strategy+businessONLINE AUGUST 13, 2012BY AVI KULKARNI AND NELIA PADILLA MCGREEVYA Strategist’s Guide toPersonalized MedicineBreakthroughs in pharmaceutical innovation are poised tochange the prevailing business model of the industry — withdramatic, disruptive effects on healthcare costs and practice.
O A Strategist’s Guide to Personalized Medicine Breakthroughs in pharmaceutical innovation are poised to change the prevailing business model of the industry — with dramatic, disruptive effects on healthcare costs and practice. by Avi Kulkarni and Nelia Padilla McGreevy1www.strategy-business.com ne of the most innovative medications of recent ly to benefit from chemotherapy. The results of this test years is Novartis’s imatinib, which is marketed can help physicians avoid prescribing drugs with no as Gleevec. Introduced in 2001, it set a record medical value; because those drugs often have severe for the fastest approval time by the U.S. Food and Drug side effects, the test greatly benefits patients as well. Administration (FDA), and in 2011 had US$4.3 billion The concept of personalized medicine is only 15 in sales. Imatinib was the first of a new class of drugs years old, and it does not have a perfect track record; that act by inhibiting a specific enzyme — in this case, some of its medications have failed to get regulatory a receptor called tyrosine kinase — that is characteristic approval or to be profitable in the marketplace. But of particular cancer cells. Because only certain cancers where it has proven successful, it is creating for health- will respond to imatinib, it is prescribed only for care businesses a fundamentally new value proposition. patients identified by specific diagnostic tests (for exam- It represents a game-changing trend for healthcare ple, the Philadelphia chromosome abnormality test). providers (hospitals and individual physicians); payors, Imatinib is an example of the products emerging including Medicare and private insurance; and patients, from a new pharmaceutical field known as personalized who can have a far more participative role in their own medicine (PMx): the tailoring of drugs and other treat- care than they would without PMx. When physicians ments to specific populations, based on their genetic and patients can draw upon a wealth of genetic and bio- profiles or other differentiating factors. (We use the logical data, personalized therapy will become the abbreviation PMx to follow Rx for prescription medi- norm, not the relatively rare occurrence it is today. cine and Dx for diagnostic tests.) The underlying tech- The greatest impact of this new approach to indi- nology for PMx marries advances in diagnostic biotech, vidualized diagnosis and treatment will probably be felt such as rapid gene sequencing, with a profound expan- in the pharmaceutical industry. Leading pharmaceutical sion of scientists’ understanding of molecular disease companies have long relied on innovation to expand the pathways. Another example is Genomic Health’s frontiers of better health — and to financially sustain Oncotype DX breast cancer test, introduced in 2004, their businesses. But that capacity for launching new which uses an analysis of multiple genetic variations to products is under severe strain today. Many pharmaceu- determine which cancers are likely to recur for a partic- tical companies have recently seen their research and ular individual. It also indicates which patients are like- development productivity erode. Biotech startups have
Avi Kulkarni Nelia Padilla McGreevy Also contributing to this article was strategy+businessis a partner with Booz & is a principal with Booz & contributing editorCompany based in San Company based in Boston. She Lawrence M. Fisher.Francisco and a member of specializes in personalizedthe firm’s global health medicine and pharmaceuticalpractice. His areas of expertise regulations.include personalized medicine,life sciences R&D, and thepharmaceutical and diagnos-tics industries. 2 firstname.lastname@example.org email@example.com to turn their scientific advances into viable (1) the subtype of their HIV infection, (2) their body’sdrugs. Companies have resorted to alternatives such as response to the infection, and (3) the stage of the over-vaccines, preventive care, and geographical outreach for all infection, they could prescribe the best tailored ther-profits, but no pharma industry breakthrough has come apy cocktail for each patient. This combination ofalong recently to create a promising pipeline of new prescribed diagnostics and pharmaceuticals has been aSuccess and Disruptionproducts. PMx offers the potential for just that sort of remarkable success story. It has improved quality of lifebreakthrough. for patients and extended the average life expectancy of Thus, despite the disruptive nature of personalized newly diagnosed HIV patients by 20 to 25 years.medicine, the pharmaceutical industry is emerging as a HIV infects different patient groups in differentdriving force in this field. The list of early PMx adopters ways; for a patient diagnosed with it, a physician mustincludes some industry giants: Roche, Pfizer, Novartis, choose from more than 20 different antiviral agents inand Lilly. The