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5.7.3 Patient Adherence
A further key modier of market size is represented by patient adherence to the new
therapy. A consensus published in 2012 characterized adherence to medications by
three major components: the initiation, the implementation, and the discontinuation
(Vrijens etal. 2012). Many potential factors can impact adherence, which can be
separated into ve broad categories: sociodemographic (e.g., income level, health
literacy); healthcare system (e.g., patient-clinician communication, access to and
cost of care); characteristics of the therapy (e.g., complexity of dosing, adverse
effects); condition-related (e.g., symptom severity, impact on quality of life); and
patient-related (e.g., perception of severity of illness and efcacy of treatment, lack
of follow-up). In the literature, good adherence has been dened with a cutoff of
80%, although the relevance of this number has been questioned (Burnier and
Egan 2019).
5.7.4 Patient Subpopulations andPersonalized Medicine
For many disease indications, there will be subpopulations of patients whose
response to a given treatment may yield enhanced efcacy or greater adverse effects.
These subpopulations may be dened by a variety of criteria including age, sex,
genetics and ancestry (see Sect. 3.5 for more on pharmacogenomics), disease sever-
ity, and disease characteristics. In instances where signicantly different efcacy or
adverse event responses are elicited by a given treatment, it is important that the
appropriate subpopulation is targeted. Targeting the appropriate subpopulation dur-
ing clinical trials should result in improved response rates, which could reduce the
size and duration of the required trial needed to show efcacy and safety. If such a
trial design provides evidence that the new product is markedly superior to compet-
ing products, premium pricing for the new product may be possible, which would
increase the potential market size for the product. Note that targeting a subpopula-
tion within a given disease indication will reduce the number of patients available to
conduct a clinical trial and will reduce the overall number of patients that might
have access to the new product. However, given the many advantages that may
accrue from targeting the appropriate subpopulation, this parameter should be a
major consideration regarding market potential.
Over the past decade, targeting patient subpopulations has been reected in the
use of personalized medicine that uses an individual’s genetic or biomarker prole
to guide decisions regarding the prevention, diagnosis, and treatment of disease.
This is most clearly seen in the emergence of targeted cancer therapies that have
been completely revolutionized, as several molecular alterations have been identi-
ed as drivers of cancer development and progression. An example of this approach
is the use of pembrolizumab, sold under the brand name Keytruda. Keytruda is a
monoclonal antibody that binds to the checkpoint inhibitor, programmed cell death
1 (PD-1), which is expressed on T cells. When Keytruda is bound, it prevents PD-1
from binding to ligands PD-L1 and PD-L2 expressed by certain cancer types and
5 Technology Transfer andCommercialization
212
therefore prevents the tumor from downregulating the activity of T cells. As a single
agent, Keytruda is indicated for rst-line treatment of patients with non-small cell
lung cancer expressing PD-L1, as determined by an FDA-approved test, with no
epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor
aberrations. The prevalence of PD-L1 expression in patients with non-small cell
lung cancer ranges from 24% to 60%; therefore, setting a cutoff for positivity at 5%
(Yu etal. 2016) could reduce the potential market for Keytruda in this indication.
Although cancer is an obvious target for personalized medicines, as new bio-
marker technologies continue to emerge, this approach may be usefully applied to
almost all therapeutic domains in which the drug target shows genetic
polymorphism.
5.7.5 Market Penetration
Another modier that helps determine market size is the ability of a new therapy to
penetrate an existing market. Some guidance for this parameter may be obtained
from prior penetration rates of comparable products. The comparative efcacy, ease
of use, and safety of the new therapy compared with competitor products will
strongly inuence market penetration; both existing competition and potential
future competition should be considered. The pricing of a new product will also
inuence its market penetration. One consideration that should be added to this
analysis is the potential for generic products to enter the marketplace, since such
generics will usually be priced very low compared with a brand name drug.
Interviews with relevant physicians and payer groups can provide insight into the
ability of a new product to penetrate a market. It is worth noting that market projec-
tions are frequently overestimated.
