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Real Time Coverage @BIOConvention #BIO2019: Genome Editing and Regulatory Harmonization: Progress and Challenges

Reporter: Stephen J Williams, PhD @StephenJWillia2

 

Genome editing offers the potential of new and effective treatments for genetic diseases. As companies work to develop these treatments, regulators are focused on ensuring that any such products meet applicable safety and efficacy requirements. This panel will discuss how European Union and United States regulators are approaching therapeutic use of genome editing, issues in harmonization between these two – and other – jurisdictions, challenges faced by industry as regulatory positions evolve, and steps that organizations and companies can take to facilitate approval and continued efforts at harmonization.

 

CBER:  because of the nature of these gene therapies, which are mainly orphan, there is expedited review.  Since they started this division in 2015, they have received over 1500 applications.

Spark: Most of the issues were issues with the primary disease not the gene therapy so they had to make new endpoint tests so had talks with FDA before they entered phase III.   There has been great collaboration with FDA,  now they partnered with Novartis to get approval outside US.  You should be willing to partner with EU pharmas to expedite the regulatory process outside US.  In China the process is new and Brazil is behind on their gene therapy guidance.  However there is the new issue of repeat testing of your manufacturing process, as manufacturing of gene therapies had been small scale before. However he notes that problems with expedited review is tough because you don’t have alot of time to get data together.  They were lucky that they had already done a randomized trial.

Sidley Austin:  EU regulatory you make application with advance therapy you don’t have a national option, the regulation body assesses a committee to see if has applicability. Then it goes to a safety committee.  EU has been quicker to approve these advance therapies. Twenty five percent of their applications are gene therapies.  Companies having issues with manufacturing.  There can be issues when the final application is formalized after discussions as problems may arise between discussions, preliminary applications, and final applications.

Sarepta: They have a robust gene therapy program.  Their lead is a therapy for DMD (Duchenne’s Muscular Dystrophy) where affected males die by 25. Japan and EU have different regulatory applications and although they are similar and data can be transferred there is more paperwork required by EU.  The US uses an IND for application. Global feedback is very challenging, they have had multiple meetings around the world and takes a long time preparing a briefing package….. putting a strain on the small biotechs.  No company wants to be either just EU centric or US centric they just want to get out to market as fast as possible.

 

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1:15PM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

1:15 p.m. – Keynote Speaker – International Genetics Health and Disease

International Genetics Health and Disease

The principles of personalized medicine and how they affect the lives of people acknowledge no national boundaries. Although there are some differences among the diverse populations around the world in terms of their genetic variation, the general principles of personalized medicine apply uniformly across many populations. Dr. Periz will discuss how personalized medicine is viewed across the many European countries with particular emphasis on how Spain is implementing it into its medical care.

Keynote Speaker

Antonio L. Andreu Periz, M.D.
Director, Instituto de Salud Carlos III, Madrid

@insalud_es  @CIBER-BBN

Governmental & Public Health National Organization like a combination of CDC and “Hybrid NIH in the US”

Personalized Medicine (PM) in Europe

Europe and Spain — PM is changing Medical Practice, regulations standard of care.

 

In Europe 28 National systems in Spain alone 17 systems

Implementation of PM in Europe: Hospitals, Regulation,

  • develop proof of concept
  • identify mechanisms
  • bring basic research to clinical
  • incorporation into a Portfolio of policies on PM

Horizon 2020 in EU – 2016 launch action on PM in various countries in EU

  • Translational level for all EC members
  • Coalition of 28 Research Centers in Europe to promote PM
  • Sharing Databases, Data on HC, infrastructure for Translational research
  • OMICS
  • Biomarkers
  • clinical trials

CSA – Coordination Support Action

  • PerMed 500,000 Euro for 5 years, 9 operating partners, representatives of Ministry of Health, Israel and Canada Ministry of Health are included
  • Research Agenda for PM in Europe – SWOT Analysis
  • Recommendations for UC to start PM in 2016
  • – basic research
  • – translation
  • – ICTs
  • – Regulatory

SPAIN – Initiatives on PM: Aggregation of Knowledge

  • One single organization collaborates with 22 Institutions on Biomedical research – Concentration in Barcelona and in Madrid
  • Projects of Excellence: PhD level Projects – Clinical Practice: Imaging, Endocrinology, genomics, cardiology
  • 2014 — 35 Applicants – not all are on Cancer 25% are in Cancer 75% are in other clinical Fields
  • 12Million Euros will fund 1/4 of the applicants
  • PhD Thesis on PM – common project 2 yr governmental institute and 2 years in biotech industry

EAPM – Europe Alliance for PM

  • raise awareness on HOW PM CAN SHAPE Healthcare in Europe: Diagnosis, Treatment,
  • Specialized Treatment for Europe’s Patient (STEPs) – Five Steps

Global alliances to shape Medical Practice based on PM – Collaboration Industry and Academia

  • PMC in the US (Personalized Medical Coalition)
  • PerMEd in Europe (coalition  in Europe  supporting innovation in personalized medicine)
  • EAPM (European Alliance for Personalized Medicine)

 

 

– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

@HarvardPMConf

#PMConf

@SachsAssociates

@insalud_es

@CIBER-BBN

@EIGlobalNet

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UPDATED: PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/1/2019

Extended DAPT with Brilinta: No Benefit for Stable CAD in T2D

Substudy in those with prior PCI might identify group where bleeding tradeoff is worthwhile

PARIS — Ticagrelor (Brilinta) as part of a dual antiplatelet therapy (DAPT) regimen didn’t improve net outcomes for stable coronary artery disease (CAD) among type 2 diabetes patients, except perhaps in the setting of percutaneous coronary intervention (PCI), the THEMIS trial showed.

Adding the potent antiplatelet agent to aspirin reduced cardiovascular (CV) death, myocardial infarction (MI), or stroke (7.7% vs 8.5%, HR 0.90, 95% CI 0.81-0.99), reported Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, at the European Society of Cardiology (ESC) congress and online in the New England Journal of Medicine.

But it also increased

  • TIMI major bleeding (2.2% vs 1.0%, HR 2.32, 95% CI 1.82-2.94) and
  • intracranial hemorrhage (0.7% vs 0.5%, HR 1.71, 95% CI 1.18- 2.48) over aspirin alone, albeit
  • without more fatal bleeding (0.2% vs 0.1%, P=0.11).

The combined effect was neutral for the exploratory composite outcome of “irreversible harm” (death from any cause, MI, stroke, fatal bleeding, or intracranial hemorrhage 10.1% vs 10.8%, HR 0.93, 95% CI 0.86-1.02).

ESC session study discussant Colin Baigent, MD, of Oxford University in England, actually calculated 12 major bleeds for every eight events prevented.

“This is a consistent story: when we add an antiplatelet agent for risk reduction, we increase the risk of bleeding,” noted Richard Kovacs, MD, of Indiana University in Indianapolis and president of the American College of Cardiology.

THEMIS is the final part of a largely-disappointing PARTHENON development program for ticagrelor, he noted. “It hasn’t changed practice. …Will the main THEMIS trial change clinical practice? In my opinion, no.”

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/81925?xid=nl_mpt_ACC_Reporter_2019-09-01&eun=g5099207d2r

 

UPDATED on 10/4/2016

Soriot’s $3.5B Brilinta dream is dashed by yet another big trial flop for AstraZeneca

by john carroll
October 4, 2016 09:00 AM EDT
Updated: 09:33 AM

Brilinta, the drug failed to demonstrate a benefit over generic Plavix (clopidogrel) for peripheral artery disease. Back in March, the heart drug flopped in a large stroke study, unable to prove that it could beat aspirin. And Soriot can chalk up those expensive studies to proving Brilinta’s serious deficiencies.

“We don’t believe the goal of $3.5 billion is attainable. I think it would be unrealistic to believe that,” Ludovic Helfgott, head of AstraZeneca’s Brilinta business, told Reuters.

Brilinta brought in a total of $619 million last year after disappointing analysts repeatedly with lower-than-expected quarterly revenue.

Heart studies aren’t cheap. AstraZeneca recruited 13,500 patients for the EUCLID study, and it had enrolled close to that number for the earlier SOCRATES trial.

SOURCE

http://endpts.com/soriots-3-5b-brilinta-dream-is-dashed-by-yet-another-big-trial-flop-for-astrazeneca/?utm_medium=email&utm_campaign=75%20Dinner%20with%20Brent&utm_content=75%20Dinner%20with%20Brent+CID_8008d3b4f16d90576238cceef624d211&utm_source=ENDPOINTS%20emails&utm_term=Soriots%2035B%20Brilinta%20dream%20is%20dashed%20by%20yet%20another%20big%20trial%20flop%20for%20AstraZeneca

UPDATED on 9/4/2014

Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction

Gilles Montalescot, M.D., Ph.D., Arnoud W. van ‘t Hof, M.D., Ph.D., Frédéric Lapostolle, M.D., Ph.D., Johanne Silvain, M.D., Ph.D., Jens Flensted Lassen, M.D., Ph.D., Leonardo Bolognese, M.D., Warren J. Cantor, M.D., Ángel Cequier, M.D., Ph.D., Mohamed Chettibi, M.D., Ph.D., Shaun G. Goodman, M.D., Christopher J. Hammett, M.B., Ch.B., M.D., Kurt Huber, M.D., Magnus Janzon, M.D., Ph.D., Béla Merkely, M.D., Ph.D., Robert F. Storey, M.D., D.M., Uwe Zeymer, M.D., Olivier Stibbe, M.D., Patrick Ecollan, M.D., Wim M.J.M. Heutz, M.D., Eva Swahn, M.D., Ph.D., Jean-Philippe Collet, M.D., Ph.D., Frank F. Willems, M.D., Ph.D., Caroline Baradat, M.Sc., Muriel Licour, M.Sc., Anne Tsatsaris, M.D., Eric Vicaut, M.D., Ph.D., and Christian W. Hamm, M.D., Ph.D. for the ATLANTIC Investigators

September 1, 2014DOI: 10.1056/NEJMoa1407024

BACKGROUND

The direct-acting platelet P2Y12 receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown.

METHODS

We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours’ duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days.

RESULTS

The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used.

CONCLUSIONS

Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion. (Funded by AstraZeneca; ATLANTIC ClinicalTrials.gov number, NCT01347580.)

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMoa1407024?query=TOC

 

 

UPDATED on 2/7/2014

PLATO Controversy Hits the Wall Street Journal

February 05, 2014

NEW YORK, NY – The controversy surrounding the PLATOtrial of ticagrelor (Brilinta, AstraZeneca) continues unabated, according to a story published in the Wall Street Journal. Specifically, a sealed complaint filed in US district court in the District of Columbia by a researcher contends that the cardiovascular events in the study “may have been manipulated” [1].

Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD), who has long been a thorn in the side of AstraZeneca and the PLATO investigators, filed the complaint under the False Claims Act, reports theWall Street Journal. The Journal notes that the US attorney’s office in Washington, DC, has contacted Serebruany and is currently investigating the clinical trial.As reported by heartwirein October 2013, the US Department of Justice issued a civil investigative demand from its civil division “seeking documents and information regarding PLATO.” AstraZeneca is complying with the request.

First reported by heart wirein 2009 , the PLATO trial was a positive study involving more 18 000 patients from 43 countries. PLATO investigators, led by Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden), showed that treating acute coronary syndrome patients with ticagrelor significantly reduced the rate of MI, stroke, and cardiovascular death compared with patients taking clopidogrel. Results were presented at the European Society of Cardiology 2009 Congress and reported in the New England Journal of Medicine.

PLATO has been dogged by questions, including prior to approval. In the sealed complaint, Serebruany takes issue with a number of things, many of which have been reported previously. He alleges that the

  • number of clinical events among those taking clopidogrel was high compared with other studies, pointing out that the rate of all-cause death was 5.9% among clopidogrel-treated patients—nearly twice as high as earlier studies. In addition,
  • the sealed complaint documents the geographic discrepancies in the trial, noting there was a trend toward worse outcomes with ticagrelor at North American sites.The complaint also alleges that
  • an initial count of clinical events suggested the two drugs were equivalent, but adjudication by the Duke Clinical Research Institute attributed another 45 MIs to the clopidogrel group, which tipped the results in favor of ticagrelor. Other questions raised about the study include
  • site monitoring and timing of clinical events. Serebruany also alleges that
  • the trial may have unintentionally been unblinded because of the shape of clopidogrel’s “split capsules,” which would have enabled doctors and nurses to know which drug patients received.

AstraZeneca rebutted these issues, telling the Journal that it is cooperating with the government. It said it is confident in the integrity of the trial and noted the overall study showed the superiority of ticagrelor over clopidogrel. There is no evidence the trial was unblinded and researchers used the same standards when qualifying all clinical events, including MIs, they noted. In addition, the company said it is not possible to compare event rates with clopidogrel in PLATO with other studies because the patient populations differ.

The Journal reports that Serebruany became embroiled in the controversy when asked by the FDA‘s Dr Thomas Marciniak to advise the agency about the PLATO data in 2010. Marciniak, who led the FDA’s review of PLATO, called AstraZeneca’s submission on serious adverse events the “worst submission” he ever encountered. According to the submission, he noted, 12 patients reported their own deaths by telephone. Before approving ticagrelor, the FDA requested an additional analysis of PLATO, and it was eventually approved in the US in July 2011. Ticagrelor was approved in Europe in December 2010 and is authorized for use in more than 100 countries.

The Journal called Serebruany an expert in the antiplatelet field but said he is a “controversial figure,” partly because of his financial ties to industry and repeated criticisms of new drug approvals. Through HeartDrug Research, Serebruany has worked on prasugrel (Effient, Lily/Daiichi-Sankyo), a competing antiplatelet agent, but has also done work for AstraZeneca.

REFERENCE

Burton TM. Doctor challenges testing of AstraZeneca’s Brilinta. Wall Street Journal, February 2, 2014. Available here.

SOURCE

http://www.medscape.com/viewarticle/820236?nlid=47583_1984&src=wnl_edit_medn_card&uac=93761AJ&spon=2

UPDATED 3/28/2013

How AstraZeneca Will Use A Diagnostic To Market Its Blood Thinner

by Matthew Harper, Forbes Staff on 3/21/2013

Earlier today I wrote about how AstraZeneca is telling investors that its blood-thinner Brilinta, used to prevent second heart attacks, could be a multi-billion dollar drug, at least twice as big as Wall Street analysts expect. So far the drug has been a disappointment.

I wrote:

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

via Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug – Forbes.

But will the Food and Drug Administration allow Astra to tell doctors that? Stratification using troponin is not in Brilinta’s FDA-approved label, and off-label promotion is illegal. But Ferguson says that communications about troponin will be allowed because all patients with high troponin are patients who would be included in the FDA-approved indication. He confirms that use of troponin testing will be part of the new marketing plan for Brilinta.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/how-astrazeneca-will-use-a-diagnostic-to-market-its-blood-thinner/

Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug

by Matthew Herper, Forbes Staff on 3/21/2013

This morning in New York, new AstraZeneca chief executive Pascal Soriot is telling investors how he is going to turn around the company that has had the absolute worst track record in research and development among any big pharmaceutical firm. The plan is fairly wide-ranging and involves a lot of the steps one might expect:

  • new layoffs (2,300 jobs);
  • a re-focusing of research and development on three areas: heart disease and diabetes; oncology; and respiratory and inflammation;
  • new R&D initiatives involving Moderna, a biotech company, and the Karolinska Instutet;
  • moving the company’s headquarters to its R&D hub in Cambridge, U.K.;
  • re-focusing on emerging markets, where AZ already gets $6 billion in sales, especially China.

But the short-term key to delivering on his promises today seems to come down to a single drug: Brilinta, the Plavix competitor thatAstraZeneca introduced in 2011 which has so far disappointed, generating  just $324 $89 million in global sales last year. This is a medicine to prevent heart attacks and strokes in patients who suffer acute coronary syndrome, the condition that occurs after a heart attack or serious heart-related chest pain. It works by preventing the formation of blood clots.

Plavix was the second biggest drug in the world, with $6 billion in annual sales, but it is now generic. The conventional wisdom is that it will be difficult to compete with cheap generics. Brilinta is actually trailing Effient, a similar medicine from Eli Lilly, in usage. Wall Street consensus currently sees Brilinta growing to become a moderate-sized drug in 2018, with $1.3 billion in annual sales. But AstraZeneca is saying that it thinks Brilinta can be a multi-billion dollar product. Astra has confirmed that this means Brilinta will have to surpass Effient. The newer drugs also cause more bleeding than Plavix.

What is the company’s argument? In his presentation today, Paul Hudson, Astra’s Executive Vice President, North America, said that the key would be focusing on one key fact: Brilinta reduced cardiovascular deaths by 21% compared to Plavix in a big clinical trial. That would mean that if everyone eligible for Brilinta got it, 100,000 lives would be saved.

But the reality is that doctors have been skeptical of that data because in the part of that trial that was run in North America, the benefit was less clear. AstraZeneca says that this may have been due to an interaction of Brilinta and aspirin and that, according to current cardiovascular guidelines, doctors should be prescribing less aspirin anyway.

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

A lot of what Astra will do in the short term on Brilinta will be blocking and tackling. It needs to pay bigger rebates to insurers to make sure that patients can get cheap access to the drug. (This is how discounts happen in the American insurance system: the patient pays a co-payment and the insurer pays full price for the drug, but then the drug maker gives the insurer money back to make the end cost cheaper.) It will also be doing a lot of medical marketing, involving its internal experts or paid, external doctors, to get the word out about the benefits of Brilinta.

Brilinta has other advantages (it stops acting quickly) and disadvantages (it must be given twice a day). But the other big question for expanding results is whether large clinical trials that are now ongoing will show that it works in a broader array of heart patients. Astra is starting a big trial to show Brilinta prevents strokes. These trials are risky and expensive, but there will be a big payoff if they work.

Astra has some other commercial levers to point to. It’s diabetes pill Onglyza, which is sold with Bristol-Myers Squibb, will have results in a big study of its efficacy in preventing heart disease before a similar study of Merck’s top-selling Januvia, which started first. Soriot has smart ideas about which drugs to advance into later testing. But Brilinta is going to be the biggest single indicator of whether Soriot’s new strategies are paying off.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/can-pascal-soriot-turn-around-astrazeneca-it-may-come-down-to-one-drug/

BRILINTA is an antiplatelet medication

Taking BRILINTA is a first step in the treatment your physician has chosen for you. At BRILINTA.com, you will find helpful information and useful learning tools to help you complete your course of BRILINTA therapy. Make sure you and your loved ones read through all of the sections.

What is BRILINTA?

BRILINTA is a type of prescription antiplatelet medication for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart. BRILINTA is used with aspirin to stop platelets from sticking together and forming a blood clot that could block blood flow to the heart and cause another, possibly fatal, heart attack. Platelets are small cells in the blood that help with normal blood clotting.

Take BRILINTA and aspirin exactly as instructed by your doctor: BRILINTA twice a day, plus one 81-mg aspirin tablet once a day. You should not take a dose of aspirin higher than 100 mg each day because it can affect how well BRILINTA works. Tell your doctor about any medicines you are taking that contain aspirin. Do not take any new medicines that contain aspirin.

Why BRILINTA?

BRILINTA used with aspirin lowers your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal. In fact, in a large clinical study BRILINTA was even better than Plavix® (clopidogrel bisulfate) tablets at lowering your chances of having another heart attack.

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death.

Complete the
Course
 Program

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack or stroke, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. Instances of serious bleeding, such as internal bleeding, may require blood transfusions or surgery. While you take BRILINTA, you may bruise and bleed more easily and be more likely to have nosebleeds. Bleeding will also take longer than usual to stop.

Call your doctor right away if you have any signs or symptoms of bleeding while taking BRILINTA, including: severe, uncontrollable bleeding; pink, red, or brown urine; vomit that is bloody or looks like coffee grounds; red or black stool; or if you cough up blood or blood clots.

Do not stop taking BRILINTA without talking to the doctor who prescribes it for you. People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase. Tell all your doctors and dentists that you are taking BRILINTA. To decrease your risk of bleeding, your doctor may instruct you to stop taking BRILINTA 5 days before you have elective surgery. Your doctor should tell you when to start taking BRILINTA again, as soon as possible after surgery.

Take BRILINTA and aspirin exactly as instructed by your doctor. You should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works. Tell your doctor if you take other medicines that contain aspirin. Do not take new medicines that contain aspirin.

Do not take BRILINTA if you are bleeding now, especially from your stomach or intestine (ulcer), have a history of bleeding in the brain, or have severe liver problems.

BRILINTA can cause serious side effects, including bleeding and shortness of breath. Call your doctor if you have new or unexpected shortness of breath or any side effect that bothers you or that does not go away. Your doctor can decide what treatment is needed.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works.

Approved uses
BRILINTA is a prescription medicine for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart.

BRILINTA is used with aspirin to lower your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal.

Please read Prescribing Information, including Boxed WARNINGS.

Please read Medication Guide.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you are without prescription coverage and cannot afford your medication, AstraZeneca may be able to help. For more information, please visit www.AstraZeneca.com.

