The second article provides an in-depth review of best practices for the least burdensome approach to selection, development, modification, and adaptation of patient-reported outcome instruments. 



The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to the patient-reported outcome instruments. The document provides additional clarifications and recommendations regarding the principles for selecting, developing, modifying, and adapting patient-reported outcome instruments to be used in medical device evaluation. It is also important to mention that provisions of the guidance are non-binding. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with existing legislation and has been agreed with the authority in advance. 


Measure Concepts Important to Patients 

As it was previously explained by the FDA, PRO instruments should be used to measure concepts that are important to patients. Moreover, focusing on the most important metrics would also allow reducing significantly the unneeded burden. Based on this, the manufacturers will be able to reflect all important aspects in labeling to ensure the devices are used safely and efficiently. Thus, the authority encourages the parties responsible for medical devices to engage patients at all the stages including the development or selection of the particular PRO instruments to be used. This will help to identify the aspects that are the most important for patients. 

Furthermore, the parties using PRO instruments should make sure they are understandable to patients. Under the general rule, patient-reported outcome instruments include such elements as instructions, items, recall period, and response options. The authority additionally emphasizes that the above should be expressed in a way making it easy for the patients to understand the information provided and to interpret it correctly, as this is important to ensure that the responses provided by the patients would be relevant and accurate. Apart from this, it is also important to ensure clarity in the benchmarks used. The wordings used in responses should be consistent so that the responses provided by the patients will be consistent as well. The authority also encourages the parties involved to conduct interviews before using the PRO instruments to discuss the key points with patients participating in a study and make sure they are correctly interpreting the information. Such interviews could be carried out with the use of tele- or video conferencing technologies. In case of any questions arising, the sponsors may also contact the relevant department of the authority within the scope of the Q-submission program. 

As it is mentioned in the guidance, it is recommended to offer PRO instruments not only in English but in other languages as well. This will help to expand the range of patients that could be involved in the process and make the results, in general, more reliable. The FDA states that adequate patient interpretation of the questionnaire items may help minimize missing data, improve the consistency of item interpretation, and potentially improve the data collected in the clinical study. 

The authority also emphasizes the importance of reducing the unnecessary burden for patients – this aspect should be duly considered when developing or selecting patient-reported outcome instruments to be used. 

PRO Instruments and Their Role

Another important aspect related to the use of PRO instruments is related to the role they should play in the study in general. According to the guidance, FDA determines the strength of evidence needed to support the measurement properties of a PRO instrument based on the role of the instrument specified in the clinical study protocol and statistical analysis plan. The appropriate information should be duly reflected in the clinical study protocol and the statistical analysis plan. In particular, it is necessary to indicate the specific role of the PRO instruments and also the endpoints to be covered. 

As it was mentioned before, the authority encourages study sponsors to interact with the Agency at all the stages of the Total Product Life Cycle. For instance, sponsors may contact the authority to decide on the applicability of the specific PRO instruments and respective benefit-risk analyses. When making references to the information collected when using PRO instruments, a sponsor should duly justify the use of patient-reported instruments and the importance of the aspects subject to evaluation in the context of benefit-risk analysis. 


Use of Existing PRO Instruments 

In most cases, clinical study sponsors prefer to choose the PRO instruments to be used from the existing ones instead of developing case-specific patient-reported outcome instruments. Thus, existing instruments could be either used as-is or modified and adapted to meet specific needs. Such a modification would anyway require fewer resources in comparison to the process of creating the new instruments. Based on the above, the authority encourages study sponsors to use existing PRO instruments when it is feasible. In case of modifications made to the patient-reported instruments before use, such modifications should be duly documented. Moreover, it would be beneficial to provide additional data to substantiate the use of such instruments and demonstrate the reliability of the results. The authority also mentions that some of the existing PRO instruments could become less effective due to the general technology development. Hence, each time deciding on the use of specific PRO instruments, it is important to assess their applicability in that specific case and in the context of the aspects to be evaluated.


Alternative Platforms and Parallel Development 

As it is mentioned by the authority, real-world evidence derived from multiple sources outside of the clinical research setting (such as electronic health records, claims, billing activities, product and disease registries, or health-monitoring devices) may be used to generate validity evidence for PRO instruments. The sponsors are encouraged to use alternative approaches to generate valid evidence for the patient-reported outcome instruments used. The Agency states that to use the resources more efficiently, the sponsors may consider developing PRO instruments in a way ensuring they could be used at different stages of medical device evaluation. 

The present FDA guidance outlines best practices to be considered by study sponsors when developing or selecting PRO instruments to be used. The authority pays special attention to the aspects that are important for ensuring the accuracy and reliability of results.



How Can RegDesk Help?

RegDesk is a next-generation web-based software for medical device and IVD companies. Our cutting-edge platform uses machine learning to provide regulatory intelligence, application preparation, submission, and approvals management globally. Our clients also have access to our network of over 4000 compliance experts worldwide to obtain verification on critical questions. Applications that normally take 6 months to prepare can now be prepared within 6 days using RegDesk Dash(TM). Global expansion has never been this simple.