The Brave New World of Biosimilars



    The FDA has been debating for many years over whether to approve biosimilars, cheaper versions of expensive and complex biological drugs used to treat a multitude of diseases.  Biological products are large protein molecules generally derived from living organisms and have chemical modifications that are very different depending on what cells are used to make them.  Biosimilar products are biologicals that are approved based on high similarity to the brand reference product, with very little differences in terms of safety, efficacy and clinical impact. 

    As developed markets see their patents expire in the next few years, there will be a rapid shift in consumer spending toward new generic medicines such as biosimilars.  A recent report from the IMS Institute for Healthcare Informatics estimates global healthcare spending will reach $1.2 trillion by 2016, with 2% or up to $6 billion accounted for by the biosimilars industry (part of the $200 billion global spending on biologics market).  Some estimates for the biosimilars market are predicted to top $44.2 billion by 2024!  In Europe the EMEA has already approved 21 biosimilars over the past 10 years.  The US has a long way to go in this area but FDA managed to approve the very first one this year.

    In March FDA released news for the approval of Zarxio, a biosimilar produced by Sandoz Inc (the generic arm of Novartis).  It is similar to the reference drug Neupogen (Filgrastim) licenced to Amgen Inc in 1991.  Neupogen has been prescribed to leukemia cancer patients undergoing harsh chemotherapy regimes who suffer from weakened immune systems.  Neupogen is used to boost the immune system of patients by producing recombinant human granulocyte colony stimulating factor to induce neutrophil production.  Sandoz Inc. filed the biosimilar application under the new Biologics Price Competition and Innovation Act (BPCI Act, 2009) and also under the Public Health Service Act’s section 351(k) provision (PHS Act § 351(k)).  The current regulations require biosimilars to show equivalence to a “reference product” without having to go through the full set of preclinical and clinical study necessary for traditional BLAs. 

    According to the FDA’s guidance:

    “A biosimilar product can only be approved by the FDA if it has the same mechanism(s) of action, route(s) of administration, dosage form(s) and strength(s) as the reference product, and only for the indication(s) and condition(s) of use that have been approved for the reference product. The facilities where biosimilars are manufactured must also meet the FDA’s standards.”

    Sandoz Inc managed showed that in a clinical trial involving 388 people with breast cancer, 174 people using Zarxio were able to break it down in the body in a similar way to the Neupogen drug without provoking an adverse immune response.  Zarxio is predicted to cost 40-50% less than Neupogen.  The approval of Zarxio opens the door for companies to start applying for more biosimilars in the United States and allows consumers to buy cheaper biologics in the coming future.

    Despite the green light from the FDA, Sandoz will be fighting Amgen over patent laws with regard to its new drug.  US law requires Sandoz to reveal their manufacturing protocols to Amgen in order to ensure licenses for manufacturing methods have not been violated.  Unfortunately Sandoz wants to keep its manufacturing techniques confidential so that they can file their own patents.  Such licensing laws do not exist in Europe hence the approval of biosimilars has been so rapid and convenient in that region.  Furthermore, Advisory Committees and groups like the Generic Pharmaceutical Association (GPhA) have voiced concerns over whether generic names for new biosimilars will be used to replace brand names that originally existed, causing confusion for patients shopping for cheaper drugs in future.

    Another issue has recently come to surface over the biosimilars guidance document.  AbbVie sent a Citizen Petition to the FDA demanding a change to the guidance entitled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”.  The guidance removed the requirement in the 351(k) provision for sponsors to show labeling of bioequivalence to a reference product (as described above) and also removed the need to indicate whether it is “interchangeable with the reference product”.  AbbVie challenged this guidance demanding that the FDA require all biosimilars to differentiate themselves from a reference product. 

    Abbvie wants to see new language in the guidance containing:

    • A clear statement that the product is a biosimilar and that the biosimilar is licensed for fewer than the reference product’s conditions of use.

    • A clear statement that FDA has not determined that the biosimilar product is interchangeable with the reference product.

    • A concise description of the data that supports license of the biosimilar and a comparison with data from studies of the reference biological product.