This product information is intended for US consumers only.

BRILINTA is a trademark of the AstraZeneca group of companies.

Plavix® is a registered trademark of sanofi-aventis.

©2012 AstraZeneca.706809-1789005 8/12

SOURCE:

http://www.brilinta.com/antiplatelet-prescription-medication.aspx#au

http://www1.astrazeneca-us.com/pi/brilinta.pdf

BRILINTA (ticagrelor)

Ticagrelor (trade name Brilinta in the US, Brilique and Possia in the EU) is a platelet aggregation inhibitor produced by AstraZeneca. The drug was approved for use in the European Union by the European Commission on December 3, 2010.[1][2] The drug was approved by the US Food and Drug Administrationon July 20, 2011.[3]

Indications

Ticagrelor is indicated for the prevention of thrombotic events (for example stroke or heart attack) in patients with acute coronary syndrome or myocardial infarction with ST elevation. The drug is combined with acetylsalicylic acid unless the latter is contraindicated.[4] Treatment of acute coronary syndrome with ticagrelor as compared with clopidogrel significantly reduces the rate of death.[5]

Contraindications

Contraindications for ticagrelor are: active pathological bleeding and a history of intracranial bleeding, as well as reduced liver function and combination with drugs that strongly influence activity of the liver enzymeCYP3A4, because the drug is metabolized via CYP3A4 and excreted via the liver.[4]

Adverse effects

The most common side effects are shortness of breath (dyspnea, 14%)[6] and various types of bleeding, such as hematomanosebleedgastrointestinalsubcutaneous or dermal bleeding. Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.[4]

Physical and chemical properties

Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity toadenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System.[1]

Ticagrelor as a nucleoside analogue

The nucleoside adenosinefor comparison

Pharmacokinetics

Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring.[7] It peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260 mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor’s plasma concentrations. Drug and metabolite are mainly excreted via bile and feces.

Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as ‘coloured’ and such with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.[4]

Mechanism of action

Like the thienopyridines prasugrelclopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible.[8] Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants).[9][10][11]

Comparison with clopidogrel

The PLATO trial, funded by AstraZeneca, in mid-2009 found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084), higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding. Rates of major bleeding were not different. Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, P<0.001)[5] The PLATO trial showed a statistically insignificant trend toward worse outcomes with ticagrelor versus clopidogrel among US patients in the study – who comprised 1800 of the total 18,624 patients. The HR actually reversed for the composite end point cardiovascular (death, MI, or stroke): 12.6% for patients given ticagrelor and 10.1% for patients given clopidogrel (HR = 1.27). Some believe the results could be due to differences in aspirin maintenance doses, which are higher in the United States.[12] Others state that the central adjudicating committees found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelor arm, which improved the MI outcomes with ticagrelor. Without this adjudication the trials’ primary efficacy outcomes should not be significant[13]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[14] This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur.[4][15]

Interactions

Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, for example rifampicin and possibly St. John’s wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9.

The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxinciclosporin and other P-gp substrates. Ticagrelor and AR-C124910XX levels are not significantly influenced by P-gp inhibitors.[4]

In the US a boxed warning states that use of ticagrelor with aspirin doses exceeding 100 mg/day decreases the effectiveness of the medication.[16]

References

  1. a b “Assessment Report for Brilique”European Medicines Agency. January 2011.
  2. ^ European Public Assessment Report Possia
  3. ^ “FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes”. FDA. 20 July 2011.
  4. a b c d e f Haberfeld, H, ed. (2010) (in German). Austria-Codex (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
  5. a b Wallentin, Lars; Becker, RC; Budaj, A; Cannon, CP; Emanuelsson, H; Held, C; Horrow, J; Husted, S et al. (August 30, 2009). “Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes”NEJM 361 (11): 1045–57. doi:10.1056/NEJMoa0904327PMID 19717846.
  6. ^ Brilinta: Highlights of prescribing information
  7. ^ Teng, R; Oliver, S; Hayes, MA; Butler, K (2010). “Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects”. Drug metabolism and disposition: the biological fate of chemicals 38 (9): 1514–21. doi:10.1124/dmd.110.032250PMID 20551239.
  8. ^ Birkeland, Kade; Parra, David; Rosenstein, Robert (2010). “Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor”Journal of Blood Medicine 1: 197–219.
  9. ^ H. Spreitzer (February 4, 2008). “Neue Wirkstoffe – AZD6140” (in German). Österreichische Apothekerzeitung (3/2008): 135.
  10. ^ Owen, RT, Serradell, N, Bolos, J (2007). “AZD6140”. Drugs of the Future 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
  11. ^ Tantry, Udaya S; Bliden, Kevin P (2010). “First Analysis of the Relation Between CYP2C19 Genotype and Pharmacodynamics in Patients Treated With Ticagrelor Versus Clopidogrel”. Circulation: Cardiovascular Genetics 3: 556–566. doi:10.1161/CIRCGENETICS.110.958561.
  12. ^ Bernardo Lombo, José G Díez. Ticagrelor: the evidence for its clinical potential as an oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndromes Core Evid. 2011; 6: 31–42. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065559/
  13. ^ Serebruany VL, Atar D. Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials—Common patterns in TRITON, RECORD, and PLATO? Thromb Haemost 2012; DOI: 10.1160/TH12-04-0251. http://www.theheart.org/article/1433145/print.do
  14. ^ Miller, R (24 February 2010). “Is there too much excitement for ticagrelor?”. TheHeart.org.
  15. ^ H. Spreitzer (17 January 2011). “Neue Wirkstoffe – Elinogrel” (in German). Österreichische Apothekerzeitung (2/2011): 10.
  16. ^ July 20, 2011 AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval Larry Husten cardiobrief.org/2011/07/20/astrazeneca-ticagrelor-brilinta-gains-fda-approval/

SOURCE:

 http://en.wikipedia.org/wiki/Ticagrelor

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Reporter: Aviva Lev-Ari, PhD, RN

With $15.5M Grant, EU Consortium to Sequence 1,100 Exomes to Develop Diagnostics for Neurologic Diseases

November 28, 2012

A consortium of 18 European and Australian institutions and industry partners will spend five years sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases to create diagnostic panels and uncover novel therapeutic targets.

The group, known as the Neuromics Consortium, is funded with €12 million ($15.5 million) under the European Union’s seventh framework program.

Headed by the University of Tübingen, the project will involve collaboration between 12 academic centers. Iceland’s Decode Genetics will do the sequencing and will support analysis and return of results to participants. The group also plans to work with Agilent Technologies to develop and validate targeted sequencing-based diagnostic panels for specific neurologic diseases, including ataxia/paraplegias, spinal muscular atrophies and lower motor neuron diseases, and neuromuscular diseases, according to Tübingen’s Holm Graessner, the manager of the consortium.

Graessner told Clinical Sequencing News in an email that the Neuromics Consortium hopes its work will yield better diagnostic panels that can increase the diagnosis rate for ten main neurodegenerative and neuromuscular disease types — including ataxia, spastic paraplegia, Huntington’s disease, muscular dystrophy and spinal muscular atrophy — as well as provide information on genes and pathways that could inform new treatments.

According to the consortium, 30 percent to 80 percent of patients with these diseases are still undiagnosed by current single-gene tests or gene panels, and cohorts for each individual disorder are small. By combining patient groups and data from many centers and looking for commonality between some of these diseases, the consortium hopes to create diagnostics that cover a greater range of causative mutations.

While each specific disorder the group will study is relatively rare, many have overlapping manifestations, which suggest similarities in disease pathways pointing to common therapeutic strategies, according to the group.

Graessner said that the project’s whole-exome sequencing component will take place mostly in the first two years. According to the consortium’s plan, Decode Genetics — which expanded last year from array-based SNP genotyping research to a next-gen sequencing approach (CSN 11/9/2011) — will use its Illumina HiSeqs to sequence at least 1,100 subjects. The group expects this to increase the percentage of disease genes known for some of the more heterogeneous diseases in the set from about 50 percent to 80 percent.

According to Graessner, RNA sequencing is also part of the plan, as well as proteomic and other ‘omic analyses, especially as the researchers move from sequencing toward diagnostic panel development and therapeutic target research.

“We plan to [do whole-exome sequencing for] 1,100 subjects for gene identification … equally distributed over 10 disease areas,” Graessner wrote. “[This] will be done mainly in the first two years. However, for some of the diseases, such as ataxia/paraplegias, we have diagnostic panels already and in that case we [will] do the panels first and send the still unclear families for WES or WGS,” he wrote.

Graessner said that the group is just now shipping its first sample package to Decode. When this is finished the group will hold a workshop to discuss and train all the participating academic centers in the use of the Decode database for analysis of the results.

He said the team plans to work with the Halo Genomics division of Agilent, to validate diagnostic panels for ataxia, spinal muscular atrophies, lower motor neuron disease, and neuromuscular diseases. Halo was acquired by Agilent last year, and had developed an enrichment technology dubbed HaloPlex that it said was especially suited for targeted gene panels less than one megabase in size (IS 12/6/2011).

The group’s bioinformatics partner, Ariadne Genomics, will also analyze data to support the diagnostics research, as well as research on potential novel therapeutic targets, according to Graessner.

In a document describing the project, the consortium wrote that at the end of the funding period, it expects “to have elucidated the genetic basis for [more than] 80 [percent] of investigated patient groups.”

According to the group, the new genes will be added to existing databases and used to develop the first overlapping gene panel that can be used to diagnose several of these individual diseases, “overcoming time consuming and costly single gene analysis.”

Molika Ashford is a GenomeWeb contributing editor and covers personalized medicine and molecular diagnostics. E-mail her here.

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Curated and Reported by: Dr. Venkat S. Karra, Ph.D.

Know How We ALL Knowingly or Unknowingly Consume Antibiotics and How it Effects Our Health

Billions of microbial cells live in the guts of humans and other animals. Research on these vast bacterial populations, called microbiomes, is just getting started, but scientists already know that some microbial boarders play a crucial role in breaking down nutrients in our diet. Some have also suspected that low-dose antibiotics, given to farm animals to make them grow bigger, could work by altering the gut microbiome.

To test this hypothesis, a team led by microbiologist Martin Blaser of the New York University School of Medicine in New York City added antibiotics to the drinking water of mice that had just been weaned. The medicine—either penicillin, vancomycin, a combination of the two, or chlortetracycline—was given at doses comparable to those approved by the U.S. Food and Drug Administration as growth promoters in farm animals. After 7 weeks, the group of mice on antibiotics had significantly more fat than a control group drinking plain water, the team reports online today in Nature. “This confirms what farmers have shown for 60 years, that low-dose antibiotics cause their animals to grow bigger,” Blaser says.

