7 jan: Clinical Research History, guidelines & regulations

Question 1

Incident: following WWII where prisoners were tested without consent, physicians were put on trial. Result = ?

Answer 1

Result: Code of Nuremberg > This ethical code (not a law) stating the requirement for voluntary ethical consent.

Question 2

Incident: Softenon (thalidomide) children. It was said to be save for childeren and mothers. it was not; small limbs for childern of mothers using softenon. FDA inspector found that there was lack of data on this. Result = ?

Answer 2

Result: declaration of Helsinki by the world medical association (doctors). Ethical standard for physicians Including the Code of Nuremberg

Question 3

Indicent: 1937 Elixir sulfanilamide, children could not swallow silver supplements, physician transformed it into DEG (anti-freeze). The country could not take it off the market, it could, however, take it off the market through mislabeling of the product. Result =?

Answer 3

Result: 1938 US Federal Food, Drug, and Cosmetic Act.

Question 4

Incident: 1972 Tuskegee Syphilis trial, (black) subjects were misinformed, did not get statusupdates, Withholding treatment, recruitment of black males that would get funural insurance. Result =?

Answer 4

Result: Belmont Report 1979 > led to the first ‘good’ clinical practice guideline
Respect for persons
beneficence “do no harm”
Justice

Question 5

1990 Wide variety of legislations, divided per region. Trials needed to be repeated because of differences in legislation, harmonize the legislation into applicable and accepted around the world. Result =?

Answer 5

Result: ICH = International Conference of Harmonization, developed guidelines for the whole process of drug development. Main actors here: US, Japan, EU. Per region: one representative from legislative authority and one from the industry + 5 seats from other regions/WHO.

Question 6

What are the SQEM guidelines?

Answer 6

1st > Quality guidelines : manufacturing, stability between batches. Coming out with a quality product
2nd > Safety guidelines: includes Pre clinical trials: testing on computer basis, in-vivo, in-vitro tests. Leads to a sounds, safety product.
3rd > Efficacy guidelines: during the clinical trial periods, does it do anything?
4th > M category: interdisciplinary, coding system to enable for statistical comparison. Applied to pre- and during clinical phase, is therefore an overlapping category

Question 7

1996: ICH E6 = GCP guideline finished. Name the characteristics. NOG NIET AF

Answer 7

• In accordance with DoH, GCP, regulations
• No unethical harm is inflicted on the subjects, anticipated benefits justify risks.
• well-being of subjects > interest S&S

Question 8

What is the 2001 Clinical Trial directive?

Answer 8

EU version of ICH E6 Good clinical practice. To make sure every nation in europe has a GCP law.

Question 9

2016: a revised version of ICH-E6 is finished. What is ICH-E6 and what does the revision entail?

Answer 9

E6 = GCP. Main change: technological improvement (more storage, faster processing)

Question 10

Ever since its introduction in 1964, the DoH has been subject to 2 major adaptations. What are those?

Answer 10

DoH has added important things in their guideline:
1) Changed the comparator, which should be the best, not the most common.
2) treatment has to be available after the trials has finished > post trial access.
Influenced by HIV trials, for specific regions (asia, africa),

Question 11

What happens when a CT is terminated because of low efficacy, but patients have been benefitting from the treatment?

Answer 11

Logistical problems are a result; how to get your product in the country when the CT has been stopped? No reimbursement, so free of charge. They first need to check if the patient would fit in a current CT. But the physicians were sent samples, even though they were not allowed to promote it. implication DoH, patients could be treated even though they were not in the CT and treatment was free of charge. Multiple programs are expanding and working on that (often logistic) problem

Question 12

What are the main principles of the DoH?

Answer 12

• Medical research is subject to ethical standards that promote and ensure report for all human subjects and protect their health and rights
• Rights and interests subjects > new knowledge

Question 13

What are the main requirements for medical research involving human subjects?

Answer 13

• conducted with appropriate ethics & science educations, training, and qualifications
• Only when benefits > risks & burdens

Question 14

What are the contents of informed consent?

Answer 14

• Aims, methods
• sources of funding
• possible conflicts of interest
• institutional affiliations of researcher
• anticipated benefits and potential risks of study and possible discomfort
• post-study provisions

-right to refuse or withdraw at any time without reprisal

Question 15

How do you go about when subjects are incapable of giving informed consent?

Answer 15

informed consent must be sought from the legally authorised representative

Question 16

How do you go about underaged subjects?

Answer 16

Assent= if you’re under age, others will make a decision but as a child still have an opinion. They assent to participate, agreement in less formal manner. Dissent should be respected.

Question 17

Can a researcher re-use data for another project without consent?

Answer 17

No. Informed consent must be sought for collection, storage and/or reuse of identifiable human material or data for medical research

Question 18

When do you use placebo-controlled trials?

Answer 18

• no intervention exists, no harm in NOT receiving treatment, otherwise not ethiccally justified

Question 19

What is the EU’s 2014 regulation, which is hopefully applied next year?

Answer 19

One portal through which all EU CTs applications are submitted and reviewed.

Question 20

According to the GCP what is required of the physician? (2)

Answer 20

1. the physiscian is responsible for the medical care of subjects
2. All individuals involved in conduct of trial should be qualified by education, training and experience

Question 21

What is in the ICH- GCP E6 addendum? (5)

Answer 21

• combining US and EU guideline on risk based monitoring (RBM)
• even more specificity on responsibilities. (Sponsor also has oversight over CRO or other third parties)
• extended expectation when significant non compliance ??)
• requirement for using electroninc systems (data processing)
• updates to essential documents