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134 Cards in this Set
- Front
- Back
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one of many MD's in Nazi Trials
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Karl Brandt
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Codes and Guidelines for Human Subjects Research
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Nuremberg Code (1947)
Declaration of Helsinki (1964, 1975, 1983, 1989, 1996, 2000) belmont report (1979) CIOMS international ethical guidelines for biomedical research involving human subjects (1993) international conference on harmonization guidelines for good clinical practices (1996) |
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10 principles of ethical research with human subjects
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1. voluntary consent
2. anticipate scientific benefits 3. benefits outweigh risks 4. animal experiments first 5. avoid suffering 6. no intentional death or disability 7. protection from harm 8. subject free to stop 9. qualified investigators 10. investigator will stop if harm occurs |
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Describe "landmark" article
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Henry Beecher, MD, anesthesiologist (prominent investigator)
-questioned the ethics of 22 research studies -intense public attention -director of NIH saw increased congressional oversight -congressional hearings led to national research act of 1974 -created assurances for PHS funded research |
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Medical Research Scandals of the 60s
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1. willowbrook hepatitis experiments
2. jewish chronic disease hospital study |
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Behavioral Research Scandals of the 60s
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1. obedience to authority experiments
2. tearoom trade study |
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Tuskegee Syphilis Study
(revealed in 1972) |
-USPHS began in 1932 to study the natural history of untreated syphilis
- more than 400 black men recruited into study without their permission -mortality 2x than controls without syphilis -1940s an effective treatment developed - PCN |
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Two major elements of National Research Act of 1974
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1. basic legal framework for oversight for human subject research, later as federal regulation
2. formation of the "national commission for the protection of human subjects in biomedical and behavioral research" |
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Belmont Report of 1979
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-created by the National Commission
-3 principles: 1. respect for persons -autonomy, liberty, right to be left alone 2. beneficence -obligation to improve health, maximize benefits and minimize risks 3. justice -fairness, treat as equals |
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Common Rule of 1991
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use basic structure utilized in many federal agencies
Mechanisms: -institutional review boards -informed consent -selection of subjects |
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Yellow fever experiments
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(Dr. Walter Reed)
-conducted in cuba following the spanish-american war -written consent in english and spanish -consent was witnessed Ethical dilemma: -excessive compensation -no ability to withdraw |
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Integrity in Research
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-everyones responsibility
-research misconduct (fabrication, falsification, plaigarism) -responsibilities of federal agencies and research institution |
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Definition of Human Subject
(for IRB purposes) |
"A living individual about whom an investigator...conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information
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IRB Members Duties
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-must acquire basic knowledge of research
-must review investigators qualifications -avoid conflicts of interest -IRB does NOT have the responsibility to make sure the investigator can logistically carry out the study (TABLE 5-1, Gallin "Requirements/Questions" |
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Risk Vs. Benefit
(IRB Role as a Human Advocate) |
-members take role very seriously
-is there potential benefit from participation? -minimal risk, well defined, INDs are NOT -levels of risk based on history of drug class AEs or previous animal or human research -all this must be explained to the IRB as well as in detail in the informed consent -remember physical, psychological and privacy, confidentiality, social and economic harms |
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Definition of Research
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"A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge"
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Criteria for IRB Review
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-risks to subjects are minimized
-risks are reasonable in relation to anticipated benefits -selection of subjects is equitable -informed consent -monitoring -confidentiality |
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Documentation the investigator owes the IRB
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-copy of protocol and amendments
-informed consent form document to be utilized -completed FDA 1572 -investigators brochure -results of previous related research -compensations to participants -justification for special populations -protection of privacy |
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Consent Forms for Research
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-must be reviewed by IRB in detail
-must "read" at elementary age -can't contain medical jargon, only lay terms -patient must sign in most situations -witness must sign that info explained -copy must be given to patient -ELEMENTS (Schuster, table 14-1 a and b) |
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Required Documentation in a consent form
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-statement that study involves research, its purpose, duration and procedures