    Abbvie contends that biosimilars, unlike generic drugs, are complex products and substitution of established biological drugs could be much riskier, result in very different clinical outcomes and are less interchangeable compared to generic drug substitutions of branded chemical drugs.  They argue that employing a “Same Labeling” approach for biosimilars as for generics in the ANDA requirements is unsound law.  Interestingly, Abbvie alleges that FDA is violating the Administrative Procedure Act (APA) by removing the provision § 351(k) that was originally in the 2012 draft version of the guidance for biosimilar products.  This could premise future litigations.

    Is your company affected by the new regulations for biosimilars?

    Since biosimilars are likely to become an increasingly prominent product in the industry, changes in legislation concerning these products are likely to affect your company.  The murky area of patent rights for licensing biosimilars, rights to naming the products and rights to manufacturing techniques is likely to affect your company’s future decisions.

    For more information, please carefully read FDA’s latest version of Scientific Considerations in Demonstrating Biosimilarity to a Reference Product and Abbvie’s latest Citizen Petition to FDA.


    Ledford H, First biosimilar drug set to enter US market. Nature, In Focus News; 517:253-254 (2015).

    IMS Institute for Healthcare Informatics, The Global Use of Medicines Outlook Through 2016 (July 2012)

    FDA Law Blog, Hyman, Phelps and McNamara June 03 2015

    FDA Press Release March 2015

    Patent Docs blog



      The Everlasting Patent or Just a 15-year Protection?



    Drug patents typically last for 20 years from the date of filing to the patent office. After expiration, other companies can submit abbreviated new drug applications (ANDAs) to the FDA for generic drugs - drugs with therapeutically equivalent safety and effectiveness as the original brand-name drug but which are cheaper.  The Hatch-Waxman Amendments to the FD&C Act were introduced in 1984 to ensure that brand-name drug manufacturers could have a fruitful patent protection period and to ensure that consumers would eventually benefit from lower-priced generic versions of the innovative drugs.  However, companies often see the 20-year patent cliff as an obstacle since they have to make as much money as possible from their brand-name drug to cover the costs of development.

    In December 2014 Senator Orrin Hatch (R-UT) introduced the Dormant Therapies Act.  This act was intended to "remove the 'ticking patent clock' that forces companies to prioritize research based on which drugs can be marketed more quickly.  Earlier this year the 21st Century Cures Act was released which contained a new provision in its Subtitle M, Title I.  Subtitle M creates a guaranteed 15-year "protection period" for new drugs and biologicals approved for "dormant therapies" (as opposed to the current 5 years for new drugs).  Dormant therapies is defined as any medical research being done to treat "unmet medical needs".  Any drug that falls under this protection would have an extended period of exclusivity, rendering the sponsor immune from competition of any ANDAs or new NDAs and BLAs for drugs which contain "forms of the active moiety of the dormant therapy and highly similar active moieties".

    One reading of the new provisions of Subtitle M statutory text could be that any old patent which is reasonably related to a drug or biologic classified under dormant therapies could be "protected" for 15 years from any new competition. The sponsor could simply apply for multiple designations of dormant therapies for the same patent and thus create an "everlasting patent".

    However, another reading of the provisions is that a dormant therapy can benefit from only one protection period, "measured from the first day of the first approved indication for a therapy" which cannot be further extended. In such a case the patent cannot be further extended. The applicant sponsor would therefore not gain exclusivity for the patent beyond the initial 15 year protection period. Furthermore according to another provision of Subtitle M, even if the same patent were ever to be extended a second time because a different active moiety was added, the "Hatch-Waxman limitations" would be enforced, limiting the extension terms.

    Thus, while the dream for sponsor companies to retain unlimited exclusivity over all their most valuable patents remains just that, the 21st Century Cures Act has opened up a new debate over whether patent exclusivity should be extended for longer periods of time for urgent medical treatments and for how long such extensions should be allowed.


    Hatch-Waxman Amendments 1984:

    FDA Law Blog, ever lasting patent renewal:

    RAPs Regulatory Explainer: The (Updated) 21st Century Cures Act:



      Who Owns CRISPR-Cas9?



