FDA Lawyers Blog

by Howard E. Rosenberg, Ph.D.

Three more Supplementary Protection Certificate ("SPC") cases were decided by the Court of Justice of the European Union ("CJEU") recently underlining and further enhancing the decisions in the two cases Georgetown and Medeva, which we previously reported on here.

In Case C 630/10, the University of Queensland owned three patents but had been unable to get any SPCs at the United Kingdom's Patent Office. The UK Patent Office rejected all the SPC applications submitted, either because: (1) the combination of active ingredients in question were not claimed in the patents concerned or (2) the Marketing Authorizations ("MAs") provided in support of the SPC applications related to medicinal products containing other active ingredients that were not claimed in any of those patents, even though the applications related to individual active ingredients that were claimed in the patents concerned. The patents related to methods of production of papillomavirus-like particles ("VLPs") of the Human papillomavirus ("HPV") Type 6 ("HPV 6") and Type 11 ("HPV 11"), the VLPs per se and vaccines produced from or comprising VLPs.

As in Medeva, the first set of questions were answered by first restating that Article 3(a) of the regulation precludes the grant of an SPC relating to active ingredients that are not specified in the wording of the claims of the basic patent (Medeva, paragraph 25). Next, the CJEU stated that Article 3(a) of Regulation No. 469/2009 must be interpreted to preclude the competent industrial property office of a Member State from granting a SPC relating to active ingredients that are not identified in the wording of the claims of the basic patent relied on in support of the SPC application.

by Brian Malkin

On December 27, FDA issued a draft guidance, "Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices," which was jointly issued by the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, the Center for Veterinary Medicine, and the Center for Devices and Radiological Health. The Guidance "updates and clarifies" FDA's current thinking and policies for providing unsolicited, off-label information to consumers, including information provided by "emerging electronic media." "Off-label" uses are unapproved or uncleared indications or conditions of use for products that are otherwise approved or cleared by FDA for other uses. Medical professionals with prescribing authority may generally prescribe any product approved by FDA for any conditions or uses, whether FDA approved or not, as part of their practice of medicine.

FDA explained that its rationale for providing the guidance is an effort to balance the desire or need of individuals to obtain additional information about approved products with the potential for a product's manufacturer to provide information that may be viewed as promotional. FDA's Guidance, however, appears motivated, at least in part by a Citizen Petition filed by seven medical product manufacturers asking FDA to clarify FDA its regulations and policies governing communication of new or off-label use of marketed products. According to the Petition, FDA's vagueness regarding permissible manufacturer speech regarding off-label use has significant consequences to manufacturers, the government, physicians, and patients., as we reported here.

As part of FDA's rationale, the Guidance stated that on the one hand, a product's manufacturer typically maintains a large database of information about their FDA-approved products, including information obtained about possible off-label uses that may over time become the medically-recognized standard of care. On the other hand, a manufacturer's statements that promote their products for off-label uses are considered potential evidence of a manufacturer's illegal intent to promote its products for those off-label uses or conditions. FDA also recognizes that the Internet with its emerging news sources, such as social media or chat rooms, provides additional opportunities for consumers to seek medical information and receive information that is both accurate and useful or biased and otherwise inaccurate from product manufacturers or third-party sources.

by Erin A. Lawrence

The number of drug shortages has escalated to a record of over 250 this year. The Associated Press reported this past December that at least 15 patient deaths were attributable to drug shortages since mid-2010.

By current law, FDA cannot force manufacturers to report supply disruptions unless they are the only maker of a life-saving drug. On December 7, 2011 and December 15, 2011 the Senate had hearings to address this drug shortage problem. Legislation has already been introduced in both the House and the Senate to mandate that drug manufacturers be required to report to FDA any discontinuous, disruption, or other change that may cause a drug shortage, not just when they are the only drug maker of a life-saving drug. Newly proposed legislation will also allow drugmakers guilty of price gouging or forcing hospitals to buy life-saving drugs that are in shortage at higher prices, to be penalized by up to $500 million dollars for each case.

The Government Accountability Office ("GAO") determined that drug shortages are mostly caused by manufacturing problems. The GAO's solution to this problem would be to give the FDA more information and more authority. When the FDA knows of a shortage, it has the discretion to prevent and alleviate the shortage with steps such as allowing foreign-approved drugs into the U.S. The FDA successfully alleviated 137 shortages over the past two years with advance notification of a potential shortage.

