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Written By: Jeff Boatman - CQA, Senior Subject Matter Expert, Quality Systems, QPharma
Quite a lot, actually!
Something that I often hear as I travel around the country preaching quality systems, Agency guidances, and Best Practices is some variety of: "I read the regulations and it doesn't say we have to do that so we won't." Often, the person making that pronouncement is a lawyer or an MBA with little experience in the real world of regulated industry and who has no personal knowledge of the range of tools that FDA—or any regulatory body—has at its disposal to make life difficult for recalcitrant firms. I’ll recap some of these, both from the news and my own experiences, in the hope that the reader may learn that instead of asking “how do we fight them,” perhaps the correct question should be “why are we fighting them at all?”
Don't get me wrong; FDA is made up of people who misinterpret requirements, let emotions and personal agendas color their decisions, and are just as bullheaded and plain wrong as anybody else. I’ve had my disputes with them, in fact I’m in the middle of arguing a client’s point right now. But when a consultant who’s been in industry for 20+ years makes a recommendation, or FDA writes a Guidance or a Compliance Guide, there’s usually a pretty good reason for it and perhaps your time might be better spent trying to understand that reason, and why it does or does not apply to you, than arbitrarily deciding “I don't have to do that so I won't.”
1. Greasing the Skids
This leads me to my first example. In my Quality System Regulation training, I used to recommend to all my medical device clients that they register with FDA while they were still in the design control phase. After all, it didn't cost anything (at the time) and was one less thing to worry about later on.
Well, of course a client—more specifically, a client's lawyer –looked up the regulation and noticed “oh, it doesn’t require registration until 30 days from commercial distribution. We’re nowhere near that so we don't have to do it.” And of course, they never came back to the consultant (me) for whose practical, real-world experience they were paying, to find out why they might want to register even if the regulation didn’t require it.
A few months later, I got a panic call from the client – the U.S. Customs Service had put a hold on their desperately needed materials for an ongoing clinical study. You can probably guess why: Customs had checked their database and found that the company had no FDA registration number! Fortunately, I knew the FDA liaison at the Customs’ office in Port Elizabeth and was able to get the product moving with minimal delay. So here's something that the consultant knew, but which you won't find in any regulation: having a registration can help get your materials through Customs. (Note that since FDA now charges to register and to re-register, I no longer give this blanket advice; but it is still something worth considering.)
2. The “Guidance” Document that's Anything But
If there’s one source of pushback I get from clients that tops the list, it’s that they don't have to follow an FDA guidance. Mind you, if I heard that they don't have to follow a guidance because they've analyzed the document and found that it does not apply to them—or that they already employ systems that are even better—I’d be very happy. Unfortunately, that’s rarely what happens; it’s usually “if it’s not in a regulation then we don’t have to follow it.” Au contraire – if it’s not in a regulation then perhaps you cannot get a 483 for not following it (maybe – try telling that to the authors of FDA’s new guidance on Process Validation), but there are all sorts of examples why that attitude is less than helpful.
For example, FDA has a guidance document on hemodialyzers; if you follow that guidance, then your product will be classified as Class II and you can market it on a 510(k) clearance, which is a far cheaper and faster way to get to market. If you don’t follow it, then to be sure, FDA cannot cite you and the Justice Department will not show up to handcuff you…but your product will automatically become a Class III device, requiring Premarket Approval and millions of dollars and years of extra work to market.
A similar and more general guidance is the one for Part 11. On many of my audits, I’ve made observations that firms don’t have inventories of their computerized systems and written risk assessments. “That’s not in a regulation, so we aren’t going to do that!” That’s absolutely correct – and absolutely self-defeating, because having those inventories and risk assessments allow you to reduce your controls and validation coverage below that strictly required by 21 CFR 11.10, 11.50, and (arguably) 820.70(i). By refusing to follow the guidance, you are condemning your firm to have to follow the strict and (even by FDA’s own admission) sometimes absurdly onerous requirements that are in the regulation.
Speaking of Part 11, I remember a statement in one of the drafts floating around in the early 2000s. Now this was not only a guidance, it was a draft. Surely it carried no weight! Until you read the clause “This draft guidance is used by FDA staff in conducting inspections.” There’s nothing “optional” about that at all – that document told you what the FDA inspector will be looking for, so shame on you if you ignored that invaluable information!
