Peer-Reviewed Scientific Publications
Lost medicines: a longer view of the pharmaceutical industry with the potential to reinvigorate discovery. Kinch MS, Kinch GA, Griesenauer RH. Drug Discov Today. 2018 Sep 14. pii: S1359-6446(18)30266-6. doi: 10.1016/j.drudis.2018.09.006
It is widely understood that the 1962 Kefauver-Harris Amendment to the Food, Drug and Cosmetics Act ushered in the modern regulation of medicines requiring a combination of safety and efficacy. However, fewer appreciate the amendment was applied retroactively to virtually all medicines sold in the USA. For various reasons, many medicines faded into history. Here, we identify and analyze >1600 medicines (including over-the-counter drugs) and their innovators prior to the enactment of Kefauver-Harris. We report 880 of these past medicines are no longer accessible. This project also reveals new insight into the pharmaceutical enterprise, which reveals an industry already mature and beginning to retract before enactment of the legislation. Beyond its historical implications, the recollection of these medicines could offer potential starting points for the future development of much-needed drugs.
2017 in review: FDA approvals of new molecular entities. Kinch MS, Griesenauer RH. Drug Discov Today. 2018 Aug;23(8):1469-1473. doi: 10.1016/j.drudis.2018.05.011. Epub 2018 May 8.
An overview of drugs approved by the FDA in 2017 reflected a reversion to the mean after a low number of NME approvals in 2016. This reversal was largely driven by the largest number of biologics-based NMEs recorded to date, which offset an average number of small-molecule approvals. Oncology indications continued to dominate followed by novel treatments for infectious, immunologic and neurologic diseases. From a mechanistic standpoint, the industry has continued a trend of target diversification, reflecting advances in scientific understanding of disease processes. Finally, 2017 continued a period of relatively few mergers and acquisitions, which broke a more-than-a-decade-long decline in the number of organizations contributing to research and development.
NIH Support for FDA-Approved Medicines. Griesenauer RH, Moore R, Kinch MS. Cell Chem Biol. 2017 Nov 16;24(11):1315-1316. doi: 10.1016/j.chembiol.2017.11.002.
An overview of FDA-approved vaccines & their innovators. Griesenauer RH, Kinch MS. Expert Rev Vaccines. 2017 Dec;16(12):1253-1266. doi: 10.1080/14760584.2017.1383159. Epub 2017 Sep 25.
A survey of FDA-approved biologicals focused upon the development of immunotherapies over time to gain insight on the challenges and trends of vaccine development today. Areas covered: A total of 135 different immune-based therapies were broadly divided into passive or active immunotherapies. Whereas just over half of passive immunotherapies targeted infectious diseases, the vast majority of active immunotherapy products (vaccines) were directed against a handful of viral and bacterial pathogens. We also analyze changes in vaccine strategy, including the use of viable antigens and subunit approaches. Expert commentary: An analysis of vaccine innovators revealed an ever-increasing presence of the private sector and a relatively diminishing role for the public sector . Whereas North American companies have contributed to the approval of two-thirds of vaccines, European companies have regained parity in terms of hosting innovators of vaccine research and development.
2016 in review: FDA approvals of new molecular entities. Griesenauer RH, Kinch MS. Drug Discov Today. 2017 Nov;22(11):1593-1597. doi: 10.1016/j.drudis.2017.06.011. Epub 2017 Jul 4.
An overview of drugs approved by FDA in 2016 reveals dramatic disruptions in long-term trends. The number of new molecular entities (NMEs) dropped, reflecting the lowest rate of small-molecule approvals observed in almost five decades. In addition, the pace of industry consolidation slowed substantially. The impact of mergers and acquisitions decreased the total number of organizations with past approval experience and continued research and development (R&D) activities to 102, divided evenly between more established pharmaceutical and newer biotechnology companies. Despite these substantial differences, the industry continued to pursue regulatory incentives, as evidenced by a continued increase in the fraction of NMEs approved using an orphan or priority designation, and almost all oncology drugs approved in 2016 utilized these mechanisms.