Most of the drug shortages are generic drugs. In response, generic drugmakers plan to set up a private-sector system to inform patients and others of supply problems. The drugmakers will work with distributors, wholesalers, and others to create an advance warning system for the medicines in short supply.

by Julie E. Kurzrok

On December 16, FDA approved EXCOR®, the first ventricular assist device ("VAD") designed for use in children. Berlin Heart, a closely-held German company, designed the mechanical heart device, which is already approved for use in Europe and Canada. FDA designated the device as a Humanitarian Use Device, which means it is used to treat or diagnose a disease affecting less than 4,000 people in the United States each year.

FDA approved EXCOR® under the Humanitarian Device Exemption ("HDE"), which allows for approval without efficacy studies, and only requires a demonstration that the probable benefit of the device outweighs the risks from its use and that the device does not pose an unreasonable or significant risk of illness or injury. The applicant must also show, for example, that there is no comparable device available to treat the disease.

EXCOR® is a mechanical cardiac support system designed specifically for children with congenital or other heart defects that prevent their hearts from pumping enough blood into their bodies. EXCOR® consists of one or two external pumps connected to tubes which are implanted into the ventricles and major arteries, and a separate driving unit. Each external pump controls one ventricle. The device comes in different sizes to accommodate newborn babies through teenagers, and functions to bridge patients while they await a heart transplant. According to FDA, "[I]n infants, the median waiting time for a donor heart is 119 days [and] . . . 12-17 percent of children and 23 percent of infants die while on the wait list for a heart transplant."

by Kyle Deighan

Drug shortages have become a major problem in the United States, resulting in countless people unable to obtain essential medications, as we have previously reported here. However, outside the obvious implications for those desperately in need of hard-to-find life-saving drugs, another troubling issue has also come to light: prescription drug price gouging. Reports of unscrupulous drug manufacturers selling medications in short supply at huge markups abound, and these so called "gray market" distributors have thankfully not escaped Washington's watchful eye.

Senator Jay Rockefeller (D-W.V.), in a statement to the Senate Committee on Finance, discussed the price gouging phenomenon:

One disturbing side effect of the current shortage of many drugs to treat cancer and perform surgery is the parallel "gray market" that has sprung up to take advantage of health care providers' urgent need to treat their patients. As documented in an August 2011 report prepared by the Premier health care alliance, gray market vendors sell drugs that hospitals are not currently able to acquire through their normal distribution networks. These vendors take advantage of supply shortages to sell the drugs at huge markups. In a survey of solicitations that hospitals actually received from gray market vendors in April 2011, Premier found that the gray market companies were selling drugs to hospitals at prices that were an average of 650% higher than the prices the hospitals normally paid.

by Scot B. Pittman

Last Thursday, Senators Chuck Grassley (R-Iowa), Richard Blumenthal (D-Conn), and Herb Kohl (D-Wis.) introduced the Medical Device Patient Safety Act, which aims "to enhance Food and Drug Administration oversight of medical device recalls [and] to provide conditional clearance of certain medical devices." The proposed legislation sets forth a program by which FDA is to gather information regarding device recalls ordered under 21 U.S.C. § 360h(e) and information submitted when a device is corrected or removed under 21 U.S.C. § 360i(g). According to the Bill, FDA is to use this information "to proactively identify strategies for mitigating health risks presented by defective or unsafe devices." The program should gather any information FDA deems appropriate, which would at least include: trends in the recalls, the most frequently recalled devices, the causes of the recalls, the time needed to complete the recall, the time FDA needs to terminate the recall, whether there have been recall audit checks, and persons who have been subjected to the most recalls.

The Bill dictates that FDA is to develop "explicit criteria" to evaluate if an individual has sufficiently complied with a recall, and FDA is to document the bases for any recall terminations, which it shall publish within 180 days of the termination. According to The Gray Sheet, members of the device industry have voiced support for an improved device recall process claiming that FDA has been "slow to classify recalls or announce when a recall has been successfully completed." (Senate Bill Would Allow 510(k) Condition of Clearance Studies - The Gray Sheet, Dec. 19, 2011.) AdvaMed's Executive Vice President of Technology and Regulatory Affairs, Janet Trunzo, stated, "FDA could do more to enhance the clarity and consistency of its recall process, and we are pleased that the agency has a number of initiatives underway in this area."

