According to Evans, S. and Pocock, S. (2001) and Lievre, M. et al. (2001), there are several solid and valid reasons for early discontinuation of a clinical study (especially with outcomes that include death, disability, etc.):
- Early evidence that an investigational drug (IP) is beneficial for a condition under study/a solid statistical evidence that an IP is better than the comparator, OR
- Early evidence that an IP is, in contrary, harmful (ADRs, SAEs, SUSARs, etc.),
- If an interim statistical analysis showed that a clinical trial has no scientific (statistical) value/power, OR
- It is not feasible to reach the planned outcomes.
So, if we go back to the example situation from this week DQ, it is clear that problems with a patent are not enough to be ethically/scientifically sufficient to stop the trial early, especially taking into account that:
a) Elderly population is considered to be a vulnerable one (especially with such pathology as PD due to possible development of dementia [Merck Manual for Professionals, 2010]),
b) Some study participants gained significant benefits from the IP.
Returning to the question of our DQ, I would agree with numerous opinions that it is not ethical when a Sponsor enrolls patients into a trial and consciously offers them to take all risks with <50% chances for any benefit (and even not a medical care) and then terminates the study because of purely economic/strategic reasons.
As fairly stated by Ashcroft, R. (2010), Sponsors must not early discontinue treatment that showed to be effective for study subjects without giving them an opportunity to receive this treatment for some period of time (usually, till it/or its analogues become otherwise available), primarily as an acknowledgement of their personal contribution (altruism and accepted risks).
On the other hand, this mostly concerns IPs at a definite stage of development (e.g. Phase III) with more or less established safety and efficacy profile (Sponsor may be obliged by regulatory authority/ethics committee to provide an IP to the trial participants for some period of time).
Unfortunately, in the situation when a Sponsor terminates a trial for other than safety/efficacy reasons and an IP is beneficial for some part of the participants there are no legal mechanisms to prevent the Sponsor from doing so (apart from the Declaration of Helsinki provisions that are not really binding for the pharmaceutical industry).
Boyd. K. (2001) stressed that approval from the ethics committee and patients’ consents are sufficient reasons for a Sponsor to be responsible for the appropriate trial conduct and results. If these elements disappear with the trial early termination, so do the grounds for the approval.
Besides, who will support further research if the Sponsor just stops paying money for it? I can hardly imagine that authorities would somehow make the Sponsor to provide treatment to the subjects in the described situation. So, it would be ethical to make the Sponsor proceed with the research, but additional legal mechanisms must be developed and the guidelines amended.
Even if any known SAEs had been reported, there still might be justification for further development:
- In many morbidity/mortality studies SAEs are used as endpoints (i.e. seriousness of the condition may justify the risks),
- Each subject will be given a chance to decide whether the risks are justified for him/her-self (whereas early termination would not leave any choice at all),
- Availability of other approved medicines for the condition.
- Ashcroft, R. (2010) ‘Responsibilities of sponsors are limited in premature discontinuation of trials’, British Medical Journal, July, 323(7303), p. 53 [Online]. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1120687 (Accessed: 12 November 2010).
- Boyd, K. (2001) ‘Commentary: Early discontinuation violates Helsinki principles’, British Medical Journal, March 10, 322(7286), pp. 603–606 [Online]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1119794/#N0x1c52310N0x35db5b0 (Accessed: 13 November 2010).
- Evans, S., Pocock, S. (2001) ‘Societal responsibilities of clinical trial sponsors. Lack of commercial pay off is not a legitimate reason for stopping a trial’, British Medical Journal, 322 (7286), pp. 569–70. Online]. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1119776 (Accessed: 12 November 2010).
- Lievre, M. et al. (2001) ‘Premature discontinuation of clinical trial for reasons not related to efficacy, safety, or feasibility’, British Medical Journal, 2001(322), pp. 603-5 [Online]. Available from: http://dx.doi.org.ezproxy.liv.ac.uk/10.1136/bmj.322.7286.603 (Accessed: 12 November 2010).
- Merck Manual for Professionals (2010) Parkinson’s Disease [Online]. Available from: http://www.merck.com/mmpe/sec16/ch221/ch221g.html#sec16-ch221-ch221g-83 (Accessed: 13 November 2010).