Fixing the failure rate

Celgene Corporation’s Kamal Shah looks at why most new drug compounds fail to progress beyond the clinical trial stage.

“Trials could be conducted either in collaboration with or maybe even independent of the pharma industry, which gives the potential for a better success rate”
-Kamal Shah

Despite all the scientific advances made over the past couple of decades, one of the main challenges in the pharmaceutical industry remains the failure of many drugs to reach successful registration and approval. According to Kamal Shah, Head of Global Trials Safety Surveillance for Celgene Corporation, the number of drugs that progress from discovery to approval hasn't changed much, in terms of the failure rate still being very high.

"The pharmaceutical industry needs to come to a consensus and perhaps learn from the past and figure out where the biggest failures are occurring," Shah says. "There are usually ample warnings from discovery all the way to the registration and approval process, but somehow the people working on these projects are missing them. This could be because they are focused on their own career aspirations.

"If you look at the development of a compound, most of the people who start working from phase I or earlier are in charge of that compound, and the failure of that compound could affect their career development. The flipside of that is that they may hype up the compound rather than thinking more scientifically and perhaps more critically about its chances of success or failure. If the drug succeeds, of course, everybody working on it gets the rewards, so it's a Catch 22 as to how to get away from that model.

"I'm sure other scientific areas have the same problem, and they have found a way of lessening it. If there was independent review in the middle of or at every stage of the trial, it might make this process more successful. We can't eradicate the failure rate completely, of course, but if it could be reduced by only 10, 20 or 30 percent, that's a huge amount of research money going somewhere else."

The other challenge Shah points to is that the US is paying for a lot of the innovation in research and discovery, which is not necessarily compensated when the resulting drugs move into other markets.

"In poorer countries where government resources are stretched, this is understandable," he says, "but for developed countries there is a need to share the burden of development rather than it being placed on only one or two countries. There are a lot of countries that can afford to pay, and they need to come together, just like the EMEA has become one body. I'm sure if the organizations like the FDA, the EMEA and the Department of Health worked together, they could come up with some formula of how to divide the expenses."

Safety first

Patient safety is obviously a critically important consideration in clinical trials, and awareness is certainly not a problem within the industry, as Shah points out: "It's not a question of whether people are aware of safety in clinical trials, because if somebody's living in today's world, I'm sure they're reading the paper, looking at the compound and probably most of them are involved in answering the questions from the regulatory agency about safety.

"The challenge on the clinical trial side is that efficacy is the driving force. Safety brings bad news occasionally to the table, and that's one of the reasons it has not been accepted as a member of the core team, maybe just by default. The bearer of bad news is never welcome anywhere, but the teams need to look at this and the critical approach of how can you ignore safety, because drugs are approved now based on the benefit-risk ratio rather than just efficacy.

"In order to reach an acceptable level of safety, you have to make sure that safety is fully in tune and working right from phase I trials into human, all the way through. There are a lot of challenges involved in improving safety and listening to the dose selection as well as all the risk mitigation strategies that make a potential failure down the road less likely."

It has become almost impossible to separate safety from efficacy in clinical trials, because regulatory agencies now ask for a benefit-risk assessment as a combination. "The problem there is that the assessment of acceptable risk is never well defined," says Shah. "For many major diseases it's not very difficult, but there is no consensus amongst different regulatory agencies in North America and Europe and Asia, for example.

"The regulatory agencies worldwide are attempting to come up with a formula for assessing and giving a number to the benefit risk, but that's another big challenge. You can put a number on efficacy, and if you reach that, you succeed. With safety, things need to be considered on an individual basis: drugs have idiosyncratic reactions and some behave differently in, say, a patient who is compromised in liver function or renal function. This has to be individualized and acted upon. It will be very difficult to come up with a fixed number where you say, 'Okay, this is the benefit-risk ratio, and if the number is one, then the drugs get approved or not.' It's an evolving science in terms of how to perfect it."

International outlook

Another change in the clinical trial landscape has been the number of trials being conducted internationally. In Shah's view, international trials are a very good way of making sure the drug is exposed to varieties of populations and individual country practices and habits as well as individual genetic considerations that may be brought in by different parts of the world.

He underlines the fact that the opening up of certain areas, such as Latin America and Southeast Asia, has brought more diversity to the trial population, making it easier to get drugs accepted worldwide. However, he also points to the challenges that develop through the need to satisfy local agencies and regulations and practices, which can occasionally throw a wrench into proceedings.

Despite this, Shah sees the internationalization of clinical trials as a continuing trend within the industry. "A lot of companies are trying it. It allows them to get good enrolment from a lot of areas outside of traditional, research-based centers. They also get exposure to patients who are not controlled in the same fashion and so might help indicate how the drug might react when it gets marketed, so you have better population exposure."

Another thing that Shah sees evolving in the next five or 10 years is the development of more collaborative partnerships with local expertise, either internally or acquired through partnerships with service providers. He predicts that service provider industries are going to continue to grow in terms being  the source of doing a lot of trials.

"The question is whether they will be able to maintain the talent pool, which keeps changing," Shah says. "Quality of service is never guaranteed for the duration of the trial, even with the best companies.

"Personally, I also feel there is a strong need for collaboration between academic centers and pharmaceutical companies, because most of the targets are being developed or invented or discovered at academic centers, and then the development of the compound goes to the pharmaceutical industry.

"There needs to be stronger, more collaborative efforts between the academic centers that can bring a lot more science to the table, rather than just a faster approach to the development process, and maybe can help in selecting the best candidate, rather than just a candidate. There are academic centers that can bring more partnership to the table, even for conducting trials, which is right now one of the biggest reasons for failure. Trials could be conducted either in collaboration with or maybe even independent of the pharma industry, which gives the potential for a better success rate.

"The active involvement of large academic centers, the involvement of good research physicians and the people who are at the forefront on the treatment side of the disease, would bring a lot to the drug development and clinical trial process."

Kamal Shah is Head, Global Trials Safety Surveillance, Celgene Corporation.