Support for the Bill's proposals is not unanimous; however, as some industry representatives claim the Conditional Clearance section is unnecessary. This part of the Medical Device Patient Safety Act would add Section 510A to the Federal, Food, Drug, and Cosmetic Act to allow for the conditional clearance of medical devices approved pursuant to Section 510(k). Currently, FDA lacks significant resources and authority to perform such monitoring. The Agency can only require post-approval studies for Class III PMA devices and certain 510(k)-cleared and PMA-approved devices. Under the proposed Bill, FDA would have the authority to rescind an approval if an applicant failed to meet the conditions for approval.

by Brian Malkin

On December 16, a group of Senators sent FDA a letter urging FDA to prohibit the use of flavorings in cigars. The letter was signed by Senator Frank Lautenberg (D-N.J.) joined by Senators Dick Durbin (D-Ill.), Sherrod Brown (D-Ohio), Jeff Merkley (D-Ore.), and Richard Blumenthal (D-Conn.).

According to the letter, more than 13 million Americans smoke cigars, including an estimated 1.8 million high school students and 475,000 middle school students. Unlike cigarettes, which FDA regulates under the 2009 Family Smoking Prevention and Tobacco Control Act ("the Act"), FDA has so far chosen not to regulate cigars as "tobacco products."

Cigars and little cigars or "cigarillos" are like cigarettes because they contain tobacco and are intended to be smoked, so they arguably contain the same ingredients that were described in the Act as "inherently dangerous and cause cancer, heart disease, and other serious adverse health effects" and are addictive because they contain nicotine, "an addictive drug." Another purpose of the Act was to reduce smoking by "young people," including minors, who may be tempted to smoke, particularly when tobacco products contain non-tobacco-type flavors.

by Howard Rosenberg

The EU ban on stem cell patents, issued in an October 2011 Court of Justice of the European Union ("CJEU") opinion, continues to generate controversy and input from a wide variety of viewpoints. This week Aurora Plomer, professor of law and bioethics at Sheffield University argued that the ban not only imperiled Europe's competitiveness but also the protection of human rights.

The professor attacked the decision from a legal perspective arguing the ruling suffered from several flaws. She stated that the drafting history of the EU directive on biotechnological inventions, showed that the intention was never to render unpatentable lawful research and that there isn't a uniform pan-European view on what respect for human dignity means with regard to human embryos, contrary to the position taken by the Court of Justice. She also pointed out that the ruling was inconsistent with the settled law of the European Court of Human Rights in that that court has applied a "margin of appreciation" doctrine in relation to the rights of the embryo accepting that the status of the embryo can differ from state to state.

The CJEU's decision, binding on all member states, was that the concept of a human embryo had to be understood in a very wide sense ensuring respect for human dignity and, consequently, stem cell lines whose derivation required the destruction of human embryos were not patentable under European law. However, if the European Convention on Human Rights has no requirement for a consistent application or understanding of embryonic human rights amongst the EU member states then the CJEU's decision may well be at odds with it. According to Professor Plomer,. the CJEU ruling raises important questions about the compatibility of EU law with the European Convention on Human Rights, which the EU is bound to respect.

Professor Plomer also felt that the ban would deter investment and frustrate the EU's goal of harmonising laws to speed up the development of regenerative treatments that are anticipated to offer huge therapeutic potential, e.g. in Alzheimer's and Parkinson's disease.

by Kyle Deighan

The Third Circuit on Monday heard oral arguments on the legality of a settlement between several pharmaceutical companies in In re: K-Dur Antitrust Litigation. Under the 1997 agreement, patentee Schering-Plough Corp. (now part of Merck & Co. Inc.) made a $60 million payment to generic companies Upsher-Smith Laboratories Inc. and ESI Lederle. At Monday's argument, Merck argued that the agreement was not to delay the generics entry into the market, but rather for a separate licensing agreement.

The suit, which was initiated in 2001, was brought by direct purchasers alleging that the agreements delayed generic versions of the blood pressure medication K-Dur 20 and violated the Sherman Act. Last year, a lower court determined that the agreements were not per se unlawful. Monday, Merck argued that reverse payment settlements often benefit consumers by allowing generics to enter the market sooner, before a patent's expiration date.

