Clinical Trials 101 Everything you need to know about what a clinical trial is, how to participate, and how it’s made

Table of contents SECTION I: The Who, What, Where, When, and Why of a Clinical Trial SECTION II: Important Terms to Know SECTION III: Participating in a Clinical Trial SECTION IV: An Example Clinical Trial Creation Process SECTION V: Sources

Section I: The who, what, where, when, and why of a Clinical trial A general overview of clinical trials

What is a clinical trial? A clinical trial is a research study that tests new treatment and prevention methods to find out if they are safe, effective, and better than the current standard of care. In a clinical trial, participants receive specific interventions according to the research plan, or protocol, created by the investigators. These interventions may be medical products, such as drugs or devices, medical procedures, or changes to participants’ behavior, such as diet modification. How does a clinical Trial work? Clinical trials work by comparing a new medical approach to: (a) a standard one that is already available, (b) a placebo that contains no active ingredients, or (c) no intervention at all. The investigators involved in the trial try to determine the safety and efficacy of the intervention by measuring certain outcomes in the participants and comparing them to control conditions.

Why are clinical trials conducted? Clinical trials are designed to add to medical knowledge related to the treatment, diagnosis, and prevention of the diseases or conditions being studied. Common reasons for conducting clinical trials include: Evaluating one or more interventions (i.e., drugs, medical devices, surgery or radiation therapy) for treating a disease, syndrome, or condition. Examining methods for identifying a condition or the risk factors for that condition Exploring and measuring ways to improve the comfort and quality of life through supportive care for people with a chronic illness Finding ways to prevent the initial development or recurrence of a disease or condition

Where Do clinical trials take place? Clinical trials can take place in many locations, including hospitals, doctors’ offices, universities, and community clinics. The location depends on who is conducting the study. How long are clinical trials? The length of a clinical trial varies depending on what is being study. Participants are told how long the study will last before enrolling. Who is in charge of a clinical trial? Every clinical trial is led by a principal investigator (PI), who is often a medical doctor. In addition to the PI, most trials will also have a research team that can include doctors, nurses, social workers, and other health care professionals. Clinical trials can be sponsored or funded by academic medical centers, voluntary groups, pharmaceutical companies, physicians, health care providers, and other organizations and individuals.

Trial Classifications Treatment Trials: Test treatments, drug combinations, or surgical approaches to alleviate symptoms and/or slow disease progression Prevention Trials: Test approaches, medicines, vitamins, minerals, vaccines, or lifestyle changes that may lower the risk of certain diseases Screening Trials: Ways to detect a disease, particularly in its early stages Quality of Life Trials: Explore ways to improve comfort and quality of life for patients with a particular disease Genetics Trials: Designed to improve the ability to look for an inherited risk of a certain disease.

Clinical trial phases PHASE I: Is the treatment safe? – Test a potential therapy, procedure or drug for the first time in human beings. Phase I generally focuses on determining the highest dose of the new treatment that can be given safely without serious side effects. Patient Size:10-80 subjects. PHASE II: Does the treatment work? – If a treatment is deemed safe during Phase 1, it can then be tested in Phase II to look for evidence that it works. Patient Size: 25-100 subjects. PHASE III: Is it better than what’s already available? – Phase III involves comparing the safety and effectiveness of the new treatment against current standard treatment. Patient Size: 100-3,000 subjects. PHAVE IV: Post marketing surveillance – Conducted after a treatment has received FDA approval and has been brought to market. The goal of Phase IV is to continue the study of the treatment and side effects.

Section II: Important terms to know Key terms that are used in every clinical trial

IRB – The institutional Review Board An Institutional Review Board (IRB) is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans, in order to protect the rights, safety, and well-being of the participants. In a Clinical Trial, the IRB reviews all aspects of the trial and approves it startup. The areas under review generally include the appropriateness of the clinical trial protocol, as well as the risks and benefits to the study participants. IRB members should be collectively qualified to review the scientific, medical, and ethical aspects of the trial. The committee should consist of: (1) At least five competent members with varying backgrounds (2) At least one member representing a non-scientific area (a lay member) (3) At least one member without affiliation to the institution or the trial site (an independent member)

GCP – Good clinical practice Organizations conducting clinical trials on a pharmaceutical, biotechnology or medical device products intended for submission to a regulatory authority, are required to follow Good Clinical Practice guidelines. The FDA defines GCP as: Good clinical practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety, and wellbeing of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. Clinical Trial Investigators The two main types of investigators involved in clinical trials are Private Investigators (PI) and Clinical Investigators. The Private Investigator is the lead researcher of a specific clinical trial. The Clinical Investigator is responsible for ensuring that a study is conducted according to the investigational plan and applicable regulations; for protecting the rights, safety, and welfare of subjects under investigator’s care; and for the control of drugs under investigation.

