A Call For Action: Integrating Payor Requirements Into Phase III Clinical Trials
Executive Summary
The biopharma industry is facing a paradigm shift in which pivotal trials, which traditionally address regulatory requirements, must also supply payors with clinically meaningful data - or the industry will continue to struggle with market access and disappointed expectations. Easton Associates foresees a two-step process emerging to address payors' needs.
The biopharma industry is facing a paradigm shift in which pivotal trials, which traditionally address regulatory requirements, must also supply payors with clinically meaningful data – or the industry will continue to struggle with market access and disappointed expectations.
By Nicolas Touchot and Marie Cassese
Easton Associates research documents the failings of recent clinical trials to provide meaningful information for market access evaluation, a phenomenon that prevents many new offerings from achieving optimal reimbursement and has ramifications for commercial success.
Easton foresees a two-step process emerging to address payors' skepticism, one focused on demonstrating comparative efficacy during clinical trials when appropriate, to achieve conditional market access, and the second on generating real-life data after approval to maintain that market access.
Performing such ambitious pivotal trials will be challenging, but, if successful, this approach could enhance likelihood of commercial success.
In the last few years, market access has turned into one of the most debated and researched topics in the biopharma industry. Biopharma leaders recognize that failing to understand and respond to payor requirements can have critical consequences for the commercial success of innovative medical products. Only 20 to 30% of novel pharmaceutical products, or novel indications for existing products, achieve a formulary listing that allows unrestricted use in line with the label, along with positive reimbursement, according to an analysis published by Panos Kanavos, MD, in the December 2010 issue of Euro Observer.
This low percentage of payor approvals is a recurring pattern in many countries, irrespective of the health care system, the nature of the payor, or the method used to assess health technology. Despite the industry's growing investment in market access capabilities, evidence does not exist of a trend toward rising payor approval rates. Payors' market access decisions regarding individual products vary significantly and, therefore, are often difficult to analyze globally. The net result is that products often fall short of revenue expectations due to a combination of lack of reimbursement, poor coverage and pricing, or significant market access restrictions. ( See "2010 Drug Launches: A Year Of Firsts Offers Hope For A Rebound," "The Pink Sheet," January 3, 2011 (Also see "2010 Drug Launches: A Year Of Firsts Offers Hope For A Rebound" - Pink Sheet, 3 Jan, 2011.).)
Low payor approval rates are mainly the result of clinical development strategies that focus purely on gaining regulatory approval. Consequently, pivotal trials fail to clearly demonstrate the relative efficacy of innovative products in ways that are clinically meaningful to payors and, thus, do not justify formulary listing and reimbursement. Secondary endpoints and other datasets derived from post hoc analysis or Phase IV studies either lack the quality and power expected by payors or answer key questions too late, when market access choices have already been decided.
The biopharma industry is facing a paradigm shift in which pivotal trials must evolve to not only address regulator's needs, but also to supply payors with reliable and clinically meaningful data that withstand critical market access evaluation. The time has come for the industry to embrace a new breed of pivotal trials for high-value assets. While many firms have invested heavily in market access capabilities, tangible changes in product development have come slowly. Biopharma companies must learn to make informed choices that meet payor expectations without disproportionately impairing their ability to gain regulatory approval. ( See "Musings On Payor-Pharma Relations," The IN VIVO Blog , October 14, 2009 .)
Efficacy Versus Effectiveness Gap
In a recent review of health technology assessment (HTA) outcomes in countries that perform systematic and routine critical appraisals of new therapies, such as Canada, Australia, France, the UK, Scotland, and Sweden, Easton Associates found that payors are deeply skeptical of the extent to which new drugs deliver meaningful clinical benefits. This observation is not surprising per se, but Easton Associates examined in further detail the nature of payors' concerns about available sponsor-driven data and the implications of its shortcomings. About 70% of products evaluated through HTA processes between 2007 and 2009 ultimately were either not listed or were covered with restrictions.
