The following case study examines the evolution of Avodart™, a drug manufactured by GSK

that is currently licensed for the treatment of benign prostatic hyperplasia (BPH). Avodart™

provides an opportunity to identify lessons for future pricing and reimbursement situations. This

is particularly so as health system payers focus increasingly on the concept of value when making

decisions. The story of Avodart™ is one where perceptions of the value of the product relative

to the other product in the therapeutic class were conservative at launch. However, as new data

emerges about the product over time, the perceptions of Avodart‟s™ value could dramatically

increase. For example:

Avodart ™ was launched into a class of medicines with an established product, Proscar™,

which was viewed as the default comparator for Avodart™. Avodart™ has a similar, but

different, mode of action to Proscar™, which GSK believed would lead to superior

outcomes relative to Proscar™. However, data available at launch for Avodart™ were

unable to show significantly better outcomes than Proscar™, making Proscar‟s™ situation in

the market very relevant to the launch strategy and pricing outcomes of Avodart™.

GSK has undertaken clinical trials since launch that demonstrate the benefits of Avodart™

when taken in combination with another product (tamsulosin). Data suggest that taken in

combination, Avodart™ and tamsulosin have superior outcomes in the treatment of BPH to

either product taken as monotherapy.

Avodart™ is now starting to face generic competition in the therapeutic class as Proscar™

comes off-patent. Hence, the relative value of Avodart™ may fall significantly in the eyes of

payers.

Avodart™ may become licensed for new indications. Studies in animals, observations in

clinical trials, and pilot prostate cancer (PCa) studies provide scientific evidence that

Avodart™ could have a significant impact on preventing and perhaps treating prostate

cancer.1 This would increase the value of Avodart™ and also differentiate it from Proscar™.

Whilst robust data to demonstrate this are not yet available, studies are in place (e.g.

REDUCE, REDEEM) to build the value case over the next three years, which coincides

with the time when Avodart™ will face increasing price pressure in the BPH market from

generic finasteride (the chemical name for Proscar™).

In this case study, we present a brief background on BPH and treatment intervention, outline

perceptions about Avodart‟s™ value proposition at launch, consider the impact of generic entry

and identify emerging evidence to support Avodart‟s™ changing value proposition. At the end

of each section, we provide some questions for members to consider.

1 Xu Y et al. Pharmacological basis for dutasteride‟s enhanced efficacy against prostatic cancers. Clin. Cancer Research. 2006; 12:

4072.

Benign prostatic hyperplasia (BPH) is a progressive disease that is commonly associated with

bothersome lower urinary tract symptoms (LUTS) such as urinary frequency, urgency, nocturia,

decreased and intermittent force of stream and the sensation of incomplete bladder emptying.

The term „BPH‟ actually refers to a condition revealed through the study of tissue within the

prostate gland, namely the presence of stromal-glandular hyperplasia.2 The condition becomes

clinically relevant if, and when, it is associated with bothersome LUTS; however, the

relationship between BPH and LUTS is complex, because not all men with BPH will develop

significant LUTS, while other men who do not have BPH will develop LUTS.

The Burden of BPH

This section reviews the primary measure used to diagnose BPH, prevalence rates across Europe,

and implications for quality of life for patients.

Studies suggest that the clinical prevalence of BPH in men over age 50 is around 20%. A

common way to assess the severity of BPH is to use a questionnaire, such as the International

Prostate Symptom Score (IPSS). The IPSS is a self-administered questionnaire that asks patients

about their urinary symptoms over the last month (e.g. how often in the last month have you

found it difficult to postpone urination?). It scores their responses on a scale of 0 to 5. There are

8 questions in total, with 7 assessing the symptoms and the final one assessing the impact of

symptoms on quality of life. IPSS scores range between 0 (no symptoms) and 35 (very severe

symptoms).3

A common clinical definition of BPH is when the prostate‟s volume exceeds 30cc (prostate size

is normally around 20cc) and the patient has an IPSS score greater than 7 (moderate lower

urinary tract symptoms (LUTS)). Using this definition, Table 1 shows estimates of the number

of men with BPH and prevalence rates in France, Germany, the Netherlands and the UK, in

men over age 50 in 2005.

Country 2005 Prevalence

France

Germany

Netherlands

UK

1,822,450

2,715,360

465,860

1,786,710

18.3%

18.4%

17.7%

18.7%

Note: The data in this table are based on projections that were reported in 2002. Source: Based on GlaxoSmithKline Worldwide Epidemiology 2002, and population data from Eurostat (http://epp.eurostat.ec.europa.eu)

BPH has a significant impact on patients‟ quality of life. Studies have compared how patients

with BPH rate their quality of life using the EuroQoL (EQ-5D) questionnaire. EQ-5D is a

2. Roehrborn CG. Benign prostatic hyperplasia: an overview. Rev Urol. 2005; 7 (suppl 9): S3–14.

3 Barry MJ, Fowler FJ, Jr., O'Leary MP, et al. Measuring disease-specific health status in men with benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. Med Care. 1995; 33: AS145–55.

health-related quality of life instrument that rates a patient‟s quality of life on a scale of 0 (death)

to 1 (perfect health) by asking questions about dimensions of health such as levels of anxiety,

mobility and pain.

