The Basics of Clinical Trials

1. The Basics of Clinical Trials Dorothy M K Keefe MD FRACP Chairman Cancer Research Advisory Committee Cancer Council South Australia

2. What is a Clinical trial? A test of a new intervention or treatment on people

3. Why are Clinical Trials conducted in Cancer? To allow medical professionals and patients to gain information about the benefits, side effects and possible uses of new drugs as well as new ways to use existing drugs To translate results of basic scientific research into better ways to prevent, diagnose, or treat cancer It is important to understand that cancer affects us all, whether we have it, care about someone who does, or worry about getting it in the future. Cancer is a common disease and a major health problem in Australia today.At current rates, it is expected that one in three men and one in four women will be directly affected by cancer before the age of 75. This year, more than 350,000 new cases of cancer will be diagnosed in the Australian population.By far the most common form of cancer in Australia is non-melanoma skin cancer, with approximately 270,000 cases annually. More than half of all Australians will develop at least one of these cancers. Although it is conventional to dismiss them as "not serious cancers" they can occasionally be fatal.Excluding non-melanoma skin cancers, about 82,000 new cancer cases are diagnosed, and there are almost 35,000 deaths due to cancer, each year. It is important to understand that cancer affects us all, whether we have it, care about someone who does, or worry about getting it in the future. Cancer is a common disease and a major health problem in Australia today.At current rates, it is expected that one in three men and one in four women will be directly affected by cancer before the age of 75. This year, more than 350,000 new cases of cancer will be diagnosed in the Australian population.By far the most common form of cancer in Australia is non-melanoma skin cancer, with approximately 270,000 cases annually. More than half of all Australians will develop at least one of these cancers. Although it is conventional to dismiss them as "not serious cancers" they can occasionally be fatal.Excluding non-melanoma skin cancers, about 82,000 new cancer cases are diagnosed, and there are almost 35,000 deaths due to cancer, each year.

4. Why do we need them? We need to know that any treatments we recommend are both safe and effective in humans Cell culture and animal work can only take us so far! Especially in Oncology, people are always looking for the miracle cure-and it is easy to get dragged into the idea Scientific, medical, evidence-based paradigm

5. Types of Clinical Trials Treatment trials Prevention trials Early-detection trials/screening trials Diagnostic trials Quality-of-life studies/supportive care studies Genetic trials There are at least 6 types of cancer clinical trials: There are at least 6 types of cancer clinical trials:

6. Types of clinical trial It can be a phase I, II or III trial It can be randomized or not It can be blinded or not It can involve a placebo or not And it can be a pilot study or not

7. Phase I 15-30 people Determines what dose is safe How the treatment should given How the treatment affects the body safety Clinical trials take place in phases. Once laboratory studies (in test tubes and animals) show that a new approach has promise, a phase 1 trial can begin. A phase 1 trial is the first step in testing a new cancer agent in humans. � In these studies, researchers look for the best way to give people the new agent (for example, by pill or by injection), how often it should be given, and what the safest dose is. These studies also include special laboratory tests such as blood tests and biopsies to evaluate how the new agent is working in the body. � In phase 1 cancer trials, small groups of people with cancer are treated with a certain dose of a new agent that has already been extensively studied in the laboratory. The dose is usually increased group by group in order to find the highest dose that does not cause harmful side effects. This process determines a safe and appropriate dose to use in a phase 2 trial. � While the primary purpose of phase 1 trials is to find the safest dose of a new agent, researchers also evaluate whether the new agent benefits patients. People with cancer who are eligible for phase 1 studies have no known effective treatment options, or they have already tried other treatment options. Many participate in these trials because they want to help others and contribute to cancer research. Phase 1 cancer trials usually have 15 to 30 participants. Clinical trials take place in phases. Once laboratory studies (in test tubes and animals) show that a new approach has promise, a phase 1 trial can begin. A phase 1 trial is the first step in testing a new cancer agent in humans. � In these studies, researchers look for the best way to give people the new agent (for example, by pill or by injection), how often it should be given, and what the safest dose is. These studies also include special laboratory tests such as blood tests and biopsies to evaluate how the new agent is working in the body. � In phase 1 cancer trials, small groups of people with cancer are treated with a certain dose of a new agent that has already been extensively studied in the laboratory. The dose is usually increased group by group in order to find the highest dose that does not cause harmful side effects. This process determines a safe and appropriate dose to use in a phase 2 trial. � While the primary purpose of phase 1 trials is to find the safest dose of a new agent, researchers also evaluate whether the new agent benefits patients. People with cancer who are eligible for phase 1 studies have no known effective treatment options, or they have already tried other treatment options. Many participate in these trials because they want to help others and contribute to cancer research. Phase 1 cancer trials usually have 15 to 30 participants.

