One aspect of the revised PMPRB Guidelines implemented in 2010 that was welcomed by the branded pharmaceutical industry was the change to the levels of therapeutic improvement. Specifically, the old three category system was expanded to four distinct levels: Breakthrough (BT), Significant Improvement (SI), Moderate Improvement (MI) and Slight or No improvement (SLNO).
The creation of a separate Moderate Improvement level of therapeutic improvement, with its own potentially more generous price test and the opportunity to show improvement via either primary factors (efficacy, reduction in side effects) or secondary factors (caregiver/patient convenience, simplification of dosage regimens etc.), was also positively received by the pharma industry.
Now, slightly more than four years after the implementation of the revised Guidelines, is a good time to take a closer look at the impact of the Moderate Improvement (MI) designation and ask ourselves some interesting questions:
- Has the availability of the MI designation had an appreciable impact on the price reviews of new patient medicines in Canada?
- Specifically, what proportion of new medicines has received the MI designation?
- What is the breakdown between the MI designations based on primary factors and those based on secondary factors?
- Coupled with the PMPRB’s stated goal of increased transparency of its decisions, do we have a better understanding of which factors are most likely to lead to a MI designation?
How Often is the Moderate Improvement Designation Granted?
Based on an examination of all decisions from 2010 to 2012, inclusive, the MI designation is overwhelming the most commonly granted designation among the elevated therapeutic improvement designations (BT, SI and MI)). Of the 277 DINs that were classified in that period, 49 (18%) were found to provide an elevated level of therapeutic improvement, of which, 25 (14%) received the MI designation; 7 DINs (3%) were granted the SI level, and another 4 (1.5%) received the top BT level (Figures 1 and 2).
– Figure 1 –
– Figure 2 –
Looking only at those 33 drugs found to provide an elevated level of therapeutic improvement (Figure 2), the MI designation – at 76% – handily outnumbered the SI and BT designations (12% each).
Within the MI group of drugs, slightly more than half (55%, or 14/25 brands) of the designations were generated on secondary factors, while the remaining 45% (11/25 brands) were based on primary factors.
Which Attributes are More Likely to Lead to a Moderate Improvement Designation?
The easiest way to deal with this question is to look at the primary factors MIs (Mod-p) separately from the secondary factor MIs (Mod-s).
Moderate Improvement Based on Primary Factors (MOD-p):
At 6% of all DINs classified in the 2010 to 2012 period, the MOD-p designation (moderate improvement in efficacy and/or reduction in side effects) was the second most frequently granted improvement level, just behind the MOD-s designation. Figure 3 below breaks out my classification of the reasons why the designation was given.
– Figure 3 –
The fact that I found seven general categories of reasons in the MOD-p decisions is good news as it shows a fairly broad approach by the PMPRB to defining what may be considered moderate improvement on primary factors. I will leave a more detailed discussion of what appears to separate SI level drugs from MOD-p drugs to another posting. Suffice it to say that the types of reasons listed in Figure 3 already provide some clues: many highlight a shortcoming in clinical evidence, whether it is lack of an active comparator, the use of a surrogate measure or the failure to show significant results at all measured time intervals.
– Figure 4 –
Differences in the Levels of Clinical Evidence Between MOD-p and MOD-s Drugs
When we compare the relative strength of the clinical evidence submitted in support of MI-p designated drugs to MI-s drugs, not surprisingly, the MI-p drugs were on average backed by stronger clinical evidence: 82% of successful Mod-p drugs were backed by clinical evidence that would support a Grade A recommendation under the Oxford CEBM Grades of Recommendation, while MI-s drugs carried Grade A recommendation level evidence in 50% of cases. In addition, the majority of all MI designated brands (primary or secondary) were consistent with Grade B or better recommendations 76% of the time (91% for MI-p, and 64% for MI-s).
– Table 1 –
Importantly though, the absence of top-level clinical support did not preclude an MI-s designation. One brand received the designation on Grade C evidence, and 3 others did so on the basis of Grade D evidence (“level 5 or troublingly inconsistent or inconclusive studies of any level”). The Grade D evidence accepted consisted of unpublished expert opinion(s) submitted by the manufacturer (In one instance, the type of evidence was not specified).
What are the Key Takeaways About the Moderate Improvement Experience To Date?
- The vast majority (82%) of DINs evaluated by HDAP/PMPRB staff are still assessed as providing Slight or No Improvement.
- The MI designation (primary and secondary) is overwhelmingly the most frequently granted of the elevated therapeutic improvement designations: 14% of all DINs and 76% of elevated designation brands, versus Substantial Improvement (3% of all DINs and 12% elevated designations) and Breakthrough (1% of DINs and 12%, respectively).
- The MI ranking based on secondary factors is the most frequently granted of the elevated therapeutic improvement factors at 43% of all elevated designations; MI-primary follows at 39%.
- Those brands ranked as MI-primary do, on balance, have better clinical support than MI-secondary ranked brands, but 28% of all MI brands (primary and secondary) had Grade B or below equivalent clinical evidence; 3 MI-secondary rated brands succeeded on the basis of Grade D evidence (expert opinions).
- While orthodox reasons for MI through secondary factors like ‘more convenient format’ (50%) and ‘less complex and/or frequent dosing’ (21%) are the most frequently reported, HDAP/PMPRB has shown some flexibility in accepting other factors as the basis for moderate therapeutic improvement.
Brands launched with more than one DIN were only counted once. By eliminating multiple DINs, 49 DINs with MI or better ratings were reduced to 33 drug brands.