On June 26, 2000, accompanied by Francis Collins and Craig Venter, competitors in the race to map the human genome, President Bill Clinton marched into the East Room of the White House, where, he noted, 200 years before, Meriwether Lewis had laid out his expedition across the American frontier to the Pacific Ocean for an appreciative Thomas Jefferson. Two centuries later, Clinton suggested that Collins and Venter’s mapping of the human genome would prove more momentous than Lewis and Clark’s journey across the American continent.
“Today the world is joining us here in the East Room to behold the map of even greater significance” than Lewis and Clark’s, Clinton claimed. “We are here to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wonderous map ever produced by humankind.”1
Never mind that the map of the human genome was not then completed, nor would it be, Clinton said, for another three years. And never mind too that in 2000 we did not even know the number of genes in the genome. It was estimated then that there were between 25,000 and 150,000. The accurate number, we later learned, was closer to 20,000.
Clinton was confident that because we “are learning the language in which God created life,” understanding the human genome would, in the words of the New York Times, “revolutionize the practice of medicine.”2 The Times gave the news a banner headline: “Genetic Code of Life Is Cracked by Scientists,” exclaiming correctly that the new map of the human genome would lead to the development of an array of new diagnostics and treatments, including ones, it thought, would exploit the body’s own mechanisms of self-repair, which later revolutionized the field of immunotherapy.
The first public reference to personalized medicine came in a Wall Street Journal article, published in 1999, titled, “New Era of Personalized Medicine: Targeting Drugs for Each Unique Genetic Profile,” which discussed the formation of a new pharmaceutical company-led Single Nucleotide Polymorphisms Consortium3. But it was not until between the years 2000 and 2003 that the promise of personalized medicine really took hold.
Francis Collins used his perch as director of the National Human Genome Research Institute to become personalized medicine’s leading apostle. In testimony to Congress in 2003, he argued that linking therapy to genomic-based diagnostics would not only further facilitate the development of targeted therapy, later rebranded by President Obama as “precision medicine,”4 but that it would also, within ten years, allow physicians to employ “predictive genetic tests” [to] “learn our individual risks for future illnesses and practice more effective health maintenance and disease prevention.”5
Assisted by Millennium Pharmaceuticals in Cambridge, Massachusetts, which became, along with Craig Venter’s Celera Genomics, personalized medicine’s leading avatar in the private sector, proponents for the new paradigm coined a new mantra: “the right drug for the right patient at the right time” to define their goal. That mantra over time—albeit not without a lot of strum und dang—reshaped the way the pharmaceutical industry developed new drugs. It was said with confidence, and believed by many, that medicine in the 21st century could and would become personalized, predictive, and preventive.
Especially considering how difficult it is to change a medical paradigm, never mind a medical practice, it has become easy to scoff at these predictions, especially in the early years when there were relatively few examples of personalized medicine. As Machiavelli explained, “There is nothing more difficult . . . than to take the lead in a new order of things.” This, he said, is partly the consequence of people’s fear of the future, but also their reluctance to “believe in new things until they have had a long experience of them.”6
Pursuing “shared value”
Based on the assumption that paradigm changes in medicine don’t happen just because science and new technologies suggest they should, in 2004 proponents of personalized medicine publicly launched a new coalition of stakeholders. It included members of the diagnostic and pharmaceutical industries, academia, venture capital, payers, providers, and patient advocacy groups whose mission it was—and remains—to increase investment in and speed the clinical adoption of personalized medicine. Their insight recognized that the “widespread adoption of personalized medicine will require the harmonization of . . . advances in technology” with “changes in healthcare infrastructure and medical practice convention,” as Brian Munroe, the Personalized Medicine Coalition’s first president and founder, wrote in the Coalition’s inaugural statement, published in Personalized Medicine in 2004.7
In other words, replacing one-size-fits-all, trial-and-error medicine with health care that was targeted, efficient, and patient-oriented was going to require, PMC’s founders believed, a systems-wide approach. No single stakeholder could push through a coherent and encompassing strategy for adoption on its own. Personalized medicine, they argued, demanded teamwork among its multiple players as well as assistance from the government that could incentivize its development through regulatory and reimbursement policies.8
What Munroe and other PMC founders were calling for was what Mark R. Kramer and Marc C. Pfitzer, writing in Harvard Business Review, in 2016 called an “ecosystem of shared value” in which competing stakeholders come together to solve social and business problems that emanate from uncoordinated actions and lead to missed opportunities.9 By linking sophisticated diagnostics to targeted therapies to treat or prevent disease, for example, diagnostic and pharmaceutical companies could combine forces to produce better outcomes for patients and greater efficiencies, if not profits, for themselves.
