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Mathieu Takeaways on the 2012 Clinical Trial Sourcebook

September 17, 2012 | Mark Mathieu—director of Strategic Research at PAREXEL Consulting—is the founding editor of the PAREXEL Biopharmaceutical R&D Statistical Sourcebook. As such, he is the ideal person to discuss the highlights and nuances that emerge in the latest edition of the sourcebook (2012-13). Mathieu recently spoke to Barnett International’s Rachel Meyers. (The following transcript has been lightly edited for brevity.)   

Rachel Meyers: Mark, which trends or metrics stood out the most this year?  

Mark Mathieu: One of the things that really stood out this year was a sharp and welcome rise in a key industry productivity metric. The industry’s performance is judged in many ways. Given that they are the lifeblood of the pharmaceutical industry, newly approved NMEs are tracked and reported on very closely and widely. These were up nicely in 2011. But unlike others, we also like to look at a slightly more upstream measure—industry NME submissions—because it gives us an idea of what  is actually in the pipeline for possible approval  in the near future…   

It’s impossible for NME approvals to grow if NME submissions don’t improve first. On a worldwide basis, we saw New Active Substance (NAS) approvals drop in 2011 after 3 consecutive years of encouraging increases. Global NAS approvals dropped from 42 in 2010 to 33 in 2011—a 3-year low. Interestingly, however, NME submissions rose to 34 filings with FDA in 2011. That doesn’t sound too dramatic, I must concede, but it represents a 79% percent surge from 2010. That matched the highs in the 2000s. It’s a very notable bounce.  

To put the 34 filings in a longer term context, it’s important to point out that the drug industry averaged 43 submissions annually in the 1990s. So the 1-year spike is still off the real highs of a decade ago.  

The 34 NME submissions to CDER don’t include the 6 BLA submissions for 2011—monoclonal antibodies and therapeutic proteins regulated by CDER—so it doesn’t include vaccines and therapeutic biologics. They too have seen an uptick, although the N remains quite small.  

One other important caveat: Not all submitted drugs to FDA are approved. FDA claims an 80% approval rate overall (that is, the percent of submitted new drugs approved at any time after submission), although it may be tracking closer to 70% in recent years. There may be a modest improvement in the past two years. It’s clear that the spike in the US is a positive, and taken together with other trends, this leads to long-awaited hope that the industry is on the cusp of reversing a long-term decline in productivity.  

Is there any evidence that other parts of the world are seeing similar spikes?  

Absolutely, there is. If we look at the European Medicines Agency (EMA), it has also seen in the last couple of years a rise in applications for new medicines… The EMEA saw submissions for NASs rise slightly in 2011, but NASs in Europe are a somewhat broader category of medicines than NMEs in the US, including important modifications of already approved medicines. NASs can be challenging to compare to FDA data, although seeing submission figures rise is certainly a positive.  

Most of the increase in submissions to the EMA has been in new medicines—rising over 40%, to 48, in 2011. These EMEA figures include orphan drugs, which continue to rise.  

How much do we know about therapeutic areas in which companies are seeking drug approvals?  

Sticking with the EU, no less than 27% of all new drugs being reviewed by EMEA (as of March 2012) were cancer medications. Next—far behind—was diabetes (7%) and immunosuppresants (4%)…  

It’s a somewhat different story in the United States. Cancer, while still a very active area, didn’t represent as high a percentage of the FDA pending workload as in 2011, partly due to the fact that many cancer products are being reviewed very quickly at FDA… As of 2011, metabolism and endocrine products represented 15% of all pending NDAs at the FDA.   

The SourceBook always offers interesting insights into the industry’s clinical development pipeline. What do the metrics tell us about the level of industry activity in clinical development?  

The overall global R&D pipeline continues to grow, according to several sources… Our own study across three key R&D pipeline databases found the Phase I-III pipeline increased 6.2%. We can also talk about the pipeline itself and the numbers inside the numbers. Previously, over the past couple of years, we’ve seen solid growth in the early-stage pipeline (Phases I-II), while we saw the all-important Phase III pipeline stagnate to a degree. There’s a clear need for companies to develop new therapies to replace those losing patent protection, so we needed to see the Phase III pipeline to grow. It’s a sign that the industry isn’t able to translate emerging science into late-stage opportunities.  

However, what we’ve seen in 2011 and into 2012 is very substantial growth in the Phase III pipeline. It’s the first time we can recall seeing two consecutive years of double-digit growth. It was up 10.6% in the 12 months up to May 2012, really reversing in dramatic fashion the prevailing trend for several years. This helps create a hope that the rise in new drug submissions that we saw in 2011 might become more than a 1-year spike.  