-risks -benefits -alternate procedures (including drugs) -confidentiality -table 5-3 Gallin "General Elements" |
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Required Informed Consent Elements
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-for research involving greater than minimal risk (compensation and treatment, if any, for any injury that happens)
-contact information for investigator and hospital risk office -assurance that participation is voluntary |
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Informed Consent Process: threshold
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-decision making capacity
-voluntariness |
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Informed Consent Process: information
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-disclosure
-understanding |
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Best Practices (GCP)
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Title 21 CFR- Food and Drugs
Parts 11, 50, 54, 56, 312, 314 Schuster, Table 14-3 |
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"The Right to Privacy"
Health Insurance Portability and Accountability Act (HIPPA) |
-how "entity" may use health info
-research is not a stated target of HIPPA -only when conducted by a member of a covered entity -research should consult their own privacy officer to evaluate how HIPPA affects their studies |
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IRB's Responsibility in Continuing Review
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-investigators must report AEs and SAEs to the IRB and explain how it relates to the trial
-annual review of protocols-virtually a resubmission of all initial paperwork with updates on numbers of pts, outcomes and side effects or AEs |
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Data Safety Review Boards: Purpose
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-to ensure safety of the study participants
-enhances scientific integrity of the study -allows import evidence to be discovered before the end of the study |
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Make-up of the Data Safety Review Board
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-individuals external/independent to the process
-in no way sponsoring the study -no financial interest -expertise in the disease state -an ethicist and patient advocate -not a FDA representative |
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DSMB:common in Phase 3 trials
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-most likely double blind design
-to avoid bias of the investigator -multiple centers involved |
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DSMB Functions and Decisions
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-monitor reports (efficacy, safety)
-new therapy may be superior (in life threatening diseases necessitating discontinuing the study) -significant safety issue may warrant change in protocol or study discontinuation -issues necessitating changes in inclusion/exclusion criteria -how external information influences study |
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Special Populations
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-prisoners
-emergency treatments -children -women and minorities (all are additional burdens on investigators as well as IRBs) |
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Rationale for Inclusion of Children
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-diseases that affect children only (advances in treatment)
-diseases that affect adults and children (treatment differences) -drugs used in children (not studied in children) |
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Policies to include children in research
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-American academy of pediatrics
-national institutes of health -food and drug administration |
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American Academy of Pediatrics
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-unethical to deny children access
-responsibility of: 1. pediatric community 2. pharmaceutical industry 3. regulatory agencies 4. general public |
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National Institutes of Health's (involvement of children)
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"Children (any individual under the age of 21) MUST be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them"
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FDA's (involvement of children)
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1994: manufacturers are required to determine if existing data support safe use of drugs in children
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Barriers to Retention of Minority Children
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-disproportionate number of minority children with limited financial or social resources
-investigators must develop strategies to ensure those with limited financial and family support in intensive clinical studies -avoid exploitation of children/families |
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Disabled Children
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-protect from disproportionate participation
-protect their right to participate -share in benefits |
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Prisoners as a special population
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-HIV/AIDS is 12x higher
-less educated -unemployed |
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Prisoner Issues
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-limits independent decision making
-"adequate" health care can be sub par -IRB member must be prisoner or prisoner representative -warden has last say |
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Emergency Rooms
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-patients often unable to give consent due to lack of consciousness
-family members seldom close by to give consent for the patient -many times in life threatening situations in need of superior therapies often offered in trials -time is of the essence |
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NIH Policy on women and minorities
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-ensure they are included in all human research
-analysis in phase 3 not valid unless they are included -not allow cost as an acceptable reason NOT to include women/minorities -programs to recruit these groups -scientifically considered "gaps" in research if not included |
