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CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY

CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY. What is research? Systematic investigation designed to develop

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CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY

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    1. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY

    2. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY What is research? Systematic investigation designed to develop– or-- add to--generalizable knowledge

    3. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY In other words, if an investigator uses a systematic design, generally using a scientific approach or protocol, that will contribute to the general knowledge of the topic in question, and a protocol application has been submitted to and approved by their IRB, it is medical research.

    4. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Also, if the intent is to publish the results of a study for the betterment of mankind medically, it nearly always means that it is medical research.

    5. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Medical research plays a critical role in providing up-to-date information on what works, and what doesn't work, in treating many different kinds of diseases and conditions. This information helps improve healthcare quality by making sure that:

    6. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY You receive the right treatment, at the right time, and in the right way. You don't receive treatments that are unnecessary, costly, or even harmful to your health.

    7. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY You may hear about the results of medical research—perhaps even studies about your condition—on the news, or read about it in a newspaper or magazine.

    8. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY That's because scientists are constantly involved in a variety of research projects supported by the Federal Government, charitable foundations, and other public- and private-sector groups.

    9. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Types of Research: Bench Science: The study of basic scientific concepts and theories. Laboratory Science: experiments done to find the cause of a disease, or how a drug or treatment works. They are usually carried out on cells or tissue, or on laboratory animals.

    10. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Types of Research: Translational Research: Bringing the laboratory science to the human subject.

    11. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Types of research: Epidemiological research looks at: The natural course of diseases in a particular group of people. Relationships between people and their health habits, life styles, and environment. Risk factors for certain diseases.

    12. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Types of research: Outcomes research uses a wide variety of information about how well treatments work in the real world. Outcomes research can tell whether treatments work better for certain types of patients or in specific situations.

    13. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Then, recommendations can be made about treatments based on whether they work or not, and which ones are most likely to give the best results with the fewest risks. This is known as "evidence-based medicine."

    14. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Types of research: Clinical trials research use different study methods to make sure the results they get are true, and not due to outside influences. People are randomly assigned to different treatment groups—

    15. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY RANDOMIZATION Some get the research treatment, others get a standard treatment or may be given a "placebo" or no treatment. The groups are tested, and results are compared to evaluate whether or not the treatment works. Or—open label trial instead

    16. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY What is a clinical trial? A research study in humans, evaluating the safety and efficacy of new therapies, designed to answer specific scientific questions using scientifically controlled methods. A research study conducted with people to find better ways to prevent and treat disease.

    17. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY a. Therapeutic clinical trials: Studies involving humans that evaluate the efficacy of an intervention in preventing, managing, or eradicating a disease or improving a treatment.

    18. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY b. Nontherapeutic clinical trials: Epidemiologic (explaining the relationship between host, agent, and environment), pharmacokinetic (the body’s reaction to drugs), cytogenic (the study of cells in relation to genetics), QOL, screening, and supportive-care studies.

    19. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Sometimes these recommendations are gathered together into clinical practice guidelines. Doctors and other healthcare providers can use this kind of information to help you weigh the risks and benefits of your treatment options—or your behaviors.

    20. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Example: Data shows that people who smoke have a higher risk of developing lung cancer.

    21. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY c. Chemopreventive clinical trials Finding a substance (usually a complementary therapy) to give a person in an effort to prevent a disease.

    22. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY The mission of clinical trials is: To study, prevent, detect, treat, and cure disease 2. To study the psychological impact of disease 3. To promote QOL

    23. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY The mission of clinical trials: 4. To determine improved means of care 5. To answer important scientific questions which can lead to future advances in patient care 6. To study ways to cut costs for patients and health care professionals

    24. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY The results of the trial allow conclusions to be drawn: which may contribute to the information base which may affect the manner in which a disease is treated which may be utilized to improve practice

    25. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY HISTORY Bible describe CTs-6th century B.C.: Meat and vegetable experiment on young Jewish prisoners in Book of Daniel. Court physician compared slaves to young sons of the king’s court

    26. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY 1st century B.C. Cleopatra tested her theory that it takes 40 days to fashion a male fetus fully and 80 days to fashion a female fetus. When her handmaids were sentenced to death, Cleopatra had them impregnated and subjected them to subsequent operations to open their wombs at specific times of gestation.

    27. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Modern History 1747: Captain James Lind performed a clinical trial using citrus to find the cure for scurvy in his sailors a. One/four British sailors who subsisted on salted meat during voyages died of scurvy. b. German sailors who ate fruits and vegetables didn’t get scurvy.

    28. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY History This was the first chemopreventive clinical trial known in modern history!

