Registration in Clinical Trials: A Brief Introduction and Comparison with Preregistration

This blogpost has been written by Xianhua (Dennis) Peng. His PhD considers the Statistical validity and variability in psychological intervention studies. Dennis is supervised by Michèle Nuijten, Paul Lodder, and Jelte Wicherts.

The term “preregistration” is well-known in the social sciences as a pillar of the Open Science movement and a safeguard against the replication crisis. However, it may be a less used term for researchers in the clinical sciences, such as clinical psychology and psychiatry. For these researchers, including me, registration is a more familiar name, and it can be done not only prospective, just as preregistration, but also retrospective.

The Development of Clinical Trial Registration
Scientists have long been concerned about publication bias: the tendency for only positive results to be published while null or negative findings remain invisible. One solution proposed to tackle the publication bias and selective reporting is the comprehensive registration of clinical trials. By recording the clinical trials, the scientists, as well as the public, can know what trials have been started regardless of whether they are published.

The idea of trial registration was firstly implemented at a large scale when the International Committee of Medical Journal Editors (ICMJE) announced that they would not publish studies that were not registered in a public registry prior to the enrolment of the first participant (De Angelis et al., 2004). Four years later, in 2008, the Declaration of Helsinki advocated that “every clinical trial must be registered in a publicly accessible database before recruitment of the first subject.”

To facilitate and standardise the implementation of prospective trial registration, the WHO International Clinical Trials Registry Platform maintains a list of primary registries, along with partner registries, that satisfy certain standard (see WHO Registry criteria) and developed a 24-item dataset defining the minimum requirement on what should be included in an effective registration (see WHO Trial Registration Data Set). A number of journals, such as those that claim to follow the ICMJE recommendations, have included prospective trial registration in WHO primary registries into their publication policy for clinical trials. The list of ICMJE following journals was not continued as of April 2025, as many of the journals claiming to follow did not really stick to the ICMJE recommendations and it is hard for the ICMJE to verify the journal’s practices.

The Difference Between Preregistration and Trial Registration
Despite surface similarities in pre-specification of study design and publishing in open repositories before data collection, preregistration and trial registration differ substantially in their purpose, timing, structure, and enforcement. The most fundamental difference lies in their historical context. Rising with the tides of the Open Science movement and the replication crisis, preregistration has become increasingly popular in the social and behavioural sciences as a means to improve transparency and reproducibility, and to tackle questionable research practices. However, besides promoting research transparency, clinical trial registration was introduced to address the selective reporting and the publication bias, ensuring that all trials—regardless of results—are publicly visible (De Angelis et al., 2004). In short, preregistration mainly aims to prevent questionable research practices, and registration mainly aims to prevent publication bias.

Because of these different purposes, there are different norms towards the timing of registration. In preregistration, research plans must be specified prior to the start of a study. Otherwise, it loses its value and meaning in preventing questionable research practice and constraining researcher degrees of freedom. However, a clinical trial registration can also be published after the start of participants recruitment willthen  be tagged “retrospective”but is still seen as necessary, as a compromise between the transparency of research design and the practicality of information sharing.

When registering studies, researchers also encounter different structure and content requirements. Clinical trial registrations are block- and itemised based on the 24-item WHO dataset, and researchers often only fill out the required items in a registry. Therefore, you usually don’t find detailed information about the trial procedure, the content of the intervention, or the specifics of statistical analysis plans (SAPs). On the contrary, preregistrations can be done more flexibly at various platforms. Without the restriction on what must be preregistered, researchers tend to provide the details as much as they can, which emphasises the specification of both research design and analysis plans.

Although many journals now encourage preregistration and give out Open Science Badge of preregistration, there’s no regulatory requirement for preregistration by journals or policymakers. And while this is the case for registrations, , journal publication policies do not have legal binding force, and there is often no formal mechanism or designated party responsible for verifying whether authors have complied with these policies. As several studies showed, around 30–40% of trials published in ICMJE ‘compliant’ journals did not adhere to the prospective registration policy (Al-Durra et al., 2020; Dal-Ré et al., 2016; Gopal et al., 2018; Scott et al., 2015).

