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In this article a "tangent" means a change from the plans or path one has agreed to follow in drug discovery, development, production or marketing. There are positive and negative tangents. It is important for companies to have a method for approving tangents in a systematic way. There are two major issues to consider about tangents: Who is proposing the tangent and what are his or her motives? and What are the "pros" and "cons" of adopting a tangent presented as a fait accompli? Tangents include changes in the major direction or orientation of a project such as pursuing a new indication, a new route of administration or a new patient population. It is important to recognize these and other proposals or recommendations as tangents when they are initially proposed. There are a series of specific issues and questions to address when evaluating tangents and a number of straightforward ways to minimize nonproductive tangents in pharmaceutical companies.

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This article describes several types of risk encountered in drug discovery, development and marketing, as well as the overall business risks in the pharmaceutical industry. Discovery risk refers to the risk companies face if they are partly or totally dependent on discovering new drugs; many avenues are presented for companies to pursue in order to decrease discovery risk. Development risk is defined as the risk that drug discoveries that enter development will not reach the market and become commercially viable drugs. To decrease development risk, it is possible to pursue one or more of the approaches presented. Significant marketing risks for a company include that the sales forecasts will not be met, the positioning of a drug may not be correct or optimal and the sales force is not performing adequately. At the corporate level there are numerous major risks involved in pursuing the specific mission, objectives, strategies and tactics of the overall company as well as those in the functional areas. Many aspects of the company's business can be adjusted or changed to decrease corporate risk. Selected issues concerning risk include venture capital funds, the appetite for risk within a company and the influence of senior and middle level managers' personalities on risk.

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When collecting data, deciding what type and how much to obtain will depend in large measure on how the data will be used and the group(s) that will be given the data, as well as the risk-taking or risk-averse position adopted. Among the most important issues involving the quality of data are knowing what plans and activities will lead to obtaining high-quality data and recognizing whether the data obtained achieve one's goals. Factors to consider in deciding on the quality and quantity of data to collect include the following: robustness of data required for extrapolatability; potential use of the data; degree of bias that is acceptable; the quantity of data that must be collected in a study or trial which must be considered separately from the quantity to be submitted in a regulatory dossier; practicality of the study; cost of the study; and time available and necessary to complete the study. In preclinical experiments involving discovery research, the protocols prepared are generally loose and can be readily modified during the study in order to take advantage of serendipitous observations or sudden ideas of the experimenter; this is not generally the case with well-controlled clinical trials, although in some circumstances feedback loops can be established to monitor data collection during a trial. A feedback loop of adjusting the amount of data to collect during a study has both advantages and disadvantages (described in the text) when compared with creating a relatively inflexible plan in advance of starting a study, as required for most clinical trials.

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Pharma sense refers to a general understanding of pharmaceutical principles and concepts. Pharma think is an active process that occurs when a person uses his or her pharma sense to think about a question, issue or problem and identifies a solution, an action plan or series of options. As a direct result of greater use of pharma sense and pharma think, the quality of decisions made in a company will increase. A company is reservoir of pharma sense and skills of pharma think will facilitate the staff is ability not only to make good decisions, but also to implement successfully the business, scientific and other decisions that are made at all levels within the organization. Companies should train their professional staff to focus on the development of pharmaceutical sense and help pharmaceutical professionals use pharma think to make better decisions.

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Systematic evaluation of a project, product or other successes, and failures, is an important method for improving the performance of a company, as well as that of an individual. One should evaluate and determine if lessons learned can be applied to the systems and procedures being used in the company. Even if the company does not have to adjust its strategies, procedures, portfolio or systems as a result of lessons it has learned, there may be pointers to communicate to staff. It is easy for many aspects of a system to become outdated, particularly in an organization that is growing or changing rapidly. It is therefore generally appropriate to evaluate the company's regulatory compliance, toxicology compliance, clinical auditing practices and other appropriate systems on an annual or biannual basis. Most lessons of success or failure are specific to a single situation because of the combination of people, drug, competition, priorities and many other factors involved, and cannot be extrapolated to other situations. Some general lessons and principles are presented that will facilitate drug discovery, development and marketing.