Food and microbiota in the FDA regulatory framework. Green JM, Barratt MJ, Kinch M, Gordon JI. Science. 2017 Jul 7;357(6346):39-40. doi: 10.1126/science.aan0836. No abstract available
Analysis of FDA-approved imaging agents. Kinch MS, Woodard PK. Drug Discov Today. 2017 Jul;22(7):1077-1083. doi: 10.1016/j.drudis.2017.03.006. Epub 2017 Mar 21.
The development of imaging agents was initially driven following the discovery of X-ray technologies, but quickly evolved and expanded to include radiolabeling of cells and tissues to assist disease diagnosis and progression. The first imaging agents preceded the Great War but the field did not gain momentum until the 1950s. The approval rate for imaging NMEs continued at a high level for the remainder of the 20th century, but substantially decreased thereafter. This decline in approval rates corresponds with industry consolidation. Such losses have stabilized, but could have important implications for a field that has conveyed direct benefits to medicine and that could ensure the future of the wider biopharmaceutical industry.
Innovator Organizations in New Drug Development: Assessing the Sustainability of the Biopharmaceutical Industry. Kinch MS, Moore R. Cell Chem Biol. 2016 Jun 23;23(6):644-53. doi: 10.1016/j.chembiol.2016.05.013. Review.
The way new medicines are discovered and brought to market has fundamentally changed over the last 30 years. Our previous analysis showed that biotechnology companies had contributed significantly to the US Food and Drug Administration approval of new molecular entities up to the mid-1980s, when the trends started to decline. Although intriguing, the focus on biotechnology necessarily precluded the wider question of how the biopharmaceutical industry has been delivering on its goals to develop new drugs. Here, we present a comprehensive analysis of all biopharmaceutical innovators and uncover unexpected findings. The present biopharmaceutical industry grew steadily from 1800 to 1950 and then stagnated for two decades, before a burst of growth attributable to the biotechnology revolution took place; but consolidation has reduced the number of active and independent innovators to a level not experienced since 1945. The trajectories and trends we observe raise fundamental questions about biopharmaceutical innovators and the sustainability of the drug-development enterprise.
2015 in review: FDA approval of new drugs. Kinch MS. Drug Discov Today. 2016 Jul;21(7):1046-50. doi: 10.1016/j.drudis.2016.04.008. Epub 2016 Apr 19.
The myriad new molecular entities (NMEs) approved by the US Food and Drug Administration (FDA) in 2015 reflected both the opportunities and risks associated with the development of new medicines. On the one hand, the approval of 45 NMEs was among the highest ever recorded. Likewise, the diversity underlying the mechanistic basis of new medicines suggests continued broadening relative to the predominate trends of the past few decades. On the other hand, closer inspection indicates that business model decisions surrounding orphan indications and consolidation could be placing the industry in an ever-more precarious position, with severe implications for the sustainability of the entire enterprise.
Academic researchers shaped the landscape of drug discovery for nearly two centuries, and their efforts initiated programs for more than half of the US Food and Drug Administration (FDA)-approved new molecular entities (NMEs). During the first 50 years of the 20th century, contributions from industry-based discovery programs steadily increased, stabilizing near half of all first publications for NMEs. Although academia and industry have made similar contributions to the discovery of FDA-approved NMEs, there remains a substantial difference in the gap-to-approval; on average, industry NMEs are 12 years closer to market at the time of the first publication. As more drug discovery efforts shift from industry to academia, including high-throughput screening resources, academia could have an increasingly crucial role in drug discovery.
Enhancing the Quality of Patent Claims Directed to Biologics with Biophysical Evidence Lathrop BK, Kinch MS – Biotechnology Law Report, 2015 – liebertpub.com
2014 in review: FDA approval of new drugs. Kinch MS. Drug Discov Today. 2017 Apr;22(4):620-624. doi: 10.1016/j.drudis.2015.06.004. Epub 2015 Jun 19.
The year 2014 witnessed the approval by the US Food and Drug Administration (FDA) of 42 new molecular entities (NMEs), which is well above recent averages. These molecules targeted a range of molecular pathways and clinical indications, although the latter was skewed toward hepatitis C virus (HCV) infection and diabetes. By contrast, a single drug was approved for cardiovascular diseases and none for neurological indications (excepting sleeping disorders). Of note is a continued trend toward consolidation because the net number of biotechnology companies has reached its lowest point in over 25 years, raising questions about sustainability.