In addition to publication policies, there is attempt to legally mandate prospective trial registration. According to Food and Drug Administration (FDA) Amendments Act (FDAAA) of 2007 and its Final Rule starting 18 April 2017, certain clinical trials, including FDA-regulated drugs, biologics, or medical devices intervention studies in the United States, should be registered in ClinicalTrials.gov no later than 21 days of the first participant recruitment by the sponsors or the principal investigators. Similarly, according to European Union Clinical Trials Regulation (EU-CTR) which came into effect on 31 January 2022, if researchers want to start a trial in one or more EU member state(s), the clinical trial must submit and get approval for the trial registration via Clinical Trials Information System (CTIS). As of now, this regulation also only applies to pharmaceutical trials—not psychotherapy trials.

Current Registration Practice in Psychotherapy Trials
Although it has been two decades since the call for the prospective registration of clinical trials , the practice remains suboptimal. For example, the prevalence of prospective registration of psychotherapy trials, although increasing, is still low:

  • Cybulski et al. (2016) identified 165 randomised controlled trials (RCT) from 25 clinical psychology journals in 2013. Among them, 73 RCTs (44.2%) were registered and 25 (15.2%) were registered prospectively.

  • Bradley et al. (2017) reviewed 112 psychotherapy trials from five high-impact clinical psychology journals between 2010 and 2014 and found that only 27 (24.1%) out of the 67 (59.8%) registered trials were prospectively registered.

  • Stoll et al. (2020) study focusing on the psychotherapy trials on depression from 2015 to 2018 found that 134 out of the 196 studies (68.4%) were registered and 78 (39.8%) prospectively.

Moreover, among the registered psychotherapy trials, researchers often observed questionable practices, such as selective outcome reporting (Bradley et al., 2017; Vassar et al., 2020), outcome switching (Hildenbrand et al., 2019; Stoll et al., 2020), and unclear or incomplete registration (Cybulski et al., 2016). As a feasibility pilot for my PhD project on registration practices for mindfulness-based interventions for depression, I did some detective work on other psychotherapies to test the feasibility, and here are some examples I personally witnessed:

  • Selective outcome reporting: Registering ten primary outcomes at the same time but only reporting four of them in the publication;

  • Outcome switching: Primary outcome and measure instrument remained the same, but the timeframe of the primary outcome changed from “post-treatment to follow-up” to “baseline to post-treatment” after the data collection completed;

  • Unclear or incomplete registration: The registeredinclusion criteria was “participants with depression”, but how to diagnose participant’s depression (e.g., SCID diagnosis; PHQ ≥ 10) was not defined.

What can be added into trial registration?
For trial registrations, I would say the first thing that could (and maybe should) be added is the compulsory registration of SAPs. Although already incorporated in many registries as an optional item, it is usually not uploaded in a lot of registrations as far as I have observed. Often researchers do prepare SAPs, but it may not be made public until a later stage and they are not easy to locate.

Secondly, a clinical trial involves numerous documents and materials that are important but not typically included in a registration. When researchers share these documents and materials outside of the registration context, it can be difficult for others to locate these files when reviewing the registration. Some registries have already incorporated the linkage between registrations and the respective publications. I think it is useful to allow registrations to link to other platforms such as OSF to enable the sharing of study protocol, treatment materials, deidentified data, analysis code, and more.

Apart from these two actions, one essential change requires a cultural shift. In my feeling, some psychotherapy trial researchers register their trials in a not too specific and precise way so that there is room to utilise their researcher degrees of freedom in case unexpected (but not rare) events occur, such as those illustrated in van Drimmelen et al. (2024). To be honest, this was an actual instruction given to a clinical psychology researcher I know by their supervisors. While this might seem pragmatic to leave room for flexibility, it’s not desirable from a methodological and ethical standpoint. While this may seem pragmatic, after all unexpected events often happening during trials, it undermines transparency when key decisions are left vague or adjusted without clear documentation. For instance, a trial might register “depression severity” as a primary outcome but leave out the specific measurement tool or timeframe, which later allows researchers to choose whichever measure or timepoint shows the most favourable result. This kind of vagueness gives room for flexibility, but in practice, it can blur the line between planned and exploratory analyses. Flexibility is not inherently wrong, but it should be explicitly acknowledged and documented, rather than implicitly “exploited.”

Conclusion
In sum, while both preregistration and clinical trial registration aim to promote transparency, their origins, practices, and enforcement differ. Psychotherapy research, situated at the intersection of clinical and social sciences, stands to benefit from adopting the strengths of both traditions. Improving registration practices, through clearer reporting, stronger cultural norms, and better infrastructure, will be essential for fostering more credible and reproducible evidence in the field.