Finally, on January 15th of this year, FDA issued a Final Guidance on the subject of registration of tobacco products. This document, clearly marked “CONTAINS NONBINDING RECOMMENDATIONS” (hah!), set forth the rules for tobacco manufacturers to get in their “905(j)” submission reports within three months (i.e. by this past March). Companies that failed to do so in accordance with the guidance are guilty of selling misbranded product, liable to confiscation and legal action.
“Nonbinding” my eye!
3. The Mystery of the Mandatory Optional SOP
Here’s an example of why you sometimes need to find a true Subject Matter Expert, and not just tell an employee to “go read the regulation.” Under 21 CFR 820.30, manufacturers and designers of Class II and Class III medical devices must have written procedures for design inputs, outputs, verification, validation, review, and transfer. 21 CFR 820.30(j) requires you to maintain a Design History File on your product. But nowhere does it say that you must have a procedure explaining how you maintain that file. So if you don’t have such a procedure, FDA cannot possibly write you up. No 483, no Warning Letter, no Consent Decree.
Of course, just because you are not gigged for a regulatory violation doesn’t mean your submission will actually get approved, and in this case it won’t. That’s because buried inside FDA’s guidance (yep, yet another guidance document) on quality information submitted in Premarket Approval applications is a list of procedures that must be provided before FDA will review your application…and your procedure for maintaining your Design History File just happens to be one of them!
4. Obey the Law
“Finished dosage form” pharmaceutical companies must produce drugs in compliance with the Good Manufacturing Practices of 21 CFR 210/211. It says so right in 210.1(a) and 210.3(a)(3). It doesn’t say anything about the vendors of the drug firm, though. Sure, there is an expectation that a drug firm ensures that their vendors provide quality products meeting their expectations (that whole “safety, purity, identity, and quality” thing, plus there’s an implied expectation under 21 CFR 820.50(a), applicable to a drug firm under 21 CFR 820.1(b) – you did know that, right?), but surely FDA cannot directly cite a vendor if the regulation doesn’t give them that authority.
À nouveau, au contraire! FDA regularly inspects Active Pharmaceutical Ingredient manufacturers and cites them against Part 210/211, as guided by ICH Q7A (yes, another of those pesky guidance documents)…because the predicate Safe Food, Drug, and Cosmetic Act’s definitions of adulterated (21 U.S.C. §501(a)(2)(B)) and drug (21 U.S.C. §201(g)(1)) authorizes them to do so.
5. Recalls, Recalls, Recalls
In case you missed this, FDA just got sweeping new authority to preemptively order recalls of food products. Prior to 2011, FDA only had such statutory authority over a narrow subset of foods (baby formula, acidified canned products); they’ve also had this authority over medical devices for years. This underlines a common confusion about which regulations actually cover recalls: generally, they’re described in 21 CFR 7, but because Congress has granted FDA preemptive authority over various industries over the years, Part 7 is often supplemented by an industry-specific regulation (in the case of devices, you’ll find those additional regulations in 21 CFR 810).
There was a move to include preemptive drug recalls in the Food Safety Modernization Act but it got dropped…for now. I expect the McNeil situation to re-ignite this debate in Congress, which had quieted down a bit since the last person was killed by adulterated heparin.
6. Miscellany
FDA’s ability to order recalls—along with their power to refuse or rescind Certificates of Foreign Governments, detain product at Ports of Entry (as opposed to outright confiscation requiring court order), suspend Clinical Trials, and their greatly underappreciated ability to pick up the phone and call Labor, EPA, OSHA, Customs, etc.—has rarely been diminished during their entire history and in fact continues to increase with time.
Often forgotten is the fact that FDA has non-judicial administrative options beyond just the approving or clearing of products, especially the rarely-invoked but powerful federal debarment of individuals. Think debarment is just a personal matter? Consider FDA’s recent move to debar the CEO of Forest Labs in connection with marketing shenanigans – if he is debarred, then he must either leave company management or Forest will lose its ability to submit for federal reimbursement from sCHIPS, Medicaid, Medicare, and Veteran’s Administration programs – money that few large pharmaceutical companies can survive without. FDA’s stated stance is they can debar him irrespective of proving his actual knowledge of wrongdoing because debarment is not a legal proceeding. As FDA chief Margaret Hamburg continues to look for outside-the-box ways of bending wayward firms to her will, I expect to only see more actions like this because FDA is simply not seeing companies change their ways in response to mere fines.
