首页 > 资讯 > 阻止仿制药标签剔除会是新的专利常青？

出自识林

2015-05-12 Lachman CONSULTANTS

过去常见的专利常青问题，就是一次次获得和列出新发布的专利，从而获得多次30个月的遏止期，基本上能够延长时间，阻止仿制药上市。这搅起许多波澜，所以最后需要法规免除来解决这个问题。现在，如果ANDA递交时已有恰当的专利声明，之后针对原研药列出的专利，ANDA申请人仍需要对专利进行声明，但不会有第二个30个月的遏止期（大多数情况）。

现在，焦点转移到Hatch-Waxman法案的标签剔除条款，最近爆发了很多关于专利剔除的请愿和法院挑战，FDA也许有点担心。我们知道当申请人引用的参照药物（RLD）有专利或市场专营期保护时，如果剔除不会导致产品比RLD不安全，可以在标签中剔除相关受保护的适应症或其它信息。

如果历史的表现有指示作用，大家可能觉得FDA允许标签剔除和对法规的使用是运行良好的，如：最佳儿童医药品法案（BPCA），和Hatch-Waxman剔除条款法案。在整个Hatch-Waxman法案期间只有少量的标签剔除要求被FDA拒绝（如：雷帕霉素和环孢霉素的联合口服使用）。但是最近，在NDA批准后和仿制药上市前，发生了一些标签受保护的案件；这些案件是非常复杂和精明老练的，可能使FDA动摇了其态度，担心，参照药物持有人可能找到了新的策略来阻止仿制药上市。FDA擅长确保在标签剔除有清晰的潜在安全性风险时延迟批准；因为标签剔除而导致产品安全性降低的情况在过去看起来很少发生，但是现在一些受保护的标签是如此的精明老练，这可能变成下一个潜在的“专利常青”游戏，这令FDA非常恼怒。

最近有声明说没有法规条款允许剔除标签中的孤儿药专营期信息，这是FDA自从Hatch-Waxman法案通过后允许的，FDA因为这涉及到最近批准的阿立哌唑，相关FDA回复信请见此处。但是据FDA官员指出，这只是“一系列相近问题的其中之一”，正在排队等待评估。我想，我们都同意现在的法规条款是要保护公众，并保证有标签剔除的仿制药获批时，不会比RLD的安全性低；但是现在，FDA面临着更复杂的关于这类情况的挑战，我们也许会看到更多标签剔除的拒绝。这当然是整个制药业都感兴趣的话题。但是，请记住，FDA做出的每个决定都会打破这个平衡，FDA不能作出不保证患者安全的决定。

Lachman CONSULTANTS - Bob Pollock先生 2015-05-08
编译：识林-榕 2015-05-11
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FDA Facing Daunting Task of Vetting More Complex Carve-Out of “Protected” Labeling – Is this the New Evergreening?
Written by Bob Pollock • May 08, 2015

Remember the problem associated with the evergreening of patents, which was the practice of obtaining and listing newly issued patents sequentially, and the resultant multiple 30-month stays that essentially kept generics off the market for prolonged periods of time? This caused so much of a stir that ultimately, statutory relief was required to resolve the problem. Now, if an ANDA has been submitted with an appropriate patent certification at the time of a later listing patent, while the ANDA applicant must still certify to the patent, will (in most all cases) not be subject to a second 30-month stay.

Now the focus may be changing relative to the Hatch-Waxman label carve-out provisions and, with the recent rash of petitions and court challenges relating to carve-outs, the FDA may be somewhat worried. We know that an applicant that cites a reference listed drug (RLD) subject to a period of patent or market exclusivity may carve out language in its label related to an indication or other protected information if the resultant carve-out does not result in a product that is less safe than that of the RLD.

If historical performance is an indication, one might think that FDA’s record of permitting carve outs and its use of tools, such as the Best Pharmaceuticals for Children Act (BPCA) and the Hatch-Waxman carve-out provisions have worked well for FDA, as only a handful of carve-out requests have been denied (e.g., Rapamnune and its titration dosing with cyclosporine) over the course of Hatch-Waxman. However, the complexity and sophistication of some of the recent protected label additions post-NDA approval and prior to generic entry has the FDA shaking in its boots, worried that the RLD holders have perhaps found a new strategy for the delay of generic entry. FDA has been pretty good at assuring that, in all but the clear cases of potential safety relative to a label carve out have resulted in delay of approval, but now the sophistication of some of these protected labels have gotten to such a level that the once seemingly rare decision to delay a generic because the carve-out would create a product that is less safe, appears to perhaps become the next potential patent “evergreening” play and is giving the FDA fits.

FDA recently responded to a claim that there is no statutory provision to permit the carve out of Orphan Drug Exclusivity information, something it has permitted since the passage of Hatch-Waxman in a response it posted on its web site (here) as it relates to its recent approval of aripiprazole. But this (according to an FDA official) is just “one in a series of similar issues” it has in its queue for evaluation. I think we all can agree that the current statutory provisions protect the public and assure that when a generic is approved with a carve out that it is no less safe than the RLD, but now, as the Agency faces more complex challenges relative to assuring such, we may see more denials of carve outs. This is certainly an issue that the entire pharmaceutical industry should show a great interest in. But, remember, there is a balance to be struck in each decision the FDA makes and it cannot make a decision that does not assure the safety of the patient.