Human Laws and Regulations

What is a human subject

living individual about whom a research investigator obtains data through intervention or interaction with the individual or from individually identifiable information (must be living)

What counts as an intervention?

both physical procedures to gather data (ie venipuncture) and manipulations of subject or subject's environment for research purposes

What counts as an interaction?

communication or interpersonal contact between investigator and subject

What is private information?

-info about behavior in which no observation or recording is taking place
-info has been provided for a specific purpose
-info will not be made public (ie medical record)

What is identifiable information?

info that's individually identifiable, the identity of the subject is or may be readily ascertained by investigator (ie date of birth)

What is privacy?

an individual's desire to control who has access to him/herself, including access to personal/private info

What is confidentiality?

the researcher's agreement with participant about how identifiable private information will be handled (how and where research documents and data will be stored)

Pure Food and Drug act/Wiley Act (1906)

-defined "misbranding" and "adulteration" (added chemicals/ingredients) in food and drugs (ie snake oil)
-drug labels had to list any of 10 ingredients that were deemed "addictive" and/or "dangerous"

What events led to the creation of the Pure Food and Drug Act?

1. formaldehyde added to milk to prevent spoiling before reaching market
2. eggs preserved in boric acid
3. meat inspection act due to blood cross contamination from injuries while cutting meat (the Jungle by Upton Sinclair)
4. markers added dye and smoke flavoring to grain alcohol to make whiskey, and sticks, sawdust, and dirt to make coffee or tea to save money (may contain methanol which can cause blindness or death)

What substances does the Pure Food and Drug Act regulate?

alcohol, morphine, opium, cannabis, etc

What are the penalties if the Pure Food and Drug act is violated?

only minor financial penalties imposed, but goods found in violation seized, no jail time

Federal Food, Drug, and Cosmetic Act of 1938

-replaced pure food and drug act
-gave the government the power to inspect plants and manufacturers
-label must not include false info about efficacy and purity
-manufacturers must prove safety but not effectiveness

What events led to the creation of the Federal Food Drug and Cosmetic Act?

-elixir sulfanilamide poisoning from Massengil company killed more than 100 people (sulfanilamide was prepared with diethylene glycol and raspberry flavor and given to children with sore throats)
-diethylene glycol can lead to kidney failure and liver damage
-no drug testing required at the time for new drugs

What does the Federal Food, Drug, and Cosmetic act regulate now vs when it was created?

when it was created:
-solely focused on food, drugs, and cosmetics
now:
-food (including gum) and food additives
-dietary supplements
-drugs
-cosmetics
-tobacco products
-medical devices (class 1 low risk like bandage, class 2 moderate risk like pregnancy test, class 3 high risk like pacemakers)

What role does the FDA play in enforcement and penalties of the Federal Food, Drug, and Cosmetic act?

-FDA used the pure food and drug act to prosecute Massengil (company that caused sulfanilamide poisoning)
-FDA requires manufacturers to file a new drug application prior to marketing (company's responsibility for drug safety and effectiveness)
-FDA regulates supplements by preventing adulteration (what is on the label is what's in the supplement)

What were the major Nazi experiments?

-Twins experiments: ie sewing twins together
-exposing prisoners to unsafe conditions (ie: freezing seawater immersion, altitude changes)
-infecting patient with tuberculosis and malaria

Explain the Nuremberg trial (1946-1947)

-prosecution of Nazi leaders for crimes (execution or jail sentences) against humanity
-aka Doctor's trial

Did Nuremberg code become law in US?

it wasn't adapted into federal law but it inspired other laws

What was the primary tenet of the Nuremberg code? (1946)

voluntary human consent is essential

Define the Kefauver Harris Amendment (1962)

amendment to Food, Drug, and Cosmetic Act

What events led to the Kefauver Harris Amendment?

response to thalidomide tragedy

What was thalidomide used for?

a hypnotic/sedative drug that can also prevent morning sickness during pregnancy

What was the role of the FDA in the Kefauver Harris Amendment?

-Dr. Kelsey prevented US from using thalidomide like Europe did
-FDA did not approve thalidomine use in the US

How did thalidomine cause phocomelia/birth defects?

-prevents blood vessel formation in limbs
-metabolite (CPS49) has antiangiogenic effects

What did the Kefauver Harris Amendment add to the FDAC?

1. required FDAC to require additional safety testing prior to approval
2. required manufacturers to prove effectiveness prior to approval
3. required drug advertising to accurately portray side effect

Define the Declaration of Helsinki (1964)

-the first set of laws/regulations to specifically address the needs of the vulnerable populations during human subjects research
-fundamental principle: autonomy, researcher's first duty is to the subject

Why was the Declaration of Helsinki created?

because the vulnerable populations were taken advantage of (ie: the Holocaust)

What are the three vulnerable populations that are covered by the FED?