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NIH Office of Research on Womens Health (ORWH)
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-established in 1990
-advises NIH director -strengthens and enhances conditions that affect women -ensures appropriately represented -develops opportunities for recruitment -supports research on womens health issues |
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Roles of Other Groups in terms of special populations
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-role of peer review
-institutional review board (yearly summary) -volunteers and their communities -scientific research community |
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All knowledge originates from 5 sources
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-tradition
-authority -trial and error -reasoning -scientific method |
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Tradition (source of where knowledge originates)
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-do what has been done before
-perhaps so, knowledge doesnt have to be reinvented for a new generation -not always a bad way to gain knowledge (chinese accupuncture) -limitations of tradition: 1. superstition 2. misguided theory 3. examples: -blood letting -trephination -ancient birth control: jump backwards 7 times after coitus |
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Authority (source of where knowledge originates): exercising caution
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-due to manipulation for personal advantage, one must exercise caution when believing persons in power
-roman catholic church insisted galileo renounce his idea that earth revolved around sun b/c it wasn't consistent with church teachings -nazis deemed albert einstein and his ideas unacceptable and removed him from university post -galen's misconceptions that the nervous system was glandular not electrical in nature and that blood ebbed and flowed rather than circulated through the body |
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Authority (source of where knowledge originates) : getting advice can be a good idea
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getting advice from an authority figure sometimes is a good idea if the information comes from a good source
-graduate student who has difficulty finishing a research project may seek advice of research advisor -developing a questionnaire, may seek input from panel of experts -research reports must include citations to trace and credit knowledge derived from authoritative resources |
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Authority (source of where knowledge originates)
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may be useful source, but it has the potential for abuse
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Trial and Error (source of where knowledge originates)
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-may take a long time to arrive at the truth using this approach
(luther burbank, 19th century plant breeder, had great success improving crops and producing new varieties of fruit using a hit-and-miss approach method of pollination) -pilot studies, viewed as dress rehearsals for more involved studies, involves trial and error to identify problems that may arise in actual experiment |
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Reasoning (source of where knowledge originates)
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-the use of logic is another source of knowledge
-the scientific method entails both deductive and inductive reasoning during research 1. deductive reasoning- given a theory, you predict future observations 2. inductive reasoning- given enough data one develops a general theory |
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Scientific Method
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-a credible means of acquiring new knowledge b/c it relies on objective observations
-probability is used to determine whether a phenomenon can be generalized or is simply due to chance -other knowledge sources tend: 1. to be less objective (tradition and authority often are not challenged) 2. to lack careful planning (trial and error can be haphazard) 3. or lack data (reasoning is not confirmed with actual data) |
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Scientific Method: Shortcomings
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-Science can't answer all questions in life
(some ?s can't be answered with the scientific method b/c there is no way to objectively observe and measure phenomena about such ?s) -findings from research studies are only as good as the quality of the work that went into the study (biased investigator, poorly conceived design and human mistakes= findings that are meaningless, misleading or unbelievable) |
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Scientific Method: Hypothesis, objectives, endpoint
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Study Hypothesis
-question to be answered Study Objectives -study design, measurements, data analysis, study conclusions Primary endpoint -careful selection, clearly defined, stated a priori |
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Biomedical Research: purpose
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Purpose of biomedical research is to improve human health
-reduce disease related suffering -increase life expectancy -improve quality of life |
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The only way to validate hypotheses related to human disease, regardless of how the hypotheses were generated
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Clinical Research
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Required before new discoveries can be applied to treatment of disease
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Clinical Research
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Medical Applications of Clinical Research
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-new disease treatments
-improve disease management (how to apply new or existing treatments, how to tune the system) -disease prevention (health screening or understanding risk, understanding exposure) |
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Uses of Clinical Research: Outline
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-basis for current practice?
