms by another team member or objective reviewer prior to submission, and

• Periodic internal audits and comparison of case report forms to source documents.

Quality Assurance: The audit

Key audit components include a regulatory component, investigational drug management, and participant case reviews.

The PI should be present at the exit interview after the audit. If the auditor doesn’t offer an exit interview, the PI should request one to provide closure for any remaining questions and to obtain the result of the audit. If the auditor found problems, the exit interview is an opportunity to remedy them.

Conducting clinical trials is a complex task. Negative comments from monitors or auditors are inevitable. Try not to take them personally. Look at them as constructive feedback and as opportunities to improve your efforts.

For NCI the Clinical Trials Monitoring Branch under NCI’s Cancer Therapy Evaluation Program oversees the auditing program for Cooperative Group Trials.

Sponsor Provided Audit Guidelines: When setting up systems and studies, ask the sponsor to provide you with audit guidelines and expectations. Your internal QA program can then be designed accordingly and can take into account additional steps or specific research-related documentation that needs to be captured. As always, your goal is to ensure data quality.

Module 8 Quiz

Question 1: Select whether the following statement is True or False:

The site must follow adverse event reporting procedures as defined by the sponsor and the IRB of record.

a) True b) False

Correct Answer: a That’s correct! The site must follow adverse event reporting procedures as defined by the sponsor, the IRB of record, and any FDA and OHRP regulations.

Question 2: Throughout the trial, the IRB of record will need to review:

a) b)

Serious adverse events

c) Any situation that affects participant risk Any changes to the protocol

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d)

Correct Answer: d That’s correct! The IRB of record must review and approve any situation that affects participant risk, including serious adverse events as well as changes to the protocol.

Question 3: Internal QA audits:

All of the Above

a) b)

Necessitate that the site develop an internal QA program

c) Can be conducted by the trial sponsor

Correct Answer: a That’s correct! Internal QA audits necessitate that the site develop an internal QA program.

Only require source documentation for auditor’s review

Module 8 Summary

Congratulations! You have now completed Module 8: Ensuring Study Integrity. You have learned

• The expectations for reporting adverse events,

• The regulatory procedures required for the protocol to continue,

• The two conditions under which the informed consent form must be revised, and

• How to prepare your site for an audit.

This module concludes the course Including Clinical Trials In Your Practice: An Overview. We hope that through this course, you have recognized the value of including NCI-sponsored clinical trials in your practice.