Ranbaxy and Teva won a victory in the U.S. Court of Appeals for the D.C. Circuit that preserved their 180-day exclusivity when patents are delisted from the FDA Orange Book. Ranbaxy et al. v. Michael O. Leavitt, Secretary of Health and Human Services et al. (06-5154). Ranbaxy and Teva had challenged the decision on the basis that it was inconsistent with the Hatch-Waxman Act.

Before marketing a new branded drug, the manufacturer must file with the FDA a New Drug Application (NDA), including evidence the drug is safe and effective, and the identifying number and expiration date of any patent or patents covering the drug. When it approves the NDA, the FDA must publish the patent information, which it does in Approved Drug Products with Therapeutic Equivalence Evaluations (a/k/a the Orange Book).

Before marketing a generic drug, the manufacturer may submit an Abbreviated New Drug Application (ANDA). Unlike an NDA, an ANDA need not contain evidence of the drug’s safety or efficacy. However, each ANDA, however, must contain "a certification ... with respect to each patent which claims [a drug or a method of using a drug listed in the Orange Book] for which the applicant is seeking approval under this subsection and for which information is required to be filed under subsection (b) or (c) of this section - (I) that such patent information has not been filed, (II) that such patent has expired, (III) [that] such patent will expire [on a specified date], or (IV) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted[.]"

The Act rewards the first manufacturer to file an approved ANDA containing the certification in paragraph IV by giving it a 180-day period of marketing exclusivity, which begins with the earlier of the applicant’s first commercial marketing of the generic drug or when the applicant prevails in a suit over infringement or the validity of the patents covering the branded drug.

When a patent is removed from the Orange Book (or delisted), the FDA by regulation requires the sponsor of the corresponding ANDA to delete its paragraph IV certification with respect to the delisted patent. If no patent covering the branded drug remains listed, then the generic applicant must file a paragraph I certification, and the FDA treats the ANDA as though it had never contained a paragraph IV certification. As a result, the generic applicant that was first to file an approved application does not get the 180-day period of exclusivity.

Merck submitted to the FDA information with respect to three patents covering the drug Zocor®: U.S. Patent Nos. 4,444,784, RE 36,481, and RE 36,520. Teva and Ranbaxy each filed an ANDA to market generic simvastatin. The two ANDAs - both of which were eligible for a 180-day period of marketing exclusivity because they involved different dosages - each contained a paragraph IV certification with respect to the '481 and '520 Patents. With respect to the '784 Patent, Ranbaxy and Teva each filed a paragraph III certification that it would expire in December 2005.

Merck, however, did not sue Ranbaxy or Teva for patent infringement based upon their paragraph IV certifications. Instead, before their ANDAs were approved, Merck asked the FDA to delist the '481 and '520 Patents from the Orange Book, which the agency did in 2004. Consequently, Ranbaxy and Teva were required to delete the paragraph IV certifications from their ANDAs and thereby lost their eligibility for a period of marketing exclusivity.

Ranbaxy and Teva each filed a citizen petition asking the FDA to relist the two patents. The FDA denied the petitions because Merck had not sued Ranbaxy or Teva for patent infringement. Ranbaxy and Teva then repaired to the district court, which entered a summary judgment for the plaintiffs, and the FDA appealed.

The D.C. Circuit held that the FDA’s requirement that a generic manufacturer’s patent challenge give rise to litigation as a condition of retaining exclusivity when a patent is delisted is inconsistent with the Act, which provides that the first generic manufacturer to file an approved application is entitled to exclusivity when it either begins commercially to market its generic drug or is successful in patent litigation.

Legislators are stepping up the pressure in the long running saga of getting generic versions of biotech drugs to market. The FDA approves generic versions of pharmaceutical (small molecule) drugs once the patents for brand-name products expire. But complex biotech drugs do not have such an approval process.

Representative Henry Waxman and Senator Orrin Hatch gave a talk to the Generic Pharmaceutical Association on the need for legislation that would balance the interests of generic drug makers and brand-name manufacturers who shoulder staggering drug development costs.

Waxman said he plans to introduce a bill to spur the U.S. Food and Drug Administration into action on the long-overdue FDA guidelines for manufacturers to follow to produce generic versions of biotechnology drugs. Hatch, on the other hand, said that the issue is too important to try to pass before the Senate recess, expected at the end of next week. Also see the letter that Hatch and Waxman sent to the FDA earlier this year.

While the FDA has approved Novartis AG's Omnitrope hormone, there has not been a change in the stance taken by the FDA on generic biotechnology drugs. Omnitrope was approved only after a federal judge ordered the FDA to decide after a long delay. Also, Omnitrope is considered less complicated than most other biologics.

Under both the Federal Food Drug and Cosmetic Act and the Food Prescription Drug User Fee Act, the FDA is required to either approve or reject new drug applications. However, no biogenerics (or follow-on proteins) have yet been approved in the US pharmaceutical market beyond Omnitrope. It is argued that the 505(b)(2) provision of the Hatch-Waxman Act (the Hatch-Waxman amendments of the Federal Food, Drug and Cosmetic Act) lays out an abbreviated approval pathway (ANDA) for generic versions of small molecule drugs) provides a route for the FDA to approve a biological therapy that is different from the originator product, yet relies on data filed by the innovator as part of the original NDA.

The reason for the lack of a regulatory pathway for approval of biogenerics lies in the complexity of the biological products themselves. Biologics are large, complex, heterogeneous molecules for which the manufacturing process can be a determinant of the end product. Demonstrating that a generic version of the product is as safe and effective as the brand name product would be a difficult at best since, for example, establishing that immunogenicity had not been altered and that any undetected differences in the product would not impact safety and efficacy would be problematic without conducting extensive clinical trials.

But the stakes are high, given biotech drug sales are expected to top $60 billion by 2010. Biogeneric companies need an abbreviated approval pathway to avoid undertaking the same large scale clinical development process as the originator companies, and thus allow them to market their product at a discount to the brand while maintaining a healthy profit margin.

With Omnitrope, the FDA, however, went out of its way to say that Omnitrope is not a generic biologic stating that "Omnitrope is not rated as therapeutically equivalent to (and therefore substitutable for) any of the other approved human growth hormone products. Omnitrope is more appropriately characterized as a "follow-on protein product."

The FDA indicated that the approval of Omnitrope in a 505(b)(2) application does not establish a pathway for approval of follow-on products for biological products licensed under section 351 of the Public Heath Service Act, nor does it mean that more complex and/or less well understood proteins approved as drugs under the Food, Drug, and Cosmetic Act could be approved as follow-on products.

Just the same, brand name biotech companies may want to get a hold of a copy of Cutting Edge Information's report "Combating Generics: Pharmaceutical Brand Defense for 2007," which includes strategies to retain market share and defend patents including, among others, patent litigation and authorized generics and corporate generics subsidiaries. (More at Philip Brooks' Patent Infringement Updates)

AstraZeneca filed a request for an advisory opinion from the FDA pursuant to 21 C.F.R, § 10.85, asking whether patents directed to drug delivery systems, such as inhalation devices, that do not recite the approved active ingredient or formulation should be listed in the "Approved Drug Products With Therapeutic Equivalence Evaluations" ("Orange Book").

21 C.F.R. § 314.53 requires that New Drug Application ("NDA") applicants submit for listing in the Orange Book the patent numbers and expiration dates of any patent that claims the drug or a method of using the drug that is the subject of the NDA "with respect to which a claim of patent infringement could reasonably be asserted... .". The regulation states that patents that claim the "drug product" that is the subject of the NDA must be listed, but also states that patents claiming "packaging" must not be listed.

Earlier, the FDA published its final rules, Applications for FDA Approval to Market a New Drug: Patent Submission and Listing Requirements and Application of 30-Month Stays on Approval of Abbreviated New Drug Applications Certifying That a Patent Claiming a Drug is Invalid or Will Not Be Infringed, 68 Fed. Reg. 36676 (June 18, 2003).

In the rules, the FDA stated that drug products include "metered aerosols,. . . metered sprays . . . and pre-filled drug delivery systems" and that patents claiming such drug products should be listed in the Orange Book and noted that "[t]he key factor is whether the patent being submitted claims the finished dosage form of the approved drug product." The FDA didn't directly address whether patents directed to drug delivery systems that do not recite the approved active ingredient or formulation should be listed in the Orange Book.

GlaxoSmithKline asked the same question in January 2005, asking:

“If the patent claims a drug delivery device or elements of a drug delivery device approved as part of a New Drug Approval (“NDA”), but the patent does not specifically claim the active ingredient or mention the active ingredient or ingredients contained in the approved drug product, or if a patent claims the protective overwrapping of a drug delivery device, should information concerning that patent be submitted to the FDA for listing in the Orange Book?"

The FDA has not responded to GSK's request. In attempt to set out its intent, AstraZeneca summed up the request with the statement: “AstraZeneca will continue to list them unless it receives guidance from FDA that such listings are improper.”

A pharmacies' right to compound prescriptions came in jeopardy after the Food and Drug Administration argued that compounding creates new and unapproved drugs. In Medical Center Pharmacy, et al. v. Gonzalez, et al., No. MO-04-CV-130, District Court for the Western District of Texas, a suit was brought by 10 pharmacies against the Food and Drug Administration regarding the practice of pharmacy compounding. The court sided with the pharmacies saying that compounding ingredients to create a drug under a valid prescription does not create a new drug.

Drug compounding, a practice in which pharmacists manufacture prescription drugs from bulk ingredients, is traditionally done for medical reasons, such as when a patient is allergic to an inactive ingredient in the commercially manufactured drug. Typically, if a patient has a condition that off-the-shelf pharmaceuticals cannot meet, then customized compounded medicines are prescribed by physicians and prepared by licensed pharmacists. Every state legislature has authorized the compounding of drugs and state governments continue to regulate the practice.

