Marketing pressures
Even if our role is on the periphery of clinical research, most of us will be able to describe the four main phases of clinical trials. From the small phase I studies conducted to specifically determine a drug's toxicity, absorption, distribution and metabolism through to the phase IV post-approval studies conducted to compare the test drug to a competitor, explore additional patient populations, or to further investigate any adverse events. However, we may not be aware of a classification of trials known as Open-Label Extension (OLE) studies. In this category of clinical study, all relevant parties are aware of the drug and dose being administered and none of the participants receives a placebo product. Although OLE studies may occur after any phase of a clinical trial, they typically follow a double blind randomized placebo controlled study of an unapproved drug. In a typical scenario participants are invited at the time of recruitment to the main study to enroll in an extension study following completion of their involvement in the randomized controlled phase of a study. The objective of OLE studies is primarily to gather information concerning the safety and tolerability of the new drug in long term, day to day use.
While the rationale behind OLE studies may be honorable, some ethicists raise concern over who is benefiting most from the studies. Dr. Gordon Taylor, senior medical statistician at the University of Bath, England and Prof. Paul Wainwright, professor of nursing at the Faculty of Health and Social Care Sciences, Kingston University and St George's Hospital Medical School, London, England have published some of their concerns in the latest edition of the British Medical Journal. In their paper entitled “Open label extension studies: research or marketing?”, the authors explore the notion that OLE studies are particularly prone to the pressures of marketing over good research methods and research ethics.
Blind leading the blind
The first concern raised by Taylor and Wainwright lies at the very beginning of the trial process – informed consent. Before participating in a clinical study, all patients or volunteers are required to provide a voluntary verification of their willingness to participate in the clinical trial, along with the documentation thereof. This well-regulated process is requested only after complete, objective information has been given about the trial, including an explanation of the study's objectives, potential benefits, risks and inconveniences, alternative therapies available, and of the subject's rights and responsibilities in accordance with the current revision of the Declaration of Helsinki. The informed consent procedure has not been designed specifically to deal with OLE studies and consequently there exists the possibility of deliberate or accidental misuse or misinterpretation.
Part of the problem lies in that study participants are invited to continue on to the OLE study as soon as their involvement in the randomized controlled phase of the study has been complete. The study sponsor will not normally unblind the study at this point and thus neither the investigators nor the study subject will know if they have been receiving the active or placebo treatment. This raises one major ethical problem. Study participants have to base their decision on their previous study experience (and for some that decision will be based on taking the placebo product). Given that participants in either arm of the trial may have had positive or negative outcomes, their experience during the trial and their perception of the efficacy of the treatment they have received cannot be a sound basis on which to make such a judgment.
Prior to enrollment in a phase I to 4 study, patients or volunteers have to comply with a strict set of inclusion and exclusion criteria. At the end of the study period (which for phase II and III studies could be several years) a participant’s health status may have changed and thus their compliance meeting study inclusion criteria may also have changed. OLE studies may continue for an undefined time period (often until the drug is licensed), and some participants may therefore be receiving a drug that is not clinically justified for an extensive time period.
Scientifically challenged
In addition to the complex ethical issues that surround OLE studies, Taylor and Wainwright also called into question the scientific validity of these studies. Participants who have experienced adverse reactions to the study product may already have been withdrawn from the trial; those remaining participants who may have experienced mild adverse events may have continued with the main study but they are unlikely to choose to continue in the OLE study. Thus the group continuing will not be statistically representative of the original study population or of the intended target population. Biostatisticians need to develop and implement methods to provide unbiased estimates of safety and tolerability when analyzing the results from these studies if the studies are to be scientifically sound.
A compassionate approach
An additional concern voiced by ethicists and explored by Taylor and Wainwright is the misuse of OLE studies as a way to provide patients with compassionate use of an unlicensed product. While providing experimental therapeutics to very sick individuals with no other treatment options may appear laudable, other regulatory procedures are already in place to deal with these situations. The most vulnerable should not become research guinea pigs.
A trial separation
Designed correctly, OLE studies can provide pharmaceutical companies with important safety and tolerability data of unapproved drugs in long term, day to day use. The problems and potential for misuse of OLE studies stems from their misclassification as “extensions” to the primary study. In reality OLE studies are quite different to the primary study and should be treated as such by research ethics committees and regulatory authorities. The OLE study frequently has a different patient population to the main study and compliance with inclusion and exclusion criteria should be addressed separately to the main study. Depending on the length of time that participants will be on the main study, research ethics committees may need to review the OLE request at the same time as the primary study. However, for OLEs that will not be implemented for some time after the start of the primary study, then the request to continue with an OLE should not be submitted too soon (perhaps 6 months) prior to its anticipated start date. Separating OLE studies from the primary study would also help answer concerns that discussing the possibility of the extension study at the time of initial recruitment places undue pressure on individuals who think their present treatment options are unsatisfactory, to participate in the study.
Clinical researchers may argue that it would be impossible to treat OLE studies as separate the main study as to do so would essentially require breaking the blinded nature of the trial. In an article by Prof. Paul Wainwright entitled “Consent to open label extension studies: some ethical issues” published in the Journal of Medical Ethics, the author maintains that not breaking the study code and informing patients as to whether they had received the active or placebo product is unethical. He states that “the only apparent justification for not giving patients the information they require seems to be the convenience of the investigators.” Prof. Wainwright also details procedures to overcome some of the potential difficulties of unblinding study product before completion of the main study. One such procedure would be ensuring that monitoring and data collection for the OLE study is managed by individuals not involved in the primary study.
Publish or perish
In the September 2004 edition of the P.I.L.S Compliance Column entitled “Show us your data”, we discussed the growing clamor for increased transparency in clinical study reporting and a plan by members of the International Committee of Medical Journal Editors (ICMJE) to compel pharmaceutical companies to register all clinical trial studies including those with unflattering or unclear results. As part of their analysis of OLE studies, Taylor and Wainwright calculated that pharmaceutical companies conduct OLE studies on a 6:1 ratio to phase III studies. However, when they conducted a Medline search for studies between 2000 and 2004, 86 OEL studies were reported compared with over 2000 phase III studies, a ratio of 23:1. This difference suggests that many open label studies are never published and this raises additional concerns. Firstly, if the studies are not producing scientific data that is worth sharing, then should the studies be conducted? Additionally, when participants agree to participate in a clinical study, many do so for altruistic reasons believing that they are helping others through their contribution to medical research. This is something that must be respected with complete transparency about trials including the results from OLE studies.
Are you worth it?
The high cost of clinical research and the difficulties in recruiting study participants exerts immense pressure on study sponsors to extract as much information as they can from every study and every participant. This in turn should lead to the most ethical approach to trial design. However, the pressing need to collect data should not pressurize researchers to collect unnecessary or statistically inappropriate data. The responsibility of protecting the welfare of participants in clinical research while producing study data that is scientifically sound may be time consuming and expensive. The process may also require input from a myriad of sources – biostatisticians, regulatory authorities, ethicists and institutional review boards – but ultimately the one person they are protecting is you.
Further reading:
Footnote:
The author would like to thank Dr. Gordon Taylor, senior medical statistician at the University of Bath, England, for his assistance with this column.