You are the project manager of an important new compound being developed for the US market, but there is the possibility that it will be licensed out for the international market. You have decided that your development plan will consider international requirements. In creating this plan, you are aware that some countries require additional toxicology evaluations, as compared with other regulatory agencies. (While the International Conference on Harmonisation has managed to minimize and, in some cases, eliminate most of the differences in toxicology requirements between regions, they still exist and are difficult to eradicate.) Also, it is known that a regulatory agency in another country usually requires more pharmaceutics data and more pharmacokinetic data in elderly patients.

Does it make sense and lead to greater efficiency simply to design the overall development program at the top level world-wide to avoid problems with various agencies and thus achieve a truly global development plan? What are your thoughts about the global development plans that should be created? What are you going to recommend?

The Food and Drug Administration (FDA) tells your company that they want you to voluntarily withdraw one indication from the labeling of a $500 million a year drug. They claim that there is no medical need or justification for this particular use. This use generates about $100 million per year of the total, and you do not want to withdraw the drug’s use from the labeling and the market; however, the FDA is insistent. What do you do?

Your company has conducted all the clinical trials on the intravenous, oral, and ophthalmologic forms of a new drug and is completing the New Drug Application (NDA) dossiers for submission. The ophthalmologic dossier is far ahead of the others (i.e., oral and intravenous) in its time to completion, but it has a significantly lower commercial potential. The largest market is for the oral form, whose dossier is the most complex and the furthest behind.

How will you decide, as head of the regulatory department, about whether to recommend submitting a single dossier with all three dosage forms, submitting the dossier of the ophthalmologic dosage form first, or adopting another particular order for submitting the dossiers?

Four of the FDA‘s statistics staff have accepted an invitation to tour your facilities in four weeks. They will be spending three days at your site, and you have been asked to be in charge of the tour. How will you organize this tour to show your site to its maximum benefit?

Should you approach a regulatory agency to request a meeting to discuss the development strategy of a new candidate drug that is in a disease area that your company has no experience in? Additionally, what do you do if it is a rare disease that few people have?

Are you asking for trouble by approaching the agency, even though you know that they would like to become involved in the drug’s development? You are concerned that they may request an excessive amount of work or that some of the activities they request will become requirements.

Joint review by the FDA and Canadian Regulatory Agency (Health Canada) may be possible if a company submits its dossiers simultaneously (or nearly so) and/or requests the joint review. You work in the United States as head of regulatory affairs for your company, and you are asked for your opinion about whether the company should seek this type of review for the drug your department has been working on. What will you say?

You are the head of regulatory affairs in the United States of a large multinational company. Over the past two days, you have received 17 reports from your clinical (or safety) department that heard from physicians in a single Canadian province of an outbreak of a single type of serious adverse event, and at first glance, the adverse event appears to be related to your product. The news media have also heard about this and want to send film crews to your offices for some footage for the 6:00 PM news. The Canadian regulatory authorities have not yet been informed about this matter. How will you deal with this if the adverse event is unlabeled? Would you react differently if it was labeled?

A regulatory agency receives many spontaneous adverse event reports each week. All are recorded and tracked. One week, it is noted that three reports state that a three-year-old drug causes blood dyscrasias that are serious but not life threatening. This adverse event is already in the product’s labeling. The regulatory agency mentions the blood dyscrasias in their monthly newsletter sent to all physicians in the country, and over the next three months, about 40 similar events are reported to the agency and in the medical literature.

Your company has two development sites, one in the United States and one in South America. The South American site wants to develop a new mousse formulation of one of your products. The marketing group at the US site has considered this proposal but has no interest in the product. If only the South American site is involved in setting technical specifications for the product, then the formulation and technical development work that has to be done there will not be approved by regulatory agencies in numerous other countries because you know that their facility will not pass a Good Manufacturing Practices inspection. If the US marketing group develops interest at a later date, it is certain that all of the technical development work will have to be redone to meet US standards. All of this work would still have to be done at the South American site because they are the ones with the appropriate facilities. You are a US regulatory director and are asked to prepare suggestions for a high-level meeting to be held on this topic. What will you do and say prior to the meeting?

Your company has decided to resurrect an old drug and to bring it to market for a new indication. Unfortunately, all of the old toxicology studies you can find were not conducted under Good Laboratory Practices conditions, even though the data are excellent and the studies were done quite carefully. How do you handle this situation from a regulatory perspective? What if the original studies were not done very well?

You are the head of regulatory affairs and are told that the regulatory agency in a country where you plan to submit a dossier insists on adverse event reports being assessed with a formal algorithm to establish causality. The specific algorithm that is to be used is not specified by that agency. You are not sure whether your company has used such a method centrally for all adverse event reports or for any of the cases in trials already completed or underway.

You are told by the head of research and development that you should not directly approach the agency to discuss whether the use of an algorithm is definitely necessary and whether a waiver could be obtained from this requirement. What can you do?

Assume that a corporate sponsor assists an academic investigator to obtain an investigator’s Investigational New Drug Application and provides drug to the investigator to conduct a trial that the investigator designed. In this situation, does the sponsor have to monitor the trial, and does the sponsor have to ensure that adverse events are reported to the regulatory authorities?

In designing a global development plan, there are many factors to consider. Knowing that it is impossible to satisfy all regulatory agencies, one must satisfy the largest pharmaceutical markets or those of particular importance to the company. Special requirements of other markets (e.g., Australia, New Zealand, Canada) can be dealt with later, if resources permit and interest warrants.

Some of the major decision factors include the following:

The first step is to find out the basis of the FDA‘s letter and its suggestion. Is it a lack of adequate evidence? Is it an abundance of adverse drug events? Is it excessive off-label use? What are the FDA‘s reasons?

If you believe that the FDA is incorrect in its conclusion, even if the evidence is not in dispute, discuss internally the possibility of collecting data that could support the use of the drug. The data might come from a clinical trial, postmarketing surveillance studies, or active drug surveillance methods. If this approach is possible, then plan to meet with the agency and propose your approach.

If you believe that the FDA is fundamentally correct, then your options must be discussed internally with senior executives from research and development, regulatory affairs, marketing, finance, legal, and corporate affairs, in addition to the Chief Executive Officer and other appropriate executives. You still might suggest collecting additional data to support the indication if you believe that there is a reasonable likelihood that the data would be supportive.