In order to introduce “a new order of things”, as Machiavelli put it, three critical players in the personalized medicine ecosphere had work together: the pharmaceutical industry, which, despite early reluctance, has led the way to personalized medicine; the diagnostics industry, which remains unfortunately mired in regulatory and reimbursement confusion; and health care providers, who are still working through issues on how to deliver personalized medicine to patients.
Towards Targeted Therapeutics
In 2004, John Lechleiter, then the Executive Vice President for Pharmaceutical Operations at Eli Lilly, correctly noted, “The power in tailored therapeutics is for us to say more clearly to payers, providers, and patients—‘this drug is not for everyone, but it is for you.’”10 In 2004 his was a visionary statement, notably by a pharmaceutical industry executive. Most pharmaceutical executives were, if not opposed to personalized medicine, deeply skeptical because, they believed, it would stratify the market and, consequently, depress sales.
In 2007, Lechleiter, who was then president and CEO of the company, exclaimed, “We at Lilly remain mystified by the skepticism that persists” in the pharmaceutical industry around personalized medicine, noting that, in his view, not only would Lilly’s “business model . . . accommodate personalized medicine, it may, in fact, depend on it.” [Emphasis his]11
In 2007 there were fewer than five personalized drugs on the market; that is, targeted therapies with biomarker strategies on their labels. As Lechleiter alluded, most of his colleagues in other companies were deeply skeptical, if not fearful, that personalized medicine would limit the size of the market for any particular drug. Mara Aspinall and Richard Hamermesh wrote in Harvard Business Review, also in 2007, that the biggest obstacle “hindering the transition from trial-and-error medicine to personalized medicine” was the pharmaceutical industry’s devotion to its “historically successful blockbuster model.” 12
Despite some early and notable successes, most pharmaceutical companies were reluctant to invest in companion diagnostics until the second decade of the century even though in the words of Paul Hudson, then President of AstraZeneca U.S., it offered “better diagnoses, fewer adverse drug reactions, increased patient adherence, improved quality of life, and ultimately, significant savings in overall U.S. health care costs.”13
The pharmaceutical industry did not just suddenly see the light, or discover a new map, however. It felt the heat—the heat coming from the FDA, which, under the direction of Janet Woodcock, Director of the Center for Drug Evaluation and Research, began insisting on higher levels of efficacy and safety before it would approve new drugs, goals that could only be achieved by tailoring medicines to treat the right patients based on selected biomarkers. Woodcock pointed out in 2015 that FDA had “been pushing for targeted therapies . . . for a long time,” noting that 60 percent of approved targeted therapies were based on a single trial and that more than 90 percent used one or more of FDA’s expedited programs.14
The results can be viewed on the PMC chart below.
In six of the last seven years, over one third of all drug approvals were personalized medicines.15 This would not have happened without governmental assistance, or “nudging,” as it has been called.16
These targeted drugs, which include prominent personalized medicines such as Herceptin (trastuzumab) for HER2 positive breast cancer patients, Zelboraf (vemurafenib) for melanoma patients with a BRAF mutation, and Kalydeco (ivacaftor) for cystic fibrosis patients with CFTR mutations have given new hope to millions. In turn, the pharmaceutical and biotechnology industries have been transformed. Nor is this unsung revolution in drug development restricted to first-generation targeted therapies as new technologies, including cell and gene therapies, open new horizons of treatment. In addition, most large pharmaceutical companies have unprecedented efforts underway to address orphan diseases.
