Claims Data Analysis of Tumor Necrosis Factor Inhibitor Treatment Dosing Among Patients with Rheumatoid Arthritis: A Systematic Review of Methods

Switching of therapy influences persistence because it often terminates the current treatment. Available studies explored either switching or they attempted to analyze characteristics of subgroups of people who switched drugs [11]. A switch is defined as a change between certain medications. Some studies defined a maximum time frame of various lengths between the last prescriptions of the former drug and the prescription of the new drug. The switch needs to take place within that frame, otherwise the therapy is considered to be terminated. Some studies also indicated if they had ensured the discontinuation of the former drug to avoid confusing co-medication with switching. The various definitions applied are shown in Table 2.

The termination of the previous therapy was assured in five studies [8, 9, 12‐14]. Most studies did not make any statement regarding termination of previous therapy. A maximum time frame was rarely specified. The length of this period mostly depends on the days of supply (DOS)¹ of the last prescription of the former medication plus an additional period of 30 or 90 days [9, 13, 15]. In one case, a time frame of 200 % of the prescribed index-DOS was chosen instead [16]. In contrast, in four cases, a time frame was not required [17‐20]. It should be noted that most studies did not indicate whether or not a time frame was implemented.

A therapy is terminated either if a switch to another medication occurs or the time frame, meaning the gap between two prescriptions, gets too large. Table 3 lists the allowable switches between medications and which time frames were accepted for the assumption of persistency. With the exception of Curkendall et al., who evaluated persistence for several drugs simultaneously, no other authors explicitly allowed a switch in medication [21]. The accepted gap between two prescriptions mostly depends on DOS or the expected dosing intervals plus a further period of 30–90 days. Expectations are usually drawn from the therapy recommendations. In contrast, a fixed maximum period was defined in six studies [8, 19, 20, 22‐24].

Adherence is sometimes difficult to evaluate in claims datasets because most TNF inhibitors are injected by the patients themselves, and thus detailed information is missing in the database. This is not the case with IFX, which is by intravenous (i.v.) application in a clinical setting. Therefore, this is registered in the claims data. In either case, it can be observed whether the prescriptions are refilled within DOS-supplied or within recommended intervals. Thus, the fraction of days with medication on hand can be determined, which is fundamental for the calculation of measures of adherence.

For the most part, adherence was examined with ratios such as the medication possession ratio (MPR) [2, 12, 21, 22, 25‐28], the proportion of days covered (PDC) [13, 22, 23, 28, 29], or the compliance ratios of Harley et al. or Tkacz et al. [30, 31]. In contrast to the MPR, which equals the sum of DOS divided by the treatment period, the PDC considers the days with DOS available to the patient by taking the storability of drugs into account.

The MPR was calculated for fixed [2, 25] or variable follow-ups [12, 21, 22] withwhere \(T_{\text{f}}\) indicates the follow-up. Variable follow-ups depend on individual treatment periods. The treatment usually starts with the index date, the date of the first prescription and ends with the end of study period or with the termination of the treatment, whereas fixed follow-ups are the same for all patients. In that case, the length of the follow-up is specified ex ante. Only patients who are persistent within that period are analyzed. With fixed follow-ups, the end of the follow-up can be exceeded by DOS_L, which is the DOS of the last prescription. That happens when the study period ends before the DOS of the last prescription are used. Therefore, Borah et al. truncated the exceeding DOS to avoid overestimating adherence [2]. In the case of variable follow-ups, the follow-up either ends with the last prescription plus DOS_L, when all DOS are used, or at the date of the last prescription. The former was usually performed, whereas the latter was used by Grijalva et al., who excluded the exceeding DOS_L from the MPR calculation according to [12]:where \(T\) indicates the whole study period.

All MPRs can get larger than 1 if more prescriptions are filled than are needed. In such cases, Tkacz et al. normalized the MPR to 1 [22]. This is not necessary with the PDC because it avoids double counting the days where daily doses are on hand [13]. In five studies, PDCs are reported [13, 22, 23, 28, 29]. Thereof, two studies lacked a precise definition of the PDC calculation. Thus, their methods are not described here [22, 29]. Li et al. [13] gave a very precise description of the PDC. Their method is shown in Figs. 2 and 3. In the case of the subcutaneous (s.c.) application of TNF inhibitors by the patient, the provided syringes are storable (Fig. 2). Therefore, DOS of prescription V ₁ exceeding the date of the next prescription V ₂ can be added to the DOS of prescription V ₂. In contrast, IFX is administered in a clinical setting. Therefore, DOS exceeding the next prescription are not storable (Fig. 3) and premature administration of i.v. drugs does not extend the next expected prescription interval. That is why Li et al. [13] used different procedures for calculating the days with drugs on hand for s.c. and i.v. TNF inhibitors, respectively. Because of the storability of s.c. drugs, the remaining DOS from a previous prescription are added to the following DOS, plus the day of the new prescription, for which adherence can be assumed (Fig. 2). DOS of i.v. and s.c. drugs exceeding the end of the study are excluded. The remaining gap equals the days without medication on hand [7]. Curtis et al. and Bonafede et al. used a similar technique, where they limited the added period in s.c. TNF treatment to a maximum of 14 days [23, 28]. Finally, they calculated the PDC for s.c. and i.v. drugs by dividing the days with medication on hand by the time of follow-up [13].