In the United States, payors that perform systematic reviews show similar patterns of negative formulary decisions. At a March 2011 meeting on evidence-based medicine organized by the RegenceRx-Delfini Group, RegenceRx, the largest Northwest/Intermountain Region Health Plan, for example, reported that it added to its formularies only 22 to 35% of new products and indications approved annually by US regulators between 2008 and 2010. Very few new therapies demonstrated well-defined advantages in clinical effectiveness (14%), safety (1%), improvement potential in patient adherence (3%), or cost (3%), a company executive said. ( See "What Payors Want: Reliable Data," "The Pink Sheet," November 30, 2009 (Also see "What Payers Want: Reliable Data" - Pink Sheet, 30 Nov, 2009.) and "The Regence Group's Methodology," "The Pink Sheet," November 30, 2009 (Also see "The Regence Group's Methodology" - Pink Sheet, 30 Nov, 2009.).)
Clearly, payors and regulators evaluate new therapies for approval based on very different criteria. Regulators focus on efficacy or the extent to which an intervention does more good than harm under ideal circumstances. Payors, on the other hand, are more concerned with systematically evaluating a therapy's relative effectiveness or, as reported at the 2010 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) annual International Meeting, the extent to which an intervention does more good than harm compared to alternatives for achieving the desired results when provided under the usual circumstances of health care practice.
These differing points of view create a significant gap in the way regulators and payors grade the quality and usefulness of data. This efficacy and effectiveness gap will only deepen as risk-sharing schemes and value-based pricing become a global reality, unless the biopharma industry changes course.
Executing a clinical trial strategy that focuses purely on gaining regulatory approval through a lower-risk path jeopardizes market access. Payors advocate for biopharma leaders to adapt the design of pivotal trials so the nature and the quality of data as accurately as possible portray the health gain that a drug provides to patients in real-world practice. They prefer products to be compared to an active comparator that is clinically relevant and expect trials to show a sizable improvement in morbidity, mortality, symptom relief, function, or health-related quality-of-life measures to win favorable coverage decisions. In this environment, the reality is that time-to-market no longer means time-to-licensing but time-to-reimbursement.
In Easton Associates' view, completely bridging this gap during clinical development is not realistic because clinical trials, by definition, are not representative of real-life practice. Therefore, we foresee a two-step process emerging to answer payors' needs. ( See Exhibit 1.)
In the first step, comparative efficacy, or the extent to which one therapy in a clinical trial setting provides a benefit compared with another, should be demonstrated, when possible, during pivotal trials to support preliminary market access and price decisions. These initial decisions mainly rely on the payors' judgment of the product's clinical value and are supported by an assessment of the technical design and reliable execution of the trial. For the most part, when evaluating the efficacy of a product, payors focus on primary endpoints, even though at times, they will consider secondary endpoints that are pre-defined and powered appropriately for statistical analysis. As explained by Omar Ali, head of a regional drug and therapeutic committee at NHS and member of the Reference Group for Cost Impact Modelling for NICE, "Payors first and foremost use primary endpoints; secondary endpoints are of interest but fall within the shadow of preliminary findings of primary endpoints."
Payors increasingly view market access as conditional, or temporary, coverage decisions and are calling for additional proof of a drug's value in a real-world setting before making final reimbursement decisions. Companies, therefore, need to generate real-life and local country data after approval, as a second step, to allow products to maintain market access and pricing/reimbursement levels.
In this two-step process, biopharma companies must obtain favorable market access decisions based upon answering the needs of payors during pivotal Phase III trials; failing to do so could impair market access for the life cycle of the product in the target indication.
Unfortunately, a number of elements of Phase III clinical trials contribute to significant payor uncertainty about actual clinical benefits. The choice of the control arm is one of the most decisive factors. Easton Associates found that the majority of Phase III studies driving formulary decisions over recent years are either placebo-controlled trials without an active comparator arm or active controlled trials with non-informative comparators. ( See sidebar, "Different Companies' Approaches To Pivotal Trials.") These approaches are used even when a clearly recognized standard of care exists, often forcing payors to make their own indirect and unreliable comparisons. Weak primary endpoints also contribute to uncertainty about clinical benefits, and include confusing composite endpoints, surrogate endpoints poorly linked to health outcomes, or endpoints chosen to show statistical significance even though they do not have obvious clinical significance.
