Managing Research and Development and Avoiding Tangents
There is, indeed, a specific fault in our system of science, and in the resultant understanding of the natural world … This fault is reductionism, the view that effective understanding of a complex system can be achieved by investigating the properties of its isolated parts. The reductionist methodology, which is so characteristic of much of modern research, is not an effective means of analyzing the vast natural systems that are threatened by degradation.
–Barry Commoner, American writer. From The Closing Circle.
Never make a threat. Reason with people.
Don Corleone (the Godfather)—Mario Puzo. From The Godfather.
INTRODUCTION
Levels and Issues of Research Management
Various levels of research and development (R and D) management are illustrated in Fig. 42.1. This figure stresses the functional responsibilities (e.g., discovery and development) rather than specific disciplines. It is intended to show that management principles, beliefs, and philosophies may be (and often are) extrapolated from one level of management to another. Some of the basic issues that frequently arise in the management of R and D are listed in Table 42.1.
Some of these issues are discussed in this chapter.
Most research, development, and medical department heads and many individuals within those departments tend to believe that the company’s R and D activities revolve around their own axis. It reminds the author of traveling to different countries and noticing world maps that place their own country in the center of the map. Science is a sensitive plant and scientists must often be careful gardeners. Many management questions arise every day, and managers must be careful about how they respond. Although one or two approaches may suggest themselves at once, there are almost always many ways of approaching any question or issue.
 Figure 42.1 Extrapolating management information and beliefs through various levels of R and D. Arrows represent extrapolations. The question marks (?) from pharmaceutical industry to nonpharmaceutical industry indicate that the extrapolation is usually in the other direction. |
In addition to the levels of research management described in Fig. 42.1, there are other levels at which basic decisions are made about research. These decisions include (a) whether a company should do any research to discover novel drugs, (b) which therapeutic areas (e.g., cardiovascular or central nervous system) should be researched, (c) which diseases should be researched, (d) which biological targets should be chosen to define activity, and (e) which methodologies should be used to approach each target? There are also issues of how much effort and resources should be expended on each research project and who should make the decisions on the five questions listed above.
Table 42.1 Selected issues frequently considered in the management of research and development | ||||||||||||||||||||||||
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The decision to pursue research in specific therapeutic areas may be made by scientists who are actively conducting and directing the research and/or by senior managers who review and supervise those scientists. Some companies allow scientists more freedom than others in this matter. If a company encourages its scientists to make decisions on which diseases to study and which approaches to use, then the managers of the scientists are probably more concerned with allocation of resources, priority setting, and review of progress, rather than controlling the specific research direction that each scientist is taking.
At most companies, however, the decision of which therapeutic areas to pursue (second level in Fig. 42.1) and often which diseases to research (third level in Fig. 42.1) are made by senior research managers. The decision of how to approach each disease (fourth and fifth levels in Fig. 42.1), however, is often decided by senior scientists. Managers may not only control the broad therapeutic areas and specific diseases that are researched, but may also control each target established within each of those diseases. The determination of specific methodologies to be used is commonly delegated to scientists at most companies.
Information Flow
It is important for managers to consider the means whereby they receive and disseminate information. This will allow them to determine whether currently used methods used for drug discovery or development of specific projects should be modified. If so, then the procedure(s) to do this should be in place. Each person who reports directly to a manager should be providing information on both a periodic and ad hoc basis. People who have a dotted-line (i.e., informal) reporting responsibility, have special relationships, or are peers of the manager, are other sources of information. If insufficient or inappropriate information is being received, then steps must be considered to rectify this situation.
Delays in the flow of information may occur anywhere along the path, and this is another aspect that may have to be addressed. Senior managers should utilize several different systems to expedite both upward and downward flow of information to themselves. Likewise, careful attention should also be given to methods used to disseminate information to others who are both higher and lower in the company as well as at the same level. It is hoped that readers of this book are not hoarders of information, but want to share it with all relevant people within their company or organization.
Types, Meaning, and Use of Target Dates
Target dates are usually established for achieving major milestones [e.g., New Drug Application (NDA) submissions and product launches] as well as for completing many of the individual activities and tasks that must occur for major milestones to be achieved. Target dates are used differently in different companies and sometimes by individual groups within the same company. Dates may be used (a) as a specific formal tool to develop work schedules and responsibilities, (b) as an informal guide to plan activities and work, or (c) as a general guide to assist people in establishing priorities. Production groups and some highly technical departments tend to use the formal “specific tool” approach and scientific staff conducting basic research or discovery research use the “general guide” approach.