The term ‘inflammation’ captures a variety of disease processes linked with the immune system. An analysis of US Food and Drug Administration (FDA)-approved nuclear molecular entities (NMEs) reveals notable trends in terms of acute and chronic inflammatory indications. The number of NMEs peaked during the 1990s and has since declined by more than 50%. Whereas pharmaceutical companies have dominated the field, biotechnology companies now receive half of new approvals and academia has a relatively large role in terms of pivotal first patents. Another notable trend is that the relative number of NMEs targeting allergy has been decreasing, whereas those targeting autoimmune indications is increasing. Unlike other indications, NMEs for inflammation tend towards nuclear receptors and cytokines, and a disproportionate number of biologics target cytokine pathways.
An analysis of FDA-approved drugs for metabolic diseases. Kinch MS, Umlauf S, Plummer M. Drug Discov Today. 2015 Jun;20(6):648-51. doi: 10.1016/j.drudis.2015.02.002. Epub 2015 Feb 11.
Metabolic diseases encompass a constellation of maladies including obesity and diabetes that are among the fastest growing epidemics throughout the world. An analysis of new molecular entities (NMEs) targeting metabolic diseases reveals the rate of approval for new drugs increased in the mid-1990s and now stands at approximately two per year. The increase is largely attributed to a recent emphasis on treatments for inborn errors of metabolism. In particular, biotechnology companies have focused on rare genetic disorders, which are often treated with biologic-based NMEs that target novel pathways and qualify for orphan drug status. By contrast, NME development by pharmaceutical companies tended toward conventional small molecular targeting of nongenetic disorders such as diabetes.
An analysis of FDA-approved drugs: natural products and their derivatives. Patridge E, Gareiss P, Kinch MS, Hoyer D. Drug Discov Today. 2016 Feb;21(2):204-7. doi: 10.1016/j.drudis.2015.01.009. Epub 2015 Jan 21.
Natural products contribute greatly to the history and landscape of new molecular entities (NMEs). An assessment of all FDA-approved NMEs reveals that natural products and their derivatives represent over one-third of all NMEs. Nearly one-half of these are derived from mammals, one-quarter from microbes and one-quarter from plants. Since the 1930s, the total fraction of natural products has diminished, whereas semisynthetic and synthetic natural product derivatives have increased. Over time, this fraction has also become enriched with microbial natural products, which represent a significant portion of approved antibiotics, including more than two-thirds of all antibacterial NMEs. In recent years, the declining focus on natural products has impacted the pipeline of NMEs from specific classes, and this trend is likely to continue without specific investment in the pursuit of natural products.
New drug discovery: extraordinary opportunities in an uncertain time. Kinch MS, Flath R. Drug Discov Today. 2015 Nov;20(11):1288-92. doi: 10.1016/j.drudis.2014.12.008. Epub 2014 Dec 17.
The way in which new medicines are discovered has irreversibly changed and the future sustainability of the enterprise is characterized by an unprecedented period of uncertainty. Herein, we convey that these changes provide unprecedented opportunities for many different players within the private and public sectors to work together and develop new models that ensure the sustainability of activities that have had an extraordinary impact; in terms of promoting public health and driving economic value. Specific examples of experiments are provided to demonstrate some of the new thinking that will be needed to ensure continuation of new drug discovery.
An analysis of US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) reveals dynamism in terms of new innovation. An assessment of the first patent for each drug shows that the pharmaceutical industry, particularly large, established companies in North America, tend to dominate the field. Over the past 10-15 years, European and Asian organizations have begun to close the gap. A dynamic inventive environment in drug discovery is suggested by the fact that NMEs for biologics or awarded to biotechnology companies often have inventors from the pharmaceutical and academic sectors. Whereas inventors continue to found biotechnology companies at a steady rate, recent trends suggest these inventors more often come from the private sector.