1. subclass B: pregnant women (baby)
2. subclass C: prisoners (cell)
3. subclass D: children (dorky)
"preggos, prisos, and kiddos"

What are the other vulnerable groups that are protected by the IRB but not the FEDs?

-mentally disabled
-economically disadvantaged
-educationally disadvantaged
-workers
-students

How was the Declaration of Helsinki enforced in the US?

not legally binding in the US, but many countries have used it as a standard to guide their own laws and regulations

Define the National Research Act (1974)

-resulted from a group of experts who attempted to describe the most important components of ethical research

What events led to the creation of the National Research Act?

1. Willowbrook Hepatitis Study:
-Dr. Saul Krugman exposed children to hepatitis via feces mixed with chocolate milk
2. Tuskegee Syphilis Study:
-started off ethical (observing incurable diseases like syphilis to find a cure)
-hypothesis that blacks would respond differently than whites to syphilis

Why was the Willowbrook Hepatitis Study unethical?

-Willowbrook chosen because it was overcrowded (easy to spread disease)
-risking the health and lives of children was not worth the potential of finding a hepatitis vaccine

Why was the Tuskegee Study unethical?

-1945, penicillin was an accepted syphilis cure
-participants in the study did not receive penicillin so that they could continue to be studied

What was the outcome of the National Research Act?

Bellmont Report

What was the Belmont Report (1979)?

a set of principles (NOT a law) that were turned into law by the Common Rule

What are the 3 Core Principles of the Belmont Report?

1. Autonomy/Respect for Persons
-subjects should be treated as autonomous agents
-subjects need to be protected (ie informed consent)
2. Beneficence
-subjects should not be harmed
-risks should not outweigh benefits
3. Justice
-fair distribution of risks and benefits
-no single group should suffer for the benefit of everyone else
-which groups should receive research funds?
-how are subjects chosen?

What is the Common Rule (1981)?

-law that enforced the principles from the Belmont Report

What was the outcome of the Common Rule?

this law made requirements for:
-assuring compliance by research institutions
-researchers' obtaining and documenting informed consent
-IRB membership, function, operations, review of research, and record keeping
-includes special protection for vulnerable groups

What was the role of the Institutional Review Board (IRB)?

-required of all institutions that undertake federally funded research
-overseen by federal government

What was the role of the IRBs for human subjects experiments?

all persons included by name on the IRB application for a study that involves human subjects must be certified

What was the power of the IRB at the institution?

-approve, monitor, and review all scientific research involving humans
-main job: evaluate a proposed experiment and perform risk/benefit analysis (benefits must outweigh risks to subjects)

What was the role of the IRB after it has approved an experiment?

-suggest modifications
-provide continuous monitoring (re-review studies at least once a year, may require full-board review)
-observe the consent process and research procedures
-suspend or terminate approval (cannot fire or report anyone)
-cannot approve or withhold grant money
-must approve any amendments or modifications prior to implementation
"what can be done about the experiment?"

The IRB must be notified within 24 hours if these following events occur:

1. adverse events or unanticipated problems involving risks to subjects or others (ie side effects)
2. incidents of noncompliance (ie forgetting to sign papers)
3. deviations from an approved study plan and violations of the terms of approval

What are the 3 Types of Review and give some examples of experiments that fall under each category?

1. Full Board:
-more than minimal risk
-involves protected human subjects
-ie: interventions involving physical or emotional discomfort or sensitive data
2. Expedited:
-not greater than minimal risk
-ie: collection of biospecimens by noninvasive means, research with existing documents/record collected for non-research purposes with identifiable subjects
3. Exempt:
-less than minimal risk
-ie: research with de-identified records, anonymous surveys

What are the requirements for a Full Review experiment?

-for all studies not eligible for expedited review or exemption status
-must be a fully convened meeting with a majority of IRB members present and a majority approving the research
-IRB must notify researchers and organization of its decision to approve, modify, or disapprove the research

What are the requirements for an Expedited experiment?

-not with protected groups
-research may not involve "more than minimal risk"
-must fall into one of nine federally defined categories

What are the requirements for an Exempt experiment?

-IRB still has to be informed
-research conducted in normal educational practices
-anonymous research (no info collected on who subject is, nothing identifiable)
-must fall into one of six federally defined categories

What research is never considered exempt or expedited?

-when prisoners included
-surveying or interviewing of children
-observations of public behavior of children when researcher is participating in activity

What requirements must be met to receive IRB approval?