Dates may be estimated on an ideal (theoretical) basis. On this basis, dates indicate when activities could be completed if all resources were available and no conflicting activities were competing for priority. Alternatively, dates may be estimated on a realistic basis that includes consideration of all projects being developed. Even using a realistic approach, dates may be chosen that are optimistic, pessimistic, or in between.
Optimistic dates are sometimes used in plans to spur and encourage the people working on a particular project. Although this method may be effective for a few activities, it is usually counterproductive over the life of a project. Most people prefer to gauge their work using target dates that are achievable without a superhuman effort. It is important for all project or milestone dates (e.g., time for Investigational New Drug Application or NDA submission and time of drug launch) to be established using the same approach and for all drug projects to use the same approach. Dates are useful guides for most people to use in planning their work, even though the targets established are not always met. Dates for obtaining regulatory approvals on various submissions are particularly difficult to set accurately. They may be expressed with confidence, however, as long as the year of approval is not listed.
BALANCING WORK EFFORT ON DISCOVERY, DEVELOPMENT, AND LINE-EXTENSION ACTIVITIES
The optimal balance between efforts expended on each of these three functions is influenced by the overall health and goals of the company. The pressures on R and D to stress either short- or
long-term horizons depend on the view of stockholders, board of directors, and R and D managers with input from marketing. If a company’s goals are heavily oriented toward short-term profits or the company is in poor financial health, it will tend to emphasize work on line-extensions. If a company’s orientation is toward long-term scientific breakthroughs and novel drug development, it will often emphasize discovery research. If a balanced concept is stressed, then efforts will be approximately balanced on all three functions.
long-term horizons depend on the view of stockholders, board of directors, and R and D managers with input from marketing. If a company’s goals are heavily oriented toward short-term profits or the company is in poor financial health, it will tend to emphasize work on line-extensions. If a company’s orientation is toward long-term scientific breakthroughs and novel drug development, it will often emphasize discovery research. If a balanced concept is stressed, then efforts will be approximately balanced on all three functions.
A long-term company commitment to drug discovery is necessary to have an efficient, effective, and motivated professional group of scientists who are attempting to discover and are actively developing drugs. As a company grows in size and it markets more novel drugs, the time spent on developing line-extensions and on other activities necessary to support marketing activities generally increases. A pharmaceutical company and its R and D managers need flexibility to adjust and maintain an appropriate balance between these three functions. The process of balancing these functions should be performed at least every two or three years, if not annually or more subtly on an ongoing basis. The drug discovery function cannot be turned on and off easily like a water tap each time a reassessment is made. Nonetheless, additional funds can almost always be spent on specific research activities of particular interest or on development activities where a bottleneck has occurred.
Should Drug Discovery Research Activities Be Isolated from the Rest of a Pharmaceutical Company?
When scientists are worried about their jobs and/or the attitudes of company managers, it becomes difficult for most to think creatively. Some people have suggested that it is desirable to remove drug discovery research from the company environment and to place it in an isolated research institute. This would theoretically allow scientists to concentrate on their research activities. The record of drug discoveries made in such research institutes of pharmaceutical companies, however, is not impressive, even though these centers often contribute significantly to basic research. If the criteria of success are based on research publications then such groups have been successful.
There is another approach that emphasizes creation of a positive work environment for basic research scientists (see Chapter 15). Scientists are not isolated from other activities and are encouraged to interact with development-oriented scientists and marketing-oriented personnel. Some discovery-oriented scientists also have the opportunity (if desired) at most companies to participate in drug development activities as members of project teams.
Preventing a Drought of New Products within a Company
There is no magic formula to achieve the goal of having a continual flow of new drugs. All companies are bound to have periods when few, if any, new products are developed. This is an important issue in all companies and a critical concern in some. In fact, much of this book is directed toward this concern. Some of the factors that tend to minimize the chances of this problem (i.e., a drought of new products) occurring are to (a) hire the best staff possible, ensuring that a sufficient number of highly creative people are present; (b) develop and maintain a positive atmosphere and environment, where people are encouraged to be bold and imaginative; (c) utilize licensing as an important adjunct to supplement in-house drug discoveries; (d) organize the company and its research departments to encourage flexibility; (e) maintain a critical mass of skills and talents; (f) build and maintain up-to-date equipment and facilities; and (g) maintain high ethical standards.
Within the project portfolio, there should be an appropriate mix of short-, mid-, and long-term projects. These groups of projects may be defined in many ways, but the specific definitions per se are not important to this discussion. What is more important is that the projects not only have appropriate medical and commercial value, but also reach the market at a steady rate. Any big gaps in this respect should be addressed through licensing, acquisition, or some other approach. Research programs should also be established to provide an appropriate mix of short-, mid-, and long-term research programs.
