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Is Achieving Trial Success a Roll of the Dice? Dissecting Trials with Positive Outcomes to Identify Strategies for Success.

SYLVIA MARECKI, PhDSenior Director, Product Management & Strategy

TrialtrovePharma intelligence |


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Drug development is a risky endeavor—some might even say a gamble—but what are the odds of running a successful trial? Although many studies have evaluated overall drug development success rates, predominantly by assessing therapeutics’ phase transition rates and probabilities of approval, none have reported trial-level success rates to date. Here, we delve into this area to take a closer look at trial-level success with an eye toward identifying strategies that may correlate with success.

Trialtrove and Trialpredict data were leveraged to identify Phase II – III, industry-sponsored trials completing

between January 1, 2008 and December 31, 2012 with a positive outcome, defined as the trial’s primary

endpoint(s) were met with statistical significance and/or the trial’s sponsor or investigator stated that it had

a positive outcome or was successful. A total of 7,005 trials were completed during this timeframe and 3,686

trials achieved a positive outcome for an overall success rate of 52.6%, slightly better than a roll of the dice.

The top 10 diseases spanned several major therapeutic areas but type 2 diabetes saw the most successful

trials completing during this period (Table 1). Major pharmaceutical companies occupied the top 10

sponsor slots, biologics factored heavily among top 10 drugs, and the US was the top location among

successful trials (Table 1). Notably, Poland and Russia were among the top 10 trial locations for successful

trials, suggesting country selection expanding into emerging markets may be starting to reap rewards and

may also signal one strategy for success.

table 1. the top 10 Most Successful Diseases, companies, Drugs, and trial locations

Diseases Sponsors Drugs trial locations

• Type 2 Diabetes

• Respiratory Infections, Vaccines

• Breast Cancer

• Asthma

• Chronic Obstructive Pulmonary Disease

• Rheumatoid Arthritis

• Non-Small Cell Lung Cancer

• Hypertension

• HIV

• Allergic Rhinitis

• Roche

• GSK

• Novartis

• Pfizer

• Merck

• Sanofi

• J&J

• AstraZeneca

• BMS

• Lilly

• Bevacizumab

• Erlotinib

• Rituximab

• Docetaxel

• Indacaterol

• Cetuximab

• Bortezomib

• Ranibizumab

• Linalidomide

• Capecitabine

• US

• Germany

• Canada

• France

• UK

• Spain

• Italy

• Poland

• Russia

• Belgium

Source: Trialtrove® and Trialpredict®, August 2013


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Some therapeutic areas experienced a higher proportion of successful trials than others (Figure 1). While

oncology and CNS had the greatest number of clinical trials completed 2008 – 2012 overall, their success

rates were 51.9% and 47.2%, respectively; both lower than the overall success rate of 52.6%. Meanwhile,

autoimmune/inflammation had the highest success rate of 56%, followed by metabolic and cardiovascular

areas. Many factors certainly underlie trial success. This analysis will explore some of them to begin to

understand factors that may correlate with success and how sponsors may be employing these strategies

to drive trial success.

Which companies sponsored these successful trials and how was success distributed among top industry

sponsors? As noted in Table 1, Roche completed the most successful trials during the 2008 – 2012 period

overall. When trial success by therapeutic area is stratified by sponsor, Roche emerges as the top sponsor

within oncology, Novartis for autoimmune/inflammation and ophthalmology, and GSK for infectious

diseases but these sponsors as well as others in the top 20 typically experienced trial success across

multiple therapeutic areas.


Figure 1. Trial Success by Therapeutic Area

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ONC = oncology, CNS = central nervous system, MET = metabolic and endocrine, INF DIS = infectious diseases,CV = cardiovascular, OPHTH = ophthalmology, GU = genitourinary diseases

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Were there any differences in country utilization across therapeutic areas among these successful trials?

What is striking is that despite differences in sponsorship across therapeutic areas, the relative utilization

of the top 20 countries within a given therapeutic area is generally consistent across therapeutic areas,

with the United States remaining the most-utilized country (Figure 3). This observation suggests that

country selection strategies are generally consistent across sponsors and therapeutic areas at a macro level

but that there is variation in the average number of countries utilized per trial within each therapeutic area,

as evidenced by autoimmune/inflammation jumping to the first position by count of country utilization

(compare Figure 1 and Figure 3).

