Michael Teitelbaum of the Sloane Foundation, speaking at a National Research Council public meeting on trends in early research careers of life scientists, asked in the open forum whether it would make a difference to entering graduate students if they knew that they only had a 10 to 20% chance of obtaining an academic research position. Clearly, to some it would, but at the same time, this partly reflects the intellectual environment in academic training.
Many academic faculties have a negative attitude toward nontraditional career paths. In fact, early in my career I was told by one department head at a major university that they would only take graduate students headed toward an academic profession.
Current science training also does not direct students toward non-traditional career paths. Generally, the "best" students are steered toward graduate school, then on to an academic career, with little discussion of the other options available. Nor is there a visible pathway for young scientists who would like to choose less traditional careers.
One such alternate pathway is that of regulatory affairs. People go into regulatory affairs for about the same list of reasons people go into science itself. Some just want a job, some have more altruistic reasons (making a difference, helping people), and some are drawn into it and find it rewarding for various personal, intellectual, and professional reasons.
For a scientist, even one without an advanced degree, this field represents a reasonable career alternative to the grant-restricted world of academic science. In addition to using the philosophy ingrained as part of scientific training, specific skills and interests gained during college, graduate school, and/or postdoctoral work can also be critical.
While regulatory affairs can affect the quality of the food you eat, the cosmetics you apply, or the medicines you take, in this chapter I will focus most specifically on regulatory affairs as it applies to the pharmaceutical industry.
What Is Regulatory Affairs?
As a discipline, Regulatory Affairs covers a broad range of specific skills and occupations. Under the best of circumstances, it is composed of a group of people who act as a liaison between the potentially conflicting worlds of government, industry, and consumers to help make sure that marketed products are safe and effective when used as advertised. People who work in regulatory affairs negotiate the interaction between the regulators (the government), the regulated (industry), and the market (consumers) to get good products to the market and to keep them there while preventing bad products from being sold.
The range of products covered is enormous, including foods and agricultural products, veterinary products, surgical equipment and medical devices, in vitro and in vivo diagnostic tools and tests, and drugs (which range from small molecules to proteins). The range of issues addressed is huge, from manufacturing and analytical testing, preliminary safety and efficacy testing, clinical trials, and post-marketing follow-up, to advertising issues, with a healthy dose of data management, document preparation, project management, budgeting, issue negotiation, and conflict resolution thrown in along the way.
Over the years, a complicated system of checks and balances has developed to set in place a process to efficiently and effectively regulate the marketing of products. On the industry side, people in regulatory affairs work with research scientists, clinicians, manufacturing groups, and sales and marketing groups to make sure that the government has the information it needs to judge a product. On the government side, people in regulatory affairs work to interpret and implement laws that Congress establishes to help protect the public. To carry out the congressional mandate, the Food and Drug Administration (FDA) requires pharmaceutical companies to generate and provide all the information deemed necessary to evaluate a given drug, biologic, and/or device with respect to safety and efficacy. This information is used by the Agency to decide whether the product should be on the market-and if so, how it should be marketed and sold.
On the consumer side, people in regulatory affairs help keep the other two groups honest and they provide the stimulus for Congress to enact the laws that regulate how government and industry treat products.
Regulatory Affairs in a Biopharmaceutical Company
Typical functions of a regulatory affairs group in a pharmaceutical company include interacting with regulatory authorities, preparing documents for regulatory submission, developing regulatory strategies, and interacting with company staff. Each of these responsibilities can have major implications on the success or failure of the company.
Interacting with the government is a crucial role within the company that is frequently restricted to the regulatory group. Whenever a company contacts the government, both sides typically document all topics discussed and the issues raised and answered. Funneling all conversations through the regulatory group prevents different people from making commitments to the government that are not fully known by the rest of the company. Typical topics for discussion include the planning of meetings, the format and content of documents to be submitted, the intended dates of submission of documents, the design of preclinical and clinical studies, changes to pre-clinical or clinical protocols, chemistry and manufacturing issues, adverse events (expected and unexpected) that occur during preclinical or clinical studies, labeling issues, international issues (permits, inspections of foreign sites, foreign regulatory actions), and other topics specific to the studies or products under discussion.