Secondary endpoints can often be a "mixed bag" of measures attempting to shed light on various aspects of a drug's clinical benefits. For the most part, however, they are not adequately powered to reliably interpret a therapy's advantages, forcing payors to aggregate different elements to estimate a therapy's value. Finally, the choice of the patient population also impacts the relevance of trials. Exclusion criteria can severely limit the trial population compared with the "target" real-life population.
The French HTA system provides a clear-cut example of the extent to which current pivotal trials fall short in demonstrating the value of novel drugs. French HTA reviews focus on analyzing the clinical/technical aspects of the clinical evidence provided using a scoring system (ASMR) that grades clinical value from 1 to 5 (major clinical benefit over the existing standard of care [SOC]) to no benefit over the existing SOC). In recent years, 12% of appraisals have resulted in rankings of major or significant (ASMR 1 or 2) and nearly 60% of reviews produced a ruling of no additional value compared with previously available products, according to published HTA reports.
Payors' skepticism extends beyond the clinical evidence. Most remark that they regularly discount industry-sponsored health economics and outcomes research (HEOR) data, since industry sponsored HEOR trials tend to be significantly more positive than independent HEOR trials. Many payors are building an arsenal of sophisticated tools and employ trained clinical development and health economic experts to analyze trials and dissect methodologies. For example, one US government payor covering about 10 million lives has a formulary committee team of nine registered pharmacists, two PhD economists, and three MDs to scrutinizing results and make hard-line coverage decisions.
Overall, payors are clear about what pivotal trial data would trigger successful initial market access decisions:
Meaningful efficacy data centered on "hard," unambiguous clinical endpoints;
Head-to-head comparisons with the appropriate comparator, showing clinically meaningful and statistically significant differences;
Primary endpoints with appropriate power (not hidden among a "mixed bag" of secondary endpoints that require constructing a complex "data puzzle");
Data quality on par with regulator's requirements.
One payor recently detailed its HTA approach. The positive predictive value (PPV) associated with the type of trial selected is used to gauge the validity of the results; for instance, a well-designed and executed randomized control trial (RCT) has a PPV equal to 0.85, whereas a well-executed observational study has a PPV of only 0.20. Next, it weighs the potential for selection, performance, and data collection bias between the intervention and comparison group by systematically reviewing patient selection, allocation, blinding, duration of treatment, discontinuation rates, and handling of missing data.
The time has come to migrate away from the old model – addressing market access after successfully clearing regulatory hurdles – to taking the plunge toward incorporating evidence of the value of a product for payors into the pivotal regulatory trial. ( See Exhibit 2.)
This approach has risk, because the design of the pivotal trial is likely to be more stringent than regulatory specifications. While the European Medicines Agency (EMA) advocates for both active and placebo comparator trials, FDA does not indicate a preference for a particular type of trial and highlights numerous challenges associated with active-control studies. FDA notes, for example, that active-control trials are "often too small to show that a clinically meaningful difference exists between the two treatments"; they "do not provide the same incentives toward study excellence"; and "finding of no difference between a test article and an effective treatment may not be meaningful." In fact, FDA guidance may actually act as a strong deterrent for the biopharma industry to answer the challenge raised by payors.
Payors understand this, but they believe the onus is on biopharma companies to work with regulatory authorities during development to identify pivotal trial designs that will be accepted by regulatory authorities and to provide the necessary data to payors.
Majority Of Recent And Current Pivotal Trials Fall Short
These conditions can be satisfied if biopharma leaders give the market access team a voice in R&D strategy. To gauge the extent to which the biopharma industry is designing pivotal trials to answer both payors' and regulators' requirements, Easton Associates used public databases to analyze more than 200 pivotal trials, including about 60 trials used to support FDA and EMA approval decisions in 2010, and about 140 currently ongoing registration trials in the US and Western Europe.
This analysis posed three main questions ( See sidebar, "Easton Associates' Methodology"):
To what extent does the primary endpoint match payor requirements in terms of clinical significance, as defined by a meaningful gain in health benefit? (Score: high, medium or low);
Does the primary endpoint exceed regulatory requirements to address payor requirements? (Score: not necessary, yes, or no);
To what extent do the structure of the trial and the choice of comparator demonstrate relative efficacy versus the best available alternative when products are available to treat the indication? (Score: high, medium or low)?