Another measure of adherence is the compliance ratio, used by Harley et al., as well as by Tkacz et al., for injections and infusions alike. It is the ratio between the number of actual and expected prescriptions within a period [30, 31]. It can be larger than 1 if more prescriptions are filled than what was expected.

Although the reported measures of adherence are continuous, it is frequently reported as a binary variable [2, 13, 22, 23, 28‐30]. To this end, a threshold for ratios, for example of 80 %, is specified, beyond which a patient is considered to be adherent [2, 13, 23, 25, 28‐30]. In one study, adherence is not defined as a continuous measure, although the MPR and the PDC are reported. Instead, the authors defined a new prescription as adherent if it is filled within 21–38 days after the previous one [22]. Similarly, Curtis et al. defined i.v. therapy as adherent if the number of infusions at least equals the expectations [25‐28].

Tkacz et al. also used other novel measures of adherence for infusions based on infusion gaps above expectations and on the number of infusions because DOS were not available for these agents [31]. They accumulated treatment gaps, which are defined as the difference between observed and expected infusion intervals. These gaps were categorized as those that are at least 20 % above expectation on those that do not increase expectation by any amount. They also identified variations in adherence by observing the occurrence of different predefined categories of gaps within a treatment period. Another measure of adherence was defined as the number of infusions in 1 year with gaps of at least 10 % above the expected interval [31].

The deviation between the last dose and its reference is used for i.v. and s.c. drugs. The variations within this category and the associated studies are shown in Table 4. As references, the index and the maintenance dose were used. The maintenance dose is employed for IFX-naïve patients because of the recommended loading period. However, with s.c. drugs without a loading period or with experienced IFX patients, the index dose was used [3, 36]. Nevertheless, three studies used the index dose for IFX-naïve patients as well [11, 30, 43]. In most cases, any change in the last dose compared with its reference was sufficient to define a changed dose. Harrison et al. as well as Blume et al. required an increase over 10 % for dose escalation [35, 44]. For IFX and GLM, an increase of the last dose compared with the index dose of at least 100 mg/application and 25 mg/week were required in four [25‐28] and three studies, respectively [25, 26, 28].

The definitions used for any dose compared with its reference over the follow-up are shown in Table 5. In such a way, the index, maintenance, recommended, or previous doses were used. These reference doses were applied to s.c. injections and infusions alike. In 19 records, any increase or decrease of a prescription was defined as a dosage change. In other studies, various minimum thresholds were defined. These thresholds ranged from 10 to 100 %. Furthermore, some methods require these changes in at least two consecutive observations [10, 17, 33, 44, 37].

In four studies, no reference for dosage analyses of ADA and ETN was used [25‐28]. These studies are shown in Table 6. Here, a weekly prescription dose of at least 40 mg ADA or 100 mg ETN was sufficient for dose escalation.

As opposed to s.c. agents, daily doses are difficult to calculate with IFX, because for infusions, DOS are not given in the claims data and appropriate IFX dosage is dependent on the patient’s weight [16, 45]. Therefore, a supplementary definition of dose increase with IFX is often defined with reduced prescription intervals [35, 34, 39, 46] or an increased number of infusions within a certain period [17, 25‐28, 38] as depicted in Table 7. Sometimes, this increase must be observed in at least two occasions [17, 38, 46]. For example, Curtis et al. considered a prescription quantity of more than 120 % of that which was expected as an increase in dose [25‐28]. In other cases, reductions in the recommended infusions period of 8 weeks [45] to either fewer than 6 or fewer than 7 weeks was defined as an increase in dose [34, 46, 39].

Wu et al. are the only individuals who defined reduced doses within this class of methods [34]. They also applied a particularly complex method to patients who did not start with the recommended dose [34]. The authors defined a change in dosage in ADA and ETN therapies from the healthcare provider’s point of view. They assigned the mean doses of the treatment of naïve patients into four dosage categories. Mean doses were calculated differently according to the prescription gaps. If gaps were small or negative, the DOS given in the prescriptions were taken as the denominator. Otherwise, the prescription interval was used. Accordingly, the prescribed mean dose was used in the former case, whereas the real mean dose seemed more appropriate to the authors in the last case. The resulting dosage categories were applied to define a change in dose using the first stable dose as a reference. An increase or decrease in dose was defined as at least two switches to a higher or lower class, respectively. The first stable dose was defined as the second prescribed dose if the first and second doses were the same. If the second and third doses were equal, the third dose was defined as the first stable dose. Otherwise, the mean value of the first three prescribed doses was used. If fewer than three prescriptions were available, the index dose was used as the reference.

With this approach of calculating mean doses, all prescriptions within a certain period are taken into account (Table 8). The recommended, the index, or the maintenance dose is compared with the mean dose of all prescriptions of a specific period. If the index or maintenance dose is the reference, it was excluded from the calculation. Two exceptions are the studies of Zeidler et al. and Fisher et al. where the maintenance dose was included [4, 39]. Huang et al. determined the mean dose for each period between the index dose and every following prescription [41]. To identify a dose escalation, at least two of these mean values had to be greater than the index dose [41]. As in the previous methods, a certain threshold was defined in some studies to determine a changed dose.