-risks are minimized and reasonable in relation to any benefits
-equitable selection of subjects (don't target a vulnerable population)
-informed consent sought and documented
-protection of privacy of subjects and confidentiality of data maintained
-additional safeguards have to be added to vulnerable population for full protection

What kind of members are required to be in an IRB?

-at least one scientist and one nonscientist member
-at least one member who is not affiliated with institution (public member)

How many members must be in an IRB?

more than 5 members

What are the requirements for IRB membership?

-must have varying background
-members must be diverse in: gender, race, cultural background, sensitivity to community attitudes
-if an IRB reviews research that involves a vulnerable group, then specialists experiences in working with these subjects should be consulted
-they cannot review their own projects

What is informed consent?

This is consent given by the patient who is made aware of any procedure to be performed, its risks, expected outcomes, and alternative.

What are the 3 key features of informed consent?

1. giving the participants enough information to make an informed decision
2. ensuring that the participants understand how their info will be protected, any potential dangers, and how the experiment will go (don't use medical jargon they can't understand)
3. ensuring that the participants understand that it is totally voluntary (do not pressure them)

When and how must informed consent be obtained?

-must be obtained prior to research
-must be fully documented in writing

Who can give informed consent and how?

-adults capable of doing so
-for adults who are unable to, they need a legal authorized representative
-children capable of understanding (ages 3+) requires "assent" (if the parent and child disagree, usually the child wins unless its a treatment to benefit their health)

What must be included in the information for informed consent to be considered "informed?"

-describe experience, benefits, and alternatives that may benefit the subjects
-subjects must be told to what extend their identifiable info will be held
-explanation of how research-related injuries greater than minimal risk will be handled (voluntary compensation and treatment required)
-subjects can't be offered illegal substances
-regulations prohibit waiving or appearing to waive any legal rights of subjects (ie: you can't tell the subject that if they get hurt they can't sue you)
-emphasize to subjects that they have a right to withdraw at anytime

What is minimal risk?

the probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests

What are some examples of greater than minimal risk?

-biopsy
-X ray
-research with vulnerable groups
-MRI with contrast
-research in which identification of subjects and/or their responses would place them at risk of criminal or civil liability, damage their reputation, or be stigmatizing to their group
-mobile medical applications that directly inform care (ie applications that provide insulin dosage recommendations)

What are some examples of minimal risk?

-blood samples from healthy, non-pregnant adults
-collection of data by non-invasive means (ie MRI, ECG, US) without contrast
-research involving materials that have been collected for research purposes (ie data, documents, records)
-research on individual or group characteristics or behavior (ie surveys, interviews)
-mobile applications that track info but don't directly inform care (ie period trackers)

What must be done for studies that contain greater than minimal risk experiments?

if a study requires greater than minimal risk then review at the IRB is complete

What were the Holmesburg prison experiments?

a series of dermatological tests performed by Alfred Kligman on inmates after WWII (injected with toxins in consideration for biochemical warfare)

What are some examples of the Holmes burg prison experiments?

-injected with dioxin (component of agent orange that causes chloracne)
-radiation dosing testing
-exposed to pathogens (staph and herpes simplex A)

What does subpart C define a prisoner as?

-any individual involuntarily confined or detained in a penal institution (ie: work release, house arrest, alchohol and drug treatment facilities, and court order)
-parolees don't count

What are the four categories of experimentation with prisoners?

1. study of the possible causes and effects of incarceration and criminal behavior (how did they end up in prison?)
2. study of prisons as an institution
3. research on what conditions affect prisoners
4. research on practices that improve health or well-being of prisoners

What are the special considerations for prisoners?

-consent: reduced autonomy
-incentive: incentives that seem trivial to outside world are more significant for prisoners
-limits to confidentiality: certain things never confidential (threats of harm to self or others, threats to escape)

What was MK ultra?

-CIA "mind control" program
-population dosed with LSD without their knowledge
-went to the supreme court

What was the stanford prison experiment?

-guards and prisoners were chosen randomly from volunteers
-guards took on the role and imposed authoritarian rules on the prisoners
-prisoners rebelled and guards used fire extinguishers on prisoners and forced them to strip (resulting in mental breakdowns of prisoners)

Why was the stanford prison experiment unethical?

participants not protected from psychological harm (ethical issues with informed consent)

What happened to Henrietta Lacks?

-her cells created the first immortalized cell line (HeLa cells)
-samples of her cells were sent to labs all over the world without her consent to study multiple diseases
-companies received millions, but no financial compensation for Lacks or her family

What Belmont principle was violated when Henrietta Lack's cells were used without her consent?

autonomy