H I G H L I G H T S
`
`FROM THE ANALYST’S COUCH
`Oncology’s trials
`
`Bruce Booth, Robert Glassman and Philip Ma
`
`The oncology market has witnessed remark-
`able growth during the past five years and is
`poised for even greater growth during the
`next three years. The total oncology market is
`expected to reach more than US $32 billion in
`size by 2005, driven by factors including a
`continued trend towards aggressive chemo-
`therapy, active patient populations that
`demand access to the latest therapies, and
`continued favourable pricing due to high
`unmet need. Moreover, nearly all of the
`major pharmaceutical companies have active
`oncology development programmes, and for
`biotech firms, oncology projects dwarf all
`other R&D programmes.
`
`Challenges from attrition
`In spite of all this positive momentum for the
`oncology market, pharmaceutical and biotech
`companies who play in this area face the crucial
`issue of late-stage clinical attrition. Even with
`more than 500 oncology compounds in
`development, only a few achieve regulatory
`approval each year and there are only ~90
`approved oncology drugs in the US today. A
`number of high-profile clinical and regulatory
`setbacks, such as the cases of gefitinib (Iressa;
`AstraZeneca) and cetuximab (Erbitux;
`Imclone), highlight the challenges that oncol-
`ogy drug candidates are facing. The dramatic
`unpredictability of single-arm, uncontrolled
`Phase II trials in cancer helps explain why
`anti-cancer drug development is so challeng-
`ing. Although oncology projects have higher
`average success rates than other therapeutic
`areas in early-stage trials (that is, Phase I and
`II), these projects have a lower average success
`rate than other therapeutic areas at Phase III.
`Oncology projects are riskier than those in
`other therapeutic areas, precisely at the stage
`of clinical development in which costs are
`highest. Moreover, early development trials
`do not seem to be very predictive of success
`rates for later development, which could
`mean that the industry might soon face a big
`series of disappointments in the form of
`failed drug candidates.
`
`Causes of high attrition
`Several key factors drive the high rate of attri-
`tion we are seeing with oncology com-
`pounds: market pressures, challenges with
`
`the underlying science and changes in the
`regulatory environment. On the market side,
`companies are under significant pressure to
`reach for the broadest possible label on first
`regulatory approval to capture a broad market.
`As such, many initial label applications target
`one or more of the ‘big four’ tumour types:
`breast, prostate, lung and colon cancer. The
`challenge in doing this is that the standard clin-
`ical practice for these tumours often involves
`multiple drug cocktails of cytotoxic chemother-
`apy agents. So, for new therapies, clinical trials
`need to show incremental improvement over
`these multiple existing chemotherapy regi-
`mens, which can be difficult to demonstrate,
`especially with smaller size trials.
`
`Scientific and regulatory challenges
`The nature of the basic science of oncology
`also leads to high attrition rates for anticancer
`compounds. With the rapid accumulation of
`new knowledge, there are more and more novel
`approaches to anti-cancer drug development.
`Indeed, more than 40% of the compounds in
`development for cancer are directed against
`novel or ‘unprecedented’ mechanisms, and
`almost 70% of the drug targets that are being
`investigated in discovery are unprecedented. In
`earlier research, we had shown that novel
`approaches had significantly higher risks than
`tried-and-tested approaches, and, notably,
`some of the more high-profile recent setbacks
`in oncology have involved novel mechanisms,
`such as drugs targeting signal transduction
`(for example, RAS farnesylation). For every
`major success such as bevacizumab (Avastin;
`Genentech) in colorectal cancer, there have
`been many more failures.
`The last factor for high attrition rates in
`oncology has been a growing conservatism
`within the US FDA and other regulatory
`approval bodies. In the past, when there were
`fewer available cancer therapies, the FDA
`often accepted surrogate endpoints (such as
`tumour reduction). Today, with better avail-
`able treatments, the FDA has moved more
`aggressively towards clinical endpoints such
`as survival, which are exceedingly tough to
`prove in populations with refractory, progres-
`sive tumours — the types that are often the
`focus of clinical trials today. Not surprisingly,
`these higher regulatory hurdles increase the
`
`Degas couch, ‘Rehearsal’, by Heather Sussman © 2002
`
`likelihood of clinical attrition. Given recent
`public pressure, however, the FDA could be
`easing its stance. For example, it recently
`approved gefitinib with only clinical response
`and no survival benefit in lung cancer.
