Bienvenue

Generics outfit Sandoz has achieved another milestone with the approval of Omnitrope in Canada. On April 20th 2009, Health Canada granted a Notice of Compliance for Omnitrope, making it the first Subsequent Entry Biologic (SEB) to be approved for sale in Canada. For those unfamiliar with the lingo, SEB is the regulatory term used by Health Canada equivalent to "Biosimilars" in Europe or "Follow on Biologics" in the USA.

Omnitrope, a somatropin (rDNA origin) for injection, is approved for the long-term treatment of children with growth failure due to an inadequate secretion of endogenous growth hormone, and long-term replacement therapy in adults with growth hormone deficiency due to an underlying hypothalamic or pituitary disease or who were growth deficient during childhood. With this authorization, Omnitrope carries the reputation of becoming the first biogeneric product to be approved in Europe, USA & Canada. The market authorization was based on quality, non-clinical, and clinical information submitted. Details about the studies found here.

Whilst the debate over cost savings versus quality continues to intensify between regulatory bodies and law makers, it is encouraging to see products trickling through a system whose effectiveness cannot be evaluated unless it is put into practice. , the current system (however skeletal it may be) needs to be tested in order to:
1)Define the parameters of substitution of biosimilars for innovator products;

2)Determine the extent of pre-clinical studies & clinical trials required to demonstrate safety and comparability;

3)See whether true copies of biologics can be made despite the original products being covered by extensive trade secrets, patents and proprietary technologies;

4) Test the financial sustainability of biogeneric manufacturers. The development of each biogeneric product will be a lengthy, complex process, and is projected to cost about $200 million, compared to approximately $30 million for a traditional generic drug;

5) Quantify the extent of cost savings and the impact of competition on cost reduction;

6) Gauge consumer confidence and acceptance.

It is clear that regulations for biosimilars or follow-on biologics will be implemented in the near future. However, What remains to be seen is whether political pressure from influential groups and an extremely cautious approach on the part of the legislators can be balanced out to develop a functional pathway to approval.

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Innovation Update

A Boost for Protein Expression:

Invitrogen has launched its GIBCO®OptiCHO Protein Expression Kit - the first kit of its kind to provide cells banked under cGMP conditions, enabling biotherapeutics manufacturers to speed regulatory submissions and time to market. The cell line development kit will provide not only the cGMP parental cells but also the components and all the protocols needed to engineer and select producing clones in a completely serum-free system. Amongst other things, cGMP requirements for production cell lines derived from parental cells include source verification, testing, history, control over cell production documentation, and ability to demonstrate chain of custody for the cells from creation through use in biotherapeutic production. Costs for testing & project management to meet these GMP guidelines can range from $30K to $50K - a significant amount for research labs.

The real kicker in this story, however, is the potentially game changing move of providing a single-fee commercial license with no royalties. Taking into account that current procurement costs for a research or commercial use license have been reported to range from $7,000 to $50,000 per year for research use licenses, and up to $500,000 per year (plus royalties on the therapeutic product) for commercial use licenses, Invitrogen’s attempt at market penetration may have a big effect on the balance sheets of cash strapped start-ups. In addition to the cost savings on licenses, royalties, documentation, & regulatory activities the GIBCO kit may also reduce productivity problems. In order to improve biosafety & regulatory approval timeline, many researchers have been removing serum and products of animal origin from cell-culture media during production of therapeutic proteins from CHO cells & using plant hydrolysates as nutrients. The drawback of using plant hydrolysates is that they often contain undefined levels of nutrients and can result in lot-to-lot variation in fed-batch performance and purification inefficiency, which are disadvantages when consistent protein yields are required. To solve this problem, the new kit makes use of chemically defined feeds which apparently not only eliminates the variability associated with using plant hydrolysates, but could also improve the productivity of biopharmaceutical protein manufacture and help move therapeutic proteins into clinical trials more rapidly.