8. Less than 100 people Determines Whether the treatment does what it is supposed to How the treatment affects the body If the drug or intervention has an effect on the cancer Does not compare with other treatments Phase II Phase 2 trials continue to test the safety of the new agent, and begin to evaluate how well it works against a specific type of cancer. � In phase 2 trials, the new agent is given to groups of people with one type of cancer or related cancers, using the dosage found to be safe in phase 1 trials. � If a new agent has demonstrated that it works against cancer and is safe for people in phase 2 trials, it enters a phase 3 trial. � In general, people with cancer who take part in phase 2 trials have been treated with chemotherapy, surgery, or radiation, but the treatment has not been effective. Participation in these trials is often restricted based on the previous treatment received. Phase 2 cancer trials usually have less than 100 participants. � Phase 2 trials continue to test the safety of the new agent, and begin to evaluate how well it works against a specific type of cancer. � In phase 2 trials, the new agent is given to groups of people with one type of cancer or related cancers, using the dosage found to be safe in phase 1 trials. � If a new agent has demonstrated that it works against cancer and is safe for people in phase 2 trials, it enters a phase 3 trial. � In general, people with cancer who take part in phase 2 trials have been treated with chemotherapy, surgery, or radiation, but the treatment has not been effective. Participation in these trials is often restricted based on the previous treatment received. Phase 2 cancer trials usually have less than 100 participants. �

9. From 100 to thousands of people Equal chance to be assigned to one of two or more groups Determines How the new treatment compares with the current standard Or how it compares with placebo Phase III Phase 3 trials focus on learning how a new treatment compares to �standard treatment� (the most widely accepted treatment, based on results of past research). Researchers want to learn whether the new treatment is better than, the same as, or worse than the standard treatment. � In most cases, trials move into phase 3 testing only after a treatment shows positive results in phase 2 trials. �� In phase 3 trials, participants have an equal chance of being assigned to one of two or more groups (also called �arms�). The process of assigning participants to groups is called randomization. Many people with cancer choose to get their first treatment in a phase 3 cancer trial. The type of participant varies, depending on the kind of question being asked about a particular cancer. Phase 3 trials usually have hundreds to thousands of participants, in order to find out if true differences exist in the effectiveness of the treatments being tested. Phase 3 trials focus on learning how a new treatment compares to �standard treatment� (the most widely accepted treatment, based on results of past research). Researchers want to learn whether the new treatment is better than, the same as, or worse than the standard treatment. � In most cases, trials move into phase 3 testing only after a treatment shows positive results in phase 2 trials. �� In phase 3 trials, participants have an equal chance of being assigned to one of two or more groups (also called �arms�). The process of assigning participants to groups is called randomization. Many people with cancer choose to get their first treatment in a phase 3 cancer trial. The type of participant varies, depending on the kind of question being asked about a particular cancer. Phase 3 trials usually have hundreds to thousands of participants, in order to find out if true differences exist in the effectiveness of the treatments being tested.