To standardize the evaluation criteria, Easton Associates excluded diagnostic products, prophylactic vaccines, and therapeutic oncology products from the analysis. However, products that treat complications of cancer therapy, such as osteoporosis in hormone-treated patients, or cancer-related pain, were included.
Our review of the data shows that the biopharma industry has been slow to change its approach to payors. ( See Exhibit 3.) Although few trials in our analysis (11%) have primary endpoints of very "low" relevance to payors, the majority still fall short of payors' expectations. Only 42% of trials analyzed have primary endpoints that payors would consider to be "high" value.
In the majority of trials analyzed by Easton Associates, endpoints either focus on surrogates that do not clearly link to clinical outcomes, or they demonstrate a statistical improvement that is not clinically relevant. An example of the former is a trial conducted for relapsing multiple sclerosis that measures only the rate of relapse without differentiating between the severity and the long-term clinical consequences of the relapses, when it is known that many will fully resolve after a short period.
An example of statistical improvement without clinical relevance is a trial on alcohol dependency, in which a primary endpoint of reduction of the number heavy drinking days per month compared with baseline might show statistical significance by reducing that number from 15 to 11. Payors would, however, question the value of that reduction, without measuring the improvement in the patient's ability to work, his or her quality of life or a reduction in the patient's use of health care resources.
Big Pharma and Big Biotech appear to be slightly better at using endpoints that meet Easton Associates' pre-defined assessment of payors' criteria, with just over 50% of its trials achieving that goal. EU-based companies have a better track record, with 49% of trials sponsored by companies headquartered in Europe using endpoints of high relevance to payors, compared with only 36% by US-based companies. Easton Associates surmises that the higher ratio of Big Pharma to biotech studies sponsored by EU companies, and the more abundant experience that EU companies have in designing trials that satisfy health technology assessment bodies, could partially account for the geographic differences observed.
Our review also identified noticeable differences across therapeutic areas. The analysis, which only included therapeutic areas with more than 10 products/indications, put infectious diseases at the top of the list, with 83% of trial primary endpoints scoring high relevance to payors, followed by respiratory (53%), cardiovascular (43%) and musculoskeletal (35%). Central nervous system (CNS) disorders, the largest category with 62 products/indications, fell short with only 30.6% of trial primary endpoints likely to satisfy payor needs.
Trials for orphan indications and rare diseases did not show better primary endpoint relevance, with only 33% scoring high. This likely reflects the easier approval route for orphan drugs and the use of regulatory fast tracks.
In the vast majority of cases (about 90%) in which primary endpoints meet payors' expectations, the situation occurs only because existing regulatory guidances and payor requirements coincide with one another. This can be illustrated by HIV trials in which EMA regulatory guidance calls for the following primary endpoint: "The proportion of subjects that achieves and maintains undetectable plasma HIV-RNA (i.e., <50 copies/mL)". In fact, only 12 of the 203 examined trials actually go beyond regulatory requirements. However, 10 of those 12 trials contain primary endpoints that are likely to be of "high" value to payors.
Once again, Big Pharma outpaced the overall industry by sponsoring eight of the trials that contained endpoints that went beyond regulatory needs.
A full 70% of pivotal trials reviewed were placebo controlled, even though in nearly three-fourths of the instances, clearly accepted standards of care already exist. In the choice of comparator, just like the choice of endpoint, Big Pharma and Big Biotech were slightly more aggressive than the industry overall, including active controls in just under 40% of their pivotal trials.
Clearly, however, the use of active comparators does not appear to be on the rise. About two-thirds of all active trials are powered to show non-inferiority. This confirms payors' views that in the majority of circumstances, they must base formulary decisions on indirect comparisons to establish the relative value of therapies. Our findings are relatively similar to those reported in a May 2011 article in the Journal of the American Medical Association by Nikolas Goldberg and colleagues, "Availability of Comparative Efficacy Data at the Time of Drug Approval in the United States," which analyzed the availability of comparative efficacy data for new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) between 2000 and 2010. Companies developing about half of all new drugs approved in the US during the study period failed to report comparative efficacy data.