Table 2 reports results from a UK study that compares EuroQoL scores for patients with BPH to

patients with asthma. Patients with moderate LUTS rate their quality of life at a similar level to

non-smoking asthmatics. A US study made a similar comparison based on the SF-36, a health-

related quality of life questionnaire that is similar in nature to the EQ-5D. The study concluded

that patients with severe LUTS rated their health as similar to, or worse than, patients with

chronic obstructive pulmonary disease (COPD).

Condition Mean EuroQoL Score

BPH-related condition:

Mild LUTS (IPSS<8) Moderate LUTS (IPSS 8-19) Severe LUTS (IPSS 20-35)

0.87 0.79 0.71

Other chronic conditions:

Non-smoking asthmatics Smoking asthmatics

0.80 0.76

The Management of BPH

There are a range of treatment options for BPH including watchful waiting, drug therapy, and

surgical intervention. Over time, treatment has shifted away from surgery and toward drug

therapy, particularly as drug therapy has evolved to provide not only symptom relief, but also to

reduce the size of the prostate and lessen the outcomes of BPH.

„Watchful waiting‟ is usually the first treatment option in patients experiencing mild LUTS.

This is indicated for patients with minimal symptoms or with moderate/severe symptoms but

with little impairment on quality of life.5 It is customary for this type of management to include

the following components: education, reassurance, periodic monitoring and lifestyle advice. The

condition is typically monitored by physicians and there is no intervention until symptoms

worsen (i.e. progress beyond an IPSS score of 7).

There are two pharmaceutical therapy options available when BPH progresses beyond the mild

stage. The first major class of drug treatments for BPH is alpha-blockers, which relieve the

symptoms of BPH. They do not slow the progression of BPH or prevent more serious

outcomes. There are two other therapies, the 5-alpha-reductase inhibitors (5-ARIs), currently

4 Source: GSK quoting from Trueman P, Hood SC, Nayak U, et al. Prevalence of lower urinary tract symptoms and self-reported

diagnosed 'benign prostatic hyperplasia' and their effect on quality of life in a community-based survey in men in the UK. BJU Int. 1999; 83: 410–5; and Garratt AM, Hutchinson A, Russell I. Patient-assessed measures of health outcome in asthma: a comparison of four approaches. Respir Med. 2000; 94: 597–606.

5 S. Madersbacher, G. Alivizatos, J. Nordling, C. Sanz, M. Emberton, J. de la Rosette. EAU 2004 Guidelines on assessment,

therapy and follow-up of men with lower urinary tract symptoms suggestive of benign prostatic obstruction (BPH guidelines).

European Urol. (46.5), 547-54.

available: dutasteride (Avodart™) and finasteride (originally launched as Proscar™ by Merck but

generic versions are now available). 5-ARIs do not provide fast symptom relief but do reduce

the size of the prostate. This leads to longer term symptom relief and reduces the risk of

outcomes associated with the progression of BPH.

Combination therapy combines alpha-blockers with 5-ARIs and can offer the benefits of both.

Combination therapy can provide more immediate symptom relief and reduce the overall risk of

disease progression and long-term outcomes such as acute urinary retention (AUR) and surgery.

Although recommended by guidelines,6 combination therapy is not yet as often used as

monotherapies; it is used mainly for patients with severe symptoms or with significant

impairment in quality of life (QoL). At time of launch, Avodart™ was not licensed for use in

combination with an alpha-blocker. Studies of Proscar™ had previously demonstrated the

benefits of Proscar™ when used in combination with the alpha-blocker, doxazosin.7

Phytotherapy (the use of plant and herb extracts), though currently not recommended by the

European Association of Urology BPH Guidelines, is a common intervention for treating BPH.

Some studies comparing the use of phytotherapy with Proscar™ have suggested the two deliver

similar improvements in lower urinary tract symptoms and urinary flow. However, these studies

tend to be based on small patient populations, vary in design and have limited outcomes data.

Historically, surgery has been a common intervention to treat BPH, although its use has declined

with the advent of less invasive treatment options. However, surgery is still a recommended

treatment for patients with moderate or severe symptoms who have not responded to medical

therapy or who reject medical therapy, or in those patients who present complications such as

AUR, bladder stones or renal insufficiency. Surgical options include minimally invasive

techniques such as transurethral microwave thermotherapy (TUMT) and transurethral needle

ablation of the prostate (TUNA), and traditional interventions to remove the prostate such as

transurethral resection of the prostate (TURP), the most common surgical procedure used to

remove part of an enlarged prostate. Open prostatectomies (in which an incision is made into

the abdomen) generally are needed only when the prostate is very large.

Figure 1 provides an overview of the typical treatment pathways for patients with BPH. In

many cases, patients will experience a combination of different pathways, depending on disease

progression and the ability of non-invasive treatment to slow disease progression.