`
`Future of oncology drug development
`Given the market, science and regulatory drivers
`behind attrition in oncology drugs, how can
`oncology drug development move forward?
`First of all, biotech and pharmaceutical com-
`panies should consider pursuing initial indi-
`cations in well-defined, potentially niche
`tumours that will allow for a potentially
`lower-risk path to get regulatory approval.
`Once the drug has received initial regulatory
`approval, there are many other opportunities
`to expand indications through additional
`post-marketing trials. About 70% of cancer
`drugs are used off label — for example,
`thalidomide, which although not even
`approved as a cancer therapeutic is a domi-
`nant drug in myeloma and melanoma and is
`being tested in renal and prostate cancer.
`There is a significant opportunity for con-
`current research into biomarkers at the same
`time that the target mechanism is being
`explored. Tissue imaging, in particular, could
`be a fruitful source of biomarkers given the
`advances in magnetic resonance imaging and
`positron emission tomography imaging. As a
`caveat, however, biochemical and molecular
`markers have not yet proven to be predictive
`of clinical response; for example, vascular
`endothelial growth factor (VEGF) and epi-
`dermal growth factor receptor (EGFR) expres-
`sion do not correlate with response to the
`appropriate antagonists.
`Finally, companies should consider other
`Phase II trial designs that are more predictive
`of Phase III success. Examples include ran-
`domized Phase II studies, Bayesian approaches,
`studies in tough, defined populations such as
`the truly refractory, and uses of 'easier' end-
`points such as time to progression1. A key
`challenge for both industry and the regulatory
`agencies in the development and approval of
`combinations of multiple novel cytotoxics and
`cytostatics in patients with minimal residual
`disease, the exact scenario in which beneficial
`outcomes are most likely, but where proving
`these benefits can be complex.
`L
`
`NATURE REVIEWS | DRUG DISCOVERY
`
`VOLUME 2 | AUGUST 2003 | 6 0 9
`
`JANSSEN EXHIBIT 2072
`Amerigen v. Janssen IPR2016-00286
`
`

`
`H I G H L I G H T S
`
`FROM THE ANALYST’S COUCH
`Market indicators
`
`Table 1 | Oncology trial examples
`Promising Phase II studies
`Multiple second- and third-generation lymphoma
`regimens showed doubling of responses and
`survival compared with first generation CHOP
`regimen.
`Phase II studies of angiogenesis inhibitor
`SU5416 showed better responses and survival
`compared with historic controls in advanced
`colorectal cancer.
`
`Negative Phase III studies
`SWOG randomized study comparing CHOP
`with second generation ProMACE-CytaBOM
`or MACOP-B showed no difference in CR, time
`to treatment failure, or OS.
`A large phase III study of standard
`chemotherapy with or without the angiogenesis
`inhibitor SU5416 in the treatment of patients
`with advanced stage colorectal cancer did not
`achieve its endpoints.
`ECOG study2 reported no differences in
`survival or time to disease progression between
`autologous stem cell transplant with high dose
`chemotherapy and conventional chemotherapy.
`
`Several Phase II studies from late 1980s
`showed higher response rates (73–100%) and
`7–18% DFS post-five-years for high-dose
`chemotherapy and stem cell transplantation
`for metastatic breast cancer.
`CR, complete response; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group;
`OS, overall survival; SWOG, South Western Oncology Group
`
`b
`
`5.0
`
`4.0
`
`3.0
`
`2.0
`
`1.0
`
`Ratio of survival rates
`
`Cardiovascular system
`Central nervous system
`Gastrointestinal system
`Systemic anti-infectives
`Oncology
`Musculo-skeletal
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`a
`
`Percentage
`
`0
`
`0.0
`
`Phase III
`Phase I and II
`Figure 1 | Project survival rates. a | Comparison of rates through Phases I/II and Phase III/registration between
`1991 and 2000 at fifteen top pharmaceutical companies. Projects without updated data after five years were
`considered failures. b | The low ratio of Phase II/registration to Phase I/II success rates for both systemic anti-
`infectives and oncology projects, is indicative of the low predictive power of early stage trials in these two areas.