Read more at:  The Global Innovations

Now, Researchers at the University of Copenhagen, Denmark, and University College Cork, Ireland, found that antibiotic concentrations within limits set by US and European Union (EU) regulators are high enough to slow fermentation, the process that acidifies the sausages and helps destroy foodborne pathogens like Salmonella or E. coli.

“At low concentrations and at regulatory levels set by authorities, they could see that the lactic acid bacteria are more susceptible to the antibiotics than the pathogens are.

“Residual antibiotics in the meat can prevent or reduce fermentation by the lactic acid bacteria, but these concentrations do not effect survival or even multiplication of pathogens.”

Antibiotics used as growth promoters or to treat disease in livestock can eventually end up in meat, and regulators in the US and EU have set limits on the concentrations of antibiotics in meat for consumption by humans.

Researchers say that fermented sausages occasionally cause serious bacterial infections, but it’s never been understood why that might be….

Read more at: sciencecodex

Related articles

 

 

 

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Patient Access to Medical Devices — A Comparison of U.S. and European Review Processes

Reporter: Aviva Lev-Ari, PhD, RN

 

Saptarshi Basu, M.P.A., and John C. Hassenplug, M.Sc.

N Engl J Med 2012; 367:485-488  August 9, 2012

The U.S. process for approving innovative, high-risk medical devices has been criticized for taking longer than the European approval process.1 This contention is often used to support the argument that the Food and Drug Administration (FDA) should lower its standards for approving medical devices, since a slow approval process is delaying Americans’ access to innovative and lifesaving technology. But a review of the data, using appropriate end points, suggests instead that it takes the same amount of time or less for patients to gain access to innovative, high-risk medical devices in the United States as it does in the four largest European markets (Germany, France, Italy, and Britain)2 — largely because patient access is generally delayed until reimbursement decisions are made, which often takes substantially longer in Europe than in the United States.

To compare the United States and Europe fairly on this front, three criteria must be considered: the level of device innovation, equivalent start and end points, and patient access as defined by time to reimbursement. First, we focused on innovative, high-risk devices because in the United States such devices require the strongest evidence of clinical benefit and are the subject of most debates about the relative effectiveness of approval processes in different countries. Furthermore, previous studies have shown that lower-risk devices achieve market access in a similar amount of time in the United States and in Europe.

Second, an accurate comparison of time to market access requires measurement of the total time that elapses between application submission and market access. Previous studies have compared the chronologic dates of application submission and market access, but the date an application is submitted varies from country to country.

Third, patient access should be equated with the availability of reimbursement rather than with device approval, because broad patient access to a new device doesn’t occur until reimbursement by a national or third-party payer is available. Previous comparisons of the U.S. and European systems have used the approval date to measure process duration, but innovative, high-risk devices don’t reach a market where most patients can benefit from them immediately after gaining regulatory approval, though they may be accessible to patients who can afford to pay out of pocket. Rather, there is a second level of review through which public or private insurers decide whether and at what price they will pay for a device. Generally, public systems take longer than private insurers to make reimbursement decisions, and significantly more Europeans than Americans have public insurance. Two thirds of the U.S. population is covered by private health insurance, whereas only a fifth receives publicly funded reimbursement, primarily administered by the Centers for Medicare and Medicaid Services (CMS).

For both private and public systems in the United States, the pathway to patient access to a device starts with the submission of an application to the FDA. The FDA reviews innovative, high-risk devices for safety and effectiveness (clinical benefit) under the premarket approval (PMA) process, and information on the duration of reviews is publicly available. In fiscal year 2011, the FDA approved 40 applications for PMA. The average review time was 13.1 months, with 8.4 months attributed to FDA review time, and 4.7 months to the time the agency waits for the sponsor to address deficiencies in the application (“sponsor time”).3 CMS provides reimbursement for the majority of devices when they earn FDA approval. For a limited number of devices each year, however, CMS conducts a national coverage determination in response to external requests for validation or for devices that have limited or conflicting evidence of clinical benefit. This process averaged 8.6 months over the past 5 fiscal years.4 Although it is difficult to obtain data on how long private insurers take to make coverage decisions, anecdotal information from private insurers suggests that decisions are made within a few weeks to a few months after FDA approval, depending on the amount and quality of evidence of clinical benefit.

In Europe, by contrast, most of the 27 member countries of the European Union (EU) have publicly financed health care systems; such systems cover approximately four fifths of the populations of the four largest device markets. All EU countries require devices to first obtain a Conformité Européenne (CE) marking, which refers to a symbol shown on products that indicates market approval throughout the EU. The CE marking process is conducted by for-profit, third-party “notified bodies” that have been accredited by a member country to assess device safety and performance but do not evaluate effectiveness (which requires more clinical data). Although publicly available data are limited, anecdotal information from notified bodies suggests that the process takes 1 to 3 months, excluding sponsor time.

Most European patients do not have access to innovative, high-risk devices as soon as the devices receive a CE marking. Each country must first make a decision about reimbursement, a process that varies substantially among countries.5 Though a CE marking can be granted on the basis of fewer clinical data than are required for FDA approval, European standards for reimbursement are often similar to or higher than those that the FDA imposes for device approval. European countries may require additional data on the device’s safety and effectiveness, as well as on cost-effectiveness.

In France, a centralized body makes reimbursement decisions after assessing the safety and effectiveness of individual devices. Reimbursement decisions in Italy are devolved to the various regions, and Britain and Germany conduct broader assessments of device types or procedures, rather than of individual devices. Typically, innovative devices not covered under an existing diagnosis-related group (DRG) require review under the lengthier Health Technology Assessment process, which assesses safety, clinical benefit, and cost-effectiveness. Government-provided information on time to reimbursement varies by country. Estimated time frames are an average of 71.3 months in Germany, a range of 36.0 to 48.0 months in France, a range of 16.4 to 26.3 months in Italy, and an estimated 18 months in Britain.

Using this information, we determined that the time it takes to bring innovative, high-risk devices to patients in the United States is similar to or shorter than that in the top four European markets (seefigureComparison of Time to Market in Premarket Approval and Reimbursement Processes.). The public (CMS) process in the United States takes approximately as long as those in Italy and Britain, approximately half as long as that in France, and less than a third as long as that in Germany. The difference in time to market access is even greater when it comes to private insurers (covering the majority of the U.S. population), which often make reimbursement decisions within a few months after FDA approval.

To further illustrate this point, we compared the time to approval for five innovative, high-risk medical devices available in France, Italy, and the United States (see tableComparison of Time to Market Access for Five Innovative Devices in France, Italy, and the United States.). These case studies indicate that the average time to market access for these devices was 26.3 months in France, 30.8 months in Italy, and 15.3 months in the United States.

These numbers may not fully capture the reasons why a device reaches the market more quickly in one country than in another and do not reflect experiences with all innovative, high-risk devices. However, unless one uses equivalent standards in terms of the level of risk, the start and end points of the process, and the key end point of market access, accurate comparisons cannot be made.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on August 1, 2012, at NEJM.org.

SOURCE INFORMATION

From the Office of Planning, Office of the Commissioner, Food and Drug Administration, White Oak, MD.

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Reporter: Aviva Lev-Ari, PhD, RN

This post addresses related issues On the Career of the Life Sciences Scientist and compliments the following two posts on this Scientific Web Site:

August 1, 2012 — Introducing Career Streams into Academic Research

https://pharmaceuticalintelligence.com/2012/08/01/introducing-career-streams-into-academic-research/

June 27, 2012 — Picturing US-Trained PhDs’ Paths and Pharmaceutical Industry’s Crisis of Productivity: Partnerships between Industry and Academia

https://pharmaceuticalintelligence.com/2012/06/27/picturing-us-trained-phds-paths-pharmaceutical-industrys-crisis-of-productivity-partnerships-between-industry-and-academia/

BEYOND THE “MALE MODEL”: AN ALTERNATIVE FEMALE MODEL OF SCIENCE, TECHNOLOGY AND INNOVATION

THE TRIPLE HELIX ASSOCIATION NEWSLETTER, VOLUME 1 ISSUE 3 JULY 2012

Hélice www.triplehelixassociation.org  Triple Helix X, 2012, Bandung, Indonesia . . . www.th2012.org

by Professor Henry Etzkowitz, President of the Triple Helix Association,  Senior Researcher, H-STAR Institute, Stanford University, Visiting Professor, Birkbeck, London University and Edinburgh University Business School

henry.etzkowitz@stanford.edu

Professor Henry Etzkowitz paper is based on his Keynote Address to the FemTalent Conference, Barcelona, Spain 2011

I am often asked: why is a man studying women in science? The answer to that question is: my mother. She graduated with high honors in Geology from Hunter College, a public women’s college in New York City during the 1930’s depression. I had long thought that the reason why she didn’t pursue a career in geology was

because of the depression, that there were simply no jobs. However, on a research trip to the University of Texas at Austin, I visited the Engineering School which had a “wall of recognition” at the main entrance, including the names of many distinguished professors and practitioners, all of them men, who had graduated during the 1930’s depression and pursued careers in Geology. Perhaps the reason why a woman did not pursue a career in geological science at the time, might be found in the gender dynamics of science and technology. The broader question is how the best results may be attained from societal investment in human capital formation.

Firstly, we will consider the implications of findings from a study done in the 1990s, in the United States, sponsored by the National Science Foundation, of women’s experience in academic science (Etzkowitz, Kemelgor and Uzzi, 2000) including over 400 in-depth qualitative interviews conducted in a dozen leading research universities in five disciplines: biology, physics, chemistry and computer science:

1. One of the lessons from this study is that in Europe and other countries, there is a move to introduce the American system of higher education, including tenure procedures, which put a very strong emphasis on early achievement which, as we shall see, has deleterious consequences for women. Higher education policy makers in Europe and other parts of the world may want to look more closely at its effects before introducing this system, which is now taken as the gold standard in higher education. The introduction of the tenure system is driven by

international ranking procedures which drive movement from a system of relatively equal universities. Before abandoning values of equality, it should be seriously asked if introducing extreme inequalities will overall advance or inhibit quality academic research, teaching, and innovation.

2. Secondly, I discuss the Vanish Box model, derived from a four country study, sponsored by the European Union, DG Research, on Women and Technology Transfer (Ranga, et. al. 2008). During interviews with women in US academic science on Athena Unbound study, some of them would talk about colleagues who were no longer in the department, they were now in jobs elsewhere. I interviewed some of these women leaving academic science, and found that they were taking up careers in science-related professions such as science journalism, technology transfer, museology. etc. They were using their scientific training in translating science into use and spreading the results of science to a broader public. Rather than being “lost to science” as presumed by the “Leaky pipeline” thesis of science career loss; they were pursuing work-life balance in their new careers. This finding inspired the study sponsored by the European Union on Women and Technology Transfer.

