We keep hearing that for patient report outcome (PRO) including patient diary data, there is no query or data clarification required and the diary data is source data and can not be queried. For example, in a paper titled “How to clean up dirty data in Patient reported outcomes”, it said “The investigator is not allowed to query any of the patient's answers which leads in general to a lot of dirty data.”. Is it true that the diary or patient reported outcome can not be queried at any circumstance no matter how horrible the data quality is? It is not true and this popular perception is just not true.
Data clarification or data query is an essential process in clinical data management to ensure that the questionable data are corrected. According to EMA reflection paper ON EXPECTATIONS FOR ELECTRONIC SOURCE DOCUMENTS USED IN CLINICAL TRIALS, “Data clarification is part of the process to ensure complete data and the clarification process is one of the processes underlining the need for the maintenance of the audit trail.”
In a clinical study with paper-based case report form, the data clarification is typically issued by the data managers to the investigation sites. The investigator then reviews the issues to provide the responses to the data query. Data managers or clinical monitors can not directly make the changes to the data without issuing query and getting approval from the investigation site. In a clinical study with electronic data capture (EDC), the data clarification/query process is built into the EDC system. The data is entered at the investigation site. The query is issued by data managers or study monitors within EDC system. The investigator will then provide the responses to the query also within EDC system and make the data corrections.
The process becomes vague for patient reported outcome (PRO) or patient diary (no matter it is on the paper or electronic). The key difference for PRO data is that the data is directly recorded or entered by the subject or patient. There is a perception that no matter how poorly the data is, there is no data clarification or query process for PRO data or diary data.
In many clinical trials, the study endpoints rely on the collection of the information provided by the patient (daily symptoms, daily activities, quality of life,…). For example, for clinical studies on urinary incontinence, the primary efficacy endpoint may be the frequency of urinary incontinence episodes (UIE) per week as determined from patient daily diary. For clinical studies on female sexual dysfunction, the clinical endpoint may be the sexual events or encounters recorded daily by the study subjects using diaries. .
I used to work on a clinical trial with irritable bowel syndrome indication where the study endpoints were collected by a touch-tone telephone system (IVR – interactive voice response system). Efficacy parameters were symptom relief, abdominal discomfort or pain, bloating, stool frequency, stool consistency, straining and urgency recorded through IVR on daily basis by the study subjects. For stool frequency, the subject were asked “how many bowel movements did you have today?” As a statistician, I had to check the outliers before analyzing the data. I found some entries with the number of bowel movements being extremely high (55, 66). When I discussed these impossible numbers with the study manager, I was told that patient diary could not be queried. I pointed out that if these obvious data errors could not be corrected, the study data would be severely compromised. Later, we identified many more entries with duplicate numbers (such as 11, 22, 33, 44, 55, 66). After inquiring to the study subjects, it was found that the subject pressed the telephone number key twice for 1, 2, 3, 4, 5, and 6. This is just an example showing that the diary data could be easily recorded wrongly in the database and the query for accuracy is necessary.
FDA’s guidance on “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims” touched on ensuring the quality of PRO data. In discussion about the ePRO, FDA guidance indicated the concern about clinical investigator inability to maintain and confirm electronic PRO data accuracy. It said “the data maintained by the clinical investigator should include an audit trail to capture any changes made to the electronic PRO data at any point in time after it leaves the patient’s electronic device.” Furthermore, the guidance indicated the concern about ability of any entity other than the investigator (and/or site staff designated by the investigator) to modify the source data”. These statements inexplicitly imply that the diary data can be queried and modified by the clinical investigator (and/or site staff designated by the investigator) and the clinical investigator has responsibility to ensure the completeness and accuracy of the diary data.