In this ruling, the court went beyond its earlier finding that the FDA does not have the authority to classify compounded products as new drugs to add that the agency cannot prohibit pharmacists from using bulk ingredients to create customized medications. While the agency has never prohibited the use of bulk ingredients for human prescriptions, it had done so for animal products. Compounding proponents believed that the FDA would soon try to apply this policy to human drugs.

First, the Court ruled that compounded drugs do not fall under the new drug definitions and, therefore, are legal. Judge Junell explained: "If compounded drugs were required to undergo the new drug approval process, the result would be that patients needing individually tailored prescriptions would not be able to receive the necessary medication due to the cost and time associated with obtaining approval ... It is in the best interest of public health to recognize an exemption for compounded drugs that are created based on a prescription written for an individual patient by a licensed practitioner."

Second, the Court ruled that pharmacies are exempt from the requirement to submit to an FDA inspection of their records unless FDA can demonstrate that the pharmacy is not compliant with applicable state laws and does not operate as a retail pharmacy.

Third, the Court ruled that compounding from bulk pharmaceutical ingredients for non-food animals is legal. This is an important issue for animal owners and their veterinarians who prescribe compounded medications to treat a variety of conditions, many of which require medications that are only available by compounding bulk pharmaceutical ingredients. Without them, animals may needlessly suffer or even die. Until now, the FDA asserted that prescribing and preparing these treatments was illegal.

In 1938, Congress passed the Food, Drug, and Cosmetic Act to empower the FDA to require approval of new drugs made by pharmaceutical manufacturers. FDA began arguing in the late 1980's that Congress intended for that law to apply to compounded preparations in addition to manufactured products. This meant that, according to the FDA, each compounded medicine was a "new, unapproved drug" subject to the same requirements as manufactured products. Because these requirements are inherently impossible for compounding pharmacists to meet, it meant that FDA considered all compounded preparations illegal.

While the FDA asserted that compounded drugs fall within the definitions of new drugs under 21 U.S.C. §§ 321(p)(l) and (v)(l), the term "new drug" is defined as "Any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof..."

The court held that compounded preparations are not new, unapproved drugs. Two other issues in the case -- the Food and Drug Administration (FDA)'s broad authority to inspect pharmacies' records and pharmacies' ability to compound from bulk active ingredients for non food- producing animals (e.g. pets, horses, zoo animals) -- are still being considered by the judge.

Now, when you really need that special cocktail of Viagra, Bisquick and the little Purple Pill, you're good to go.

If you're familiar with the drug industry, it should come as no great shock that the Generic Pharmaceutical Association (GPhA) disagrees with a report put out by the Pharmaceutical Research and Manufacturers of America (PhRMA).

According to a recent report commissioned by the Pharmaceutical Research and Manufacturers of America (PhRMA), wholesale price discounts off brand prices on average were 15.8% greater in markets with authorized generics than in those without them.

The GPhA released its own analysis of authorized generics that concluded that the practice of introducing authorized generics (AGs) "significantly reduce incentives for independent generic firms to challenge invalid brand name patents and to develop non-infringing processes." This analysis also raised questions about the validity of the PhRMA study. The study concluded that, despite PhRMA's claims to the contrary, "the long-term effect of allowing authorized generics on the market during the 180-day generic exclusivity period will be less competition and reduced access to cheaper drugs."

The GPhA study of the PhRMA study concluded that the prices consumers pay will be virtually unchanged by the presence or absence of authorized generics (the GPhA claims that much of PhRMA's alleged "discount" associated with authorized generics is accounted for by higher brand name drug prices). It should be no big surprise that the GPhA also claims that allowing authorized generic entry during the 180-day exclusivity period harms the incentives generic firms have to challenge invalid patents or develop products.

An authorized generic is the brand's product repackaged and marketed either through a subsidiary or third-party. Because the brand is selling part of its inventory as a generic, it can currently compete with the true ANDA generic during the exclusivity period.

In creating the Hatch-Waxman Act, Congress determined that it was in the best interest of consumers to create the 180-day incentive to encourage generic companies to challenge questionable or frivolous brand pharmaceutical patents as part of the complex, intellectual property-based U.S. generic drug approval process. The 180-day exclusivity provision of the patent challenge process provides the check and balance in the drug patenting process, while also providing generic companies with a mechanism to recoup the significant costs of litigation and provides incentives to challenge more questionable patents in the future.

When authorized generics are marketed during the Act’s 180-day exclusivity period for first generic entrant, they reduce incentives for independent generic firms to challenge brand name patents and to develop non-infringing processes. Supporters argue that authorized generics offer significant consumer benefits.

The Drug Price Competition and Patent Term Restoration Act, known as the Hatch-Waxman Act, added section 505(j) to the Food, Drug, and Cosmetic Act. This created the Abbreviated New Drug Application (ANDA) process. The Hatch-Waxman Act, and specifically the ANDA process, were designed to provide independent generic firms a strong incentive to develop and introduce lower cost generic drugs to consumers. To implement this policy goal, Congress provided that the first generic ANDA filer that challenged an invalid brand name firm patent on which the brand name product relied, or that developed a non-infringing means to produce the same drug, would be granted a 180-day marketing exclusivity period. This process is known as the paragraph IV certification process.

The brand name firm may challenge the generic firm’s paragraph IV certification, claiming that the generic product violates the brand name firm’s patent rights. If a patent infringement action is filed within 45 days by the brand name firm, the FDA may not approve the ANDA for 30 months, or until the patent dispute has been resolved, whichever is sooner.

An ANDA applicant whose ANDA contains a paragraph IV certification is protected from competition from subsequent generic versions of the same drug product for 180-days after either the first marketing of the first applicant’s drug or a decision of a court holding the patent that is the subject of the paragraph IV certification to be invalid or not infringed.

Don't look for this sparring over authorized generics to end soon. This political football is hotly contested by the generic and brand-name drug companies, due to the billions of dollars at stake. The fact is that the number of authorized generics produced by the name brand companies has increased considerably over the past few years, and the issue will only get hotter. Where brand name drug pipelines are not as full as they could be, these companies will do whatever it takes to hold on to market share.

See the GPhA Report here.

For more on the FTC’s investigation into the matter, see here.

For the bill introduced to limit authorized generics, see here.

Without going into how much fun it is to look like a geriatric smoker walking around with an attractive nose cannula, there seems to be more and more interest in breathing in oxygen (at least air that has more oxygen than normal). There was even an oxygen bar at BIO this year. Now, the air may be sucked out of the market if these products are deemed drugs.

The Food & Drug Administration has stepped in and warned a company that makes and markets portable "oxygen enriched air" (OEA) for the treatment of a variety of ailments that it is selling a drug without an approved new drug application.

The FDA's letter warns BetterThanAir that it was making false and misleading promotional claims when it said that the company's canned air could cure or treat AIDS, lung cancer, cystic fibrosis, tuberculosis and high blood pressure. The BetterThanAir website claims that the proof of the effects of normal air (what they consider low oxygen) is the number of cases of cancer, AIDS, heart attacks and other illnesses that cripple and kill our bodies.

Among other products, BetterThanAir markets canned air under the brand names "Hangover Air," "Oxygen Kit," "B1ueAir," the "Personal Oxygen System," "O 2 Go," "Oxycan," "Oxygen Shot," the "3rd Lung Kit" and the "BetterThanAir Emergency Oxygen M6 Travel Unit."

The company claims its products can cure chronic mountain sickness, sleep apnea and hyperventilation and prevent other diseases. "Oxygen deprivation can, and is believed by the Medical Society to cause life-threatening diseases such as cancer," according to their website. BetterThanAir claims "Certain health specialists say oxygen therapy is now a critical adjunct treatment for cancer, AIDS, diabetes, stroke, depression, chronic fatigue, lupus and fibromyalgia."

Because BetterThanAir's oxygen enriched products are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and to affect the structure or function of the body, the FDA considers these to be drugs, as defined by Section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (Act), [21 U.S.C. § 321(g)(1)].

Moreover, the FDA claims that these products are new drugs, as defined by section 201(p) of the Act, [21 U.S.C. § 321(p)], because they are not generally recognized as safe and effective for their labeled uses. Under sections 301(d) and 505(a) of the Act, [21 U.S.C. §§ 331(d) and 355(a)], a new drug may not be introduced or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it.

Further, the FDA claims that these oxygen products are also prescription drugs within the meaning of section 503(b)(1) of the Act, [21 U.S.C. § 353(b)(1)], because they are not safe for use except under the supervision of a practitioner licensed by law to administer such drugs. Therefore, the FDFA contends that the "BetterThanAir™ oxygen enriched products" are misbranded within the meaning of section 503(b)(1) and 503(b)(4) of the Act, [21 U.S.C. §§ 353(b)(1) and 353(b)(4)] because they are marketed without a prescription and they lack the statement, "Rx only." The inclusion of the disclaimer, "Not for medical and prescription use," on the product's label does not remove the product from the prescription dispensing requirement of section 503(b)(2) of the Act [21 U.S.C. § 353(b)(2)].

The FDA feels that because these products are offered for use for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written so that a layperson can use these products safely for their intended uses. Thus, the "BetterThanAir™ oxygen enriched products" labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under Section 502(f)(1) of the Act, [21 U.S.C. § 352(f)(1)]. These products are not exempt from the adequate directions for use requirement because they do not meet the conditions set forth in 21 CFR § 201.100.

Finally, these products are considered misbranded under section 502(o) of the Act, [21 U.S.C. § 352(o)] and the products are subject to the Current Good Manufacturing Practice (CGMP) regulations at 21 CFR Parts 210 and 211. They may be considered adulterated under section 501(a)(2)(B) of the Act, [21 U.S.C. § 351(a)(2)(B)], if the methods used in, or the facilities or controls used during the product's manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with CGMP.

The FDA has directed BetterThanAir to immediately correct these violations.

I noticed that BetterThanAir will host parties and events featuring oxygen-enriched air with and without aroma. No word on the effects of the aromas.

See the Warning Letter here.