    29. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY History: In the late 1700s and 1800s, CTs tested vaccines for such infectious diseases as cholera, diphtheria, and smallpox (Jenner) These CTs caused congress to recognize the importance of research

    30. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY HISTORY 1887: The U.S. government established the National Institutes of Health (NIH) “To provide funding for research on the prevention, detection, and treatment of disease in an effort to promote public health”.

    31. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY HISTORY 1931: First documented CT in the U.S. using a matched control group, randomization, placebo, and “blinding”. It used gold in the treatment of pulmonary TB.

    32. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY HISTORY 1937: FDR signed the National Cancer Institute Act Established the NCI as a division of the NIH. The NCI funds cancer research and training

    33. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY HISTORY Research on vulnerable populations, ie., slaves, prisoners, mentally handicapped, poor, children, minorities, was conducted between the mid-1800s to the mid-1900s without regulations or informed consent—often without their knowledge.

    34. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY HISTORY Past abuses: 1932: Tuskegee--syphilis 1950s: Willowbrook State School Injected hepatitis in mentally handicapped children

    35. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY HISTORY However, it was not until the exposure of the medical atrocities on prisoners during WWII that a code of ethics for human experimentation was developed.

    36. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY 1949: Nuremburg Code Serves as the foundation of the ethical principles governing clinical research on humans from then on.

    37. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY 1949: Nuremburg Code Anyone entering a trial “—should have sufficient knowledge and understanding of the elements of the subject matter as to be able to make an understanding and enlightened decision.”

    38. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY HISTORY 1950s-1960s: Thalidomide babies Kefauver-Harris Amendment

    39. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY 1977: Women excluded from clinical trials due to possible fetal damage 1986: NIH establishes policies for the inclusion of women into clinical trials again

    40. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY History of Regulation 1974: National Research Act—a real patient advocacy act The research design must offer a high probability of generating useful knowledge Probable benefits must outweigh the risks

    41. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY 1974: National Research Act Selection of patients must be just (randomization and blinding) Subjects must give their informed consent (not written consent yet)

    42. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY 1974: National Research Act Each institution conducting research must submit a research proposal to an internal review board (IRB) for evaluation of safety and efficacy before any funding can take place

    43. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY 1974: The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research developed policies for the protection of human subjects. Published in 1978 and called the Belmont Report.

    44. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY The Belmont Report Mandated the establishment of institutional review boards (IRBs) Outlined protocol design criteria Required that written informed consent be provided to every subject Set the ethical standards for subject protection!

    45. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY The Belmont Principles: Respect for Persons: (dignity, freedom from coercion. Beneficence: benefits must outweigh the risks. Justice: equitable selection and recruitment and fair treatment. Autonomy: Patients right to accept or reject treatment and his right to information.

    46. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY 1990s Good Clinical Practice (GCPs) The International ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involves human participation. This standard provides public assurance that the rights, safety, and well-being of trial subjects are protected.

    47. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY GCPs are consistent with the principles that derive from the Declaration of Helsinki (1964), assuring us that the data is credible. Declaration of Helsinki: World Medical Association declared: “The interests of science and society should never take precedence over subject well being”

    48. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY GCPs require us to maintain records of ALL aspects of a trial. Documentation is a major component of GCPs

    49. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Document as though the reader is being told what happened. “If it isn’t documented, it didn’t happen!”

    50. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Pros: Clinical Trials are a critical part of research—the final step CTs translate basic scientific research into better ways to prevent, diagnose, and treat disease

    51. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Pros: CTs contribute to the knowledge of and the progress against diseases Today’s most effective treatments from previous studies a. aspirin b. cortisone People are living longer

    52. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Pros: Critical research questions answered sooner We learn the true effectiveness Diseases are controlled

    53. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Pros: CTs give you a chance at the most advanced treatment

    54. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Pros: When a new treatment is successful, you are the first to benefit. example: Herceptin for breast cancer

    55. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Pros: Rigorous patient testing Closer MD/patient relationship

    56. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Pros: When you take part in a CT, you are helping yourself and future patients

    57. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Pros: Approx. 553,400 die of cancer 1500/day Second leading cause of death Approx. 1,268,000 new diagnoses per year

    58. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY CONS: In the U.S., currently less than 25% of potentially eligible patients are offered participation in a clinical trial. Only 4-5% eventually enroll.

    59. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Cons: Expenses for MDs: Staff salaries Paperwork Supplies Low reimbursement

    60. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY CONS: Because of this, it is taking longer than desired to accrue enough patients to finish a trial and get the drug/device to market.

    61. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Cons: Expenses for patients: Travel Childcare Parking Meals Lost work Medicare/Insurance

    62. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY CONS: Patients are also denied access to the fullest range of treatment options.