Efficient Eye-Screening:

Using a technology originally developed at the Department of Energy's Oak Ridge National Laboratory to understand semiconductor defects, people at risk of becoming blind can now be screened for eye diseases such as diabetic retinopathy and age-related macular degeneration. The technology involves taking pictures of the retina and relaying them back to a database for comparison. Comparison with thousands of images of known retinal diseases, will determine if the patient passes the screening or is in need of follow-up care.

Manufacturers of semiconductors have used this technology for over a decade, to rapidly scan hundreds of thousands of tiny semiconductors to learn quickly about problems in the manufacturing process. "Right now, with 21 million diabetics in the United States, we need to be screening 400,000 patients for diabetic eye disease every week. Less than half of these diabetics receive the recommended annual eye exam, which is absolutely essential to minimize serious eye complications and potential blindness." says Edward Chaum, who is leading the medical portion of the project. Utilizing an automated process of this kind has the potential to not only improve ophthalmic care in rural areas but also reduce the burden on outpatient clinics & primary care physician offices in urban centre’s. The goal is to have hundreds of cameras installed in the US and beyond, for early detection of disease in a cost effective manner.

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Of mice and men ...

On March 4, 2009, the U.S. Supreme Court issued a 6-3 majority decision in Wyeth v. Levine, No. 06-1249 against the pharmaceutical giant. The Court held that the Food and Drug Administration's (FDA) prescription drug labeling judgments, and specifically, its approval of the label for Wyeth's Phenergan, do not preempt state law tort claims alleging inadequate warning. At issue was a lawsuit by Vermont guitarist Diana Levine, who lost an arm to gangrene after Wyeth’s antinausea drug Phenergan was INADVERTENLTY injected into one of her arteries during a push IV injection. Ms. Levine had gone to a clinic for treatment of a migraine headache. Ms. Levine argued that Phenergan’s labeling, though approved by the Food and Drug Administration, didn’t provide proper warnings of the risk of administering the drug through a push IV injection instead of using an IV-drip.

For those following the case over the past few months, it was evident that heads would turn regardless who the court ruled in favour of. But few were expecting the decision to go against Wyeth, especially since the courts had ruled in favour of pre-emption in a similar case involving a medical device (see Riegel vs Medtronic). Ultimately, what it came down to was the presence of explicit wording in the Medical Devices Act saying “no State ‘may establish or continue in effect with respect to a device . . . any requirement’ relating to safety or effectiveness that is different from, or in addition to, federal requirements …”. Nothing of that sort is present in the Food, Drugs, and Cosmetics Act. So why did Wyeth’s legal team even consider pre-emption to be a plausible defense? Apparently the FDA was in the mood for an ol fashioned power trip in a preamble to a 2006 regulation the agency issued on prescription drug labeling. This included statements that the agency can indeed pre-empt state law as they provided for not only a floor but also a ceiling to such labeling language, and so on. Wyeth seems to have relied a bit too heavily on this preamble. So this decision might look like a whack at the drug industry, but it's actually a case of a federal agency being told that its powers aren't as broad as it occasionally seems to think. You wouldn't necessarily guess it to see that way the justices lined up in this case, but the verdict looks like a real endorsement of federalism. And in the same way, you might not guess it, but the drug companies would probably like for the FDA to be that powerful, actually - that way, some of the responsibility could be offloaded, and there would be a single place to go for regulatory clarity.

Of equal importance and worth mentioning is that this unfortunate incident could easily have been avoided but for the EMT’s negligence in administering the drug in a way the manufacturer did not intend. This litigious society is going down the toilet. Obviously, Ms Levine should be compensated, but by those who made the mistake, not by those who provided the cure, that when administered properly would have helped her, not harmed. I cannot help but think the main reason they went after Wyeth is because Wyeth is seen as the party with the deepest pockets. This is not to say that Wyeth was completely devoid of fault. The bigger issue is clearly whether or not it is pharma’s responsibility to provide adequate warnings in conflict with FDA approval. As it stands, and regardless of what the FDA says, the burden of proof is not on the FDA to prove harm, but rather on the manufacturer to prove its product is safe. The FDA warning requirements provide a “basement not a ceiling” - e.g., the manufacturer has some responsibility to update its labels and warnings over time, when more evidence is obtained as to the safety or danger of its products.

