Medical Education, 1978, 12, 176-181

A novel adaptation of the Information Game for the development of a new drug

B. T. M A R S H A N D C. MAXWELL*

Medical Department, Leo Laboratories Limited, Hayes, atid Association of Medical Advisers in the Pharmaceutical Industry, and *Clinical Research Services Liniired

summary

Medical advisers in the pharmaceutical industry have an important function and place in the develop- ment and evaluation of new drugs. Although mainly involved in the human and clinical investigations, it is essential that they have the background knowledge and experience to evaluate the results of pre-clinical studies and to apply these safely and effectively to the clinical situation. It is rare nowadays for a medical adviser to obtain direct experience in all areas of drug research due to its complexity. Simulation exercises are a means of obtaining this experience without suffering the results of a wrong decision. An adaptation of the Information Game proved to be a useful and acceptable means of illustrating the decisions that need to be made in a drug development programme and at the same time provided experience in coping with the various problems that might arise in such a programme. The training objectives of the game should be clearly defined at the outset in order to concentrate on the parts of the game that really matter and cover the maximum number of teaching opportunities.

Key words: *DRUG EVALUATION; *DECISION MAKING ; *EDUCATION, MEDICAL, CONTINUING; GAMES, EXPERI-

DRUG SCREENING; GREAT BRITAIN MENTAL; ToxIcoLocY/educ ; PHARMACOLOGY/edUC ;

Introduction

The processes involved in developing and evaluating

Correspondence: Dr B. T. Marsh, Medical Director, Leo Laboratories Ltd, Hayes Gate House, Uxbridge Road, Hayes, Middlesex UB4 OLF, England.

a new drug are highly complex and costly in time, resources and money. It is essential, therefore, that the personnel involved in drug research and evalua- tion are aware of the difficulties and problems that may arise in this field. In particular, the medical adviser needs to be aware of the pre-clinical investi- gations and the decisions resulting from these investigations, when considering the organisation of human pharmacological and clinical studies. In 1974, The Association of Medical Advisers in the Pharmaceutical Industry (AMAPI) held a post- graduate training course in pharmaceutical medicine (Marsh, 1976a), which took place on 12 separate days over a period of 12 months. It covered the main areas of drug evaluation, together with certain specialized aspects of a medical adviser’s function. An integral part of the whole educational exercise was a 5 day residential course in which an informa- tion or decision game was played based on the development of a new drug, which this paper de- scribes. By involving themselves in such a game, students were able to gain both practical and theoretical experience in drug evaluation without recourse to the laboratory or to patients. They were able to design animal and human studies and obtain results from these studies in a structured pattern, so building up a dossier of information on which courses of action could be discussed and decisions made and implemented.

(A) Objectives

The main teaching objective was to stimulate awareness of the many factors and problems involved in new drug development. This overall objective can be broken down into six subsidiary ones that more accurately describe the concept of the exercise,

0308-01 10/78/0500-0176$02.00 0 1978 Medical Education

Information Game for new drug development 177

namely (i) to encourage original thinking in the field of drug development, (ii) to expose the students to the problems involved in such development and to capitalize on the collective experience of all those present at the course utilizing peer-learning tech- niques; (iii) to support this learning process by a limited amount of didactic teaching; (iv) to generate enthusiasm for the task; (v) to make the learning process enjoyable by introducing a reward mechan- ism (permission to progress to the next stage); and (vi) to develop a deep and broad understanding of the subjects involved.

As far as we are aware, this is the first time that such a simulation exercise has been played in the drug evaluation field.

Principles of game

The student’s objective was to plan and implement a drug development programme for a new compound thought to have good diuretic activity. To do this, students had to ask specific questions and design studies sufficient to define the profile of the drug and satisfy the drug regulatory authorities (and them- selves) as to its efficacy and safety.

A minimal amount of information was provided at the start of the game, namely: (i) structural for- mula; (ii) acute toxicity data (LD6J in mouse, rat and rabbit; (iii) a simple statement that a pilot study in man had shown the drug to have diuretic activity. The game fell into four main sections, each of which had to be fully considered and either completed or at least started before proceeding to the next. These sections were: (i) chemistry, pharmacy and pre- clinical animal investigations; (ii) human phar- macology; (iii) clinical studies preceding marketing; and (iv) marketing considerations.