What about the direction of the clinical development pipeline?  

Our friends at EvaluatePharma assess this from several perspectives. First from the perspective of biotechnology versus conventional synthetic drugs. As of May 2012, just under two thirds all development pipeline products—from early research to filed for approval status—were conventional small molecule products…. It’s consistent with the idea that biologics are becoming of greater importance for the industry. Therefore, biotech products comprise 34.6% of the pipeline, up from the previous year.  

For the biotech products, it’s also interesting that monoclonal antibodies make up more than one quarter biotech pipeline products… followed by vaccines and recombinant protein products. Together, these are the big three in biotech and represent 72% of the biotech total.   

We also know that about 68% R&D projects are active in-house projects, while in-licensing accounts for 16%, and another 8% of projects are obtained by acquisition. Among top-tier companies, 49% of Sanofi’s pipeline has been in-licensed, compared to 32% at Pfizer, 42% at GSK, and on the lower end, 22% for Lilly. Biogen Idec in-licenses 49% of its pipeline, compared to 17% for Amgen.  

We can also look at shifts in research activity by therapeutic area… Our best data comes from tracking industry research submissions (commercial investigational new drug applications, or INDs) to the FDA… Not surprisingly, cancer still represents much of the focus of the R&D pipeline—indeed it is becoming even more intense. Our data tell us that no less than 24.5% of all FDA-regulated clinical trial starts in 2011 were in oncology (not including leukemia and other hematologic oncologies). This is a spike from a year earlier. The next most-active areas are metabolism, endocrinology, and neurology (at 8%), which gives you an idea of how active oncology is compared to other popular therapeutic categories.  

FDA-regulated clinical trials rose 12% in 2011, after two years of declines from the record high in 2008. Trial starts for therapeutic biological products declined in 2011, continuing a trend of volatility in the last few years.  

Putting aside new trial starts, what do you see when looking at the entire clinical trial pipeline?  

We still see oncology representing a plurality of R&D projects… In 2011, oncology represented 17.6% of all FDA-regulated clinical trials. This figure is well above other therapeutic areas. The next most active areas are neurology and metabolism. Taken together, all these metrics provide a decent picture of what the industry’s R&D pipeline looks like.  

What trends do you see in shifting clinical trials from the US/Europe into emerging markets?  

This year, we have some interesting metrics, some suggesting there may have been a temporary repatriation of R&D investment in North America. According to TTC data tracking annual trial grant costs, TTC calculated the total clinical trial spend by region in 2011. Spending in North America rose in 2011, to 60% of the total. Interestingly, Latin America was the only other region to see a proportional increase last year.   

Europe captured only 24.1% of 2011 spending, down from 26% in 2010. Unfortunately, we’re not able to see how things may differ between western and eastern Europe, but overall spending was down in the region. Asia and Africa saw modest declines as well. Overall, we put the clinical trial spend in the US in 2011 at almost $81 billion, compared to $32 billion in Europe, $13 billion in Asia, $7 billion in Latin America, and $2 billion in Africa.  

We also feature an update on our own analysis of the number of clinical trials by region, with just over half of today’s clinical trials having sites in the US, and almost one third of today’s trials having sites in Asian countries and Europe.   

The SourceBook includes a large collection of regulatory data. What stands out there?  

We’re in a very interesting period in terms of NDA reviews at FDA. Particularly in context of PDUFA 5 [Prescription Drug User Fee Act], which goes into effect in October 2012.  Under PDUFA 5, the FDA will be adopting a new regulatory model for NMEs… But whatever iteration of the user-fee program is in effect, our data show just how important first cycle approvals are. Over the last several years, NMEs that were cleared in the first FDA review cycle were approved roughly 20 months faster than drugs that took 2 or more review cycles to gain approval…  

 This review-time gap translates into an estimated $560 million in incremental sales, according to EvaluatePharma sales projections for those drugs. The good news is that record percentages for NMEs are being reviewed by CDER are gaining first-cycle approvals. These higher rates will be the benchmark against which first-cycle approvals under PDUFA 5 will be judged.   

For priority-rated NMEs submitted in 2011, about 90% have been approved in the first review cycle… We’ve seen this rate as high as 80% in earlier years and as low as 54% (as recently as 2009). We’re also seeing high approval rates for standard graded NMEs—about 55% in 2011, up from 35% in previous years.  

Details on the 2012-2013 PAREXEL Sourcebook can be found at  


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