5.7.6 First-in-Class or Best-in-Class
It is also important to determine whether the new potential therapy will be a rst-in-
class or a best-in-class. These two parameters are clear determinants of future com-
mercial success and should therefore be an essential consideration when constructing
a TPP.First-in-class molecules are those that use a novel and unique mechanism of
action to treat a medical condition, while best-in-class offers a clinical advantage
over what is currently available on the market for a given indication. An example of
a best-in-class molecule that was a late entry to the market was Lipitor, the HMG-
CoA reductase inhibitor that was the fth statin to reach the marketplace and was
launched nine years after the rst statin. Despite its late launch, Lipitor captured
double the peak annual sales of other statins. This might suggest that it is more
important to be best-in-class rather than rst-in-class. However, an excellent analy-
sis of drug launches in the 1990–2010 period by Shulze and Ringel (2013) indicated
that it is slightly better to be rst, rather than best (Schulze and Ringel 2013). The
analysis showed that the value of late entries to the market falls dramatically, if the
D. Mochly-Rosen et al.
213
second entry is not rapid. The analysis highlighted additional factors that may sig-
nicantly modify the rst-in-class/best-in-class guidelines: (1) If the compound can
target a patient subpopulation where it shows certain key advantages; (2) if the use
of the drug can be expanded to additional therapeutic indications beyond its initial
approval; (3) if the drug targets a large market, where different drugs might be
cycled as part of the treatment regimen of a patient; and (4) if the drug is being
marketed by a formidably strong commercial organization. Overall, however, the
timing of market entry and actual therapeutic advantage remain the dominant
parameters determining commercial success and these two considerations should
remain pre-eminent in the TPP.
5.7.7 Selecting theAppropriate Therapeutic Area
For a given research project, there may be several different options for diseases to
target. It is worthwhile to consider these options in terms of the costs that might be
incurred to bring such a therapy to the market, since these vary signicantly depend-
ing on the therapeutic area. A recent study indicated that between 2009 and 2018,
the mean capitalized research and development investment to bring a new drug to
market was estimated at $1335.9 million. These costs were highly dependent on the
therapeutic area in which the drug was being developed. For example, median esti-
mates by therapeutic area ranged from $765.9 million for nervous system agents to
$2771.6 million for antineoplastic and immunomodulating agents. Furthermore,
several studies have indicated that clinical trial success rates from phase 1 to FDA
approval varied widely by therapeutic area, with the highest success rate in ophthal-
mology with a phase 1 to FDA approval rate of 32.6%, whereas in oncology, this
rate dropped to 3.4% (Wouters etal. 2020).
Box 5.9: Some Questions for Target Groups
1. For patients:
• What is the current treatment for their medical condition?
• Are patients satised with current treatment options? And if not,
why not?
• Is their quality of life improved by their existing treatment?
• Do they fully adhere with the treatment regimen as recommended by
their physician?
• Is the dosing schedule or formulation inconvenient?
• What would they like from a new treatment?
2. For physicians, nurses and caregivers:
• What is the current standard of care that they use?
• What challenges exist in treating this disease?
• Are there dose-limiting interactions with other drugs?
5 Technology Transfer andCommercialization
214
5.7.8 Parties toBeConsidered When Identifying Unmet
Medical Needs
The most obvious customer for a potential new therapeutic is the patient that will
hopefully benet from the new treatment. However, physicians, nurses, and other
caregivers will also have signicant input on how and whether the new treatment
will be adopted. Additionally, those that might offer reimbursement for the new
treatment, for example, a health insurance company, will also inuence whether a
treatment will be utilized. Similarly, hospital administrators will also have a signi-
cant input in deciding whether a new treatment will be used. Some of the questions
that each of these groups will consider are listed in Box 5.9.
• Where is the current treatment administered (at home, hospital)?
• Are patients readily able to access the treatment?
• Is the prescribing physician a specialist or a primary care physician?
• Is recruitment and/or patient retention difcult within this patient pool
(e.g., competing trials, non-adherent subjects)?
• Are there subpopulations of patients who will respond optimally or
adversely to treatment?
• How costly would a trial be in this indication (size, duration,
endpoints)?
3. For hospital administration/payers:
• How costly would a trial be in this indication (size, duration,
endpoints)?
• Are there challenges for reimbursement?
• What is necessary to prove cost-effectiveness in clinical development?
The Bottom Line
Clearly, the dominant parameter determining the selection of the optimal clin-
ical indication should be the science that underpins the research driving the
development, but careful consideration of the advantages and disadvantages
of different therapeutic options should enhance the ability to fundraise and
provide future partnering opportunities.
