Innovation in the pharmaceutical industry: New estimates of R&D costs

The most comprehensive survey of clinical success rates across the drug industry to date shows productivity may be even lower than previous estimates.

Clinical development success rates for investigational drugs.

The past 60 years have seen huge advances in many of the scientific, technological and managerial factors that should tend to raise the efficiency of commercial drug research and development (RD). Yet the number of new drugs approved per billion US dollars spent on RD has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms. There have been many proposed solutions to the problem of declining RD efficiency. However, their apparent lack of impact so far and the contrast between improving inputs and declining output in terms of the number of new drugs make it sensible to ask whether the underlying problems have been correctly diagnosed. Here, we discuss four factors that we consider to be primary causes, which we call the 'better than the Beatles' problem; the 'cautious regulator' problem; the 'throw money at it' tendency; and the 'basic research-brute force' bias. Our aim is to provoke a more systematic analysis of the causes of the decline in RD efficiency.

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Diagnosing the decline in pharmaceutical R&D efficiency.

Therapeutic peptides: Historical perspectives, current development trends, and future directions.

Since the commercialization of the first therapeutic monoclonal antibody product in 1986, this class of biopharmaceutical products has grown significantly so that, as of November 10, 2014, forty-seven monoclonal antibody products have been approved in the US or Europe for the treatment of a variety of diseases, and many of these products have also been approved for other global markets. At the current approval rate of ∼ four new products per year, ∼ 70 monoclonal antibody products will be on the market by 2020, and combined world-wide sales will be nearly $125 billion.

https://www.tandfonline.com/doi/pdf/10.4161/19420862.2015.989042

The therapeutic monoclonal antibody market

This study utilizes both public and private data sources to estimate clinical phase transition and clinical approval probabilities for drugs in the development pipelines of the 50 largest pharmaceutical firms (by sales). The study examined the development histories of these investigational compounds from the time point at which they first entered clinical testing (1993-2004) through June 2009. The clinical approval success rate in the United States was 16% for self-originated drugs (originating from the pharmaceutical company itself) during both the 1993-1998 and the 1999-2004 subperiods. For all compounds (including licensed-in and licensed-out drugs in addition to self-originated drugs), the clinical approval success rate for the entire study period was 19%. The estimated clinical approval success rates and phase transition probabilities differed significantly by therapeutic class. The estimated clinical approval success rate for self-originated compounds over the entire study period was 32% for large molecules and 13% for small molecules. The estimated transition probabilities were also higher for all clinical phases with respect to large molecules.

Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs

We examined development risks for new cancer drugs For the full study period, the estimated clinical approval success rate for cancer compounds was 134% (99% for the first half of the study period, 198% for the second half) Small molecules had a somewhat higher clinical approval success rate than did large molecules (143 vs 115%) Compounds studied solely in hematologic indications had markedly higher estimated clinical approval success rates than did compounds studied only in solid tumor indications (360 vs 98%) The first, second, and third cancer indications pursued had estimated clinical approval success rates of 90, 82, and 69%, respectively Success rates of second and third indications were found to be highly dependent on the success or failure of the first indication pursued (549 and 424%, respectively, for second and third indications if the first indication is a success, but 25 and 18%, respectively, if the first indication is a failure)

Clinical Pharmacology & Therapeutics (2013); 94 3, 329–335 doi:101038/clpt2013117

Clinical Approval Success Rates for Investigational Cancer Drugs

Background Previous studies have suggested that anterior cruciate ligament (ACL) reconstruction surgeries are being performed with increased frequency in children and adolescents. The purpose of this study was to evaluate the trend in the frequency of ACL reconstructions normalized by total orthopaedic surgeries at pediatric hospitals nationwide. Methods The Pediatric Health Information System (PHIS) database was queried for patients age 18 years or younger who underwent orthopaedic surgery at any of the PHIS-participating hospitals 2004-2014. The subset of patients who had been treated with ACL reconstruction were identified using Current Procedural Terminology (CPT) and International Classification of Diseases, Ninth Revision (ICD-9) procedure codes. The yearly rate was expressed as the number of ACL reconstructions per 1000 orthopaedic surgeries, and a linear model was used to fit the data to illustrate the relative trend. Results In total, 470,126 orthopaedic surgeries, including 15,231 ACL reconstructions, were performed for patients 18 years or younger at 27 pediatric hospitals. ACL reconstructions were performed at a yearly rate of 32.4 per 1000 orthopaedic surgeries. Between 2004 and 2014, the number of ACL reconstructions increased 5.7-fold, whereas orthopaedic surgeries increased 1.7-fold; there was a 2.8-fold increase in ACL reconstructions relative to total pediatric orthopaedic surgeries. The 10-year relative fold increase was nearly equivalent across sexes, and the increasing trend in ACL reconstructions relative to orthopaedic surgeries was also seen across age groups. Conclusions The number of ACL reconstructions performed for children and adolescents in pediatric hospitals nationwide markedly increased by nearly 3 times relative to orthopaedic surgeries over a recent 10-year period. Level of evidence Level IV.

Trends in Pediatric ACL Reconstruction From the PHIS Database.

Purpose Research on venous thromboembolism events (VTE), such as deep venous thrombosis (DVT) and pulmonary embolism (PE), in pediatric orthopaedic trauma patients is sparse. We describe the incidence in the USA of VTE associated with pediatric lower extremity orthopaedic trauma, and characterize injury patterns and VTE treatment methods. Methods The Pediatric Health Information System (PHIS) was queried from 2004 to 2013 using ICD-9 codes for lower extremity fractures (pelvis, femur, tibia, ankle, foot) and dislocations (hip, knee, ankle, subtalar) and VTE. Records were queried for age, diagnoses, and VTE treatment. Results During the study period 285,611 clinical encounters reported lower extremity trauma. Of those, 167 patients were simultaneously coded with VTE (99 DVT, 50 PE, 18 combined DVT/PE), to give an incidence of VTE associated with pediatric lower extremity trauma of 0.058 %. Patients were from 39 centers, with an average age of 12.9 years (range 0–19). There were 249 fractures and 2...

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Pediatric orthopaedic lower extremity trauma and venous thromboembolism

We compared clinical trials described in package inserts from noncancer orphan and nonorphan drugs from 1 January 2001 to 31 December 2011. Among the 37 orphan and 58 nonorphan drugs approved by the US Food and Drug Administration (US FDA) during this period, orphans had fewer clinical trials (2.8 vs. 3.5, P < 0.05) and fewer total participants (390 vs. 2,566, P < 0.001), but proportions with randomization, blinding, and placebo-controlled clinical end points were similar, as were development times. We conclude that small studies of appropriate design can support US FDA approval of new medicines for rare diseases.

Lanna Feldman

Papers

Trends in Risks Associated With New Drug Development: Success Rates for Investigational Drugs

Clinical Approval Success Rates for Investigational Cancer Drugs

Trends in Pediatric ACL Reconstruction From the PHIS Database.

Pediatric orthopaedic lower extremity trauma and venous thromboembolism

Raising orphans: how clinical development programs of drugs for rare and common diseases are different.