Learning Which Regulatory Guidances and Standards May Be Modified
The pessimist sees difficulty in every opportunity. The optimist sees the opportunity in every difficulty.
–Winston Churchill
Success is not achieved based on how much FDA law you know, but by howwell you play the game.
–Jerry Halperin, former Food and Drug Administration official and President of the Food and Drug Law Institute.
INTRODUCTION AND DEFINITIONAL ISSUES
This chapter is not about the shortcuts that the Food and Drug Administration (FDA) and other regulatory agencies offer companies via special procedures and applications such as accelerated approval, priority review, expedited approval, and Fast Track, that are briefly discussed in Chapter 85. These and similar procedures or mechanisms that are part of guidances and regulations are “officially sanctioned.” The main advice on each officially sanctioned method is to carefully read the fine print, consult with experts about the pros and cons, and when relevant, discuss questions and issues with the regulatory agencies.
The importance of having a complete understanding of the issue cannot be overemphasized. At least one company has gone out of business by failing to understand the full requirements that were expected for an accelerated approval (i.e., the product was required by the FDA to offer a meaningful therapeutic benefit over all existing products, not just marketed products labeled for that indication). Other companies have had a variety of serious commercial problems because they did not fully understand the implications of not meeting the regulatory standards that were discussed with them by the FDA.
This chapter deals with learning about other approaches that may greatly speed development and under certain conditions are acceptable to regulators.
Definitional Issues
Senior executives at the FDA have been saying to the industry for decades: “Read the title of the FDA‘s guidance on X.” They go on to explain that they are referring to the meaning of the word guidance, which contains the word “guide,” meaning that what
is written is a suggested path and not an absolute requirement. This obviously means that a company that has a valid scientific, medical, or ethical rationale for not following the guidance has every right to follow the most relevant and scientifically appropriate path instead of what is outlined in the guidance. Of course, the FDA wishes to learn about this variance at relevant meetings before the variance is actually implemented, so that they can opine as to whether or not they are in agreement with the company’s view and plans. Any company that does not discuss such variances with the FDA is taking a substantial risk.
is written is a suggested path and not an absolute requirement. This obviously means that a company that has a valid scientific, medical, or ethical rationale for not following the guidance has every right to follow the most relevant and scientifically appropriate path instead of what is outlined in the guidance. Of course, the FDA wishes to learn about this variance at relevant meetings before the variance is actually implemented, so that they can opine as to whether or not they are in agreement with the company’s view and plans. Any company that does not discuss such variances with the FDA is taking a substantial risk.
Types of Regulatory Standards
The cascade of regulatory standards from the most to the least legally binding are as follows:
Laws
Regulations
Guidelines
Points to consider
Suggestions
Podium policy
Informal comments
Laws and regulations are difficult to challenge and impossible to ignore. Any planned or desired deviations from them must be discussed in advance with the regulatory agency. The rationale for one’s deviation must be strong and convincing to have any chance of succeeding.
Guidelines and points to consider must be initially looked at in terms of the actual names of these standards, i.e., they are able to be modified if a sponsor has a sound rationale based on medical, scientific, or even practical considerations in a specific situation. It may or may not be mandatory to discuss this in advance with a regulatory agency, but it usually is a good idea to do so. There are over 400 final and draft guidances on the FDA‘s website.
Suggestions from a regulatory agency, either directly to a sponsor or indirectly via “podium policy” may simply be accepted or discussed with the agency. A company should seek to convince them of your position, and if that fails then to seek a compromise position that is a win-win situation and allows everyone to save face. Company staff should try to understand the rationale for the regulators’ view prior to discussing the issue with the agency.
Requirements from regulators are often mentioned as suggestions to a company at a regulatory meeting or in correspondence. A company must determine if what sounds like a suggestion is in fact a suggestion or a requirement. Making assumptions about an agency’s intent may lead to serious problems for a company (a common event); thus, failure to clarify statements made at regulatory meetings or in correspondence may also lead to problems.
REGULATORY STANDARDS THAT MAY BE QUESTIONED OR MODIFIED
Specific Categories of Standards that May Be Questioned or Modified
Chemistry, Manufacturing, and Controls and Drug Quality
The standards of chemistry, manufacturing, and controls and drug quality are almost never modified, even if the patient population that needs the drug has a prevalence of less than one hundred and the disease is life threatening. The most that an agency will usually bend (if there is a sense of urgency by the regulators to get the drug to market) is in terms of the number of batches required to be made and tested on stability prior to marketing. For example, it is possible to place the first commercially produced product on sale under continuous validation, while the company completes validation with their third lot. Limited stability data, even with reliance on the most validated projections of future degredation using data from tests performed under accelerated conditions can be accommodated by the FDA with temporarily shortened expiration dating. There may also be a few other chemistry, manufacturing, and controls modifications that the agency will allow in exceptional circumstances. However, chemistry, manufacturing, and controls is not an area that the FDA or other regulatory agencies is usually willing to compromise.