Sections (i) and (ii) relate to the information required by the Committee on Safety of Medicines for a clinical trials certificate. Section (iii) involves the extra information required for a product licence and may also include section (ii) again. Additional data on non-clinical studies may be needed, of course, at any time.

Starting from clearly inadequate initial informa- tion students were required to submit details of all the studies they wished performed. Each request had to contain fairly specific information on, for example, animal species and numbers, duration of study, dose levels, and route of administration of drug, to allow the organizers to provide realistic

results which were supplied to the students piece by piece. In this way, the students were able to build up a dossier of information on the drug and make decisions on further studies as they went along. Unsatisfactorily designed studies or requests were rejected and reasons for the rejection were given.

Before proceeding to the next section, each group of students had to present their data to the whole course at a plenary session. After completing sections (i) to (iii), each group developed a marketing programme for the drug, indicating how they would present the medical facts to the medical profession. To ensure consistency in the provision of information and results, the organizers worked to a rule book which is described later.

The residential course

The programme was arranged so that adequate time could be given to each of the four sections, which were interspersed with prepared lectures. Thirty-six students attended the course and they were divided into six groups of six students. Each group was asked to elect a chairman and a secretary whose duty it was to pass on requests for information and studies to the organizers and maintain the dossier of information.

A total of eight organizers and tutors, all experi- enced medical advisers in the pharmaceutical industry, were available to give advice to the various groups. The tutors moved from group to group (each group working in a different seminar room) and only interfered when it was obvious that a stalemate had been reached or that a group was unable to proceed further without some help. All queries and requests for studies from the groups were delivered to a central area where they were pro- cessed in the order in which they were submitted.

Each day consisted of a mixture of lectures, group discussions and plenary sessions for presentation of data. There was no fixed time for ending the day’s work and individual groups could and did work late into the night. A ‘post box’ was available for out of hours requests and when it was used, the answers were provided at the beginning of the next day’s work. All the lectures were related to the develop- ment of a new drug. Care was taken that the lectures were given after the period in which knowledge of the lecture contents might influence the students’ requests for information.

178 B. T. Marsh and C. Maxwell

Rule book and drug profile

In any information or decision game it is essential to have a rule book to provide advice and instruction for the organizers. One of the most important factors in any such game is the retention of as much realism as possible. The problem must be plausible, as must the answers to the students’ queries. In addition, to be fair to all groups, the answers must be consistent. Although the majority of requests for information can be anticipated prior to the game, some unexpected ones always arise. A comprehensive and well-thought-out set of rules should be able to cover these circumstances.

The rule book consisted of both prepared (antici- pated) information and rules for generating con- sistent results when prepared material was not available. The following pre-clinical information was prepared before the residential course started : (i) LD6,, for mouse, rat, rabbit, dog and guinea-pig, (ii) sub-acute toxicity for rat and dog at three dose levels; (iii) chronic toxicity for rat and dog at three dose levels; (iv) teratology in mouse, rat, rabbit and hamster at three dose levels; (v) fertility study in rat at three dose levels; (vi) absorption, distri- bution, metabolism and excretion studies in rat, and dog; (vii) pharmacodynamic studies in rat, dog, guinea-pig and monkey ; (viii) human pharmacology, report on site of action in animals and man, and drug kinetics in man; and (ix) stability studies of tablets and injection at laboratory, sub-tropical and tropical temperatures.

The rules also indicated certain arbitrary option points for the provision of specific information. For example, in the toxicity tests, it was expected that each request would stipulate that the drug be administered at three dose levels, and some effort would be made to specify these levels. The organizers could give a different result for each dose level; or two or three identical results if the requested doses fell into the same pre-decided band. Additional LD,,s in other species and data on the pharrnaco- dynamics of the drug were also available but only provided on receipt of a specific request. In the teratology section, results were available for four species of animal and thus students only received results for the species of animal they requested. Certain other data was only given (on request) after human studies had commenced; chronic toxicity data for example fell into this category, since in the real-life situation such studies take between 6 months

and 2 years to complete. Finally, the organizers had the choice as to which groups of students were to receive two cases of agranulocytosis used to illustrate the problems of recognizing adverse reac- tions in a clinical trials programme. There were virtually no option points in regard to the clinical studies. The profile of the drug was clearly and tightly defined in a deliberate attempt to simplify the organizers’ task in generating results for the studies submitted by the students.

