Innovative drugs will bypass NICE approval process to build cost effective dataBMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b2887 (Published 15 July 2009) Cite this as: BMJ 2009;339:b2887
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We understand that the UK government, with NICE, will introduce an
“Innovation Pass”, making selected drugs available across the NHS for a
set period to provide data for cost-effectiveness analyses. Apparently,
the main goal of this initiative is economic and not medical; to support
the British life sciences industry.1 However, it is explicitly stated that
the creation of the “Innovation Pass” should give patients faster access
to ‘cutting-edge’ medicines. It was already replied that unless it has
been established that a treatment has at least some beneficial effects,
there is no basis to reliably estimate an intervention’s cost
effectiveness.2 Safety should be guaranteed and efficacy should, wherever
possible, be based on RCTs. We would like to share with you some
reflections on this initiative in the hope it would not only lead to a
stronger economy but also to better and more affordable health care.
Gathering the required data to be able to calculate an intervention’s
cost effectiveness, such as information on quality of life (QoL), is the
initial responsibility of the company marketing the intervention. Patient-
relevant endpoints, including generic QoL measurements needed for economic
evaluations, should be included in phase III studies. The company knows it
will need these data to be able to calculate the intervention’s cost
effectiveness and should take the responsibility to gather these data
correctly and in due time.
If one of the main interests is improving health care in a
sustainable health care system, than the role of UK government (and
decision makers in other countries) could/should go further and provide a
research design for gathering evidence on possibly better treatment
regimens. Ideally, this should happen at the moment of phase III trials.
However, when this did not happen and if Health Technology Assessment
(HTA) agencies consider this of importance, adding an active treatment arm
to the industry-proposed treatment regimen should be demanded in a field
One of ‘cutting-edge’ medicines to illustrate this is trastuzumab
(Herceptin®). For this relatively expensive drug, which normally is
administered during a full year, the results of the FinHer trial (n=231),
in which trastuzumab was administered for 9 weeks only, were excellent
news for patients and governments, pending study confirmation.3 A reversed
-order trastuzumab treatment regimen similar to the one used in FinHer had
also been explored in the E2198 phase II study, where a regimen with 10
weeks of trastuzumab was compared with the same regimen plus an additional
year of trastuzumab. Despite its small sample size, the 5-year overall
survival rates of this head to head comparison in 234 patients were
respectively 88% and 83% (p = 0.29) and suggest there may be no advantage
for a prolonged trastuzumab administration.4 Researchers and industry
remained silent about these results and a treatment arm with shorter
treatment duration was not included in any of the industry-sponsored phase
III trials. Nevertheless, this shorter and reversed-order treatment
regimen is very promising for several reasons. Taking into account the
full length of treatment (i.e. inclusive surgery, radiotherapy and
chemotherapy), the current trastuzumab regimen has a total treatment
duration of more than 600 days versus less than 200 days for FinHer and
twice as much day-care stays.5 This improves QoL of treated patients and
requires less resources. From an economic perspective, the cost
effectiveness of the shorter treatment regimen is much better and its
budget impact lower,5 6 releasing resources for reimbursement of other
‘cutting-edge’ treatments. Cost savings were even possible due to the
combination of the cheaper short treatment regimen and the prevention of
expensive metastatic cancer treatment.6 In addition, there are indications
that more women, especially those with a borderline cardiac function,
could be treated safely, as cardiotoxicity seems to be a lesser problem
with the short duration therapy.5 Unfortunately, at that time, both
treatment regimens were not compared towards each other in a single phase
III trial as industry had no interest in doing so.
Based on this example, the initiative may offer an opportunity in
performing further research towards the optimal treatment regimen for
several drugs. With a good underlying research design gathering
information on patient-relevant outcomes, the guided introduction of the
expensive cutting-edge medicine could make a full HTA possible and provide
evidence on the intervention’s cost-effectiveness under the alternative
treatment regimen. In some cases, cost savings would even be possible
without reducing effectiveness. That would be innovation at the interest
of patients and also governments!
