Comparative efficacy should have a "formal role in drug licensing"
This article was originally published in Scrip
Comparative efficacy ought have a formal place in the drug approval process, argue experts writing in British Medical Journal on 7 September.
Pharmaceutical and biotech companies should be made to produce comparative efficacy data as a condition of marketing authorisations for new drugs, the researchers from the London School of Economics believe.
The comments, which add to the pressure on industry to produce comparative data earlier in the drug development process, were met with a lukewarm response from the industry. EFPIA's director general Richard Bergström insisted to Scrip that there was no need for regulators to go so far as to routinely require comparative trials for drug approvals.
The growing need for comparative effectiveness data to secure reimbursement is already making itself felt in industry, with this becoming a key criterion for go/no-go decisions during the pre-licensing drug development phase. An increasing number of development programmes are being cancelled by manufacturers because of the lack of ability to demonstrate unique effectiveness benefits rather than benefit-risk considerations. Expanding this requirement for drug approval will bring further changes to the way industry develops its drug candidates, and place a further burden on companies.
But while some experts have raised concerns that comparative effectiveness research will stymie progress in personalised medicine, others say that conversely it could be a boost for it, with the added benefit of developing drugs with proven added value for subsets of patients.
At the moment head-to-head comparisons are only needed for approval when the use of a placebo is deemed unethical. This means that comparative efficacy data are only available for between 50 and 70% of new molecular entities at time of approval, and this varies across therapeutic areas. Moreover, only a fraction of this evidence is actually accessible at the time of market authorisation.
According to the researchers led by Corrina Sorenson from the London School of Economics and the European Observatory on Health Systems and Policies, the lack of comparative efficacy data at the time of product launch means that patients, clinicians, and healthcare decision makers cannot tell whether a new drug is better than, equivalent or inferior to its existing alternatives. This can lead to the "widespread use of potentially less efficacious and unsafe drugs, as highlighted by the recent case of the diabetes drug rosiglitazone [ GlaxoSmithKline's Avandia]". Also, in some cases studies performed after drugs have reached the market have questioned the true value added value offered by new (and often more expensive) drugs compared with older treatments, they noted, citing the ALLHAT study that showed that coronary heart disease risk was not reduced for any of the three newer and more costly drug classes tested compared with the older and cheaper thiazide-based diuretics.
"When one or more treatment alternatives are available, demonstrating lack of inferiority through comparative effectiveness should be a formal requirement, and there are ways to support this objective in European drug licensing," the researchers say.
hurdles
The authors do acknowledge the major stumbling block that no one particular type of study is ideal for assessing comparative efficacy. The various options include traditional active comparator randomised controlled trials, adaptive clinical trials, pragmatic clinical trials, network meta-analyses and observational studies, but there are advantages and disadvantages to each of these.
"There is the inherent challenge of ensuring studies adequately address the most relevant clinical and policy questions to support safe and effective use of new therapies. Some approaches may be more appropriate under certain conditions and with different goals in mind," they admit.
Nevertheless, they do not believe that the challenges are insurmountable. The available study designs should be considered as complementary methodological tools. "For example the EMA might recommend that submissions be supported by one traditional and one pragmatic randomised clinical trial, and where possible, collect cost and quality of life data," they say.
"Comparative efficacy assessment at the time of drug approval serves as an important tool to help ensure that the most beneficial and safest treatments reach patients and that limited healthcare resources are invested wisely," they say, meaning that despite the difficulties, this should have a formal role in drug licensing decisions.
As a first step, they are calling for open dialogue and agreement between the EMA, manufacturers, payors and governments on the outstanding methodological questions and hurdles associated with the types of studies used to show comparative efficacy.
They suggest that an independent advisory board could be established to lead such discussions and ultimately provide guidance on what type of study design(s) can be accepted for generating comparative efficacy evidence and other questions on comparator selection, endpoints, dosing schemes, study size, and superiority and non-inferiority margins. "The board should collaborate with the national health technology agencies (such as NICE) to achieve better congruence between licensing and reimbursement requirements."
industry response
But industry figures say there is no need to go so far in demanding comparative efficacy data for marketing authorisation, as the pendulum is swinging in this direction in any case. EFPIA's director general Richard Bergström's commented to Scrip that more and more medicines have been studied against active comparators at the time of approval. "You can never reach 100% as per definition most orphan drugs are unique and cannot be compared. I believe payers are already requiring comparative trials to assess added value, so there is no reason for regulators like EMA to routinely require the same.
"These days we need to take down costs for drug development – not routinely add studies that may not be needed. Companies are regularly consulting both regulators and payers that have different needs. That explains why there are more comparative studies than ever."
The ABPI broadly agreed. "There are occasions comparison against a placebo is more appropriate however, such as in the study of a new illness or where there are no licensed medicines available for a particular condition. For these reasons, the ABPI believe this process does not suit a 'one size fits all guideline' and is better addressed on a case by case basis. In addition, data on clinical trials performed in the EU is now publically available and it is a regulatory obligation to publish the results of clinical trials that compose a marketing authorisation application."
The UK industry association added that joint working between key stakeholders "should always be encouraged and the ABPI would welcome greater dialogue between regulators, manufacturers and government agencies to achieve better congruence between licensing and reimbursement requirements and better public access to comparative data on the effectiveness and safety of new drugs".
Meanwhile, the EMA has already noted the writing on the wall with regards to the need for more comparative effectiveness data at the regulator-payor interface, and says that this will prompt rethinking of current paradigms. In a review last year in Nature Reviews Drug Discovery, the chair of the agency's committee for medicinal products, Eric Abadie, and the agency's senior medical officer, Hans-Georg Eichler, wrote: "Although the paradigm changes will be difficult for some drug manufacturers in the short term, we hope that relative effectiveness assessment and an alignment of the needs of regulators and payors in their domain will eventually benefit the drug development endeavour as a whole by helping to sustain interest and investment in drug development."