-intended use of the results (explore disease mechanisms, regulatory submission/ therapeutic intervention, individual patient care decisions, health services management, evaluating risk and the environment) -dissemination, conclusions and challenges |
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Clinical Research: Basis for Clinical Practice- standards of care
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Standards of care:
-historical: set by panels of experts with limited objective evidence -problem: humans are inherently biased by their (recent) experience -solution: objective evidence |
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Clinical Research: Basis of Clinical Practice- standards of care and outcomes examples
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-cardiovascular databank at duke
-quality assurance databases -science of clinical research has matured remarkably over the past 25 years (quality and quantity of data, regulations surrounding acquisition of data) |
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Impact of Clinical Research
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-goes beyond the critical role in establishing mechanisms of disease in humans or the benefits of new treatment
-by offering laboratory oriented, patient oriented and population oriented scientists opportunities for collaboration, clinical research also helps integrate such disparate activities as scientific investigation, medical education and patient care |
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Discovery in Clinical Research
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-biology and biomedicine must first be advanced at a fundamental (basic) level before new treatments that will eventually improve human health can be developed
-however, the links between discovery and treatment are not unidirectional not connected by a straight line |
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Clinical Observations
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-less well appreciated is how often important new insights into the origins of disease are first the result of novel clinical observations
-examples: 1. the role of hypercholesterolemia in premature atherosclerosis 2. the role of smoking in lung cancer 3. the role of inhibiting angiotensin-converting enzyme inhibitor to improve survival independent of its effect on blood pressure -the role of the bacterium Heliobacter pylori on duodenal ulcers -in each case, the first hypothetical statements of potential cause and effect were based on clinical studies and later confirmatory clinical investigations and other types of research were performed to determine the underlying mechanisms |
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Clinical Research: simplified definition
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-patient oriented
-epidemiologic and behavioral studies -outcomes and health services |
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Clinical Research: patient oriented
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-research on mechanisms of human disease
-therapeutic interventions -clinical trials -development of new technologies -excluded in NIH definition: is in vitro studies in which human tissue samples are used but direct interaction w/ the patients are absent |
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CR: lab oriented research
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-in vitro studies
-animal physiology/pathophysiology studies -disease oriented research |
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CR: patient oriented research
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(clinical trials)
-human physiology/ pathophysiology studies -diagnostic and therapeutic studies of disease |
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CR: population oriented research
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(clinical practice)
-epidemiology -behavioral studies -outcomes/health services research |
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Schusters Definition of Clinical Research
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Clinical research: any scientific investigation in which the unit of analysis is the person
-to determine whether a study includes clinical research, the investigator needs only determine what "n" represents in the data analysis -if "n" represents the number of human beings from which the info is derived, the study can be characterized as clinical research |
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Other CR information
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-all drugs and treatments must be subjected to the rigors of objective testing before any claim can be made to substantive benefit
-the importance of designing and conducting safe clinical trials in the development of drugs or medical devices can't be overstated -it is imperative that clinical research studies be conducted w/ great care and integrity yet quickly and efficiently to reduce the time required to bring the benefits of the research investment to fruition |
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Translational Research
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-an attempt to bring information that has been confirmed in the laboratory into the realm of clinical medicine
-example: a gene recently discovered in mice appears to have important functions in regulating a cells life cycle. is the gene present? is the function of the gene similar? what role does the gene play in disease? -translational research is a TYPE of inquiry whereas experimental research is a METHOD if inquiry |
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Clinical Research is divided into two types of research:
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1. experimental
2. observational |
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Experimental Research
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-a method by which measurements are specifically obtained after an intervention controlled by the investigator