It also is noteworthy that these top 20 countries include Eastern European, Latin American, and Asia Pacific

regions and their relative utilization is roughly proportional to other top 20 countries, apart from the United

States. It is clear that Eastern Europe has become an important region and that we are likely to see growth

in utilization of countries in Latin American and Asia Pacific regions in the future.


Figure 2. Successful Trial Activity by Top 20 Sponsors

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ONC MET A/I INF DIS CNS CV OPHTH GU

Daiichi Sankyo Forest Laboratories Novo Nordisk Amgen Astellas Celgene AbbVie Bayer Takeda Boehringer Ingelheim Eli Lilly BMS AstraZeneca Johnson & Johnson Sanofi Merck & Co Pfizer Novartis GSK Roche

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It is clear that Eastern Europe has become an important region and that we are likely to see growth in utilization of countries in Latin American and Asia Pacific regions in the future.


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Among the top therapeutic areas with the most successful trials, GSK, Lilly, and Roche are among the top 5

sponsors in three out of four areas presented in Table 2. The US and UK remain top locations across these

therapeutic areas but only within autoimmune/inflammation does Poland appear among the top 5 locations

for successful trials. It is intriguing to speculate that trial success may somehow correlate with country

utilization. Given that the trial success rate was highest within autoimmune/inflammation and that it was the

only therapeutic area where an Eastern European country appeared in the top five most utilized countries,

this area served as a case study to investigate the potential impact of country selection on trial success and

to investigate other potential strategies for success.

Figure 3. Successful Trial Activity by Therapeutic Area: Top 20 Countries

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Romania Mexico Austria Sweden Japan India Hungary Czech Republic Netherlands Australia Belgium Russia Poland Italy Spain United Kingdom France Canada Germany United States

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It is intriguing to speculate that trial success may somehow correlate with country utilization.


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When trial success is evaluated at the disease level within autoimmune/inflammation, asthma, rheumatoid

arthritis, and chronic obstructive pulmonary disease (COPD) emerge as the top three diseases, both in terms

of the most successful trials and most overall completed trials during 2008 – 2012 (Figure 4). The success

rate for asthma (52%) was slightly lower than the 52.6% average for the full dataset and somewhat lower

than the average for this therapeutic area (56%); whereas rheumatoid arthritis and COPD trials experienced

success rates over 62%. Could country utilization provide insight into potential strategies for success?

table 2. top therapeutic areas By trial Success

therapeutic area

Success rate (% of complet-

ed)

top 5 Sponsors top 5 Diseases top 5 Drugs top 5 trial

locations

Oncology 51.9% (809/1,560)

Roche

Sanofi

Celgene

Lilly

GSK

Breast Cancer

Non-Small Cell Lung Cancer

Non-Hodgkin’s Lymphoma

Colorectal cancer

Multiple myeloma

Bevacizumab

Erlotinib

Docetaxel

Cetuximab

Bortezomib

US

France

Germany

UK

Italy

Autoimmune / Inflammation

56% (713/1,274)

Novartis

GSK

Roche

Merck

AbbVie

Asthma

Rheumatoid arthritis

Chronic Obstructive Pulmonary Disease

Allergic Rhinitis

Psoriasis

Indacaterol

Adalimumab

Tocilizumab

Olodaterol

Tofacitinib

US

Germany

Canada

UK

Poland

CNS 47.2% (650/1,376)

Pfizer

J&J

GSK

Lilly

Merck

Pain (nociceptive)

Pain (neuropathic)

Depression

Schizophrenia

Parkinson’s Disease

Pregabalin

Paliperidone

Aripiprazole

Pramipexole

Duloxetine

US

Germany

Canada

France

UK

Metabolic 55.1% (600/1,089)

BMS

AZ

Lilly

Roche

Novo-Nordisk

Type 2 Diabetes

Diabetic complications

Osteoporosis

Constipation

Obesity

Sitagliptin

Insulin degludec

Exenatide

Epoetin beta

Linagliptin

US

Germany

Canada

UK

Spain



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The relative impact of Eastern Europe becomes even more apparent in autoimmune/inflammation, with

four of the top 15 countries coming from this region: Poland, Hungary, Russia, and Romania (Figure 5).

Furthermore, Mexico and Argentina appear among the top 20 countries, providing further evidence to

suggest that expanding geography may play a role in trial success.