According to amicus appellant the Federal Trade Commission ("FTC"), so-called reverse payment agreements significantly delay generic entry into the market. They estimate that generic entry is delayed an average of 17 months as a result of these agreements. FTC argued that the decision should be vacated and sent back to the district court to determine whether the payment was to delay generic entry, or whether it was in fact for a licensing agreement.

by Scot Pittman

This coming Friday, December 16, 2011, the Food and Drug Administration will hold a public meeting to discuss and solicit comments regarding its December 7th Federal Register Notice titled "Proposed Recommendations for a User Fee Program for Biosimilar and Interchangeable Biological Product Applications for Fiscal Years 2013 Through 2017." This proposal is the result of numerous discussions among FDA, the regulated industry, and public stakeholders. FDA will continue taking public comments through early January and has until January 15, 2012 to make any changes before submitting the agreement to Congress.

The proposed recommendations outline anticipated user fees and set forth performance goals and procedures for the biosimilar product review program (see previous post here). Overall, the proposal recommends collecting initial and annual fees aimed at getting the biosimilar review program up and running. FDA has stated that it will need $20 million in non-user fees to support the biosimilar review program before it will spend the user fees it collects. FDA is authorized to spend user fees on activities related to the review of biosimilar submissions, which will cover activities in the pre-submission, review, and post-approval stages.

The program proposes the following types of user fees: (1) biosimilar product development (BPD) fees; (2) marketing application fees; and (3) establishment fees and product fees.

BPD fees would come in two types. First, an initial BPD fee will be due on the same day an investigational new drug application (IND) is submitted or within five days of FDA granting a request for a BPD meeting (explained below). The initial BPD fee is retroactive and will apply to applicants who have previously submitted biosimilar INDs. The initial BPD fee for a product will cover all proposed indications. The fee is to be equal to 10 percent of the fee established for a human drug application under PDUFA for that year. Second, there will be an annual BPD fee due on or before October 1 of every fiscal year until the sponsor gets its marketing application approved.

by Brian Malkin

Whose seafood is your seafood, or, more appropriately, how do you know the fish you ordered is the fish you ordered? In October, FDA approved a new DNA barcoding system that can identify fish species similar to a supermarket scanner to prevent mislabeling of locally produced and imported seafood in the United States. Reportedly, other national regulators are considering adopting similar measures, which are described as fast, reliable, and cost-effective.

In most cases, the DNA barcoding system should prevent restaurant patrons from consuming inferior fish from the one that they thought they were consuming. In other cases, it may prevent unwanted health consequences for individuals who may be allergic to specific types of seafood, including exotic species that are banned. Just in 2007, several individuals became seriously ill following consumption of illegally imported toxic pufferfish from China that had been mislabeled as monkfish to circumvent U.S. import restrictions.

Seafood mislabeling is notorious. For example, a a pair of high school students in New York found 25% of the fish that they sampled around New York was incorrectly labeled as higher-end-type seafood.

by Kyle Deighan

According to Representative Louise M. Slaughter (D-NY), the United States Food and Drug Administration ("FDA") "has not acted in the best interest of public health, and continues to postpone, prolong, and de-prioritize important measures that are necessary to protect the American people." Rep. Slaughter expressed her displeasure with FDA in a letter dated November 28th, 2011, in which she addressed several concerns with FDA's approach with regard to antibiotic use in agriculture.

Rep. Slaughter's letter highlighted three major concerns:

1. The finalization of Guidance #209, "The Judicious Use of Medically Important Antimicrobial Drugs in Food Producing Animals," has been unacceptably delayed. In the past few months alone, 136 people were infected with the outbreak strain of antibiotic resistant Salmonella Heidelberg after consuming contaminated ground turkey. It is irresponsible to delay regulatory measures when public health is at stake.
2. FDA has consistently neglected to report critical information on antibiotic use in agriculture. At a time when antibiotic resistance is of growing global concern, reporting should be expanded, not limited.
3. FDA's rejection of two citizen petitions, asking for the withdrawal of approvals for the nontherapeutic uses of medically important microbials in food animals, has demonstrated an inability to address safety concerns in an acceptable or timely manner . . . The American people deserve better.