Reviewing Projects
There are many groups that review projects in a company. Reviews occur at different levels and for different reasons. A number of important considerations and questions for review groups are presented as follows.
Purpose of meeting. Are the meetings held to review projects intended as an information-sharing exercise or as a time to discuss issues, set strategies, and/or solve problems? If issues are to be discussed, it may be useful for the reviewers to identify the issues before the project leader or others are invited in to the meeting.
Asking the right questions. In reviewing potential research activities and projects and making decisions, it is important to ask the best questions. The question, “Is this something we can do,” may elicit a different answer than if the managers ask “Is this something we should do?”
Reaching decisions. Are decisions reached by consensus, by vote, or by the chair making a ruling? The first method is usually best since unpopular executive decisions often are not enacted or meet great resistance and may adversely affect morale.
Where is the focus directed. Do reviewers focus both on basic objectives of the project and the specific details and issues, or do they sometimes lose sight of the former and thereby allow the project to head in an inappropriate direction away from its goals? Are goals reassessed at appropriate intervals?
Focus on past versus future activities. Do reviews focus solely on the project’s past achievements and current status (i.e., a retrospective review) or do they also focus on the next steps in the project and on future activities (i.e., a prospective future-oriented review)? Do reviewers evaluate the overall direction in which the project is moving? Do reviewers confirm (insofar as possible) that several years into the future the market potential for the anticipated drug will still be adequate to justify the drug’s development?
Allocating priorities. Priorities in the overall portfolio often change, and a project may have to be slowed to allow others to speed up. How does the group handle this? Unless this step is carried out carefully, it may be demotivating to a company’s staff. If this occurs, a project’s momentum may slow or even come to a complete stop.
Sharing of information. Since information is power, how do senior and other managers deal with information? Do they
share it openly or guard it carefully and only provide it to others as necessary? Is it easy or difficult for each group to obtain the information it needs to operate effectively?
Preparation for meetings. Do reviewers come to meetings prepared to conduct their reviews? Have they read and digested material sent to them ahead of time or do they spend time being walked through material they should already know?
Assessing the Reality Level of Plans and Proposals: How to Spot Unrealistic Plans
Various types of unrealities either creep into plans or are purposely put there. It is essential for all professionals and all managers to be able to recognize problem zones, eliminate them where possible, and question them where not.
The first type of problem is familiar to everyone who understands statistics. That is the problem of using numbers incorrectly, such as inappropriately describing the effects of a drug that affects the heart rate or any of hundreds of other parameters by terms such as 5.434% or 5.434 beats per minute. This practice gives the veneer of being highly precise and accurate, but is often misleading because the degree of accuracy is incorrect and may be deceptive. Two examples of where this occurs in drug development plans are:
Planning to complete a drug study in 15.33 months
Planning to submit a particular NDA in 5.72 years
Given the number of years and number of uncertainties in drug development, the 5.72 years is misleading and the 0.72 should be dropped or the date changed to 6 years. Alternatively, the time to NDA submission may be expressed as a range of five to six years.
Another type of unreality in drug development plans is where an excessive number of events are described in minute detail. This is highly unrealistic because all development plans are usually modified several times before they are completed. In fact, it is more accurate to say that many drug development plans are modified several times per year. One example of an unrealistic plan is when a highly detailed clinical plan up to the time of a drug’s marketing is established before the drug is ever administered to humans. Another example is where a highly developed and detailed plan of all steps from Phase 1 through NDA submission is formulated at the time when a compound is made a project and the plans for the Investigational New Drug Application are also being developed. The author has seen this type of unrealistic plan on many occasions.
Unrealistic plans may sometimes be identified by discussing how each of the outcomes would be based on the proposals and recommendations. Unrealistic ideas may be found through contradictions, unrealistic outcomes, or conflicting logic. It is always disheartening when this type of problem is discovered by a retrospective analysis instead of a prospective one.
Planning for Meetings
A calendar of all important company meetings should be established about a year in advance. This provides various advantages to individuals who must attend and assists in organizing which meetings should precede or follow others. Thus, a group or committee that presents their results to another group may schedule their meeting(s) appropriately. An international as well as national calendar may be developed. This may be done at the level of the entire company, a specific function (e.g., marketing or production), a department, and/or a section within a department.