field is also populated with upstart com- six unique drug classes. While undergoing antiretroviralpanies such as Genomic Health, XDx, and Prometheus therapy, patients are monitored with advanced diagnos-Labs that offer specialized approaches to segmenting tic blood tests every three to four months to assess thedisease, as well as the recognized pioneers in personal severity of infection and confirm that the virus is beinggenomics: 23andMe, deCODE Genetics, and DNA suppressed. Some of these tests can predict how indi-Direct. In adopting PMx, they are all embracing a new vidual patients will respond to specific therapies, thushealthcare model that emphasizes segmentation of increasing their odds of survival. For instance, Selzentry,patients, and decisions and practices tailored to individ- an antiretroviral drug developed by Pfizer, works byuals or small groups. Although this approach might binding to and thereby blocking the CCR5 receptor,lead to smaller revenue pools for pharmaceutical pro- which is found on the surface of certain human cellsducers, PMx can actually improve their profits. A busi- and is necessary for the entry of the virus into the hostness model based on differentiated products can reduce cell. But in some people, HIV can use other receptorsthe system-wide costs and complications of one-size- instead, which would render Selzentry ineffective.fits-all medications, provide new opportunities for mar- Therefore, before Selzentry can be prescribed, patientsketing, and establish new efficiencies in production and are given an HIV tropism test called Trofile to deter-distribution. mine whether the drug will be effective for them. Personalization of anti-HIV drugs benefits all con- stituents. Payors and governments maximize the valueAs an example of the impact of personalized medicine, of therapies on the market, squeezing the best effectsconsider the evolution of treatment for human immun- from the cheapest anti-HIV drugs. Physicians and clini-odeficiency virus (HIV), the retrovirus that causes cians, who have had to rethink their management ofAIDS, during the 1990s and 2000s. Physicians found HIV/AIDS treatment, have dramatically improved suc-that by grouping patients into smaller subsets based on cess rates. Patients are the ultimate beneficiary: An HIV-
A New Form of Pharma R&D3www.strategy-business.com positive test used to be a short-term death sentence. First, the prospects for innovation; second, the right Now HIV is considered a chronic, manageable disease, value proposition; and third, the capabilities needed to with treatment costs that are considered acceptable and deliver on that proposition. affordable even in sub-Saharan Africa. Pharmaceutical companies have also benefited greatly. The PMx approach to HIV/AIDS treatment, for Back in the age of economies of scale, most drug com- example, has helped make Gilead Sciences Inc. the panies’ business models depended on producing thera- world’s second largest biotech company, after Amgen pies for the largest number of people with unmet Inc., with a market cap of $38 billion. The use of com- medical needs: cimetidine (GlaxoSmithKline’s Tagamet) panion diagnostics allowed Gilead to improve the over- for excess stomach acid, lovastatin (Merck’s Mevacor) all efficacy of its portfolio of drugs for HIV/AIDS, for high cholesterol, and naproxen (Bayer’s Aleve) for cementing its lead in that market. aches and pains. Even biotech’s early successes, starting But of all the constituents, pharma companies face in the 1970s, were conceived as mass-market products: the greatest disruption from personalized medicine. It recombinant insulin (Lilly’s Humalog) for diabetes, forces them to adopt a new business model with a coun- epoetin alfa (Amgen’s Epogen) for anemia, and etaner- terintuitive value proposition, requiring unfamiliar new cept (Pfizer and Amgen’s Enbrel) for autoimmune dis- capabilities to make it work. For many pharma compa- eases like rheumatoid arthritis and psoriasis. Each nies, PMx means changing established practices in all represented a multibillion-dollar franchise sustained for aspects of the business — from the earliest stages of tar- many years — and together, they reduced many causes get identification and drug discovery, through clinical of early mortality, helping raise the average human life development, regulatory approval, commercial develop- span. ment and operations, and marketing and sales. But an aging population also means that chronic PMx is only one of several strategies that pharma- diseases — including immune-mediated diseases such ceutical companies will adopt in the next few years. as cancer, metabolic diseases such as diabetes, and neu- Some will seek to retain the same business model even rological diseases such as dementia — have become as their innovation pipeline dwindles. They will use more prevalent. Unlike the acute killers of previous gen- their marketing capabilities to sell so-called branded erations, these diseases tend to affect people in a rela- generics, off-patent versions of their own former block- tively heterogeneous manner. Depending on their busters, accepting lower margins in return for high vol- genetic makeup, people are susceptible