If the individuals who approve and supervise clinical development plans are conservative, they will not wish to take chances with the plan they endorse. This type of senior manager will tend to initiate most of the clinical trials that can be justified. This is often a positive characteristic and usually leads to eventual approval of regulatory submissions. The essential question, however, is whether fewer clinical trials could be conducted with the same or better (i.e., faster) results?

Unless two (or more) groups within the same company (but at different geographical sites) work in harmony and collaborate on a unified plan, there will usually be repetition of trials and gaps and, possibly, results that raise questions and slow the program’s progress. The standards of clinical trial conduct for trials sponsored by each site may vary greatly. Some trials may be designed, conducted, or monitored at an inadequate standard to meet regulatory requirements in countries where the dossier will eventually be submitted. Effective collaboration will prevent this problem from occurring.

Not only are poorly designed clinical trials unethical, but also they do not make sense from a business perspective. They waste resources, raise unnecessary questions that must be addressed, and can cause a company to spend years to learn an answer that could often be learned in months. One of the most flagrant examples of this is the use of open-label designs for Phase 2 pilot trials, but there are many others.

Some drugs are developed using a spontaneous seat-of-the-pants approach or at least using a plan that has not been adequately thought through. The most egregious example is of choosing an inappropriate indication to pursue (for any of a myriad of reasons), although there are numerous other examples. These include:

To be able to conduct more clinical trials with a fixed amount of resources, it is necessary to improve one’s planning, efficiency, or both. To improve planning, it is necessary to differentiate among clinical trials that provide essential information and will achieve registration in the shortest period and those trials that are thought to provide useful information. A streamlined strategy of focusing on the former group of trials, which will reach the go-no-go decision points and regulatory submissions most rapidly, will conserve resources that otherwise would be used to evaluate less important patient populations or indications but that would not be sufficient to carry the drug to market if the primary indication should fail. Trials that provide useful information include those that should be completed prior to launch or shortly after launch (e.g., marketing comparisons, cost-effectiveness trials), as well as trials that are rarely necessary for the sponsor to conduct (e.g., quality of life trials on a breakthrough drug).

A basic clinical plan does not include those trials a group wants to conduct purely for scientific interest, but rather only includes those trials the group knows it must do to achieve their goals. It is nice when these two categories of clinical trials are identical. The group must then resist the temptation to deviate from this plan, unless there is overwhelming agreement that a deviation is appropriate. If a tangent is a good one, then it will become the new main route.

The art of planning multiple clinical trials to accomplish numerous objectives is far from perfect. It is so far from perfect, in fact, that careful scrutiny of most plans reveals numerous approaches that could have improved efficiency. Most importantly, this observation need not be made in hindsight after various blunders have occurred. From viewing the plans of clinical groups from many countries presenting information formally at professional meetings or while reviewing licensing drug opportunities, it is clear that the plans contain serious flaws.

Certain pitfalls are so obvious and apparent that it is incredible that companies seem to continually fall into them. One of the most obvious errors is to conduct open-label clinical trials as pilot trials in early Phase 2, and a second is to use active drug controls when a placebo or a low dose of the test drug could be used as the control, or as an additional control group.

Almost every company has been approached by numerous others offering drugs for licensing or even sale. In many cases, anyone’s interest would be extremely high based on exciting preclinical data. But if poorly conceived clinical trials were conducted, a company’s overall interest would decrease markedly or vanish. The author has seen numerous cases where well-known companies
have so messed up a drug’s development that virtually no effort could save what might have been an exciting new drug. This statement is based primarily on a large number of poorly designed and conducted clinical trials that led to problems which would have to be explained to regulatory authorities.

The great irony in this area is that it usually takes less time and less money to conduct an appropriate clinical program than it does to conduct a skimpy one. The latter approach is sometimes followed by a company in the hope of learning from a regulatory authority what deficiencies exist in its application. They can then go back and conduct trials to meet their objective.

Regulatory authorities are conservative by nature and must review all major submissions at several levels within their hierarchy. Therefore, a balanced but conservative clinical development program must be implemented by a company for the majority of new drugs. When a regulatory submission is made, the sponsor should be confident that it will not be challenged by a regulatory agency in a major way, although one often faces surprises from regulators.

Companies should not conduct clinical trials outside their development plan without substantial reasons. Scientists or others, both inside and outside a company, are always suggesting novel clinical trials to explore indications or alternatives to the agreed-upon plan. Extreme care must be taken to prevent negative tangents from diverting activities in inappropriate directions.

Some companies routinely plan and conduct many defensive trials and studies (e.g., in toxicology, in metabolism) to obtain data that could be used to answer questions posed by regulatory authorities. There is a balance between conducting studies to answer potential questions that almost certainly will be asked and conducting an excessive number of studies to provide data that are unlikely to be requested. Senior executives must select which trials and studies are to be done. There is a great deal of guesswork involved, but the most important principle is not to spend time and resources conducting trials and studies that are highly unlikely to provide essential data.

The approach that works best to address this issue is to determine the following:

In order to adequately address this issue, it is necessary to have content experts review the protocol elements to help address these questions.

Ensure that all investigators are aware of the trial’s details, pitfalls, and complexities and that it fits their practice and/or they are pleased about conducting this trial. The more exiting the drug is, the less overage will be necessary; and, the closer the drug is to being judged as a “me-too” drug, the more investigators will be required. In addition, the better the assessment is of potential patients who are likely to enroll, the fewer additional investigators will be needed.

Inclusion criteria decrease the available pool of possible patients from whom to find those to recruit and enroll, from 100% to a smaller number. The more restrictive the inclusion criteria and the more criteria that are included, the smaller the size of the potential pool of patients becomes. (Exclusion criteria are assumed to be inclusion criteria expressed in a different way.)

One desires a fairly homogeneous population in Phase 2 studies to answer the question of “Does this product work as anticipated in the patients for whom it is intended?” This means that one should utilize the fewest and least restrictive inclusion criteria that are consistent with this goal. Making the inclusion criteria too loose may make it difficult to collect clean data from the subjects whose responses one wishes to measure. On the other hand, too strict inclusion criteria may make it too difficult to recruit subjects and there may be important types of patients who are excluded from participation.

Each company should have a library of case report forms (CRFs) that are used for all clinical trials. There will undoubtedly be a few CRFs that will have to be created for most specific trials. These should all be in portrait format for ease of entering data into computers. While one must not collect more data than required, the number of pages (whether in paper or electronic format) is secondary to being complete, so do not force too much information onto a single page. Consider broad questions instead of many detailed ones. For example, ask whether the subject is eligible rather than listing whether the subject met each of the individual entry criteria. Do not standardize CRFs by phase of development but, instead, by therapeutic or disease area. The number of CRFs can be very minimal in large mega-trials where a simple question is being addressed.

Although protocol amendments are an “accepted fact of drug development,” every effort should be made to try to eliminate or reduce their number as much as possible. This means that one must focus on doing things right the first time. There is no excuse for using the army’s motto: “There is never enough time to do it the first time, but there is always enough time to do it over.” Rushing a trial’s protocol often leads to flaws and subsequent protocol amendments that slow a trial’s eventual timeline. Having a set of questions with which to review one’s own protocol is essential (see Chapter 62), and having an excellent protocol review committee is another step to increase the likelihood that the protocol will be “bulletproof.” Two other approaches that the author believes have great value is to use external consultants who are expert methodologists or use a company that specializes in assuring companies that their protocols have no internal inconsistencies (e.g., Fast Track Inc. and their “Disambiguation” procedures).