An important and unique feature of this particular game was the use of ‘absolution sheets’. It was anticipated that reasonable requests for informa- tion would be made although the organizers would not wish, for logistical reasons, to provide that information, e.g. manufacturing procedures, flow charts, chemical specifications, etc. Such requests were answered by giving an ‘absolution sheet’ stating that the request was both reasonable and necessary and should be included in their submission. In this way, the organizers ensured that each group was aware of the information required by a drug regulatory authority, without having to prepare material not necessarily in the province of medical advisers. These sheets were mainly used in the pre- clinical phases although they did provide a face saver if the organizers had forgotten any essential point in preparing the game.

The design of the clinical studies was left entirely to the individual groups. The results were generated by the organizers and prepared in the form of a summary, briefly outlining the responses and any side effects. For the initial clinical studies, three protocols were required. Depending upon the results from these studies, two further detailed studies had to be devised, aimed at eliciting the main profile of the drug. On receiving the final set of results, sufficient information overall should have been available to draw up in outline a medical brief for the medical profession and to present this brief at a plenary session.

The aim of all the pre-clinical, human and clinical investigations was to elucidate and define the pro- file of the drug and its safety. Clues were given in the game to indicate that the drug had the following profile: (i) it was an extremely powerful ‘loop’ diuretic; (ii) the urinary excretion of potassium was nil; (iii) it had a marked, dose dependent, hypo- tensive effect; and (iv) there were, generally speaking, no side effects or adverse reactions except that agranulocytosis would appear in one in 750 patients.

Information Game for new drug development 179

The overall incidence of side effects was set at nil simply to reduce that number of variables in the time allowed for the game. However, the organizers did want to emphasize the need to look for and recognize adverse reactions or side effects that had major importance.

The incidence of agranulocytosis was set at I in 750, since it was anticipated that the total number of patients included in all the studies devised by the six groups would be in the order of 1500. Two of the six groups were, therefore, arbitrarily assigned one case of agranulocytosis. The Occurrence of this effect would, we thought, emphasize the difficulties in fully defining all the possible adverse reactions of a drug in the clinical trial stage. For example, the incidence of blood dyscrasia following the administration of chloramphenicol has been esti- mated at between 1 in 10,OOO and 1 in 100,000 (Alstead & Girdwood, 1974). It is unlikely that any antibiotic would be administered to 10,000 patients in the clinical trial stage. Recognition of an adverse effect with this incidence (providing animal toxi- cology was clear) could only come some time after marketing the drug and its use in many thousand patients .

The game in practice

The total time spent playing this game was just over 4 days. The programme ran to a fairly tight schedule, and the groups had to organize themselves efficiently to be ready to present their data at the appropriate plenary session. Although crises, both minor and major, did arise, all groups completed the programme on time.

The course and the game produced a vast number of teaching opportunities for both didactic and peer- learning methods. We believe that many such opportunities were well exploited, especially when experienced tutors were present amongst the working groups. Alas, we also realize that many valuable opportunities were lost. That is, perhaps, inevitable in a tightly run course of this nature.

The first of the option points was the selection of dose levels for the sub-acute and chronic toxicity studies. Applying certain rules-of-thumb, some groups selected inappropriate dose levels but recognized this from their results and they then set about designing more suitable studies. One group asked for ‘fullest information’ without specifying

any further details. In this case, the organizers insisted that they must name the species, dose levels and route of administration at least; they then dealt with the problem most competently. This simple manoeuvre at an early stage in the game allowed the organizers to impress on this particular group what they wanted without being unfair to the other groups who had asked more proper questions. Overall, the toxicology was well handled although some queries on methodology were raised that the organizers did not feel competent to answer themselves. A lecture was given by an expert in this field and this provoked one of the most interesting and valuable discussion periods of the whole course. Hopefully, the question on methodology was answered to the group’s satisfaction.

When it came to clinical pharmacology and clini- cal trials, the students came into their own. A wide variety of shrewd, ingenious, scientifically sound and ethical trials were proposed. The rule book defined three major aspects of the drug profile for the students to identify - the diuretic effect, an important hypotensive effect and a serious, but almost impossible to discover, adverse reaction (agranulocytosis). All groups successfully designed studies to identify the therapeutic effects and com- mon side effects in volunteers and patients.