to different dis- ume sales. Others will play the specialty pharmaceuticals ease strains and may respond in different ways to the game, repurposing old drugs in new delivery systems for same medication. For illnesses like these, the healthcare different diseases than those for which they were origi- system can no longer afford a trial-and-error approach nally approved. This is a well-established low-risk model to pharmaceutical research, in which physicians attack that investors understand. diseases with one compound after another in hopes of But a number of pharmaceutical companies will finding one whose benefits to the patient will outweigh adopt the personalized medicine paradigm. They recog- its side effects. nize the competitive advantage that could accrue from a With personalized medicine, segmentation begins segmented customer base with structures, processes, and at the research stage. A PMx team seeks out patient pop- capabilities to match. They are just unsure about how to ulations that can be identified using biomarkers. A bio- leap ahead into practice. marker is a measurable substance in an organism — a That is why they need a plan for implementing per- gene, protein, or other biological element — whose sonalized medicine. To be successful, they will need to presence has been linked to a pathology, such as cancer take into account three elements of their current reality: or autoimmune disease. A biomarker may also be a
types, such as tissues, bodily fluids, management. Biopharmaceutical and DNA/RNA and other proteins. companies are accustomed to out- Map the patient’s journey from diag- sourcing research, development, nosis to treatment, and use Dx tests and clinical trials. But PMx is differ-The experience of biopharmaceuti- to develop efficient patient–disease ent. It involves partnership capabili-cals suggests that seven processes stratification. ties that many companies do notand practices are required for profi- 3. Cross-functional (Rx and Dx) possess. A partnership for a com-ciency in personalized medicine. regulatory and clinical expertise. panion diagnostic test, for example,Together, these could become the Drugs that are aimed at patient sub- has regulatory, quality control, legal,basis of a distinctive capability in this sets and paired with companion marketing, and sales aspects,field. diagnostics make new demands of involving both the test and the drug. 1. Biomarker discovery and iden- regulators, so applicants must come It is critical to define in advance howtification. The first step is to identify prepared. Start by building optimal much value the drug contributesa biological trait that indicates the indications — explanations of the versus how much the enabling diag- 4presence or progression of a dis- diseases the drug is licensed to treat nostic contributes, and to build aease. Next, develop a test that can — and labels, which are the FDA- win-win model for the Dx and Rxdetect the presence or quantity of compliant texts that specify how the participants.these biomarkers. That test drug should be used. Introduce 6. Marketing. A pull-based strate-becomes the diagnostic. Costs need these materials early to key opinion gy requires a knowledge-intensivenot be excessive because many rele- leaders in the relevant field of medi- effort aimed at key opinion leaders www.strategy-business.comvant biomarkers have been discov- cine. and decision makers. You will alsoThe Essentials ofered and classified by academic and 4. Pricing, reimbursement, and need to reach out to national andindependent research labs and are billing systems. Develop a sophisti- regional payors.PMx Practiceavailable in public databases. The art cated knowledge of health econom- 7. Sales. Retrain your sales forcelies in establishing biomarkers’ clin- ics modeling, and cultivate policy to be conversant in complex science,ical utility by separating the disease experts. Base your projections on including genomics, proteomics, andsignal from biochemical noise. the idea that patients who gain no bioinformatics. Revenues from each 2. Assay development. Create in benefit from a drug will not take it; drug will be spread over fewervitro tests that scale beyond the lab- this will cut costs throughout the patients and total prescriptions, sooratory setting to clinical or com- healthcare system. The right drug to each staff member will need to man-mercial use. Develop assays on all the right patient at the right time is a age a larger number of products.major technology platforms and powerful value proposition.across multiple analyte and sample 5. Partnership selection andgenetic variant that indicates an individual’s potential ed levels of a protein marker called HER-2 in patientsresponse to a particular drug. Drugs are tailored to rela- who responded. The FDA approved the medication fortively small, well-defined patient groups, segmented by only that group of people. Herceptin is now a drug withthese markers; the Dx enables the Rx. yearly sales of $6 billion. This type of pharmaceutical research first led to a Since Herceptin, companies have used pharma-marketable product in 1998, when the FDA approved cogenomic assays (tests based on genetic biomarkers) toHerceptin — a