D. Mochly-Rosen et al.
215
5.8 Commercial Assessments
JuliePapanekGrant and LeonChen
Companies, inventors, and investors complete commercial assessments to estimate
the future revenue of a potential new therapy. Revenue from product sales provides
funds for research and discovery investments, drives investor interest, and nances
the delivery of products to patients. During the R&D stage of a product, commercial
assessments inform whether the expected revenue is likely to provide an attractive
nancial return on the millions of dollars invested in the drug development process.
Although it is unlikely that you will have to create a highly detailed commercial
assessment as a translational scientist, identifying the key drivers will enable you to
understand the market and product characteristics that make companies and investors
take notice.
5.8.1 The Formula
Most pharmaceutical companies use the same formula when estimating annual sales:
Market size numberof potentialpatientsProductshare takingy
%oour product
Priceper patient paid for your productAnnualsa
llesrevenues
Think of the formula like a pie chart. The market size is the entire pie. The prod-
uct share is the size of your product’s slice expressed as a percentage. Price per
share estimates the dollars that will be charged for the product and converts units
into dollars in a given year.
This simple formula makes it easy to see trade-offs between different commer-
cial and development strategies. Some companies prefer to pursue very large mar-
kets where there are lots of competitors because even a small slice of a big pie will
provide a large return. Markets for statins, anticoagulants, and angiotensin receptor
Box 5.10: How Many Potential Markets Should You Analyze for Your Drug?
If your drug may be used for multiple indications, evaluate only two to three
markets and ignore the rest;evaluating each and every potential market in
which a drug could be used is unnecessary. Most pharmaceutical companies
believe in gated investing, which means that the drug must show promising
activity in the rst few indications before more investments are made. Focus
on evaluating the rst two to three indications where the product could launch
and then list areas for future exploration without valuations. Notably the rst
indication does not have to be the largest market. Gated investing allows you
to create a balance between market size and time/risk of demonstrating clini-
cal utility. It will save you time and give you credibility.
5 Technology Transfer andCommercialization
216
blockers are good examples. Other companies might choose to develop products for
smaller markets with high unmet medical needs, few competitors, and few pricing
constraints. In these markets, a larger product share and higher price per course of
treatment can offset a small patient population to ensure adequate revenue.
Companies and investors seek to maximize the commercial potential of their
products. Decision-makers focus on the variables that can be manipulated or inu-
enced and have the largest impact on value. We will explore each of these drivers,
so that we can see where drug development decisions impact commercial value.
5.8.2 Market Size
The market size is the number of patients with a specic disease who could be
treated with a product in a given year. Start with the number of patients who are
diagnosed with the disease each year. This initial number can then be adjusted up or
down to reect potential patient subpopulations or changes in diagnosis rates, treat-
ment rates, the incidence of the disease, and the product’s expected FDA label state-
ment. When estimating changes in incidence, diagnosis, and treatment rates,
consider external factors such as the (in)convenience, cost, and behavioral changes
your product may impose upon physicians, nurses, and patients. These consider-
ations are discussed more in the previous section, Sect. 5.7.
The expected FDA label statement is directly within the control of the team
designing the clinical trials, in particular the pivotal trial(s), for a new product. The
eligibility criteria for patients participating in the phase 3 studies will inform the
FDA approved indication statement, which then drives which patients will receive
the new product once it is approved. Diagnostic tests, drug–drug interactions, mini-
mal vital sign requirements, age, ancestry, gender, and other patient characteristics
can all dramatically change the number of patients who can receive a product. Each
of these constraints should be considered when estimating the market size.
The inclusion criteria not only impact the commercial value but also the trial
size, timelines, and probability of meeting the primary endpoint. Larger markets
tend to require larger numbers of enrolled patients and more expensive clinical tri-
als. As a result, trade-offs in phase 2 and phase 3 trial design should be debated by
diverse teams including clinicians, biostatisticians, and commercial
representatives.
Box 5.11: Real World Example
When estimating the market size for crizotinib, a drug approved for anaplastic
lymphoma kinase (ALK) positive non-small cell lung cancer, Pzer needed to
account for the drug’s specicity. Fewer than 2000 of the 221,000 patients
diagnosed with lung cancer each year actually harbor the ALK mutation and
are expected to respond to crizotinib. When FDA approved the drug in 2011,
its use was restricted to patients with advanced stage non-small cell lung can-
cers that express the ALK gene. As a result, the FDA label reected an
approved market size of 2000 patients; not 221,000 patients.