10. From hundreds to thousands of people Usually takes place after drug is approved to provide additional information on the drug�s risks, benefits and optimal use Phase IV

11. Randomised Clinical Trials Phase 3 trials are randomised clinical trials, and some phase 2 trials may also be randomised. 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.Phase 3 trials are randomised clinical trials, and some phase 2 trials may also be randomised. 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.

12. Randomisation 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. 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.

13. Open versus Blinded Clinical Trials Open Label clinical trials The doctor and patient know which drug or vaccine is being administered Blinded clinical trial Single Blind: the patient doesn�t know which treatment he/she is getting Double Blind: neither doctor nor patient knows

14. Placebo control The new treatment is tested against an inactive (or dummy) treatment that looks the same

15. Pilot Study A small study that helps develop a bigger study A first foray into a particular area Used to iron out possible difficulties, and help with design of the bigger, more pivotal study.

16. Involve people who have cancer Test new treatments, new combinations of drugs or new approaches to surgery or radiotherapy Determine the most effective treatment for people who have cancer Test safety and effectiveness of new agents or interventions in people with cancer Treatment Trials Most cancer clinical trials are treatment trials. These clinical trials involve people who have cancer. These studies try to answer specific questions about the effectiveness of a new treatment or a new way of using an existing treatment. 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 � � � � Most cancer clinical trials are treatment trials. These clinical trials involve people who have cancer. These studies try to answer specific questions about the effectiveness of a new treatment or a new way of using an existing treatment. 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 � � � �

17. Evaluate the effectiveness of ways to reduce the risk of cancer or prevent the recurrence of cancer Enroll healthy people at high risk for developing cancer Assess new means of detecting cancer earlier in healthy people Prevention Trials � 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 Unlike treatment trials, cancer prevention clinical trials are studies involving healthy people who are at high risk for developing cancer. These studies try to answer specific questions about and evaluate the effectiveness of ways to reduce the risk of cancer. include medicines, vitamins, vaccines or lifestyle changes � � � 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 Unlike treatment trials, cancer prevention clinical trials are studies involving healthy people who are at high risk for developing cancer. These studies try to answer specific questions about and evaluate the effectiveness of ways to reduce the risk of cancer. include medicines, vitamins, vaccines or lifestyle changes � �

18. Early-detection trials/screening trials Test the best way to detect early cancer, Pap smears, Mammograms Blood tests, X-rays Detect disease at an earlier stage, resulting in improved outcomes Diagnostic trials Develop better tools for classifying types and phases of cancer and managing patient care Usually include people who have signs or symptoms Early detection/screening/diagnosis Early-detection/screening trials seek to discover new ways of finding cancer in people before they have any cancer symptoms � Diagnostic trials seek to find out how new tests or procedures can better identify cancer in people when we think it is thereEarly-detection/screening trials seek to discover new ways of finding cancer in people before they have any cancer symptoms � Diagnostic trials seek to find out how new tests or procedures can better identify cancer in people when we think it is there

19. Quality-of-life/supportive care studies Aim to improve comfort and quality of life for patients and their families Genetic trials Determine how one�s genetic makeup can influence detection, diagnosis, prognosis, and treatment Broaden understanding of causes of cancer Develop targeted treatments based on the genetics of a tumor 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 Genetic trials determine how one�s genetic makeup can influence detection, diagnosis, prognosis, and treatment 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 Genetic trials determine how one�s genetic makeup can influence detection, diagnosis, prognosis, and treatment

20. What happens in a clinical trial? Clinical research team check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial, monitor the participant carefully during the trial, and stay in touch after the trial is completed. Tests Doctors visits Frequent follow up The clinical trial team includes doctors and nurses as well as social workers and other health care professionals. They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial, monitor the participant carefully during the trial, and stay in touch after the trial is completed. Some clinical trials involve more tests and doctor visits than the participant would normally have for an illness or condition. For all types of trials, the participant works with a research team. Clinical trial participation is most successful when the protocol is carefully followed and there is frequent contact with the research staff The clinical trial team includes doctors and nurses as well as social workers and other health care professionals. They check the health of the participant at the beginning of the trial, give specific instructions for participating in the trial, monitor the participant carefully during the trial, and stay in touch after the trial is completed. Some clinical trials involve more tests and doctor visits than the participant would normally have for an illness or condition. For all types of trials, the participant works with a research team. Clinical trial participation is most successful when the protocol is carefully followed and there is frequent contact with the research staff