breast cancer drug developed by resuscitate drugs that would have failed clinical trials, orGenentech. Herceptin works in only about 25 percent to manage the potential danger of side effects. Becauseof breast cancer patients. Ordinarily a drug that did not many cancers are prompted by mutations in the genet-work for three-quarters of the patient population would ic code, oncology has been the most fertile early groundhave failed to win regulatory approval. But researchers at for these drugs. For example, Erbitux and Vectibix wereDako AS, a diagnostics company based in Denmark, developed for colorectal cancer, but they work only indevised an accompanying assay (an analysis of the pres- people whose tumors have a mutation in the EGFRence of a substance or genetic indicator) showing elevat- gene and a normal KRAS gene, and thus are prescribed
5www.strategy-business.com only after positive responses to assays for those variants. with global distribution and advertising, are too expen- Personalized medicine could be applied to a wide sive and cumbersome for personalized therapies. range of chronic diseases. As knowledge of the human Moreover, decisions about the use of personalized pre- genome expands, new and old drugs alike can be made scription drugs are made by a relatively small number of more viable through genetic testing. Strattera (atomox- sophisticated payors — hospitals, major providers, or etine), a drug used for attention-deficit hyperactivity large payors — and not by general practitioners, who disorder, was linked to liver damage for patients with a are disinclined to prescribe drugs that will not be reim- mutation in the CYP2D6 gene. It is now marketed with bursed by Medicare or private insurance. a pharmacogenomic assay to rule out this population. As PMx 2.0 unfolds, popular demand will drive its Warfarin and Plavix, two blood thinners, can cause growth. Because it takes into account each patient’s excessive bleeding among patients with particular genet- unique pathophysiology; the biochemistry of the tumor, ic variations. Testing can show which patients should get bacteria, or virus; and the individual’s ability to proper- other medicines. ly react to and metabolize different drugs, it will repre- All this innovation still represents what might be sent a step change in medical confidence and in called version 1.0 of personalized medicine: diagnostic protection against side effects. tests applied only after a drug’s development to salvage Already, the appeal of personalized medicine is or increase its value. Industry leaders now are moving changing the way people spend their own money on toward another form of PMx innovation — call it ver- healthcare. In 1996, for example, when Myriad sion 2.0 — in which new drugs are developed concur- Genetics Inc. launched BRACAnalysis, a predictive test rently with companion diagnostics. Under this R&D for hereditary breast and ovarian cancer, Medicare and model, researchers identify target patient subgroups in private health insurance did not reimburse for it. A New Business Model advance and design drugs for these specific populations. Nonetheless, many patients paid the $3,000 cost out of PMx 2.0 has been held back, somewhat, by cost. pocket. So many of them forwarded the receipts to their The first human genome sequence cost $3 billion and insurers and argued on behalf of the test that took many years to completely map. But now the costs BRACAnalysis is now commonly reimbursed. are shrinking and the effectiveness is growing at an People have shown a willingness to pay for many exponential pace. Several companies offer personal other personalized forms of healthcare as well. genome sequencing for a few thousand dollars or less; Hundreds of thousands of people have opted for a sys- within 10 years, it is reasonable to expect that sequenc- tem known as “concierge medicine.” They pay $59 a ing a personal genome will take an hour and cost per- month, or more, for 24/7 access to a physician’s advice haps $300, or less than an MRI. It is not too much of a and counsel, without other types of insurance included. reach to postulate cell phone–sized analytical devices Thousands of others flock to alternative medicine, able to test for 500 biomarkers that cross the body’s despite the lack of clinical evidence. At least in part, more than 50 organs in a single drop of blood. patients are attracted by the perception that alternative As it becomes more prevalent, the pairing of diag- medicines are tailored to individual attributes. (For nosis and therapy will yield big gains in R&D produc- example, some popular medical self-care books propose tivity. The patient subgroups that stand to benefit from different regimes of food and herbal remedies based on a drug will be identified in advance of clinical trials. This blood type.) could lead to a meaningful improvement in the average Personalized medicine will change the way individ- response rate for drugs, which is currently 50 percent uals learn about their health. It will lead to more across all categories and just 22 percent in oncology. involvement of patients in managing their therapy, and That improvement, in cancer alone, would more than better tracking of patient activity during and after treat- compensate for the cost of diagnostic technology. ment. Today, any newly diagnosed cancer or autoim- mune disease patient can consult countless online forums devoted to his or her disease. The information The rise of personalized medicine provides pharma there runs the gamut from accurate and helpful to well- companies and healthcare providers with a value propo- meaning but inadequate to utterly fallacious. sition different from the one they’re accustomed to. The Genentech discovered early on with Herceptin that standard pharmaceutical mass-marketing approaches, innovative, proactive educational materials are essential
