Timely Access: The Waiting Game

Janssen’s Dr Thomas Stark believes the speed of innovation is not matched by that of the medicines approval process.

Innovation in pharma is in itself a complex and drawn-out process – where inspiration and perspiration merge over years to produce a novel compound or molecule that will benefit human health. Yet while this process has been increasingly streamlined as science and technology progresses, drug approval processes remain a painstaking process that can significantly delay access to groundbreaking and effective therapies.

Despite the central role of industry in healthcare delivery, outcomes and development, innovation in the form of lifesaving or life-prolonging medicines is now being scuppered by lengthy gaps between marketing authorization and eventual reimbursement.

Dr Thomas Stark, Janssen Vice President EMEA Medical Affairs, Janssen, recently spoke at an Irish industry conference on why he believes the global medicines approval process is thwarting the speed of innovation.

Contribution of innovative medicines

The contribution of innovative medicines to the exponential increases in life expectancy cannot be undervalued, argued Stark. Indeed, average life expectancy increased by almost two years between 2000 and 2009, and innovative medicines have been estimated to be responsible for as much as 73 per cent of this growth in longevity. For example, increases seen in life expectancy of cancer patients over the past three decades are also thought to be largely due to new treatments and medicines. Patients diagnosed with cancer can nowadays expect to live three years longer than those diagnosed in 1980, and pharmaceutical breakthroughs have contributed to a staggering 83 per cent of this increase, Stark noted, adding that “the data is quite impressive”.

For example, advanced melanoma historically had an extremely poor prognosis – 10-year survival was less than 10 per cent. Stark explained that new advances have recently led to dramatic increases in progression-free survival for advanced melanoma patients. A late breaking session at the American Society of Clinical Oncology in Chicago last year outlined early data from trials that showed the combination of immunotherapies ipilimumab and nivolumab has impressive activity on advanced melanoma – “one of the most difficult solid tumors to treat”.

“The verdict was that this should be considered the new standard of care straight away.”

Yet these welcome findings were delivered with the stark caveat that there would be a price to pay. Stark explained: “Interestingly, for the first time at ASCO, the agenda was not just clinical data, but the emphasis was also placed on value demonstration. It’s not just the health technology assessors that are starting to estimate value, the medical societies are also starting to look at that as well – this is a new and emerging trend.

“One of the speakers commented ‘though the efficacy of these regimens is clear in this study, their value in terms of cost and associated benefits is still in question’.”

Revolution after revolution

As the speed of innovation increases, this can mean that game-changing breakthroughs can quickly become old news.

In the last five years, a revolution has happened. I have never seen anything like this. Nowadays we talk about eight to 12 weeks of treatment, with a more than 96 per cent chance of cure. This is a massive transformation.

One such example was what Stark termed “the golden age of IFN-free short-term therapy” in the treatment of chronic hepatitis C. Previously, patients had to undergo up to a year of grueling treatment with interferon-based regimens, which only offered a 40 per cent chance of cure. The introduction of protease and polymerase inhibitors, followed shortly by the availability of combination therapies for the disease has led to a “revolution”, he said.

The first wave of innovation came in 2011, with direct acting antivirals delivering unprecedented outcomes. Yet this breakthrough essentially was rendered obsolete in 2014 when the combination therapies became available. Stark said he believes this example clearly demonstrates how the speed of innovation within the pharmaceutical industry is rapidly increasing.

“In the last five years, a revolution has happened. I have never seen anything like this. Nowadays we talk about eight to 12 weeks of treatment, with a more than 96 per cent chance of cure. This is a massive transformation.”


Innovation in diabetes is particularly hampered by HTAs; Stark outlined data from the Empagliflozin Outcome Study, this being just one example in the relatively new class of sodium-glucose co-transporter type 2 (SGLT2) inhibitors.

They were evaluated on their early data and we got a lot of pushback from some major HTAs, who said they wanted to see solid data in terms of relevant patient outcomes.

“What this class of drugs does is reduce glucose in the kidneys by increasing its excretion – from a medical point of view this is a very useful mechanism of action. It’s not like insulin where you simply move glucose from one compartment to another in your body. This is the first time ever that it could be demonstrated that a drug led to a reduced rate of hospitalization for heart failure, a reduced rate of death from cardiovascular disease and an improved overall survival by reducing all-cause mortality. This is impressive but these data were not available when the value of these compounds was first discussed; they were evaluated on their early data and we got a lot of pushback from some major HTAs, who said they wanted to see solid data in terms of relevant patient outcomes.”

The pharmaceutical industry remains firmly committed to investing in innovative solutions to address key unmet needs, Stark continued. An analysis from 2012 found there to be over 16,000 registered pipeline compounds at various stages of the development process; the vast majority of these are in the area of oncology.

If we see more of these products coming along, is the process of value evaluation and value definition appropriate or do we need a more flexible approach? This is a very valid question because we will see that more and more.

