Three of the key principles in the statement have been the subject of much debate, and we discuss the rationale behind them in more detail below.
Registering all types of trials
“Protocol information and results from all trials related to health or healthcare—regardless of topic, design, outcomes, or market status of interventions examined—should be registered and publicly available.”
Some people have argued against requiring registration of early or post-marketing exploratory trials and uncontrolled trials, citing the need to protect commercial interests for interventions under development.11,15
Such trial designs may also be deemed less important for registration because they rank lower in the hierarchy of evidence to guide healthcare decisions. Furthermore, pharmaceutical companies have suggested restricting the registration of results to commercially available drugs because many researched drugs never make it to market and cannot affect healthcare.
However, these arguments ignore the fundamental ethical obligations to research participants. Most importantly, the potential risks of their voluntary participation, which exist in any type of trial, are justified primarily by the presumed social good resulting from the creation of publicly accessible knowledge. This social contract to accurately disseminate information and results from all trials takes precedence over commercial or other interests. A decision not to bring an intervention to market—whether for economic or scientific reasons—does not invalidate this ethical obligation to participants and has little bearing on the importance of knowledge gained from trials. For example, information gained in early trials about an ineffective or harmful intervention that has not been marketed should be made publicly known to avoid unnecessary and potentially harmful duplication by other researchers.
Several additional justifications exist for including all trials. Certain interventions and uncommon diseases are less amenable to controlled study designs. The best evidence for these interventions is thus limited to less rigorous designs such as prospective case series. Even so, information from exploratory and uncontrolled trials can be clinically important for generating future hypotheses and for documenting potential harms and preliminary efficacy data. Despite supporting registration of results from all hypothesis testing trials of market approved drugs, the pharmaceutical industry has offered to report results from early exploratory trials only if they are deemed to be medically important.11,15
This is, however, no different from what happens now with exploratory trials. The conflict between disclosure and commercial or other interests must be avoided by mandating registration for all trials on approved and unapproved interventions; voluntary disclosure is inherently subjective.
Timing of public release of protocol information
“The public should have cost-free access to the Unique ID, minimum protocol items, and consent forms prior to participant enrolment. Registered amendments should be made publicly available as they occur.”
Concerns have been raised over the public release of commercially sensitive information and intellectual property contained in trial protocols, such as trade secrets and novel methods or hypotheses. Competitors could use registered information to their advantage. Likewise, other academic researchers could use detailed protocol information to complete and publish a similar study earlier.
However, details of the trial have to be publicly available before recruitment to fully inform potential participants about the nature of the study. Protection of trade secrets can be a legitimate concern, but detailed pipeline information on interventions and research from the preclinical phase to the market phase is already available through various subscription websites.16-18
Thus, public release of protocol information does not pose a new threat to commercial interests. Furthermore, specific details about an intervention's design properties need not necessarily be registered, so trade secrets would be uncompromised. With regards to protecting novel ideas, protocol registration will establish a form of intellectual property by publicly documenting methods and their date of registration.
Registration and early public release of accurate information about all trials is necessary to fulfil an ethical obligation to participants
Although protection of commercial and other interests is important, the social contract with participants should take precedence
All trial results should be registered and publicly available, along with sufficient protocol information to enable critical assessment of their validity
The Ottawa Group will continue to foster international dialogue on the principles of trial registration and their implementation
Registering unpublished results
“At a minimum, results for outcomes and analyses specified in the protocol (as approved by the institutional review boards/independent ethics committees), as well as data on harms, should be registered regardless of whether or not they are published.”
Much debate has focused on the use of unpublished results that are not peer reviewed.19,20
If such results are produced with incorrect analyses or biased methods, they may be inappropriately interpreted and applied. Therefore, when citing registered results, it is important to continue to draw a distinction between peer reviewed and non-peer reviewed data. As an additional safeguard against potential misuse of invalid registered results, the public availability of protocol details in the register will enable critical appraisal of trials' methods and analyses. Finally, we should, of course, remember that peer review is not infallible and does not in itself guarantee validity.21,22