The Diagnostic conundrum
In 2006, two years after the introduction of a first of its kind genomic assay that could predict the likelihood of breast cancer recurrence and thereby allow thousands of patients to avoid the additional costs and often grueling side effects of chemotherapy, Kim Popovits, president and chief operating officer of Genomic Health, exclaimed, “The system has to recognize diagnostics with the same value proposition that [it does for] therapeutics.”17 Suffice it to say, two decades later, her wish is still not reality.
Thankfully for patients, Genomic Health, later acquired by Exact Sciences, won its battle to break out of the poorly compensated, commodity-based diagnostic world. Unfortunately, though, diagnostics, by and large, have not yet come close to winning the war, first identified by Popovits, to be recognized for the value they bring in determining the right treatment for the right patient at the right time. This diagnostic conundrum, unfortunately, is rate limiting for personalized medicine, which depends on sophisticated diagnostics, as well as, paradoxically, the diagnostics industry itself.
The reasons the diagnostics industry has failed to take off in keeping with the promise of personalized medicine are manifold.
Whereas the pharmaceutical industry has had over a century of experience being regulated by the U.S. FDA, which it has used to its full advantage to assure the public, if not the world, regarding the quality and value of drugs researched and developed in the United States, the federal regulation of diagnostics has not been updated since 1976, a quarter century before that celebrated map was unveiled in the White House, and at a time when diagnostics were essentially a backwater in health care.
In consequence, confusion reigns in the field especially regarding highly innovative laboratory developed tests, as regulatory bodies compete for authority and multiple diagnostic companies seek competitive advantage through reimbursement from the Centers for Medicare and Medicaid Services, which, if left to its own devices, does not reward innovation because, as in other countries, it is essentially the government’s purchasing agent. The price for diagnostics, unlike drugs until recently, is for the most part determined by the government in the United States. Despite marginal efforts to use its purchasing power to encourage innovation, CMS is today predominately interested in reigning in the cost of health care even at the expense of innovation.
The indeterminate discussion regarding the regulation of laboratory developed tests began at the dawn of genomic medicine and has diverted attention from putting in place reasonable standards to evaluate the analytical validity and clinical utility of diagnostic tests in favor of preserving low barriers of entry into the market. A low barrier of entry may encourage innovation, but it comes at the expense of returns on investment and clinical adoption if untested new diagnostic products are not trusted by payers, conditioned to be skeptical, and providers, who are trained to be conservative.
In 2012, Sue Siegel, then a partner at Mohr Davidow Ventures, pointed out on behalf of investors, “If the rules of the road are clear, industry can develop the diagnostic products patients need.”18 Suffice it to say, those rules are more contested than ever. As a result, because for the most part diagnostic tests are not rewarded for the value they bring to determine the correct treatment, investors have been slower to support personalized medicine products than they otherwise might have been.
Implementing personalized medicine
In a groundbreaking study published in JCO Precision Oncology at the end of 2022 titled “Impact of Clinical Practice Gaps on the Implementation of Personalized Medicine in Advanced Non-Small-Cell Lung Cancer,” researchers from the Personalized Medicine Coalition and Diaceutics, a United Kingdom-based diagnostic company, documented that only 36 percent of patients with advanced non-small cell lung cancer received the precision medicine strategy that would have helped deliver the best treatment for them. This so-called “practice gap,” the result of seven identified causes, reminds us that personalized medicine does not occur just because the science suggests it should. According to the paper, “More than one third of U.S. patients with cancer miss out on precision oncology treatment because of suboptimal testing practices.”19
Bill Clinton may have been correct when he said in 2000 that the map of the human genome “was the most wonderous map ever produced by humankind.” Unfortunately, as seems to be the case a quarter century later, most physicians treating cancer, not to mention many other diseases, are still unnecessarily flying blind.
Conclusion
Testifying before Congress in 2003, Francis Collins confidently predicted that by 2020 “gene-based designer drugs are likely to be available for conditions like diabetes, Alzheimer’s disease, hypertension, and many other disorders. Cancer treatment will precisely target the molecular fingerprints of particular tumors, [and] genetic information will be used routinely to give patients more appropriate drug therapy.”20
Although Collins’ timeline may have been too short, he was not wrong in understanding where medicine was, and is, headed.