21. Who can participate in clinical trials? All clinical trials have guidelines about who can participate. Using inclusion/exclusion criteria is an important principle of medical research that helps to produce reliable results. The factors that allow someone to participate in a clinical trial are called "inclusion criteria" and those that disallow someone from participating are called "exclusion criteria". These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. Before joining a clinical trial, a participant must qualify for the study. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy participants. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to studyAll clinical trials have guidelines about who can participate. Using inclusion/exclusion criteria is an important principle of medical research that helps to produce reliable results. The factors that allow someone to participate in a clinical trial are called "inclusion criteria" and those that disallow someone from participating are called "exclusion criteria". These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. Before joining a clinical trial, a participant must qualify for the study. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy participants. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study

22. Do Many People Participate in Cancer Clinical Trials? Less than 5% of Adults with cancer participate in clinical trials Fewer than 5 percent of 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. Fewer than 5 percent of 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.

23. Barriers to Participation in Clinical Trials Physicians and other health professionals may: Be unaware of appropriate trials Be unwilling to lose control of patient�s care Believe that standard therapy is best Believe that clinical trials are more work Have concerns about the patient�s care or how the person will react to suggestion of clinical trial participation

24. Patients may: Be unaware of clinical trials Lack access to trials Fear, distrust, or be suspicious of research Have practical or personal obstacles Be unwilling to go against their physicians� wishes Barriers to Participation in Clinical Trials

25. At a minimum, the best standard treatment Early access to new treatments. If the new treatment or intervention is proven to work, patients may be among the first to benefit Participation in advancing medical knowledge. Patients have a chance to help others and improve cancer care Active role in own health care The medical team conducting the trial will carefully and regularly monitor the patient�s progress Benefits of Participation in Clinical Trials 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. 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.

26. Risks of Participation in Clinical Trials 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 Unpleasant, serious or even life threatening side effects May require more time and attention than a non-protocol treatment 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. Trips to study site, more treatments, hospital stays Disappointment if does not work 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. Trips to study site, more treatments, hospital stays Disappointment if does not work

27. How Are Patients� Rights Protected? Ethical and legal codes that govern medical practice also apply to clinical trials Informed consent Review boards Scientific review Institutional review boards (IRBs) Data safety and monitoring boards Participant rights and safety are protected in a number of ways.Participant rights and safety are protected in a number of ways.

28. Informed Consent Informed consent is a document designed to inform the patient of the purpose and design of a clinical study, possible side effects and benefits and if there are any other options. It should also include information on Voluntary participation Duration of trial Insurance and compensation Name and phone number of contact person Procedures Individual rights and confidentiality 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 and data managers, 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. The information given to the patient should include the purpose of the trial and a statement on the fact that the trial is a research project. Information should also be given that participation is voluntary and that the patient is free to withdraw at any time and the availability of alternative treatments. Duration of the trial and the number of patients to be treated. All procedures, possible side or after effects, discomforts, the duration and measures to be taken if an adverse event occurs and treatment for these. A statement on the insurance and compensation available in case of an injury. A statement that patient records may be inspected for the purposes of source data verification, but confidentiality will be maintained. Name and phone numbers of contact people for the trial. 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 and data managers, 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. The information given to the patient should include the purpose of the trial and a statement on the fact that the trial is a research project. Information should also be given that participation is voluntary and that the patient is free to withdraw at any time and the availability of alternative treatments. Duration of the trial and the number of patients to be treated. All procedures, possible side or after effects, discomforts, the duration and measures to be taken if an adverse event occurs and treatment for these. A statement on the insurance and compensation available in case of an injury. A statement that patient records may be inspected for the purposes of source data verification, but confidentiality will be maintained. Name and phone numbers of contact people for the trial.

