The Optimal Blend: The Approved Synopsis and the Final Protocol

The main objective is the rapid realization of a final protocol that accurately meets the development objectives, reflects the results of protocol feasibility, and can be implemented without unnecessary amendments. To recapitulate, the steps to an approved protocol are as follows: 1. The approved draft protocol synopsis. This is the penultimate version of the core of the final protocol and is used to assess protocol feasibility, as described in chapter 4. 2. The approved protocol synopsis. The synopsis has been amended as appropriate to ensure optimal feasibility without diminishing the validity of the study and has been approved. At this stage, the protocol is, in effect, locked and ready to be implemented. 3. The approved final protocol. This step involves incorporating the contents of the approved protocol synopsis into the template for the full version of the protocol and having it approved for completeness and consistency. Unfortunately, approval of each step is essential, with its implications of time-wasting micromanagement, formality, pedantry, and bureaucracy. How to minimize these aspects while ensuring that the essential value of the approval process is maintained is described later in this chapter. But first, we review the final steps to the definitive protocol. The only difference between this version of the synopsis and the draft synopsis is that all changes resulting from the feasibility process have been incorporated. The protocol is now complete from a purely operational perspective. That begs the question: “Why go through the process of approving this version and not just go on to the full, definitive protocol?” The reason is that it is much quicker and simpler, and less likely to lead to inconsistencies, to amend the draft synopsis and get on with all that can be done, without having to wait for the full protocol or having to plow through all the redundant (from an operational perspective) material it contains. The synopsis and the protocol have differing important functions, so that finalizing both as soon as possible is a priority.

Planning the Individual Clinical Trial

All sites should be ready to enroll by the planned study start date. Realistically, this can only be achieved if the process is initiated 52 weeks before the planned start date. The components of each step and the associated timelines are described below. There may be considerable overlap of these steps, and the time needed to complete each one can vary greatly from project to project or study to study. This chapter gives an overview of the key activities and their timelines; details of how the activities are carried out are described in subsequent chapters. As always, these are guidelines, and flexibility is the key. Timelines are defined by the activities that need to be carried out and the time each activity will take. Some of these activities are necessarily sequential, as the next activity cannot start until the previous one has been completed. Some of these rate-limiting activities are defined as milestones, and time to their successful completion is used as a relative measure of efficiency. Metrics have a valuable role to play in process improvement, but a potential drawback is that people will concentrate disproportionately more effort on achieving what they know is being measured, sometimes to the neglect of other activities. It is therefore essential that what is being measured be a true and important measure of efficiency. One of the most popular metrics to measure the efficiency of the clinical trial startup process is how short the time is between availability of the final protocol and when the first patient is randomized, the shorter the better. This metric, so often quoted, is the most useless and misleading because the completion of the study depends not on when the first patient was randomized but on when the last patient was randomized. The mad rush to enter the first patient is therefore a futile endeavor unless everything is in place to ensure that all, or most, sites can start randomizing patients by the planned start date.

The Brain-Scrambling, Fit-Inducing, Mind-Numbing Technicolor Laser Show

The main objective is to make presentations less painful and more presentable. Presentations are made in order to provide information to an audience in such a way as to achieve a desired objective, whatever that may be. The objective is unlikely to be achieved unless the audience • wants to listen; • remains interested; • understands; • is convinced. A natural talent for presenting material effortlessly in an informative, entertaining, and engrossing way is shared by few, so most of us put disproportionate reliance on props. The most commonly used props are slides and pointers. Unfortunately, the use of slides and pointers has almost become an end in itself, often obscuring the message. As with all the processes described in this book, the aim here is to apply a core of common sense. This will not address every aspect of the use of slides and pointers or result in the perfect presentation every time (something even the most comprehensive manuals and training courses rarely achieve). What should result with consistency is more clarity and comprehensibility, and less frustration and confusion, all of which should serve to keep an audience from losing interest and fiddling with their cell phones after five minutes. Why use slides? After all, the greatest orators of all time managed to keep audiences spellbound with long recitations (just think of Homer and the Iliad) without using any props or prompts. Okay, so their audiences didn’t have TV or many other alternatives for entertainment, but that does not detract from the underlying principle, namely that audiences are generally primarily interested in what the speaker has to say, not in the props. After all, why else go to a presentation when information is so widely available today in many forms, especially electronically? The question may be answered by thinking about the good reasons for using slides. This is a common reason for most presenters, especially in situations when there is new, lengthy, detailed, or complicated information. Just as presenters have difficulty remembering detailed information, so audiences need time and different types of input (visual, as well as auditory) in order to assimilate new details.