Figure 1 also indicates how treatment models have changed over time, with a gradual shift away

from surgical intervention towards less invasive treatment. This is important in the context of

the treatment role of the 5-ARIs, as they are a group of medicines that are primarily focused on

slowing BPH disease progression by reducing prostate volume.

6 Ibid. 7 McConnell JD et al. The long-term effect of doxazosin, finasteride and combination therapy on the clinical progression of benign

prostatic hyperplasia. N Engl Jnl Med. 2003; 349: 2387-98.

Avodart™ was licensed in Sweden8 in 2002 for the treatment of moderate to severe BPH

symptoms and the reduction in the risk of acute urinary retention and surgery in patients with

moderate to severe lower urinary tract symptoms. GSK drew on data from two phase II and

three phase III clinical trials to support value messages about Avodart™. The phase III trials

involved more than 4,000 patients with moderate to severe BPH and prostate volumes in excess

of 30cc. The majority of the data were based on placebo-controlled trials, rather than direct

head-to-head comparisons with Proscar™. Key features of the available data included:

Data for Avodart™ were based on endpoints at 24 months. Data for Proscar™ available at

the time used endpoints at 48 months.

Avodart™ generated comparable outcomes relative to Proscar™. For instance:

Avodart™ reduced the risk of acute urinary retention by 57% at 2 years, whilst

Proscar™ showed the same reduction at 4 years.

Avodart™ reduced the risk of BPH-related surgery by 48% at 2 years. Proscar™

reduced this risk by 55% over a 4-year period.

Avodart™ was reported to be a potent inhibitor of both the Type 1 and Type 2 5-alpha-

reductase isoenzymes whereas Proscar™ inhibited only Type 2. The consequence of this is

that Avodart™ leads to greater reductions in dihydrotestosterone (DHT) concentrations than

Proscar™. Raised levels of DHT are thought to be a causative factor in the enlargement of

the prostate and hence the development of BPH. However, data at the time did not show

that the difference in potency between Avodart™ and Proscar™ was clinically significant for

the treatment of BPH.

One 12-month study (EPICS – Enlarged Prostate International Comparator Study),

compared Avodart™ with Proscar™. It found that Avodart™ produced numerically, but

not statistically significantly, greater improvements in urinary flow rate and symptom scores

after 1 year of treatment.

In its reimbursement support dossier and product monographs,9 GSK highlighted Avodart‟s™

value proposition at launch along three key themes:

There was a significant clinical unmet need in the treatment of BPH;

The 5-ARIs reduce prostate volume and hence reduce the risk of developing complications

from disease progression; and

Avodart™ is superior to the other 5-ARI, Proscar™ (finasteride) because of its different

mode of action (dual inhibition of Type 1 and Type 2 isoenzymes).

Table 3 summarises Avodart‟s™ value proposition at launch, with an assessment of how it fit

with other market and treatment factors at the time.

8 Avodart first received marketing authorisation in Sweden, which served as the Reference Member State as part of Europe‟s mutual

recognition procedure.

9 Product monographs are internal documents prepared by a manufacturer that highlight information related to a product, such as its

efficacy, safety and tolerability, place in therapy, impact on patient quality of life and its cost effectiveness. These documents will

often also contain data on the economic burden of the relevant disease that the drug treats. Reimbursement support dossiers

contain much of this information, and explicitly draw-out a product‟s value proposition.

Value theme Value message Commentary

Unmet clinical

need

BPH is a common condition,

affecting over 20% of men over

age 50.

Avodart™ provides a new treatment

option for BPH, but within an

existing therapeutic class. GSK draws

comparisons with Proscar™ to

demonstrate the benefits of 5-ARIs

relative to alpha-blockers.

Avodart™ slows

disease

progression

Alpha-blockers relieve

symptoms of BPH but do not

slow progression or reduce the

risk of developing

complications of BPH.

Taken in combination,

Avodart™ and alpha-blockers

might provide immediate

symptom relief and reduce risk

of disease progression and

long-term outcomes such as

AUR and surgery. (GSK did

not seek licensing for

Avodart™ for use in

combination at initial launch).

GSK reports results of clinical trials of

Avodart™ (two phase II and three

phase III trials).

Data tend to focus on the benefits of

Avodart™ relative to placebo. The

emphasis was on the ability of

Avodart™ to reduce prostate

volume, improve lower urinary tract

symptoms, and reduce the incidence

of acute urinary retention.

Data demonstrated the benefits of

Avodart™ over a 24-month period.

One phase III trial assessed the

benefits of Avodart™ in combination

with alpha-blockers over a 36-week

period.

Avodart™ vs.

Proscar™

Relative to Proscar™,

Avodart™ is not only a more

potent inhibitor, it is also a dual

inhibitor, of Type 1 and Type

2 isoenzymes that are thought

to contribute to the

development of BPH.

Data were not available at launch to

demonstrate that Avodart™

produced greater improvements in

BPH symptoms than Proscar™.

However, GSK believed that

Avodart‟s™ dual inhibition of Type

1 and Type 2 isoenzymes would be

an important differentiator from

Proscar™, and sought to develop

post-launch data to demonstrate

benefits of dual inhibition.