Success rates in trials involving any of these top 20 countries was above average for this therapeutic area,

highest among trials involving South Korea, where nearly 76% of trials involving this country were successful.

Clearly, simply including a particular country in a clinical trial is no guarantee for success but a closer look

at trials that involved this country may provide some insight into successful strategies.

Figure 5. Trial Success Rate Among Top 20 Countries in Autoimmune/Inflammation, 2008 – 2012

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Figure 4. Top 10 Diseases in Autoimmune/Inflammation, 2008 – 2012

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Not only were asthma, COPD, and rheumatoid arthritis the top three indications in autoimmune/inflammation

overall, they also accounted for 68% of all successful trials involving South Korea. In fact, South Korea was

the only country among the top 20 in autoimmune/inflammation that was utilized in clinical trials for all

three indications where there was a success rate of more than 75% (Figure 6). Success rates in Estonia and

the Philippines also exceeded 75% in these three indications but because of the smaller sample size, they

were not analyzed. To gain clarity around the types of trials that were conducted in South Korea, a deeper

analysis of these highly successful trials was undertaken.


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Figure 6. Top 30 Countries In Asthma, COPD, And RA

Other outcome

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Expanding to a wider geography for country selection is one strategy sponsors are employing that

appears to correlate with trial success. Indeed, when we look at asthma, COPD, and rheumatoid arthritis,

successful trials involved more countries on average than trials completed during this same timeframe that

were not successful (Figure 8a) and they also involved more sites per trial than trials that were not successful

(Figure 8b). Intriguingly, the target accrual for successful trials was higher than for other trials completing

during this timeframe, suggesting that these were larger trials. Despite the expanded geography of these

trials, the increased number of sites and higher average target accrual, the average enrollment period was

shorter among successful trials in all three diseases compared with other trials completing during this timeframe

in these diseases. Future analyses are required to gain clarity around other factors influencing trial success.

Top drug mechanisms of action for these South Korean trials included long-acting beta-2 adrenergic

(LABA) agonists, long-acting muscarinic antagonists (LAMA), CD80/CD86 antagonists, Jak inhibitors,

and TNF alpha antagonists, reflecting drugs with more novel as well as established mechanisms of action.

In addition, Boehringer Ingelheim, GSK, Novartis, and Pfizer conducted 60% of these successful South

Korean trials. Therefore, it is unlikely that success was driven solely by established drugs or a single

drug development program.

The vast majority of successful trials involving South Korea were multinational; only 20% were conducted

exclusively in South Korea. Among these multinational trials, 70 different countries were utilized alongside

South Korea, the top 20 of which appear in Figure 7. In 62% of these South Korean trials, sites within the

United States also were involved; consistent with the observation already noted that most clinical trials

tend to involve the United States. What is intriguing is that among these top 20 countries, many more

countries in Latin America, Eastern Europe, and Asia Pacific were utilized along with South Korea as

compared with the dataset overall (Figure 3). This trend suggests that country selection spanning a wider

geography is taking hold and that these countries in emerging regions are playing an increasingly important

role in trial success, hinting at one strategy for success.

Figure 7. Country Selection Strategies in Autoimmune/Inflammation Trials Involving South Korea

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Trials completing during the 2008 – 2012 period had a slightly better rate of achieving success than a roll

of the dice but at 52.6%, it was only slightly better than chance overall. These odds are much better than

the drug development success rates reported in recent analyses from Tufts Center for the Study of Drug in

a recent analysis conducted by Hay and colleagues where the likelihood of approval for a drug in Phase I

development was a mere 10.4% (Hay, M., et al Nature Biotechnol. 2014 Jan 9, 32(1): 40 - 51). With ever-

increasing drug development costs and lower-than-house odds of drug approval, insight into successful

clinical trial strategies can help drive the odds of trial success in a more favorable direction.

While country selection may be one factor influencing success of clinical trials, trial design, the nature of

the therapeutic tested, and site/investigator selection are all likely to impact the potential for trial success

and will be investigated in future analyses. This insight then can be leveraged to design and conduct

better trials, improving trials success rates and potentially driving overall drug approval rates higher.

Figure 8. Average Enrollment-Related Metrics for Successful Trials and Other Trials Completed 2008 – 2012 in Asthma, COPD and Rheumatoid Arthritis

Figure 8a

Figure 8b

Figure 8d

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Other outcome Positive outcome


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