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Open Label Extension
Open label extension (OLE) definition
An open label extension (OLE) is a type of clinical trial that typically comes after an initial double-blind, randomized controlled trial (RCT). In an OLE study, participants are offered access to an investigational drug/product that was shown to be effective in the preceding controlled trial. Both participants and investigators are aware that all participants are receiving the study drug. Thus, it is a type of single-arm open label clinical trial. The aim of open-label extension clinical trials is to collect additional data about the medicinal product over a longer period of time.
What are the benefits of open label extension studies?
There are several potential benefits of open label extension studies. To begin, the long-term effects of treatments can usually only be observed through extended follow-up periods, such as those supported by open trial extensions. When well designed and executed, open label extensions can provide valuable insights into aspects of the safety and efficacy profile of a drug that may not have been monitored or noticed in earlier trials.[1] Patients who complete a randomized controlled trial may appreciate the option to continue participating in an OLE, as it allows them continued access to a new therapy that appears to be effective, and which may still not yet be available to the public - and at a lower cost.
Ethical concerns with open label extension studies
One ethical concern regarding open label extension studies is that participants typically enroll in the extension without knowing their allocation from the previous trial (i.e., without being unblinded). They are thus unaware whether they received the study drug during the initial blinded RCT. This means that, although they will have first-hand experience from the prior trial, they will not be able to know whether the drug was working for them. Some argue that this means that they cannot make a properly informed decision going forward because they lack full understanding of the context.
Furthermore, when it is already planned in advance, participants may be informed about the possibility to enroll in the OLE before enrolling in the prior RCT. Some prospective participants may be drawn to the idea of being guaranteed the study drug after a shorter randomized trial, which could potentially be seen as a form of coercion.[1] This may pertain particularly to patients lacking current treatment options, which could also skew or bias the study sample.
Other points of contention about open label extension trials
Beyond the ethical concerns, other issues have been raised about open label extension trials. A prominent question is whether these studies actually produce valid results or are just marketing schemes disguised as research projects or compassionate use programs, lying outside of the equitable access guidelines established for clinical trials.[1]
Compassionate use is another topic of debate in the context of OLE studies. As there is usually a (potentially significant) delay between the end of a phase III RCT or pivotal trial and marketing approval, research ethics committees may feel compelled to approve an open label extension study on the grounds that it will help patients continue to enjoy the medical benefits of the study drug. However, it has been argued that prescribing a medicinal product for compassionate use does not fit the definition of research, and that long-term effects may be better studied through other means such as post-marketing surveillance studies (i.e., phase IV trials).[1] Further, compassionate use may be permitted, even for unapproved medical products, on a per-patient (named) basis, and it would be possible to continue monitoring the patient in that case similarly to monitoring in an OLE.
Finally, it can be argued that the strict eligibility criteria applied to the original trial means that the sample is not representative of the broader population, and thus that OLEs do not actually generate real-world data or real world evidence.[2]
Potential benefit of unblinding before open label extension trials
Unblinding has not been a common practice between randomized controlled trials and open-label extension clinical trials. However, unblinding patients before they enroll in an open label extension could alleviate or eliminate some of the ethical concerns we discussed above, by ensuring that each participant has a complete understanding of what they were receiving during the prior controlled trial and how it may have related to their health outcomes.[2]
Unblinding after the original blinded trial would prevent the unethical situation wherein a participant whose symptoms or condition resolved or improved while receiving placebo is then given the study drug, while assuming that it was the study drug that improved their condition.[2]
Conclusion
Open label extension studies offer continuity for participants receiving benefits from treatment they have received during a randomized controlled trial, while simultaneously providing valuable safety/efficacy information to sponsors. However, it has been argued that continued treatment is not the purpose of OLEs, and that the long-term safety data can be collected through more robust and appropriate trial designs such as post-marketing surveillance studies. Maintaining the blind from the RCT is a common practice, but it means that participants may not actually have sufficient information to make a fully informed decision. This raises issues related to ethical consent for open-label extension clinical trials. A potential solution to the ethical concerns regarding OLEs is to unblind the participants, but it is yet to be seen whether this practice will be implemented.