Demystifying Research for Medical and Healthcare Students. John L. Anderson

of animal models closely mimicking drug behavior in humans can be developed.’

      BIA 10–2474 Trial

      In one phase trial, BIA 10‐2474 (an orally administered reversible FAAH inhibitor) was given to healthy volunteers with a view to assessing its safety.

       ‘Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10‐2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10‐2474 per day (6 participants)’. ‘They had received the highest cumulative dose (250 to 300 mg) administered to humans’ (Kerbrat et al. 2016). In this final cohort, four of the six participants developed an acute, rapidly progressing neurological reaction. This included headaches, memory impairment and altered consciousness. Magnetic Resonance Imaging (MRI) scans showed symmetric, bilateral cerebral lesions ‘including microhemorrhages and hyperintensities on fluid‐attenuated inversion recovery and diffusion‐weighted imaging sequences predominantly involving the pons and hippocampi’. ‘One became brain dead. Two recovered. One person had memory impairment and one had a residual cerebellar syndrome.’

      Two of the four had previously taken part in other Phase I trials. Kerbrat et al. (2016) suggest that the adverse reactions were related to an accumulation of the drug. They conclude:

       severe toxic effects in the central nervous system as a result of an increased level of endocannabinoids have not been reported previously; this suggests the possibility of an offtarget effect of the drug, owing to the low specificity of BIA 10‐2474 for FAAH, or an effect of a metabolite.4 These unanticipated severe adverse events were caused by the drug and reflect the complexities of clinical drug research.

       (Kerbrat et al. 2016)

Why Do People Take Part in these Trials?

      Chen and her colleagues (2017) carried out a survey of 654 healthy volunteers who had taken part in a Phase I trial in USA, Belgium, and Singapore. The asked them about their willingness to enrol in such trials. They found that their participants were willing to take part in many kinds of Phase I trials – including those involving diverse side effects and procedures. They were keener to participate in trials with low risk, familiar procedures. Their willingness did not vary with their income. They were least likely to agree to invasive procedures like lumbar punctures and bone marrow biopsy, or where there was a risk of irreversible damage – such as kidney damage or death – or where there might be a chance of effects on their minds. ‘In addition, respondents reported that more money, fewer total procedures, the importance of a study, and the doctor performing the procedure would influence their willingness to participate in a given study. Money is an important factor in healthy volunteers' decisions to participate in phase 1 clinical trials, thus it is not surprising that more money might influence their decisions’ (Chen et al. 2017). Not surprisingly, those with lowest incomes express desire to take part in clinical trials. Chen et al. (2017) reported that there was a relatively high proportion of participants with incomes of less than half the national average income in the three countries in their study.

      So, there may be a potential to exploit people who are financially disadvantaged in clinical trials – as in all types of research – and I shall discuss later when considering ethical issues.

To Sum Up

       Phase I and Phase II clinical trials are the earliest tests of new treatments on human volunteers. The examples shown demonstrate that they are quantitative, hypothetico‐deductive. and experimental.

       The difference between these and the majority of experimental approaches we have discussed so far, is that these do not include a control group. They are all tightly controlled and usually conducted under close clinical supervision. They are part of the progression to the next step – Phase III Clinical Trials or Randomised Control Trials.

So, remember, earlier I asked you to consider two questions about Arkenau et al.'s work (2008): (i) What sense do you make of these findings? (ii) What is missing from these trials? In answer to my questions:

      1 There is the possibility of their results being due, in a large part, to a placebo effect. There are a lot of negative side effects – including the occasional death.

      2 How do we rule out the placebo effect? We use a control group. That is what is missing in the studies they included in their review.

      Clinical trials have to be done if we are to develop new medicines. The challenge for us is to make them fair and ethical.

       Remember: ‘Research is the art of the possible!’

References

      1 ABPI. (2014). Guidelines for phase 1 clinical trials: 2012 edition. (Updated in 2014 by Arnold & Porter LLP on behalf of the ABPI.)

      2 Arkenau H‐T, Olmos D, Ang JE, et al. (2008). Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience. British Journal of Cancer 98, 1029–1033.

      3 Attarwala H. (2010). TGN1412: from discovery to disaster. Journal of Young Pharmacists 2(3), 332–336.

      4 Cancer Research UK. (2020). Phase 1 trial. Available at https://www.cancerresearchuk.org/about‐cancer/find‐a‐clinical‐trial/what‐clinical‐trials‐are/phases‐of‐clinical‐trials (accessed 6 May 2020).

      5 Chen SC, Sinai N, Bedarida G, et al. (2017). Phase 1 healthy volunteer willingness to participate and enrollment preferences. Clinical Trials 14(5), 537–546.

      6 Health Research Authority. (2020). Phase 1 clinical trials. Available at https://www.hra.nhs.uk/planning‐and‐improving‐research/policies‐standards‐legislation/phase‐1‐clinical‐trials (accessed 6 May 2020).

      7 Kerbrat A, Ferre JC, Fillatre P, et al. (2016). Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. The New England Journal of Medicine 375, 1717–1725.

      8 Matt L and Carl E. (2018). Avoiding exploitation in phase I clinical trials: more than (un)just compensation. The Journal of Law, Medicine & Ethics 46, 52–63.

      9 Suntharalingam G, Perry MR, Ward S, et al. (2006). Cytokine storm in a phase 1 trial of the anti‐CD28 monoclonal antibody TGN1412. The New England Journal of Medicine 355(10), 1018–1028.