Regulatory Affairs: The Hub of the Wheel
Pharmaceutical companies' regulatory affairs units are more vital than ever, but, traditionally, they have not been known for their flexibility. Peter Lassoff explains why this image is outdated, and how working more co-operatively with your regulatory department will help to maximize your success in the market place.
According to popular myth, older elephants instinctively leave their group when they reach a certain age, and direct themselves to a special area known as the elephants' graveyard, where they die, alone and far from the group. There are those who believe that the elephants' graveyard is an accurate analogy for regulatory affairs in the pharma industry, where old, exhausted R&D folk migrate over to Regulatory for their last few years before retirement.
Perhaps this is how things used to be, but those of us working in regulatory affairs these days believe that our department is the hub of the R&D wheel, driving the complex machine towards successful marketing.
Back in those prehistoric times, Regulatory (or 'Registration', as it was then) was more or less a 'post office,' and the work essentially involved compiling reports written by the experts in R&D and mailing them to the various regulatory authorities. The modern view of regulatory affairs is as a dynamic, business-oriented unit, focused on getting products to the market with a commercially viable label, as quickly as possible and for the least possible expense. Regulatory is involved at a very early stage in the development process, often helping with 'portfolio management,' choosing which products should progress to the clinic.
Experienced regulatory professionals are a very valuable resource for development in a variety of ways. Recently we have seen some dramatic failures to obtain regulatory approval in large blue-chip companies; the quest to find the new aspirin or warfarin is as difficult as ever, and even the largest companies are now reconsidering regulatory strategy as a result. No longer can companies take the "we know best"attitude and expect government agencies to agree; partnerships with the major authorities are an essential part of doing business, and obtaining and following agency advice is more important than ever, and should be done from a very early stage in development.
Going back only ten years, many R&D professionals thought that the job of a regulatory professional was to say "No." It was common to see regulatory experts in meetings sigh, look to the heavens, purse their lips and explain, in great detail, why it was not possible to file for submission with the data then available. It was as if R&D were asking for directions, and the answer came back as, "You don't want to start from there." Regulatory was the group that liked to say "No": no, you cannot use that ingredient/process/study; no, you have no chance for registration; no, you need a few more years before you can consider filing. Risk-averse was an understatement; regulatory personnel did not like to file without near-100% certainty of success.
A new era
So, what has changed? In short, business. Historically, most regulatory professionals started their professional lives in the R&D laboratories, until beginning their 'retirement' in Regulatory. These days, there are many more healthcare professionals in Regulatory who have intentionally chosen the field as a career, and frequently switch between industry and the regulatory authorities. The best advice companies can obtain is from a combination of ex-regulators combined with that of industry development experts with a business focus. The attitude now is not "We can't do that," but rather "How can we get it done? Within given time and money constraints, how do we get the product onto the market? What is the best route? Which market or markets first?"
The best regulatory people work hand-in-hand with marketing and R&D to develop innovative, risk-taking development plans that take advantage of new technological and regulatory developments to accelerate time to market. With new products expected to have significant revenues from Day One, small decreases in time to market equate to material gains in revenue and profit. Employing adaptive clinical trial strategies, obtaining early buy-in from the major regulatory authorities, and avoiding pitfalls in processes can accelerate development and help to prevent costly errors.
In the days before email, the regulatory function was usually combined with a quality assurance (QA) or compliance role (and this is still frequently the case in the medical device industry). This fitted in very well with the perceived role of Regulatory as the 'company police,' ensuring compliance with all relevant legislation, regulations and guidelines. Today, these two roles are separated. Regulatory affairs should be the driver of development, accelerating rather than putting a brake on projects. Compliance and QA are, of course, critical functions, but should be entirely separate.
These days, one reads about companies 'breaking the paradigm' of development, skipping clinical development phases and using novel strategies to submit early and beat the competition. A good Regulatory department should be doing this every day. Do we really need formal dose-ranging studies with this novel topical product? Could we convince FDA and EMEA that this new salt only requires minor bridging studies? If we focus on a narrow label, could we get to market much earlier and use the revenue to fund wider indications? Thinking out of the box, with a thorough, internalized knowledge of all relevant guidelines, precedents and competitors, should be mandatory for all regulatory professionals.
Dealing with diversity
Different companies have different regulatory needs. A SEBCO (small emerging biopharmaceutical company) will need very different support from a mature FIBCO (fully integrated biopharmaceutical company). SEBCOs frequently need to obtain venture capital funding and costed, timed regulatory development plans can assist in this as well as in helping to attract partners. Often these small companies have an abundance of researchers and little actual development experience, and a guiding hand is needed to focus and lead the development effort. In contrast, mature FIBCOs will often concentrate on risk-management strategies, promotional activities and large, global, co-ordinated submissions of major new products. However, it is essential that dynamic, forward-thinking regulatory professionals are involved in both types of companies, otherwise stasis and stagnation can occur. Appropriate risk-taking and innovation are the life-blood of our industry and stifling these can be a much greater risk than encouraging them.
