








































Bangladesh Journal of Bioethics 2011;2(2):26-29

JUSTIFICATION OF PARTICIPATION OF HUMAN SUBJECTS IN PHASE 1 CLINICAL TRIALS: 

AN ETHICAL ANALYSIS

Dr. Inayat Ullah Memon 

Chief Pathologist & Incharge Bioethics Unit, 

Peoples Medical College Hospital, Nawabshah, PAKISTAN

Email: memon.inayat@gmail.com

Abstract: In the process of clinical trials, after ascertaining the safety of drugs or other therapeutic interventions 
in animals or in vivo, phase I clinical trials are conducted as initial step on healthy human volunteers (or patients 
with specific disease) to observe pharmacokinetics, safety and side effects associated with escalating doses of 
the drugs.     

Participation of human subjects having different biological system than animals is not without risks in these trials; 
this fact raises some important ethical issues. In the light of international research ethics guidelines, this paper 
analyses moral justification of use of humans as research subjects in phase I clinical trials, discusses what groups 
of participants should be involved, their economic status, questionable coercive effect of monetary remuneration 
on the subjects and soundness of informed consent obtained for the trials. These issues are also discussed in the 
perspective of four founding principles of bioethics i.e. autonomy, justice, beneficence and non-maleficence.    

Keywors: Phase I trials, human subjects, ethics, participants’ protection

Introduction: Tremendous development in medical science and consequent discoveries resulting into successful 
prevention  and  cure  of  various  diseases  are  shared  by  the  clinical  research  involving  human  participants. 
Preceding the trials in human subjects, to ensure safety the proposed drug or any other intervention is either 
tested in laboratory (in vitro) or in animals (in vivo) to assess initial safe starting dose for human beings and to 
identify the benchmarks for clinical monitoring for potential unfavourable effects.1 But these pre-human trials may 
not necessarily safeguard against untoward effects in human beings, as happened in case of thalidomide tragedy, 
which disabled and killed thousands of babies born to mothers taking this medicine.  2,3 Use of healthy human 
subjects in preliminary experiments (phase I clinical trials) reduces or excludes the risks of subsequent unwanted 
effects in future trails and use in respective patients. Participants of phase I trials (or phase 0 trials) in some cases 
are the victims of such unpredictable and life-threatening effects as in case of TG1412.4,5 Apart from this ethically 
questionable  situation,  history  of  clinical  trials  reveals  that  either  investigators  or  the  research  sponsors 
camouflaged the information conveyed the to prospective subjects or exploited either their social vulnerability or 
economic and intellectual poverty to lure them to the study. 6,7 Regular and frequent visits by the researchers to 
specific geographic location on international level or particular communities within a country or region not only 
stigmatize  them  but  target  research  subjects  because  of  financial  incentives  offered  to  them  rely  on 
remunerations for their livelihood and welcome future researchers without need of knowing consequent ill-effects. 
Spirit  of  non-coercive  and  fully  informed  willingness  does  not  absolve  the  researchers  from  the  ethical 
responsibilities even when the documentary consent was obtained from participants,  as participants have no 
knowledge of possible adverse effects of on-going research.              

Cases of tainted consent in research negate the principle of respect for autonomy.  Moreover the fact that there 
are only meagre probabilities of benefit to the participants of phase I trials, except the financial remuneration 
offered to  them, while  future users of  that  particular intervention would benefit  from such trials,  negates the 
principle of justice and beneficence. The principle of non-maleficence is violated when vulnerable groups of the 
communities are favourite subjects for the studies, resulting into their  addiction for the participation in the trials 
with potential of harmful effects. This paper discusses following issues from ethical perspectives.   

1. Whether is it justifiable to involve human volunteers in phase I trials? 

2.  If  yes  what  groups  of  human  volunteers  be  involved,  casual  participants  or  those  who  meet  their  living 
expenses from monetary remuneration or reward earned from such studies.  

3. How much the subjects be paid for participating in these trials? Isn’t the paid amount so voluminous that it 
deceives subjects’ decisional capacity to participate?

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Bangladesh Journal of Bioethics 2011;2(2):26-29

4.  Issue  of  perception  of  phase  I  trials  by the  participants  and  ethical  soundness  of  the  obtained  informed 
consent. 

Justifiability of involving human beings: A necessary but  not the sufficient requirement of justifying human 
involvement in clinical trials is that experiment has to be scientifically valid, based on reasonable hypothesis and 
should  have  a  research  methodology  that  can  be  expected  to  reach  its  stated  endpoint.8 If  we  apply  this 
requirement on phase I  clinical  trials (as well  as phase 0 trials),  then we do not have difficulty to justify the 
involvement of human models. But we have difficulty in meeting this requirement in oncology phase 0 trials as we 
do not have capabilities to measure the effects of the drug on its targets. Another requirement which is necessary 
and  sufficient  one  to  justify  human involvement  in  clinical  trials  is  that  research  needs  to  be  of  benefit  to 
participants. Accepting the practices of clinical research the benefits include direct or indirect to participants and to 
others as well.8  The phase I trials carried out on healthy human volunteers are not coupled with any direct or 
indirect benefit to them. But those carried on patient volunteers such as suffering from cancer have a component 
(though a small one) of benefit to them directly as there is small chance of therapeutic benefit from these trials. 
Moreover the pro-phase I commentators may make their argument worthier and ethical by adding the factor of 
‘benefit to others’ as a result if phase I trials prove successful. Additional component in favour of involving human 
models in these trials is participants’ wish to help others (altruism).                              