“Not all of these will make it, of course, but it’s a massive demonstration of the commitment of industry to progress in medical research in high unmet need areas,” he said

The pipeline also has more multi-indication products than ever before, and this will continue to grow. Stark said it is his belief that what will be seen in the future is market entry of a new drug in a small indication, while other indications continue to be developed in parallel; this means that the clinical value of a drug will grow over time.

“If we see more of these products coming along, is the process of value evaluation and value definition appropriate or do we need a more flexible approach? This is a very valid question because we will see that more and more.

“The other aspect is that 42 per cent of this pipeline have the potential to be personalized medicines, and if you look at just the cancer pipeline, this is over 70 per cent. This is a big topic too and I think there is a lot to do in the space of personalized medicines and companion diagnostics, because many things are unclear, both in the regulatory and approval process, as well as HTA.”

The 1,000 day wait

Median regulatory approval times for the six biggest regulatory authorities – the FDA, the EMA, the Pharmaceuticals and Medical Devices Agency, HealthCanada, SwissMedic, and the Chinese FDA – can range between 200 and 1,000 days on average. In Europe the criteria examined can differ wildly across jurisdictions, with countries examining varying combinations of parameters including therapeutic benefits, innovative characteristics, availability of therapeutic alternatives, patient benefits and cost-effectiveness.

“The HTA system asks us on behalf of society to demonstrate value and it is clear that this is a legitimate request, absolutely, but I think from a medical perspective and an industry perspective we have to prove value against a very diverse set of criteria and that is something that we need to have a discussion on how we can come together on this, but in the absence of a European-wide agreement on how to do HTA evaluation, this is what we are faced with,” Stark commented.

“If you look at the timings there [the EU], we are talking about 300 to 500 days from marketing authorization to reimbursement decision. An analysis from IMS Institute for Healthcare Informatics also looked at the method used to assess value and they found that countries that used the [quality adjusted life years] QALY approach have significantly longer approval times than countries using alternative methods.”

Life and death

Stark outlined what he termed the “fascinating case” of Josh Hardy and Chimerix; the seven year old boy suffering from an adenovirus infection required the company’s investigational antiviral drug, brincidofovir, but was denied compassionate use access to the therapy. A widespread social media campaign was mounted, and the company’s CEO Kenneth Moch received several death threats and was placed under armed escort. Moch was eventually forced to resign, but Stark said this case illustrated the “life and death” scenarios that delayed access to drugs can create.

“As long as these processes last, we as an industry are also faced with challenges like this; because we want to give terminally ill patients, who have no time to wait, access. How do we do that in a more timely way? It is a complex issue. Patients want the best health, the health service wants maximum health but the industry needs commercial return; it is in that space I think we have to move forward.”


Accelerated approval pathways show potential; the US, Canada, the EU, Japan and Singapore have developed “fast-track” methods that make drugs available in cases of serious or life-threatening illnesses, or areas where there is significant unmet need. This should be applauded but also built upon, according to Stark.

“A good example is to point out what happened in the regulatory space over the past 10 years; across the globe there are several examples of regulatory approval being expedited; this we have to acknowledge has been a great advance on the regulatory side,” he said, explaining that one such example is that of “parallel review”, currently being employed in Canada and Australia.

This involves a medical product going through processes of market authorization (i.e. regulatory review) at the same time as aspects of its cost-effectiveness and coverage for reimbursement are decided via pharmacoeconomic review; by focusing on aligning timeframes and logistical aspects of the review processes, efficiency is greatly improved, Stark advised, adding that it has been particularly useful within the setting of oncology, and Canada is now using it for all oncology drugs.

Another example is the various stakeholder engagement Initiatives becoming popular in the US and Canada. These involve stakeholders at different parts of the pathway communicating and collaborating; according to Stark, this helps to align the expectations and priorities of stakeholders along the pathway to reduce duplication of effort. Engagement can be introduced at all stages of the adoption pathway, and can be used either to accelerate the development of specific drugs that appear to provide a clear clinical impact. Successful examples include the US FDA‘s Critical Pathway Initiative, and also the Canadian MaRS Excellence in Clinical Innovation Technology Evaluation (EXCITE).

“It is complex because there are diverse interests. We need to come together and we need to work together in order to move things forward. The principle is that you bring all the stakeholders and particularly the patient advocacy groups, who are consistently either kept out of the discussion or else not really heard, and you bring everyone together from day one as you move along with your development – I think this is the most critical aspect.”

Lessons from Ebola

Stark concluded by stating that collaboration between industry and the regulatory authorities is key to limiting delays in access to treatment.

“It can work; we have seen that collaboration and stakeholder engagement has worked – it working in the HTA discussions now and it worked in the 1990s with HIV and in more recent times with hepatitis C. If you look at the example of Ebola, in particular, all of the mechanisms I have described have been applied in a time of crisis in order to move forward and fast-track vaccines as fast as possible and ensure timely access to those who need them.

“What we need is faster, more transparent processes, with greater predictability and longer term sustainability. We need enhanced collaboration of science, academia, patients, society and decision-makers. And we need early collaboration of all stakeholders in the development process of innovative medicines. We have to work together.”

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