In many markets there are a variety of ways to obtain market access, with pros and cons for each. Some result in faster time to market with weaker commercial prospects, whereas others are much more costly in terms of time and resources. In Europe, in particular, it is generally left up to the company to decide how their product should be regulated: whether as a drug, a device, a biocide, a cosmetic and so on. With EU harmonization efforts resulting in a very fragmented regulatory arena, regulatory professionals have the opportunity to be creative and explore opportunities not available in other markets. In one example, a simple preserved cream can be sold in different European member states as a drug (for the treatment of eczema), a device (providing physical protection for the skin), a biocide (that 'disinfects' the skin) and a cosmetic (for use as a moisturizer). It is important that Regulatory works hand-in-hand with marketing and senior development executives at an early stage to consider all the possibilities in each intended market. On the other hand, it is also essential that marketing drives the choice of procedure — return on investment, the size and type of market, and long-term corporate strategy is crucial to the choice, and the matter should not be left entirely to regulatory. Even basic decisions such as choice of Rapporteur should always be at least partially market driven.
An issue that occurs regularly is the regulatory group advising against submitting dossiers to the authorities due to incomplete or inadequate data. Although a judgement call, it is vital that all aspects are closely scrutinized before making such decisions. If there is a true medical need for the product, then companies could be pleasantly surprised at the willingness of regulatory authorities to take a less stringent view than anticipated. However, even orphan drug submissions will be turned down if the data do not support a positive risk/benefit assessment. Unfortunately, often the only real way to determine is to submit a dossier, openly pointing out the deficiencies but explaining that the overall risk/benefit ratio is positive.
Even in this era of the global dossier and the Common Technical Document (CTD), there remain significant differences in the content of dossiers, especially between the US, Europe and Japan. The European system uses a 'top-down' assessment by the authorities, and relies on a thorough critical appraisal of the dossier by the experts for the clinical, non-clinical and quality modules. The FDA (and, to some extent, the Japanese Ministry of Health, Labour and Welfare) perform a 'bottom-up' assessment, and prefer to do their own assessment of the data. For this reason, it is not unusual for an American company to be very reluctant to allow submission of a clinical overview that they see as being overly critical of their long and costly development programme. However, a critical, transparent clinical overview that discusses all major deficiencies in the data set will lead to faster approval by the regulators. It is a good business decision to submit well written, thought-out overviews that freely and frankly discuss the problems and obstacles that occurred during development. Trying to hide deficiencies, submit mere summaries or patronize the regulators often leads to delays or worse. Ideally, all major issues will have already been discussed with the major regulatory authorities before submission. Clever regulatory affairs professionals with major new products will even go so far as to obtain pre-approval comments of the clinical, non-clinical and quality overviews from the regulatory authorities. This does not guarantee approval but helps to ensure that the dossier meets the needs of the regulators and thus generally speeds up the regulatory process.
In some cases, overly detailed data can cause headaches not only during the approval process but for many years after. Submitting a quality module with very detailed specifications for equipment means that variations will need to be filed if the manufacturer decides to make even minor changes to the process. Providing ranges for specifications rather than exact numbers allows flexibility for the process. Regulators also prefer more flexibility as it means less work in terms of inspections and variations or amendments over time. Experienced regulatory professionals, working directly with QA and other staff at the manufacturing facilities, will ensure the maximum flexibility and minimum additional expense. It is vital that the quality data are checked prior to submission by the staff responsible for making the product, otherwise they will be expected to follow the procedures in the dossier exactly, without having had an opportunity to ensure that they are acceptable. The days when regulatory staff were seen as 'suits' with no real-world knowledge by manufacturing professionals should be very much in the past. Teamwork and partnership between Regulatory, Production and other R&D departments are the best methods to ensure regulatory and commercial acceptability.
There are a variety of different mechanisms to speed up submissions in most major markets, such as fast-track, conditional approvals and priority review. All carry risks and rewards and it is important for a regulatory professional to help to guide the company through this maze. There are companies reluctant to use some of these techniques in the belief that products approved under these conditions are somehow less commercially viable than those approved through the usual channels. Post-market commitments can be costly but the extra revenue available through early approval usually far outweighs the cost of the Phase IV studies.
It makes good business sense to ensure that regulatory affairs is placed in a position to co-ordinate and lead development efforts. That way, regulatory professionals are given the insight to ensure that all aspects of a sound development plan are considered, decided upon, and incorporated at the right points in time to drive approvable results and safe and effective products to market. Modern regulatory professionals need to have a fusion of skills and incorporate scientific, regulatory and business expertise to drive the company forward. Obtaining experienced personnel is not easy but the pay-off is well worth the effort.
Source: Pharmaceutical Executive Europe (www.pharmexeceurope.com)