6 www.strategy-business.comto successful PMx. Similarly, Gilead, the world leader in traditional competencies such as those of medicinalHIV/AIDS drugs, has a long tradition of working with chemistry, molecular biology, and high throughputAIDS activists — including some who massed angrily in screening; they augment them.front of its headquarters in the 1990s — to enlist them The capabilities that distinguish a company in per-in spreading information about the drugs and the vary- sonalized medicine are not just tools, of course; theying effects of each drug on different individuals. represent combinations of processes, technologies, To realize the business potential in personalized knowledge, skills, and organization that have beenmedicine, pharma companies will need to emphasize developed over time. Nor can they be thought of in iso-diagnostics — which, historically, has been a very dif- lation. Distinctive capabilities are always cross-function-ferent business from pharmaceuticals, with far lower al. For example, a pharmaceutical company may decideprofit margins, making it unattractive to drug compa- to develop its prowess in a particular type of medical • Build a mind-set in which personalization is notnies in the past. Most pharma companies do not have practice, such as oncology, immune system disorders, or an option but a necessity — even in the face of thethe requisite Dx identification, development, or com- mental illness. This will necessarily bring together pro-mercialization capabilities to play effectively in this fessionals in genetic research (for biomarker discoveryspace, and will have to build, buy, or borrow them. and development), patient outreach, finance (for devel- Fortunately for the companies, version 1.0 of per- opment of pricing and economic models for stratifiedsonalized medicine has already raised the value of diag- patient populations), and sales and marketing (for • Retain flexibility. Place a premium on portfolionostic tests. In the past, they typically sold for $300 or working with clinics). These are not separate processesless. Today, some tests, such as Oncotype DX, produced and systems; personalized medicine requires synchro-by Genomic Health, are priced at about $4,000. This nized adjustments in every part of the value chain fromThe Capabilities System of Personalized Medicinetest is expensive because it is based on years of propri- discovery to development to commercialization to life-etary genetic research and multiple large-scale clinical cycle management.trials to confirm its predictive capability. Even so, it is After 20-odd years of business process reengineer-seen as affordable; without it, chemotherapy is far more ing, most pharma company managers understand how • Build PMx capabilities into the existing capabilitiesexpensive and toxic. to make structural changes, though they are often blasé system. In an era of constrained spending and a vital Several leading pharma companies are beginning to or cynical about the ultimate benefits. Personalizedbuild or buy the capabilities required to fulfill the goals medicine could also require changing hearts and mindsof the patient-centric model. For example, Novartis because it affects the character of an enterprise.acquired Genoptix for $470 million in 2011 — a deal Although individual companies will develop new capa-that demonstrated, to many in the industry, that the bilities in their own way, all successful PMx initiativeslargest companies were interested in PMx. In August will need to include these imperatives:2012, GlaxoSmithKline paid $3.6 billion to acquireHuman Genome Sciences, one of the earliest companiesto mine the genome in search of innovative drugs. inevitable failures that occur with new drug candidates. As the bidding for diagnostics assets accelerates, Assume that all molecules in the pipeline will be tailoredsome target companies are likely to be overvalued, and to specific patient populations; non-tailoring willsome acquirer companies may overpay. But sitting on become the exception.the sidelines is not a viable option. Payors and physi-cians are increasingly unwilling to support drugs with management skills, determining as early as possibleonly a fractional response rate. Moreover, the PMx which molecules to advance from research to develop-promise to raise R&D productivity while improving ment, and when to drop a hitherto promising candidatepatient outcomes is simply too compelling to ignore. for which the PMx case is weak. Similarly, remain tech- nologically agnostic; don’t commit to only one biotech- nology research platform.One way to think of PMx capabilities is as a set of newinstruments that will provide new insights into diseaseand treatment. But just as ultrasounds and CT scans need for R&D efficiency, essential PMx capabilitieshave not displaced stethoscopes and thermometers in must be identified and integrated into the existing valuethe physician’s bag, the tools of PMx do not supplant chain. Build the kind of organizational discipline that