3. Third, I outline a four phase model of women’s experience in science, technology, and innovation, “the Vanish Box”: after the magic trick of the “disappearance of re-appearance of a woman”. “The vanish box” model shows the dynamics of the historical experience of women in science, and questions the taken for granted “male model” of science that does not work for women or men who seek work-life balance.

4. Finally, we address the question of whether the Gender Revolution in science and technology is stalled or moving forward.

Gender Inequalities in Academic Careers

The historical relationship between status and gender provides a clue to understanding the underlying dynamics of women and men’s careers in science. Typically, there is strong participation of women in the early stages of development of a new discipline, but as the new area becomes prestigious and rewards increase, women disappear. As fields attain recognition and fruition, and the Nobel and other prizes are awarded, it is men who are there to receive them. There were a significant number of women working in “the fly room,” the drosophila genetics lab headed by Thomas Hunt Morgan at Colombia University, but as the field became prestigious, women virtually disappeared from classical genetics (Kohler, 1994).

Does this historical relationship between gender and science still hold today or has it changed? The most important finding from all the specific instances that we came across was that the most important thing holding back women’s advance in academic science was “inflexibility” of rules and procedures. It didn’t matter what the specific procedure was. For example, in the US it’s expected that that you should pursue your PhD at a different University than your undergraduate degree. This is the highest route to achievement. If a woman has a relationship, and the man moves will she leave the relationship to seek her competitive advantage?

On the other hand, if the man in the relationship moves, and the woman goes along, she may then have to move to a school that is not as good as the one which she otherwise might have gotten into with a broader range of selection. Thus, this informal rule of exogamy, mandating leaving the previous school or worksite at each point of progression, from undergraduate degree to PhD to entry level position, works against women’s advancement.

On the other hand, in Sweden the rule is the opposite. Instead of saying that you should move from one university to another, the rule is that you should stay at your own University; that if you are a highly successful junior scholar you will be kept within that University. A Swedish professor said, “why would I send my best

graduate student away? He is going to replace me when I retire.” So the rule in Sweden is endogamy that you stay within one university. Again, if a woman’s partner moves, and she moves with him, it will hurt her career, because she has left her university of origin. So which ever way the rule is, it is an inflexible rule, it has more negative consequences for women than for men. The gender policy implication is to increase flexibility in the system.

A female model of science, balancing work and family life, has been invented but it is a subsidiary and undervalued format that needs to be brought to the forefront and institutionalized. However, this would necessitate re-thinking aspects of the academic system, especially the US model, that unintentionally yet systematically works against women’s inclusion in the higher level of academic science. The US model of academic hierarchy, front loading in the academic career with a strong emphasis on youth and achievement

in the early years, is partly based on a mistaken idea that youth are more productive in science than people who are of an older age. That finding was documented in a study done by Merton and Zuckerman of “Aging and Age Structure” (1973). They found that “productivity was as high or even higher at the later stages of a scientific career”, and that makes sense. When you are more advanced in your career you have more access to resources, more

graduate students, more research associates, more people working with you. Co-authorship arises from having members of your research group being highly productive. Nevertheless, there is a strong belief that youth makes disproportionate scientific advances, and this has been the basis of a system in which there is a strong emphasis on early achievement during the first years of your career. There is a race to accumulate publications and research grants in order to be given a permanent position in a high status American University.

In Europe, the tradition has been once you are hired there is a probationary period and then you continue to be promoted or not. But in the United States there is a very sharp dividing line: an “up or out” system. The implications for women’s advancement in science, includes the contradiction between the “tenure clock”, typically of seven years, and the “biological clock”, the time when is possible to have children, and these coincide. Thus, women have to make the choice to postpone having children to after tenure, which then becomes their middle or late 30s. There were some women who didn’t want to postpone, and some of them rethought

their commitment to academic science and left for that reason. Occasionally, in some universities there has been some reform of these procedures to try to accommodate women by extending the clock. i.e. you can apply for a year extension to reduce your time in the workplace and/or take a break in order to have more time for one’s young children. Even this attempt to ameliorate the male model of science and make it more amenable to women’s

participation contains a contradiction: women are concerned that if they apply for this privilege that it will be held against them in the final review. The academic system requires a demonstration of full commitment to racing the clock, otherwise you will be viewed as insufficiently competitive. Moderating the conditions will be held against you, or at least that is the fear. The attempted reform has its dangers since many women feel that they may be given points off for taking advantage of the attempt to change the rules. The contradiction between the tenure clock and the biological clock encourages some women in academic science to seek an alternative career path.

An American professor talked about a leading female student who stayed in the same city and took a job at a local teaching college. But an exception was made for her because she was such an outstanding scholar that she was then brought back to the leading University in the same city where she had received her PhD and allowed to pursue a career at that university. The rule was counterproductive to the best use of talent, but this case was an

unusual exception. However, it is one that can be more regularly made if we are thinking of how to revise the system that works against women by following an implicit male model of science. Another negative factor is the “two out of three” time bind. In interviews in the US and Mexico, it was found that if you are trying to do three things, most women usually find it was too much, they could do advanced research in a highly productive way, and manage their family relationship, but that didn’t leave time for spending time in local politicking and talking with people, which is the way towards advancing within the academic system. So they could advance in their research career, but not in the career that would lead to becoming a chair person or administrator within academia. So this is the two out of three time bind.

Traditionally there has been a gendered division of labor where men worked with men and women with women, in gendered occupations. Some think that this occurred as a basis of naturally occurring gender divisions. But historically we can see that these gendered occupations change over time. I did my masters thesis on the male nurse, titled “the Precarious Identity of the Male Nurse” (Etzkowitz, 1971). The nursing profession in the

nineteenth century was entirely male, and began to change over to a female profession by the end of the nineteenth century, and by the middle of the twentieth century it was virtually entirely female. Thus, gendered professions can change over time and are subject to revision.

From “Leaky Pipeline” to the “Vanish Box”

The pipeline model has been based upon the movement from schooling into higher education and into careers; the premise that there should be an unimpeded flow. Over a period of twenty years, at maximum, women should be at the highest level of any occupation. Recruitment has taken place: young women now make up equal numbers in bachelor’s degrees, and the numbers are moving up in the PhDs. But they have not moved up at the same rate to the associate and full professor levels. The pipeline has not worked by filling it at one end, and expecting a changed result at the other. We need to make changes in the system to make the pipeline work. A gender neutral occupation would be one with flexibility in the role, and with balance between on-site and off-site work, and the possibility of equal participation of both genders in the occupation. What happens to women who, for one reason or another, don’t continue in an academic career in science? This was the question that we posed in: “Women in Science and Technology”(WIST) sponsored by the European Union. We identified that women who had left academic science, were reappearing in science related professions, using their scientific, networking and social skills in these new professions. In the UK, when opportunities opened up in the mid 1990s, female PhDs entered this career, following the States where women had risen to the top of their profession as heads of offices at major universities. From this study of women disappearing and reappearing from academia to science related professions, we developed a concept that we called the “vanish box” model (Etzkowitz and Ranga, 2011), that takes place in four stages:

1. The first is the disappearance of women: the disappearance that we found in the Athena Unbound study, the exclusionary practices, or the taken for granted male model of science which did not take account of women’s needs, of women’s life chances and lifestyles. They weren’t found at the highest levels of academic science to the extent that would be expected if the pipeline was working as it was supposed to, with women flowing in and being promoted up over a period of time. So disappearance.

2. The disappeared women are in the reserve army: at home or in part time positions unemployed or underemployed. The reserve army is called back when there is an emergency or a shortage. For example, during World War ll women PhD’s who had been unemployed or working as volunteers in their husband’s laboratory were called into full-time positions in the Manhattan Project and other Labs. After the War, some began to get academic positions and rose to the highest level after having been in the reserve army for many years.

3. The third phase of the model is the creation of new opportunities; either by emergency situations, or by the creation of new professions that require people with scientific training. An example of this was the Technology Transfer profession that we studied: a new profession that required people with scientific training and background and business training, and typically people with a scientific background would learn the business skills, take courses or even a master’s degrees in business. This provided opportunities, but there are still limitations: the new profession wasn’t as prestigious as the old one, and it had both advantages and disadvantages: working in a technology transfer office gives more of an opportunity for a work life balance, but the prestige of the profession isn’t that high and the opportunities for advancement are limited.

4. On the other hand, as the knowledge society advances, professions that translate knowledge into use become more prestigious and the profession also rises in status and prestige over time. That is what has been happening with technology transfer. The question that arises is, will it follow the same model of classical genetics, or will it lead to a new model of a gender neutral profession, with men and women working at the highest levels in a situation that allows for work-life balance? There is some evidence that this may be happening in small biotech firms. A recent study found that women recruited into these firms were taken seriously in their work, they were being promoted, and so the start-up biotechnology firm has offered evidence that there may be a changing relationship between gender and career advancement and new possibilities available in this area.

Beyond the “Male Model”: An Alternative Female Model

The American sociologist Cecilia Ridgeway has set forth the thesis of a stalled revolution, in the 1970’s large numbers of women entered professions in law and medicine but more recently advancement of women has halted. Pay differentials continue to exist. Women have not risen to positions in board of directors of firms to the same extent that might be expected. On the other hand, women now make up a majority of bachelor’s degrees recipients – over fifty percent in some places and as high as sixty percent in others. Forty years ago the percentage of women at MIT could be counted on the fingers of one hand. Today half of the undergraduate students at MIT are female. Once you get to the level of twenty percent social relations within organizations start to change; but they really transform at the fifty percent level. Typically in women’s entrepreneurship the service occupations make up the majority; but in Catalonia, there is a major change going on as the majority of the women in a program to support

entrepreneurship were in science and technology related occupations. The woman running this program said that the key issue is working with these entrepreneurs is how to grow their firms and still retain a work life balance. So the revolution is moving here. Academia is still resistant to change, but business has been moving faster, and Academia has to learn from industry. That is the next stage in making the gender revolution in science and technology.

To this end, the relationship between career structure and life cycle needs to be rethought (Etzkowitz and Stein, 1978). The current taken-for-granted career path is based on implicit male assumptions that do not take into account women’s greater responsibilities for family maintenance and societal reproduction that persist, even given good faith efforts on the part of men to play a greater role in child care (Kayyem, 2012). In the male model,

imposed on women as well, significant early achievement, typically involving a high time commitment, is the prerequisite for subsequent high-level positions. It is hypothesized that women’s difficulties in conforming to this model explains at least part of the variance in the paucity of women in high-level positions even as their participation rates increase.