Trials sponsored by European companies utilize active comparators more often (39%) than trials sponsored by US companies (19%). This difference reflects the fact that a higher proportion EU trial sponsors are Big Pharma and also suggests that EU companies take to heart the EMA guidances recommending the use active controls for many indications.
In terms of the choice of comparator, distinctions also exist across therapeutic areas. CNS stands out as being least likely to offer comparative data, with 76% of CNS trials designed as placebo-controlled, even though in the vast majority of cases (78%) an SOC exists. By comparison, in cardiovascular disease, 53% of trials compare compounds with placebo, although an SOC was available 60% of the time. Infectious disease studies were most likely to demonstrate comparative effectiveness with 50% of trials having an active arm, whereas in those instances when a placebo-controlled trial was used, an SOC was available in half. Again trials for orphan or rare indications failed to outscore other trials, with 90% conducted against placebo and an SOC was available in half of those.
When combining both the choice of endpoint and the choice of comparator, only 13% of the pivotal trials reviewed ranked high on both primary endpoint and comparator selected. ( See Exhibit 4.) Overall, a total of about 35% of trials include at least one high element (primary endpoint or comparator) and one medium element. This corresponds more or less to the proportion of products that received favorable payor evaluations.
By comparison, more than half of pivotal trials fail to contain either a primary endpoint or a comparator that allows payors to make an informed decision on the value on the new product or new indication. These findings suggest that formulary approval rates will continue to be low.
Several examples highlight the issues from the payors' point of view. A number of trials involve new methods of delivery or formulations. About 20% of these formulation and delivery trials were conducted against placebo rather than against the existing formulation of the product, failing to demonstrate the value of a new approach. In the vast majority of other trials on new delivery methods, sponsors chose a non-inferiority design, leaving payors unclear as to the value of the product beyond convenience or how convenience could translates into improved compliance. A rare example of a well-designed trial for a novel route of administration (ROA) is assessing the superiority of levodopa-carbidopa intestinal gel against the standard tablet delivery for the treatment of Parkinson's disease. The intestinal gel is anticipated to result in continuous delivery of levodopa-carbidopa, avoidance of pulsating gastric emptying, and decreased motor fluctuations and dyskinesia. Superiority on mean daily "off" time will clearly demonstrate value of the novel ROA to payors.
Easton Associates also found that better approaches were seldom factored into trial design. Endpoints that measure the mean difference from baseline were favored almost 2 to 1 over the use of responder rates with a pre-specified and clinically relevant definition of responder, even though using responder rates could provide payors with a more realistic estimate of what proportion of patients is likely to show a clinically significant benefit from the therapy. Co-primary endpoints combining a symptomatic endpoint and an outcome endpoint are also very rarely used, except when mandated by regulatory requirements.
This represents a missed opportunity for biopharma companies to demonstrate value to both regulators and payors. One primary endpoint could address regulators and the other could focus on the definition of "value" appealing to payors. Finally, three-arm trials are also very seldom used despite their theoretical appeal since they can demonstrate clear superiority to the regulator and allow payors to perform a direct "value" comparison to the SOC.
Industry Barriers To Change
Discussions with industry executives and payors highlight the hurdles they face integrating payors' needs in Phase III trials. These hurdles fall into three main categories: structural, organizational and cultural. Structural barriers reflect the diversity that exists in payors' values and priorities across countries. Biopharma executives point to the complexity associated with producing data at a local level that payors consider relevant to their health care system, and find it overwhelming to conduct trials with the clinical and economic endpoints payors prefer across geographies. Payors acknowledge that their needs could magnify the regulatory risk substantially, but question the value of an approved drug without coverage. Payors that we spoke to believe that the diversity argument is a smoke screen and that fundamentally their technical/clinical standards are very similar across countries. The main differences that exist across geographies center on the economic element of the assessment, which is not what they are seeking from a pivotal trial. Payors recommend that such studies could be carried out in parallel or shortly after the pivotal trial to measure local economic benefits.