Informed consent form An informed consent form is a patient’s consent to a medical or surgical procedure, or participation in a clinical study, after being properly advised on the relevant medical facts and risks. A common clinical trial consent form contains: Introduction / Study Background Why is this study being done? What is involve din the study? What are my responsibilities in this study? What are the risks and discomforts of the study? What will happen if I am injured as a part of this study? Are there benefits to taking part in this study? Who is paying for this study? What are my costs? Will I be paid to participate in this study? What are my alternatives to being in this study? What if I want to withdraw or am asked to withdraw from this study? Who do I call if I have questions or problems? What about confidentiality?

Section III: participating in a clinical trial Common FAQs

Should I participate in a clinical trial? Choosing to participate in a clinical trial is not an easy decision, and is usually dependent on the risks and benefits associated with the trial. For some patients, a clinical trial may be the best treatment option available; for other patients, the added uncertainty of a clinical trial may not be worth it. The more a patient knows about their disease, condition, or health issue, the easier it can be to make a decision. Steps that should be taken when deciding whether or not to participate in a clinical trial include: (1) Researching different clinical trials being done and how they are designed (2) Talking with your doctor about which clinical trial might be right for you (3) Finding out what the associated risks and benefits of participating in the trial are (4) Learning what costs associated with the clinical trial you will be responsible for

What are some common risks/benefits? Benefits: Participants of clinical trials are directly contributing to medical knowledge. The results of studies can not only make a difference in the lives of the participants, but also in the lives and care of future patients. Common benefits of participating in a clinical trial include: Gaining access to research treatments before they are widely available Obtaining medical care at health care facilities during the trial Playing an active role in ones health care Helping others by contributing to medical research Risks: There can be some risk of harm or injury associated with participating in a clinical trial. These risks include: Unpleasant, serious, or life-threatening side effects The experimental treatment may not be effective The study protocol may require more time and attention than a non-protocol treatment, including trips to the study site, hospital stays, or complex dosage requirements.

How are participants protected? Patient safety and protection are the two main concerns of any clinical trial. To ensure a study is safe and scientifically relevant, all clinical trials are regulated and monitored by IRBs, federal agencies, and data safety monitoring boards (DSMB). Federal Agencies: Federal agencies responsible for approving and monitoring clinical trials include the U.S. Food and Drug Administration (FDA) and the National Institute of Health (NIH). DSMB: The DSMB is an independent group made up of medical ethicists, doctors, statisticians, and other health professionals, that monitors a clinical trial for safety and scientific relevance. While an IRB typically looks at a clinical trial before it starts, the DSMB is responsible for reviewing the study after it starts, and making any necessary recommendations to the IRB about stopping or continuing the study. In addition to study monitoring, research institutions are required to obtain informed consent form from any individual that decides to participate in the clinical trial. Participant informed consent is obtained using an Informed Consent Form.

What will it cost to participate? The Affordable Care Act (ACA) requires health insurance companies to cover the routine costs associated with approved clinical trials, but not the associated research costs. Routine costs include any drugs, procedures, and/or services needed while participating in a trial that an insurer would normally cover outside a trial. Research costs that don’t require insurance coverage include: the treatment or procedure being studied, any procedure done only to collect data for the study, and anything that is not related to the standard treatment for the condition. The best way to find out the cost of a particular study is by talking to your doctor and the clinical trial research team. They will be able to tell you what is covered, and what patients are expected to pay for. For more information on the ACA and clinical trial costs, visit: http://www.cancer.net/sites/cancer.net/files/clinical_trials_coverage_aca_fact_sheet.pdf

Where can I find details on a trial? All necessary clinical trial details are located in the clinical trial study protocol. The study protocol is designed to answer specific questions, and ensure the health and safety of all participants. The protocol will contain the following information: Reasons for conducting the study The length of the study What participant information will be gathered The number of participants needed Who may participate in the study (eligibility criteria) The schedule of tests, procedures, or drugs and their dosages Can I withdraw from a study? Participation in a clinical trial is always voluntary. An individual is allowed to withdraw from a study before the study starts, during the study, or during the follow-up period.

How do I find a clinical trial? The best way to find a clinical trial is by talking with your doctor. There are also organizations that offer clinical trial search engines, including: ClinicalTrials.gov: (ClinicalTrials.gov) A web-based resourced maintained by the National Library of Medicine (NLM) and the National Institute of Health (NIH). It provides information on studies in all 50 states and 189 counties. CISCRP: (SearchClinicalTrials.org) The Center for Information and Study on Clinical research Participation (CISCRP) offers an online clinical trial search engine, as well as a toll-free number when patients can receive help locating a clinical trial.