7. When You Can’t Beat ‘Em, Join Their Competitors
Speaking of outside-the-box thinking, I’ve saved for last the item that triggered this blog entry. Consider KV Pharmaceuticals: GMP issues, recalls, FDA inspections, 483s, Warning Letters, Consent Decree, third-party oversight. FDA essentially shuts down their operations, two of their three divisions promptly go out of business, several rounds of layoffs. Income stream is, well, challenged.
In a move no doubt intended to inject some much-needed cash, KV buys the exclusive rights to distribute a prenatal care medication, Makena, an Orphan drug that provides critical health benefits and for which there is no real alternative. Note that KV is a generics company, so this is something of a foray into the tradename business for them; patent owner Hologic developed the drug in conjunction with NIH.
The medicine in Makena was a true bargain at $20 per injection. KV decided to raise the price a little: $1,200 a dose!
FDA doesn’t regulate pricing, so what exactly can FDA do about this? Here’s what: FDA just announced that they intend to exercise “enforcement discretion” against pharmacies that compound their own version of Makena and sell it to prescribers. It’s unclear what recourse KV or Hologic may have in suing these pharmacies for intellectual property violations, but with this announcement FDA has basically declared open season on KV by promising that if you make your own version of Makena (and presumably don’t sell it for $1,200) then FDA will not go after you for misbranding.
I bet KV management didn’t see that one coming!
Conclusion
All too often, I find that Top Management of Life Science firms believes that the best and most cost-effective strategy is to always do as little as possible. That top-level philosophy inevitably trickles down to middle management and brews a culture of noncompliance – spend your time on figuring out ways to avoid complying with FDA’s recommendations rather than efficient ways to implement Agency expectations.
In my nearly quarter-century in this industry, I have yet to see a single instance where this approach actually worked, but I have seen countless cases where it backfired in ways that management never dreamed of. In the March 2005 Gold Sheet (volume 39, number 3), no less a personality than David Elder, Director of Enforcement for FDA's Office of Regulatory Affairs, said it best:
Quite a lot, actually!
Something that I often hear as I travel around the country preaching quality systems, Agency guidances, and Best Practices is some variety of: "I read the regulations and it doesn't say we have to do that so we won't." Often, the person making that pronouncement is a lawyer or an MBA with little experience in the real world of regulated industry and who has no personal knowledge of the range of tools that FDA—or any regulatory body—has at its disposal to make life difficult for recalcitrant firms. I’ll recap some of these, both from the news and my own experiences, in the hope that the reader may learn that instead of asking “how do we fight them,” perhaps the correct question should be “why are we fighting them at all?”
Don't get me wrong; FDA is made up of people who misinterpret requirements, let emotions and personal agendas color their decisions, and are just as bullheaded and plain wrong as anybody else. I’ve had my disputes with them, in fact I’m in the middle of arguing a client’s point right now. But when a consultant who’s been in industry for 20+ years makes a recommendation, or FDA writes a Guidance or a Compliance Guide, there’s usually a pretty good reason for it and perhaps your time might be better spent trying to understand that reason, and why it does or does not apply to you, than arbitrarily deciding “I don't have to do that so I won't.”
1. Greasing the Skids
This leads me to my first example. In my Quality System Regulation training, I used to recommend to all my medical device clients that they register with FDA while they were still in the design control phase. After all, it didn't cost anything (at the time) and was one less thing to worry about later on.
Well, of course a client—more specifically, a client's lawyer –looked up the regulation and noticed “oh, it doesn’t require registration until 30 days from commercial distribution. We’re nowhere near that so we don't have to do it.” And of course, they never came back to the consultant (me) for whose practical, real-world experience they were paying, to find out why they might want to register even if the regulation didn’t require it.
A few months later, I got a panic call from the client – the U.S. Customs Service had put a hold on their desperately needed materials for an ongoing clinical study. You can probably guess why: Customs had checked their database and found that the company had no FDA registration number! Fortunately, I knew the FDA liaison at the Customs’ office in Port Elizabeth and was able to get the product moving with minimal delay. So here's something that the consultant knew, but which you won't find in any regulation: having a registration can help get your materials through Customs. (Note that since FDA now charges to register and to re-register, I no longer give this blanket advice; but it is still something worth considering.)