    A new revolution is sweeping through the world of genetic engineering and medicine called CRISPR-Cas9. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, or segments of DNA used by bacteria to cut out unwanted invading DNA from phages (viruses that invade bacteria). Cas9 (CRISPR associated protein 9) is a protein which aids the function of CRISPR to cut out undesirable foreign genes. A few years ago it was found that CRISPR-Cas9 could be engineered to edit the entire genomes of a panoply of organisms from bacteria all the way to mammals and humans, thus potentially curing many genetic diseases. It has been heralded as the technology that could cure anything from liver diseases to muscular dystrophy to HIV. The implications of this technology are so huge that Science magazine has recently dedicated a special edition to include all recent papers, commentaries and news articles about CRISPR.

    But who discovered it and who has the patent rights to it? In April 2014, a broad U.S. patent was awarded to Feng Zhang, a scientist at the MIT-Harvard Broad Institute who claims to have discovered the effectiveness of CRISPR-Cas9 on gene editing in human cells. Zhang filed his patent with a priority date of Dec 2012. Just a few months later, a Breakthrough Prize was awarded to Jennifer Doudna and Emmanuelle Charpentier from UC Berkeley and Vienna, Austria, for their contribution to the discovery of CRISPR. Doudner and Charpentier filed a patent with a priority date of May 25, 2012, which includes 155 claims, encompassing numerous applications of the system for a variety of cell types.

    All parties have founded startup biotech companies in the race to develop CRISPR as a viable clinical drug. Zhang co-founded Editas Medicine with Doudner before Doudner dropped out and went on to found Caribou Biosciences and Intellia Therapeutics. Charpentier is the founder of CRISPR Therapeutics but has now sold the rights for that company.

    Several challenges have arisen in lieu of these rival patent claims. Firstly, Doudner and Charpentier argue that they filed the patent documents for CRISPR before Zhang because they had an earlier priority date but Zhang was awarded the patent first. Zhang was awarded the broad patent because he had a laboratory notebook demonstrating his group was doing CRISPR genome editing in human cells before anyone else and also because he paid for an expedited patent review. Lawsuits are likely to be complicated and as Charpentier said, “It all sounds very confusing for an outsider, and it’s also quite confusing as an insider.”

    Furthermore, according to MIT technology review, “This isn’t the end of the patent fight. Although (Zhang) moved very swiftly, lawyers for Doudna and Charpentier are expected to mount an interference proceeding in the U.S.—that is, a winner-takes-all legal process in which one inventor can take over another’s patent.”

    Secondly, over 100 patents have already been filed by many scientists, including Zhang and Doudner, which make use of the CRISPR-Cas9 technology. This could land many scientists with patent infringements if CRISPR-Cas9 were ever licensed.

    Thirdly, the patent for CRISPR-Cas9 itself may be contentious since it uses DNA technology which has already existed in bacteria for millennia and can seem “obvious” for many scientists who can now easily use it in their laboratories. In a sense CRISPR was in fact “invented” by nature and not by any individual, so claiming a patent over the mechanism would be an act of god. Answering such an issue can be a headache not only for the legal field but also for bioethics philosophy.

    Some solutions to these challenges may lie in history. For example, when small interfering RNAs (siRNA) and when polymerase chain reaction (PCR) were first discovered similar debates arose in the science community about whether people could use the technology without a licence. With the discovery of recombinant DNA, Stanford University was assigned the Cohen-Boyer patent which allowed Stanford to non-exclusively hold the patent, enabling non-profit research institutes to use the technology without a licence. Stanford also developed a graduated royalty system with small companies to ensure some share of profits if companies used their technology effectively. For the discovery of siRNA, MIT was awarded the “Tuschl” patent, which also granted nonexclusive licences to companies selling the technology and allowed academic scientists to work on the molecules with no licence. Similarly, with the invention of the PCR, patents were adapted through a strategy known as “rational forbearance” to prevent researchers from being sued for patent infringement everytime they used the technology and to allow adaptive licences to be held by business partnerships.

    Perhaps ultimately the patent disputes for CRISPR-Cas9 will be sorted out by following one of the historical models of adapted patents for biomedical discoveries. However, since large-scale clinical trials using this technology are still a long way off it is hoped that this current dispute can be sorted out soon so that the safety of the CRISPR technology can be established.