• Access new capabilities through partnerships —7 • Build a sales force with new capabilities. Sales Managing a Disruptive Innovationwww.strategy-business.com to act is now. + eschews drug candidates with a potentially large market gest that PMx could be disruptive in a way that the but lower probability of success. Favor smaller-market healthcare industry cannot long ignore. “The advent of drugs that are more likely to succeed. With this precision medicine,” write the authors, “heralds prod- approach, you may reap many benefits, such as faster uct-line fragmentation in pharmaceuticals. Volumes per clinical trial enrollment, faster achievement of goals, therapeutic compound will drop significantly, as the lower clinical costs, and greater likelihood of success. number of therapeutic compounds expands. Blockbuster drugs will become rare. This will necessitate for example, for diagnostics development and commer- a reshaping of the business model of today’s major phar- cialization. Ensure access to world-class diagnostics maceuticals companies because — to borrow words without significant capital outlays by collaborating with from oil exploration, in the future there will be fewer assay developers and other companies. Understand that big gushers to cover the costs of drilling a lot of dry these are truly strategic partnerships that share fully in holes.” the creation of value; they are not the routine outsourc- An ongoing theme in Christensen’s work is that the Resources ing of a fungible function. leading practitioners of an old order tend to be the vic- tims of disruption, not the initiators. But The teams will need to pair targeted therapies with sophisti- Innovator’s Prescription proposes that today’s healthcare cated diagnostic tests. In addition, they will need to be leaders can educate themselves and play a major role in well versed in biological and disease pathway intelli- disrupting their own businesses, as IBM did when it gence, and well-informed about patient segment attrib- introduced the personal computer. There may not be utes that can impede successful treatment. much time to make the shift; across many disease areas, PMx and novel diagnostics are already changing the practice of medicine, and already accepted as a new way Like all innovations, personalized medicine has been the to play in the life sciences market. That is why person- focus of a great deal of hype, and it is worthwhile to take alized medicine should be on the senior agenda of every a few steps back to put it in perspective. It may be over- pharmaceutical company. Major new capabilities are sold at times — particularly in oncology, where it has not built overnight, and mind-sets are slow to change. been heralded as the next “cure for cancer.” Because can- Some leading companies are already moving, and so are cer is many different diseases, with many different mod- major stakeholders like payors and providers. The time ulators and multiple mutations even within a single tumor site, personalized medicine cannot be that kind of cure. It will never be a panacea. But it also is not a placebo. Eric Topol, a cardiolo- gist and geneticist, and the current director of the Scripps Translational Science Institute in La Jolla, Calif., paints an optimistic picture in his recent book, The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care (Basic Books, 2012). He proposes the integration of basic PMx tools — such as biomarkers for specific pathways and special- Marcus Ehrhardt, Robert Hutchens, and Susan Higgins, “Five Steps toward a Revitalized Pharmaceutical Supply Chain,” s+b, Spring 2012, ized diagnostic technologies — into everyday life. www.strategy-business.com/article/00094: Companies embracing person- Perhaps biomarker-sensitive devices embedded in alized medicine will need to build these operational capabilities. mobile phones could detect cancer cells circulating in Gil Irwin, Art Kleiner, and Joyjit Saha Choudhury, “When Disruptive the blood or warn people of an imminent heart attack. Integration Comes to Health Care,” s+b, 03/01/10, www.strategy- Topol also says that many of these innovations must business.com/article/00020: The Innovator’s Prescription coauthor Jason Hwang talks about the next wave of healthcare business models. overcome the medical community’s profound resistance to change. In The Innovator’s Prescription: A Disruptive Alex Kandybin and Vessela Genova, “Big Pharma’s Uncertain Future,” Solution for Health Care (McGraw-Hill, 2009), Harvard s+b, Spring 2012, www.strategy-business.com/article/00095: As the era of the blockbuster drug comes to an end, the industry must cope with new Business School professor Clayton M. Christensen and unknowns. physicians Jerome H. Grossman and Jason Hwang sug-