In 2006, FDA issued a draft Guidance for Industry "Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims" This guidance describes how the FDA evaluates patient-reported outcome (PRO) instruments used as effectiveness endpoints in clinical trials. Here the patient-reported outcome is typically collected through subject diary. However, the use of subject diary to collect the information on efficacy is just one of many usages. Subject diary can also be used to collect the information about:
- Daily symptoms, dialy activities
- Safety assessment (such as adverse events, exacerbations)
- Usage of the study medication to measure the compliance
- Usage of the concomitant medication
- Disease episodes on daily basis
Diary does not have to be filled out on daily basis. There are studies using diary and the subjects write down in a diary each time they take the medication,
FDA guidance listed three reasons to collect the data reported by the subject:
- Some treatment effects are known only to the patient;
- There is a desire to know the patient perspective about the effectiveness of a treatment;
- Systematic assessment of the patient’s perspective may provide valuable information that can be lost when that perspective is filtered through a clinician’s evaluation of the patient’s response to clinical interview questions.
The drawback of the diary data is the reliability of the data or the quality of the data. Subject could lose the diaries, forget to complete them or forget to complete the diaries in real time, and in worse situation, falsify information. To ensure that subject diaries comply with GCP standards, the followings are critical (adapted from Good Clinical Practice: A Question & Anwer reference)
"At the beginning of a study, site staff should explain to each subject (or parent) the importance of the diary and how the subject should record data within it. Site staff should review the diary at each visit; deficiencies and attempts to correct these deficiencies should be noted in source records. Site staff must ensure that the diaries are returned at the time designated in the trial protocol. If a patient diary is not returned, the site should make several attempts to retrieve it. These attempts should be documented in the subject’s medical record.
Although clinical auditors and FDA inspectors recognize that diaries often pose a source documentation problem, they expect to see documented efforts to minimize these problems. Diaries that are too neat, all look the same, or have been rewritten by the study coordinator are sure to raise suspicious. "
Subject diary data is often subjected to the audit findings. For example, in one of FDA's warning letters, it cited the violation about subject diary data.
"Protocol (b)(4) specified that subjects were to be distributed patient daily diary cards every 4 weeks, beginning with Week 0, and ending on Week 53. Per the protocol, patients should only have received one set of diary cards for each four-week period. However, during its inspection, FDA discovered that your records contained multiple diary entries for the same subjects on the same dates. Furthermore, the information you reported to the CRF excluded some of the data from one or more sets of patient diaries. This is a violation of 21 CFR 312 .70.
Protocol (b)(4) specified that the study coordinator was to review the patient diary cards with the patient during each scheduled visit and, if possible, query the patient to obtain any missing information at the scheduled visit. Thus, patient diaries should have only contained dated entries for dates that occurred between two scheduled visits.
The daily diary cards included information concerning whether the subject took the doses of medication in the morning and the evening (diary question #1), whether any concomitant medications were taken (diary question #2), the name of the concomitant medication taken (diary question #3), usual daily activity interruptions due to (b)(4 ) pain (diary question #4), whether any medical facility was visited due to ( b) (4) pain (diary question #5), the name of the medical facility visited (diary question 7T6), and the daily pain level experienced on a scale of 0 to 10 (diary question #7). Per the protocol, information in patient diary cards was to be recorded onto the appropriate case report form (CRF).
FDA's audit identified that 2 of 12 subjects enrolled in the study, Subjects #003 and #0 10, had two sets of patient diaries which contained different information for the same dates . From our review of the two sets of patient diaries, we were unable to determine which diary provided the correct information. In addition, we note that the information reported to the CRF was either (1) obtained from one diary but not the other, or (2) could not be verified in our review of either version of the duplicate diaries' entries for specified dates. The discrepancies we observed included, but were not limited to, the following: ...."
In terms of the handling of the subject or patient diary data, there are many different ways depending on the diary technology and the purpose of the diary. Subject diary data could be directly transmitted to the data management group without review by the site investigator or study coordinator. The data clarification (query) process is omitted. For example, in a study with Irritable Bowel Symdrome, diary data collected through IVRS was directly transferred to teh data management group and biostatistics group for analysis. Subject diary data could also be collected by the site and reviewed by the site staff (investigator or study coordinator). In this situation, the subject diary is a tool to assist the site staff in evaluating the subject about the disease status, any significant event, drug compliance,... For example, the subject diary could used to collect the COPD exacerbation (subjects record the dialy symptoms, antibiotic use, steroid use,...). in this case, the subject diary should be periodically reviewed by the site staff.