Do Outcome Measures in Pain Trials Hamper Drug Development?

Chronic pain and other pain disorders are notoriously hard to treat, with approximately 40% of patients reporting insufficient relief from their medication¹. There is a huge unmet need for safe and effective drugs, referred to as analgesics, designed to treat pain as their primary function. Unfortunately, it is challenging to get market approval for new analgesics. This is not surprising, as the very nature of developing drugs that can successfully and safely penetrate the central nervous system (CNS) is very difficult. However, there is some criticism that health outcomes in clinical trials set out by regulatory bodies are exacerbating an already hard process by being too conservative, and failing to align with the needs of payers, manufacturers and patients. This was the topic of the third issue panel at the 19th ISPOR European Annual Conference 2016 in Vienna, Austria.

Three panellists: Will Dunlop, Head of Market Access at Mundipharma International Ltd, Professor Daniel Mullins from the University of Maryland School of Pharmacy, and Professor Ben van Hout from the School of Health and Related Research, University of Sheffield; came together to debate whether outcome measures in pain trials are hampering drug development. Ron Akehurst, Strategic Director at BresMed Health Solutions acted as moderator for the panel. Each panellist gave an interesting perspective on the topic in a lively and interactive debate. The main points have been summarised below.

One major hurdle facing analgesic clinical testing, is a great amount of variability in health outcomes for pain. Furthermore, these outcomes, for instance quality of life assessments and pain scales, are usually subjective. This makes it hard to get a clear picture of how effective a new drug is at relieving pain and giving long-term improvements for patients. It is also a struggle to prove that a new therapy is inherently better than current treatments; many clinical trials do not include active comparators. As a result, estimating the cost-effectiveness of new drugs is difficult. Payers would prefer a greater focus on comparator studies and more flexibility on pain study design by regulatory bodies. There is even talk of asking governments to pressure regulatory bodies, to increase their flexibility on the requirements for analgesics. However, allowing regulators to be influenced in matters of efficacy and safety when making decisions on drugs is a slippery slope that could ultimately put patients in danger.

Patient safety is at the heart of conservative decision making. Regulatory bodies that lay out strict clinical outcomes do so for good reason. After the initial approval of thalidomide in the 1950s, the FDA acted cautiously on concerns of safety and refused approval unless further studies were conducted. Through conservative decision-making, the FDA were able to avoid the epidemic of birth defects seen in countries where thalidomide was approved for the treatment of morning sickness. Taking a conservative approach to health outcomes and safety is particularly necessary when dealing with drugs working within the CNS, as side effects can be detrimental. To add another dimension to the issue, chronic pain is often the result of an underlying disease, such as diabetes or cancer, meaning that there is a wide range of treatment regimens to consider in terms of efficacy and safety. For example, regulators have to be extremely careful not to let potentially harmful drug-drug interactions slip through the cracks. So yes, while conventional and variable health outcomes make it hard for new pain therapies to get approval, it is the price to pay for ensuring utmost patient safety.

For regulators, whose primary responsibility is to protect patients, this cost is justified. But to manufacturers the desire to bring new, improved products to the market takes precedent. While both sides make strong arguments, the determining factor is how much do we value pain. While some patients may see pain as a crippling illness, others are able to adjust their lifestyles to accommodate it. As pain, along with depression and anxiety, form a 'Triad of Suffering', perhaps treatments should target the psychological effects, with an aim to help patients cope better with pain. If people learn to live with pain, would new treatments be needed? Or is more sympathy needed for people who cannot adjust and require medical care?

As Ron Akehurst stated at the end of the panel "pain has a different kind of character" compared to other diseases. Due to the drastically variable nature of pain, it is hard to create a one-size-fits-all approach for clinical outcomes and approval. Perhaps the solution is to view pain in a similar scope as mental health. Different types of pain could be assessed as individual illnesses with an understanding that every patient has a unique experience. Instead of comparing new drugs to the current 'gold standard' treatment, healthcare professionals could take into account that some drugs will work better with certain patient groups than others. This could potentially be a route to a compromise between regulatory bodies, payers and manufacturers. Perhaps the question should not be 'do outcome measures in pain trials hamper drug development?' but rather 'is pain being viewed correctly?'

References

1. Monti S, Caporali R. Chronic pain: the burden of disease and treatment innovations. Reumatismo. 2015 Oct 23;67(2):35-44.