1. Cohen D. Innovative drugs will bypass NICE approval process to
build cost effective data. BMJ 2009;339:b2887.
2. Cohen D. Academics criticise plan to allow new drugs to bypass NICE.
3. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, Alanko T, Kataja V, Asola
R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab
for breast cancer. N Engl J Med 2006;354(8):809-20.
4. Sledge G, O'Neill A, Thor A, Kahanic S, Zander P, Davidson N. Adjuvant
trastuzumab: long-term results of E2198 (Poster 2075). SABCS Breast Cancer
Research and Treatment. December 2006;100, Supplement 1(Special issue,
29th Annual San Antonio Breast Cancer Symposium):S106.
5. Huybrechts M, Hulstaert F, Neyt M, Vrijens F, Ramaekers D. Trastuzumab
in early stage breast cancer. Health Technology Assessment (HTA).
Brussels: Belgian Health Care Knowledge Centre (KCE), 2006:KCE reports
6. Neyt M, Huybrechts M, Hulstaert F, Vrijens F, Ramaekers D. Trastuzumab
in early stage breast cancer: a cost-effectiveness analysis for Belgium.
Health Policy 2008;87(2):146-59.
Competing interests: No competing interests
With the introduction of an innovation pass, innovativeness will need to be carefully defined.
An innovative medicinal product has been defined as ‘a completely or partially new active substance or biological entity, or [a] combination of such entities, acting against a disease, relieving symptoms, or preventing a disease through pharmacological or molecular mechanisms, and developed and made available as a medicinal product that can improve the quality of patient management and outcomes.’1 A codicil to this definition states that it can include new indications, new technological and manufacturing processes, new formulations (including combinations), and new delivery systems of known drugs.
In drug development there are five broad areas in which innovativeness might be claimed: structural, pharmaceutical, pharmacokinetic, pharmacological or pharmacodynamic, and clinical.2
- Structural A novel chemical structure is not sufficient to make a compound innovative. The antihistamines (H1 receptor antagonists) have many disparate structures, but only the first was pharmacologically innovative. Structural novelty may provide a route to other forms of innovativeness, but not necessarily.
- Pharmaceutical A formulation that confers a new clinical advantage can be innovative. A nasal formulation of insulin would be innovative, provided that it was as clinically effective as insulin given subcutaneously. In this case it is the medicinal product rather than the compound itself that is innovative.
- Pharmacokinetic A compound whose pharmacokinetic properties confer a new clinical advantage can be innovative. Benorylate delivered paracetamol and aspirin by an innovative pharmacokinetic mechanism, reducing adverse effects, although it did not offer pharmacological innovativeness.
- Pharmacodynamic A compound whose pharmacological target is new and whose clinical effects are beneficial is potentially innovative. Cimetidine was innovative—it was the first clinically useful H2 histamine receptor antagonist. Lack of adverse pharmacological actions can also confer innovativeness. Ranitidine, which followed cimetidine, was not mechanistically innovative but it lacked some of the adverse effects of cimetidine.
- Clinical The most important form of innovativeness is clinical innovativeness, since it is the end result that really matters. Clinical innovativeness is possessed by a medicinal product that produces significantly more benefit than its predecessors and/or significantly fewer adverse effects (including drug–drug interactions), resulting in a better benefit to harm balance at an affordable cost.
We should be prepared for a great deal of debate about what really constitutes innovativeness in drug development. In doing so we should not lose sight of cost-effectiveness.
1. Erice Group. Erice Statement on Drug Innovation. Br J Clin Pharmacol 2008;65(3):440-1.
2. Aronson JK. Something new every day: defining innovation and innovativeness in drug therapy. J Ambul Care Manage 2008;31(1):65-8.
JKA is President of the British Pharmacological Society and a member of one of NICE's technology appraisal committees.
Competing interests: No competing interests