The biopharmaceutical industry translates fundamental understanding of disease into new medicines. As part of a comprehensive analysis of FDA-approved new molecular entities (NMEs), we assessed the mechanistic basis of drug efficacy, with emphasis on target selection. Three target families capture almost half of all NMEs and the leading ten families capture more than three-quarters of NME approvals. Target families were related to their clinical application and identify dynamic trends in targeting over time. These data suggest increasing attention toward novel target families, which presumably reflects increased understanding of disease etiology. We also suggest the need to balance the ongoing emphasis on target-based drug discovery with phenotypic approaches to drug discovery.
Post-approval fate of pharmaceutical companies. Kinch MS. Drug Discov Today. 2015 Feb;20(2):170-4. doi: 10.1016/j.drudis.2014.10.013. Epub 2014 Nov 4.
For a fortunate subset of pharmaceutical companies, a regulatory approval is the culmination of massive investment in time, work and money. What happens next? Some companies proceed to build a pipeline and obtain additional approvals. Others do not. In this present report, post-approval fate is evaluated and it was found that most companies are ultimately acquired. A subset achieved a second approval six-to-eight years after the first approval, whereas a shrinking subset, designated as ‘singlets’, remains active in drug discovery with only a single approval. The likelihood that a company will remain a singlet or be acquired relates to therapeutic indication, with oncology associated with increased acquisition potential and infectious-disease-based companies being less commonly acquired.
Recombinant DNA technologies revolutionized medicine. Herein, the approvals and mechanistic basis of biologics-based medicines are analyzed. The overall and relative rate of FDA approvals for recombinant proteins grew from the 1980s through the first half-decade of the new millennium. Over time, the number of biologics gaining approval for an orphan indication has climbed to more than 50% in the current decade. The field has been dynamic in terms of the types of biologics, indications targeted and the mechanistic basis of drug activity. Despite impressive increases in recombinant-protein-based medicine, the rate of new biologics approvals could have leveled out.
The need to alleviate pain is among the first recorded uses for medicines, dating back to the onset of the Neolithic period. The need persists and many of today’s best-known drugs (e.g. aspirin, acetaminophen, morphine) are included within this category. An analysis of FDA-approved new molecular entities (NMEs) for pain and anesthesia reveals a fluctuating rate of new introductions, which has plummeted in recent years. The largest emphasis has been placed on acute pain, largely targeting G-protein-coupled receptors and a relatively narrow subset of molecular pathways. NMEs targeting anesthesia tend to focus on channels and four molecular pathways capture a large majority of NMEs for this indication.
An analysis of the approval of new molecular entities (NMEs) targeting psychiatric disorders reveals a remarkably steady approval rate over time. The overall rate of new drug approval for some indications, such as depression and schizophrenia, has remained stable over time. NMEs addressing anxiety and psychosis peaked in past decades and new approvals are now uncommon. From a mechanistic basis, three classes of targets dominate the field and perhaps, more notably, two different pathways encompass two-thirds of all psychiatric NMEs. In recent years, serotonin-based drugs have dominated new approvals. In parallel, neurotransmitter reuptake inhibitors have gained increasing prominence.
Following the introduction of antibiotic therapy and widespread inoculations, cardiovascular diseases have leapt ahead of infectious diseases in terms of prevalence in much of the developed and developing world. Herein, we assess FDA-approved drugs for the treatment of cardiovascular diseases. The drug development enterprise around cardiovascular diseases has remained stable in contrast to turbulent changes in other therapeutic indications. However, upon closer inspection, the results identify narrow scope in terms of the breadth of targets and the mechanistic actions of new drugs. From the public health point of view, it is important to balance incremental change with orthogonal innovations that are needed to combat a leading cause of morbidity and mortality.
Cancer remains the second leading cause of death globally. The number of new medicines targeting cancer has grown impressively since the 1990s. On average, ten new drugs are introduced each year. Such growth has partly been achieved by emphasizing biologics and orphan indications, which account for one-quarter and one-half of new oncology drugs, respectively. The biotechnology industry likewise has become the primary driver of cancer drug development in terms of patents, preclinical and clinical research, although pharmaceutical companies are granted more FDA approvals. Many targeting strategies have been successful but recent trends suggest that kinase targets, although tractable, might be overemphasized.