Preparing documents for regulatory submission is probably one of the most widely known functions of an industry regulatory group. Classic pictures of regulatory affairs groups often show them surrounded by steep piles of paper that cover dozens of tables as they prepare to submit an NDA (New Drug Application, asking for permission to make a drug available as a product). In fact, this is a monumental task (pictures don't lie), but it typically is preceded by years of previous submissions and months of work.
Most of that pile of paper on the tables was probably already submitted to the government in one form or another-at least if the company was smart. Realistically, this NDA, which usually represents about a decade of work at the company, has been preceded by dozens of previous submissions, meetings, and discussions, all of which are reflected in this huge mound of paper.
The filing of an application for a waiver to initiate clinical trials is critical to initiation of the process-in the United States; this is termed an IND (Investigational New Drug) application. Testing of a new drug in humans is only legal in the United States if the IND has been filed and the testing has not been put on clinical hold by the FDA. Clinical hold means that the FDA has concerns-usually for safety reasons-about the study design or about the preclinical work done to date. The format, content, and submission of this document are all done under the aegis of the regulatory group.
Following the initial IND filing, numerous other filings to the IND take place over the following years. Some of these are part of an annual update; others are filed separately as specific issues arise. During clinical trials, any adverse events are reported to the FDA. If the adverse reactions are serious, unexpected, or more frequent than expected, the events must be filed with the FDA within 3 total days of the event, depending on whether the event was fatal or life-threatening. Typically, these reports cite the nature of the problem, with background information concerning the problem and/or the patient, and they contain a summary evaluation of what this problem is likely to mean in terms of the potential risk to other patients still being tested with the drug. Dealing with this problem requires quick action and coordination with the clinical group and any other groups involved (preclinical and/or manufacturing), and is essential to building and maintaining the trust the FDA has for the company and its products.
Interacting with the internal company staff is an essential and sometimes difficult part of the job. It is the responsibility of the regulatory group to prepare reports for submission, to the government that contain all the information necessary under the various regulations and guidelines, and to make sure that the data contained in these reports are accurate and verified. They must also make sure that key people within research and development have the necessary training to perform the tasks relevant to the drug in development, and that this training is documented, is complete, and is up-to-date. Often, basic researchers do not take kindly to what appear to be meddling paper-pushers bugging them about how to do their jobs.
The regulatory group also participates in the strategic planning for each group to help make sure that they operate within government guidelines and are able to provide the necessary information required at each stage of product development. Since the information required at each stage varies according to the nature and scope of the preclinical and clinical studies to be done, it also varies according to the particular government that will re view the data. Because the requirements change over time, this can be a case of shooting at a moving target. This means that the negotiations required within a company to extract the necessary information and cooperation from people not in tune with government regulations during the product development cycle can be at least as challenging as dealing with the various governments that are reviewing the documentation.
Developing tactics for efficient product development and approval that can play a key role in the overall strategic plan for a company is another facet of regulatory affairs. Will the company file in the United States, in Europe, in Japan, or in all three? Although there is a movement toward harmonization in terms of the information required in these three very different markets, this process is not complete. Attempting to meet the requirements of all three regions can increase the cost of drug development sharply. Some companies enter into partnerships for foreign markets precisely because they do not want to grapple with these issues.
Some of the issues that must be examined include the kind of data that are critical for making the claims that will allow the drug to be marketed profitably and the minimum amount of data that must be gathered to support a successful filing. We must also ask whether these minimum data will support rapid development of the drug for other uses if the first indication falls through in the clinic. Is it more important to get on the market for one indication, then follow with supplements for other indications later, or should a broader use be claimed from the beginning? Should one go after an Orphan Drug indication (a situation where there are so few patients that the FDA gives 7 years of market exclusivity and special tax breaks to the developer)? Clearly, the answers to these questions can have a major financial impact on the companies. The wrong decision can delay marketing of the drug for years, or limit the market-and the profitability-of a drug.
Because the regulatory group is on the critical path to marketing products, this group is key to a company's success. While a company may have the brightest and best research scientists in the world working for it, unless it can bring to market the fruits of that research, the income stream for the company will be severely limited and investors will become very unhappy.