Source: Based on GSK product monographs and reimbursement support dossiers.

Market and Pricing Strategy at Launch

Avodart™ was launched in the EU beginning in the second half of 2002 and in most major

European markets during the first half of 2003 (Netherlands in December 2002, UK in

September 2003, Germany in April 2003 and France in September 2003). At time of launch,

Merck‟s Proscar™ was the only other 5-ARI on the market in Europe, but GSK‟s data did not

suggest that Avodart™ represented a clinically significant advance on Proscar™. GSK‟s pricing

strategy was to aim for price parity with Proscar™. A higher price was hard to justify without

good evidence showing Avodart™ had significantly superior outcomes or was better-tolerated

than Proscar™. Aiming for a price premium risked exclusion from formularies. Discounting

relative to Proscar™ was not considered an optimal strategy as it was thought unlikely to lead to

an increase in sales, might be matched by a price cut for Proscar™, and might lower physicians‟

expectations about the product.

Figure 2 summarises the pricing outcomes that were achieved at launch. Overall, GSK was

successful in its objective of achieving price parity with Proscar™.

When Avodart™ was launched, there was good evidence to support GSK‟s case that the product

was effective in the treatment of BPH, but there was little data to suggest it was superior to

Proscar™, the established treatment in the same therapeutic class. However, GSK believed that

Avodart‟s™ dual inhibition would, in the future, lead to superior outcomes.

? What is the most appropriate reimbursement approach at launch for a product that is

unable to demonstrate superiority to an existing product in its therapeutic class? Does

the answer to this change if there are good scientific reasons to believe that a clinically

relevant difference to existing products may be demonstrable in the future?

? When data suggest a product has similar outcomes to existing therapies in a class, could

an accelerated reimbursement process be defined to speed-up market access? If so, how

might this work?

In general, the prices of both Proscar™ and Avodart™ have fallen since Avodart™ was first

launched. This has been due to general pricing and reimbursement reviews as well as the

introduction of generic finasteride. Beginning in 2006, Proscar™ began to go off-patent and

generic finasteride (the chemical name for Proscar™) started to enter EU markets. Prices for

generic finasteride are up to 57% lower than for Proscar™.

Table 4 demonstrates the relative market share and pricing as of November 2007 for generic

finasteride in six of the Member States represented in the Network. Data were not available for

Czech Republic and generic finasteride will not be available in France until 2009. As of

November 2007, Proscar™ was selling at the generic price in Spain and the UK; Avodart™ has

come under pricing strain as well, but has been able to hold higher prices than Proscar™.

Country (date of generic introduction)

5-ARI

market

share of

BHP

medicines

Generic

finasteride

market

share of

5ARIs

Price of generic as % of Proscar

(Nov 2007)

Price of generic as % of Avodart

(Nov 2007)

Germany (4/07) 7.74% 25.56% 53% 57%

Italy (8/07) 27.69% 2.28% 93% 77%

Netherlands (5/07) 24.48% 28.42% 60% 51%

Spain (6/06) 17.35% 8.01% 100% 58%

Sweden (9/07) 45.18% 10.79% 43% 41%

United Kingdom (5/07) 35.61% 32.04% 100% 60%

? When a product goes off-patent, how should the relative value – and hence the prices –

of other products in its therapeutic class be altered?

? What are the consequences of using the patent expiry of the first product in a class as a

signal that the relative value of a therapeutic class has shifted downwards?

? What is the impact of generic entrants on commercial incentives to undertake post-

launch clinical studies to strengthen value messages and to develop new value

propositions? How might this differ in situations where there is a long lag between first

and subsequent patented entrants as is the case with Proscar™ and Avodart™?

10 GSK provided based on IMS data.

Since the launch of Avodart™, GSK has developed, or soon will have developed, data that it

believes will demonstrate an improved value proposition for Avodart™. This derives from

Avodart‟s™ improved efficacy in treating BPH when used in combination with alpha-blockers,

and from a belief that Avodart™ may have a role to play in preventing prostate cancer.

5-ARIs in combination with alpha-blockers

Two key trials have been conducted that examine the effect of 5-ARIs used in combination

with alpha-blockers: MTOPS11 (Medical Therapy of Prostatic Symptoms) and CombAT

(Combination of Avodart™ and Tamsulosin). In 2003, the results of MTOPS were published.

MTOPS was a US-only trial designed to assess the effects of combining Proscar™ with the

alpha-blocker doxazosin. In MTOPS, combining Proscar with doxazosin yielded no significant

symptom improvement compared to use of the alpha-blocker alone after one year.

Furthermore, evaluations in MTOPS‟ were done at 1 and 4 years, and the primary endpoint was

a composite of “disease progression” that included symptomatic progression, AUR, renal

insufficiency, recurrent urinary tract infection and urinary incontinence. This composite

endpoint made it difficult to tease out the separate effects on symptoms and outcomes.