An alternative female model, with a higher time commitment after child-rearing years, may be discerned. A Rockefeller University Professor, who started on her PhD at a later than usual age, and US Secretary of State Hilary Clinton, exemplify this alternative model that needs to be legitimized as an alternative path to high achievement. The current offering of a relaxed early career path in law firms is stigmatized as a “mommy track”

and reified into a permanent blockage to later high flying. When an alternative “female model” is available for women and men, gender democracy in science, technology and innovation, as well as in the larger society, will be a reality.

REFERENCES

Etzkowitz, H (1971), The Male Nurse: Sexual Separation of Labor in Society, Journal of Marriage and the Family.

Etzkowitz, H, and P. Stein. (1978) The Life Spiral: Human Needs and Adult Roles Journal of Economic and Family Issues. 1:4: 434-446

Etzkowitz, H, Kemelgor, C and Uzzi, B (2000), Athena Unbound: The Advancement of Women in Science and Technology Cambridge University Press.

Etzkowitz, H and Ranga, M (2011), Gender Dynamics in Science and Technology: From the “Leaky Pipeline” to the Vanish Box, Brussels Economic Review, 54:2/3.

Kayyem, J. (2012) The working moms debate International Herald Tribune June 27 Wednesday p.8.

Kohler, R. (1994) Lords of the Fly: Drosophila Genetics and the Experimental Life. Chicago: University of Chicago Press

Ranga, M et al (2008), Gender Patterns in Technology Transfer: Social innovation in the making?, Research Global, 4-5.

Ridgeway, C (2011), Framed by Gender: How Gender Inequality Persists in the Modern World, Oxford: Oxford University Press.

Zuckerman, H and Merton R (1972), Age, Ageing and Age Structure in Science. In Ageing and Society, Riley, M, Johnson, M and Foner, A, eds, Vol 3. New York: Russell Sage Foundation.

 

 

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Curator: Aviva Lev-Ari, PhD, RN

For IP and Legal aspects of Biosimilars, go to:

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

For CMC and Regulatory Affairs of Biosimilars, go to:

Biosimilars: CMC Issues and Regulatory Requirements

https://pharmaceuticalintelligence.com/2012/07/29/biosimilars-cmc-issues-and-regulatory-requirements/

The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approval and eventually biosimilar generic drugs.

With the upheld ObamaCare, critical parts of the PPACA constitutional, and with it the BPCIA giving the FDA authority to approve biosimilars.

Had the PPACA been stricken in part or in its entirety, it would have presented obstacles to the BPCIA surviving in its present form. The US government has been critical of the 12-year data exclusivity period for Pioneer Innovators, calling for it to be shortened to 7 years (12 years is favorable to Pioneer Innovators and less favorable for Biosimilar manufacturers). The upheld ObamaCare, PPACA and BPCIA, constitutional, has prevented a multiyear delay in biosimilar approval. Thus, it was the best scenario for the biologics industry.

Thus, projection of Sales for Biosmilars as % of top 100 U.S. Pharmaceutical will receive a special meaning and an expected enhanced market share for 2012 year end and beyond 2012.

Biosimilars are occupying the Following ranking in the U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales: 10, 11, 12 13, 15, 24, 27, 29, 33, 35, 39, 57, 58, 62, 65, 70,  72, 74, 90, 98, 99. In addition the following biosimilars did not make the Top 100 list:

Biosimilar Drugs by US Sales – not included in the Top 100 Drug List 

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant) by Baxter 5.7 Billion in 2012

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease by Genzyme 200 millions in sales

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011 by Elan and Biogen

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk – $1.5Billion

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca  $570 millions

Humulin $1.1 1992 Insulin Human by Eli Lilly $ 1.2 Billion

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer $1.4 billion

U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales – Small Molecule Drugs (in green) and Biosimilars (in red)

The following is a list of the top 100 pharmaceutical drugs by retail sales in 2012, listed by U.S. sales value and drug name. Last updated: July 2012 (updated quarterly)

http://www.drugs.com/stats/top100/sales

Rank Drug

Sales ($000)

   
1 PlavixBristol-Myers Squibb Company

1,620,790

Stats

2 NexiumAstraZeneca Pharmaceuticals

1,395,981

Stats

3 AbilifyOtsuka Pharmaceutical Co.

1,340,200

Stats

4 SingulairMerck & Co., Inc.

1,238,134

Stats

5 SeroquelAstraZeneca Pharmaceuticals

1,161,141

Stats

6 Advair DiskusGlaxoSmithKline

1,139,182

Stats

7 CrestorAstraZeneca Pharmaceuticals

1,117,904

Stats

8 CymbaltaEli Lilly and Company

1,029,262

Stats

9 atorvastatinGeneric Drug

952,407

Stats

10 HumiraAbbott Laboratories

928,124

 

Stats

11 RemicadeCentocor Ortho Biotech, Inc

899,453

 

Stats

12 EnbrelAmgen Inc.

890,135

 

Stats

13 NeulastaAmgen Inc.

849,971

 

Stats

14 LipitorPfizer Inc

840,715

Stats

15 RituxanGenentech, Inc

756,875

 

Stats

16 CopaxoneTeva Pharmaceuticals

748,585

Stats

17 AtriplaGilead Sciences, Inc.

694,901

Stats

18 OxyContin

662,876

Stats

19 SpirivaBoehringer Ingelheim Pharmaceuticals, Inc

659,818

Stats

20 AvastinGenentech, Inc

632,183

Stats

21 ActosTakeda Pharmaceuticals North America, Inc

630,970

Stats

22 JanuviaMerck & Co., Inc.

583,603

Stats

23 TruvadaGilead Sciences, Inc.

546,098

Stats

24 LantusSanofi-Aventis

520,584

Stats

25 DiovanNovartis Corporation

509,615

Stats

26 LexaproForest Pharmaceuticals, Inc

491,053

Stats

27 EpogenAmgen Inc.

489,570

 

Stats

28 LyricaPfizer Inc

458,171

Stats

29 Lantus SolostarSanofi-Aventis

448,388

 

Stats

30 enoxaparinGeneric Drug

442,263

Stats

31 EloxatinSanofi-Aventis

431,928

Stats

32 CelebrexPfizer Inc

430,993

Stats

33 HerceptinGenentech, Inc

425,687

 

Stats

34 Diovan HCTNovartis Corporation

415,475

Stats

35 LucentisGenentech, Inc

409,547

 

Stats

36 SynagisMedImmune, Inc

396,556

Stats

37 NamendaForest Pharmaceuticals, Inc

391,638

Stats

38 GleevecNovartis Corporation

391,072

Stats

39 AvonexBiogen Idec

388,623

 

Stats

40 VyvanseShire US Inc

387,167

Stats

41 olanzapineGeneric Drug

385,867

Stats

42 IncivekVertex Pharmaceuticals

371,349

Stats

43 One Touch Ultra

366,294

Stats

44 SuboxoneReckitt Benckiser Pharmaceuticals Inc.

338,840

Stats

45 methylphenidateGeneric Drug

337,211

Stats

46 ZetiaMerck & Co., Inc.

328,653

Stats

47 AndroGelAbbott Laboratories

311,850

Stats

48 ProvigilCephalon, Inc.

303,029

Stats

49 LidodermEndo Pharmaceuticals

301,354

Stats

50 TriCorAbbott Laboratories

298,834

Stats

51 SymbicortAstraZeneca Pharmaceuticals

290,669

Stats

52 CombiventBoehringer Ingelheim Pharmaceuticals, Inc

285,487

Stats

53 ProAir HFATeva Pharmaceuticals

284,647

Stats

54 Seroquel XRAstraZeneca Pharmaceuticals

282,416

Stats

55 amphetamine/dextroamphetamineGeneric Drug

275,447

Stats

56 NasonexMerck & Co., Inc.

274,748

Stats

57 NovologNovo Nordisk Inc.

266,305

 

Stats

58 ProcritJanssen Pharmaceuticals, Inc

264,190

 

Stats

59 AlimtaEli Lilly and Company

263,024

Stats

60 ViagraPfizer Inc

260,678

Stats

61 GeodonPfizer Inc

260,514

Stats

62 Rebif

258,088

 

Stats

63 budesonideGeneric Drug

257,243

Stats

64 NiaspanAbbott Laboratories

255,383

Stats

65 HumalogEli Lilly and Company

244,587

 

Stats

66 Flovent HFAGlaxoSmithKline

241,552

Stats

67 LovazaGlaxoSmithKline

239,845

Stats

68 LevemirNovo Nordisk Inc.

239,576

Stats

69 Adderall XRShire US Inc

239,097

Stats

70 NeupogenAmgen Inc.

238,427

 

Stats

71 ReyatazBristol-Myers Squibb Company

238,151

Stats

72 AranespAmgen Inc.

231,643

 

Stats

73 metoprololGeneric Drug

231,395

Stats

74 NovoLog FlexPenNovo Nordisk Inc.

227,228

 

Stats

75 VytorinMerck & Co., Inc.

218,215

Stats

76 JanumetMerck & Co., Inc.

212,596

Stats

77 IsentressMerck & Co., Inc.

211,526

Stats

78 escitalopramGeneric Drug

210,171

Stats

79 CialisEli Lilly and Company

206,996

Stats

80 AciphexEisai Corporation

203,097

Stats

81 PradaxaBoehringer Ingelheim Pharmaceuticals, Inc

201,065

Stats

82 SolodynMedicis Pharmaceutical Corporation

198,909

Stats

83 fentanylGeneric Drug

197,350

Stats

84 ZyprexaEli Lilly and Company

194,460

Stats

85 VelcadeTakeda Pharmaceuticals North America, Inc

188,583

Stats

86 RestasisAllergan, Inc

188,501

Stats

87 LunestaSunovion Pharmaceuticals Inc.

187,941

Stats

88 acetaminophen/hydrocodoneGeneric Drug

185,374

Stats

89 PrezistaJanssen Pharmaceuticals, Inc

182,859

Stats

90 PegasysGenentech, Inc

181,693

 

Stats

91 ZyvoxPfizer Inc

179,523

Stats

92 Prevnar 13Wyeth

179,085

Stats

93 LovenoxSanofi-Aventis

178,957

Stats

94 BenicarDaiichi Sankyo

174,619

Stats

95 VESIcareAstellas Pharma US

174,524

Stats

96 Ventolin HFAGlaxoSmithKline

172,707

Stats

97 OrenciaBristol-Myers Squibb Company

172,202

Stats

98 BetaseronBayer Healthcare Pharmaceuticals

172,143

 

Stats

99 ErbituxBristol-Myers Squibb Company

171,513

 

Stats

100 DexilantTakeda Pharmaceuticals North America, Inc

171,179

Stats

Source: IMS Health (Midas).