29. Review boards Scientific review Panel of experts Institutional review boards (IRBs) Qualified people to evaluate new and ongoing trials All institutions that conduct clinical trials must, by law, have a IRB that approves the protocol 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 protected through two review panels, which must approve each study protocol before it begins. Scientific Review Clinical trials that are sponsored by the NCI or NHMRC�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. 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. 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 or NHMRC�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. 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.

30. Are they Ethical? Yes, in general they are. We (the scientific community) strive to make them so. There are unscrupulous people (and companies) in any area Guidelines make it easier for us to check up on ourselves! Dr James will discuss

31. Are they safe? Yes (usually) There are stringent guidelines in place Safety and toxicity are closely monitored Trials have built-in stopping rules Subjects are indemnified

32. How can we tell they are done properly? The Declaration of Helsinki GCP guidelines Transparency and good communication Use of Institutional Ethics committees

33. So what do I personally do if I have an idea for a trial? Consider the question I want to answer Write a draft protocol Decide if it is a phase I, II, III or pilot study Write the Ethics Committee application Submit that Work out where funding will come from

34. RAH Cancer Centre Clinical Trials A wide variety of clinical trials are performed. These include phase I/II and III studies of new drugs, and ongoing program in supportive care and psychosocial research

35. The Protocol A study plan on which all clinical trials are base (recipe or blueprint) Provides background about the trial Describes trial�s design and organisation Ensures that trial procedures are consistently carried out Each study enrolls people who are alike in key ways Clinical trials follow strict scientific guidelines. These guidelines clearly state the study�s design and who will be able to participate in the study. Every trial has a head person in charge, usually a doctor, who is called the principal investigator. The principal investigator prepares a plan for the study, called a protocol, which acts like a �recipe� for conducting a clinical trial. � The protocol explains what the trial will do, how the study will be carried out, and why each part of the study is necessary. � Every doctor or research center that takes part in the trial uses the same protocol. This ensures that participants are treated identically no matter where they are receiving treatment, and that information from all the participating sites can be combined and compared. Clinical trials follow strict scientific guidelines. These guidelines clearly state the study�s design and who will be able to participate in the study. Every trial has a head person in charge, usually a doctor, who is called the principal investigator. The principal investigator prepares a plan for the study, called a protocol, which acts like a �recipe� for conducting a clinical trial. � The protocol explains what the trial will do, how the study will be carried out, and why each part of the study is necessary. � Every doctor or research center that takes part in the trial uses the same protocol. This ensures that participants are treated identically no matter where they are receiving treatment, and that information from all the participating sites can be combined and compared.

36. The Sponsor Sponsor can be Pharmaceutical company Co-operative group (NHMRC, TROG, NSABP) Another Investigator Foundation Responsibilities of the sponsor update available data liaise with the appropriate regulatory bodies communication between trial centre and sponsor monitoring trial at the site ensuring all data collected The sponsor is usually a pharmaceutical company, but it may be a funding body or another Investigator. It is the responsibility of the sponsor to provide an update of available data on the specific agent under study, including pre clinical studies and toxicology. The sponsor liaises with the appropriate regulatory bodies. In Australia this is the TGA (Therapeutic Goods Authority). Adverse events are also reported to the TGA by the sponsor. Before the trial starts, communication between the trial centres and the sponsor usually occurs via a monitor (CRA) who is an employee of the sponsor. The monitor is required to be adequately qualified and have full knowledge of the protocol and the agent under investigation. The monitor visits the centre to assess it�s suitability and explains the protocol and trial procedures and CRF�s with the investigator and trial staff. The monitor also confirms that the regulatory requirements are met. During the trial the monitor maintains contact with the trial staff and ensures good conduct of the trial, protocol adherence, quality data and record keeping especially of source data. At the end of the trial the sponsor compiles a study report. The sponsor is usually a pharmaceutical company, but it may be a funding body or another Investigator. It is the responsibility of the sponsor to provide an update of available data on the specific agent under study, including pre clinical studies and toxicology. The sponsor liaises with the appropriate regulatory bodies. In Australia this is the TGA (Therapeutic Goods Authority). Adverse events are also reported to the TGA by the sponsor. Before the trial starts, communication between the trial centres and the sponsor usually occurs via a monitor (CRA) who is an employee of the sponsor. The monitor is required to be adequately qualified and have full knowledge of the protocol and the agent under investigation. The monitor visits the centre to assess it�s suitability and explains the protocol and trial procedures and CRF�s with the investigator and trial staff. The monitor also confirms that the regulatory requirements are met. During the trial the monitor maintains contact with the trial staff and ensures good conduct of the trial, protocol adherence, quality data and record keeping especially of source data. At the end of the trial the sponsor compiles a study report.