`Source: PBJ Publications Pharmaprojects; US FDA/Center for Drug Evaluation Research; McKinsey analysis.
`
`L
`
`Phase II trials in oncology do not show signifi-
`cant predictability for Phase III outcomes
`(TABLE 1). A comparison of trial success rates
`across different therapeutic areas again shows
`the poor correlation between Phase II and
`Phase III success rates for oncology trials (FIG. 1).
`One of the key drivers for the high clinical
`attrition rates for oncology compounds is the
`high proportion of unprecedented targets that
`these compounds are directed against (FIG. 2).
`Historically, compounds directed against
`unprecedented targets have a higher level of
`clinical attrition than compounds against
`targets with a precedent. The total oncology
`market is expected to reach more than US $32
`billion by 2005 (FIG. 3).
`Bruce Booth and Philip Ma are members of
`McKinsey’s Pharmaceuticals and Medical Products
`Practice at 55 East 52nd Street, 21st Floor, NY,
`NY 10022 (BB) and 3075A Hansen Way, Palo Alto,
`CA 94304 (PM). Robert Glassman is a Vice-President
`in Global Private Equity at Merrill Lynch at 4 World
`Financial Center, NY, NY 10080 and haematologist-
`oncologist at Cornell Medical College.
`E-mails: Bruce_Booth@McKinsey.com, Philip_Ma
`@McKinsey.com, RobertG@exchange.ml.com.
`doi:10.1038/nrd1158
`
`1.
`
`2.
`
`Fossa, S. & Skovlund, E. Selection of Patients May Limit
`the Generalizability of Results from Cancer Trials. Acta
`Oncologica. 41, 131–137 (2002).
`Stadtmauer, E. et al. Conventional dose chemotherapy
`compared with high dose chemotherapy plusautologous
`hematopoietic stem cell transplantation for metastatic breast
`cancer. N. Engl. J. Med. 342, 1069–1076 (2000).
`
`Online links
`DATABASES
`The following terms in this article are linked online to:
`LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
`EGFR | VEGF
`Access to this interactive links box is free online.
`
`100% =
`US $32.3 billion
`10% CAGR
`3% CAGR
`
`6%
`
`100% =
`US $23.4 billion
`
`15%
`
`9% CAGR
`
`100% =
`US $16.9 billion
`
`10%
`
`16%
`
`28%
`
`46%
`
`1998
`
`ROW
`
`7%
`
`16%
`
`28%
`
`49%
`
`26%
`
`8% CAGR
`
`53%
`
`12% CAGR
`
`2002
`
`Japan
`
`2005
`
`Europe
`
`USA
`
`Figure 3 | Expected growth of global oncology
`market. CAGR, compound annual growth rate.
`
`a Total number of oncology compounds in
`development
`600
`
`b Projects against precedented versus
`unprecedented targets — 2001
`
`100% = 513
`42
`
`100% = 63
`68
`
`58
`
`32
`
`Unprecedented**
`
`Precedented
`
`Number
`
`513
`
`CAGR = 15%
`
`126
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`Number
`
`1991
`
`2001
`
`Number of targets
`Total number of compounds
`in development
`in development
`Figure 2 | Target mechanisms for oncology development projects. Roughly 40% of compounds in
`development are novel. In the period 1996–2001 only nine novel targets had compounds against them app-
`roved, whereas today 15 novel targets are being tested in Phase III trials. CAGR, compound annual growth rate.
`Source: PBJ Publications Pharmaprojects; US FDA/Center for Drug Evaluation Research; McKinsey analysis.
`
`610 | AUGUST 2003 | VOLUME 2
`
`www.nature.com/reviews/drugdisc