Rep. Slaughter's concerns center around the excessive use of antibiotics and the potential resistance issues that can arise due to overuse. According to the letter, researchers at Tufts remarked that "there is no doubt that human misuse and overuse of antibiotics are large contributors to resistance, particularly in relation to bacteria associated with human infection." However, the letter remarks that the U.S. has fallen behind other countries that have begun to ban the use of antibiotics as growth promoters in food animal production.

FDA recognizes that the overuse of antibiotics can cause resistance, noting on its website that "[b]acteria and other microorganisms that cause infections are remarkably resilient and can develop ways to survive drugs meant to kill or weaken them. This antibiotic resistance, also known as antimicrobial resistance or drug resistance, is due largely to the increasing use of antibiotics." While FDA clearly recognizes a link between resistance and antibiotic overuse, Rep. Slaughter's letter highlights growing concerns over inaction in mitigating the problem.

Rep. Slaughter concludes by asking FDA to deliver on its promise to protect public health, rather than protecting the interests of the agriculture industry. As reports are released every day concerning potential cases of drug-resistant infections, it will be interesting to see how FDA responds to pressure from Congress to develop more information on and eventually eliminate antibiotic overuse.

by Scot Pittman

On Monday, the Supreme Court heard oral argument in Caraco Pharm. Labs. Ltd. v. Novo Nordisk A/S (previously discussed here and here) to decide whether a generic drug manufacturer can use the counterclaim provisions of the Hatch-Waxman Act, as amended by the 2003 Medicare Prescription Drug Improvement and Modernization Act, to require a brand company to modify a "patent use code narrative." The Court's response to the arguments appears mixed. Justices Scalia and Alito questioned Caraco's counsel closely while Justices Sotomayor and Kagan scrutinized Novo Nordisk's counsel with the same degree of attention. The justices were plainly concerned with the statutory construction, the context of the counterclaim provision in the FDCA, and the recourse available to generic applicants who assert misuse of the use code narrative.

Statutory interpretation will play a key role in the Court's determination. Indeed, the justices debated the correct interpretation of "does not claim either . . . (bb) an approved method." The majority Federal Circuit opinion construed "an approved method" to mean "any approved method" -- not "all approved methods." Justice Alito asked Caraco's counsel: "Suppose I said your brief does not cite a Supreme Court decision. Would that be a correct statement?" (emphasis added). In other words, Justice Alito appears to argue that despite the use of the article "a" following the negative "not," the plain reading of the statute would translate to "any Supreme Court cases" and not "all Supreme Court cases." Under this interpretation, a counterclaim will be permitted only when the patent does not claim any approved methods of use. Applied to this case, the statute would bar Caraco's counterclaim because Novo's patent claims one approved method of use. Based on this discussion, it appears that Justices Scalia and Alito were more sympathetic to Judge Rader's majority opinion in the Federal Circuit decision.

The justices also struggled with the meaning of "patent information." At issue is whether "patent information" narrowly covers only the information described in subsections (b) and (c), namely patent number and patent expiration date, or is broad enough to encompass use codes. Again, Justices Alito and Scalia appeared to favor a more literal interpretation covering only patent numbers and use codes. However, Justice Breyer, citing FDA regulations, asked why the Court should not interpret "patent information" to include use codes.

By Julie E. Kurzrok

On November 30, 2011, Walgreen Co., The Kroger Co., Safeway Inc., Supervalu Inc., HEB Grocery Company LP, and American Sales Company, Inc., ("defendants") filed suit against Wyeth Inc. and Teva Pharmaceuticals USA, Inc. in the District Court of New Jersey under sections 1 and 2 of the Sherman Act, 15 U.S.C. §§ 1 & 2, and section 4 of the Clayton Act, 15 U.S.C. §15(a). The complaint alleges that Wyeth (a wholly-owned subsidiary of Pfizer) and Teva conspired to maintain a monopoly power and to delay the approval and marketing of generic versions of Wyeth's antidepressant, Effexor XR® (venlafaxine hydrochloride). Wyeth's marketing exclusivity for Effexor XR® was scheduled to end on June 13, 2008, with the expiration of U.S. Patent No. 4,535,186 ("the '186 patent"), the original compound patent for Effexor XR®.

