The importance of data integrity in rare diseases

Posted on: Thursday 22 February 2024
Author: Dr Tony Lockett

How to cite: Lockett, T. (2024), 'The importance of data integrity in rare diseases', 22/02/2024. Available at: [ADD LINK HERE]

This blog article has been prepared by Dr Tony Lockett.

The article presents the views of the authors and not necessarily those of the Faculty of Pharmaceutical Medicine.

Well, data integrity is important in all clinical development programs, is it not….

Clinical trials in rare diseases pose some challenges that are different to clinical trials that are performed in common diseases. Rare diseases are sometimes difficult to diagnose; the pathophysiology may not be completely understood and the disease may be heterogeneous. Populations are, by definition, small, and recruitment is a major barrier to getting the evidence needed to indicate benefit 1.

Given these challenges, establishing the dose early on in the development program is of key importance. Experience has shown that dose finding in rare disease requires that data from a wide variety of sources needs to be integrated. The data used to determine the dose in rare disease indications includes data from healthy volunteer studies, data from patients in the target population (collected most often during the conduct of clinical efficacy trials in the form of Phase II data and often interim in nature) and data from the use of the candidate molecule in indications other than the target indication. The data used in determining the dose in rare disease indications also often incorporates biomarker data, rather than direct evidence of clinical benefit 1. Data collected on registrations for rare oncology indications suggest that the dose was determined using a dose finding trial in up to 18% of market applications2. Many early phase trials in rare diseases are sponsored and run by academic or non-commercial sources. The early phase trials in rare diseases are increasingly expensive, making the management of scare resources also an imperative.

Given the diversity of information used, the small available populations, and the scarce resources involved, ensuring the highest standard to the methods used to collect the data becomes an imperative. Studies have indicated that the design and reporting of dose finding studies have been variable in quality3.

Ensuring that data reaches the highest standard starts with the protocol and ends with the reporting and publication. To maintain the standard of protocols the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) was established as the minimal essential content of protocols. While the considerations of SPIRIT are widely applicable, there are some instances where the contents of SPIRIT should be enlarged upon. A particular challenge has been in early stage dose finding trials – such as those seen in the development of treatments for rare diseases and cancers. Late in 2023, the first steps were taken to redress this deficit with the publication of the Dose Finding Extensions (DEFINE) to the SPIRIT protocols 4 4–6. The DEFINE extensions also have been applied to the reporting of early dose finding studies, with an extension to the Consolidated Standards of Reporting Trials (CONSORT) statement. Taken together the DEFINE-SPIRIT and DEFINE – CONSORT statements should improve the quality and success of clinical trials in rare diseases, and it is to be encouraged that journals adopt them in the publication of trial data.

Other gaps remain, however, in the reporting of pilot and feasibility studies that also provide the backbone of rare disease drug development. Calls to extend the SPRIT and CONSORT reporting statements to pilot and feasibility studies should be supported 7.


1. Wang, L. et al. Dose-finding studies in drug development for rare genetic diseases. Orphanet J. Rare Dis.17, 156 (2022).

2. Mitra, A., Lee, J. B., Steinbach, D., Hazra, A. & Krishna, R. Rare oncology therapeutics: review of clinical pharmacology package of drug approvals (2019–2023) by US FDA, best practices and recommendations. J. Pharmacokinet. Pharmacodyn. 50, 475–493 (2023).

3. Villacampa, G. et al. Assessing the reporting quality of early phase dose-finding trial protocols: a methodological review. eClinicalMedicine 60, 102020 (2023).

4. Yap, C. et al. Enhancing reporting quality and impact of early phase dose-finding clinical trials: CONSORT Dose-finding Extension (CONSORT-DEFINE) guidance. BMJ 383, e076387 (2023).

5. Solovyeva, O. et al. Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study. BMC Med. 21, 246 (2023).

6. Espinasse, A. et al. SPIRIT and CONSORT extensions for early phase dose-finding clinical trials: the DEFINE (DosE-FIndiNg Extensions) study protocol. BMJ Open 13, e068173 (2023).

7. Bond, C. et al. Pilot and feasibility studies: extending the conceptual framework. Pilot Feasibility Stud. 9, 24 (2023).