Spring 2017 - Current Topic
FINDING THE GOOD IN GOOD SCIENCE
Note: This document expresses Dr. Jenke’s personal views and opinions and is not a position established and supported by Triad Scientific Solutions, LLC. This document is not professional advice and does not constitute a professional service provided by either Dr. Jenke or Triad Scientific Solutions.
When members of the E&L community gather to develop standards, guidelines and best demonstrated practice recommendations, there are three principles they should obey:
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The standards must be based on “good science”,
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The standards must be effective and efficient, and
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The standards must fit every conceivable circumstance well.
It is the inability to achieve these principles that makes the generation of standards, guidelines and recommendations so frustratingly challenging.
Consider the last principle, for example. It is intuitively obvious in a diverse field such as pharmaceuticals that this principle is impossible to achieve as it is clear that a rigorous standard (which is specified set of tests coupled to a specified set of acceptable test results) cannot fit all the diverse circumstances equally well. It is the same problem as trying to design a glove that fits every human being. If the underlying purpose of the glove is “to keep one’s hands warm”, then a standardized glove can be designed that will address this requirement, to some degree, for most people. However, because the glove must keep everybody’s hands warm, it is logical that there will be design tradeoffs which will mean that while it keeps everyone’s hands warm, it does not keep everyone’s hands as warm as they would personally like it. Furthermore, there may be other trade-offs, such as “these gloves are not very sexy”, or “these gloves do not match my coat” or “these gloves make my hands itch”.
While the challenges in making standards that are generally applicable in the greatest number of circumstances are considerable, this is not the point that I want to address in this discussion. Rather, I want to address the challenges associated with good science.
Good science suffers from with the same problem as designing a standardized glove. As good scientists, we learned and we understand that there are very few universal scientific truths; rather, a scientific truth is a truth only under the rigorously defined set of circumstances upon which it is based. When we perform an experiment and draw a conclusion from that experiment, we understand the conclusion is only perfectly valid for the set of defined experimental circumstances we started out with. Extension of that same conclusion to other circumstances involves a certain measure of risk, specifically the risk that in changing the circumstances we have invalidated (knowingly or unknowingly) some fundamental principle that defines the applicability of our conclusions. Thus, we understand that there is an inherent trade-off when we make scientific generalizations and put them into standards, guidances and recommendations. That is, we sacrifice some of the good in good science for the sake of providing a direction that is generally right in the greatest number of circumstances.
The challenge we face as practitioners of good science is not in recognizing good science per say but recognizing the boundaries that differentiate between good science properly applied and good science improperly applied. When we are tempted to use a standard, or leverage a “rule of thumb” or “do this because everybody else is doing it”, as good scientists we must ask ourselves “am I taking a good idea in certain circumstances and applying it to the wrong circumstances?”. If the answer is yes, then surely this is as bad as using “bad” science in the first place.
Let me illustrate this with an example. I use this as an example not because it a particularly bad practice but because it effectively illustrates my point. The following, taken from the PQRI OINDP Best Practice recommendations, is well known and commonly applied in the E&L community.
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The Working Group recommends that analytical uncertainty be evaluated in order to establish a Final AET for any technique/method used for detecting and identifying unknown extractables/leachables.
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The Working Group proposes and recommends that analytical uncertainty in the estimated AET be defined as one (1) standard deviation in an appropriately constituted and acquired Response Factor database OR a factor of 50% of the estimated AET, whichever is greater.
The question I would ask you to consider is “where is the good science and the not so good science in these recommendations?”
Here is my answer. It is well known that response factors will vary among the universe of compounds that could be extractables and leachables. Thus, it is good science that a general concept such as the AET, which presumably is applicable to all possible extractables/leachables, take this variation into account. Furthermore, we all understand that basing actions on relevant and sufficient data is the cornerstone of good science, and thus that the requirement to consider “an appropriately constituted and acquired Response Factor database” is a requirement to do good science. However, it must be obvious that the direction to universally “use a factor of 50%” is not necessarily good science. While the derivation of the 50% is itself good science, as it was based on a response factor database (which is somewhat small in the context of the databases available today), it is obvious that the 50% is only relevant for the compounds in that database and the analytical method with which the data was generated. Universal and unquestioned application of the factor of 2 rule to compounds that were not in the original database and to analytical methods other than the method used to generate the data is not the best science; rather, it is poor science, not because the science itself is bad but because the good science aspects are being applied out of context.
To a good scientist, arguments such as “it is better than nothing” or “everybody else is doing it” are inexcusable. Certainly, the idea that “it is better than nothing” has to be examined objectively and harshly. The improper application of science is not guaranteed to be better than doing nothing because it is not the case that the improper application of science will always make things better. In fact, the history of improper application of good science is littered with examples of bad outcomes derived from applying good sciences incorrectly.
Listen, nobody said doing good science was easy. We understand that part of the driving force for recommending that the factor of 2 be universally applied is that back then few people could access a database. Thus, it was nearly impossible to practice the good science required in the recommendation and people, rather than do nothing, gravitated to the other part of the recommendation. However, today, it is virtually impossible to run into a reputable E&L laboratory that is not eager to talk about their database. Thus, in this case, our ability to do good science has finally caught up with our responsibility to do good science. It is proper that we accept that responsibility and be held accountable for meeting that responsibility.