Redistillation: Eliminating Impurities by Carrying out Protocol Feasibility

The main objective is to make sure that a protocol designed by a committee can be carried out in the real world. Protocol feasibility is the process for determining whether or not a proposed protocol is practicable from ethical, patient, and medical practice perspectives. If not, the next step is to determine which parts need to be amended to make it practicable without undermining the objective of the proposed study. Once the operational core of the protocol has been drafted, the next essential step is to find out if there are any aspects that are either completely impracticable or impede the conduct of the study unnecessarily. Finding the balance between the fully loaded protocol that could, if the study were ever finished, provide the perfect answer for a tightly defined population, and the minimalist protocol that, although easy to carry out, might be too nonspecific and even put patients at risk, is largely an art dependent on experience. There are, however, many objective measures that can be taken to reduce uncertainty to the minimum possible. This process is called “protocol feasibility.” The term means exactly what it says (finding out if it is possible to carry out the study described in the protocol), but it has frequently become confused with or combined with other study startup activities that have nothing to do with protocol feasibility, to the detriment of all of them. Even when the term is understood, the process for determining feasibility is rarely performed rigorously in practice. Protocol feasibility includes the collection of all relevant information to determine whether or not the protocol can be carried out as planned, with subsequent modification of the protocol to bring it more in line with reality. Although most of the effort of protocol feasibility is concentrated at the site level, because the major factor is whether or not patients conforming to the protocol selection criteria actually exist in numbers large enough to make the study possible, country-specific aspects are also important and should be included in the feasibility process.

Aiming for Excellence

Clinical trial processes are what we repeatedly do in clinical research, but, unfortunately, the habit of excellence is not as prevalent as it might be. Processes are only as good as the ways in which they are carried out, so this aspect is worth looking at before examining the processes themselves. Excellence means the very best that is achievable in a given situation with the knowledge and resources available, and it is not to be confused with perfection, which is rarely attainable, and trying to achieve it is a waste of time. Although the rational implementation of the various approaches described later can help to make the clinical development process significantly more efficient, this will not in itself achieve excellence. Implementation needs to take place in a cultural, intellectual, and operational environment that lends the necessary support. There are many possible components of such an environment, but one can go far by • instituting some basic behavioral elements; • doing things as well as they can be done all the time; • simplifying processes; • not allowing regulations to develop into liabilities. I have included this section risking that it might be considered unnecessary and patronizing by some. After all, everybody believes that their behavior is impeccable, just as everybody is a perfect driver. It only takes a few people to behave badly to poison an organization (or to injure others). . . . Laws control the lesser man. Right conduct controls the greater one. . . . . . .—Chinese proverb. . . . . .Good behavior is the last refuge of mediocrity.. . . . . . —Henry S. Haskins, stockbroker who was expelled for alleged misconduct and published his aphorisms anonymously. . . Can principles be applied that encourage positive, ethical, complex, and intelligent behavior without retreating into the lowest common denominator of mediocrity? One can argue the extent to which principles can help to achieve these objectives, but what is undeniable is that, in their absence, the results can be extremely damaging. This is exemplified not only by the poor performance metrics but also by the poor reputation of the pharmaceutical industry in the public’s view.