How do I find a clinical trial? The best way to find a clinical trial is by talking with your doctor. There are also organizations that offer clinical trial search engines, including: EmergingMed Navigator: (EmergingMed.com) A phone and internet-service that help patients identify clinical trials relevant to their specific diagnosis, stage, and treatment history. The World health Organization (WHO): (http://apps.who.int/trialsearch/Default.aspx) WHO has a clinical trial registry platform that allows patients to search clinical trial registration information from many different countries’ registries.

SECTION IV: An example clinical trial process How a medical device clinical trial is created and conducted

Medical Device Clinical trial process 1. Study Protocol Development 2. Document and Device Preparation 3. Site Selection and Qualification 4. 5. 6. IRB Submission Patient Screening and Selection Trial Master File Creation 7. Data Management 8. 9. SIV and Study Launch Study Completion

1. Protocol synopsis and development The first step to setting up any clinical trial is drafting a protocol outlining the whole study. Sections commonly found in a medical device clinical trial protocol are: Introduction Study Objective Device Description Study Design Clinical Procedures and Training Statistics Data Management Adverse Events and Serious Adverse Events Compliance Investigator Qualifications and Responsibilities Quality Control and Quality Assurance Sponsor’s Commitments Publication Policy Appendices References

2. Prepare Research Documents/devices The next step is finalizing all the necessary documents, applications, registrations, and supply orders needed to complete the study, including: Patient Informed Consent Form Registering the trial with ClinicalTrials.gov and an insurance company Order study-related supplies IRB applications for the study and the site locations 3. Select and qualify sites Step three involves: (1) selecting and qualifying the sites where the studies will take place, (2) executing any necessary site NDAs and contracts, and (3) collecting any CVs, medical licenses, GCP training, financial disclosures, etc., from the sites

4. Irb submission 5. Patient Screening In parallel with steps 1-3, a submission to the Intsitutional Review Board (IRB) must be made that contains: The study application CVs, Medical Licenses, and GCP Training for Principal Investigators Financial disclosures for principal investigators Advertisements, telephone scripts, referral letters, etc. Any document a subject (patient) will see such as a survey or questionnaire 5. Patient Screening Once a study is approved by the IRB, and all study sites have been selected and qualified, the clinical and principal investigators will use the study eligibility criteria to select qualified participants

6. Trial master file 7. data management Step 6 is the creation of a Trial Master File, which is a hard copy of all the documentation relating to a clinical trial, and, specifically, of the documentation held by the sponsor (i.e., a filling system containing the essential documents). Step 6 also includes: Preparing tools to support sites such as laminated cards of eligibility criteria and schedule of examinations Preparing for investigator meeting(s), if any 7. data management Step 7 involves developing a way to capture and analysis any data collected throughout the study. This involves developing: A statistical analysis plan A management plan A validated database

8. Study launch 9. Study Completion The final steps in creating a clinical trial are listed below. Once these steps are complete, the Site Initiation Visits (SIV) occur and the study is officially started. Assuring IRB approval of protocol and informed consent form prior to enrollment Confirming shipment of devices Confirming shipment of supplies including regulatory binders and other study supplies Reviewing investigator responsibilities and GCP 9. Study Completion Once a clinical trial is complete, the study data is collected and analyzed in order to determine the treatment’s safety, effectiveness, and side effects. Whether or not testing is stopped, or moved onto the next phase, depends on this data.

Section vi: sources Context and image sources

Appendix 1 – Context Sources FDA Good Clinical Practice Guidelines: http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf CenterWatch Volunteering for a Clinical Trial: http://www.centerwatch.com/clinical-trials/volunteering.aspx MDAnderson Cancer Center: Joining a Clinical Trial: http://www.mdanderson.org/patient-and-cancer-information/cancer-information/clinical-trials/joining-a- clinical-trial/index.html ClinicalTrials.gov – Clinical Studies: https://clinicaltrials.gov/ct2/about-studies/learn#WhoCanParticipate ClinicalTrials.com – Institutional Review Board (IRB): http://www.clinicaltrials.com/investigators/irb.htm ASCO Affordable Care Act Information: http://www.cancer.net/sites/cancer.net/files/clinical_trials_coverage_aca_fact_sheet.pdf Cancer.Net – Finding a Clinical trial: http://www.cancer.net/navigating-cancer-care/how-cancer-treated/clinical-trials/finding-clinical-trial

Appendix 2 – Image sources http://www.clinicalresearchsociety.org/gcp/ http://www.indianaretina.com/#!clinical-trials/cx2d https://www.ciscrp.org/ https://www.emergingmed.com/ http://www.who.int/ictrp/en/ http://www.clinicaltrials.com/investigators/irb.htm http://d7.library.gatech.edu/research-data/home

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