The defendants allege that Wyeth fraudulently procured three method-of-use patents for extended release venlafaxine hydrochloride, listed them in the Orange Book, and initiated 17 sham litigations in order to manipulate the Hatch-Waxman statute and delay the entry of generic versions of Effexor XR®. The method-of-use patents are U.S. Patent Nos. 6,274,171, 6,419,958, and 6,403,120, all of which expire on March 20, 2017, nine years after the expiration of the '186 patent. Teva was the first generic company to file an Abbreviated New Drug Application for extended-release venlafaxine hydrochloride with a paragraph IV certification to the method-of-use patents (amending its 2002 ANDA).

by Andrew S. Wasson

FDA recently released a draft guidance setting forth recommendations for device applicants who plan to submit an Investigational Device Exemption ("IDE") or a premarket approval ("PMA") application for an Artificial Pancreas Device System ("APDS"). Throughout the draft guidance, FDA maintains that its goal is to provide maximum flexibility to sponsors and applicants but at the same time maintain stringent safety and effectiveness standards.

Despite the connotations surrounding a term like "artificial pancreas," the APDS is not a synthetic organ or tissue system. Rather, the "artificial pancreas" contemplated by the FDA draft guidance is a combination of existing technologies which would work together to automatically regulate blood glucose levels in the human body. For example, an APDS would comprise a continuous glucose monitor, a control algorithm, and an infusion pump to deliver the glucose according to the algorithm. FDA takes pains to note that the patient is also an integral part of the APDS because the levels of circulating glucose depend closely on diet, activity level, and metabolism.

According to FDA, the draft guidance seeks to: (1) facilitate an expedient path to outpatient studies for sponsors, (2) create "maximum flexibility" for sponsors to determine clinical study size and duration, (3) describe standards for both non-inferiority and superiority criteria, and (4) explain approaches to allow for the "leveraging" of existing safety and effectiveness data from currently-marketed devices. FDA recommends that an APDS product be studied in an Early Feasibility Study phase, a Transitional Study phase, and a Pivotal Study phase.

by Kyle Deighan

A maker of a computer-assisted sedation system has reached a settlement with the United States Food and Drug Administration ("FDA"), withdrawing its request to go before a dispute resolution panel to contest FDA's decision not to approve its product. FDA had denied approval of the device developed by Ethicon Endo-Surgery ("Ethicon"), a division of Johnson & Johnson. After Ethicon appealed the decision to FDA Commissioner Margaret Hamburg, MD, it was granted a hearing that was scheduled for December 14th. However, a letter from Ethicon dated November 28th informed Hamburg of a deal to settle the appeal with FDA's Center for Devices and Radiological Health ("CDRH").

The device at issue, called Sedasys, is a computer-assisted sedation system that uses propofol, a sedative hypnotic drug, to provide moderate sedation during colonoscopy or endoscopy procedures. The system allows doctors or nurses to provide the sedation, eliminating the need to have an anesthesiologist present. Notably, propofol is approved for use only by those able to administer anesthesia. However, Ethicon has developed a program to train non-anesthesiologists to use the device.

The device was seemingly on its way to approval when the FDA's Anesthesiology and Respiratory Therapy Devices Advisory Committee voted 8 to 2 to approve the device in 2009. However, FDA rejected it in 2010, stating the "the Sedasys System is associated with an increase incidence of deeper-than-intended sedation," and that "the data and information offered in support of the PMA did not provide a reasonable assurance that the device is safe under the conditions of use prescribed, recommended, or suggested in the proposed labeling, as required by section 515(d)(2)(A) of the FD&C Act." FDA argued the device should have been limited to administration by those trained in general anesthesia. FDA pointed to Ethicon's clinical trial, in which five patients treated using Sedasys drifted in and out of consciousness. Following FDA's rejection, Ethicon appealed, and the hearing was to follow.

The dispute resolution procedure was to consider several questions, including whether a new trial of the device should have been required, whether the five incidents in the clinical trial should have been a concern, and whether the training program offered by Ethicon was adequate. However, the settlement indicates that some of these concerns have been alleviated or will be in the near future.

According to Karen Licitra of Ethicon, "we've worked cooperatively with the FDA in recent months to address the agency's concerns and we're optimistic that we now have a path forward that will allow us to bring this important innovation to market." Karen Riley, of FDA, stated "suffice it to say, CDRH and the company found a pathway to move the application forward that should address the agency's safety concerns."