Dawn Van Dam, General Manager
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Ernie Bush: The Case for Investing in Predictive Safety Technologies
Why should my company consider a drug safety application for our drug discovery technology? What is benefit for the company and investors?”
Demonstrating ‘predictivity’ requires a large investment.
Significant data is necessary to establish the predictivity of a drug safety test to a pre-clinical safety department. The time and cost of producing this data for an in vitro screen is often very high. The investment usually involves the assessment of anywhere from 100 to as many as 500 compounds, with known liabilities, to demonstrate the tool’s ability to predict adverse effects.
This naturally leads us to consider the value of a safety test. If the standard is higher for a safety test, and if the cost of convincing the users of its value is also significantly higher, then why invest in creating a safety test? Why not develop a biology or pharmacology screen to aid discovery screening?
Accepted safety tests are used across ALL development programs.
The answer to this question tends to be remarkably simple and well documented. Discovery screens may have a lower hurdle to adoption, but they are usually much more narrowly defined. Often, they are used by pharmaceutical companies only for specific targets or diseases. Safety screens, on the other hand, once adopted, are used across the portfolio by project teams on nearly all molecules. Therefore the fee for entry is higher for developing a safety screen, but the target market and sales potential is five to ten times greater than the market for discovery screening tests.
So, my advice is that you take a long, hard look at your technology, to identify whether it is applicable in a drug safety environment for pharmaceutical and biotech companies. If it is, it would be well worth your time to consider how you can invest the appropriate resources to provide this technology to drug safety customers; you will find there are more uses for the technology beyond the drug discovery phase.
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Ernie Bush: Can My Efficacy Screening Test Also Be a Drug Safety Screen? “Is there a difference between a discovery stage efficacy test and an early stage drug safety test?”
A drug safety test must be “predictive”
The main answer to this question is frustratingly simple. The expectation, or hurdle, for a drug safety test is that it must be ‘predictive’ of an in vivo outcome. Of course, predictivity is always a goal of any test, but the degree of predictivity is quite different across these two applications, even though the test mechanics may be identical. The degree of ‘predictivity’ for safety testing is often a hotly debated topic because many practicing toxicologists have little confidence that an in vitro screen can be predictive of an in vivo outcome, particularly of human clinical adverse events. Still, all agree that they expect a safety test to have fewer false positives (if any) and a lower false negative rate than a routine efficacy screen.
The importance of ‘predictivity’ as a critical quality for safety screens was recently confirmed in a survey of the Drug Safety Executive Council (DSEC) community. When the scientists were asked to rate the importance of the various drug safety test performance features they rated ‘predictivity’ as much more important than any of the other leading parameters including such items as cost per compound, turn-around time, through-put, and concentration sensitivity.
A good example of an early safety test that is widely used and whose predictivity is often debated is the hERG test which is routinely utilized to predict adverse cardiovascular effects. Many in the pharma R&D community claim that the hERG test has too many false positives (and thus has poor predictivity), and yet several recent reports indicate that when normalized for free plasma concentrations, the routine hERG test is predictive of lengthening QT in the clinical setting 80-85% of the time.
To prove predictivity a drug safety test requires a higher degree of qualification
A further difference between an efficacy and safety screen is not only the higher degree of predictivity, but also then the higher burden to ‘prove’ or demonstrate that predictivity. Traditional toxicologists in safety departments tend to be more conservative and thus need more data in order to have confidence in the value of a new test as compared to their colleagues on the discovery side.
So, simply put, another main difference between an efficacy and a drug safety screen is that the latter requires a much higher degree of qualification or scientific validation before it will become widely adopted by the safety assessment marketplace. Before fully accepting a new safety test, it is not uncommon for pharmaceutical companies to demand the assessment of 100 or more compounds with known liabilities to demonstrate the ability of a test to ‘predict’ these adverse effects.
Clearly, the difference between a safety test and an efficacy screen is well documented predictivity.
Entry into the drug safety market requires more work than entry into the discovery market. So, why should your company consider the safety market? My next article will detail why there is a greater revenue opportunity in safety testing tools than in discovery screening.
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Ernie Bush: Why I Didn’t Sleep Last Night: Three Reasons Why Preclinical Safety Heads Can’t Sleep and How Technology Providers Can Help (July 18, 2011).jpg?n=6688 "IPR report cover")
Relationship Marketing: Four Ideas to Produce Valuable Content, By Eric Glazer : Marketing is as much about engaging in productive conversations with your customer base as it is about targeting and messaging. How do you begin these conversations? Whether it is through social media or more traditional distribution channels like email or brochures, relationship marketing (and selling) starts with listening and then providing valuable content to your customers.