In 2003, GSK began the CombAT trial to assess the long-term benefits of using Avodart™ in

combination with the alpha-blocker, tamsulosin. CombAT was designed to assess whether

combination therapy is superior to each monotherapy alone in terms of demonstrating improved

IPSS scores at 2 years and reducing risk of outcomes such as AUR and surgery at 4 years.

CombAT is a four-year international trial involving over 4,800 men diagnosed with moderate to

severe BPH symptoms and at increased risk of disease progression (i.e. PSA levels >= 1.5 and

prostate volumes >= 30cc). This is a higher risk population than that investigated in the

MTOPS trial where PSA entry thresholds differed and prostate volumes were not included.

This made the population in CombAT potentially more suitable to exploring the effects of

combination therapy than was the population investigated in the MTOPS trial. In addition,

evaluations were done every 3 months providing more clarity on impact of combination therapy

on symptoms and outcomes than MTOPS could provide. Key differences between the two

study designs are highlighted in Table 5.

11 John D. McConnell, M.D., Claus G. Roehrborn, M.D., et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl Jnl Med. 2003; 349: 2387-98.

CombAT MTOPS

Treatment groups Dutasteride monotherapy Tamsulosin monotherapy Dutasteride and tamsulosin

Finasteride monotherapy Doxazosin monotherapy Finasteride and doxazosin

Placebo

n 4844 3047

Location of study centres International US only

Entry criteria

PV (cc) ≥30 NA

PSA (ng/mL) ≥1.5 ≤10

IPSS ≥12 8-30

QMAX (mL/s) 6-15 4-15

Primary endpoints

2-year Improvement in IPSS NA

4-year Reduction in risk of AUR/surgery

Composite endpoint of BPH clinical progression

Other differences Patients with clinical progression may continue

study but not switch treatment

Patients who reached endpoint were censored but could continue on alternative

medication

AUR, acute urinary retention; BPH, benign prostatic hyperplasia; CombAT, COMBination of Avodart and Tamsulosin; IPSS,

International Prostate Symptom Score; MTOPS, Medical Therapy of Prostatic Symptoms; PSA, prostate-specific antigen; PV, prostate volume; QMAX, peak urinary flow rate.

Results from the CombAT study at the two-year point suggest that Avodart™ taken in

combination with tamsulosin produces a significantly greater improvement in BPH symptoms

relative to either product when taken as monotherapy. The data show that combination therapy

produces a statistically significant improvement in IPSS scores after 3 months (compared to

receiving Avodart™ monotherapy) and 9 months (compared to receiving tamsulosin

monotherapy). A statistically significant improvement in symptoms is maintained for 2 years

from the initiation of treatment. The CombAT study is continuing for a further 2 years to

examine the effects at 4 years.

Currently, GSK does not have data that compares the effect of using Avodart™ in combination

with the effect of using Proscar™ in combination. The American Urological Association

recommends the use of 5-ARIs in combination with alpha-blockers in patients with moderate to

severe BPH symptoms. It notes that currently the “best tested” combination is Proscar™ with

doxazosin, but indicates that “the combination of any effective alpha-blocker and 5-alpha-

reductase inhibitor probably produces a comparable benefit”.12

In April 2008, GSK gained regulatory approval13 for combination use of Avodart™ and

tamsulosin, based on the results of the CombAT study. In November 2008, GSK plans to apply

for use of a fixed dose combination consisting of tamsulosin (0.4mg) and dutasteride/Avodart™

(0.5mg) in a single tablet. To be called Duodart™, the product will help patients achieve the

clinical benefits demonstrated in CombAT, with a reduced number of pills. GSK does not

currently propose to charge a price premium for Duodart™ compared with Avodart

monotherapy and therefore this brand will offer additional value over Avodart™. GSK believes

that the superior clinical benefits from Duodart™ will result in more patients being prescribed

this than the monotherapy.

? Does the improved efficacy of Avodart™ for treating BPH, when used in combination

with tamsulosin, constitute a significant change in Avodart‟s™ value proposition? Does

the introduction of the fixed dose combination, Duodart™ constitute a significant

change in Avodart‟s™ value proposition?

? Under what circumstances do combination therapies warrant consideration of a higher

price?

A Potential Role for Avodart™ in the Prevention of Prostate Cancer

There is considerable evidence to suggest that androgens influence the development and growth

of prostate cancer (PCa). One way this occurs in the male body is through the conversion of

one androgen, testosterone, into the more potent androgen dihydrotestosterone. This

conversion is aided by the 5-alpha-reductase isoenzymes (5-ARI). The 5-ARI class of drugs

work by inhibiting this conversion, and a number of studies have assessed whether inhibiting 5-

alpha-reductase has a significant impact on reducing the incidence of prostate cancer.

Early clinical trials of this focused on the ability of Proscar™ to reduce the incidence of prostate

cancer. The Prostate Cancer Prevention Trial (PCPT)14 was a 7-year study of 24,482 males

recruited between January 1994 and May 1997. There was no negative prostate biopsy entry

criterion and all men underwent an end-of-study biopsy. End-of-study analyses of over 9,000

subjects15 yielded a statistically significant 24.8% reduction in detection of prostate cancer for

those receiving Proscar™ versus those receiving the placebo. Prostate cancer was detected in

18.4% of participants in the Proscar™ group and in 24.4% of participants in the placebo group.