Toxicology and Pharmacokinetics
Even for a drug that has a high degree of medical value and is expected to become a standard therapy, a comprehensive database of toxicology data is required to support product labeling. Exceptions are sometimes made for products classified as “generally regarded as safe” or where a large amount of clinical data already exists for the same formulation. A drug of high medical value may have the required amount of toxicology data decreased by regulators if (a) there are sufficient published reports of toxicology results in the literature (even though the raw data are not present), (b) there has been a long marketing history of the drug for a different indication or in another dosage form, and (c) there have not been any significant safety problems. Likewise, the amount of pharmacokinetic data required to support a regulatory application [e.g., Investigational New Drug Application (IND) or New Drug Application (NDA)] may be less than otherwise would be required.
Clinical Testing
The area where standards are most often modified is with respect to the amount of clinical data required for the initial marketing approval. The use of a surrogate endpoint that is not 100% validated may be accepted under some conditions. Other areas where compromises on established standards are possible include the number of well-controlled studies (current regulations permit a single clinical trial to be the basis of marketing approval in some circumstances such as accelerated approval) and the total number of patients in a database, particularly if there are few patients in the population to be treated.
Current International Conference on Harmonisation guidelines suggests a safety dataset on the order of 1,500 patients exposed to the product, including 300 patients treated for six months and 100 patients treated for a year. When the drug addresses a major medical need or a small patient population, the FDA may accept a smaller database with respect to safety. When the prevalence is extremely small (e.g., fewer than 100 patients), a drug that has been tested in as few as eight patients has been approved for marketing (i.e., Polyethylene Glycol-Asparaginase in patients with severe combined immunodeficiency disease).
Being Realistic about What Modifications of Standards Are Acceptable
Almost every company has a rationale why some or many of the tests that are traditionally conducted prior to approval should be delayed to Phase 4. Regulators must hear this request almost every
day. While the rationale may sound reasonable (“Our drug is chemically similar to Drug X so that we should not have to do as many clinical studies in Phases 2 and 3 or as many toxicology studies.”), a careful review of drug development history and literature will show many examples of minor changes in chemical structure having profound changes on safety and/or efficacy. Such requests are, therefore, only granted when there is a sound scientific rationale to do so.
day. While the rationale may sound reasonable (“Our drug is chemically similar to Drug X so that we should not have to do as many clinical studies in Phases 2 and 3 or as many toxicology studies.”), a careful review of drug development history and literature will show many examples of minor changes in chemical structure having profound changes on safety and/or efficacy. Such requests are, therefore, only granted when there is a sound scientific rationale to do so.
Examples Where Sponsors Do More Work than Regulatory Standards Require
A few of the many areas where sponsors often do more work than is required by regulatory standards include:
Monitoring large clinical trials more frequently than is required or relevant
Collecting too much data on a single patient at each visit, having too many visits in a clinical trial, conducting too many clinical trials
Performing too many procedures on patients in a clinical trial; this is a form of procedure bloat
Including too many secondary endpoints and measures that are not particularly relevant for the drug or dossier
HOW TO LEARN ABOUT REGULATORY FLEXIBILITY
Listening to and Interpreting Podium Policy and Hallway Chatter
The FDA and some other regulatory agencies are relatively open about having their senior officials and some middle-level staff present talks at both major and minor conferences. It clearly is a sign of prestige for those invited to speak and is important for those in industry and the public who want to hear what these regulators are thinking about on important issues.
If the speaker at a professional meeting is the FDA‘s Commissioner, a high-ranking regulatory executive, or a regulatory agency attorney, then they will usually read their talk and their words have been carefully reviewed and approved before they speak. They are trained to say little that is extemporaneous, although some of these people are fairly open, particularly when answering questions after their formal talk. These executives are well rehearsed and are rarely ever “off-message.” On the other hand, some mid-level regulatory executives are not as highly trained and sometimes say things that provide important insights into FDA thinking and plans.
The FDA uses meetings of the Drug Information Association, public hearings, Congressional testimony, meetings with trade associations such as Pharmaceutical Research and Manufacturers of America, Biotechnology Industry Organization, plus other such venues to present “Podium Policy.” One key issue that companies face is how to interpret the FDA‘s remarks, and whether to act on such statements. The points made sometimes are intended as trial balloons to see how the industry reacts to various proposals, or the statements may represent one individual regulator’s opinion. This is particularly relevant when they mention that their comments do not necessarily reflect those of their regulatory agency.
It is difficult to know what level of credibility to place when interpreting such comments and whether to adjust a company’s plans based on what has been heard. Of course, a company would want to confirm with the FDA reviewing division, if it is possible to do so, any statements that are (or might be) of great importance to the company and one or more of their products (or projects).
In some situations, the author has been privy to sessions of senior industry executives who seek to dissect these types of comments. There are some senior managers who lead the discussion as if the words from junior level regulatory agency staff were from the Oracle at Delphi, where every word is believed to have hidden meanings. The situation resembles the reading of tea leaves to obtain the wisdom of what was really meant.
The only wisdom one can truly offer someone who listens to such information from regulators is to let the buyer beware. Clearly, one can usually distinguish between hearsay, someone’s personal views and a possible new regulatory policy. Also, one can readily understand what are meant as official or soon to be official policies at an agency. Companies should make every effort to attend meetings where they can listen to FDA staff, both in formal meetings and in hallways, where much of the informal chatter is heard and stored.
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