    Shwerkow JS, Law, history and lessons in the CRISPR patent conflict, Nature.  Vol 33 (3): 256-257, 2015.

    Regalado A, Who Owns the Biggest Biotech Discovery of the Century? MIT Technology Review, Dec 4 2014.




      The Food and Drug Law Blogs



    In recent months I have been studying for a degree in Quality Assurance and Regulatory Affairs in pharmaceutical drug development. While at first glance regulatory affairs may seem like a tedious subject to study, especially for a basic research scientist involved in cutting edge academic research, it turns out that courses taught in the curriculum can be a perfect complement for any biomedical scientist wishing to pursue a career in industry.  Regulatory affairs in drug development is a science in and of itself, dealing with the study of various paths a drug manufacturer can/should navigate in order to develop a drug from preclinical testing to clinical trials to postmarket research.  All the while companies must coordinate with contract research organizations, institutional review boards, hospitals, health care providers, patients and of course the Food and Drug Administration. I am taking one of the core course modules this summer, which is Food and Drug Law. As part of the course I must write a weekly blog about an aspect of food and drug law that I find fascinating and make a presentation about the theme at the end of the semester. I have decided to focus my theme on drug law patents and the most current topics concerning that field. I thought it would be a good idea to simply post up my blog assignment onto my website for each week. So in the above blog entries, you will find essays concerning my reviews about drug patent laws as well as legal issues concerning the FDA.

    Why have I chosen to write about drug patents? My explanation begins in the introduction:

      Food, Drug and Biological patent disputes in the 21st Century

    New innovations happen all the time in the biomedical sciences field and new drugs are being developed at a faster rate than ever before. When a company submits a new patent to the U.S. Patent and Trademark Office and it gets approved, it is the responsibility of the sponsoring company to submit the patent information to the FDA’s database of Approved Drug Products with Therapeutic Equivalence Evaluations, otherwise known as the “Orange Book” within 30 days (21CFR314.53).  However, since multiple companies and laboratories are often tackling the same problems with the same available resources, similar patents are often filed by different parties at similar times.  Furthermore, the FDA itself does not review drug patents since the Agency’s statute only requires the publication of patent information.  With patent rights for drugs usually lasting 20 years (with the exception of Title II of the Hatch-Waxman Amendments of 1984) and with time taken for drug development sometimes lasting over 10 years, it is natural for sponsors to scrupulously guard a patent in order to make good on financial returns once the drug can be marketed.  Thus in our current landscape of technological innovation and financial competition it is not hard to see how patent disputes can often arise between rival companies.



      The Big Idea: Reeve Foundation's Ambitious New Campaign to Cure Paralysis



    When Christopher Reeve appeared in the 2000 Superbowl advert to rise up miraculously from his wheelchair and walk toward a gasping audience, he was probably dreaming about a day like today. The Christopher and Dana Reeve Foundation (or Reeve Foundation) launched a new campaign at the end of last year called The Big Idea in which they plan to raise $15 million funding for clinical trials to test epidural electrical stimulation on 36 paralyzed spinal cord injury patients. This trial will be based on a series studies that started in Louisville Kentucky under Susan Harkema and thanks to the electrical medical devices invented by Reggie Edgerton's team at Neurorecovery Technologies Inc. The innovative new treatment has already brought life changing improvements for four patients, as has been reported in the news. Thousands of people have already lined up for the procedure on the victory over paralysis registry.

    More about Susan Harkema:HarkemaMore about Reggie Edgerton:Edgerton

    More about Neurorecovery Technologies Inc:Neuroinc

    For some time now the data from epidural electrical stimulation has been making headwinds in the neuro regeneration community. Essentially, electrode arrays are implanted over the dura of the lower spinal cord (T12-S1 region) and activated to send continuous electrical currents at alternating frequencies to stimulate the lumbar spinal cord. Electrical currents stimulate the Central Pattern Generator (CPG) which, with sensory feedback from muscles of the lower extremities of the body, becomes reactivated after injury. However, reinnervating sensory feedback from damaged muscles to a lesioned spinal cord is difficult. One way to stimulate sensory nerves is to place patients through rigorous locomotor training activities with physiotherapists. Another way is to locally administer drugs to serve as receptor agonists that induce axon regeneration. It is through a combination of these approaches that the CPG can be reactivated. The CPG provides centralized command for many of our most basic rhythmic movements, including walking, climbing, breathing and swimming. By stimulating the CPG successfully in animals with severed connections from the brain, it shows that movement of certain muscles in our bodies are not dependent on the brain or on supraspinal propriosensory neurons, but on rhythmic sensory feedback from the muscles themselves.