Biosimilars Drugs by US Sales – not included in the Top 100 Drug List 

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant) by Baxter 5.7 Billion in 2012

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease by Genzyme 200 millions in sales

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011 by Elan and Biogen

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk – $1.5Billion

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca  $570 millions

Humulin $1.1 1992 Insulin Human by Eli Lilly $ 1.2 Billion

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer $1.4 billion

2011 US Sales vs. 2008 US Sales (in Billions) for Top Selling Biologics

Source for 2008 Sales

http://www.tbiweb.org/tbi/file_dir/TBI2009/Bao-lu%20Chen.pdf 

Source for 20011, Q1 2012 Sales

http://www.drugs.com/stats/top100/sales

Drug Name,  2008 Sales, Year approved , Indication

[i.e. Drug Name Enbrel,  2008 Sales $8.0B, Year approved 1998 , Indication RA]

Enbrel $8.0 1998 — RA, psoriatic arthritis, or ankylosing spondylitis indication

Q1 2012 12 (1) $890,135 1.92% 823 -4.63%
Q4 2011 11 (1) $873,343 1.67% 863 1.77%
Q3 2011 12 (1) $858,997 1.27% 848 -2.97%
Q2 2011 13 (2) $848,230 3.77% 874 3.19%
Q1 2011 11 $817,401 847

http://www.drugs.com/stats/enbrel

Remicade $7.9 1998 — RA & Chron’s Disease

Q1 2012 11 (2) $899,453 10.04% 1,556 10.04%
Q4 2011 13 (3) $817,365 -7.02% 1,414 -9.82%
Q3 2011 10 $879,054 1.52% 1,568 1.03%
Q2 2011 10 (2) $865,903 7.61% 1,552 7.11%
Q1 2011 12 $804,699 1,449

http://www.drugs.com/stats/remicade

Humira $7.3 2002  — treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis

Q1 2012 10 $928,124 2.50% 546 -2.85%
Q4 2011 10 (1) $905,527 3.18% 562 2.55%
Q3 2011 11 (3) $877,641 3.95% 548 3.01%
Q2 2011 14 $844,296 6.32% 532 2.31%
Q1 2011 14 $794,076 520

http://www.drugs.com/stats/humira

Rituxan $7.3 1997 — cancer medicines to treat non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.

Q1 2012 15 (1) $756,875 -1.91% 547 -0.91%
Q4 2011 14 (2) $771,622 6.96% 552 4.74%
Q3 2011 16 $721,408 -1.77% 527 -1.86%
Q2 2011 16 (4) $734,378 7.26% 537 5.09%
Q1 2011 20 $684,666

http://www.drugs.com/stats/rituxan

Second Quarter 2012 Highlights: RITUXAN(R) (rituximab) revenues from our unconsolidated joint business arrangement were $285 million for the quarter, an increase of 31% year-over-year. As previously disclosed, during the second quarter of 2011 our share of RITUXAN revenues from unconsolidated joint business was reduced by approximately $50 million to reflect our share of damages and interest that might be awarded in relation to an intermediate decision in Genentech, Inc.’s ongoing arbitration with Hoechst GmbH

http://www.marketwatch.com/story/correcting-and-replacing-biogen-idec-increases-revenue-18-to-14-billion-in-the-second-quarter-2012-07-24

Herceptin $5.7 1998 —  treat metastatic breast cancer that has progressed after treatment with other chemotherapy

Q1 2012 33 $425,687 -0.06% 155
Q4 2011 33 (2) $425,931 7.61% 155 4.73%
Q3 2011 31 (1) $395,804 -0.64% 148 -0.67%
Q2 2011 32 (4) $398,348 3.62% 149 1.36%
Q1 2011 36 $384,428 147

http://www.drugs.com/stats/herceptin

Lantus $5.1 2000 — long-acting form of the hormone insulin.

Q1 2012 29 (5) $448,388 9.81% 3,737 7.32%
Q4 2011 34 $408,336 8.54% 3,482 7.07%
Q3 2011 34 (2) $376,208 4.53% 3,252 6.00%
Q2 2011 36 (5) $359,907 7.80% 3,068 8.30%
Q1 2011 41 $333,878 2,833

http://www.drugs.com/stats/lantus-solostar

Epogen/Procrit $5.1 1989Anemia, low RBC

Worldwide, sales of the two drugs – sold under the brand names Epogen, Procrit and Aranesp – exceeded $9 billion in 2005 for Amgen and Johnson & Johnson, their makers.  Johnson & Johnson, which sells epoetin under the brand names Procrit in the United States and Eprex everywhere else, reported sales of $2.4 billion in the first nine months of 2006, down slightly from 2005.

Amgen Recalls Anemia Medications for Glass Fragments09/24/2010 – Drug-makers Amgen (AMGN) and Johnson & Johnson (JNJ) are voluntarily recalling two brandsof an injectable anemia medication because vials containing the drug may have tiny glass flakes. The drug, Epoetin alfa, is marketed under the brand names Epogen and Procrit.Known as lamellae, the glass fragments are created by the interaction of the drug with glass vials during storage, Amgen said in a statement announcing the recall. The recall is being conducted in cooperation with the Food and Drug Administration, Amgen said.

Latest study shows anemia drugs Epogen, Aranesp and Procrit cause strokes, says FDA

Posted on January 7, 2010

Anemia drugs sold by Amgen and Johnson & Johnson have been reported to cause strokes when prescribed in high doses, according to an article from the FDA, recently published in the The New England Journal of Medicine. The law firm of Aylstock, Witkin, Kreis & Overholtz is investigating the FDA’s recent announcement.

The FDA commentary said the latest study and previous studies “raise major concerns” about the use of these drugs to treat anemia caused by kidney disease. The drugs are also used to treat anemia caused by chemotherapy. Studies over the past several years have revealed a link between the drugs and heart attacks, strokes, and other problems.

Amgen’s anemia drugs include Epogen and Aranesp. Johnson & Johnson sells anemia drug Procrit, which is produced by Amgen. The drugs are designed to raise red blood cell levels, to promote delivery of oxygen to body tissues.

http://www.awkolaw.com/news/heart-attacks/anemia-drugs-epogen-aranesp-procrit-cause-strokes-says-fda/

Epogen / Procrit / Aranesp: The July 2012 News Report Which Tells Story Of Big Pharma Profits Over Patient Safety And Drug Efficacy

Once The FDA Started Paying Attention The Writing On The Wall Became Apparent, Albeit Too Late For Some

(Posted by  at DrugInjuryWatch.com)

This lengthy and well-presented news report, “Anemia drugs made billions, but at what cost?”, written by Peter Whoriskey and published July 19, 2012 by The Washington Post (free registration required), is a must-read for anyone with a concern or interest in how larger pharmaceutical companies might put corporate profits ahead of patient safety and drug efficacy.

Here is an excerpt from this Washington Post article which will give you a sense of what went on that, in hindsight, is so disturbing:

For years, a trio of anemia drugs known as Epogen, Procrit and Aranesp ranked among the best-selling prescription drugs in the United States, generating more than $8 billion a year for two companies, Amgen and Johnson & Johnson. Even compared with other pharmaceutical successes, they were superstars. For several years, Epogen ranked as the single costliest medicine under Medicare: U.S. taxpayers put up as much as $3 billion a year for the drugs.

The trouble, as a growing body of research has shown, is that for about two decades, the benefits of the drug — including “life satisfaction and happiness” according to the FDA-approved label — were wildly overstated, and potentially lethal side effects, such as cancer and strokes, were overlooked.

Last year, Medicare researchers issued an 84-page study declaring that among most kidney patients, the original and largest market for the drugs, there was no solid evidence that they made people feel better, improved their survival or had any “clinical benefit” besides elevating a statistic for red blood cell count.

As for some of the key events which led up to this revelation of sorts, we start with a June 24, 2011 FDA press release, “FDA modifies dosing recommendations for Erythropoiesis-Stimulating Agents — Cites increased risk of cardiovascular events when used to treat chronic kidney disease”, which included the following:

The U.S. Food and Drug Administration today recommended more conservative dosing guidelines for Erythropoiesis-Stimulating Agents (ESAs) when used to treat anemia in patients with chronic kidney disease (CKD) because of the increased risks of cardiovascular events such as stroke, thrombosis, and death….

Procrit —  (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Q1 2012 58 (3) $264,190 -2.13% 295 -4.22%
Q4 2011 55 (2) $269,937 3.58% 308 3.01%
Q3 2011 53 (12) $260,610 -21.61% 299 -21.32%
Q2 2011 41 (7) $332,466 7.04% 380 5.56%
Q1 2011 48 $310,606 360

http://www.drugs.com/stats/procrit

Epogen —  (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Q1 2012 27 (7) $489,570 -24.54% 555 -17.04%
Q4 2011 20 (2) $648,794 4.67% 669 3.40%
Q3 2011 22 (2) $619,828 -13.96% 647 -18.41%
Q2 2011 20 (1) $720,376 3.32% 793 4.48%
Q1 2011 19 $697,224 759

http://www.drugs.com/stats/epogen

Neulasta $4.2 2002 — used to prevent neutropenia, a lack of certain white blood cells caused by receiving chemotherapy. stimulates the bone marrow and promotes the growth of white blood cells called neutrophils

Q1 2012 13 (1) $849,971 3.33% 331 1.53%
Q4 2011 12 (2) $822,578 4.59% 326 3.49%
Q3 2011 14 (1) $786,464 -3.86% 315 -5.69%
Q2 2011 15 $818,068 4.04% 334 3.41%
Q1 2011 15 $786,288 323

http://www.drugs.com/stats/neulasta

Novolog $3.7 2000 —  Insulin aspart is a fast-acting form of insulin. NovoLog is used to treat type 1 (insulin-dependent) diabetes in adults and children who are at least 2 years old. It is usually given together with a long-acting insulin.

Q1 2012 57 (6) $266,305 5.67% 2,980 3.72%
Q4 2011 63 (3) $252,015 0.97% 2,873 -0.48%
Q3 2011 60 (1) $249,591 -0.96% 2,887 -2.66%
Q2 2011 61 (5) $252,010 3.16% 2,966 -0.70%
Q1 2011 66 $244,297 2,987

http://www.drugs.com/stats/novolog

Erbitux $3.6 2004 — used to treat cancers of the colon and rectum. It is also used to treat head and neck cancer.