An analysis of FDA-approved drugs for infectious disease: antibacterial agents. Kinch MS, Patridge E, Plummer M, Hoyer D. Drug Discov Today. 2014 Sep;19(9):1283-7. doi: 10.1016/j.drudis.2014.07.005. Epub 2014 Jul 17.
Drugs targeting infectious diseases have greatly improved public health. A study to evaluate all US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) reveals that the number of new agents targeting infectious disease peaked during the 1990s and declined rapidly thereafter. Molecules targeting bacterial pathogens represent the most common component of anti-infectives followed by antivirals and antifungals. Focusing on antibacterial agents, an increase in new NMEs predominated from the 1960s through to the 1990s, dropping sharply thereafter. Obsolescence and resistance has eliminated one-third of these drugs. Consequently, the arsenal of antibiotics peaked in 2000 and is declining. Likewise, the number of organizations awarded at least one NME for a bacterial indication has declined to a level not seen in more than a half century.
Trends in pharmaceutical targeting of clinical indications: 1930-2013. Kinch MS, Merkel J, Umlauf S. Drug Discov Today. 2014 Nov;19(11):1682-1685. doi: 10.1016/j.drudis.2014.05.021. Epub 2014 May 29.
An analysis of FDA-approved new molecular entities (NMEs) reveals trends in therapeutic applications. Four groupings (infectious diseases, cardiovascular diseases, autoimmune/inflammatory diseases and cancer) capture more than 60% of NMEs. Infectious diseases are the most targeted indications. Near the turn of the new millennium, the rate of new approvals for infectious diseases decreased. The absolute and relative number of NMEs targeting psychiatric, neurological and pain/itch indications also declined. By contrast, NMEs targeting cancer have risen in the past two decades as have NMEs targeting orphan indications. These results suggest the drug development community has largely been responsive to public health and market needs. However, finite resources might indicate emphasis on some unmet needs could come at the cost of others.
HIV/AIDS is one of the worst pandemics in history. According to the World Health Organization, 26 million people have died since 1981 – 1.6 million in 2012 alone. The dramatic rise in HIV/AIDS mobilized a swift and impressive coordination among governmental, academic and private sector organizations to identify the virus and develop new treatments. Herein, we assess the arsenal of 28 new molecular entities (NMEs) targeting HIV/AIDS. These data demonstrate that the first approval of zidovudine presaged an expansion of the antiviral repertoire over the following years. Whereas the rate of HIV/AIDS NMEs is rapidly declining, so is the number of organizations developing NMEs. We speculate that decisions to abandon further research reflect, in part, growing costs and time required for development.
The rise (and decline?) of biotechnology. Kinch MS. Drug Discov Today. 2014 Nov;19(11):1686-1690. doi: 10.1016/j.drudis.2014.04.006. Epub 2014 Apr 18.
Since the 1970s, biotechnology has been a key innovator in drug development. An analysis of FDA-approved therapeutics demonstrates pharmaceutical companies outpace biotechs in terms of new approvals but biotechnology companies are now responsible for earlier-stage activities (patents, INDs or clinical development). The number of biotechnology organizations that contributed to an FDA approval began declining in the 2000s and is at a level not seen since the 1980s. Whereas early biotechnology companies had a decade from first approval until acquisition, the average acquisition of a biotechnology company now occurs months before their first FDA approval. The number of hybrid organizations that arise when pharmaceutical companies acquire biotechnology is likewise declining, raising questions about the sustainability of biotechnology.
The pharmaceutical industry is undergoing fundamental change and its future is unclear. We performed a meta-analysis by cataloging FDA-approved legacy drugs and new molecular entities (NMEs). Objective information regarding scientific, medical and commercial activities was captured and provides insight into processes governing drug development. In this report, we review the rates of NME introduction through to the end of 2013. Recent trends show the emergence of a handful of companies that controls two-thirds of NMEs. We also report growth in the number of NMEs controlled by marketing organizations that have little or no internal drug discovery or development activities. This trend has increased dramatically since 2000 and could raise important questions about the future landscape and viability of drug discovery and development.