1. Clinical Trials: An Overview
Ted Wun, M.D.
Professor of Medicine
PI/Director, UC Davis Clinical Translational Science Center
Chief, Division of Hematology and Oncology

2. What Are Clinical Trials?
Research studies involving people
Try to answer scientific questions and find better ways to prevent, diagnose, or treat people with diseases or predisposition to disease
Clinical trials are research studies involving people. Clinical trials are the final step in a long research process that includes preliminary laboratory research and animal testing.
Clinical trials try to answer specific scientific questions to find better ways to prevent, detect, or treat diseases, or to improve care for people with diseases.
In cancer research, a clinical trial is designed to show how a certain anticancer approach—for instance, a promising drug, a new surgical procedure, a new diagnostic test, or a possible way to prevent cancer—affects the people who receive it.

3. Why Are Clinical Trials Important?
Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease
The more people that take part, the faster we can:
Answer critical research questions
Find better treatments and ways to prevent disease
It is important to understand what clinical trials do to fight cancer:
·         Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat cancer.
·         Clinical trials contribute to knowledge and progress against cancer. Many of today’s most effective cancer treatments are based on previous study results. Because of progress made through clinical trials, many people treated for cancer are now living longer.
·         The more people that participate in clinical trials, the faster we can answer the critical research questions that will lead us to better treatment and prevention options for all cancers.
     

4. Do Many People Participate in Clinical Trials?
Not enough
For example, only 3 percent of U.S. adults with cancer participate in clinical trials
Nearly 70%+ of pediatric patients participate !
Fewer than 5 percent of U.S. adults with cancer participate in clinical trials—far fewer than the number needed to answer the most pressing cancer questions quickly.
We’ll talk more later about why so few participate.

5. Clinical Trial Protocol
A written, detailed action plan that:
Provides background about the trial
Specifies trial objectives
Describes trial’s design and organization
Ensures that trial procedures are consistently carried out

6. Clinical Trial Design
Eligibility criteria: Can range from general (age, sex, type of cancer) to specific (prior treatment, tumor characteristics, blood cell counts, organ function); eligibility criteria also vary with trial phase
Varies with protocol and phases
Endpoint: Measurable outcome that indicates an intervention’s effectiveness

7. Phases of Clinical Trials
Phase 1: people
What dosage is safe?
How should treatment be given?
How does treatment affect the body?
Phase 2: Less than 100 people
Does treatment do what it is supposed to?

8. Phases of Clinical Trials
Phase 3: From 100 to thousands of people
Compare new treatment with current standard
Phase 4: From hundreds to thousands of people
Usually takes place after drug is approved
Used to further evaluate long-term safety and effectiveness of new treatment

9. Randomized Trials
Participants have an equal chance to be assigned to one of two or more groups:
One gets the most widely accepted treatment (standard treatment)
The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than standard treatment
Phase 3 trials are randomized clinical trials, and some phase 2 trials may also be randomized.
Randomization is a method used to prevent bias in research. Treatment assignments are generated by a computer, and each participant hae an equal chance of being assigned to one of two or more groups, the control group and the treatment group:
The control group is made up of the people who get the most widely accepted treatment (standard treatment) for their cancer
The investigational group is made up of the people who get the new treatment being tested.
The next slide illustrates how randomization works.

10. Randomization
Explain slide

11. Why Is Randomization Important?
So all groups are as alike as possible
Provides the best way to prove the effectiveness of a new agent or intervention
If participants or doctors choose a particular group based on what they think is best, then one of the groups would likely be very different than the other, making comparison between the groups difficult.
Randomization eliminates this bias because participants have an equal chance of being assigned to either group and the subgroups are as similar as possible.
Comparing similar groups of people taking different treatments for the same type of cancer is a way to ensure that the study results are caused by the treatments rather than by chance or other factors.

12. Types of Clinical Trials
Treatment trials
Prevention trials
Early-detection trials/screening trials
Diagnostic trials
Quality-of-life studies/supportive care studies
There are at least 5 types of cancer clinical trials:
1. Treatment trials seek to find out:
·         What new treatment approaches can help people who have cancer
·         What is the most effective treatment for people who have cancer
2. Prevention trials seek to find out what approaches can prevent a specific type of cancer from developing in people who have not previously had cancer
3. Early-detection/screening trials seek to discover new ways of finding cancer in people before they have any cancer symptoms
4. Diagnostic trials seek to find out how new tests or procedures can better identify cancer in people when we think it is there
5. Quality-of-life/supportive care trials seek to find out what kinds of new approaches can improve the comfort and quality of life of people who have cancer

13. Benefits of Participation
Possible benefits:
Patients will receive, at a minimum, the best standard treatment
If the new treatment or intervention is proven to work, patients may be among the first to benefit
Patients have a chance to help others and improve care
Making a decision about taking part in a clinical trial is a very personal one. This is a question that only the person with cancer (or at high risk for cancer) can answer for him or herself.
Some of the possible benefits of participating in a clinical trial are listed here.

14. Risks of Participation
Possible risks:
New treatments or interventions under study are not always better than, or even as good as, standard care
Even if a new treatment has benefits, it may not work for every patient
Health insurance and managed care providers do not always cover clinical trials
While a clinical trial is a good choice for some people, there are possible risks. People need to consider these as they think about joining a trial.
Some of the possible risks of participating in a clinical trial are listed here.

