Alan Minsk is a Partner at the U.S. law firm Arnall Golden Gregory LLP in Atlanta, Georgia, where he leads the Food and Drug Practice Team. Mr. Minsk advises pharmaceutical, biological, medical device and food companies on all legal and regulatory matters relating to the U.S. Food and Drug Administration and the Drug Enforcement Administration. He also co-chairs the International Life Sciences and Health Law Committee of the American Bar Association.
In an email interview with ILSI, Mr. Minsk discusses FDA regulatory matters and offers some tips for companies that face FDA review. Mr. Minsk notes he could speak or write in more detail on each issue (and has at conferences and in articles) but, for this forum, he touches on only certain areas.
Q: What are the implications of the new FDA restrictions (like the ones regarding medical devices) for a young company pursuing FDA approval?
Minsk: It is true that FDA is asking many more questions about applications and requesting additional clinical data, at times at the end of a long review. This can delay the approval/clearance process and sometimes leads companies to re-evaluate whether to pursue marketing authorization outside of the U.S. first. FDA is overworked and underfunded, and it appears that there are times when FDA doesn't complete its review in a timely manner, doesn't review the application as completely as one might hope, doesn't provide timely comments to allow the process to move forward, or seeks more time by asking for additional information.
There is a perception, right or wrong, that FDA doesn't want to make a mistake and, if there are comparable products on the market with which FDA has experience and comfort, there is little incentive to authorize a new product that the agency perceives as having potentially minimal value. If a company attempts to point out the added value, FDA then becomes concerned that the product is new and will require more data to support authorization.
To complicate matters, there are some review divisions at FDA that discourage email correspondence and want to formalize questions and set meetings, which again delays the review. A company needs to be sure that its business timeline takes into account these regulatory delays.
A company should also do its own research by looking at what the agency has done with similar applications, by listening to FDA comments about its application, and by recognizing a product’s potential pitfalls. Identifying a product’s possible regulatory and safety concerns in advance allows a company to proactively plan, rather than merely react. No product is perfect. I joke with clients that we all think our babies are beautiful but, frankly, not all are and FDA sees many "beautiful babies." My seven- and three-year-old children are my joy, but I know they don’t impress everyone. One must be self-critical and recognize where FDA might raise challenges.
In addition, companies must remember that, while this process can be exasperating, FDA is not always correct, but it’s good to be the king. It is the company’s burden to make its points with FDA and convince the agency to approve a product. Companies should be aware that FDA sees many applications and, often, it will ask questions about a company’s product that seem off base. It might be that FDA has seen similar issues with other products and is concerned that your product might have the same problem. The agency might actually be doing the company a favor, identifying a potential risk the company did not see. It's up to the company to demonstrate to FDA that either the issue is not present in the particular case or, if it is, how it is addressed in the application. Consider interacting with FDA as if it were a game of chess: If you can anticipate the agency’s next move based on past performance, you might be able to make the right move going forward.
Q: Is there a rule of thumb that a CEO or a CTO should follow when "negotiating" with FDA in an attempt to receive a special status (like orphan drug, fast track etc.)?
The first thing a company should do is review the law and any FDA guidance and similar product precedents to evaluate whether the product clearly meets the special status requirements. (Such a review might also identify existing data that can negate or streamline the need for additional data, reducing costs and possible delays.) For example, the orphan law and requirements are relatively straightforward. There is also a list of orphan drug designations and approvals. The company should review these and, if appropriate, consult with outside counsel to determine whether its product meets the criteria. In such a case, little negotiation is needed and the purpose of any interactions with FDA on the subject will be to confirm its understanding. If the issue is less clear and you are not certain whether you will obtain special status, the company should review what FDA has done in similar circumstances, know where FDA could challenge your position (be a healthy skeptic about your product and anticipate the agency question) and then proactively ask FDA to confirm your request.
Another suggestion is to discuss issues with FDA earlier in the process rather than later. While it might be difficult for FDA to provide a definitive answer if it doesn't believe it has enough information or it's too soon to make a decision, the issue is now on the table for consideration. Similarly, if FDA is raising concerns early, it provides the company with an opportunity to regroup and prepare its regulatory strategy earlier in the process. The company can use early communication to its advantage.
As to orphan drug status specifically, while the FDA magic number is 200,000 patients affected by a rare disease or condition, a company should attempt to ensure that the figure it provides is well under that total. Coming in with 199,000 patients runs the risk that FDA will be concerned that the real number is larger than 200,000 and disallow orphan drug designation.