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Every professional discipline has current fashions. Certain ideas or topics are promoted by those who are most closely associated with the idea. These people often have a great deal to gain when ideas are accepted. The traditional approach of testing a hypothesis and finding important results before forming a new company seems to be old-fashioned today. Important innovations such as biotechnology and gene therapy have had a monumental impact on the pharmaceutical industry and have created new related industries. Probably the greatest threat to a pharmaceutical company from new fads is the strong encouragement to adopt the latest management fad to redesign, reengineer or simply reorganize the company. One new fad is the creation of gerontology as a new medical specialty. On the other hand, two examples of important innovations are quality of life and pharmacoeconomics. There are clearly both positive and negative reasons for certain ideas to be popularized.

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Different types of standards that can be created are ideal, realistic, desirable and minimally acceptable. A different approach to viewing types of standards is to view them as existing along a spectrum from very formal to informal. Basic research, medical research and market research can each develop and use standards that are entirely formal or informal or that exist at any stage along that spectrum. Pharma sense dictates that there are times when high, medium or low standards are appropriate. The main goal of all professionals is to know when to use which approach. Situations where pharma sense requires using either high or low standards are mentioned for basic research, clinical research and market research. Standards for basic research are usually established to answer the question: What level of activity must the test compound exhibit to be worthy of passing onto the next test? Issues concerning standards are: Who sets standards? When do standards interfere with achieving useful results on a project? What are the possible consequences of using low standards in research? What are the tradeoffs between quality and quantity of standards? How should appropriate standards be taught? and What are the internal versus external pressures on decision making about standards? By using pharma sense and pharma think to approach any issue or question of research standards on its own, it is likely that a company will determine the appropriate level of standards.

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A variety of focuses are used in this article to discuss four types of perspectives; these focuses are self, others, drugs/issues and company/industry. There is a hierarchy of concern about the topics one deals with. This hierarchy ranges from identifying whether there is a question to address or whether the topic is more serious and there is an issue to consider. If the matter is even more serious, it may be a real problem or there may be an actual crisis. It is important to use one's senses to achieve optimal interactions with all individuals and groups one associates with. When focusing on perspectives of drugs and issues, it is important to obtain a broad perspective. This may often be achieved by viewing all drug development (or marketing, discovery, production, etc.) using multiple approaches (e.g., consider different customers and groups). Developing pharma sense and skills in pharma think must be achieved concomitantly with developing a pharmaceutical perspective. This is essential to fully achieve one's professional goals and enable the company to achieve its goals.

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Reality has many faces, depending on who is judging or describing a situation or event. A person's view of reality is strongly influenced by his or her perceptions, values, biases and beliefs, and reality is therefore a relative term. Even the ability to determine the reality of an object through objective instruments and measures is limited. Most people accept the principle that there is not a single absolute reality about an event, but many realities which depend on the perceptions of the observer. Reality can be shaped in various ways: governments often attempt to shape reality for their citizens; myths and misconceptions abound; and personal activities influence our beliefs. Trying to understand reality teaches one to understand that there is no single reality or truth and no simple answer or approach to achieve a full understanding. In the pharmaceutical industry, to develop pharma sense, one must understand the universe of perspectives that can be brought to the specific issue or question being addressed.

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In a corporate setting, the term "team" usually refers to members of a group with different responsibilities and/or skills working together to achieve a common goal or objective. The major reason why a company desires group as opposed to individual involvement is to derive sounder decisions. Two essential issues to resolve in establishing teams or committees are 1) who should be a member or representative; and 2) what is the charter or mandate for the group. Representatives join a team or group in numerous ways; four common methods are 1) appointment by the group member's supervisor; 2) recruitment by the team leader; 3) appointment by a senior manager; and 4) volunteering. There are various profiles of how groups can approach a decision, including "groupthink," the "ideal group process" and the "debating society" approach. Group meetings must be structured to ensure that decisions are reached and then implemented. Foresight and planning are essential prerequisites to have efficient teams and committees that work effectively and achieve their goals.

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This article describes nine separate elements that are part of any course: 1) the teachers, 2) the students, 3) expectations and attitudes of the teachers, 4) expectations and attitudes of the students, 5) a strategy of how to achieve the expectations, 6) materials to use, 7) types of presentations, 8) organizing the individual sessions, and 9) time and place for the course and each of its sessions. The relationship of each of these elements to a course on clinical-trial research methods is discussed. Approaches to use for designing an overall curriculum for a school, company, or regulatory authority also are discussed. Sixteen separate courses are identified and briefly described. Several methods to enhance the effectiveness of individual lectures or discussions are mentioned. Potential courses, as well as those currently offered, should be periodically evaluated by all institutions that are involved in the area of clinical-trial research methods.

