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Yes. Abnormal investigation findings that develop in the course of a study is an adverse event.

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An abnormal liver function test could be due to a multitude of causes, such as:  

• Cumulative side effect of the study drug ⁽¹⁰⁾
  • For example, liver toxicity may only manifest after a drug builds up to a certain level in the body.
    
    
• Overdose of the study drug or other drugs, including alcohol or paracetamol
  • While overdoses can be accidental, they can also be deliberate, such as in a suicide attempt. Some drugs may cause suicidal ideation as a side effect. It is important to consider both physical and psychological effects of your study interventions.
    
    
• Concomitant illnesses affecting the liver
  • Such as hepatitis or gallstones
    
    
• Pregnancy
  • Pregnancy can lead to changes in liver function test results which may be normal physiological changes or abnormal (such as in preeclampsia).
    
    
• An anomalous result for a perfectly healthy person

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All preventative measures that are mentioned in the previous scenarios would apply in this case.

If the abnormal liver function test is caused by a pregnancy, it could have been prevented if you require that subjects practice effective contraception while participating in the study.

• Contraception may be important in this case because some drugs or supplements can have detrimental effects on foetuses (unborn babies).
• Regular pregnancy tests may also be done during follow-ups to pick up unexpected pregnancies at an early stage.

Accidental overdoses may be prevented by improving compliance to the drug regime. For example, doing pill counts, using pill organisers for the elderly or absent-minded, and giving reminders via phone calls.

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You identified this AE by performing a blood test. You could have detected it earlier if you conduct more frequent blood tests, but they may be unnecessary and can cause more pain / discomfort / harm.  

You should also make sure that your team members who are conducting follow-ups are competent in eliciting abnormal symptoms and signs through history-taking and physical examination,  and are able to interpret test results. Otherwise, you could miss AEs easily.

Sometimes, side effects / complications of medical interventions do not show up until much later. For example, radiotherapy may cause secondary skin cancers after many years. You may have a better chance of identifying these late AEs if you monitor patients for longer periods of time, even after an intervention is discontinued. ⁽¹⁰⁾

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You should investigate the cause of the abnormal liver function test. Besides reviewing previous literature to check if the study drugs are known to cause liver damage, you may also decide to take one or more of the following actions, based on best medical judgement:

• Give the subject a phone call to ask more questions
• Ask her to come in for a repeat examination and blood test at the soonest opportunity
• Carry out other investigations that are more sensitive or specific, such as a liver scan, hepatitis test or pregnancy test
• Stop her study drug, do another blood test to check if the AE resolves, then re-start the drug to see if the AE recurs ^(10,12)
• Watch and wait until the next scheduled blood test
• Consult an expert if you are unsure

While it is very important to investigate the cause of an AE carefully, you should be aware that the process of investigation may cause anxiety to research subjects.

This is even more so if you are testing for pregnancy and hepatitis in an unmarried woman. The incidental discovery of an unwanted pregnancy or sexually-transmitted disease (Hepatitis B or C) could lead to psychological, social and even financial harm.

If the subject is pregnant and there is a possibility that the study drug(s) may cause harm to an unborn infant (for example, evidence of congenital defects from previous animal testing), you should inform the subject about such risks. You should also ensure that appropriate care is available to her, such as specialist referral, antenatal monitoring and counselling.    

Under all circumstances, you must communicate with the subject sensitively and provide adequate support to her. 

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As before, you should document all your investigation findings in the subject’s case report form. You may also want to monitor for this AE across all your research subjects.

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You may need to report this AE to the study’s sponsor, the ethics committee and the regulatory authorities, depending on your investigation findings.

Even if abnormal liver function test is a known side effect of your study drug(s), you may still need to report it on an urgent basis if the seriousness of the side effect is more than what you would expect (e.g. acute fulminant liver failure). ⁽⁷⁾  

Where necessary, you may need to inform and re-consent other subjects.

Further guidance on adverse event reporting will be provided in Module 8: Ethics review.