Clinician or Clinical Trialist: The Physician’s Dilemma

The main objective is to help physicians carry out those aspects of clinical trials described in this book. . . .Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). . . . . . . —[ICH-GCP 2.8]. . . It is hardly rational to expect people to do things properly unless they are shown how, so that the importance of formal training and education for everyone involved with the pharmaceutical industry should be self-evident. The perpetuation of bad habits by those who are poorly trained and educated, whether in pharmaceutical companies or at investigator sites, is one of the root causes of the inefficiencies in drug development. Yet, while few people (whether or not they actually educate people properly) would dispute the importance of well-trained employees, it is uncommon for most companies to insist that all of those upon whom they depend are properly trained as well. Among those who are rarely trained to meet the required standards of excellence are CRO staff and investigators and their site staff. Negotiations with CROs rarely involve an assessment of how the various tasks are performed and whether or not they are carried out to the standards expected by the sponsor staff. This is not to imply that sponsor employees are better at what they do than CRO staff. What is true, however, is that sponsor employees should know how to do things the way the sponsor wants them done, which in turn should correspond to the sponsor’s notion of excellence. CROs will always profess to have all the processes requested by a sponsor, so that a laissez-faire attitude pervades negotiations. However, CROs quite understandably have their own ways of working, and unless alternatives are specified contractually, what the CRO does is what the sponsor gets. The next logical step after specifying what is wanted is to provide the necessary training for CRO staff. Where education and training are most needed and are carried out most poorly is in the case of clinical trial investigators.

Of Chickens and Eggs: The Sponsor’s Dilemma

Q. Which comes first, the sites or the patients? A. The patients. Find the patients and the sites will follow. The main objective is to select only those sites that have definitively identified the required number of study-specific patients. To ensure that objective, whenever it is feasible, these patients should be lined up and ready to be enrolled before the sites are initiated. Screening is the means for identifying potential volunteers for a trial by assessing whether or not they satisfy the inclusion, exclusion, and other relevant criteria for a given study. Screening and identification can be carried out long before a study is scheduled to start. Recruitment is the formal process of getting agreement from patients that they will take part in a study and getting their informed consent. Patients who give informed consent can then be enrolled in the study. Some procedures to determine eligibility may need to be carried out immediately before enrollment, so the fact that a patient has been recruited does not automatically indicate that the patient will be enrolled. Enrollment is the process of entering a patient who has given consent into the study by carrying out whatever initial procedure is needed. The initial procedure may be randomization, a run-in phase, or dosing if the study is open label. . . .If the matter is one that can be settled by observation, make the observation yourself. Aristotle could have avoided the mistake of thinking that women have fewer teeth than men by the simple device of asking Mrs. Aristotle to keep her mouth open while he counted. . . . . . . —Bertrand Russell, philosopher. . . Everyone is aware of the uncertainty and inefficiency that characterize clinical research. It is therefore hard to explain why those few aspects that can be quantified with some degree of accuracy and certainty continue to be the very ones that are usually approached subjectively and irrationally. No two aspects illustrate this paradox more vividly (and no two aspects are more responsible for time delays, wasted money, and poor data) than poor clinical trial site selection and inadequate patient screening and identification before the study starts.

Distilling the Essence of the Protocol: The Protocol Synopsis

The main objective is to get the preparatory phase of the trial, especially protocol feasibility, up and running as rapidly and efficiently as possible. The protocol synopsis is the most important document for ensuring a successful trial. It comprises all the elements essential for planning and carrying out a clinical trial, and is quicker to write, easier to read, less likely to have inconsistencies, and much easier to modify than a full protocol. A protocol synopsis is usually between five and seven pages long, whereas a typical protocol can run from 60 pages (rarely fewer) to 100 pages (sometimes more). The synopsis is therefore the ideal document to use for all the early preparatory activities, as the full protocol adds no value for planning and operational purposes. A fairly typical protocol synopsis template is shown in the appendix at the end of this chapter. The first step is to get an approved draft protocol synopsis. This version of the synopsis should be as complete as possible in every respect, except for those changes that will need to be made as a result of feasibility testing. It is, in effect, the penultimate version of the core of the final protocol. It should go through as many iterations as needed until it reaches the stage at which it can be approved, pending feasibility. At this stage, all aspects relating to the objectives, design, endpoints, investigations, lab tests, and treatment and procedural schedules should be final; otherwise, doing feasibility is a waste of time. This chapter describes how to get to the approved draft protocol synopsis. There are then two more steps that will be described in detail in the following chapters. The second step is the approved protocol synopsis. The draft synopsis has been amended as needed to ensure optimal feasibility without diminishing the validity of the study and has been approved. At this stage, the protocol is, in effect, locked and ready to be implemented.