2. The “Guidance” Document that's Anything But
If there’s one source of pushback I get from clients that tops the list, it’s that they don't have to follow an FDA guidance. Mind you, if I heard that they don't have to follow a guidance because they've analyzed the document and found that it does not apply to them—or that they already employ systems that are even better—I’d be very happy. Unfortunately, that’s rarely what happens; it’s usually “if it’s not in a regulation then we don’t have to follow it.” Au contraire – if it’s not in a regulation then perhaps you cannot get a 483 for not following it (maybe – try telling that to the authors of FDA’s new guidance on Process Validation), but there are all sorts of examples why that attitude is less than helpful.
For example, FDA has a guidance document on hemodialyzers; if you follow that guidance, then your product will be classified as Class II and you can market it on a 510(k) clearance, which is a far cheaper and faster way to get to market. If you don’t follow it, then to be sure, FDA cannot cite you and the Justice Department will not show up to handcuff you…but your product will automatically become a Class III device, requiring Premarket Approval and millions of dollars and years of extra work to market.
A similar and more general guidance is the one for Part 11. On many of my audits, I’ve made observations that firms don’t have inventories of their computerized systems and written risk assessments. “That’s not in a regulation, so we aren’t going to do that!” That’s absolutely correct – and absolutely self-defeating, because having those inventories and risk assessments allow you to reduce your controls and validation coverage below that strictly required by 21 CFR 11.10, 11.50, and (arguably) 820.70(i). By refusing to follow the guidance, you are condemning your firm to have to follow the strict and (even by FDA’s own admission) sometimes absurdly onerous requirements that are in the regulation.
Speaking of Part 11, I remember a statement in one of the drafts floating around in the early 2000s. Now this was not only a guidance, it was a draft. Surely it carried no weight! Until you read the clause “This draft guidance is used by FDA staff in conducting inspections.” There’s nothing “optional” about that at all – that document told you what the FDA inspector will be looking for, so shame on you if you ignored that invaluable information!
Finally, on January 15th of this year, FDA issued a Final Guidance on the subject of registration of tobacco products. This document, clearly marked “CONTAINS NONBINDING RECOMMENDATIONS” (hah!), set forth the rules for tobacco manufacturers to get in their “905(j)” submission reports within three months (i.e. by this past March). Companies that failed to do so in accordance with the guidance are guilty of selling misbranded product, liable to confiscation and legal action.
“Nonbinding” my eye!
3. The Mystery of the Mandatory Optional SOP
Here’s an example of why you sometimes need to find a true Subject Matter Expert, and not just tell an employee to “go read the regulation.” Under 21 CFR 820.30, manufacturers and designers of Class II and Class III medical devices must have written procedures for design inputs, outputs, verification, validation, review, and transfer. 21 CFR 820.30(j) requires you to maintain a Design History File on your product. But nowhere does it say that you must have a procedure explaining how you maintain that file. So if you don’t have such a procedure, FDA cannot possibly write you up. No 483, no Warning Letter, no Consent Decree.
Of course, just because you are not gigged for a regulatory violation doesn’t mean your submission will actually get approved, and in this case it won’t. That’s because buried inside FDA’s guidance (yep, yet another guidance document) on quality information submitted in Premarket Approval applications is a list of procedures that must be provided before FDA will review your application…and your procedure for maintaining your Design History File just happens to be one of them!
4. Obey the Law
“Finished dosage form” pharmaceutical companies must produce drugs in compliance with the Good Manufacturing Practices of 21 CFR 210/211. It says so right in 210.1(a) and 210.3(a)(3). It doesn’t say anything about the vendors of the drug firm, though. Sure, there is an expectation that a drug firm ensures that their vendors provide quality products meeting their expectations (that whole “safety, purity, identity, and quality” thing, plus there’s an implied expectation under 21 CFR 820.50(a), applicable to a drug firm under 21 CFR 820.1(b) – you did know that, right?), but surely FDA cannot directly cite a vendor if the regulation doesn’t give them that authority.
À nouveau, au contraire! FDA regularly inspects Active Pharmaceutical Ingredient manufacturers and cites them against Part 210/211, as guided by ICH Q7A (yes, another of those pesky guidance documents)…because the predicate Safe Food, Drug, and Cosmetic Act’s definitions of adulterated (21 U.S.C. §501(a)(2)(B)) and drug (21 U.S.C. §201(g)(1)) authorizes them to do so.
5. Recalls, Recalls, Recalls
In case you missed this, FDA just got sweeping new authority to preemptively order recalls of food products. Prior to 2011, FDA only had such statutory authority over a narrow subset of foods (baby formula, acidified canned products); they’ve also had this authority over medical devices for years. This underlines a common confusion about which regulations actually cover recalls: generally, they’re described in 21 CFR 7, but because Congress has granted FDA preemptive authority over various industries over the years, Part 7 is often supplemented by an industry-specific regulation (in the case of devices, you’ll find those additional regulations in 21 CFR 810).
