No house should ever be on any hill or on anything. It should be of the hill, belonging to it, so hill and house could live together each the happier for the other.
–Frank Lloyd Wright. From An Autobiography (1932).
Excessive delegation is abrogation.
–Dr. Alan Eggleston. The Wellcome Foundation.
Striving for excellence motivates you; striving for perfection is demoralizing.
–Harriet Braiker, psychologist and writer.
THE NEED FOR STANDARDS TO EVALUATE DRUG DISCOVERY AND DEVELOPMENT
Many of the problems faced by pharmaceutical companies indicate that there is a need for a set of standards to guide the drug development process. A few typical problems are in:
How to determine how good a new compound must be in terms of its efficacy and safety to justify moving the compound into development
How to determine whether a competitor’s newly approved drug should influence the company’s decision to spend large sums of money on its drug’s further development
How to know when an investigational drug should be terminated —when its profile no longer justifies pursuing the drug’s development or when the marketplace is changing and physicians are no longer using the type of drug being developed
How to assess whether development of a new drug should be continued when certain safety or efficacy characteristics are less than expected, although other characteristics (e.g., convenience, cost of goods) are better than expected
Three sets of scientific/medical standards can be used to judge the discovery of new compounds and their further development as new drugs: Ideal, Realistic, and Minimally Acceptable. The author proposes that the best standards to use for evaluating compounds in discovery and drugs in development should be Minimally Acceptable (see Fig. 50.1 for an illustration of these major and some minor sets of standards).
Another way of looking at the three sets of standards is through the metaphor of a high jump (see Chapter 3). The high jump’s bar represents the standards that the newly discovered compound or drug must achieve or surpass. Separate high jump bars exist for safety and efficacy. A compound or drug must achieve the established standards to be viable in terms of medical, commercial, and public relations image value. For example, if the high jump bar for safety is set so high using Ideal standards that only a perfect compound could meet those standards, then those standards do not indicate how high is “enough” for a very good and acceptable (but not perfect) compound to jump. The same metaphor can be used for a drug in development. For example, a perfect drug will be effective in 100% of patients with a given disease but may only have to treat 50% of the patients effectively to be approved and widely used.
This chapter focuses on scientific/medical characteristics, although the same set of standards may be applied to the category of commercial characteristics used by marketing groups to judge a new drug. Some companies refer to commercial standards as hurdle rates (i.e., the anticipated commercial return needed to justify and continue the drug’s development).
RELATIONSHIP OF THE TERMS STANDARDS AND CHARACTERISTICS
The relationships among the terms standards and characteristics must be clear if the approach described here is to be used to expedite a compound’s discovery or development. The term characteristics refers to the parameters that are assessed during discovery or development. It is these characteristics to which the standards are applied. For example, characteristics for a compound being evaluated during the discovery phase of research are likely to include the following representative examples (selected from many hundreds of potentially important characteristics).
What is the:
Activity of the compound in each of the standard in vitro and in vivo screening tests
Activity of the compound compared with the currently marketed drugs for this indication in screening tests
Safety of the compound in the in vivo animal models in terms of measures of heart rate, blood pressure, and innumerable laboratory measures
Safety of the compound compared to currently marketed drugs in the following measures
Absorption (or metabolism) of the compound when given orally to species X, species Y, and species Z
Penetration across the blood-brain barrier (which could be desired or not desired)
During a drug’s development, the most essential characteristics might include:
Safety of Drug X versus the market leader
Specific adverse event profile of aplastic anemia for Drug X versus the market leader
Can Drug X be taken fewer times a day than the market leader?
Percentage of migraine headaches that are reduced significantly by Drug X within six hours of ingestion
Any drug interactions that will cause issues with Drug X
Any tolerance to the efficacy of Drug X
The major relationships are shown in Table 50.1. When a company is establishing the standards it wishes to use to judge the compounds in discovery or the drugs in development, it is likely to choose one of these three sets of standards (i.e., Ideal, Realistic, and Minimally Acceptable). However, it is important to note that the specific scientific and/or medical characteristics would be the same for each set of standards, although the standards themselves would differ. It would be desirable to have these standards quantified, although this is not always possible. Actual examples of characteristics and standards are provided in Table 50.2, although that table presents a simple example. A more complex example would include more characteristics and would indicate linkages among characteristics for any one set of standards (e.g., if characteristic number 3 is not achieved, then numbers 2, 4, and 5 must be).
Table 50.1Relationship of standards and characteristics
List important scientific and medical characteristicsa for the compound/drug
A.
Qualitative
B.
Quantitative
II.
Realistic set of standards
Standards to achieve for each characteristic
List of important scientific/medical characteristics for the compound/drug (same characteristics are listed as in I above)
A.
Qualitative (may be the same or different than in I above)
B.
Quantitative (may be the same or different than in I above)
III.
Minimally Acceptable set of standards
Standards to achieve for each characteristic
List of important scientific/medical characteristics for the compound/drug (same characteristics are listed as in I above)
A.
Qualitative (may be the same or different than in II above)
B.
Quantitative (may be the same or different than in II above)
a Separate or overlapping lists of marketing, production, and other characteristics may be identified and listed with scientific/medical standards, or they may be listed separately. Examples of selected scientific/medical characteristics are listed in Table 50.5.
b Examples of standards to achieve for each characteristic are shown in Table 50.2.
Table 50.2Examples of Ideal, Realistic, and Minimally Acceptable standards for a hypothetical antiepileptic drug during its clinical development
a Activity is defined in terms of the number of seizures. Improvement for any drug is described in the specific terms in which it is measured (e.g., overall clinical improvement judged by the investigator at the end of a clinical trial or change of a specific disease parameter measured objectively).
b These must be more clearly and specifically identified and quantified (if possible) in the text or in another table (e.g., no interaction with Drugs Y or Z at their usually given doses).
IDEAL STANDARDS
Using Ideal Standards in Research
Ideal standards help to set one’s research targets, much as a beacon of light illuminates the path one is moving along. It provides both the correct direction and illuminates the goal at the end of the trail. But these standards do not enable a scientist to know how far along the path or how close to the goal he is and at what point he can make a decision about advancing the compound into the development phase. As a result, perfect or Ideal standards do not facilitate business decisions, as one will never know using these standards whether or not one is close enough to the goal to have a successful drug or should continue to search for better compounds.
Examples include seeking an elimination of all seizures in certain animal models at a given dose rather than seeking a compound that decreases seizures by a certain percentage. Clinically, one can seek to prevent patients from having any asthmatic or migraine attacks, both of which are Ideal standards but unrealistic. A set of hypothetical Ideal standards is shown in Table 50.2 for an antiepileptic drug.
One can create the Ideal standards of any drug for any disease. It is also useful to compare new compounds with standard drugs to judge how much closer the new compound approaches the ideal. Any compound can be judged by how close it is to a number of Ideal standards. The advantages and disadvantages of using Ideal standards are summarized in Table 50.3.
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