“What information do potential buyers expect and value as a part of the qualification document package?”
It’s one of the most common questions asked by new technology providers and the response varies among biopharmaceutical companies as well as individuals within those companies. There is no industry standard for the minimum data requirement (i.e. “table stakes”) needed by pharmaceutical companies to warrant further time evaluating a new technology or service. Thus it is important that technology innovators are rigorous in providing comprehensive and detailed data in their marketing and sales documentation so they are not simply added to the pile of vendors on a R&D executive’s desk waiting for a call back. Below are the three items new technology buyers are most interested in seeing in a new technology qualification package.
1) Publications or Posters Supporting the Science
Most new technology tools are based on a fundamental advance in scientific knowledge or practice and it is important to demonstrate that these advancements have been reviewed by an objective authority in the scientific community. Publication in peer-reviewed journals is of most value, but posters that have been presented at national professional meetings can also lend credibility to the science. Marketing materials such as PowerPoint presentations produced by the technology vendor present the least compelling case. There is a perception that these pieces lack detail and may be biased towards the vendor.
2) Data from the ‘Real World’
Actual examples of how the technology solved a problem that was difficult or impossible to solve using conventional solutions is an important differentiator. Technology vendors must provide authentic examples if they want to convince biopharmaceutical organizations to consider the time and expense associated with replacing an existing technology or adding another solution to the overall preclinical safety decision making “tool box.” Two important areas of emphasis are worth highlighting:
a. Modern ‘Pharmacophores.’ The industry desires data from compounds using modern ‘pharmacophores.’ We have often heard from preclinical safety managers and pharmacologists charged with the responsibility of evaluating new tests that they don’t want to see data just from the usual standard compounds because those compounds are well known and are often fairly simple molecules. Safety managers and pharmacologists want to see data-based results from the complex chemical scaffolds common in today’s drug candidates.
b. Problem-focused. The fact that new technology can produce lots of interesting data is less compelling than the fact that the technology solves current, relevant, problems for those working in pharmaceutical research and development. Therefore the data package should focus more on showing how the system improves decision making and less on data generation.
3) Showcase Repeated Analyses
Since most evaluators of new technology are experienced scientists they are especially eager to see data on the new technology’s reproducibility and robustness. Therefore, results of multiple analyses conducted over a span of several months on the same test compounds are highly valued (especially if the analyst was kept blind to the compounds they are analyzing). These examples of the test systems stability and reproducibility are absolutely essential to gaining the confidence of the prospective buyers regarding the value and utility of your test platform. According to a recent DSEC survey (March, 2009), over 80% of data packages are “lacking substance” especially in the areas of reproducibility and robustness. Our own personal experience bridging relationships between vendors and pharmaceutical companies confirms this statistic. Vendors that present repeated analyses will significantly improve the odds of reaching prospective clients.
Ultimately the decision on whether to purchase a new technology is dependent upon how the technology performed on tests requested by the prospective buyer. However, a high quality data package used to introduce and support the evaluation process will often determine whether prospective buyers proceed with the evaluation and can significantly shorten the process.
“What information do potential buyers expect and value as a part of the qualification document package?”
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In both my personal experience as a senior manager at large pharma for over 20 years, and in my role facilitating peer evaluations of new technologies at CHA for the past five years, I have noticed that there a few reasons that are consistently offered for why a particular new technology for safety evaluation was not adopted. Below are the top four.
1) “We could not determine a favorable value proposition.”
When prospective buyers calculate the overall cost of the new method, versus the cost of the existing approach, they often find that the added value does not justify the added expense. This is especially true when buyers can establish a similar tool using in-house resources for far less investment. Safety evaluators were once perceived as having a “blank check” when it came to spending money on developing new compounds but now, with the push to conduct safety testing much earlier in the discovery process, this is clearly no longer the case. New technologies must demonstrate a true return on investment, and new technology vendors must therefore develop thorough and robust cost-effectiveness business cases that clearly demonstrate added value (time and money saved) for their new technology to be deemed worth the expenditure.
2) “We were not convinced the new technology would deliver as promised.”
Most vendors have some validation data, but usually not the breadth or depth that has become the expected norm. Prospective clients are especially eager to see “real world” examples and are increasingly disappointed when presented with data on a few well-documented examples. We strongly recommend that vendors target a validation of at least 50 compounds and, ideally, a total greater than 100. This data should include adequate quantities of known non-active compounds to understand the false positive rate.
