"Take up to eight tablets per day": Incorporating free-text medication instructions into a transparent and reproducible process for preparing drug exposure data for pharmacoepidemiology

Purpose: Routinely collected prescription data provides drug exposure information for pharmacoepidemiology, informing start/stop dates and dosage. Prescribing information includes structured data and unstructured free-text instructions which can include inherent variability, such as “one to two tablets up to four times a day”. Preparing drug exposure data from raw prescriptions to a research ready dataset is rarely fully reported, yet assumptions have considerable implications for pharmacoepidemiology. This may have bigger consequences for “pro re nata” (PRN) drugs. Our aim was, using a worked example of opioids and fracture risk, to examine the impact of incorporating narrative prescribing instructions and subsequent drug preparation assumptions on adverse event rates.
Methods: R-packages for extracting free-text medication prescription instructions in a structured form (doseminer) and an algorithm for transparently processing drug exposure information (drugprepr) were developed. Clinical Practice Research Datalink GOLD was used to define a cohort of adult new opioid users without prior cancer. A retrospective cohort study was performed using data between 01/01/2017-31/07/2018. We tested the impact of varying drug preparation assumptions by estimating the risk of opioids on fracture risk using Cox proportional hazards models.
Results: During the study window, 60,394 patients were identified with 190,754 opioid prescriptions. Free-text prescribing instruction variability, where there was flexibility in the number of tablets to be administered, was present in 42% prescriptions. Variations in the decisions made during preparing raw data for analysis led to marked differences impacting the event number (n=303-415) and person years of drug exposure (5,619-9,832). The distribution of hazard ratios as a function of the decisions ranged from 2.71 (95% CI: 2.31, 3.18) to 3.24 (2.76, 3.82).
Conclusions: Assumptions made during the drug preparation process, especially for those with variability in prescription instructions, can impact results of subsequent risk estimates. The developed R packages can improve transparency related to drug preparation assumptions, in line with best practice advocated by international pharmacoepidemiology guidelines.