The trial was stopped 15 months before scheduled completion on the basis that the study

objectives had been met and the conclusions were unlikely to change.

However, one of the key findings from the PCPT study is that while Proscar™ demonstrated

effectiveness in reducing the risk of prostate cancer, the rate of high-grade disease detected in the

12 American Urological Association. Guideline on the Management of Benign Prostatic Hyperplasia (updated 2006, available from

http://www.auanet.org/guidelines/bph.cfm). 13 Sweden acted as the Reference Member State as part of Europe‟s mutual recognition procedure. GSK anticipates approvals in

other European countries in the coming months.

14 Thompson IM et al. The influence of finasteride on the development of prostate cancer. N Engl Jnl Med. 2003; 349: 215-24. 15 The final analysis in the study included 9,060 males, with 4,368 in the finasteride group and 4,692 in the placebo group.

Proscar™ group was significantly higher than in the placebo group.16 Hence Proscar™ reduces

the risk of developing prostate cancer, but appears to increase the risk of developing high-grade

tumours. On the face of it, this is concerning, and a number of explanations have been put

forward. The first potential explanation is that finasteride reduced the prostate volume and thus,

increased the likelihood of detecting all cancers and high-grade tumours due to an increased

biopsy sample density (i.e. more tissue obtained per unit of volume). In a prostate that has been

shrunk because of 5-ARI intervention, a proportionately larger sample of the prostate is required

for testing, hence making it more likely that an aggressive cancer is detected. Another

explanation could be that finasteride has less effect on high-grade tumours compared with low or

moderate-grade tumours. Finasteride has also been shown to increase the diagnostic

performance of PSA. In those patients who underwent a biopsy in the PCPT trial, the

sensitivity and AUC of PSA to detect any prostate cancer and high-grade prostate cancer were

statistically significantly better in the finasteride treated patients than in the placebo treated

patients.17

Doubt has also been expressed about some aspects of the PCPT trial. The rates of prostate

cancer detected in the placebo group were far higher than rates seen in other trials and were

closer to prevalence rates detected in histological studies at autopsy. One explanation is the

screening and biopsy undertaken at the end of the PCPT trial was detecting a larger number of

clinically insignificant and localised cancers, rather than cancers that would progress rapidly and

require treatment.18

Proscar™ was never licensed for the prevention of prostate cancer. The common view after the

PCPT trial was that Proscar™ was effective in reducing the risk of prostate cancer, but that

further studies were needed to better understand the consequences of using Proscar™ for this

indication. When the PCPT trial was reporting, Proscar™ was getting towards the end of its

patent period, which would have made pursuit of a new indication for Proscar™ less attractive

for the manufacturer from a commercial perspective. Hence, when Avodart™ was launched:

Both Proscar™ and Avodart™ were indicated for the treatment of BPH;

Neither Proscar™ nor Avodart™ were indicated for the prevention of prostate cancer;

There was good evidence that Proscar™ was effective in reducing the risk of prostate cancer,

but there was considerable doubt about the impact of Proscar™ on the risk of developing

high-grade prostate cancer tumours; and

There was a strong belief that Avodart™, because of the dual mechanism of action relative

to Proscar™, would have an impact on reducing the risk of developing prostate cancer.

The Value of Preventing Prostate Cancer

The epidemiology of prostate cancer suggests that significant value would be derived from a

product that is able to significantly reduce the prevalence of the disease. Prostate cancer is the

most common non-skin cancer found in men and there are over a quarter of a million new cases

16 Thompson IM et al. The influence of finasteride on the development of prostate cancer. N Engl Jnl Med. 2003; 349: 215-24. 17 Thompson IM et al. Effect of finasteride on the sensitivity of PSA for detecting prostate cancer. Jnl Nat Cancer Inst. 2006; 98:

1128-33.

18 Scardino P. The prevention of prostate cancer-the dilemma continues. N Engl Jnl Med. 2003; 349: 297-9.

per year in the EU.19 Studies of prostate tissue have suggested that more than 70% of men over

the age of 80 have evidence of prostate cancer (although not all will have been diagnosed with

it) and that around 35% of men over the age of 50 show evidence of prostate cancer.20 Whilst

prostate cancer appears to be highly prevalent and can often go undiagnosed, it is a leading cause

of cancer deaths. It is the second leading cause of cancer-related deaths among men, and

accounts for 9% of all cancer deaths in the EU.21

Incidence of prostate cancer varies widely across countries and is significantly influenced by

screening practices. Data suggest that the diagnosis of low risk prostate cancer is increasing,

which is partly attributable to a higher propensity to screen individuals early.22

Figure 3 shows that the age-standardised incidence rates can vary quite widely and the link with

mortality is not clear. Low mortality in some countries may partly reflect that early intervention

is effective and that many of the diagnoses in countries with high incidence rates are early

cancers that are not yet clinically relevant.