    A simplified diagram explaining epidural electrical stimulation from the NIH website:EES

    According to the study reported in the journal Brain, the four subjects who have undergone epidural stimulation have seen a dramatic recovery in voluntary movement of legs, knees and ankles and body weight support. However, apart from the loss of voluntary movement, a variety of disorders usually afflict spinal injury patients, including loss of bowel and bladder control, loss of sexual function and autonomic dysreflexia. The study promises to improve function in all of these systems by restoring electrical innervation. Whether this is the case remains to be seen. There are also many regulatory hurdles this study must undergo with the FDA before it becomes approved for early stages of clinical trials.

    What is for certain is that epidural stimulation and locomotor rehabilitation has already proven successful in functional recovery of spinalized rats. A recent TED talk by Gregoire Courtine, a former postdoc of Reggie Edgerton who now runs his own lab in Switzerland, expounded on the dramatic improvements he found when using this technology on rats undergoing treadmill rehabilitation. Although I believe TED talks have gained a cult-like status with their slick presentations and charismatic speakers at times exaggerating the truth, there is merit in seeing this talk, especially for those working in the field:




      Holding People Accountable for Retractions


    Image from NPG

    Last week acclaimed cell biologist and cartoonist Leonid Schneider wrote to Retraction Watch with a very smart idea for holding principle investigators (PIs) and institutions accountable for research paper retractions. I mentioned in a previous post that an increasing number of research papers have been retracted in recent times because it emerged that data manipulation, plagiarism and fraud were at play. Often the fall person, the first or middle author has suffered a little in their career while the senior PI and the university or institution has been able to get away with it relatively scot-free (though this has not always been the case). Many laboratories have become multiple re-offenders with a litany of retractions. Websites like Retraction Watch and PubPeer can only do so much to shed light on scientific misconduct since few regulations are in place to stop such bad behavior.

    In order to bring in some justice and to stem the rising tide of retractions, Schneider suggested that funding agencies should include a new refund clause in every application and force every applicant to sign it. The clause would enforce a monetary fine on the laboratory and the university if a paper is retracted. Since research funding is usually distributed among the PI's salary, personnel salary, university overhead and equipment, the funding agency would have to take money out of all these elements in order to make the reimbursement. Such a reimbursement would need to come ultimately out of the university's expenses. The refund to the grant agency would have to be commensurate to the impact of the paper being retracted - with retractions from Nature, Cell and Science constituting a heavier fine than from smaller journals. Furthermore, since big funding agencies also play a role in paying for scientific journals, they should play the biggest part in pressurizing editors of prestigious magazines to come clean about their mistakes and admit to publications that turn out to be false.

    Obviously there may be academics who find such a reform controversial or even downright abhorrent given that such an overhaul could cost them a life time of work and leave their labs empty. Perhaps laboratories that suffer a one-time retraction but demonstrate that they are very careful with subsequent publications can be provided an opportunity to appeal for a remit. The best outcome is for all PIs to encourage a sense of ethical standard in their students and postdocs and to pay attention to how data is interpreted and published. Graduate schools may do better by putting all new students through an "oath swearing" ceremony, to drill the principles of abiding by ethical scientific conduct into every new scientist. This would be rather like medical students swearing by the Hippocratic Oath in the White Coat ceremony. In an ideal world I will not have to read or write about scientific paper retractions again. But we will have to wait and see if regulatory reforms can ever take off.

    Read Leonid Schneider's article on Retraction Watch: What if universities had to agree to refund grants whenever there was a retraction?



Front page . <-- Previous . 1 . 2 . 3 . 4 . 5 . 6 . 7 . 8 . 9 . Next -->