Organizational barriers related to the internal decision process and incentives of the clinical team can derail the integration of market access and development. Most clinical teams are incentivized solely on bringing products to market without milestones tied to market access success. While payors recognize these organizational barriers, they think the biopharma industry must alter its course and adapt incentives aligned with the changing environment. Payors perceive this hurdle as an internal issue that today impacts their ability, as the customer, to secure relevant data to properly evaluate products.
The third hurdle, and probably the most difficult to overcome, is cultural. Biopharma executives, perpetually under pressure from Wall Street, stress that investors judge the industry by how many novel products they develop and launch. That argument also holds little water with payors. They believe that a launched product without reimbursement offers little value to investors and R&D success should include market access as well, which is the whole point – delivering highly valued products.
Easton Associates believes the best way to address these hurdles is to view the integration of payors' needs in registration trials as a business decision, rather than solely clinical development or market access decisions. Conducting a scenario-based net present value (NPV) analysis of various trial designs supported by well-defined and realistic assumptions can help biopharma leaders make informed choices about the best path to take. Clearly, performing a "regulatory only" trial provides a faster and easier route to approval. However, the price of such a decision may be steep if speed to regulatory approval results in a poor market access position, potential restrictions to use and reimbursement, sub-optimal pricing, and a heavy investment in post-approval market access activities.
On the other hand, performing pivotal trials that answer regulators' needs and demonstrate relative efficacy for payors will most likely lead to larger and most expensive trials, increased technical risk, and delay of launch. Nevertheless, if successful, the approach will enhance the likelihood of reimbursement and listing for a broad population, increase likely reimbursement value and pricing, speed up adoption, and enhance the ability to succeed in a novel pharma environment based around value pricing.
Such an approach may not be right for every asset, however. For each important and innovative product, the R&D and market access teams can jointly determine the best strategy by completing a thorough analysis prior to entering Phase III trial development. An integrated decision process with input from each stakeholder can lead to a joint buy-in. By aligning the clinical development strategy with the market access strategy, the ultimate choice will be based on the likely trade-offs and their ultimate impact revenue expectations. ( See Exhibit 5.)
The skills involved in spearheading "strategic" analysis of market access requirements during development are different than those called for in conducting HEOR trials or developing value dossiers. Market access teams must be highly proactive, identifying likely hurdles early in the product development process – along with developing strategies and tactics to prevent, rather than react, to them – and also focusing on implementation. They should be involved in key steps of strategic planning to provide critical input into development and budget allocation decisions. This will allow companies to consider changing, or potentially stopping, product development due to market access risk.
Early collaboration with medical affairs departments regarding Phase IV programs is also important to maintain initial listing and reimbursement. Innovative biopharma companies are stepping up to the challenge by putting in place market access teams that draw on talent from product development and strategic marketing to complete the proposed complex, but necessary, analysis. Failing to do so will maintain the efficacy effectiveness gap and will lead to products continuing to face market access restrictions and failing to meet financial expectations.
Future Market Access Road To Success
Despite a growing focus on market access and sizeable investments in large market access teams, the commercial success of many novel pharmaceutical products and new indications continue to be hampered by market access issues. Biopharma leaders are challenged to harvest the value of their investments, while payor pressures are growing to shift away from the old models of clinical development toward an integrated model that uses the pivotal trial to address regulatory requirements and demonstrate to payors the value of the product. Easton Associates' review of pivotal trials used for recent and upcoming approvals confirms that a majority of pivotal trials continue to fall short of payors' expectations, bearing out why market access efforts continue to deliver disappointing results and suggesting that HTA and formulary decisions in the short to mid-term are likely to remain disappointing for the industry.
Easton Associates challenges biopharma leaders to take a strategic and measured approach to introducing market access considerations into Phase III trial planning for innovative products. By involving all the key stakeholders and adopting a systematic analysis of trial design options, companies can calculate the pros and cons associated with a "regulators only" versus a "regulators and payors" approach, align the needs and incentives of various internal stakeholders, and gauge the potential trade-offs between risk, time to market, market access position, and revenue expectations.
Nicolas Touchot, PhD, and Marie Cassese are Managing Directors with Easton Associates. Nicholas operates out of EA's European offices in London and Paris, while Marie is based in New York and New Jersey. E-mail the authors at: [email protected] , [email protected].