D. Mochly-Rosen et al.
217
5.8.3 Product Share
The product share estimate is usually the most subjective and heavily debated aspect
of a valuation. Market share predicts the percentage of patients expected to be pre-
scribed your product. In the end, most companies are looking for products that are
rst to market and/or the best drug on the market versus the competition. Better
products and very novel products tend to have greater product share. Competition
includes any and all therapies or procedures that can be used to treat a disease, not
just drugs with the same mechanism of action. Surgical procedures and lack of treat-
ment should also be considered as competition. Do not just include marketed prod-
ucts, because products in late-stage development (phase 3) and products that are
similar to your product but ahead in development are all competitively relevant.
Speed and differentiation are critical components to determining product share.
When a product is launching a year or more after a similar competitor, the second
product will have a much harder time displacing the entrenched market leader.
Being rst to market carries the advantage of establishing a base of patients that are
well served. As a result, the second product will often target patients not served by
predecessors or seek to take market share by virtue of being better than the incum-
bent. Speed also inuences the duration of patent coverage following market launch.
Most investors want at least 5years of patent protection after launch to allow time
to recoup development costs before facing competition from generics or
biosimilars.
Differentiation is a product’s uniqueness in comparison to other options avail-
able to treat a specic disease or condition. It is relatively easy to imagine products
differentiating on efcacy or safety, and indeed most second-in-class products aim
to improve on one or both of these parameters. However, differentiation can be
much more nuanced. Characteristics such as route of administration, dosing fre-
quency, and contraindications can make meaningful differences in capturing market
share. Other factors such as supply chain, storage conditions, and shelf-life can be
competitive points of differentiation as well. While there are multiple ways to dis-
tinguish your product from predecessors, it will be important to compare all features
of the different products in totality. Depending on the disease and treatment alterna-
tives, patients and providers will probably show little tolerance for trading conve-
nience for reduced safety or efcacy.
Finally, keep in mind payers’ priorities when calculating product share. Consider
whether your product is more cost-effective or improves patient outcomes over
competitors. Make sure your reimbursement strategy at a high level is not a hurdle
to physicians and patients adopting your product. As you move closer to launch, a
detailed reimbursement strategy will be required.
By combining speed, differentiation, and competition, you will be able to make
an educated guess about the product’s market share. As a rule of thumb, a product
will only be broadly adopted if it is better than existing options based upon criteria
that matter. If a market has many undifferentiated competitors, speed matters most.
Therefore, it is not surprising that companies pursue those therapies that could be
rst-to-market or best-in-class.
5 Technology Transfer andCommercialization
218
5.8.4 Price
The nal step in the formula is converting the number of patients treated with your
product into sales revenues. A rough estimate of revenues can be calculated by mul-
tiplying price by number of patients. “Price” can encompass total cost to insurance
companies per patient per year. This generalization accounts for different therapies
with variable dosing schedules and frequency.
Whereas the dosing schedule and frequency will likely be xed in the clinical design,
the pricing estimate is unquestionably exible. The same competitive assessment of
speed, differentiation, and competition that informs product share also informs pricing.
If a product meets a signicant unmet medical need and dramatically improves out-
comes or standard of care, a higher price (a.k.a. premium price) can be charged and will
likely be reimbursed by insurance companies. Other improvements in safety, conve-
nience, patient adherence, etc., typically do not command premium pricing.
Box 5.13: Guidelines for Thinking About Market Share
1. Current options:
• Are physicians, patients, and payers satised with the current options
available?
• What criteria would motivate them to switch to your product?
2. Similar products:
• How many other products are being developed in the same market with
the same or similar mechanisms of action as your products?
• How is your product better?
3. Other novel approaches:
• Approximately how many other products being developed in the same
market have a different mechanism of action?
• Which are most promising?
• When will they launch?
• How is your product better, the same, or worse?
Box 5.12: Deciding on a Market Share Percentage
Weighing the importance of speed, differentiation, and number of competitors
is highly subjective. There is no right answer. Similarly, precision down to the
exact percentage point is not the goal. Instead, forecasters just want to ensure
they are in the right range (0–15%, 15–30%, 30–60%, 60–80%, 80%+). The
best evidence to support an assumption is analogies from similar products and
similar markets. For instance, if a company is developing a rheumatoid arthri-
tis therapy that will likely have lots of competitors, examples from the TNFα
inhibitor market would be informative.