This is true not only to adjusting the AET for analytical uncertainty but in numerous other places where our current capabilities enable our ability and address our responsibility to practice and preach a higher degree of good science than has ever been possible. Currently applied recommendations, standards, guidelines and practices must be adjusted, as appropriate, to leverage this new and higher degree of good science and new recommendations, standards and guidelines must be drafted to reflect this new and higher degree of science. We aspire to better science because we are capable of better science. More importantly, if we are going to talk the talk, we best start walking the walk.
An Introduction to Triad Scientific Solutions
We all know why we are here. After years of development, a health or welfare product is ready for commercialization. The development effort, which likely took multiple years and considerable capital to complete, has resulted in a product that is effective, safe, pure, stable and complaint with relevant quality standards. However, the fact remains that in order for the product to useful to its user, and to generate revenue for its sponsor, it must undergo the necessary processes of manufacturing, storage and distribution, and delivery. Unfortunately, each of these necessary and unavoidable processes provides the opportunity for the health or welfare product to interact with the manufacturing equipment, the storage/distribution system, or the delivery device. As a result of this interaction, substances may be added to or removed from the product, potentially affecting its efficacy, safety, purity, stability and its ability to meet quality standards. It is therefore necessary to establish that the product, at the point that it is used by the user, remains safe, effective, appropriately pure and compliant.
Now we may come together to address these circumstances from a variety of different directions. We may, in fact, be the owner or sponsor of the product itself. Alternatively, we may be the supplier of the equipment, systems or devices used in the product’s manufacturing storage, distribution or delivery. It is possible that we are somewhere in the supply chain, as raw material suppliers to either the product’s sponsor or the equipment, systems or devices suppliers. We may be regulators, charged with the responsibility of protecting and promoting public health and safety. Or, as is the case with Triad, we may be individuals or organizations which offer services that involve assessing the extent and establishing the effect of the inevitable interactions between the product and the contact items.
Regardless of our role, we share the common purpose of establishing that a product is suitable for its intended use, meaning that it is safe, effective, appropriately pure, and of the necessarily quality at its time of use. Although the industry has evolved to a significant extent in terms of its ability to address the challenge of establishing the suitability of a product for its intended use, the fact remains that meeting this challenge requires a significant, and not inconsequential, effort. It is a constant challenge to balance the responsibility for insuring product safety, quality, efficacy, purity stability with the investment necessary to provide such assurance.
Given the enormity of the challenge of establishing suitability for use, meeting the challenge requires the combined capabilities, facilities, efforts and contributions of a team of scientific, technical and business experts in a number of disciplines involving the physical, chemical, biological and applied sciences. Triad has established its proper place on this team based on the needs of the sponsors, the roles of the other participants and the capabilities and resources of its own members. Specifically, Triad is that organization which simplifies and optimizes the complex and extensive process of suitability for use assessment via the practical application of the necessary good science, both in terms of principles and practices. Based on its long experience with, and broad understanding, of the scientific and practical aspects of suitability for use assessment, Triad helps sponsors, suppliers, vendors, CROs and consultants to devise and implement the right studies at the right time, to produce and assess the right information, to generate the right assessment, and to communicate and defend those studies, information and assessments properly and effectively. In so doing, Triad helps its partners manage both the science and the budget, recognizing that while it is essential to produce products that are suited for their intended use, it is also necessary to produce such products at the lowest possible cost, as so doing insures that the greatest benefit is realized.
More specifically, Triad is positioned to be your valued partner, trusted advisor and preferred provider for the following services related to suitability for use assessment:
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design (and justification thereof), implementation, data review and interpretation, and reporting of experimental studies involving:
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material, component or system characterization and selection,
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product/material compatibility (drug binding and degradation),
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system qualification (extractables),
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product qualification (leachables.
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technical and quality review of facilities, processes, practices and personnel.
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capability and capacity review and assessment.
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general, focused or customized technical training
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advocacy and representation for clients during product design, development, registration, commercialization, and marketing.
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strategic planning of company policies and procedures.
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vendor qualification and management.
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analytical method development, optimization, validation and remediation.
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problem identification, investigation, troubleshooting, resolution and prevention
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technical writing in preparation of manuscripts, technical documents and submission files or dossiers.
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wild card opportunities (until you describe the opportunity, how can we know for sure whether we can help or not?)
The above services can be provided to support products throughout their life cycle, including development, registration, commercialization and time in market (change control and product retirement).
While Triad is not an analytical testing laboratory, it can advise clients in terms of identifying, selecting and managing CROs which share Triad’s passion for good science, practically applied. Although Triad may not possess all the answers in all the circumstances, it can leverage its extensive network of both chemistry and toxicology experts to ensure that clients have access to highly and appropriately qualified expert partners.
I believe that while an organization may be defined by its mission and vision, its ability to achieve its mission and realize its vision rests squarely on the shoulders of its members. When that mission and vision involves providing a service to others, the efficiency and effectiveness with which that serve is provided depends on both the capabilities and principles of the provider’s members. As the principal and founding member of Triad, it is the largely the case that I am Triad and Triad is me. For those of you who know me and know my work, that may be recommendation enough; for others, you can get to know me better by reviewing information (such as my vitae, personal statement and list of publications) that is provided elsewhere on Triad’s website.
In any event, welcome to Triad, thank you for your interest and I do hope that there is an opportunity for us to work together on our shared mission to enhance, sustain and save lives.