Treatment for prostate cancer depends on the stage of the disease, as well as patient and surgeon preferences. Watchful waiting could be an appropriate intervention for patients with low-grade, low-volume and organ-confined tumours. As the disease can take many years to progress, watchful waiting is also often an appropriate intervention in elderly patients, who are more likely

19 Bray F, Sankila R, Ferlay J, Parkin DM. Estimates of cancer incidence and mortality in Europe in 1995. European Jnl Cancer.

2002; 38(1): 99-166. 20 Holound B. Latent prostatic cancer in a consecutive autopsy series. Scand Jnl Urol Nephrol. 1980; 14: 29-35; and Sakr WA et al.

The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. Jnl Urol. 1993; 150: 379-85.. 21 Black RJ, Bray F, Ferlay J, Parkin DM. Cancer incidence and mortality in the European Union: cancer registry data and estimates

of national incidence for 1990. European Jnl Cancer. 1997; 33(7): 1075-1107. 22 Cooperberg MR et al. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from

CaPSURE) . Jnl Urol. 2003; 170 (6.2): S21-5.

to die with prostate cancer rather than because of prostate cancer. For patients with high-grade, high-volume tumours that are still confined to the prostate, surgery and radiotherapy are potentially curative options. One of the main difficulties with current approaches to diagnosis is that determining the grade, volume and extent of early cancer is difficult and often underestimates the extent of the cancer. Once prostate cancer progresses, treatment is less likely to cure the disease and more likely to cause long-term morbidity.23 Given the long-term evolution of the disease, a treatment that could delay PCa progression and thus contribute to avoiding potentially more aggressive therapies could be beneficial to patients.

The Evidence Base

Dutasteride is not a curative medicine, but could reduce the risk of developing prostate cancer or

delay its progression. GSK does not currently have an evidence base specific to Avodart™ that

illustrates its benefits in preventing prostate cancer. Evidence from the Prostate Cancer

Prevention Trial, based on Proscar™, provides a strong suggestion that Avodart™ will show

some impact on preventing prostate cancer. GSK‟s expectation is that Avodart™ will prove to

be more effective than Proscar™ in preventing prostate cancer. An important difference

between the two products is that Avodart™ inhibits both the Type 1 and Type 2 5-alpha-

reductase isoenzymes, whereas Proscar™ inhibits only Type 2. Studies have shown that there is

a relative increased expression of Type 1 isoenzymes in some prostate cancers and that expression

of Type 1 isoenzymes also increases in localised high-grade cancers. This might explain the lack

of efficacy of finasteride in the PCPT and suggests the promise of dutasteride‟s providing better

outcomes.24 25

Several studies are currently underway to develop an evidence base for Avodart™ as a preventive

intervention (i.e. primary prevention) as well as one that slows the progression of prostate cancer

(i.e. secondary and tertiary prevention). GSK is currently conducting one trial with intent to

pursue registration of an indication for dutasteride in the reduction of risk of developing prostate

cancer:

REDUCE (REduction by DUtasteride in prostate Cancer Events) - REDUCE is designed

to investigate the role of dutasteride in primary prevention of prostate cancer (i.e.

dutasteride‟s ability to decrease the risk of developing PCa) in men at higher risk. It is an

international, four-year study based on males aged 50-75 years, who have had a negative

prostate biopsy within 6 months of study entry, and who meet other criteria related to PSA

levels.26 REDUCE is expected to report findings in 2009.

In addition, GSK is also conducting several trials to develop supporting evidence that Avodart™

slows disease progression in men diagnosed with prostate cancer. The following trials are

expected to report findings in 2010, 2011 and 2012 respectively:

REDEEM (REduction with Dutasteride of clinical progression Events in Expectant

Management) – REDEEM explores the role of Avodart™ in secondary prevention in men

23 Barocas D et al. What percentage of patients with newly-diagnosed carcinoma of the prostate are candidates for surveillance? An

analysis of the CaPSURE database. Paper presented at the ASCO Prostate Cancer Symposium 2007.

24 Thomas LN, Douglas BC, Vessey JP, Gupta B, Fontaine D, Norman RW, et al. 5alpha reductase type1 immunostaining is

enhanced in some prostate cancers compared with benign prostatic hyperplasia epithelium. Jnl Urol. 2003; 170: 2019-25. 25 Thomas, L.N., Douglas, R.C., Lazier, C.B., Gupta, R., Norman, R.W., Murphy, P.R., Rittmaster, R.S. and Too, C.K.L. Levels

of 5α-reductase type 1 and type 2 are increased in malignant but not adjacent benign tissues from high grade as compared to low

grade prostate cancer. Jnl. Urol. 2008; 179: 147-151.

26 Prostate Specific Antigen levels must be ≥2.5 and ≤10ng/ml.

presenting with low-grade, low-volume tumours who are otherwise potential candidates for

a watchful waiting approach. The trial is designed to determine whether dutasteride can

delay the time of progression to more advanced stages of prostate cancer as compared with

watchful waiting.