Q: What is the best way to use the possibility of consulting with the FDA before handing them a drug application?
There are opportunities along the way, particularly with drug applications, to consult with FDA. The same applies for medical device applications. Much of the discussion will be informal, between a company's regulatory group and the FDA review division project manager. These are the most important people at the outset. If the company can establish credibility and a rapport with the FDA reviewer, it will be in a good position to have candid discussions. Remember, FDA has a job to do and, if you can make that job easier by doing your homework, preparing a quality application and listening respectfully (rather than arguing), a good dialogue can be established. I emphasize listening because, too often, early-stage companies become frustrated with FDA and then are surprised by a negative outcome or critical response. Frequently, those companies were not carefully listening to FDA or thoroughly reading the agency’s correspondence. No one likes criticism but with FDA expect it, as well as skepticism. Dialogue, not confrontation, is better and more productive.
One has to be aware that many companies are seeking the agency's time and review, so patience and tenacity are virtues. There are certain times when a formal meeting or a phone call, involving a larger number of people at the company and FDA, is needed to address specific issues that are central to the application (e.g., study protocol, labeling). The regulations and FDA written guidance help companies decide at what phase of the process FDA is more likely to grant a formal request for a meeting. Again, much of the discussion is behind the scenes with the company's regulatory person and the reviewer.
Another point to consider is knowing when to ask for FDA assistance and what types of questions to ask. We have seen too often, particularly with early-stage client companies, that FDA is expected to be a consultant to problems. A meeting with FDA, if granted, is limited in time. It is ill advised to ask simple questions that can be answered by studying the law or by reviewing what FDA has already said about your product or a comparable one. The meetings are intended to resolve outstanding, complex issues or to confirm points. A successful meeting is one that offers a game plan and a better understanding of FDA’s expectations, rather than wasting time on small, unimportant issues.
Also, it is important for companies to know the difference between an agency requirement versus a guideline or request (and when a request is essentially a requirement). A company must understand why FDA is asking for more information, in order to respond effectively. Ask yourself what might be FDA’s concern and is it specific to the product or the general technology. There might come a time when a company can and should push back. However, that decision must be made carefully, without emotion, and the company should consult with advisers to evaluate the benefits and risks before taking any action that could potentially hurt the review process.
Finally, FDA acknowledges that it does not know everything. A company might have to educate FDA about its product. Conversely, FDA may have more experience with your type of product than you think, because it has access to volumes of data. Communications is a two-way street. In the end, you must listen to FDA to get a clear understanding of its expectations and, as much as possible, its buy in. It is important to work with FDA to set clear objectives and focus on your product’s approval.
Q: Based on your observations, what are the common features/obstacles for Israeli companies that face the FDA regulation process? Do you have any recommendations for Israeli companies?
First, remember FDA is focused primarily on product safety. If there’s another product like yours on the market, the burden is on you to convince FDA to approve it or clear it for marketing. Remember, it’s not hard for FDA to say no or ask for more information and data.
Second, lower your expectations. FDA is less concerned about your expenses and time commitments. Your time isn’t FDA’s time. And FDA does not always meet its deadlines or communicate effectively. Be prepared to adjust accordingly.
Third, prepare. Get inside FDA’s head and do your homework. Evaluate what were the safety issues previous products faced and how were they resolved. Engage consultants who are familiar with the division that is going to review your product.
Fourth, FDA does not give smaller companies or ex-U.S. companies any free passes because of size or limited revenues. I’ve already commented on listening, accepting criticism, communicating with FDA, preparing for meetings, and acting as a healthy skeptic of the product and the regulatory process. A company’s location, economic future and size are not of paramount importance to the agency.
Fifth, companies frequently seek the home run with marketing claims that might necessitate clinical data. Rather, if appropriate, consider a base hit, get into the game and submit new applications to advance base to base. Keep things simple with FDA.
Q: You are also a member of the American-Israel Chamber of Commerce. Where, in your opinion, can the best Med-Tech opportunities for Israeli-American co-operations be found?
There is no right or wrong answer concerning location. We have some clients, including Israeli clients, that prefer to be on the East Coast because FDA is there and the time difference is not as great. Some companies go where their investors or clinical sites or hospitals are located. Others set up offices close to where the new U.S. management is based or where they know there is plentiful employee talent in a particular therapeutic area. Some prefer to be near major airports, while others have personal reasons (e.g., family) for settling in a certain location. And there are companies that are enticed by money, incentives and benefits they receive from state or local governments. We have Israeli clients with offices throughout the U.S., so location decisions are based on a number of factors. | 