Unfortunately, he underestimated the length of time and the amount of investment it would require in Machiavelli’s words, “to introduce a new order of things” in health care, assuming incorrectly that more biomedical research alone would lead inexorably to the promise of personalized medicine that Bill Clinton had envisioned at the dawn of the 21st century. Without reference to the regulatory and reimbursement structures that govern the translation of science and technology into practice and without a concerted effort by both providers and payers to integrate innovative new discoveries in science and technology into clinical care, patients will have to wait longer for medicine to truly become personalized, predictive, and preventive.
Edward Abrahams, PhD, is president of the Personalized Medicine Coalition, an education and advocacy organization in Washington, DC. The views expressed here are his own and not those of the Coalition.
- Text of the White House Statements on the Human Genome Project, New York Times, June 27, 2000.
- New York Times, June 27, 2000, p.1.
- Cited in Jan Trost Jorgensen, “Twenty Years with Personalized Medicine: Past, Present, and Future of Individualized Pharmacotherapy,” The Oncologist, 2019; 24:1-9. Available at https://pubmed.ncbi.nlm.nih.gov/30940745/.
- Barack Obama, “Medicine’s Next Step,” The Boston Globe. July 7, 2016. Available at https://www.bostonglobe.com/opinion/2016/07/06/medicine-next-step/tPdgf4XfOHvUckHpTTbuvN/story.html.
- Statement of Francis S. Collins, M.D., Ph.D., to Congress on Thursday, May 22, 2003. Available at: https://www.genome.gov/11007447/2003-francis-collins-testimony-the-future-of-genomics.
- The Prince, Chapter VI.
- “A coalition to drive personalized medicine forward,” Personalized Medicine (2004), 1 (1), 9-13. Available at https://pubmed.ncbi.nlm.nih.gov/29793218/.
- Edward Abrahams, et al, “The Personalized Medicine Coalition: Goals and Strategies,” American Journal of Pharmacogenomics, 2005 (5) 6: 345-355. Available at https://pubmed.ncbi.nlm.nih.gov/16336000/.
- “The Ecosystem of Shared Value,” Harvard Business Review, October 2016. Available at https://hbr.org/2016/10/the-ecosystem-of-shared-value.
- Alexandra Hallen O’Herman. “Personalized Medicine: Tailored Therapeutics and the Pharmaceutical Organization,” Unpublished Manuscript, Harvard Business School, December 22, 2004.
- “Markets of One: The Pharmaceutical Industry and the Pursuit of Personalized Medicine,” Remarks by John C. Lechleiter, Conference on Personalized Medicine – Boston, November 29, 2007.
- “Realizing the Promise of Personalized Medicine,” Harvard Business Review, October 2007, 108-117. Available at https://hbr.org/2007/10/realizing-the-promise-of-personalized-medicine.
- “Personalized Medicine and the ‘Immense Opportunities’ Before Us,” Education and Advocacy (Blog), Personalized Medicine Coalition, October 29, 2015.
- “FDA Continues to Lead in Precision Medicine,” FDA Voice (Blog), March 23, 2015.
- Personalized Medicine Coalition. Personalized Medicine at FDA: The Scope & Significance of Progress in 2023. Published February 29, 2024. Available at https://www.personalizedmedicinecoalition.org/wp-content/uploads/2024/02/report-3.pdf.
- See Richard Thaler and Cass Sunstein, Nudge: Improving Decisions About Health, Wealth, and Happiness (N.Y.: 2009).
- “Genomic Health: Launching A Paradigm Shift . . . and an Innovative Test,” Stanford Graduate of Business, Case OIT-49, 2-14-06.
- Sue Siegel to author, February 22, 2012.
- Helen Sadik et al. “Impact of Clinical Practice Gaps on the Implementation of Personalized Medicine in Advanced Non-Small-Cell Lung Cancer.” JCO Precision Oncology. October 31, 2022. Vol. 6. Available at https://ascopubs.org/doi/full/10.1200/PO.22.00246.
- Statement of Francis S. Collins, M.D., Ph.D., to Congress on Thursday, May 22, 2003.
