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Fit for purpose?

The objectives and outcomes of clinical trials do not necessarily meet the demands of payers who need to know how a drug will perform in a real life setting

Nobody could have anticipated that a liquidity shortfall in the US banking system would have resulted in the collapse of our global economy. What began with the collapse of the US housing bubble in 2006 has now impacted all continents and industry sectors and the pharmaceutical industry has not been spared. In order to respond to the crisis, the industry has made significant cuts and changes to the way it operates. Manufacturers have merged with competitors, downsized sales forces, reduced their outsourcing, cut R&D budgets and rationalised pipelines, based on the potential commercial viability of products.

Commercial viability of a product assumes that it achieves market authorisation (MA), generates willingness among physicians to prescribe it and achieves optimal market access, which means that health technology assessment (HTA) bodies and payer stakeholders approve the drug for reimbursement, without placing any significant restrictions on its use beyond those defined by the MA.

Restrictions can take many forms. Drugs can be restricted to sub-populations. This usually happens in the case of products considered to be high cost. The restricted target population will be a well-defined population for whom, based on the available data, there is greater confidence of a positive clinical benefit. Drugs can also be restricted by being made available for prescription by specialists only and/or hospital use only. In some cases, restrictions may be lifted once end users, ie. clinicians and payers, are confident in, and satisfied with, the clinical performance of the product. However, in the interim, this significantly limits uptake.

Payers have not changed their views because of the financial crisis alone. The surge in high cost products during  the late 1990s and early 2000s, of which the targeted oncology therapies  such as Rituxan (1997), Herceptin (1998), Glivec (2001), Erbitux (2004) and Avastin (2004) are good examples, has definitely driven payers to be more aggressive in their assessments of drugs and what they get for their money. The brakes were put on in 2007, when Tyverb, a novel treatment for metastatic breast cancer, was launched.

Today, payers take health-economic assessment much further and are more demanding with regard to both the clinical outcomes and the medico-economic case. In order to achieve optimal market access, manufacturers have to satisfy not only the requirements for MA but, as discussed, must also meet the demands of payers. Market access differs significantly from MA, which is mainly concerned with safety, efficacy and public health, yet both MA and market access assessments rely on the results of clinical trials.

Since the primary objective of clinical trials is to satisfy regulatory authorities and support MA, the outputs have normally been in the form of absolute efficacy data, obtained in a placebo-controlled double-blind trial setting. Such controlled trials, while providing unbiased efficacy data, with internal validity, operate under artificially ideal conditions, with motivated health care professionals and compliant patients who fulfil restrictive inclusion and exclusion criteria.

This is of limited value to payers who need to understand how a technology will be implemented and perform in a real life setting, relative to the current standard of care, in order to make informed judgements on resource allocation, market access and funding.

Trial design
Clinical trial design is regulated by healthcare authorities such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). It is also further restricted by the competitive landscape at the time the trial is set up, in that comparators can only be selected from alternative therapeutic products already approved for use on the market. Finally, clinical trials are restricted by safety requirements imposed by healthcare authorities due to the limited knowledge available on the product being tested and the requirement for extra caution in the patient selection and inclusion criteria.

As a result, the populations studied and included in trials are not fully reflective of the population in whom the products will be used in practice. There remains, therefore, significant uncertainty regarding the applicability of clinical trial results to the real world situation. Where active comparators have been employed in clinical development, selected comparators may not represent standard of care at the time of trial completion, which will make establishing even relative efficacy difficult at launch.

In addition, often the duration of trials is not reflective of the real life course of the disease in question, which leaves further doubt over the long-term performance of a drug in clinical practice. Finally, the design of a trial, which may include a crossover, makes hard clinical endpoints such as overall survival available only through modelling. For all these reasons, payers often view controlled trial results with scepticism.

They require a minimal level of uncertainty and robust evidence of comparative effectiveness which supports a clear understanding of budget impact, with minimal likelihood of variation. For example, the French Transparency Commission, which is becoming ever stricter, now insists that manufacturers demonstrate overall survival, should they wish to achieve higher ASMR (Evaluation of Therapeutic Benefit, or Amelioration du Service Medical Rendu) scores and, as a result, a greater opportunity to negotiate premium pricing. The German authorities (G-BA and/or IQWiG) also now require new products to provide an early benefit assessment, demonstrating the incremental benefit of a product and evidence of cost-effectiveness, based on patient relevant endpoint, such as mortality and morbidity, in order to achieve reimbursement.

Bridging the gap
Trial results are now being used to highlight gaps in the information required to ensure optimal clinical use of a technology. In essence, trials are becoming pilot studies for the post-launch studies, imposed by healthcare authorities and health technology assessment bodies. These post-launch studies will verify whether or not the real long term performance of technologies mirrors that seen in the controlled true clinical setting. These studies are also being used as the basis for value based pricing and industry is being forced to put post-launch studies in place to achieve commercially desirable prices at launch and maintain these prices over time.

Impact on pricing
Not all post-launch studies will support the value proposition put forward at launch. As a result, many approved and funded drugs will be reassessed and their prices reduced, either directly or through rebates to the statutory health authorities. On the potentially rare occasions when real world data would support an increase in price, is that really likely to be the case? Thus, the commercial viability of a product will no longer be based on the price to obtain access, but rather the price to retain access during critical phases of the lifecycle.

With requirements at launch for MA and market access being so different, will there be a need to delay launch of products to allow the additional information required to satisfy market access criteria to be collected prior to launch? Should this happen, how will the detrimental delay in the introduction of potentially innovative products to patients be perceived?

Finally, how will industry be compensated for the time lost on patent? Will health insurers be willing to pay even higher prices in exchange for the assurance that products perform according to expectations?

To continue launching commercially viable products with successful market access strategies, the industry has to prepare to meet the requirements of market access as early as it does the requirements for MA. Trial design must take into account the most likely target population and identify means of clearly defining it. Where this is not possible, companies must be prepared to undertake phase IV or post-launch studies demonstrating efficacy in sub-populations. Trials must be powered to demonstrate clear patient-relevant endpoints and, if this is not possible, robust models must be put in place to predict long-term outcomes.

The Author
Natalie Shalet
is senior consultant at Bridgehead International

To comment on this article, email

28th March 2011


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