Introduction: Cutting the Gordian Knot

Time and money have always been important, intertwined factors in the context of drug development, but never more important than they are now, especially time. There are many reasons why. Competition has never been as keenly felt. Fewer, larger companies spend huge amounts of money on research and development (R&D) and, for the most part, have the same targets. Worldwide, first launches of new medical entities (NME) are decreasing. In the 10 years from 2001 to 2010, the number fell from 31 to 21, and only one-third of these launches were by major companies, defined as those spending more than two billion dollars on R&D in 2009 (2011 CMR International R&D Factbook). Investment in innovative biotechnology has done little to change this so far. Market exclusivity (meaning the time during which a new entity has no competition on the market) has diminished to the point of being weeks, rather than the 10 years enjoyed by Imperial Chemical Industries (ICI) with the first beta blocker. A recent estimate for the loss of revenue for each day that a drug is in clinical trials is between $600,000 and $8,000,000 (J. Hess and S. Litalien, Cutting Edge White Paper). The five-month market advantage that celecoxib had over rofecoxib was worth between $500,000,000 and $750,000,000 and established a competitive edge that was never lost. So it doesn’t take a genius to appreciate the importance of time above other things because, unlike other things, time can never be recovered. Given these pressures, it would seem that making any improvement that would give a competitive advantage would be a priority. Although all the elements of drug development, from discovery to regulatory submission, are interdependent and important, the clinical phase of development is crucial for success or failure. Everything else becomes irrelevant if clinical benefit for the patient cannot be demonstrated. The careful, efficient management of this phase is essential to ensure that reliable data can be generated rapidly and cost-effectively. It should come as a surprise, then, that performance measurements for the clinical trial process show a continuing and steady worsening. A good dose of antidepressants is needed to be able to read them with equanimity. This is a small but relevant sample: •About 80% of trials do not meet their original enrollment times. (J. Hess and S. Litalien, Cutting Edge White Paper).

About Time: Making Meetings Matter

The objective is to ensure that meetings are both efficient and effective. It is possible to be efficient without being effective and vice-versa. Most people acknowledge that meetings, especially formal, routine, scheduled meetings, waste more time than any other business activity. Time is wasted for two main reasons: redundancy and inefficiency. Often, meetings substitute random motion for useful activity, serving no more purpose than to mask indecision by deferring and diluting the decision-making process. Even when there is a genuine need for a meeting, time during the meeting is often wasted because of poor preparation, inappropri­ate attendance, unprofessional meeting behavior, and lack of follow-up. Pithy sayings, some centuries old, denigrating the value of committees and meetings, underline the ubiquity of the problem. And yet, meetings continue to be held and probably always will be, so it is as well to try and make them as efficient and effective as possible. The responsibility of every attendee for making a meeting as efficient and effective as possible is rarely considered or practiced. The way in which individuals behave in meetings is not only the major cause of time-wasting and inefficiency, but also provides unexpected insights into how apparently responsible people think. So what if I arrive late, I haven’t read the briefing material, I don’t listen attentively, I answer my phone, I read my e-mails, and send text messages? I may join in endless discussions on subjects about which I know nothing, chat with the person seated next to me, take too long to present my section, and leave early, but who cares? After all, isn’t the chairperson responsible for running the meeting? This section specifically addresses the typical, common, routine meetings related to drug development, at whatever the hierarchical level, in which data are presented and strategic and operational decisions are made. However, most of the principles described apply equally to most types of meetings. Good planning and preparation are the foundation for efficient meetings.