Preemption has a place but not in this case and not with these facts. That Wyeth could have requested a label change to reflect its growing awareness of possible heightened risk from certain routes of administration is incontrovertible. That Wyeth claimed that it could not have done so flies in the face of reason and past experience. None of this suggests, however, that a good case cannot be made for preemption. This just wasn’t that case. The facts were not on Wyeth’s side. All this is simply to suggest that I don’t think this is the last we’ll hear of preemption or the last the Supreme Court will have to say on the doctrine.

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The 28 day round-up

Despite the rumblings of layoffs, downturns, redundancies and bailouts, February seems to have been a good month for drug approvals globally. Following are some noteworthy developments.

-Matrix Labs received the first and only World Health Organization (WHO) approval for Lopinavir/Ritonavir Tablets, 200 mg/50 mg. Matrix's version of this product is heat-stable and affordable, making it practical for distribution and use in warm climates. A WHO approval indicates that a drug meets international safety, efficacy and manufacturing quality standards. With such status, Matrix can sell the treatment in most countries outside the United States and Europe. The company's emphasis on producing affordable products has allowed it to drive down the average annual cost per patient of effective therapies. Approximately 30% of HIV/AIDS patients in the developing world depend on Matrix's ARV products.

- The US FDA has approved ATryn® (Antithrombin [Recombinant]) for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients. The GTC Bio & Ovation Pharma collaboration is the first ever transgenically produced therapeutic protein and the first recombinant antithrombin approved in the U.S. Along with the approval of ATryn, the FDA’s Center for Veterinary Medicine also approved GTC’s New Animal Drug Application, the first of its kind for the regulation of a genetic construct stably integrated into the genome of genetically engineered animals. This is now required for a recombinant technology used to develop transgenic animals, such as the goats that produce recombinant antithrombin.

-Good news for patients with osteoarthritis of the knee. The FDA has finally approved Genzyme's Synvisc-One which could potentially change the face of viscosupplementation therapy. Viscosupplementation is a procedure in which hyaluronic acid or a derivative such as hylan G-F 20 is injected into the knee joint to replace synovial fluid that typically becomes degraded in patients with osteoarthritis. Synvisc-One is an important therapy for OA of the knee because it delivers long-term pain relief (upto 6 months) through a single injection without the systemic side effects that can be caused by steroids and anti-inflammatory medication.

-Over 5 million gout patients with hyperuricemia have a new treatment option for the first time in 40 years. Teijin Pharma's new molecular entity, Febuxostat, is licensed to Takeda for marketing in the US where it will be available as ULORIC.

- The European Commission has granted marketing authorisation for Servier's Valdoxan(R) /Thymanax(R) (agomelatine), the first melatonergic antidepressant for the treatment of adult patients with major depressive episodes. Valdoxan is the first antidepressant with melatonin receptor (MT1) and (MT2) agonist properties and 5-hydroxytryptamine (serotonin) receptor 2C (5-HT2C) antagonist properties. This unique receptor profile of Valdoxan allows for the first time the restoration of the circadian rhythms of depressed patients. Valdoxan's mechanism of action is unlike those of the commonly-prescribed antidepressants, the SSRIs and SNRIs, as Valdoxan exerts its antidepressant efficacy without having an impact on serotonin levels.

-Dapoxetine has received marketing authorisation in Finland and Sweden for the on-demand treatment of premature ejaculation (PE) in men 18-64 years of age

-A big bump for companies in Canada, as some potential major earners received approval. The 44 NOC's issued by Health Canada included- Lilly's Cymbalta for Generalized Anxiety Disorder; Schering Plough's much anticipated contraceptive NuvaRing; Shire's Vyvanse for ADHD; Wyeth's antidepressant Pristiq; and a new indication for Avastin by Roche. The increasing number of drug submissions in Canada is a sign that manufacturers now consider the Canadian market to be substantial and profitable enough to hit those earning targets despite price controls, a public payer system, and generics friendly IP laws.

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