37. The Investigator Profile Adequate qualifications to conduct research in a given area Necessary resources Sound knowledge of the investigational drug and protocol Sound knowledge of GCP Responsibilities training of staff ethics submission facilities and equipment resources for data collection informed consent reporting of serious adverse events PROFILE The investigator, or investigators are expected to be adequately qualified to conduct research in the given area, have the necessary resources to participate and take full responsibility for the conduct of the trial. In addition, the investigator should have a sound knowledge of the investigational drug, the trial protocol and GCP. RESPONSIBILITIES Training of staff, including data managers and clinical staff is the responsibility of the investigator. The investigator submits the protocol, investigators brochure, the consent form, indemnity details, patient information brochure and application form to the ethics committee for approval. Ensures that appropriate clinical facilities and equipment are available and that the necessary resources for data collection and recording are present. The investigator also takes responsibility of ensuring that a potential trial participant is informed of why the study is being conducted, what is involved and any risks or benefits to him or her. On agreeing to participate the patient is required to sign consent form along with the investigator. Reporting of serious adverse events to the sponsor and the ethics committee. Also annual updates. PROFILE The investigator, or investigators are expected to be adequately qualified to conduct research in the given area, have the necessary resources to participate and take full responsibility for the conduct of the trial. In addition, the investigator should have a sound knowledge of the investigational drug, the trial protocol and GCP. RESPONSIBILITIES Training of staff, including data managers and clinical staff is the responsibility of the investigator. The investigator submits the protocol, investigators brochure, the consent form, indemnity details, patient information brochure and application form to the ethics committee for approval. Ensures that appropriate clinical facilities and equipment are available and that the necessary resources for data collection and recording are present. The investigator also takes responsibility of ensuring that a potential trial participant is informed of why the study is being conducted, what is involved and any risks or benefits to him or her. On agreeing to participate the patient is required to sign consent form along with the investigator. Reporting of serious adverse events to the sponsor and the ethics committee. Also annual updates.

38. The Clinical Trials Nurse Patient education Emotional support Management of side effects Source documentation Vital signs Adverse events - CTC Protocol deviations ECOG Performance status Nurses play an important and supportive role within clinical trials Nurses play an important and supportive role within clinical trials