-it is important to note that although control of the intervention is the critical event that distinguishes an experimental study from an observational study, the simple act of imposing an intervention by itself doesnt eliminate the problem of confounding |
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Observational Research
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-research that isn't experimental, is observational
-regardless of whether or not measurements are made after an intervention, the scientist is simply an observer if the intervention is NOT under his/her control (assuming that there is an intervention) |
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Goals of Research
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Descriptive:
-accurately describe phenomena or relationships Explanatory: -to explain the causes of biomedical phenomena and to make predictive statements about them Although the overall goal of biomedical research may be to improve human health, the means by which the objective is achieved may vary Causal statements are the link between simple descriptions of what we believe to be real and predictive statements that allow us to affect reality |
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Identifying Causation: 3 cardinal rules
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1. the putative cause must precede the designated effect in time
2. the effect must be related to the putative cause 3. there must be no plausible alternative explanations (confounders) |
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Observational Studies
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-can provide evidence of the first 2 cardinal rules, but can only show association, not causation
-they CANT eliminate the potential effects of confounding, especially unknown confounders -inferences about causation can be made from observational studies, but not with the same level of confidence that occurs w/ a properly conducted experimental study |
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Value of Observational Research
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-often easier and more practical to perform
-generally less costly and time consuming -often hypothesis-generating for further testing by later interventional (experimental) studies -may be more ethical in that a particular intervention might require unacceptable safety risks to the subject (would you want to show that endotoxin causes shock in humans by administering the material to demonstrate the point? in contrast, a highly specific inhibitor of endotoxin administered to patients in septic shock would provide evidence for such a hypothesis) |
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Observational vs. experimental research
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-observational studies describe the real world b/c the investigator doesnt interfere with the world (always confounded by known and often unknown variables; makes it difficult to declare causation based on the results)
-experimental studies have the powerful ability to link events causally, yet the studies may have to be so tightly controlled and narrowly defines as to be irrelevant to meaningful questions about human health -experimental studies create the most significant disadvantage by imposing the intervention on humans in a design that rarely presents an accurate picture of reality (example: designing one variable that differs b/w an experimental and a control group; results may not extrapolate well to the human population of interest) |
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Goals of experimental studies
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-mechanisms of disease
-efficacy -effect of biochemistry and physiologic factors on biophysical outcomes tests of drugs/devices -disease-centered -inventing technology |
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Goals of observational studies
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-impact of disease on patient
-effectiveness -effect of socioeconomic factors on patient centered outcomes -tests of processes and delivery of care -patient and community centered -assessing technology |
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5 main phases of the research process
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1. developing a question
2. developing a method to answer the question 3. collecting data 4. analyzing, interpreting and reflecting on the data 5. sharing the information |
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The anatomy of clinical research
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1. research question
-why am i performing the research? 2. significance -why is the study important? what is the background? 3. study design -how will the study be designed to answer the question? 4. variables -what will be measured to answer the question? 5. statistics -how will the data generated be analyzed to make a conclusion on the study findings? |
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Study Subjects
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-who will be enrolled in the study to answer the research question?
-how narrow should the group of study subjects be to prevent variability in the data? (inclusion/exclusion criteria) -study population (gender, age, disease, others) |
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types of clinical studies
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-case reports
-case series -retrospective case control studies -prospective cohort studies -clinical trials (uncontrolled; historical studies; internal (concurrent) controls) |
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competing objectives of clinical trials
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-validity
-generalizability -efficiency |
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one of the most difficult tasks in doing research requiring patience and perseverance:
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identifying a good question
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what will point the investigator down a very specific path-hopefully but not necessarily a path of discovery?