D. Mochly-Rosen et al.
219
Leveraging existing pricing estimates from the current standard of care is a good
starting point. Similar to demonstrating clinical benet on top of standard of care in
a clinical trial, payers will compare price to standard of care options. If predecessors
do not exist because the product is rst-in-class, comparable pricing is more chal-
lenging. You may need to extrapolate from unrelated markets, but similar proles.
For example, many enzyme replacement therapies for different orphan diseases
have similar pricing models despite treating distinct diseases. Gene therapy and
CAR-T therapy are other analogous examples.
5.8.5 Making Informed Decisions Early
Commercial assessments should be incorporated at the earliest stages of a drug
discovery project. Conviction in the fundamental biology and the ability to drug a
target and impact disease is insufcient to achieve the goal of delivering a therapeu-
tic solution to impact public health. A good commercial assessment will help attract
the nancing required for development and pave a path to adoption by providers and
payers, all of which are essential for your drug to reach patients.
Embedded in commercial assessment is the clinical path to market approval.
Understanding how choice of clinical indication and patient selection strategies can
mitigate risk and impact development costs and timeline are important consider-
ations in this assessment. Fortunately, investors and companies do not expect
detailed market values from you, the inventor. They will appreciate whether you
understand how your product will t into the competitive landscape and how this
impacts its ultimate value and the path to success.
5.9 Making aCompelling Pitch toPotential Investors
LeonChen
Effectively communicating your pitch to potential investors is a critical skill in
attracting the necessary resources for starting a company. While investors may vary
signicantly in their criteria for evaluating new opportunities, common themes and
practices can help entrepreneurs better communicate their ideas. This section
reviews both substance and style of a successful pitch.
The Bottom Line
Before investing in a novel therapeutic, investors (e.g., a company or venture
rm) will want to ensure that future revenues will justify the development
costs and provide a positive return on investment. When analyzing potential
future revenues, it is important to consider the number of eligible patients
(total market), your product’s market share, and price. Pricing and market
share will depend upon the unique advantages that your product offers over
existing therapies and other potential new competitors.
5 Technology Transfer andCommercialization
220
5.9.1 What Is theProblem?
There are fundamental questions that every pitch should address. First, what is the
problem you are trying to solve? Second, perhaps less obvious but equally impor-
tant, who cares? An understanding of which technical improvements in efcacy,
safety, or convenience will result in a signicant commercial opportunity can be a
more challenging question to answer. Unlike other industries where a new product
is not objectively better, but just different (food, music, etc.) the pharmaceutical
industry and the gatekeepers to market access, such as health insurers, require that
new products be objectively better than standard of care. Although there are a num-
ber of ways to marginally improve upon existing options, market adoption from
payers and patients is more likely to be driven by safety and efcacy. Therefore,
pitches that solve for these two parameters will generally be more appealing.
5.9.2 What Is theSolution totheProblem?
Moreover, is your solution commercially practical and viable? To realize their full
potential, technically elegant solutions to difcult problems must also be convenient
and t easily within the current commercial environment. A common trap for scien-
tist entrepreneurs is to develop solutions that can yield a signicant safety or ef-
cacy benet, but at the cost of convenience or the right physician or payer channels
to support the market. For example, the oncolytic virus tamilogene laherparepvec
(Imlygic) showed profound efcacy data in melanoma, but has limited market adop-
tion because it requires direct tumor injections, a practice that few oncologists are
comfortable doing. Similarly, very high-priced therapies with a high cost of goods
(gene and cell therapies) have limited market adoption. A discussion of the pros and
cons of your innovation from the point of view of patients, prescribers, and payers
can help clarify the likelihood of clinical and market acceptance. You must convince
potential investors that your solution is both feasible and attractive to those who will
drive its adoption.
Box 5.14: The Basics of Every Pitch
1. What problem are you trying to solve?
2. What is your solution to the problem?
3. How do you know the solution will work?
4. Who else is trying to solve this problem?
5. How big is the opportunity?
6. What will it take to achieve success?
D. Mochly-Rosen et al.