In situations where class labeling is required, new investigational drugs and medical products must adhere to the class label. There is limited ability to modify the label to suit the company’s specific focus. Fortunately, most drugs are not in this restrictive situation.

Except in rare cases, companies prefer to obtain the broadest and most general label that can be negotiated with a regulatory agency, as this has great importance from a commercial perspective. The company’s approach is to try and negotiate an acceptable label with regulators by gradually accepting more and more restrictions, whereas regulators often adopt the opposite approach by starting with a highly restricted label and gradually loosening their position, as the company provides data that support a broader label.

If a drug is studied in patients on ancillary therapy or in patients with a certain history of previous treatment, or if the subjects in the clinical trials had known risk factors, then the agency is likely to require that those restrictions be present in the label. It is difficult to justify allowing the drug to be used in a broader patient population than was tested in pivotal (or other) clinical trials and in specialized trials conducted in specific groups of patients (e.g., the elderly, renal impaired, immunocompromised). Yet, that is exactly what many companies usually expect the regulators to agree to.

Companies should be pleased that short-term studies of several months’ duration have usually been sufficient to obtain chronic labeling for a patient’s entire life. This is gradually changing as studies of one to two years are being required more often to obtain chronic labeling. The author supports this trend as both medically and scientifically sound, as well as ethically required in some situations.

One benefit of preparing a draft label is that it can be stored electronically and be readily accessed and reviewed by staff in research and development and marketing and by senior executives. This helps to ensure that all professionals are comfortable with the anticipated or desired outcome of the development program and with the projected product profile. Often, a draft data sheet will be created, based on marketed products sold by competitors or the company itself. In that way, one can try to focus on areas where the “label” for a new drug will reflect hoped-for improvements in safety and/or efficacy.

However, while there are a number of reasons to support this practice, the author personally thinks it is not only a significant waste of time and resources, but it complicates product development as well. One has to ask whether this practice offers any advantages under circumstances where relevant professionals in each department or division of a company are (or should be) fully aware of the drug’s progress and the evolving clinical, regulatory and marketing plans for its development.

It is important to stress that development issues or problems being addressed in these departments are not generally listed as part of a draft label. However, they are the very core of what has to be addressed by the project team and to be monitored and reviewed by senior executives.

So, who actually benefits from having a draft label? Of course, the marketing staff must be in agreement that the clinical profile is one that is acceptable for the product’s commercialization and that the value of the product warrants continued development. But the author doubts that they need a draft label to be fully aware of the current status and profile of the product.

A company that has a sophisticated and well worked out and agreed upon set of criteria that must be met in order for development to continue will hopefully be using “minimally acceptable criteria” and not a set of “desirable” or “realistic criteria” (see Chapter 50). Yet, it is the latter two types of criteria (i.e., desirable and realistic) that are invariably used as the basis for creating a draft label.

It would be totally unrealistic and unwise to create a draft label using minimally acceptable criteria, since the company’s true goals and expectations are much greater. The anticipation is that the product will have a clinical profile at the end of the investigational period that is closer to the “desirable” set of criteria than those that are minimally acceptable. From another perspective, using a realistic or desirable product description may have a dangerous selfdelusional effect, whether conscious or not, by influencing the interpretation and extrapolation of data from clinical trials. In other words, seeking more positive interpretations of results than are justified by the data could become a self-fulfilling prophecy.

It is, therefore, better to prepare the first draft label sometime during Phase 3, when there is sufficient time to have it prepared, reviewed and approved prior to submission.

The company has to decide throughout the development period what criteria their investigational drugs must meet to justify continuation of the program. Without such criteria, they are simply
operating under nonsystematic ad hoc conditions, similar to saying: “Let’s do a clinical trial and see what the results are, and then we will decide if we think the data justify continuation.” A senior manager who may not be the best person to decide about the criteria to advance or terminate a drug is often the very person who makes the go-no-go decision. Even if that senior executive is a physician or PhD scientist, he will be subject to many biases for or against the product that will influence his decision. In other words, many intangibles are likely to play a role in deciding if the data are sufficient to justify continuing a drug’s development.

If the company uses minimally acceptable criteria that the marketing department has helped create to advance a product through development, then it is unnecessary to create a draft label until the regulatory dossier is assembled. Moreover, by having a draft label based on hypothetical, “desirable criteria,” there is the possibility of misleading the staff by generating false hope about an exciting clinical profile that may be unrealistic and will never be achieved.

In deciding on the overall picture to create of the drug’s safety, efficacy, and other attributes, it is similar to looking at a jigsaw puzzle of a thousand pieces all scrambled but face up on a table. Different people will put the pieces together differently and create very different pictures of the drug, some leaving out some important pieces and others not. This picture can also be thought of as separate pictures, each of a different part of the label that will be ultimately sent in to the regulatory agencies and then negotiated with them.

The picture is slowly completed as the individual pieces are put into place. Until the final piece is in place, the picture is not whole. The design chosen by the company is the one that they believe will support their marketing strategy most effectively. Regulators are likely to look at the same individual pieces face up on a table and create a very different picture. This often becomes apparent when a regulatory agency, the media, healthcare professionals, or an antagonistic consumer group makes comments about your product. There is rarely complete agreement on the picture that is created by any of these groups.

The most important principle when assembling the pieces and creating the picture you want to present is to be guided by the most important data available. No matter how wonderful or important a drug, and no matter how straightforward the development plan, there will always be extra pieces that do not fit the picture and others that create undesirable images (i.e., adverse events) in the final picture. It is essential that these difficult to use pieces not be turned upside down or hidden in a corner of the picture. These must be placed so that they are clearly visible and are identified appropriately as issues of safety, efficacy, or another aspect of the overall picture.

Overall, when presenting a drug to a regulatory agency, it is important to remember to maintain consistency in the drug’s story. This is strengthened by the creation of a “core message,” with which the company can attain a “single voice” on the product. Finally, it is suggested to make all presentations to regulatory agencies transparent by making all data visible and suggesting further action before an actual or even potential issue becomes known to the public.

One approach to dealing with loose ends that do not fit the picture created of a drug is to discuss why and how these ends suggest additional studies that should be created to shed more light on the issue. These studies may be proposed to be done during the next phase of development or after marketing has begun. If the data suggest that there are issues that may significantly affect the benefit-to-risk balance, the company may want to suggest limitations on the distribution or use of the product by patients at higher risk of experiencing the problem/adverse event.

This open approach and frequent dialogue often helps to shorten drug development time because it facilitates regulatory review of a dossier and precludes most, if not all, occasions of a regulatory
agency’s finding a “problem” with the submission, which leads to their asking the company to conduct additional studies. It also may minimize the issues that can arise from various groups strongly criticizing your drug by preempting the criticism that the company is not dealing with relevant issues.

Many drugs cause the same or very similar adverse events that are part of the constellation of those associated with the disease itself. It is incumbent on a company to attempt to understand how best to differentiate between these if possible and to provide whatever information and data they are able to collect on this point.