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| Journal of the New Zealand Medical Association,
12-August-2005, Vol 118 No 1220
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PHARMAC responds to Stewart Mann on dihydropyridine calcium
channel antagonists
Associate Professor Stewart Mann recently described changes
in PHARMAC’s funding of dihydropyridine calcium channel antagonists (DHP
CCBs) and resultant changes for patients over the past 5–10 years (http://www.nzma.org.nz/journal/118-1218/1569/).
We found the article to be a good summary of a complex issue.
We make the following observations:
PHARMAC’s processesPHARMAC’s legislative objective is “to secure
for eligible people in need of pharmaceuticals, the best health outcomes that
are reasonably achievable from pharmaceutical treatment and from within the
amount of funding provided.”1 Two of the ways in which PHARMAC achieves
this is by reference pricing and by negotiating sole supply contracts with
pharmaceutical suppliers. When managed appropriately,2 these strategies free up
funding to invest in other unsubsidised medicines, gaining additional clinical
benefit elsewhere.
Reference pricing and sole supply occurs only where it is
clear that a loss of choice between one equivalent brand of drug and another is
not considered critical. PHARMAC bases such decisions on available clinical
evidence; it is not part of PHARMAC’s Operating Policies and Procedures2
to conduct compliance and/or bio-equivalency testing. Before a medicine can be
marketed in New Zealand it must first meet the necessary standards set by the
Ministry of Health. As part of the registration process, the New Zealand
Medicines and Medical Devices Safety Authority (Medsafe) requires safety and
compliance testing of all medicines.
With every reference pricing initiative, PHARMAC seeks
independent expert clinical advice from PTAC,3 and consults (and is required to
consult) with relevant clinical and patient groups4–6 to ensure it has all
the information before making a decision. PHARMAC is always looking to improve
its processes, and although for practical reasons we may not have replied
individually to each consultation response we received, every response is (and
was) provided to and considered by PHARMAC’s Board before a decision is
made. This is an obligation that the PHARMAC Board takes extremely
seriously.
Reference pricingReference pricing is a commonly used strategy to control the
cost of multiple drugs within a drug class, and in New Zealand is based upon the
principle that reimbursement is set at the price of the least expensive
member(s) of a drug class. Reference pricing happens in a number of countries
including Germany, Canada, The Netherlands, France, Japan, Sweden, and
Australia,7,8 and has been used in New Zealand since PHARMAC’s inception
in 1993.
There is limited evidence on the impact of reference pricing
of DHP CCBs on health outcomes:
The putative lack of any significant
observable impact on blood pressure control in New Zealand may of course have
been more short-term due to increased awareness and medical monitoring
(Hawthorne effect) than the change to the newly subsidised DHPs themselves, and
there was no evidence that such improvements would be maintained long-term with
just routine management of blood pressure. Nevertheless, there was no evidence
that changing to the newly subsidised DHPs caused deterioration across users, at
least short term in the context of more intensive dedicated monitoring.
Although the British Columbian data are less than ideal,
they are possibly the best available under the circumstances.†
As noted by Associate Professor Mann, PHARMAC put in place
Special Authority provisions to allow fully funded access to alternative DHP
CCBs based on advice from PTAC’s Cardiovascular Subcommittee and the
Cardiac Society.
While we acknowledge arguments around patient inconvenience
and resistance to change, these must be considered against the
alternative—that when funds are constrained, tradeoffs must be made, so
that patients elsewhere in the health sector are less likely to have to pay for
their own treatment, or simply miss out.
BioequivalenceIt is important to note that Adalat CC (coat core) was
assessed and approved by Medsafe, the Medicines Regulator, as a new medicine on
the basis of clinical trial and other data supplied by the sponsor of the
product in New Zealand. Medsafe has advised PHARMAC that it did not consider
Adalat CC to be either bioequivalent to, or interchangeable with, Adalat Oros
(Medsafe, personal communication).
When it was considering a submission by the supplier
(separate to the application for Medsafe registration), the Cardiovascular
Subcommittee of PTAC noted that several pharmacokinetic parameters of the CC
product differed from those seen for Adalat Oros. The subcommittee also raised
questions about whether these differences would impact on patient well being if
patients were changed from other formulations of Adalat to the CC formulation.
The subcommittee took advice on this issue from both the Cardiac Society and
Associate Professor Richard Robson (who is the current Chair of Medsafe’s
Medicines Assessment Advisory Committee (MAAC)) before making a recommendation
on funding within this therapeutic group.
The Cardiovascular Subcommittee also took into account
several other factors including dropout rates and adverse effects in the CC
groups versus the Oros groups, the overall blood pressure control in the Glasser
et al study,13,14 and also the fact that the CC preparation was unlikely to gain
registration in New Zealand for the angina indication.