Merck is on the verge of losing patent protection for its multi-million dollar drug compound Simvastatin, paving the way for euphoric generic players to enter the U.S. Simvastatin market, which was worth around U.S. $4.4 Billion worldwide in 2005. Even though there is no current Para IV litigation for the Simvastatin tablet, the story so far is quite interesting, and central for the future of the U.S. generic industry, and more particularly for the First Para IV filer and subsequent Para IV filers. On June 23, 2006, generic players will start commercializing their generic versions of Simvastatin tablets, but the debate surrounding the generic launch and entry still continues to prevail. That is, if all generic players get the FDA final nod to market their generic versions, or if only Teva and Ranbaxy would reap the benefit of 180-day exclusivity for their generic Simvastatin tablets.

The Food and Drug Administration (the "FDA"), which earlier denied Ranbaxy and Ivax’s citizen petitions for not approving subsequently-filed ANDAs (before expiry of their 180-day exclusivity for respective strengths, and for reinstating the delisted patents to the Orange Book) has already made an appeal with the U.S. Court of Appeals against the decision of the U.S. District Court, which remanded and sent the case back to the FDA for a decision. Now interestingly, rather than being a conventional generic tussle between Innovator and Generics, this case is turning out to be decisive regulatory tussle between the FDA and the First Para IV filers, concerning a 180-day exclusivity issue.

Let us go back and revisit this unusual case history from its inception, to figure out the issues involved, and their impact on future generic industry, particularly when the Authorized Generics are turning out to be next big hurdle for the 180-day exclusivity holder.

Merck’s Goldmine

Merck hit a gold mine when the Merck scientists synthetically derived Simvastatin from a fermentation product of Aspergillus Terreus, while developing and researching lovastatin. In 1980, Hoffmann et al. filed a U.S. patent application for Simvastatin (its pharmaceutical composition and use thereof to treat hypercholesterolemia, against which U.S. Patent No. 4,444,784 was issued on April 24, 1984). Merck filed the new drug application (the "NDA") for simvastatin and for anti- hypercholesterolemia indication, being approved by the FDA on December 23, 1991, in 5 mg, 10 mg, 20 mg, and 40 mg strengths. Subsequently, the FDA listed the Simvastatin tablet along with the ‘784 Patent, with the Approved Drug Products, and with the Therapeutic Equivalence (Orange Book) under 21 U.S.C. § 355 (b) (1).

Listing Additional Patents & PTE

On May 20, 1993 the USPTO, under 35 USC § 156, extended the term of the ‘784 Patent for a period of 1,704 days, adjusting the patent expiry of the ‘784 Patent from April 24, 2001 to December 23, 2005. The FDA later approved the 80 mg strength of the Simvastatin tablet in 1998. In 2000, Merck further listed two additional patents, stating them to be metabolites of Simvastatin, namely:

1. U.S. reissued Patent No. RE36,481 (the ‘481 Patent)
2. U.S. reissued Patent No. RE36,520 (the ‘520 Patent)

Later, Merck also obtained Pediatric Exclusivity from Simvastatin tablets, extending the patent terms of the ‘784, ‘481, and ‘520 patents with additional 6 months.

Ivax Para IV Attack

Like other blockbuster drugs, Simvastatin also became a Para IV target in the same year when Merck listed additional patents for Simvastatin tablets. On December 14, 2000 Ivax submitted ANDA, with the FDA seeking marketing approval for its generic version of the Simvastatin tablet, in 5 mg, 10 mg, 20 mg, and 40 mg strengths. Ivax filed a Para III certification, with respect to the ‘784 Patent, but filed a Para IV certification with respect to additional patents, contending that the ‘481 and ‘520 patents were invalid or unenforceable, or that their drugs would not infringe the patents. Ivax notified Merck of the Para IV certification, detailing the factual and legal basis for its belief, and that its generic drug would not infringe the patents, or that the patents are invalid or unenforceable.

Ranbaxy Joins the Para IV Race

In November 2001, Ranbaxy became the second generic player to file Para IV certification with the FDA, seeking marketing approval for its generic version of the Simvastatin tablet in 5 mg, 10 mg, 20 mg, 40 mg, and 80 mg strengths. Ranbaxy was, however, first to file Para IV certification in the case of the 80 mg strength, as Ivax’s Para IV certification was intended for 5 mg, 10 mg, 20 mg, and 40 mg strengths. Like Ivax, Ranbaxy also filed a Para III certification with respect to the ‘784 Patent, and a Para IV certification with respect to additional patents, contending that the ‘481 and ‘520 Patents were invalid, unenforceable, or that their drugs would not infringe the patents. Ranbaxy also notified Merck of the Para IV certification, detailing the factual and legal basis for its belief that its generic drug would not infringe the patents, or that the patents are invalid or unenforceable.

Conquering 45 day Barrier

Merck did not sue Ivax and Ranbaxy within 45 days as required under 21 U.S.C. 355 (j) (5) (B) (iii), to trigger an automatic 30-month stay of the FDA approval of the ANDAs. As a result of this, both Ivax and Ranbaxy were entitled to a 180-day exclusivity for their respective strengths, and expected to launch their generic Simvastatin tablet after expiry of the ‘784 Patent. Until this, everything seems to be clear and evident that, with the expiry of the ‘784 Patent, Ivax and Ranbaxy would enjoy a 180-day marketing exclusivity and would be the sole generic players in U.S. Simvastatin market.

Big celebrations for Big Generic Predators!

FDA 2003 Rulemaking

On June 18, 2003, the FDA published its Revised Rules, clarifying the types of patents that must and must not be submitted to FDA for listing in the Orange Book, effective as of August 18, 2003. Under the Revised Rules, NDA holders are not allowed to submit patent information for listing in the Orange Book for: drug packaging, drug metabolites, and intermediates of a drug. In addition to this, the Revised Rules also added requirements for submission of: (1) polymorph patents (only if the NDA holder must have the test data, demonstrating that a drug product containing the polymorph will perform the same as the drug product described in the NDA) and (2) a product-by-process (only if the product is novel).

However, these developments had no role to play in the Ranbaxy and Ivax’s 180-day party.

Merck Unexpected Maneuver

Following the FDA revision, on October 10, 2003, Merck submitted a letter to the FDA requesting that the ‘481 and ‘520 Patents be delisted from Orange Book. The following month, the FDA received a letter from Kenyon & Kenyon (an intellectual property law firm) challenging the listing of additional patents under revised an FDA regulation published on June 18, 2003. The FDA forwarded this letter to Merck, which renewed its request that the patents be withdrawn. In June 2004, Merck sent a third request to the FDA to delist the patents. In September 2004, Ivax and Ranbaxy learned that the FDA had delisted the ‘481 and ‘520 Patents from the Orange Book.

FDA Nullify 180-day Exclusivity

Discovering that the FDA had delisted the ‘481 and ‘520 Patents, both Ivax (on January 05, 2005) and Ranbaxy (on February 1, 2005) submitted citizens' petitions with the FDA, requesting that the FDA confirm it would not approve subsequent ANDAs, until after the 180-day period, and the FDA relist the patents in the Orange Book. On October 24, 2005, the FDA denied both petitions, deciding that it would not relist the disputed patents, that no applicant would be eligible for a 180-day exclusivity for delisted patents, and that it would approve all subsequent ANDAs for simvastatin tablets. Following the FDA denial, Ivax and Ranbaxy separately sued the FDA, challenging the FDA’s refusal to relist the ‘481 and ‘520 Patents, and their refusal to grant any ANDA Applicant eligibility for the 180-day exclusivity for generic Simvastatin tablets. All three parties moved for summary judgment. Ranbaxy and Ivax moved for summary judgment, seeking to vacate the FDA decision. The FDA filed a cross-for-summary judgment seeking to maintain its decision.

Thumbs Up for Ranbaxy & Ivax!

On April 30, 2006 Judge Richard W. Roberts of U.S. District Court for the District of Columbia, in his memorandum opinion, ruled in the favor of Ranbaxy & Ivax by granting them summary judgment and contending that the FDA has acted contrary to the clear intent of Congress in its decision to deny Ranbaxy and Ivax’s citizen petitions. The issue was sent back to the FDA by the District Court for a decision giving Ranbaxy and Ivax much expected relief.

FDA Not Ready to Give Up

On May 24, 2006, the FDA appealed against the decision of District Court and filed a Motion with U.S. Court of Appeals, seeking expedited review concerning Ivax and Ranbaxy’s 180-day exclusivity issue, and also proposed a schedule whereby the appeal will be fully briefed over the summer, with arguments to be heard at the Court’s earliest convenience thereafter. Teva (which earlier acquired Ivax) has agreed to an expedited schedule as proposed by FDA.

The Generic 23/6: The Day Belongs To?

As of now, FDA has already relisted both the delisted patents to the Orange Book, which implies that Teva and Ranbaxy will receive the final marketing approval for their generic Simvastatin tablets on June 23, 2006, and will market their respective strengths with 180-day exclusivity period. Considering that appeal will be briefed over the summer, and Teva and Ranbaxy will commence their marketing in June 2006, there can be either of two situations:

1. If the U.S. Court of Appeals rules in favor of Generics, then Teva and Ranbaxy will enjoy marketing exclusivity, until the end of December; or

2. If U.S. Court of Appeals rules against Generics, then the FDA will grant their final marketing approvals to the rest of generic players, and end Teva and Ranbaxy’s marketing exclusivity before the 180 days.

Whatever the outcome of the appeal would be, four things are very much evident on June 23, 2006:

1. Simvastatin will lose its patent protection;
2. Generics would enter the U.S. Simvastatin market;
3. Dr. Reddy’s Laboratories will be there as Authorized Generics; or
4. Merck will continue to market its branded Zocor.

But what remains critical is, should the U.S. Court of Appeals rule in the favor of the FDA, delisting may become one more viable strategy for innovators to negate the 180-day exclusivity. However, if the U.S. Court of Appeals rules in favor of Generics ... Well!!! That will keep their hope intact with this High Risk, High Returns strategy.