3) “Our ‘test drive’ did not go well.”
The reason car dealers like to get you behind the wheel of a potential new car is to create the vision of a new reality with you as the owner of the shiny new car. A lot of effort goes into detailing the car, training the sales rep, etc., to ensure that the test drive is a powerful and motivating experience. Similarly, the sales evaluation process should be efficient, effective and motivating. We are surprised when we conduct surveys and find that the majority of new technology evaluations are considered by prospective clients to be unsatisfactory. Vendors must adjust their sales evaluation processes so that they are productive for potential clients.
4) “We questioned the science behind the technology.”
Safety evaluation staff can appreciate the need for trade secrets and proprietary information when producing and marketing new technology, however vendors must present enough documented evidence to convince someone who is experienced in validating the proposed tools. Too often vendors either cannot provide the supporting information requested or they claim it is proprietary and cannot be shared with potential customers. One of the most widely accepted forms of scientific validation is publication in peer-reviewed journals. Another is endorsement or utilization by a person or institution with a reputation for conducting good science. Vendors must strive to provide a strong scientific rationale for why their new technologies are feasible and they should be prepared to provide potential clients with a wealth of supporting data.
In the current economic climate, pharmaceutical companies are looking for new technologies to help reduce costs and improve the bottom line, and the opportunities have never been greater for new safety technologies.
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The successful commercialization of new predictive safety platforms is an incredibly challenging and resource-intensive process. These challenges are often exacerbated when new technology providers approach the market with products that have not been adequately qualified or scientifically validated; or worse, when the products are poorly positioned to meet the needs of the of the bio-pharma marketplace. All too often the buyers of these technologies spend millions of dollars on their due diligence and purchase only to find the new tools do not provide significant improvement over current approaches. Therefore, a major advantage exists for those vendors who are appropriately prepared when they engage potential buyers. Based on CHA’s experience in helping new technology providers to introduce new products into this space, we have compiled a list of five questions that technology vendors should ask themselves before beginning the process.
1) Am I delivering data, results, or decisions?
High quality and robust data are always necessary, but nonclinical safety managers at biopharma are ultimately seeking the answer to a very simple question: “Is compound A or B the better candidate to move forward?” A new technology must not only to provide high-quality data; it must also provide insights into how to utilize the results to make optimal development decisions.
2) How many compounds should be in my proof-of-concept or scientific validation data set?
In general, safety scientists are perhaps the most conservative investigators in the biopharma R&D space. They are typically highly data-driven and require strong evidence to evaluate the value of new assays. While there is no definitive answer to the question of how many compounds should be presented, most believe that at least 30 compounds are necessary and quantities in the range of 100-300 are generally considered optimal.
3) Can I determine who decides and who pays?
As the fields of Discovery Toxicology or Exploratory Safety become more established within early compound screening, there is an increasing need to appreciate the role that safety scientists play in the new technology purchase and implementation process. It has become typical to conduct early safety evaluations within high-throughput screening groups however it is crucial that these new tests be vetted by the safety scientists before they are purchased and utilized. Therefore, technology evaluators are often associated with multiple groups, and may not be associated with the group that has the budget to purchase a particular instrument. Indeed, in most test systems whose primary function is to perform a safety assessment, the ultimate decision makers will be the safety scientists, even if the budget is not theirs. Because of this, it is important to survey a representative sample of the market in advance to gain a clear understanding of the areas of opportunity and the entry points.
4) Do I have a robust process for supporting new customer evaluations?
In a 2010 survey conducted by DSEC, the biopharma R&D community lists the following factors as the greatest inhibitors of new technology evaluations:
• Evaluations are too expensive or utilize too many resources
• Evaluations take too long
• Evaluations do not produce actionable results
New technology vendors must have a well-planned, economical and actionable process for potential customers to assess the value of a platform.
5) Can I demonstrate a pertinent price-to-value ratio?
There have been instances when a new technology vendor has failed economically despite having a strong platform that was validated and supported through a robust evaluation process. In many of these cases the vendor miscalculated the price-to-value ratio. The price of the new test per compound ultimately outweighed the perceived value. Vendors often calculate value based on a big picture assessment (e.g. if one bad actor is prevented from getting into late-phase development, then the company can save hundreds of millions of dollars). In reality, these types of justifications rarely have much impact even if they are true. Purchase decisions are often based on a much more mundane calculation, i.e. “given my operating budget, what type of test can I afford to run?” Technology innovators must develop a business model that not only weighs cost and perceived value, but also incorporates the increase (or decrease) in department run rates that can be recognized with the adoption of the new tool.