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

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CLINICAL TRIALS THE GOOD, THE BAD, AND THE
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• What is research?
• Systematic investigation designed to develop
  or-- add to--generalizable knowledge

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• 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.

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• 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.

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• 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

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• 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.

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• You may hear about the results of medical
  researchperhaps even studies about your
  conditionon the news, or read about it in a
  newspaper or magazine.

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• 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.

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• 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.

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• Types of Research
• Translational Research Bringing the laboratory
  science to the human subject.

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• 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.

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• 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.

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• 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."

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• 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

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• 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.
• Oropen label trial instead

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• 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.

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• 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.

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• b. Nontherapeutic clinical trials
• Epidemiologic (explaining the relationship
  between host, agent, and environment),
  pharmacokinetic (the bodys reaction to drugs),
  cytogenic (the study of cells in relation to
  genetics), QOL, screening, and supportive-care
  studies.

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• 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 optionsor
  your behaviors.

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• Example Data shows that people who smoke have
  a higher risk of developing lung cancer.

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• c. Chemopreventive clinical trials
• Finding a substance (usually a complementary
  therapy) to give a person in an effort to prevent
  a disease.

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• 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

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• 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

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• 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

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• 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 kings court

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• 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.

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• 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
  didnt get scurvy.

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• History
• This was the first chemopreventive clinical
  trial known in modern history!

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• 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

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• 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.

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• 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.

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• 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

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• 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
  consentoften without their knowledge.

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• HISTORY
• Past abuses
• 1932 Tuskegee--syphilis
• 1950s Willowbrook State School
• Injected hepatitis in mentally
  handicapped children

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• 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.

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• 1949 Nuremburg Code
• Serves as the foundation of the ethical
  principles governing clinical research on humans
  from then on.

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• 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.

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• HISTORY
• 1950s-1960s Thalidomide babies
• Kefauver-Harris Amendment

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• 1977 Women excluded from clinical trials due to
  possible fetal damage
• 1986 NIH establishes policies for the inclusion
  of women into clinical trials again

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• History of Regulation
• 1974 National Research Acta real patient
  advocacy act
• The research design must offer a high probability
  of generating useful knowledge
• Probable benefits must outweigh the risks

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• 1974 National Research Act
• Selection of patients must be just (randomization
  and blinding)
• Subjects must give their informed consent (not
  written consent yet)

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• 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

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• 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.

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• 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!

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• 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.

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• 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.

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• 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

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• GCPs require us to maintain records of ALL
  aspects of a trial.
• Documentation is a major component of GCPs

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• Document as though the reader is being told what
  happened.
• If it isnt documented, it didnt happen!

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• Pros
• Clinical Trials are a critical part of
  researchthe final step
• CTs translate basic scientific research into
  better ways to prevent, diagnose, and treat
  disease

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• Pros
• CTs contribute to the knowledge of and the
  progress against diseases
• Todays most effective treatments
• from previous studies
• a. aspirin
• b. cortisone
• People are living longer

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• Pros
• Critical research questions answered sooner
• We learn the true effectiveness
• Diseases are controlled

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• Pros
• CTs give you a chance at the most advanced
  treatment

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• Pros
• When a new treatment is successful, you are the
  first to benefit.
• example Herceptin for breast cancer

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• Pros
• Rigorous patient testing
• Closer MD/patient relationship

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• Pros
• When you take part in a CT, you are helping
  yourself and future patients

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• Pros
• Approx. 553,400 die of cancer
• 1500/day
• Second leading cause of death
• Approx. 1,268,000 new diagnoses per year

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• 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.

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• Cons
• Expenses for MDs
• Staff salaries
• Paperwork
• Supplies
• Low reimbursement

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• 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.

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• Cons
• Expenses for patients
• Travel
• Childcare
• Parking
• Meals
• Lost work
• Medicare/Insurance

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• CONS
• Patients are also denied access to the fullest
  range of treatment options.

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• Cons
• Language/Literacy Barriers
• Communication barriers due to lack of bilingual
  providers
• a. Consent forms
• b. Other patient literature
• Lack of public education/awareness

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• Cons
• MDs afraid of losing patients care
• Side effects unknown until tested on large
  numbers of people
• Drug will not work for everyone

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• CONS
• Eligibility (Inclusion/Exclusion) criteriatime
  constraints
• Protocols not available at preferred site/lack of
  protocols for specific population

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• 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

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• 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

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• 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

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• Phase III contd
• 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

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• Phase IV
• Postmarketing studies
• Huge number of subjects
• After FDA approval in Phase 111 trials

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• 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

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• CT Sponsors
• NIH
• Pharmaceutical Companies
• Cooperative Groups
• Medical Institutions
• Private Organizations
• Individual MDs

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• 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 partners
  review and IRB process locally and/or nationally

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• 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

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• Protocol
• (Blueprint)
• Elements
• Specific Aims primary and secondary aims
• Background and Significance
• Preliminary Studies
• Research Design and Methods

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• Protocol Elements
• Research Design and Methods contd
• Subject design
• Inclusion/Exclusion
• Rationale for subject selection
• Study Plan
• Medication schedule-Dosing
• 6. Statistics

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• Protocol Elements
• 7. Assessments
• Efficacy
• Safety
• 8. Biochemical Measures
• 9. Data Analysis Plan (statistical design

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• Protocol Elements
• Data and Safety Monitoring Plan (or board)
• Enrollment and consenting
• Study medications
• Other Interventions
• Physician/clinician availability
• Study stopping rules

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• 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)

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• Protocol Elements
• Consent
• Bibliography
• Forms
• 1. Case report forms (CRFs)
• 2. Other forms

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• 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

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• 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.

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• Consent Form
• Primary ethical requirement underpinning research
• Reflects basic principal of respect for persons

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• 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)

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• 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).

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• Consent Language
• They dont understand
• a. verbal descriptions
• b. written instructions
• c. Audiovisuals
• Even though they may be educated to some extent.

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• 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.

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• 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

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• Consent Form
• Sentence length/ Active voice
• Larger type/ white space
• Instructional graphics
• Pictures
• Headers
• Questions
• Document length

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• For whom is the consent form created?
• Physician?
• Medical institution?
• Patient?

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• WHY?
• Regulations govern everything in research
• Filling out forms
• black ink pens
• Initials vs signature (Rules and Responsibility
  Log)
• Appropriate corrections