Disclaimer: This piece includes language and editorial suggestions generated with the assistance of ChatGPT (OpenAI), which was used to improve clarity, structure, and grammar. The content, ideas, and interpretations expressed remain my own and reflect my personal academic understanding and analysis.

References

 Al-Durra, M., Nolan, R. P., Seto, E., & Cafazzo, J. A. (2020). Prospective registration and reporting of trial number in randomised clinical trials: global cross sectional study of the adoption of ICMJE and Declaration of Helsinki recommendations. BMJ, 369, m982. https://doi.org/10.1136/bmj.m982

Bradley, H. A., Rucklidge, J. J., & Mulder, R. T. (2017). A systematic review of trial registration and selective outcome reporting in psychotherapy randomized controlled trials. Acta Psychiatrica Scandinavica, 135(1), 65–77. https://doi.org/10.1111/acps.12647

Cybulski, L., Mayo-Wilson, E., & Grant, S. (2016). Improving transparency and reproducibility through registration: The status of intervention trials published in clinical psychology journals. Journal of Consulting and Clinical Psychology, 84(9), 753–767. https://doi.org/10.1037/ccp0000115

Dal-Ré, R., Ross, J. S., & Marušić, A. (2016). Compliance with prospective trial registration guidance remained low in high-impact journals and has implications for primary end point reporting. Journal of Clinical Epidemiology, 75, 100–107. https://doi.org/10.1016/j.jclinepi.2016.01.017

De Angelis, C., Drazen, J. M., Frizelle, F. A., Haug, C., Hoey, J., Horton, R., Kotzin, S., Laine, C., Marusic, A., Overbeke, A. J. P. M., Schroeder, T. V, Sox, H. C. H. C., & Van Der Weyden, M. B. (2004). Clinical Trial Registration: A Statement from the International Committee of Medical Journal Editors. The Lancet, 141(6), 477–478. https://doi.org/10.7326/0003-4819-141-6-200409210-00109

Gopal, A. D., Wallach, J. D., Aminawung, J. A., Gonsalves, G., Dal-Ré, R., Miller, J. E., & Ross, J. S. (2018). Adherence to the International Committee of Medical Journal Editors’ (ICMJE) prospective registration policy and implications for outcome integrity: a cross-sectional analysis of trials published in high-impact specialty society journals. Trials, 19(1), 448. https://doi.org/10.1186/s13063-018-2825-y

Hildenbrand, A. K., Conour, C., Straus, J. A., Moufarrej, S., & Palermo, T. M. (2019). Trial Registration and Outcome Reporting in Child and Pediatric Psychology: A Systematic Review. Journal of Pediatric Psychology, 44(9), 1024–1033. https://doi.org/10.1093/jpepsy/jsz054

Scott, A., Rucklidge, J. J., & Mulder, R. T. (2015). Is Mandatory Prospective Trial Registration Working to Prevent Publication of Unregistered Trials and Selective Outcome Reporting? An Observational Study of Five Psychiatry Journals That Mandate Prospective Clinical Trial Registration. PLoS ONE, 10(8), e0133718. https://doi.org/10.1371/journal.pone.0133718

Stoll, M., Mancini, A., Hubenschmid, L., Dreimüller, N., König, J., Cuijpers, P., Barth, J., & Lieb, K. (2020). Discrepancies from registered protocols and spin occurred frequently in randomized psychotherapy trials—A meta-epidemiologic study. Journal of Clinical Epidemiology, 128, 49–56. https://doi.org/10.1016/j.jclinepi.2020.08.013

van Drimmelen, T., Slagboom, M. N., Reis, R., Bouter, L. M., & van der Steen, J. T. (2024). Decisions, Decisions, Decisions: An Ethnographic Study of Researcher Discretion in Practice. Science and Engineering Ethics, 30(6), 59. https://doi.org/10.1007/s11948-024-00481-5

Vassar, M., Roberts, W., Cooper, C. M., Wayant, C., & Bibens, M. (2020). Evaluation of selective outcome reporting and trial registration practices among addiction clinical trials. Addiction, 115(6), 1172–1179. https://doi.org/10.1111/add.14902