There was a move to include preemptive drug recalls in the Food Safety Modernization Act but it got dropped…for now. I expect the McNeil situation to re-ignite this debate in Congress, which had quieted down a bit since the last person was killed by adulterated heparin.
6. Miscellany
FDA’s ability to order recalls—along with their power to refuse or rescind Certificates of Foreign Governments, detain product at Ports of Entry (as opposed to outright confiscation requiring court order), suspend Clinical Trials, and their greatly underappreciated ability to pick up the phone and call Labor, EPA, OSHA, Customs, etc.—has rarely been diminished during their entire history and in fact continues to increase with time.
Often forgotten is the fact that FDA has non-judicial administrative options beyond just the approving or clearing of products, especially the rarely-invoked but powerful federal debarment of individuals. Think debarment is just a personal matter? Consider FDA’s recent move to debar the CEO of Forest Labs in connection with marketing shenanigans – if he is debarred, then he must either leave company management or Forest will lose its ability to submit for federal reimbursement from sCHIPS, Medicaid, Medicare, and Veteran’s Administration programs – money that few large pharmaceutical companies can survive without. FDA’s stated stance is they can debar him irrespective of proving his actual knowledge of wrongdoing because debarment is not a legal proceeding. As FDA chief Margaret Hamburg continues to look for outside-the-box ways of bending wayward firms to her will, I expect to only see more actions like this because FDA is simply not seeing companies change their ways in response to mere fines.
7. When You Can’t Beat ‘Em, Join Their Competitors
Speaking of outside-the-box thinking, I’ve saved for last the item that triggered this blog entry. Consider KV Pharmaceuticals: GMP issues, recalls, FDA inspections, 483s, Warning Letters, Consent Decree, third-party oversight. FDA essentially shuts down their operations, two of their three divisions promptly go out of business, several rounds of layoffs. Income stream is, well, challenged.
In a move no doubt intended to inject some much-needed cash, KV buys the exclusive rights to distribute a prenatal care medication, Makena, an Orphan drug that provides critical health benefits and for which there is no real alternative. Note that KV is a generics company, so this is something of a foray into the tradename business for them; patent owner Hologic developed the drug in conjunction with NIH.
The medicine in Makena was a true bargain at $20 per injection. KV decided to raise the price a little: $1,200 a dose!
FDA doesn’t regulate pricing, so what exactly can FDA do about this? Here’s what: FDA just announced that they intend to exercise “enforcement discretion” against pharmacies that compound their own version of Makena and sell it to prescribers. It’s unclear what recourse KV or Hologic may have in suing these pharmacies for intellectual property violations, but with this announcement FDA has basically declared open season on KV by promising that if you make your own version of Makena (and presumably don’t sell it for $1,200) then FDA will not go after you for misbranding.
I bet KV management didn’t see that one coming!
Conclusion
All too often, I find that Top Management of Life Science firms believes that the best and most cost-effective strategy is to always do as little as possible. That top-level philosophy inevitably trickles down to middle management and brews a culture of noncompliance – spend your time on figuring out ways to avoid complying with FDA’s recommendations rather than efficient ways to implement Agency expectations.
In my nearly quarter-century in this industry, I have yet to see a single instance where this approach actually worked, but I have seen countless cases where it backfired in ways that management never dreamed of. In the March 2005 Gold Sheet (volume 39, number 3), no less a personality than David Elder, Director of Enforcement for FDA's Office of Regulatory Affairs, said it best:
“If we ask a question and the answers are so guarded that they are one-syllable answers, you are creating an impression. When you could clarify something, but choose not to under corporate policy or advice of counsel, you are creating an impression. I do not know if it is doing you any good, because you are extending the period of time we will be there...if we do not get the full answer that we are looking for, we are going to ask the question six different ways, and on different occasions. The people that are proud of their operations...have nothing to hide.”When FDA finds that a firm goes out of its way to avoid adopting best practices and Agency recommendations, that creates an impression. Impressions are formed by strategies, strategies are formed by culture, and culture is established by management’s attitude. If Top Management doesn’t understand that FDA has ways of punishing them that go far beyond anything taught in an MBA class, they may be dooming the very business objectives they are trying so hard to achieve.
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