Today's post comes from Varun Chhonkar, Senior Officer - Patents with J.B. Chemicals & Pharmaceuticals Ltd., Mumbai, India (varun.chhonkar[at]jbcpl.com). © Varun Chhonkar.

The U.S. Food and Drug Administration (FDA) announced new steps to strengthen existing protections against the growing problem of counterfeit drugs. The measures, which were recommended in a report by the agency's Counterfeit Drug Task Force, emphasize certain regulatory actions and the use of new technologies for safeguarding the integrity of the U.S. drug supply. FDA officials believe that the prevalence of bogus drugs is low but said drug counterfeiters are becoming increasingly sophisticated. The FDA's Office of Criminal Investigations opened 32 counterfeiting cases last fiscal year and 58 in fiscal 2004, compared with fewer than 10 cases a year five years earlier. Some of the most commonly counterfeited drugs are Viagra and Cialis for erectile dysfunction, the antipsychotic drug Zyprexa, Lamisil for nail fungus and Procrit, which is often used by cancer and AIDS patients to treat anemia, according to the FDA.

Among other new measures, FDA will implement regulations requiring drug distributors to provide documentation of the chain of custody of drug products -- the so-called "pedigree" -- throughout the distribution system. FDA had placed on hold certain regulatory provisions because of concerns raised at the time about the impact on small wholesalers. Most recently, in early 2004, FDA delayed the effective date of certain regulatory provisions regarding pedigrees to allow the industry time to adopt electronic technology (RFID) for tracking drugs through the supply chain. The FDA had expected this technology to be in widespread use in the drug supply chain by 2007, but it now appears that this won't happen. The FDA felt that continuing the hold would perpetuate the current confusion and further allow opportunities for counterfeit and diversionary practices. FDA determined that it can no longer justify not implementing these regulations. Therefore, the hold, which will expire in December, will not be continued.

The FDA also announced that, during the next year, its enforcement of the pedigree regulations will focus on products most susceptible to counterfeiting and diversion. The FDA intends to announce in the Federal Register the availability of a draft compliance policy guide for public comment describing this enforcement approach. By providing guidance on the types of drugs that are currently of greatest concern to the FDA, the agency intends to give wholesale distributors a better idea on where and how to focus their initial energies to come into complete compliance with the regulations (21 CFR Part 203) for all the prescription drugs they distribute. The draft guidance clarifies how the FDA intends to prioritize its pedigree-related enforcement resources in 2007. The FDA may initiate regulatory action including criminal prosecution, for pedigree violations that do not meet the factors listed in the guidance.

A Task Force report recommends the widespread use of e-pedigrees using electronic track and trace technology, including RFID, would provide an electronic safety net for our nation's drug supply. The report recommends that companies continue to work toward that goal, and that their implementation of RFID technology be used first on products most susceptible to counterfeiting and diversion.

Additional subjects discussed in the Task Force's report include the following key issues related to electronic track-and-trace that are in need of resolution:

All Task Force Reports are posted on FDA's Web here.

The Boston Globe on ran a story on Senate Finance Committee Chair Chuck Grassley (R-Iowa) and his role as the driving force behind a congressional charge to change FDA. According to the Globe article, Grassley has "exposed internal FDA memos, emails and conversations to unprecedented public scrutiny" in his attempts to "prod the agency to change a culture that stifles and punishes dissenters." Grassley feels the FDA puts too much emphasis on approving drugs and not enough on follow-up on the safety of already approved drugs. Grassley has proposed legislation that would create an Office of Drug Safety at FDA that would operate separately from drug safety reviewers at the agency's Office of New Drugs. According to the Globe, many at the FDA oppose the legislation.

Grassley has urged lawmakers to consider legislation that would address FDA's postmarket regulation of approved drugs. Grassley is pushing his bill (S 930), co-sponsored by Sen. Christopher Dodd (D-Conn.), which would authorize FDA to conduct postmarket drug reviews. Citing a GAO report that said the FDA "lacks a clear and effective process" for tracking safety issues related to approved drugs, GAO researchers concluded that that disputes between FDA's Office of Drug Safety and Office of New Drugs slowed the evaluation process.

Currently, both the Office of Drug Safety (ODS) and the Office of New Drugs (OND) are part of CDER, an arrangement that some feel results in an improper balance of power between postmarket safety and the reviewing decision. The GAO does not specifically advise taking the drug safety office out of CDER but recommends that the FDA commissioner clarify its role. The GAO reports that the Office of New Drug has sometimes excluded analyses by drug safety staffers at advisory committee meetings held to review particular medications. The GAO also recommended that Congress consider expanding the FDA's authority to require drugmakers to conduct postmarket safety studies.

One of the FDA problems that have attracted the attention of Senator Grassley include investigations into misconduct during the largest of three key trials to measure the safety of the antibiotic Ketek, made by Sanofi-Aventis. An FDA official called in May for a drug company to halt clinical trials of an antibiotic in children because the drug could be deadly, according to internal memorandums sent to other FDA officials. Ketek is being tested as a treatment for ear infections and tonsillitis in nearly 4,000 infants and children in more than a dozen countries, but Ketek, which is currently approved for use only in adults, has been reported to cause liver failure, blurred vision and loss of consciousness in adults.

An official in the Office of Drug Safety at the FDA wrote that there is growing evidence that Ketek is unusually toxic and that the agency should consider forcing Sanofi-Aventis to withdraw Ketek from the market, severely restrict its uses, even in adults, or add a prominent warning to its label about potentially fatal side effects. The FDA said it dismissed the study's results and instead asked the company to report its experience with Ketek in Europe, where it was approved in 2001. In April 2004, the FDA approved Ketek to treat sinusitis, bronchitis and pneumonia based on data in Europe.

Since then, problems with the drug have surfaced with reports of 110 cases of liver problems associated with Ketek, most of which occurred in otherwise healthy people, according to the safety review. Sanofi-Aventis has now suspended enrollment in studies of Ketek in children. Sanofi said the Food and Drug Administration did not request the action. It also said the suspension was not linked to a report in the New York Times that said an FDA official last month requested the trials be halted because Ketek could be deadly.

The U.S. Food and Drug Administration has approved Novartis AG's Omnitrope hormone in what could mark a sea change in the stance taken by the FDA on generic biotechnology drugs. This precedent setting event marks the first follow-on version of a previously approved recombinant biotechnology drug in the U.S.

Earlier, a federal judge ordered the FDA to decide after a long delay whether Sandoz can market a version of human growth hormone as a bioequivalent to the one already sold by Pfizer Inc. Sandoz, the generics arm of Novartis, sued the FDA last September for leaving its application for a generic approval in limbo, a move designed to break a stalemate over so-called biogenerics. Under both the Federal Food Drug and Cosmetic Act and the Food Prescription Drug User Fee Act, the FDA is required to either approve or reject new drug applications.

The FDA, however, went out of its way to say the Omnitrope case is not precedent setting, even putting out a question-and-answer sheet to indicate that Omnitrope is not a generic biologic:

Is Omnitrope a generic biologic?

No. Omnitrope is not rated as therapeutically equivalent to (and therefore substitutable for) any of the other approved human growth hormone products. Omnitrope is more appropriately characterized as a "follow-on protein product."

Is this FDA's first approval of a follow-on protein product?

No. FDA has approved other follow-on protein products under section 505 of the Food, Drug, and Cosmetic Act. These include GlucaGen (glucagon recombinant for injection), Hylenex (hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), and Fortical (calcitonin salmon recombinant) Nasal Spray.

Does today’s approval of Omnitrope create a new pathway for follow-on versions of all protein products?

No. The approval of Omnitrope in a 505(b)(2) application does not establish a pathway for approval of follow-on products for biological products licensed under section 351 of the Public Heath Service Act, nor does it mean that more complex and/or less well understood proteins approved as drugs under the Food, Drug, and Cosmetic Act could be approved as follow-on products.

The majority of protein products are licensed as biological products under the Public Health Service Act, not approved as drugs under the Food, Drug, and Cosmetic Act. There is no abbreviated approval pathway analogous to 505(b)(2) or 505(j) of the Act for protein products licensed under section 351 of the Public Health Service Act. Such a pathway for the approval or licensure of follow-on protein products under the Public Health Service Act would require new legislation.

See further information here.

Forbes.com reports that Merck is close to obtaining approval for a vaccine against common viruses that lead to cervical cancer. An FDA advisory committee voted 13-0 to approve Merck's Gardasil, a vaccine that protects against four types of sexually transmitted viruses-- two of which are believed to be responsible for about 70% of cervical cancer cases. According to Merck, approval and widespread use of the vaccine could cut worldwide deaths from the disease by two-thirds.

Amid uncertainties regarding the age group for treatment, the extent of the campaign, and how routine pap smear screening will be affected, are some medical concerns. In particular, the FDA has questioned whether the vaccine could make disease progression worse among women already infected and whether the benefit is partly mooted by the fact that the vaccine does not protect against all viral strains linked to cervical cancer. Of further note, the agency is expected to discuss the five congenital defects of children born to women who were vaccinated with Gardasil around the time of conception.

The good news for Merck is that the FDA usually follows the recommendations of its outside panel of experts, who in this case all support approval of the vaccine. The final decision is expected by June 8. The anticipated cost of treatment, administered in three shots over six months is $300-500. According to analysts, this could translate into over a billion dollars in sales. This may be the break Merck needs-- approval could help offset mounting legal costs as the company continues to defend against Vioxx lawsuits.

Merck recommends that the vaccine be used for females aged 9 to 26. The Advisory Committee on Immunization Practices is considering these recommendations and whether routine vaccination should be endorsed. GlaxoSmithKline PLC is working on a similar vaccine, hoping to submit it for approval by the end of the year.

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 requires drug companies to file certain agreements with the Federal Trade Commission and the U.S. Department of Justice. The FTC's Bureau of Competition has now issued a summary of agreements filed with the Commission in fiscal year 2005 by generic and branded drug manufacturers. The summary provides information regarding the 20 agreements that were filed with the FTC in FY 2005, involving 16 different products.

For the first time since 1999, brand and generic companies are entering settlements in which the generic receives compensation from the branded manufacturer and there is a restriction on the generic’s ability to market its product. Based on the information reported in the Commission’s 2002 study and on settlements reported between 1999 and 2004, no patent settlements included both compensation to the generic and a restriction on the generic’s ability to market its product. In contrast, three settlements submitted in FY 2005 included those terms.

The summary also concluded that 1) 11 of the 20 agreements filed in FY 2005 were final settlements of patent litigation between a branded and generic company; 2) five were interim agreements that occurred during patent litigation between a brand and a generic company, but did not resolve the litigation; 3) the remaining agreements were between a first-filer generic company and a subsequent generic filer.

Drug companies began entering into these agreements in the 1990s, but the FTC concluded they were unfair to consumers and anti-competitive and the agency successfully challenged them.

However, the U.S. Court of Appeals for the 11th Circuit concluded that the FTC had overstepped its authority when it blocked an agreement between Schering-Plough Corp. and Upsher-Smith Laboratories Inc. The FTC has appealed to the Supreme Court.

The Washington Post reported that in a speech on Monday to the In-House Counsel's Forum on Pharmaceutical Antitrust, FTC Commissioner Jon Leibowitz said that if the appeals court decision remains in effect, drug makers will have "carte blanche to avoid competition and share resulting profits." Leibowitz said the agreements mutually benefit the brand-name and generic drug makers because the brand-name company gets to maintain its patent exclusivity, while the generic competitor receives a payment. In addition, the "generic companies ... often enter into agreements to produce lower-priced version of the brand-name company's drug at a predetermined date -- far in the future," the Post reports.

For example, Cephalon earlier this year made agreements with four generic companies over the drug Provigil, a sleep disorder treatment. Under the agreements, the generic companies pledged to stay out of the market until 2011, and Cephalon agreed to pay them licensing payments of $136 million. Leibowitz said, "Until recently, payments by brand-name companies to generics were the exception, but now they're the rule." (Washington Post, 4/24).

Copies of the Bureau’s summary of agreements filed in FY 2005 are available on the FTC’s Web site.

For more information on the laws that the Bureau enforces, the Commission has published “Promoting Competition, Protecting Consumers: A Plain English Guide to Antitrust Laws."

A federal judge has ordered the U.S. Food and Drug Administration to decide after a long delay whether Novartis AG can market a version of human growth hormone as a bioequivalent to the one already sold by Pfizer Inc.

The order by Judge Ricardo Urbina of the U.S. District Court for the District of Columbia could put pressure on the FDA to come up with guidelines for approving generic copies of biotechnology drugs. The agency has said it was close to issuing such guidelines for years now. In January 2006, the European Medicines Agency (EMEA) announced draft guidelines for the first four biogeneric products - recombinant human insulin, somatropin, erythropoietin (EPO), and recombinant granulocyte colony-stimulating factor (rG-CSF). In December 2005, the EMEA reported that it had provided scientific advice to companies on the development of 15 other biosimilars. In contrast, the FDA has over the past year done almost nothing to move toward clearer biogeneric regulations.

Sandoz, the generics arm of Novartis, sued the FDA last September for leaving its copycat product in limbo, a move designed to break a logjam over so-called biogenerics. The FDA in November sought a dismissal of the suit, saying the charges were unfounded since its experts had not finished their review of the drug, Omnitrope.

Under both the Federal Food Drug and Cosmetic Act and the Food Prescription Drug User Fee Act, the FDA is required to either approve or reject new drug applications.

Sandoz filed its application for Omnitrope in July 2003. On Sept 2 2004, Sandoz announced that FDA had notified the company that the agency was unable to reach a decision on whether to approve the company's application for Omnitrope. According to the FDA letter issued to Sandoz, the agency has completed its review of Omnitrope and did not identify any deficiencies in the application. However, the agency stated it had been unable to reach a final decision on the application due to uncertainty regarding scientific and legal issues. No action on the application has been taken since then.

No biogenerics (or follow-on proteins) have yet been approved in the US pharmaceutical market. It is argued that the 505(b)(2) provision of the Hatch-Waxman Act (the Hatch-Waxman amendments of the Federal Food, Drug and Cosmetic Act) lays out an abbreviated approval pathway (ANDA) for generic versions of small molecule drugs) provides a route for the FDA to approve a biological therapy that is different from the originator product, yet relies on data filed by the innovator as part of the original NDA.

The reason for the lack of a regulatory pathway for approval of biogenerics lies in the complexity of biological products. Biologics are large, complex, heterogeneous molecules, for which the manufacturing process can be a determinant of the end product. Demonstrating that its product was as safe and effective as the originator's would be a difficult task, since establishing that immunogenicity had not been altered, and that any undetected differences in the product would not impact safety and efficacy, would be problematic without conducting clinical trials.

Biogeneric companies need an abbreviated approval pathway to avoid undertaking the same large scale clinical development process as the originator companies, and thus allow them to market their product at a discount to the brand while maintaining a healthy profit margin.

But, even if biogenerics are approved, don't go spending all your projected savings just yet. The high barriers to market entry will necessitate a smaller price differential between brand and generic products than that seen in regular generics, and initial physician and patient reluctance to take up biogenerics may limit the impact of competition on originator companies.

The Federal Trade Commission (FTC) is considering conducting a study to analyze the use and likely short- and long-run competitive effects of authorized generic drugs in the prescription drug marketplace. An authorized generic is chemically identical to a particular brand-name drug, but the brand-name manufacturer authorizes it to be marketed in a generic version.

In the United States, the Food and Drug Administration (FDA) must approve the marketing of any pharmaceutical drug, whether brand-name or generic. The Hatch-Waxman Act establishes the regulatory framework under which the FDA may approve a generic drug to be marketed. Typically, a brand-name drug obtains FDA approval through a New Drug Application (NDA), and a generic drug manufacturer obtains FDA approval through an Abbreviated New Drug Application (ANDA) in which it may be allowed to rely on the clinical data first submitted by the brand-name drug manufacturer.

To encourage generic entry as soon as is warranted, the Hatch-Waxman Act allows generic drug manufacturers, in certain circumstances, to market a generic drug prior to the expiration of claimed patent protection for the corresponding brand-name drug. To be permitted to do so, a generic drug manufacturer must first submit a paragraph IV ANDA in which it certifies that (a) its generic drug will not infringe patents listed in the FDA’s Orange Book, as claiming the relevant brand-name drug product, and/or (b) the relevant Orange Book patents are invalid.

If the paragraph IV ANDA leads to litigation, then 30 months after the litigation was filed (or after final decision in the litigation, if earlier), the FDA may authorize the marketing of the generic drug under the ANDA application. At that point, the first-filed paragraph IV ANDA applicant becomes entitled to a 180-day marketing exclusivity period, during which the FDA cannot approve any other, later-filed paragraph IV ANDA for a generic drug corresponding to the same brand-name drug product. This protects the first FDA-approved paragraph IV ANDA applicant from competition with other generic ANDA applicants during this time.

The 180-day marketing exclusivity period does not preclude competition from NDA-approved “authorized generics,” however. An authorized generic is chemically identical to a particular brand-name drug, which the brand-name manufacturer authorizes to be marketed in a generic version under the NDA-approval that the FDA granted for the brand-name drug. The brand-name manufacturer either sells the authorized generic itself through a subsidiary or licenses a generic firm to sell the authorized generic.

In recent years and with increasing frequency, brand-name drug manufacturers have begun to market authorized generic drugs at precisely the same time that a paragraph IV generic is beginning its period of 180-day marketing exclusivity. In the short run, the entry of an authorized generic drug may benefit consumers by creating additional competition that lowers generic prices further than if only the paragraph IV generic were marketed. Many generic manufacturers assert, however, that in the long run, consumers will be harmed because an expectation of competition from authorized generics will significantly decrease the incentives of generic manufacturers to pursue entry prior to patent expiration.

The FTC now proposes to undertake a study to examine both the likely short-term competitive effects of authorized generic drug entry and, to the extent possible, the likely long-term impact of entry by authorized generic drugs on competition by generic manufacturers.

Comments on the FTC’s "Authorized Generic Drug Study" will be accepted until June 5, 2006.

See additional information in the Federal Register Notice.

The Food and Drug Administration (FDA) released an initial list of priority research projects that could advance innovation in medical products. The announcement of the Critical Path Opportunities List signals the next major step in FDA's Critical Path Initiative aimed at modernizing medical product development, so new medical discoveries are brought to patients faster and at a lower cost.

Critical Path is the FDA's initiative to identify and prioritize the most pressing medical product development problems and the greatest opportunities for rapid improvement in public health benefits. Its primary purpose is to ensure that basic scientific discoveries translate more rapidly into new and better medical treatments by creating new tools to find answers about how the safety and effectiveness of new medical products can be demonstrated in faster timeframes with more certainty, at lower costs, and with better information.

The Opportunities List outlines an initial 76 projects to bridge the gap between the quick pace of new biomedical discoveries and the slower pace at which those discoveries are currently developed into therapies.

The Critical Path Opportunities Report is organized into six broad topic areas: development of biomarkers; clinical trial designs, bioinformatics, manufacturing, public health needs and pediatrics. FDA's outreach efforts uncovered a consensus that the two most important areas for improving medical product development are biomarker development and streamlining clinical trials.

Over the next few weeks, the FDA will identify several priority Critical Path research opportunities. Some of the projects in the list could be undertaken by one organization; some will require collaborations coordinated and supported by the FDA.

Information on the Critical Path Initiative, is available here.

Recently, Philip Brooks sent me a note from one of the readers of his excellent Patent Infringement Updates site. The note was regarding the generic challenge where a brand-name drug has recently gone generic and the drug manufacturer wishes to launch the product in a new indication. The reader asked if the manufacturer would be eligible for the three year market exclusivity extension for a new indication of a known drug. Philip asked if I could post a response summarizing some of the particulars about the new indication extension.

The short answer is that yes, they could get market exclusivity for a new indication and even longer if they are able to obtain a patent on the new indication. However, the drug company would generally need a new dosing strength or formulation to make this commercially reasonable since doctors could, and would, write prescriptions for the old version for the new indication (assuming the drugs are the same.

Patent term exclusivity and FDA market exclusivity are inexorably intertwined. Beyond the normal 20 year patent term, there are generally two mechanisms for gaining additional time added to the exclusivity.

Currently, there exist five ways to extend patent term: (1) patent term adjustments under 35 U.S.C. 154 to remedy U.S. Patent and Trademark Office ("USPTO") delay during patent prosecution; (2) patent extensions under 35 U.S.C. 156 to remedy delays due to regulatory approval; (3) interim term extensions; (4) extensions under the General Agreement on Tariffs and Trade ("GATT") Act; and (5) private extensions via Congressional legislation.

But market exclusivity can be gained separate from patent term extension. The FDA rules currently provide qualified drug products competition-free periods by preventing FDA or USDA approval of identical generic products. Market exclusivities enforced by either the FDA or the USDA include: (a) Five-year New Chemical Entity Exclusivity; (b) Three-year New Use/New Clinical Studies Exclusivity; (c) Seven-year Orphan Drug Exclusivity; (d) Six-month Pediatric Exclusivity; (e) 180-day and 30-month stays of FDA Approval; and (f) Animal Product Exclusivity.

(a) Five-year New Chemical Entity Exclusivity. New chemical entity exclusivity is granted to a drug that does not contain an active moiety previously approved in a FDA new drug application ("NDA"). The term of exclusivity is 5 years if the abbreviated new drug application ("ANDA") does not contain a Paragraph IV certification to a listed patent, and 4 years if it contains the certification. This market exclusivity can be coupled with a six-month pediatric exclusivity.

New chemical entity exclusivity precludes approval and can delay submission of certain Section 505(b)(2) applications (that is, an application with clinical data produced by a third party without permission from the third party to use the data) or certain ANDAs.

(b) Three-year New Use/New Clinical Studies Exclusivity. New indications or dosage forms of previously approved drugs can receive new use or new clinical study exclusivity. The application must contain reports of new clinical investigations conducted by the applicant. The exclusivity term runs for three years from NDA approval and it bars the FDA from approving any ANDA or 505(b)(2) application by another party that relies on the same clinical studies. This exclusivity can be coupled with a six-month pediatric exclusivity.

(c) Seven-year Orphan Drug Exclusivity. For orphan drugs or biologics (those intended to treat rare diseases or conditions with less than 200,000 patients), orphan drug exclusivity bars the FDA from approving any other application (i.e., ANDA, 505(b)(2), NDA or BLA) for that drug used to treat the same orphan disease for seven years. Thus, if two companies are pursuing the same drug for the same orphan indication, whichever wins approval first will obtain exclusivity over its competitor. However, this exclusivity does not block approval of the same drug for a different indication, nor does it block approval of another version of the same drug if the new version offers clinical advantages over the prior product (e.g., greater safety, tolerability, or convenience of administration). This market exclusivity can be coupled with a six-month pediatric exclusivity.

(d) Six-month Pediatric Exclusivity. Pediatric exclusivity may be granted after submission of pediatric studies on the drug at the FDA's request. The FDA may issue a request for pediatric studies at the drug sponsor's request or on its own initiative. Pediatric exclusivity grants an additional six months of market protection at the end of listed patent(s) and/or other exclusivity terms for all drug products containing the active moiety. Frequently, a second pediatric study is sought via a supplemental NDA for a drug already granted pediatric exclusivity; thus, a pharmaceutical can potentially receive two pediatric exclusivity terms subject to certain limitations.

(e) 180-Day and 30-Month Stays of FDA Approval. ANDA approval and timing depends partially on a drug's patent(s). Innovator drug applicants must identify in their NDA any patent(s) that covers the drug, which are then listed in the FDA's Orange Book. Subsequently, any ANDA applicant must submit a certification for each patent listed in the Orange Book for the subject drug. This certification corresponds to one of four statutory paragraphs, the most important for exclusivity extension being a Paragraph IV certification.

Paragraph IV certification starts the legal process of determining whether the listed patent is valid or will be infringed by the proposed generic product. The ANDA applicant with a Paragraph IV certification must notify the patent owner and the NDA holder for the listed drug that an ANDA containing a patent challenge has been filed. The patent owner may then sue the ANDA applicant for patent infringement. If the patent owner files suit, the FDA will stay approval of the ANDA for 30 months from the date of the notice. This 30-month stay (and associated exclusivity period) remains effective until the court reaches a decision in the suit or otherwise alters the stay period.

The first ANDA applicant to make a Paragraph IV certification receives the benefit of a 180-day market exclusivity period during which no other ANDA can be approved for that drug. ANDA applicants with certifications other than Paragraph IV are not eligible for the 180-day exclusivity. The 180-day exclusivity begins the earlier of the first date of the generic drug's commercial marketing or a court decision on the patent.

Under the Federal Food, Drug, and Cosmetic Act (FDCA), patents that claim an approved drug, or that claim an approved method of using a drug, are required to be submitted for inclusion in FDA’s publication Approved Drug Products and Therapeutic Equivalence Evaluations (the Orange Book). The effect of an Orange Book listing is to require advance notice to the patent holder and New Drug Application (NDA) sponsor whenever a generic applicant seeks approval to begin marketing a competing version of a drug prior to the expiration of any Orange Book listed patent. Upon such notice, the patent holder may bring an action for patent infringement within 45 days of the notice, and thereby impose an automatic 30-month stay of approval of the generic product (which stay is terminated upon a judicial determination that the patent is invalid, unenforceable, or would not be infringed by the commercial marketing of the proposed generic product).

(f) Exclusivity for Animal Drugs. Veterinary drugs can also receive market exclusivity under the Generic Animal Drug and Patent Term Restoration Act ("GADPTRA"). Exclusivity is for either 3 or 5 years, during which time no other generic copy may be approved (in the case of 3-year exclusivity) or no other generic application may be submitted (in the case of 5-year exclusivity).

Allergies are second only to the weather in hot conversation topics around here in the Midwest. So, there was a collective groan when sales of generic Flonase were halted by a judge's temporary restraining order. This comes two days after the U.S. Food and Drug Administration approved a generic nasal spray for the active ingredient fluticasone, the first generic version of the brand name drug Flonase.

The FDA's approval of the Roxane Labs version was announced Feb. 20, GlaxoSmithKline filed a court motion Feb. 21 seeking to temporarily ban sales of generic Flonase based on two counts. Glaxo argued that the FDA had not established a method of proving the "bioequivalence" of the generic drugs to Flonase and said that the government agency had applied one set of quality standards to Flonase and a separate set to generic versions of the drug.

A district court judge granted a 10-day restraining order on Friday, blocking sales of the generic spray although Roxane Laboratories expects the restraining order would be lifted after a hearing on March 6. Since Glaxo has a deal with Par Pharmaceuticals to make an approved generic version of Flonase, the ruling stops Par's product as well.

Fluticasone Propionate Nasal Spray treats the nasal symptoms of seasonal and chronic (long-lasting) allergic and nonallergic rhinitis, an inflammation of the lining of the nose that can make it stuffy and runny. This product is approved for use in both adults and children 4 years and older.

Fluticasone Propionate Nasal Spray contains a synthetic, trifluorinated corticosteroid with anti-inflammatory activity. Corticosteroids are natural substances found in the body that help fight inflammation. Fluticasone propionate, like other corticosteroids, does not have an immediate effect on allergic symptoms. A decrease in nasal symptoms (stuffiness, runniness, itching, and sneezing) has been noted in some patients 12 hours after initial treatment. Common side effects of fluticasone propionate nasal spray are headache, sore throat and nose bleed.

The brand name product or innovator drug for fluticasone propionate is Flonase, manufactured by GlaxoSmithKline and approved in October, 1994. The drug's patent, including the pediatric exclusivity, expired in May 2004 and the new dosing schedule exclusivity with its associated pediatric exclusivity expired on November 23, 2005. Roxane Laboratories, based in Columbus, Ohio, will market the new drug.

The FDA's statement regarding fluticasone emphasized that the generic drug is the "bioequivalent to a brand name drug and is its equal in dosing form, strength, route of administration, quality, performance characteristics and intended use."

Given that Flonase brought in more than $920 million in U.S. sales in 2005, even a 10-day restraining order can mean a huge profit. We'll keep you posted on the result.

The U.S. Federal Trade Commission (FTC) is concerned about the recent use of anti-competitive drug patent deals in light of recent court rulings, which may spur drug companies to step up a practice of paying generic rivals to keep alternatives off the market.

The FTC has filed a series of lawsuits challenging patent settlement agreements between major drugmakers and their generic rivals. The agency contends that in some cases those settlements stifle competition because drugmakers are paying generics to stay out of the market.

Under federal law, drugmakers are allowed to seek U.S. Food and Drug Administration approval for generic versions of brand-name drugs before a drug's patent expires. They must certify that the patent is invalid or will not be infringed by the new generic version.

In March, a federal appeals court overturned the FTC's challenge to a patent settlement between Schering-Plough Corp. and Upsher-Smith Laboratories and American Home Products, now Wyeth. The FTC had issued a finding that the settlement illegally kept cheaper versions of Schering-Plough's blood pressure drug K-Dur off the market but the appeals court said the companies were within their rights to use their patents to lock competitors out of the market.

The decision in Schering-Plough makes it very difficult (if not impossible) for parties challenging patent settlements to do so based on the terms of the settlement itself (i.e., the inclusion of a reverse payment). Plaintiffs will need to show that the generic company’s product did not infringe on a valid patent – a high hurdle to get over indeed.

Interestingly, under the applicable rules for appealing FTC administrative actions, respondents are entitled to choose which circuit court will hear their appeal. Bet you can imagine that anyone caught in similar administrative litigation would choose to bring its appeal in the Eleventh Circuit.

Currently, the FTC is seeking certiorari from the Supreme Court in Schering-Plough, and stated in its petition that the Eleventh Circuit’s decision "could seriously impede the Commission’s law enforcement efforts."

In the FTC's Petition for Certiorari from the Supreme Court in Schering-Plough, the questions presented are:

1. Whether an agreement between a pharmaceutical patent holder and a would-be generic competitor, in which the patent holder makes a substantial payment to the challenger for the purpose of delaying the challenger’s entry into the market, is an unreasonable restraint of trade.

2. Whether the court of appeals grossly misapplied the pertinent “substantial evidence” standard of review, by summarily rejecting the extensive factual findings of an expert federal agency regarding matters within its purview.

Download the FTC's Petition for Certiorari here.

In November another federal appeals court upheld a lower court decision to throw out a similar case that private parties had filed against Barr Pharmaceuticals Inc. and AstraZeneca.

The patent settlement challenged in that case involved AstraZeneca's Novaldex. Novaldex (tamoxifen citrate) is a drug sold by AstraZeneca that is used to treat breast cancer. The tamoxifen litigation involves an agreement between Imperial Chemical Industries, PLC (an affiliate of AstraZeneca) and Barr Laboratories to settle patent infringement litigation relating to Imperial’s patent for tamoxifen (the ‘516 patent).

Imperial sued Barr for infringement of the ‘516 patent, and the patent was found unenforceable after trial. Imperial appealed but Barr and Imperial reached a settlement agreement during the appeal and moved jointly to vacate the judgment of the district court. Under the agreement, Imperial licensed Barr to sell Novaldex, and Barr (which was the first ANDA filer) agreed not to pursue final approval of its ANDA prior to the expiration of the ‘516 patent.

It is worth noting that in subsequent litigation AstraZeneca obtained three decisions upholding its Tamoxifen patent in cases against other generic companies.

The Second Circuit court upheld the district court’s decision granting the defendants’ motion to dismiss the antitrust case. The Second Circuit panel emphasized that settlements are pro-competitive, and dismissed the views of the plaintiffs (and the FTC in Schering-Plough) that there is something inherently anticompetitive about reverse payments.

The court stated that because the Hatch-Waxman Act permitted generic companies to challenge patents without putting themselves at risk for significant damages, generic companies are in a strong position to demand a large premium in order to settle high-stakes cases. This is true even where the branded manufacturer may be reasonably confident of victory but wishes to avoid the litigation burden and uncertainty.

The plaintiffs in Tamoxifen have filed a petition for re-hearing en banc, and the FTC has submitted an amicus brief supporting the petition. In evaluating the petition for re-hearing, we expect the Second Circuit to focus, among other things, on (1) whether the "sham" standard used by the court was proper, and (2) whether dismissal at the pleading stage was appropriate.

The Food and Drug Administration (FDA) announced steps to advance the earliest phases of clinical research in the development of innovative medical treatments. This should make it easier for universities and small drug companies to test promising therapies in humans without having to pay the enormous amounts of expenditures normally required.

In guidance documents released today, Exploratory IND Studies and INDs - Approaches to Complying with CGMP During Phase 1, the FDA lays out specific approaches for researchers who are planning to conduct very early clinical studies in people and offers approaches for performing appropriate safety testing and producing small amounts of drugs safely. In line with the aims of FDA’s Critical Path Initiative to modernize the drug development process, these changes will enable U.S. medical researchers to evaluate much more efficiently the promise of scientific advances discovered in their laboratories.

Currently, the FDA says 9 of 10 experimental drugs fail in clinical testing that can cost companies millions. And many experimental drugs go untested in humans because the current system requires massive investments before the make-or-break stage of drug development.

The FDA approved only 20 new drugs last year and, from 2002 to 2004, newly approved drugs took an average of 8.5 years for approval. If the length of clinical trials were shaved by one-quarter, drug manufacturers would save $129 million while halving the time spent on clinical trials would lower drug development costs by 29 percent, saving drug companies $235 million.

In related draft guidance, INDs-Approaches to Complying with CGMP During Phase 1, the FDA outlines a suggested approach to complying with current good manufacturing practice (CGMP) requirements for drugs intended for use solely in phase 1 studies. With this new guidance and an accompanying regulation, FDA formally recognizes specific standards for the manufacture of small amounts of drug product for phase 1 studies and formulating an approach to cGMP compliance that is appropriate for the particular stage of drug development.

Direct Final Rule: Current Good Manufacturing Practice Regulation and Investigational New Drugs

Exploratory IND Studies

Federal Register

INDs — Approaches to Complying with CGMP During Phase 1

Novartis AG's generics unit Sandoz said it has filed a lawsuit against the US Food and Drug Administration, seeking a ruling on its pending new drug application for the human growth hormone Omnitrope.

Under both the Federal Food Drug and Cosmetic Act and the Food Prescription Drug User Fee Act, the FDA is required to either approve or reject new drug applications.

Sandoz filed its application for Omnitrope in July 2003. On Sept 2 2004, Sandoz announced that FDA had notified the company that the agency was unable to reach a decision on whether to approve the company's application for Omnitrope. According to the FDA letter issued to Sandoz, the agency has completed its review of Omnitrope and did not identify any deficiencies in the application. However, the agency stated it had been unable to reach a final decision on the application due to uncertainty regarding scientific and legal issues. No action on the application has been taken since then.

Despite being available outside of western markets, no biogenerics (or follow-on proteins) have yet been approved in the US or European pharmaceutical market. It is argued that the 505(b)(2) provision of the Hatch-Waxman Act (the Hatch-Waxman amendments of the Federal Food, Drug and Cosmetic Act) lays out an abbreviated approval pathway (ANDA) for generic versions of small molecule drugs) provides a route for the FDA to approve a biological therapy that is different from the originator product, yet relies on data filed by the innovator as part of the original NDA.

The reason for the lack of a regulatory pathway for approval of biogenerics lies in the complexity of biological products. Biologics are large, complex, heterogeneous molecules, for which the manufacturing process can be a determinant of the end product. Demonstrating that its product was as safe and effective as the originator's would be a difficult task, since establishing that immunogenicity had not been altered, and that any undetected differences in the product would not impact safety and efficacy, would be problematic without conducting clinical trials.

However, the large market potential makes biogenerics an attractive prospect for companies. Biogeneric companies need an abbreviated approval pathway to avoid undertaking the same large scale clinical development process as the originator companies, and thus allow them to market their product at a discount to the brand while maintaining a healthy profit margin.

But, even if biogenerics are approved, don't go spending all your projected savings just yet. The high barriers to market entry will necessitate a smaller price differential between brand and generic products than that seen in regular generics, and initial physician and patient reluctance to take up biogenerics may limit the impact of competition on originator companies.

It seems that more and more generic drug companies are popping up and are developing more and more low-cost drugs, putting pressure on makers of name-brand drugs and raising fears of an FDA bottleneck. Generics already make up 54 percent of the prescription market, which should increase when Medicare offers more drug discounts on Jan. 1, 2006.

The Food and Drug Administration's Office of Generic Drugs is expecting to receive 771 applications for generic drugs this year, a one-third jump from 563 the year before -- and more applications are on their way. Teva Pharmaceuticals Industries alone has more than 200 applications being processed by the FDA.

This could mean that the FDA will become overburdened by the application process (although it has been trimming the process -- getting the approval process for generic applications to 15.7 months from 17 months in 2004. A single new drug application comprises up to 200,000 pages bound into 400 volumes, although abbreviated new drug applications (ANDAs) for generic drugs are not nearly as large.

About $100 billion worth of name-brand drugs will lose patent exclusivity in the next five years, with $21 billion going off-patent in 2006, according to WR Hambrecht & Co., the biggest-selling drug losing exclusivity in 2006 is Zocor, the cholesterol-reducing drug from Merck & Co. that had $5.2 billion in 2004 sales.

Another closely watched patented drug is Pfizer's Lipitor, which could become an unprecedented $14 billion blockbuster by 2007, or could take an $8 billion hit to sales, depending on the outcome of its multiple patent lawsuits with Indian generic drug maker Ranbaxy Laboratories over Pfizer's two patents for Lipitor, which are scheduled to expire in 2010 and 2011.

Another worry for the name-brand companies is that Indian generic drug firms may be eclipsed by China if enters the market with its own cheap copies of drugs. China has already established itself as a source of raw materials, known as Active Pharmaceutical Ingredients (API). Taking the next step to create packaged drugs seems inevitable.

China is expected to seek US Food and Drug Administration approval for its first generic drug by 2006, introducing even cheaper generics into the market and adding further pricing pressure. This could be good news for consumers and insurance companies (not to mention the federal government) who will benefit from lower prices.

An FDA advisory panel announced that Novartis AG's Foradil asthma drug, marketed by Schering-Plough Corp., should have a warning about the risk for worsened breathing similar to that on GlaxoSmithKline Plc's Advair and Serevent. The drug shares the ingredient salmeterol with London-based Glaxo's Advair and Serevent. All three medicines work by easing constriction within the lung. The FDA panel also voted to say Serevent, Advair and Foradil are safe enough to remain on the U.S. market.

Advair and Serevent, which is the same drug combined with a corticosteroid, together outsell competing asthma treatments as well as Glaxo's other products. The drugs' sales last year totaled 2.5 billion pounds (about $4.4 billion). Foradil's sales last year lagged at about $320 million. About 15 million Americans have asthma, which causes inflammation in the airways of the lung and constriction of nearby muscle.

The Serevent and Advair labels contain information based on results of a study that Glaxo began in 1996, Glaxo stopped the study early after 50 people taking Serevent died or had severe life-threatening breathing complications, compared with 36 people given a placebo. The FDA advisers also suggested the agency look at ways to more clearly explain those findings to consumers and doctors.

The U.S. Court of Appeals for the District of Columbia Circuit ruled that Pfizer and other drug companies have the right to sell unbranded versions of their own drugs even if they undercut sales of generic competitors in a suit by Teva Pharmaceutical, which sought to stop Pfizer from selling its own generic version of the epilepsy drug Neurontin. (see

In Teva Pharmaceutical Industries Ltd. v.Lester M. Crawford, Jr., Acting Commissioner of Food And Drugs, et al. (No. 05-5004 , Decided June 3, 2005), Teva Pharmaceutical Industries sued to overturn the Food and Drug Administration’s denial of its “citizen petition” requesting that the agency prohibit Pfizer, Inc., the holder of the approved New Drug Application (NDA) for gabapentin, from marketing that drug in “generic” form during the 180-day exclusivity period provided by the Drug Price Competition and Patent Term Restoration Act, also known as the “Hatch-Waxman Amendments” to the Food, Drug, & Cosmetic Act. Because the exclusivity provision does not apply to the holder of an approved NDA, the district court entered a summary judgment for the FDA.

Section 355(j) of 21 U.S.C. provides that a drug manufacturer may submit an “Abbreviated New Drug Application” (ANDA) for approval to market a so-called “generic” drug, which is the bioequivalent to a “branded” drug previously approved pursuant to a NDA filed under 21 U.S.C. § 355(b). Unlike a NDA, an ANDA need not contain clinical evidence of the safety or efficacy of the drug.

The ANDA must certify either that the approved product is not protected by a patent or “that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted.” 21 U.S.C. § 355(j)(2)(A)(vii)(para. IV). The statute rewards the first generic applicant successfully to challenge the patent on an approved drug with a 180-day exclusivity period during which no other ANDA for the same drug may be approved.

The Federal Trade Commission, at the urging of three U.S. senators, is looking into whether authorized generics are anti-competitive. Under federal law, the first generic-drug maker to challenge patents on a drug wins six months of exclusive marketing rights. Teva argued that Pfizer, the world’s largest drug company, sought to thwart competition by undermining that incentive.

In the appellate case, Teva’s argument stemmed from the following premises: (1) the purpose of the 180-day exclusivity period was “to encourage generic companies to file Paragraph IV challenges to brand-drug patents”; (2) the marketing of a brand-generic competitor during that period will reduce the revenues going to the first to file an ANDA; and (3) such “brand-generic intrusion [into the exclusivity period] developed only recently as a routine brand-company business strategy.”

The Appeals Court held that:

..when Teva goes on to argue that because the Congress could not have anticipated brand-generic competition during the exclusivity period, adhering to the “literal” terms of the statute would lead to an absurd result, namely, that § 355(j)(5)(B)(iv) grants only a “meaningless” exclusivity against subsequent ANDA filers rather than a “commercially effective” exclusivity that runs against the NDA holder as well.

It does not follow, however, from the Congress having intended to create an incentive to challenge brand-drug patents --as it clearly did --that the incentive it created is without limitation. Rather, as even the formal name of the Hatch-Waxman Amendments (the Drug Price Competition and Patent Term Restoration Act) reflects, the Congress sought to strike a balance between incentives, on the one hand, for innovation, and on the other, for quickly getting lower-cost generic drugs to market. Because the balance struck between these competing goals is quintessentially a matter for legislative judgment, the court must attend closely to the terms in which the Congress expressed that judgment.

The DC Circuit affirmed stating that § 355(j)(5)(B)(iv) of the Act clearly does not prohibit the holder of an approved NDA from marketing, during the 180-day exclusivity period, its own “brand-generic” version of its drug.

Get the entire opinion here.

Food and Drug Administration regulators turned down a request from Johnson & Johnson to expand the approved uses for Risperdal, a treatment for bipolar disorder. J&J received a not approvable letter from the FDA to use Risperdal in Alzheimer's-related psychoses.

This is after last weeks announcement that the FDA rejected J&J's application to market Risperdal for patients with autism after it petitioned for an additional use of the drug.

It seems the FDA is taking a slow and cautious route on new approvals, especially after the Vioxx withdrawal, as we noted before. In April, the FDA ordered new warnings on all antipsychotic drugs, including Risperdal, to alert physicians to a higher death rate when the medicines are prescribed for the atypical use of treating dementia in elderly patients.

Things are not all bad for J&J, though. It announced that it plans to file and receive marketing approval for 10 to 13 new drug compounds by 2007. J&J said that it expects to grow even though it will likely lose patent protection on some of its top-selling drugs. Obviously, this is geared to rev up confidence in the company. J&J, like lots of big pharmas these days, is staring down the barrel of a growing number of patent expirations.

The company expects new growth would come from therapies to treat cancer; viruses such as HIV; urology treatments, including a drug for premature ejaculation; and antibacterials to treat serious infections. J&J said it could have as many as 70 product filings between 2005 and 2011, including 23 new drug compounds and 47 line extensions.

Interestingly, the company said it is rapidly expanding its research into drugs based on biotechnology, or live organisms. While this brings great potential, this will certainly not be without risks. Earlier, when two patients taking Tysabri, a new drug for multiple sclerosis, developed a rare brain disease, the $3 billion a year in potential profits suddenly vaporized. Shares of Biogen Idec fell by nearly half, and Elan, trading at $30, took a sickening swan dive to $4.

It's an exciting time but biotechnology's risks will make for some stomach-churning thrills.

Barr Pharmaceuticals Inc. announced that it dropped its lawsuit against the Food and Drug Administration (FDA) over exclusive marketing rights to a generic version of the Allegra allergy drug made by France's Sanofi-Aventis.

In February, Barr sued the FDA to challenge its decision to make the company share a 6-month exclusive selling period. The company said it is now dismissing the suit because the FDA has said it can obtain sole exclusivity by slightly modifying its application for the drug.

Barr's version of the 12-hour Allegra-D tablet has tentative FDA approval, meaning the company cannot sell the drug until its patent protection expires. Sanofi-Aventis' first patent related to the drug expires in 2012. Barr's stock was up on the news.

I am glad right now that the only thing I am suffering from is a common head cold, thanks to my two toddlers wanting to “share.” If I had arthritis like my grandmother did, I would really be starting to worry. It seems that even after the talk of using “black box warnings” from this past February’s hearings at the FDA, today, the FDA asked Pfizer to pull Bextra (valdecoxib), another beleaguered Cox-2 inhibitor, from the market today as part of a broad-ranging Public Health Advisory on the entire class of NSAIDs.

In making this announcement, the FDA cited inadequate information on possible heart risks from long-term use of the drug as well as "life-threatening" skin reactions, including deaths. The regulatory agency also called for the strongest warning possible on Pfizer's other arthritis product, Celebrex. These decisions come about six months after rival drugmaker Merck & Co. pulled its blockbuster arthritis drug Vioxx off the market, also due to safety concerns.

In calling for a stronger warning on Celebrex labels, the FDA cited increased risk of cardiovascular "events" and gastrointestinal bleeding and said all similar drugs should have label warnings.

Pfizer said it "respectfully disagreed" with the FDA decision and it plans to hold talks with the agency about returning Bextra to the market.

Just when you thought it was safe to say “FDA”, and things seemed to be calming down ever so slightly with the uproar over COX-2 inhibitors and scrutiny over the FDA approval processes, the issue of suspect drugs plaguing the pharmaceutical industry has now spread to the biotech sector, with one of its best performing companies and a partner pulling their highly touted multiple sclerosis drug from the market.

Biogen, Inc., the makers of Tysabri, a new drug used to treat multiple sclerosis, announced Monday they are voluntarily suspending sales of the drug after one patient died and another developed a serious disease of the central nervous system.

Biogen Idec hammered out the details of the marketing suspension over the weekend in talks with FDA officials. The decision by Biogen Idec and the FDA to immediately suspend distribution and administration of Tysabri is a cautious approach that may have been influenced by the recent disclosure of newly discovered risks associated with the COX-2 inhibitors. Recall that in September, Merck pulled Vioxx off the market citing a new study linking the medication to increased risk of heart attack and stroke.

Ten members of the Food and Drug Administration advisory panel who voted that a group of COX-2 inhibitors should continue to be sold had ties to the drug makers, a new analysis shows.

A study by the Center for Science in the Public Interest indicates that 10 of the 32 panel members had ties to either Pfizer Inc., or Merck & Co., ranging from consulting fees and speaking honoraria to receiving research support from the companies.

As if the waters at the FDA needed further muddying, a special panel of the US Food and Drug Administration voted last Thursday to allow Pfizer's pain killer Celebrex to remain on the market, despite a finding that it can cause heart problems in some patients. The panelists voted 31-1 to keep Pfizer’s Celebrex on sale and, after a revote, favored Pfizer’s Bextra 17-13 with two abstaining. The vote for Merck’s Vioxx was 17-16, in favor of keeping the drug on the market. The panel noted that Celebrex, Bextra and Vioxx all pose a risk of heart trouble, but should be available to those who need them.

Apparently, not all cox-2 inhibitors are created equally. Structurally, they are very similar but based upon data from the clinical studies, these 3 drugs provide different side-effect profiles. Pfizer must be happy about that.

Well, somehow I managed to miss the next round of American Idol this past Wednesday night and found myself watching 60 Minutes Wednesday night edition, with their interview of Dr. David Graham. Dr. Graham is a senior scientist within the FDA’s Office of Drug Safety and now a whistleblower at the FDA. Graham blames the FDA for allowing dangerous drugs to stay on the market. Specifically, he blames the FDA for not pulling a drug that he claims contributed to the deaths of thousands of Americans. He also points the finger at FDA management for running a dysfunctional organization.