What group of human beings should be involved: Careful selection of human participants is needed to justify 
their involvement in phase I trials to ensure avoidance of their exploitation. In the past, poor and desperate-for-
money people were recruited to participate in these trials such as in Eli Lilly case, where homeless alcoholics 
were recruited for these studies.6 While in some other investigations, immigrants with doubtful health condition 
were recruited who later developed tuberculosis and contracted same to some others as well.7 Another factor 
augmenting exploitation is practice of involving for-profit Institutional Review Boards (IRB) as supervisory and 
overseeing bodies for the research trials.6 

Monetary status of paid volunteers and volume of financial remuneration: A study carried out in recent past 
regarding  socio-economic  status  of  the  participants  revealed  that  financial  incentive  was  one  of  the  strong 
motivating factor as well as the most valued one for low income people while had no or opposite influence on 
people with higher earnings. Moreover lower educational level played a role to attract such people to participate in 
the phase I  trials.9 To pay for  participation in  clinical  trials  is  neither  a  new practice nor  it  is  controversial.6 

Moreover it is not unlawful to offer payments for research participation.10 But core issue is the volume of the 
monetary need of the prospective phase I participants and the influence of financial inducement on various strata 
of the society resulting into possible deception of their decisional capacity. Same volume of money may not be 
tempting for a wealthy person but that could be very attractive for economically less privileged person of the 
society.6 This fact leads to the undue inducement for the participants and ethically undesired exploitation by the 
investigators or research sponsors. As a result, more will the chances that poorer become research participants 
and lesser will be the probabilities that they would benefit from such trials if the drug under question becomes 
available in the market (after successful trial and approval) but beyond the purchasing power of the poor. This 
situation negates one of the seven requirements (social value) of Ethical Research Trials9 and violates the article 
19th of the Declaration of Helsinki which requires that medical research is ethically justifiable, only if there is a 
reasonable chance that the population in which it is conducted will benefit from the results. Origin of some of 
these  issues  is  based  on  the  fact  that  clinical  research  has  been  changed  into  business  adventure.  As  a 
consequence the research participants, taking part in phase I trials perceive it as a sort of job or employment. 
Their perception is not based on false beliefs but is truly based on offer of high remuneration for participation, 
which in many cases is more than minimum job wages and is consequently sufficient to mislead them. This 
situation also plays a part in distortion of medical history as because of temptation of disproportionately high 
incentives the prospective participants conceal their illnesses so as to avoid their disqualification from taking part 
in the trials.6 Beside the financial incentives for the participation in phase I trials there is ongoing discussion about 
relationship between the risks and hazards associated with phase I trials. Some commentators argue that not only 
the participants be paid but the volume of benefits and incentives be related to the degree of the risks.10 They 
argue that in today’s rights-based society and value for individual autonomy it would be unduly paternalistic to set 
limits for financial inducements offered for the trials and they corroborate their position by the fact that monetary 
benefits do not affect the understanding of risks by the participants.10,11 An analogy has been offered by Jones and 
Liddell10 in this regard, where comparison of high-risk phase I trials is made with high-risk financial investments. I 
strongly disagree with their stance, contending that risk to life (or health) can’t be legally and ethically compared 
with  risk  to  financial  investment,  they are  entirely  different  and  unmatchable  entities.  Financial  loss  can  be 
regained while human loss is irrecoverable. They also justify high incentives for risky and hazardous associated 
with phase I trials by exemplifying the high wages for dangerous industries or fire-fighting services10 Again, I argue 
against them, as in dangerous industries and fire fighting, the risks are more or less predictable and reasonably 
assessable, while in these trials the situation is entirely different. If it were the situation (predictability, even of high 
risk) in case of  TGN1412 trials carried out  by Parexel  International,  none of  the six participants would have 
adventured to take part in the trials like this one, where their heads and necks swelled three times their normal 

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Bangladesh Journal of Bioethics 2011;2(2):26-29

size.12 I am with Saunders’s opinion who rightly argue that ‘level of the risk should not be so high as to necessitate  
payments  in  the  first  place’.13 Moreover  the  financial  benefits  offered  should  not  be  of  such  degree  as  to 
encourage people to take part in risky trials.                                            

Perception by the phase I participants and soundness of informed consent: As has already been argued 
that poverty of the participants and the high financial benefits distort participants’ perception as they take their 
involvement in the research trials as some sort of job.6,9 This misperception coupled with incomplete disclosure of 
the research risks and hazards, make the informed consent tainted with consequent disrespect and negation of 
the spirit embodied in the doctrine of informed consent.   