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a carefully constructed research question
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first step in conducting research:
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identifying a good question
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Sources for research questions
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-attempts to explain the cause of novel observation
-verifying the predictions of existing theory -literature sources (questions raised by new reports; resolving conflicts among reports) -technology (applying new technologies to a new field, applying improved technology to validate findings of a previous study, developing new technology to resolve an existing problem) |
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Characteristics of a good research question
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-feasible
-interesting -novel -ethical -relevant |
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importance of the research question
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-sets the objective for your study
-how the question is written will have a major effect on how the study is designed in order to answer it -it will target your study population -it will influence what is measured |
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Types of research questions, # of variables and # of groups:
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1. descriptive:1 variable, 1 group
2. relational: 2 or more variables, one group 3. comparative: two or more variables, two or more groups |
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3 good places to identify a problem:
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1. patients
2. lectures and articles 3. existing theory |
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conduct a literature search: this is critical for:
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-developing question
-determining whether your question has been answered already -staying current in your field |
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"Search Areas" for a literature search:
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-internet searches
-journals -health statistics -government documents and technical reports -dissertations -papers presented at meetings -people and organizations -current events -textbooks |
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Narrowing the identified problem that will be used for your research study
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-gradually narrow the problem down to one specific question that can be answered in one study
-general problems are too broad and require too many studies to solve in one instance -use the funnel approach to narrow your scope |
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overview of the role of biostatistics in clinical trials
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-program development
-protocol development -data collection -statistical analysis and reporting -regulatory submissions |
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Biostats "Program development" role includes:
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-study design
-endpoint selection -sample size calculations |
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Experimental study definition from biostats lecture:
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series of observations made under conditions in which the influences of interest are controlled by the research scientist
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Non-experimental study definition from biostats lecture:
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scientist collects observations but doesnt exert control over the influences of interest
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Design considerations: characteristics of a good design
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-allows investigators to satisfy ethical considerations
-minimizes and quantifies random error -isolates the treatment effect from confounding influences -reduces selection bias and observer bias (nonrandom error) -increases the external validity of the trial -simplifies and validates the accompanying statistical analyses |
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Design Principles: Minimizing Bias using "blinding"
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-avoids bias in selection of patients, assignment of treatment groups, treatment of subjects, resolution of data issues, evaluation of safety data, and evaluation of protocol violations
-double blind: subject and investigator arent aware of actual treatment assignment -open label or single blind: sometimes necessary for practical or ethical reasons; need to establish procedures to minimize potential bias (importance of SOPs) |
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Design Principles: Minimizing Bias using Randomization
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-randomization schedule: pre-planned random allocation of treatment to subjects
-provides sound basis for statistical analysis of treatment effects -background characteristics should be allocated evenly across treatment groups |
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Example of what can go wrong without randomization:
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School Milk Experiment (lanarkshire-1960s): to assess the impact of milk on height and weight
-10,000 children received milk and 10,000 did not -randomization planned (but not strictly followed by teachers) -results suggested: not receiving milk resulted in better growth -review showed that teachers (presuming benefit of milk) had given milk to those (poorer) children who needed it most -teachers bias invalidated experiment (additional study needed) |
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Randomization in blocks:
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helps assure equal distribution across treatment groups
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Stratified randomization:
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separate randomization schemes by strata
-by center to ensure even distribution of treatment groups within center -by prognostic factors (severity of disease, age, gender |
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Dynamic randomization:
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when multiple strata are desired
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Generalizability definition
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"the extent to which the findings of a clinical trial can be reliably extrapolated from the subjects who participated in the trial to a broader patient population and a broader range of clinical settings"
(ICH E9, statistical principles for clinical trials) |
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Design considerations: multicenter studies
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-ability to generalize (wider population, variety of types of investigator sites)
-necessary for recruitment -assumption: homogeneity of treatment effect |
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Parallel Group Design
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Patients randomized to two or more treatment groups
-investigational product at one or more doses -placebo controlled -comparator controlled Each subject receives only one treatment Comparison of treatments therefore requires comparing the responses of one group of individuals (the drug treatment group) with those of the second group of individuals (the control treatment group) |
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Crossover studies
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-patients randomized to sequences of two or more treatments
-each subjects response to one treatment can be compared directly w/ the same subjects response to the other treatment -advantage: less patients needed -disadvantage: carry over effect |
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Types of open label studies
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-phase 1 dose ranging
-large simple safety studies -phase 2 or 3 continuation/ extension studies -life threatening diseases -compassionate use studies |
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Various types of trials have different goals:
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superiority
equivalence non inferiority bio-equivalence |
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Superiority Trials
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conducted to demonstrate to the satisfaction of regulatory agencies that a new drug is "superior" in efficacy than placebo, or possibly superior in efficacy to an active comparator
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Equivalence Trials
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conducted to demonstrate therapeutic equivalence with an active comparator drug, which is often the current "gold standard" treatment. the intent is to provide compelling evidence that the efficacy of the new drug is "equivalent" to that of the active comparator drug. this type of trial is typically conducted if it is believed that the new drug has benefits such as a better safety profile
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Non-inferiority Trials
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similar to equivalence trials, but they take the concept a little further. it is possible that a new drug may have such a better safety profile than the active comparator that clinicians are prepared to accept slightly less efficacy. the definition of slightly less is couched in terms of the new drug being "non-inferior"
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Bioequivalence Trials
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typically conducted to demonstrate that a new formulation of a drug has "equivalent" characteristics to an existing formulation of the drug, and to investigate whether a different way of administering the drug is preferable, or a good alternative in certain situations when the original method of administration is not feasible. in this study design, both efficacy and safety are addressed
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Bioequivalence in plasma concentration profiles
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to demonstrate equivalence, rate and extent of availability must be assessed and compared. the parameters Cmax and AUC are typically used here, and they are regarded as surrogate markers for clinical safety and efficacy. if they are "too much higher" in the new drug formulation T, they could lead to unwanted side effects. On the other hand, if they are "too much lower" in the new formulation T, the formulation may be less effective in treating the condition
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What authorized FDA to approve biosimilars?