15. Patient Protection
There have, unfortunately, been past abuses in patient protection
Federal regulations ensure that people are told about the benefits, risks, and purpose of research before they agree to participate
Although we now have strong safeguards for protecting those who participate in research, these protections have resulted from notorious abuses of human rights in the past.
The first formal statement of protection for individuals in research emerged from the Nuremberg trial in Germany where Nazi scientists and physicians who conducted experiments on World War II concentration camp victims were convicted. The Nuremberg Code outlined broad concepts for the protection of human subjects and forms the basis of today’s international code of ethics for the conduct of research.
In the United States, several controversial research studies alerted us to the critical need for protection for those participating in clinical trials. None of these studies sought to inform the participants about the research or gain their consent for participating.
·         From 1932 to 1972, the infamous Tuskegee Syphilis Study followed poor African American men with syphilis but did not treat them. During the study, the men were offered free medical care and were told that they would be treated for “bad blood.”
·         In the 1960s, two other research studies received major public attention. The first was a series of experiments with mentally retarded children; another involved debilitated elderly participants.
In response to these tragedies, regulations and policies were developed to ensure that people are told about the benefits, risks, and purpose of research for which they volunteer.

16. How Are Patients’ Rights Protected?
Scientific review
Institutional review boards (IRBs)
Informed consent
Data and Safety Monitoring Boards
Participant rights and safety are protected in four main ways.

17. How Are Patients’ Rights Protected?
Scientific review
Institutional review boards (IRBs) are required by Federal law for trials that are:
Federally funded
Subject to FDA regulation
Participant rights and safety are protected through two review panels, which must approve each study protocol before it begins.
Scientific Review
Clinical trials that are sponsored by the NCI —whether funded by a grant, run by a cooperative group, or run through a cancer center—are reviewed through different types of panels that include experts who review the scientific and technical merit of the proposed research. Many other clinical trial sponsors, such as pharmaceutical companies, also seek expert advice on the scientific and technical merit of their trial protocols.
Institutional Review Boards
IRBs are made up of people who are qualified to evaluate new and ongoing clinical trials on the basis of scientific, legal, and ethical merit. They include medical specialists as well as lay members of the community. The IRB determines whether the risks involved in a study are reasonable with respect to the potential benefits. IRBs also monitor the ongoing progress of the trial—from when it begins to when it ends.

18. How Are Patients’ Rights Protected?
Informed consent:
Purpose
Procedures
Risks and potential benefits
Individual rights
Informed consent is a process, not a form
Participant rights and safety are protected through informed consent.
Informed consent is a process where potential participants learn the purpose and the potential risks and benefits of a study before deciding whether they wish to participate. This process continues throughout the study.
The research team, which is made up of doctors and nurses, first explains the trial to potential participants in understandable language. The team explains the trial’s:
·         Purpose
·         Procedures
·         Risks and potential benefits
·         Participant rights, including the rights to:
Make an independent decision about participating
Leave the study at any time without jeopardizing future treatment
This discussion is the beginning of the informed consent process.
After discussing all aspects of the study with a potential participant, the team gives him/her an informed consent form, which includes written details about the information that was discussed. The form also describes the confidentiality of the participant’s records. If a person agrees to take part in the study, he or she signs the form.
The informed consent process does not end once the form is signed. If new benefits, risks, or side effects are discovered during a study, the researchers must inform study participants. In addition, participants are encouraged to ask questions at any time about what is happening during the study.

19. How Are Patients’ Rights Protected?
Data and safety monitoring boards:
Ensure that risks are minimized
Ensure data integrity
Stop a trial if safety concerns arise or objectives have been met
Participant rights and safety are also protected through data and safety monitoring boards (DSMBs).
For phase 3 trials that take place in many locations, a DSMB may be appointed to help ensure participants’ safety.
DSMBs:
Ensure that any risks associated with participation are minimized to the extent practical and possible
Avoid exposing participants to excessive risk
Ensure the integrity of data
Stop a trial if safety concerns arise or as soon as its objectives have been met
DSMBs are made up of physicians, statisticians, other scientists, and laypeople, the majority of whom must have no affiliation with the institution leading the study.

20. Why Do So Few Patients Participate in Clinical Trials?
Sometimes patients:
Don’t know about clinical trials
Don’t have access to trials
May be afraid or suspicious of research
Can’t afford to participate
May not want to go against physician’s wishes
Many people with cancer do not participate in clinical trials. Common barriers include:
Lack of awareness
Lack of access
Fear, distrust, or suspicion of research
Financial and personal concerns

21. Why Do So Few Patients Participate in Clinical Trials?
Doctors might:
Lack awareness of appropriate clinical trials
Be unwilling to “lose control” of a person’s care
Believe that standard therapy is best
Be concerned that clinical trials add administrative burdens
Doctors might:
Lack awareness of appropriate clinical trials. Physicians are not always aware of available clinical trials. Some may not be aware of the local resources, or some may assume that none would be appropriate for their patients.
Be unwilling to “lose control” of a person’s care. Most doctors feel that the relationship they have with their patients is very important. They want what is best for the patient, and if the person must be referred elsewhere to participate in a trial, doctors fear they may lose control of the person’s care.
Believe that standard therapy is best. Many health care providers may not adequately understand how clinical trials are conducted or their importance. Some believe that the treatment in clinical trials is not as good as the standard treatment. They also might be uncomfortable admitting that there is uncertainty about which treatment is best in a phase 3 clinical trial.
Be concerned that clinical trials add administrative burdens. The length and details of most research protocols may deter providers from participating in clinical trials. The possibility of incurring additional costs and expenses that might be inadequately reimbursed is a deterrent for many.

22. Releasing the Results of Clinical Trials
Peer-reviewed journals
Public announcements
Results not made public until end of trial

23. The Sickle Cell Disease Pipeline
What this means in practice:
There are going to be many SCD-related clinical trials in the foreseeable future.
They will all need patients from the same limited population.
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24. Thank you for your willingness to serve your community!