    63. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Cons: Language/Literacy Barriers Communication barriers due to lack of bilingual providers a. Consent forms b. Other patient literature Lack of public education/awareness

    64. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Cons: MDs afraid of losing patient’s care Side effects unknown until tested on large numbers of people Drug will not work for everyone

    65. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY CONS: Eligibility (Inclusion/Exclusion) criteria—time constraints Protocols not available at preferred site/lack of protocols for specific population

    66. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Clinical Trial Phases Phase I: Establish the maximum tolerated dose (MTD), dosing schedule, and toxicity profile of a new drug Usually up to 100 subjects In subjects in which all treatment options have failed

    67. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Phase II: To evaluate the efficacy in subsets of patients with the same disease to determine a response To determine toxicity profile again in a larger number of subjects

    68. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Phase III: Compare to standard treatment in a randomized, prospective fashion If no standard treatment available, placebo control group is used Very large groups of subjects are used to have sufficient statistical power to assess treatment group differences

    69. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Phase III cont’d: The primary endpoints of a Phase III trial are response rates, survival, and QOL They are often performed in multiple institutions simultaneously and may be single-or double-blinded

    70. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Phase IV: Postmarketing studies Huge number of subjects After FDA approval in Phase 111 trials

    71. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Accessing Clinical Trials: PDQ Physician Data Query The most comprehensive clinical trial registry 1,800 on-going national and international clinical trials Multiple parameters to help narrow searches

    72. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY CT Sponsors NIH Pharmaceutical Companies Cooperative Groups Medical Institutions Private Organizations Individual MDs

    73. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY CT Sponsor Pharmaceutical and biotech companies conduct their own trials, both locally and nationally. Partners with universities, cancer centers, hospitals, private MDs, or NCI Trials are subject to company and partner’s review and IRB process locally and/or nationally

    74. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Clinical Grants Program Many clinical trial protocols are carried out under the direct support of an NIH peer-reviewed grant Grant application written according to strict guidelines

    75. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Protocol (Blueprint) Elements: Specific Aims: primary and secondary aims Background and Significance Preliminary Studies Research Design and Methods

    76. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Protocol Elements: Research Design and Methods cont’d: Subject design Inclusion/Exclusion Rationale for subject selection Study Plan Medication schedule-Dosing 6. Statistics

    77. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Protocol Elements: 7. Assessments Efficacy Safety 8. Biochemical Measures 9. Data Analysis Plan (statistical design

    78. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Protocol Elements: Data and Safety Monitoring Plan (or board) Enrollment and consenting Study medications Other Interventions Physician/clinician availability Study stopping rules

    79. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Protocol Elements: Adverse Events Plan IRB Oversight Subject Confidentiality Potential Benefits/Risks (shift in thinking over the past 25 years from emphasis on subject protects from risks to benefits for patients)

    80. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Protocol Elements: Consent Bibliography Forms 1. Case report forms (CRFs) 2. Other forms

    81. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Form The NCI defines the consent form as: “The communication process that allows individuals to make an informed choice about participation in a clinical trial”

    82. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Form Consent must be documented in the medical record regardless of risk level. Verbal: Oral consent if minimal risk. Short form that subject signs after it is read or spoken to him. Written: More than minimal risk or if minors are involved.

    83. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Form Primary ethical requirement underpinning research Reflects basic principal of respect for persons

    84. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Process An ongoing process that assures prospective human subjects will understand nature of the study and knowledgeably and voluntarily decide to participate or not. (OHRP Guidebook)

    85. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Language Twenty-one to 23 percent -- or some 40 to 44 million of the 191 million adults in this country -- demonstrated skills in the lowest level of prose, document, and quantitative proficiencies (Level 1).

    86. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Language They don’t understand: a. verbal descriptions b. written instructions c. Audiovisuals Even though they may be educated to some extent.

    87. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Language 25 to 28 percent of the respondents, representing about 50 million adults nationwide, demonstrated skills in the next higher level of proficiency (Level 2) on each of the literacy scales.

    88. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Language They are only marginally competent in language skills: Unable to order from catalog Unable to follow instruction sheet Unable to read a thermometer Unable to read an aspirin bottle

    89. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY Consent Form Sentence length/ Active voice Larger type/ white space Instructional graphics Pictures Headers Questions Document length

    90. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY For whom is the consent form created? Physician? Medical institution? Patient?

    91. CLINICAL TRIALS: THE GOOD, THE BAD, AND THE UGLY WHY? Regulations govern everything in research Filling out forms: black ink pens Initials vs signature (Rules and Responsibility Log) Appropriate corrections

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