Some groups looked specifically at the hypotensive effect of the drug using the classical hypertensive patient for their study. Other groups used a homo- geneous population of patients to maximize their chances of demonstrating a specific diuretic effect. By doing this, they denied themselves the oppor- tunity to define clearly the hypotensive effect and learnt the leasson that different patient populations may react differently and reveal important additional advantages in a drug.

Two groups were each presented with one case of agranulocytosis. One of these was, in addition, con- founded by the concurrent administration of a drug known on rare occasions to cause such an effect. Neither group recognized this adverse reaction as a true drug effect, although one group did draw attention to it as an adverse reaction at a plenary session. What was astonishing and inexcusable, however, was that the other group did not report it at all. The general and specific discussions that took place when the second case was revealed were most illuminating and beneficial to everyone. This incident alone probably justified all that had gone on in the preceding days. The students are now well

180 B. T. Marsh and C. Maxwell

forewarned and their experience playing this game has demonstrated dramatically the dangers of missing such a serious adverse reaction and the ease with which this can happen.

Discussion

There is an increasing awareness of the need for more realistic techniques in the teaching of medicine, and simulation exercises are one approach. A computer- ized simulation exercise, called Instant Experience in Clinical Trials has shown itself to be both a useful teaching aid and fun to play (Maxwell et al., 1971 ; Maxwell et al., 1972). Instant Experience provides both practical and theoretical experience in designing and analysing a clinical trial without the need for patients. Its main disadvantage is a certain rigidity of the computer programme, and the need for the organizers to understand computer techniques and have access to a computer (Marsh et al., 1975).

Information games, however, are more flexible and therefore have a wider application. The game can be as long or as short as the organizers desire, and can be rigidly structured or free-floating. All that is necessary is that the game is designed in such a way that the organizers have a planned series of responses to the questions asked. If a specific out- come to the game is required, rather than a consensus of opinion or the stating of various options, the organizers must ensure that the problem is answer- able by a logical sequence of questions and answers. The use of a rule book and preparation of material prior to the course are essential (Marsh, 1976b). This particular course, using the information game, appeared to be remarkably successful. The partici- pants found it enjoyable and stimulating, and some very important teaching opportunities were exploited to varying degrees. Nevertheless, it is open to debate as to whether such games, expensive in time and manpower fully justify themselves as teaching aids (Maxwell, 1976).

With the increasing complexity of drug research it is rare for one person to be involved in the whole process of new drug development. The game pro- vided a unique opportunity for the student to become totally involved in his own group’s submission and to make decisions not normally within his province. It taught him the complexity of the problem, some of the pitfalls, and the ‘language’ used in some areas of pre-clinical research. The response of the students

was overwhelmingly favourable to this type of game and it is one they would like to see repeated.

We made a serious mistake at the onset by not defining clearly and unambiguously the particular training objectives of the game and the course. Due to this omission, several important teaching opportunities were missed or not fully exploited. There is no doubt that a game such as this will always generate enthusiasm and enjoyment, but without a clear statement of the objectives, it is impossible to control and concentrate on the parts of the game that really matter.

From the organizational point of view, several clear lessons were learnt. The most important one was the need for one full-time tutor for each group so that a rapport can grow up between the group and their tutor, with problems being answered or at least anticipated at an early stage. The second important lesson was the need to have more course organizers: on this course there were three, one acting as the administrative coordinator and not being involved with the game itself. In retrospect, at least two other organizers would not have been excessive considering the amount of information that was provided, the need to chair plenary sessions and the need to ensure that teaching points were fully dealt with.

The areas we chose to contain ‘option points’ (sub-acute and chronic toxicity dosages, human volunteer studies and the design of clinical trials) were successfully discussed. On the other hand, it is impossible to assess how much the participants learned in the other subjects such as pharmacology, pharmaceutics and metabolism. It is also impossible to assess whether any wrong learning occurred.

If it is not possible to provide sufficient experienced tutors for each working group, suitable expert lec- tures should be given earlier in the programme. While there is a real risk of groups designing their studies leaning heavily on the information provided by the lectures, skilful design of the game and sup- porting material can overcome this problem. All is dependent upon a clear statement of the objectives and the judicious mixing of heuristic and didactic teaching methods. A major problem in the area of pharmaceutical medicine is that every situation is likely to be sufficiently different from the last one to put a premium on experience. Simulation exer- cises, whatever their failings, at least give the oppor- tunity to gain some experience, without suffering the disastrous results of a wrong decision.

Information Game for new drug development 181

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