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A phenomenon known as regression of seizure frequency toward the median was observed in a previous clinical study performed in patients with partial seizures. Regression of seizure frequency is a situation in which patients with a frequency of seizures above the median value for the group during an initial period have a tendency to have frequency of seizures decrease during a subsequent period, and other patients with a lower frequency of seizures during the initial period increase their frequency during a subsequent period. To investigate this further, eight published sets of clinical data obtained in epileptic patients with various seizure types were identified by a literature search. Three separate analyses were conducted for each data set. All three analyses clearly demonstrated that regression to the median was present in the studies evaluated. It was concluded that this phenomenon is a real effect in epilepsy and occurs in patients with a wide variety of seizure types. The implication of this phenomenon for physicians treating epileptic patients is that there is value in establishing pattern of seizure frequency for individual patients. This information can be used in assessing those patients whose seizure frequency has increased. The implications of this phenomenon for designing and evaluating antiepileptic drug studies are also discussed.

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Cinromide was evaluated versus placebo as add-on therapy in a double-blind crossover study in epileptic outpatients with partial seizures at three sites. Four-week base lines were used before, between, and after the two 12-week treatment periods of the crossover. An operational definition was used to classify each partial seizure as Type A, B, or C. Doses of concurrent antiepileptic drugs were adjusted to maintain pretreatment therapeutic plasma levels. Doses of cinromide ranged from 1,200 to 4,800 mg/day, depending on patient response. Seven patients were withdrawn from the study because of adverse experiences (two receiving placebo and five receiving cinromide). Twenty-eight patients completed the entire 36-week study. A decrease in the average frequency of seizures/week was observed in 12 patients receiving cinromide and in 16 patients receiving placebo. The median frequencies with cinromide and placebo were 3.3 and 2.9 seizures/week, respectively (median initial base-line frequency 3.5 seizures/week for all 28 patients). Although patients were randomly assigned to receive either cinromide or placebo first, the median base-line seizure frequency was greater at the start of the first treatment period in the cinromide group (4.3 versus 2.5 seizures/week) and greater at the start of the second treatment period in the placebo group (3.8 versus 1.4). The median seizure frequency in each higher group decreased with treatment, whereas it increased in each of the lower groups. This study did not demonstrate a beneficial effect of cinromide over placebo for Type A, B, or C partial seizures. The data suggested the presence of an oscillation of seizure frequency in our population of epileptic patients having partial seizures, as well as a placebo effect. No significant carry-over effects were observed. Cinromide has previously been shown to have significant antiepileptic activity in various animal models of epilepsy. The lack of an antiepileptic response to cinromide in humans may have been due to factors other than species differences but indicates that a positive results of a drug in animal models is not the sole factor necessary to predict beneficial antiepileptic activity in humans.

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The influence of 35 commonly used drugs on measurement of metanephrines in urine was evaluated. Two concentrations of drugs were chosen for study based on usual doses and the percent of dose excreted unchanged in the urine. At "medium" drug concentrations, only phenylephrine falsely elevated metanephrine levels, whereas at a 10-fold higher drug concentration, guanethidine, hydrocortisone, imipramine, isoetharine, levodopa, phenobarbital, and phenylephrine caused positive interference. Propranolol and theophylline caused a negative interference at the two concentrations studied. The significance of these results is discussed.

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A system is presented to increase efficiency in planning, initiating, conducting, and analyzing the results of a clinical trial. The procedures to be used are designed to assist clinical investigators of sponsored or unsponsored studies, as well as drug corporations and other sponsors of drug studies. The series of checklists and steps to follow may be easily modified for individual trials. The procedures and steps to be implemented are described in terms of the following nine categories: Interview and Selection of Investigator(s); Clinical Study Initiation: I. Internal Documents and Procedures; Clinical Study Initiation: II. Information for the Investigator to Send to the Sponsor; Clinical Study Initiation: III. Information for the Sponsor to Send to the Investigator; Prestudy Roundtable Meeting; Conducting the Clinical Study; Monitoring and Troubleshooting a Study; Clinical Study Termination; and Clinical Study Data Entry and Analysis.

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