SIDEBAR: Different Companies' Approaches To Pivotal Trials
Two companies are developing innovative products for a small indication where patients typically have a life expectancy of five years and suffer from significant deterioration in their functional capacity and quality of life. Several products are already on the market, using different mechanisms of action, including two becoming generic prior to or at the time of new product launches. Companies A and B are both conducting pivotal trials against placebo. Company A chose the traditional surrogate endpoint, based upon regulatory requirements. Company B chose a mortality/morbidity endpoint that goes beyond regulatory requirements to differentiate the product for payors and clinicians. Company A's pivotal trial is significantly smaller (460 patients at 130 sites) than Company B's trial (700 patients at 190 sites). Company A's trial is also substantially shorter (estimated 3.5 years to completion compared with estimated 4.5 years), due in part to a shorter follow-up duration for measuring the primary endpoint (12 weeks versus one year).
Preliminary feedback with experts also suggests that the trial designed by Company B may be delayed, due to a lower than expected rate of mortality morbidity events. This case illustrates the balance of benefits and risks of designing a trial going beyond regulatory requirements. One would expect Company B to secure better market access than Company A, on the basis of a significantly harder and more relevant primary endpoint. However, Company B has committed to a significantly higher investment, more risks, and a delayed launch. Both companies may actually be following strategies that reflect both their market position and their expectations. Company B is already present in that market and its novel product may in part cannibalize its existing business. Company A is a new entrant whose product is also in development in another indication where it may be more differentiated, and is looking to generate early revenues and visibility in the indication.
SIDEBAR: Easton Associates' Methodology
Easton Associates conducted a comprehensive review of on-going pivotal trials (N=142) as well as those that resulted in 2010 EMA and FDA approvals (FDA=44; EMA=17) to quantify the degree to which pivotal trials address regulatory and payor market access data requirements. The analysis included 85 products from Big Pharma and Big Biotech (the top 25 companies by 2009 pharma revenues), 61 from mid-sized pharma companies (with commercial revenues), and 57 from small biotechs without commercial revenues.
Sponsors were headquartered in the US for 96 products/indications, in Europe (including Israel) in 94 cases, and in Asia in 13.
To assess the value of primary endpoints, EA used the following definitions:
High:
True clinical efficacy measure such as death, hospitalization, stroke or myocardial infarction;
Clearly validated surrogate endpoint, with demonstrated correlation between the surrogate endpoint and a true clinical endpoint and where the surrogate endpoint captures the net effect of treatment on the clinical endpoint;
Composite endpoint where all elements are individually clinically relevant and where the sum of the individual elements captures the overall effect of treatment;
Co-primary endpoints that assess the key components of clinical outcome in a multifactorial disease.
Medium:
Surrogate endpoint with a well-accepted (according to the scientific literature) likelihood to predict clinical benefit;
Composite endpoint where several (but not all) elements are individually clinically relevant; but where the sum of the individual elements fails to capture the overall effect of treatment;
Primary endpoint that assesses one key component of a multifactorial disease.
Low:
Surrogate endpoint that is not established as a predictor of clinical benefit;
Endpoint that addresses a minor component of a multifactorial disease;
Endpoints that fail to meet any of the definitions of High or Medium.
To determine if the primary endpoint exceeds regulatory requirements to address payor requirements, we first reviewed approved and proposed FDA and EMA guidance documents on regulatory requirements. If no guidance existed, we used as a benchmark the endpoints and trial structure used in the most recent (pre 2010) product approvals in the indication. We then compared the actual endpoint of the target trials with these benchmarks.
For each product/indication, we determined if a standard of care existed for the target population. We then assessed the extent to which the trial and the choice of comparator evaluated relative efficacy versus the best available treatment by using the following definition:
High:
An SOC is available and was chosen for the trial; the trial was designed to show superiority, or is a non-inferiority trial with clear convenience ROA benefits associated to the product tested;
An SOC is NOT available and a placebo controlled trial design was utilized.
Medium:
An SOC is available and was chosen for the trial; trial was designed to show non-inferiority but no clear additional benefit.
Low: