FDARA and “Chiral Switch”

To date, one of the most interesting strategy to monopoloise the pharmaceutical market is a recourse to "chiral switch". Chiral Switch is a shift to an optically-active enantiomer from an optically-inactive racemate. AstraZeneca utilized this concept in retaining its share of the drug market for treating gastrointestinal diseases, by transferring doctors and patients from its blockbuster omeprazole (marketed as the drug product LOSEC) to omeprazole sodium (marketed as NEXIUM) before the original omeprazole patent expired. This particular move of chiral switch has done wonders for AstraZeneca and omeprazole remains to be one of the best selling molecule in their portfolio.

Another interesting case is that of Citalopram (racemate, Celexa) and escitalopram (enantiomer, Lexapro). In the future, one would not be srprised if chiral switch becomes main weapon to maintain the monopoly in the pharmaceutical market. Provigil (racemate) and Nuvigil (enantiomer), dextromethorphan, PLAVIX ((S)-clopidogrel are already on their way to follow the suit.

Chrial switches have highlighted the importance of chiral molecules. In fact, the focus of whole drug industry has been shifted to chiral molecules. For stastical consdieration, the nine out of first ten block bluster molecules in the year 2006 were chiral in nature.

A review by John Caldwell of the University of Liverpool and organic chemists Israel Agranat and Hava Caner at the Hebrew University of Jerusalem indicates that since 1990, the proportion of single-enantiomer drugs among approved new chemical entities worldwide has been consistently greater than that of racemates [Nat. Rev. Drug Discovery, 1, 753 (2002)]. Chiral effects in pharmaceuticals are being exploited in several ways: as mentioned above by chiral switching, by discovering distinct therapeutic uses for enantiomers of chiral drugs, and by creating non-racemic mixtures of enantiomers.

Probably, keeping in mind the importance of Chiral molecules, the US Senate on May 09, 2007 passed FDARA (Food and Drug Administration Revitalization Act)

The main feature of this act, is that, it provides an opportunity, to elect 5-year exclusivity under certain circumstances for enantiomers.

According to provision of this Act, Specifically, FDARA § 264, if an application is submitted under [§ 505(b)] for a non-racemic drug containing as an active ingredient a single enantiomer that is contained in a racemic drug approved in another application under [§ 505(b)], the applicant may, in the application for such non-racemic drug, elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug . . . .

Thus, if a single enantiomer is not considered to be the same active ingredient as that contained in the approved racemic drug, FDA may consider it to be a new chemical entity eligible for 5-year exclusivity. However, such an election of 5-year exclusivity can only be made if:

• (A) (i) the single enantiomer has not been previously approved except in the approved racemic drug; and (ii) the application submitted under [§ 505(b)] for such non-racemic drug –
• includes full reports of new clinical investigations (other than bioavailability studies) – (aa) necessary for the approval of the application under subsections (c) and (d); and (bb) conducted or sponsored by the applicant; and
• does not rely on any investigations that are part of an application submitted under [§ 505(b)] for approval of the approved racemic drug; and
• (B) the application submitted under [§ 505(b)] for such non-racemic drug is not submitted for approval of a condition of use— (i) in a therapeutic category [(as identified in the list referenced at42. USC § 1860D-4(b)(3)(C)(ii)

in which the approved racemic drug has been approved; or (ii) for which any other enantiomer of the racemic drug has been approved.

In addition to these requirements, which essentially necessitate the submission of a “full” 505(b)(1) NDA, FDARA § 264 also includes two significant limitations that may offset the incentive for electing 5-year exclusivity.

• First, FDA may not approve a single enantiomer of a previously approved racemate granted 5-year exclusivity for any condition of use in the therapeutic category in which the racemic drug has been approved “[u]ntil the date that is 10 years after the date of approval of a non-racemic drug described in [proposed FDC Act § 505(t)(1)].”
• Second, “the labeling of a non-racemic drug described in [proposed FDC Act § 505(t)(1)] and with respect to which the applicant has made the election provided for by such paragraph shall include a statement that the non-racemic drug is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.”

Thus, a mere reading of this act suggest that USFDA wants pharmaceutical companies to develop the single enantiomers for new therapeutic indication and not for the same therapeutic indication, in which the chiral drug is approved.

Therfore, whether the implemenation of FDARA would limit the strategy of Chiral swithes and enhance the use of single enantiomer for new therapeutic indications need to be seen.

Patent Battles: The Way Ahead -II

In continuation to my previous post related to patent battle, herein the effort is made to review the situation in India. The patent scenario in India is also changing to be at par with other so called advanced or highly regulated market, especially in pharmaceutical sector.

With the implementation of Product patent regime and honoring the importance of adequate patent protection life, India is on track to see a major change in pharmaceutical scenario. Further, the efforts are being carried out to implement data protection, as outlined by Satwant reddy committee report. These developments are strong indicators of changing winds in Pharmaceutical sector in India. It’s only a matter of time, for Pharmaceutical Industry in India, to witness a high number of patent litigations.

The forecast of high number of patent litigation is based only on desire of pharmaceutical companies to capture the untapped market due to the pressure for ever increasing profits at pharmaceutical companies. The capability of Indian companies to capture lucrative markets of US and Europe is well proven. Therefore, this battle, when fought at their own backyard, i.e. in India, appears to be far more brutal. India, being a country of vast population and legislation offering or attempting to offer adequate Intellectual protection is certainly a big pharmaceutical market of future.

Once it is accepted that, even in India, which has moved a long way from process development, there would be a large number of patent litigations, the future pharmaceutical market would be governed by litigations, then obviously the next big question which comes in mind is that whether our judiciary system is capable of handling such a huge task?

In India, where normal civil and criminal cases take unwarranted time to dispose, the future of patent litigations, involving technical subject matter is ambiguous. The existing infra structure and corrupt system only adds to this ambiguity.

Therefore, whether Indian Legal System as well as Health Regulatory System would be able to cope with the demands of future would need to be seen.

If we look at China, a neighboring Country, the Pharmaceutical industry picture is clearly depicting a birth of another giant. China, similar to India, has huge population and therefore, remains to be a big Pharmaceutical market.

Chinese legal system has already shown to the world their preparedness about Health issues. The recent Judgment of Beijing court slamming the death penalty to Zheng Xiaoyu, who was found guilty for taking over $850,000 worth of bribes in the form of cash and gifts when inappropriately approving hundreds of drugs and medical devices, at least six of which proved to be fake is clear indicators of strong pharmaceutical environment.

Whether there would be any stringent and/or bold decision in Indian scenario would need to be wait and watched.

In an effort to mimic regulated countries atmosphere for IP issues, how far India, China or similar countries like Brazil could go would determine, which would be the Best Pharmaceutical market of twenty-first century.

Biogenerics: Opportunity In Abundance

In The Midst of Thick Challenges

A number of factors are coinciding to make biogenerics a hot topic at the moment: Government agencies around the globe especially US and Europe are busy devising a balanced regulatory policy for biogenerics to address the rapid and a more urgent priority for governments and consumers healthcare spending on ageing populations.

As key patents on some of the early recombinant protein therapeutics have started to expire the generic companies are developing the capabilities to develop and create their own versions of these off-patent products while Innovators on the other side are trying there best to exert a much greater influence and slow down the reforms.

In this context the people’s representatives in US have taken a big leap forward to open the much debated market barrier for biogenrics. The bill passed by the Senate health, Education, Labor and Pension committee by a Voice vote is fairly assumed to be included in the broad FDA bill expected to be passed in the coming months is one such effort taken by US and being eagerly tracked by all the stake holders involved.

The authors who wrote the bill say "The bill reflects a balanced approach that enables patients to have safe, effective and affordable biological drugs, while preserving the incentives that have brought these life-saving advances to the American public,"

The major highlights being provision of a 12 years of marketing exclusivity for Biologic medicine to the Innovator against the traditional 5 years of marketing exclusivity for new chemical entities.

If this becomes law it could open doors for multibillion dollar biotech products such as Epogen (Amgen), Procit (Johnson & Johnson) since their patents have expired and have already enjoyed at least 12 years of monopoly.

So what this means to generic drug maker is an Opportunity in abundance: The big attraction in terms of market potential for biogenerics however in the midst of thick challenges in terms of massive barriers to entry.

Basic barriers to market entry in biogenerics are much higher than for any small molecule generics such as

¨ High development costs since the investment needed to put a biogeneric through the necessary clinical trials is considerable
¨ Greater time in development (due to required clinical testing)
¨ Quality requirements, as well as demanding and uncertain regulatory approval and not but the least
¨ Intellectual property issues in terms of Patent.

As a result, the situation demands the companies to move beyond typical generic company strengths and develop new skills in biotechnology, manufacturing, clinical trials, regulatory compliance, pharmacovigilance testing and marketing.

The investment needed to put a biogeneric through the necessary clinical trials is considerable and illustrates the great importance of strong financial backing and regulatory expertise.

All in all, generics companies will have to create an entirely new business model for biogenerics: in many ways closer to the branded biotech model.

Industry observers says that only a select bunch of top biogeneric players are expected to make use of this opportunity and have an initial impact on the market due to there present strength and capabilities. Five key players will be Novartis's Sandoz, Teva, BioPartners, BioGenerix a subsidiary of Ratiopharm and Stada through its affiliate Bioceuticals. However, based on the current outstanding success of Indian pharmaceuticals companies on follow on generics we can certainly look forward for Biotech Industries in India joining the race.

Patent Battles: The Way Ahead

Intellectual property (IP) is a buzz word in today’s knowledge based era. The value of IP is enormous and ever increasing, especially in the field of pharmaceutical industry. Moreover, thanks to computers and internet, which make transfer of information even faster than speed of light. The advent of e-communications has brought everyone on global level and the competition in each filed of technology is fierce.

If we look at various patent related cases, which are filed in all Federal District Courts of USA, we would note that from June 01, 2007 to June 26, 2007, at least 224 new cases have been filed. The number is mind-boggling. Statistically it is approximately 10 new patent related litigations per day! A list of few of these cases, mainly related to Pharmaceutical field is given in Table – 1. By virtue of these litigations, multimillion-dollar molecules such as Oxaliplatin, Depakote are under generic attack. The battle of Sertraline is special as it involves fight of generic companies with each other.

The US generic market is definitely a lucrative option for generic companies and beyond any doubt, the provisions of Hatch-Waxman Act has catalyzed early generic entry. In fact all major life savings drugs have seen an early entry by the provisions of Hatch –Waxman in USA. Further, one should thank to the apex Court of USA, for raising the standard of obviousness in USA recently through a judgment in KSR case.

Therefore, patent battles would continue to drive pharmaceutical market in USA.

Patent Talk

Every one of you out there! interested to know all about Intellectual Property : Especially Patents.

Welcome to this new blog PATENT TALK

This is our first attempt to write Interesting things about patents and hope you would enjoy reading the same

till then wait for OUR first writeup !!!!!!!!!!

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Nishid & Prashant