39. The Clinical Trial Coordinator or Data Manager Responsible for the collection, handling, manipulation, tracking and quality of the data. Ensure clinicians adhere to the protocol, trial patients receive the therapy dictated by the protocol, provide support to the patients All in accordance with Good Clinical Practice (GCP) GCRP A set of guidelines specifically designed for the protection of research subjects and the collection of good quality data. Human subjects must be protected whenever they participate in clinical trials. The health and welfare of individuals treated with investigational drugs or devices must take precedence over purely scientific interests. To ensure adherence to this, guidelines to ethical conduct have been established by several institutions and countries. NHMRC established it�s medical research ethical committee in 1982 and this provided a major stimulus for the establishment of Institutional ethics committees in hospitals. There are Australian guidelines for GCRP published by the TGA in December 1991, and the NHMRC has provided guidelines in it�s statement on human experimentation which are regularly updated. These are based on principles first adopted internationally by the World Medical Assembly at Helsinki in Finland in 1964 and formalised into the �Declaration of Helsinki�. GCP organises the principles of good clinical research conduct into a set of guidelines, including guidelines pertaining to the responsibilities of the different individuals and groups involved in the conduct of a clinical trial, specifically aimed at the protection of research subjects and the collection of good quality data. GCP provides a minimum standard for the different areas of trial conduct. A knowledge of the GCP standards is recommended for any person with responsibility in a clinical GCRP A set of guidelines specifically designed for the protection of research subjects and the collection of good quality data. Human subjects must be protected whenever they participate in clinical trials. The health and welfare of individuals treated with investigational drugs or devices must take precedence over purely scientific interests. To ensure adherence to this, guidelines to ethical conduct have been established by several institutions and countries. NHMRC established it�s medical research ethical committee in 1982 and this provided a major stimulus for the establishment of Institutional ethics committees in hospitals. There are Australian guidelines for GCRP published by the TGA in December 1991, and the NHMRC has provided guidelines in it�s statement on human experimentation which are regularly updated. These are based on principles first adopted internationally by the World Medical Assembly at Helsinki in Finland in 1964 and formalised into the �Declaration of Helsinki�. GCP organises the principles of good clinical research conduct into a set of guidelines, including guidelines pertaining to the responsibilities of the different individuals and groups involved in the conduct of a clinical trial, specifically aimed at the protection of research subjects and the collection of good quality data. GCP provides a minimum standard for the different areas of trial conduct. A knowledge of the GCP standards is recommended for any person with responsibility in a clinical

40. What should you consider before joining a clinical trial What is the purpose of the study? Why do researchers believe the new treatment being tested may be effective? What kinds of tests and treatments are involved? How do the possible risks, side effects, and benefits in the study compare with my current treatment? How long will the trial last? Who will pay for the treatment? How will I know that the treatment is working? Can I leave the study after it has begun? People should know as much as possible about the clinical trial and feel comfortable asking the members of the health care team questions about it, the care expected while in a trial, and the cost of the trial. The following questions might be helpful for the participant to discuss with the health care team. Some of the answers to these questions are found in the informed consent document. What is the purpose of the study? Who is going to be in the study? Why do researchers believe the new treatment being tested may be effective? Has it been tested before? What kinds of tests and treatments are involved? How do the possible risks, side effects, and benefits in the study compare with my current treatment? How might this trial affect my daily life? How long will the trial last? Will hospitalization be required? Who will pay for the treatment? Will I be reimbursed for other expenses? What type of long-term follow up care is part of this study? How will I know that the treatment is working? Will results of the trials be provided to me? Who will be in charge of my care? People should know as much as possible about the clinical trial and feel comfortable asking the members of the health care team questions about it, the care expected while in a trial, and the cost of the trial. The following questions might be helpful for the participant to discuss with the health care team. Some of the answers to these questions are found in the informed consent document. What is the purpose of the study? Who is going to be in the study? Why do researchers believe the new treatment being tested may be effective? Has it been tested before? What kinds of tests and treatments are involved? How do the possible risks, side effects, and benefits in the study compare with my current treatment? How might this trial affect my daily life? How long will the trial last? Will hospitalization be required? Who will pay for the treatment? Will I be reimbursed for other expenses? What type of long-term follow up care is part of this study? How will I know that the treatment is working? Will results of the trials be provided to me? Who will be in charge of my care?

41. How do you find out about Clinical Trials? Oncologist NCI Web site www.cancer.gov NHMRC Web site www.ctc.usyd.edu.au National Breast Cancer Centre www.nbcc.org.au RAH Cancer Centre www.rah.sa.gov.au/cancer/medical1.php