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Patient protection and affordable care act of 2010
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To get approval of a biosimilar:
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have to show more than bioequivalence due to complexity of molecular structure and manufacturing
-small differences in cell lines, or manufacturing may result in differences in side effects (including diff immunologic responses) |
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Adaptive Design
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A trial design which allows changes to important trial characteristics, in response to accumulating data
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Group Sequential Design
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-pre defined interim analyses
-pre established rules for stopping the clinical trial (for efficacy failure/success or for safety) -changes to: randomization ratios, sample size, primary efficacy or safety endpoints, subject inclusion/exclusion criteria -adding or dropping treatment arms |
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Adaptive Design Benefits
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Scientific:
-study more doses -estimate more precisely (minimum efficacious dose, maximum tolerated dose) Ethical (enhancing IRB acceptability) -enroll fewer participants -direct participants towards best doses -reduce #s of treatment failures Efficiency -finish some trials more quickly -answer scientific ?s earlier in the trial (might justify starting phase 3 before finishing phase 2) |
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Primary Endpoint
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"variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial"
-for ex: tumor response rate vs. patient survival rate -usually a single efficacy variable -sometimes safety -rarely quality of life -reliable and validated measure -clinical relevance |
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Secondary Endpoints
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Endpoints supportive of efficacy
-primary measure at diff. times -related efficacy measures -surrogate measures of efficacy (reliable predictors of clinical benefit; may be used when direct measures arent practical) Measures related to secondary objectives -safety measures -quality of life Should be limited in # |
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Estimating Sample Size
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Generally dependent on the study's primary objective
-superiority -noninferiority Principles -large enough to provide a reliable answer to the primary question -practicality -detect clinically meaningful differences |
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Factors in calculations when estimating sample size
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-null hypothesis specified
-expected treatment difference -analysis method defined (test statistic) -probability of falsely rejecting the null hypothesis= type 1 error (alpha=.05) -probability of falsely accepting the null hypothesis= type 2 error (B: Power= 1-B) -one sided or two sided test -other factors dependent on test statistic (estimates of variance, response rates, event rates, survival rates) Noninferiority trial considerations -confidence interval for treatment difference within acceptable clinical range |
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Programs available for estimating sample size
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NQuery
PASS |
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Sample size adjustment during the trial
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interim analyses in long trials
recalculate assumptions based on study data |
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Protocol Development
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-review of study design
-review of detailed primary and secondary endpoint selection -formal sample size calculation -writing statistical methods section |
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Data Collection
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Review of Case Report Forms
Review of Data Validation Plans Review of data edit checks Statistical data checks and observations from preparation of statistical deliverables |
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Data Review Meeting for data collection
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collaborative review of blinded CRF data to prepare for database lock
-sponsor and full PPD team -meeting often hosted by biostatistics Preparations -build analysis database -product draft tables, listings and figures Statistical review based on analysis plan Written summary of questionable data issues Database ready for lock with known certainty |