Quid Pro Quo in Setting Budgets in Terms of Performance
A long-term company commitment of resources to research and discover drugs includes the responsibility of senior managers for an appropriate number of research activities to succeed. This means that the heads of research and research departments, plus section heads of research departments are willing to accept accountability for discovering new drugs. Their budgets may be lightly tied to their productivity in extreme cases. This could mean that the amount of increase in a budget from year to year would depend (in part) on the number and quality of compounds that reach development. For example, there could be a minimum budget established, plus an amount based on performance within research, R and D, or within the entire company. If this practice were followed, it would be necessary to prevent wide fluctuations in budgets and in head counts. Care would also have to be taken to ensure that productivity was real and that compounds were not advanced primarily to increase the research budget. One means of preventing abuses and establishing a fair system would be to use a moving five-year average in determining the number of compounds advanced for development. Failure by some managers to meet reasonable objectives would have to be seriously reviewed. A more common approach is to fire or reassign managers whose performance is not judged to be adequate.
Subcategories of Drug Discovery, Drug Development, and Line-extensions
In addition to balancing drug development efforts between drug discovery, drug development, and line-extension activities, it is necessary to balance efforts within each of these three major categories.
Drug Discovery
Subcategories primarily relate to the number of therapeutic areas and diseases being researched and the depth to which each is pursued (see Chapters 8 and 15 for discussion of this topic).
Drug Development
Subcategories refer to the number of drugs being developed, the resources applied to each, and the current stage of each project.
Line-extensions
The subcategories used for drug development may also be applied to line-extension activities.
Because development costs increase as a drug progresses through the pipeline, a larger sum of money is generally spent on all of a company’s drugs in Phase 3 than on drugs in Phases 1 and 2. If this is not the case, a serious review of the situation should occur. It may mean that the company has (a) an insufficient number of drugs in Phase 3, (b) a surfeit of drugs in Phases 1 and 2, or (c) a serious imbalance in the allocation of resources.
Contracting Drug Development
Many aspects of drug development may be contracted to outside groups. For the past ten to 25 years, it has been common for research-based pharmaceutical companies to contract a number of their clinical trials to contract research organizations for implementation and oversight. These contractors either conduct the studies themselves (primarily for Phase 1 studies) or act as middlemen to place the trials with academic or private investigators.
In the past decade, there has been a gradual increase in the types of contracting services available and a steady increase in the amount of work that companies place with contractors. The major motivation in using contractors is to save time, which is especially important during periods of peak workload. In addition, going to contract research organizations eliminates the need for a company to hire more people when there is more work to be done and to let them go or to reassign them when the amount of work decreases. In other situations (e.g., specialized toxicology studies), a company may be unable to do the work itself. This subject is discussed in Chapter 74 and also in Chapter 58 of Guide to Clinical Trials (Spilker 1991).
In the past decade, there has been a gradual increase in the types of contracting services available and a steady increase in the amount of work that companies place with contractors. The major motivation in using contractors is to save time, which is especially important during periods of peak workload. In addition, going to contract research organizations eliminates the need for a company to hire more people when there is more work to be done and to let them go or to reassign them when the amount of work decreases. In other situations (e.g., specialized toxicology studies), a company may be unable to do the work itself. This subject is discussed in Chapter 74 and also in Chapter 58 of Guide to Clinical Trials (Spilker 1991).
Contractors versus Consultants
Although contractors could be considered to be consultants (and vice versa) a sharp distinction is drawn between these two groups. Consultants provide advice, opinions, evaluations, and recommendations, whereas contractors provide a service that is usually more tangible (e.g., a specific report or study). Consultants are mainly discussed in Chapter 15. Contractors are considered as for-profit businesses and, therefore, must also be differentiated from academicians, government agencies, and institutions that interact with pharmaceutical companies.
Locating Contractors
Locating contractors is not usually a problem for any pharmaceutical company because most contractors advertise heavily and are frequently approaching companies directly. Each relevant group (e.g., clinical, toxicological, or regulatory) should retain files of available contractors. Evaluations of their past performances, plus references and other related information, should be kept in a readily accessible place and available to appropriate staff. Ex-employees of a company often make excellent contractors for certain purposes (e.g., writing final medical reports) if they are not employed at a competing company and conflict-of-interest issues do not arise.
Services Provided by Contractors
In general, contractors are pleased to tailor their activities to the needs of the companies. Most contractors offer to provide the entire clinical trial process, including preparing a protocol, conducting the trial, editing data, entering it into computers, quality assuring the data, preparing a statistical report, and preparing a medical report. Other contractors specialize in only certain of these processes, such as entering data and preparing statistical reports. Contractors also are available to conduct toxicology and other preclinical studies and to prepare regulatory submissions. Another role they fill is to prepare final medical reports for numerous studies using one company-prepared report as a template or model. A few contractors are willing to develop a company’s entire program on a new dosage form or totally develop a new chemical entity all the way to providing a completed regulatory submission.
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