ARTS (Avodart™ after Radical Therapy for prostate cancer Study) – ARTS explores the

role of Avodart™ in tertiary prevention in men who have suffered a biochemical relapse

after already having been treated for prostate cancer with a theoretically curative treatment

(i.e. surgery or radiotherapy). ARTS is designed to investigate whether or not dutasteride

can delay time of disease progression and therefore avoid implementation of more aggressive

therapies.

TARP (Therapy Assessed by Rising PSA) – TARP evaluates the benefits of Avodart™ in

men who have failed first-line hormonal treatment therapy for prostate cancer. Specifically,

can dutasteride, in combination with the antiandrogen Casodex delay time of disease

progression in these prostate cancer patients?

The implication of these trials is that beginning in 2010, GSK aims to have clinical trial data to

support their belief that Avodart™ will be effective in reducing the risk of prostate cancer. The

value proposition will then be based on an unmet need in the prevention of prostate cancer,

highlighting that:

There are no products on the market for the primary prevention of prostate cancer; and

Prostate cancer has detrimental effects on patients and is a burden on health systems.

Another anticipated outcome from trials of Avodart™ is that they will demonstrate that it does

not increase the risk of high-grade tumours in patients that do develop prostate cancer, as

suggested in the PCPT study of Proscar™. Animal studies suggest that the dual suppression of

both Type 1 and Type 2 isoenzymes with Avodart™ could reduce the risk of developing high-

grade tumours.

? If Avodart™ demonstrates a significant effect on preventing prostate cancer, does this

alter the product‟s value proposition?

? If so, how might this change affect market access negotiations, inclusion in formularies

and price?

Issues to Address

In addition to collecting compelling trial data, there are several other issues that need to be

addressed in the run-up to presenting the case for the role of Avodart™ in the prevention of

prostate cancer. A key issue is defining the target population for Avodart™ as a preventive

medicine, and tests for prostate cancer are not particularly reliable. In the last 20 years, the use of

prostate-specific antigen (PSA) in screening for prostate cancer has become increasingly

widespread in the Western world. However, there is by no means a precise relationship

between PSA level and the risk of developing prostate cancer. Limitations in the sensitivity and

specificity of PSA for the prediction of prostate cancer are well understood.27 Although the

balance of detection at different PSA levels remains intensely debated, the curvilinear relationship

with risk, and the lack of a clear value at which sensitivity and specificity are optimal, makes

27 Roehrborn CG. Benign prostatic hyperplasia: an overview. Rev Urol. 2005; 7 (suppl 9): S3–14.

selecting a threshold level problematic.28 Higher PSA levels used as a biopsy indication increase

specificity, but many cases of cancer are missed. At lower thresholds, sensitivity is improved, but

the number of unnecessary biopsies is increased. Thus, prior to discussions with reimbursement

authorities about market access, an important task for GSK will be to identify a well-defined

population of men at risk of developing prostate cancer.

As with many drugs, there will be discussions with reimbursement authorities on whether the

target population should mirror entry requirements for the clinical trials that are supporting the

reimbursement case. For Avodart™, one entry criteria for the REDUCE trial is that patients

should have had a negative prostate biopsy within 6 months of study entry. If this were

replicated in the general population, either screening costs would be high or the target

population would be small. This has health system cost and commercial implications.

Reimbursement authorities are also likely to ask for health economic evidence to support the

reimbursement case. Currently, the best data on the economic burden of prostate cancer is in

the United States. Initial modeling of this suggests that Avodart™ will deliver cost effective

outcomes as a preventive intervention, and that this cost effectiveness improves as the target

population is more tightly defined (i.e. it improves if Avodart™ is given to patients who have a

family history of prostate cancer and PSA levels above a certain threshold). At this stage,

however, the modeling is based on assumptions about the efficacy of Avodart™. Key tasks are

to develop an evidence base based on data from EU countries and to validate efficacy

assumptions through REDUCE and other trials.

The experience of Avodart™ raises a number of questions about how reimbursement authorities

deal with a product that has a value proposition that changes significantly over its lifetime. In

the case of Avodart™, it appears that the pricing outcomes at launch fit with perceptions of the

product‟s value at the time (i.e. parity with Proscar™). However, the product is now in a

position where there is emerging evidence it will demonstrate additional value because of its

improved efficacy when used in combination for treating BPH and its expected role in

preventing prostate cancer. Whilst this can occur with many products, an interesting and

complicating factor with Avodart™ is that the other product in the same therapeutic class now

has generic competitors and was never licensed for the prevention of prostate cancer.

? What conditions warrant industry‟s seeking and a payer‟s granting a reimbursement

negotiation?

? Is it realistic to expect price to change in response to a product‟s changing value

proposition? Is higher volume enough of a reward, or must both price and volume be

considered?

? If a product demonstrates different value for different indications, how should

reimbursement reflect this?

? How might authorities address the complication that Avodart™ has generic competition

in the therapeutic class for the BPH indication, but might not have competition in the

market for prostate cancer prevention?

28 Speakman MJ, Kirby RS, Joyce A et al. Guideline for the primary care management of male lower urinary tract symptoms. BJU

Int. 2004; 93: 985–90.