Four  Founding Ethical  Principles  Of  Beauchamp And Childress And Phase I  Clinical  Trials:  The four 
founding principles i.e. autonomy, beneficence, non-maleficence provide some valuable guidance in resolving the 
ethical issue of human participation in phase I clinical trials. Research participants are fully autonomous to take 
part (or not) by virtue of their self-governance but at the same time there should be some limits of governance. If 
the Western right-based society considers the ‘right-to-die’ as entirely and solely personal affair and confers this 
right to individuals such as in cases of euthanasia and PAS (Physician Assisted Suicide), then how many such 
countries  have so far  legally conferred their  citizens  the right-to-die? The situation is  so such complex and 
controversial that in the Northern Territory (NT) of Australia, euthanasia legitimized by ‘Rights of Terminally Ill Act 
1995’ was overturned by Federal Parliament just after 9 months of its enactment.  14 While in other instances, 
because of difference of opinion amongst jurists, legal battles pertaining to mercy killing lingered for as long as 
seven years, as in case of Terri Schiavo.15 Therefore, supporting the issue of participating in phase I clinical trials 
with crunches of autonomy and self-governance is not without legal and moral weaknesses and shortcomings. 
Regarding the principle of beneficence; though these trials, meet the seven requirements of ethical conduct of the 
research set by Emmanuel et al 16, but need balancing of the principles and rules as suggested by Beauchamp 
and Childress,  keeping in view the nature of  individual  research.  There is almost no benefit  to the research 
participants in phase I trials except a minor fraction anticipated in those trials conducted on cancer patients. But 
benefit to others (for the society in future) provides reason for ethical justification of phase I trials. The scope and 
quantity of  maleficence is low but its  degree / severity might be high in some cases, like TGN 1412 cases. 
Depending upon the nature of cases, again decision should be made on case to case basis. One may infer from 
the  basic  notion  of  justice  i.e.  treating  like  situations  in  like  ways,  that  no  one  should  be  preferentially  or 
discriminately induced to take part in phase I trials. Then there should not be undue financial inducement or other 
forms of benefits for these trials to allure participants. Neither poor financial situation nor low educational level be 
exploited to tempt individuals to participate in these experiments.6 As the beneficiaries of the research results are 
the affluent people, therefore same group of people should offer themselves for the studies rather than guinea 
pigging the resource-starved communities.                

Conclusion And Suggestion: There are no unequivocal guidelines by the international ethics organizations to 
set limits for the financial inducements offered to participations in research trials, particularly phase I. There are 
recommendations by some national organizations, but these are either vague or controversial such as those of 
British Pharmaceutical Industry (delinking benefits to the risks) and Royal College of Physicians (linking benefits 
to degree of inconvenience and incurring risks). There is need for some consensus principles on which Ethics 
Committees could base their decisions. There is need to set, define and explain the responsibilities of monitoring 
bodies engaged in overseeing the Phase I research trials, so that no such events occur in future like TGN1412, 
moreover  establishment  of  for-profit  IRBs  should  be  discouraged  in  order  to  make  justice  with  research 
participants. There is no disagreement with the fact that scientific, including medical knowledge can’t grow without 
research  including  phase  I  trials,  but  tremendous  scientific  development  requires  balancing  with  increased 
sensitivity  for  bioethics  with  its  broadened and deepened dimensions  There  is  need to  completely  identify, 
understand and resolve these issues without the judges (such as bioethicist and members of IRBs and Review 
boards)  being  unduly  influenced  by  the  glamorous  temptations  offered  by  the  some stakeholders  such  as 
powerful pharmaceutical. In these situations we need to protect the most vulnerable subjects of the research trials 
(phase I trials), particularly when their vulnerability is compounded by economic or intellectual poverty.  

References:

1.Sellers EM, Souich PD, ‘Phase I Trials’ Human Pharmacology.  http://www.iuphar.org/pdf/hum_40.pdf

2. Thalidomide Victims Association of Canada, Thalidomide: The Canadian Tragedy 
http://www.thalidomide.ca/the-canadian-tragedy/

3. The Thalidomide Tragedy: Another example of animal research misleading science 
http://www.pnc.com.au/~cafmr/online/research/thalid2.html

3

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Bangladesh Journal of Bioethics 2011;2(2):26-29

4. Hawkes N, ‘The Drug Trial that went horribly wrong’, Sunday Times, March 16, 2006, 
http://www.timesonline.co.uk/tol/news/uk/health/article741405.ece

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22, pp. 2316-2317  

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12. Six Healthy Volunteers in Phase I Drug Trial Critically Ill UK, 2005.

<http://www.ahrp.org/cms/content/view/110/84/>

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4145 

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16. Emmanuel JE, Wendler D, Grady C, ‘What makes clinical research ethical’, JAMA, 2000, vol. 283, no. 20, pp. 
2701-2711

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