Medsafe advises that Adalat CC and Adalat Oros utilise
distinct dose release systems and are designed to have different release
characteristics. This is not the case for Felo and Plendil, where both were
designed to be taken once daily and were amenable to standard bioequivalence
testing. While MAAC’s Generic Subcommittee (GSC) did note and discuss
differences in the bioequivalence studies conducted to demonstrate that Felo and
Plendil were bioequivalent, these issues were resolved as more data were
provided. Medsafe is of the opinion that it is inappropriate to link the issues
of the differences in pharmacokinetics between Adalat CC and Adalat Oros with
those noted and discussed by the GSC with respect to Felo and Plendil (Medsafe,
personal communication12).
Generic changesGeneric substitution of brands of the same active ingredient
(such as Felo ER for Plendil ER) is a very regular occurrence internationally,
with it being common place in counties such as Hungary, Canada, Italy, Germany,
the United Kingdom and Australia. Furthermore, in many of these countries the
patient is potentially switched (again and again) every time they go back to the
pharmacy. Some countries, for example Denmark, have mandatory substitution at
pharmacy level. This is accepted in those countries because of the regulatory
requirement that bioequivalence is to be shown before a generic can be marketed.
The regulatory requirements in New Zealand are no
different—bioequivalence must be demonstrated. As well, the guidelines for
showing equivalence used in New Zealand are based on the guidelines used
internationally.15 Generic medicines are also required to meet the same quality
and manufacturing standards as all manufacturers of branded medicines; this
makes it difficult to compare them to used cars.
CommentIt is not uncommon for a greater than usual number of people
to report adverse events when reference pricing, or a brand change through the
tender, occurs. We understand from Medsafe that usually there is a
“spike” in reports to Medsafe’s Medicines Adverse Reactions
Committee (MARC), which then quickly returns to a normal level. It is difficult
to ascertain the exact reason for this phenomenon, or indeed how many additional
patients are able to take the ‘new’ medicine when they were unable
to tolerate the previously subsidised one. The same “spike” can
occur when there is no change to a drug other than the name—for example as
occurred with simvastatin’s brand name changing from
‘Zocor®’ to ‘Lipex®’ (Medsafe, personal
communication16).
Reference pricing and generic substitution are methods that
are accepted in many countries as a clinically acceptable way of managing
pharmaceutical expenditure. PHARMAC is careful to consult with interested
parties and take clinical advice before undertaking reference pricing, and hopes
to maintain a constructive line of communication with the medical community. To
deem these processes “experiments” is comparable to calling every
prescription a doctor writes an experiment, as none of us know with absolute
certainty how a particular patient is going to react to a particular drug.
Provided we are all aware of the risks and benefits generally associated with a
particular treatment as they are highlighted in clinical studies, we can manage
changes in medication both from a funding and clinical perspective.
Remember too that all on-patent medicines are sole supply.
PHARMAC considers that tendering for off-patent medicines is an effective way to
secure the supply of pharmaceutical agents and to achieve lower prices for
generic medicines. Reference pricing frees up funding from the pharmaceutical
budget that can then be reinvested into other priority areas. In this sense,
reference pricing has a positive effect on health outcomes, as it allows PHARMAC
to invest in new medicines that either extend or improve the quality of life
that otherwise would not happen.
Footnotes:
*The analysis was careful to caveat that evaluators had
no control over experimental design or data collection, and that the reliability
and the validity of the raw data (which had not been collected in a controlled
research environment) could not be assessed – particularly the accuracy of
the blood pressure recordings. It was stated that deficiencies in claim form
design, lack of standardised protocols for blood pressure measurement, and some
inconsistencies in interpretation of claim form items meant that these results
must be reported cautiously.
†To clearly determine whether there were
excessive risks from switching associated with reference pricing would require a
very large randomised controlled trial (to control for confounding and other
bias), for what is likely to be small difference between the drugs. Such studies
would be unlikely to be feasible/affordable, particularly in New Zealand.
Otherwise there are ongoing issues of comparability (differences in measurement,
different patient populations, selection bias, measurement bias etc.). The only
alternative would be to allow the original supplier’s patented monopoly to
remain in perpetuity.
Conflict of
interest: Scott Metcalfe is externally contracted to work with PHARMAC
for public health advice. Andrew Davies, Wayne McNee and Peter Moodie declare no
conflicts.
Andrew Davies
Hospital Pharmaceutical Contracts Manager PHARMAC Wellington Scott Metcalfe
Public Health Physician Wellington Peter Moodie
Medical Director PHARMAC Wellington Wayne McNee
Chief Executive PHARMAC Wellington References:
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