Q1 2012 99 (2) $171,513 2.30% 266 3.91%
Q4 2011 97 (7) $167,657 -0.15% 256 0.79%
Q3 2011 90 (3) $167,909 -2.48% 254 -1.93%
Q2 2011 93 (2) $172,185 -0.89% 259 -0.38%
Q1 2011 95 $173,735 260

http://www.drugs.com/stats/erbitux

Aranesp $3.2 2001 — Anemia, low RBC,  (darbepoetin alfa) is a man-made form of a protein that helps your body produce red blood cells. 

Q1 2012 72 (6) $231,643 -5.86% 293 -7.86%
Q4 2011 66 (15) $246,056 -6.07% 318 -3.64%
Q3 2011 51 (3) $261,967 -10.25% 330 -11.29%
Q2 2011 48 (3) $291,873 -1.03% 372 -1.33%
Q1 2011 51 $294,912 377

http://www.drugs.com/stats/aranesp

The article reports on the decline of worldwide sales of Aranesp drug from Thousand Oaks, California-based Amgen Inc. as of the second quarter of 2007. According to Amgen, the 10% decrease of Aranesp worldwide sales was due to the reimbursement issues related to the anemia drug and the drop of U.S. demand for drug, in which the U.S. Aranesp reported sales in the second quarter of 2007 was only $578 million from $713 million in 2006.

http://connection.ebscohost.com/c/articles/26375335/amgen-posts-lower-aranesp-sales

1/24/2011, Amgen boosts prices to offset Aranesp sales

Amgen is hiking prices to make up for the shrinking sales volume of its anemia drug Aranesp. Bloomberg reports that Amgen raised the price tag on Aranesp itself by 4.4 percent, but also marked up the white-blood-cell-boosting meds Neulasta and Neupogen by 2.9 percent.

http://www.fiercepharma.com/story/amgen-boosts-prices-offset-aranesp-sales/2011-01-24

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant)

BioScience core franchises include: Hemophilia, Biotherapeutics, BioSurgery and Vaccines. BioScience products represent approximately 45 percent of Baxter’s annual sales, totaling $5.7 billion in 2010.

2007 Outlook – Sales within Baxter’s BioScience business totaled $1.2 billion, an increase of 18 percent from the same period last year. This growth was driven by record sales of ADVATE, Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (rAHF-PFM) for the treatment of hemophilia A, antibody therapy products, including GAMMAGARD LIQUID(TM) [Immune Globulin Intravenous (Human)] (IVIG) 10% Solution for the treatment of primary immunodeficiencies, specialty plasma therapeutics and biosurgery products. Medication Delivery sales increased 7 percent to $1.0 billion, with increased sales of infusion systems, intraveneous solutions and parenteral nutrition products, along with accelerated growth in the company’s drug delivery business. Renal sales increased 6 percent to $537 million reflecting accelerating gains in peritoneal dialysis patients globally.

Lucentis $2.7 2006 intraocular injection. (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A).

Date Range Sales Rank Sales ($000) Units (000)
Q1 2012 35 (5) $409,547 -6.89% 224 -5.88%
Q4 2011 30 (2) $439,867 2.44% 238 2.59%
Q3 2011 28 (2) $429,393 1.13% 232 0.87%
Q2 2011 30 (3) $424,611 0.95% 230 1.32%
Q1 2011 33 $420,635 227

http://www.drugs.com/stats/lucentis

http://www.gene.com/gene/about/ir/historical/product-sales/lucentis.html

Lucentis brought in $1.7 billion for Roche last year, according to data compiled by Bloomberg.Alimera Sciences Inc. (ALIM), based in Alpharetta, Georgia, and Psivida Corp. (PSDV) also are developing a diabetic macular edema treatment known as Iluvien. The FDA has twice rejected Iluvien, most recently in November.

The FDA pooled results from two Roche clinical trials and found 39 percent of patients who used the 0.3 milligram dose were able to read three additional lines of letters on an eye chart after two years compared to 41 percent who had the same effect on the 0.5 milligram dose, according to an FDA staff report released July 24.

Genentech recommended approval of the 0.3 milligram dose in its application to the FDA since there isn’t evidence of additional benefit of the higher dose, Terence Hurley, a spokesman for the company, said in an e-mail.

Patients who received the monthly injection also were significantly more likely than those who received fake doses of the drug to achieve 20/40 vision, enough eyesight to drive.

http://www.bloomberg.com/news/2012-07-26/roche-s-lucentis-backed-by-fda-panel-for-diabetic-blindness-1-.html

Avonex $2.6 1996 —  Multiple Sclerosis, a form of protein called beta interferon that occurs naturally in the body. Interferons help the body fight viral infections. Avonex is used to treat patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability. This medication will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 39 (1) $388,623 2.22% 130 -3.70%
Q4 2011 38 (5) $380,189 0.19% 135 -2.17%
Q3 2011 33 $379,457 -0.05% 138 -1.43%
Q2 2011 33 (4) $379,639 2.45% 140 -1.41%
Q1 2011 37 $370,570 142

http://www.drugs.com/stats/avonex

Second-quarter net income surged 34 percent to $386.8 million, or $1.61 a share, from $288 million, or $1.18, a year earlier, the Weston, Massachusetts-based company said today in a statement. Earnings excluding some items of $1.82 topped by 26 cents the average of 21 analysts’ estimates (BIIB) compiled by Bloomberg. Revenue beat estimates by about $90 million.

Biogen said profit this year is expected to be more than $6.20 a share, 5 cents higher than its May 1 forecast (BIIB). The company has been increasing sales of Avonex, Rituxan and Tysabri, another MS therapy, while developing new medicines to introduce to the market.

http://www.businessweek.com/news/2012-07-24/biogen-second-quarter-profit-rises-as-avonex-sales-increase

AVONEX(R) (interferon beta-1a) revenues increased 16% year-over-year to $762 million.

Novolin $2.5 1991  —  Novolin R (insulin regular) is a short-acting form of human insulin, Diabetes, Type 1 Type 2

Date Range Sales Rank Sales ($000) Units (000)
Q1 2012 74 (2) $227,228 8.96% 2,489 13.81%
Q4 2011 76 (4) $208,552 10.19% 2,187 6.73%
Q3 2011 80 (6) $189,267 4.15% 2,049 4.92%
Q2 2011 86 (7) $181,733 3.71% 1,953 29.60%
Q1 2011 93 $175,235 1,507
http://www.drugs.com/stats/novolog-flexpen
Novo Nordisk launches iPhone app Posted 17th September 2010, 15:11:54
An iPhone app has been launched by Novo Nordisk in the US which lets healthcare staff check dosage guidelines for diabetes patients.

Novo Dose provides product-specific data for the company’s insulin analog agents Levemir (insulin detemir), NovoLog (insulin aspart) and NovoLog Mix (insulin aspart protamine/insulin aspart injectable).

Combined sales of the three medications increased by 24% last year, feeding a double-digit growth in Novo Nordisk sales and profits.

Novo Dose, the second diabetes app created by the industry, tells professionals when and how to dose the drugs, how to titrate and provides information on the blood glucose goals of patients.

Commenting on the new technology, Anup Kumar Sabharwal, an endocrinologist at the University of Miami Clinics’ Diabetes Research Institute, said: “This is where modern medicine is headed.”

Humalog $2.2 1996  Humalog is used to treat type 1 (insulin-dependent) diabetes in adults. Insulin lispro is a fast-acting form of insulin. It is usually given together with another long-acting insulin. It works by lowering levels of glucose in the blood. Humalog is also used together with oral (taken by mouth) medications to treat type 2 (non insulin-dependent) diabetes in adults.

Q1 2012 65 $244,587 -2.70% 2,570 -3.85%
Q4 2011 65 (2) $251,367 3.78% 2,673 2.81%
Q3 2011 63 (4) $242,208 -0.75% 2,600 -1.78%
Q2 2011 67 (5) $244,050 4.83% 2,647 1.15%
Q1 2011 72 $232,809 2,617

http://www.drugs.com/stats/humalog

Pegasys $2.0 2002 — (peginterferon alfa-2a) is made from human proteins that help the body fight viral infections. Pegasys is used to treat chronic hepatitis B or C. It is often used together with another medication called ribavirin (Copegus, Rebetol, RibaPak, Ribasphere, RibaTab).

Q1 2012 90 (1) $181,693 3.92% 87 3.57%
Q4 2011 91 () $174,833 84

http://www.drugs.com/stats/pegasys

Rebif $1.7 2002 — (interferon beta-1a) is a protein identical to one found in the body. Interferon beta-1a is made from human proteins. Interferons help the body fight viral infections. Rebif is used to treat relapsing multiple sclerosis (MS). This medication will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 62 (1) $258,088 -0.21% 540 -9.09%
Q4 2011 61 (7) $258,643 0.43% 594 -0.34%
Q3 2011 54 (5) $257,535 1.48% 596 -1.49%
Q2 2011 59 (2) $253,780 0.25% 605 -0.66%
Q1 2011 61 $253,143 609

http://www.drugs.com/stats/rebif

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease.

Last year Genzyme was forced to temporarily close its manufacturing plant in Boston due to a viral contamination. The interruption lead to shortages of two key drugs: Cerezyme for Gaucher disease and Fabrazyme for Fabry disease.

That crisis sent the company’s stock price plummeting from nearly $84 in 2008 to a low earlier this year of $45.39. Sanofi’s offer to acquire the company for $18.5 billion, or $69 a share — along with a 14 percent rise in the NYSE Arca Biotech Index since late July — have helped the shares rebound.

But Genzyme is now on a mission to prove to shareholders that it is worth more than Sanofi is offering, and executives told investors on a conference call that the third quarter marks the beginning of its financial turnaround.

Third-quarter sales of Cerezyme, the company’s top drug, rose to $179.8 million from $93.6 million a year earlier, beating analysts’ average forecast of $175 million.

“In the third quarter we saw our financial recovery start to take effect, and we expect that this will accelerate during the fourth quarter as Cerezyme patients are able to return to normal dosing levels and we begin to increase shipments of Fabrazyme,” Genzyme CEO Henri Termeer said in a statement.

Cerezyme is the principal drug for Gaucher patients. In the first quarter of 2012 Genzyme (now part of Sanofi (SNY))reported Cerezyme sales of 149 million euros (approx. $194 million), up 5.8% from the same quarter of the previous year. The other supplier Shire (SHPGY) reported $72 million in Vpriv sales, up 22%. There is now a third supplier, Pfizer (PFE), teamed up with the Israeli company Protalix Biotherapeutics (PLX), whose product was approved by the FDA in May 2012. Elelyso (taliglucerase alfa) is now available in the US.
Product Cerezyme
2009 2010 2011
 Total 793 720 885
 Ann. Growth Total -9% 23%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=15461&componentID=1002

Tysabri $1.4 2004 — Multiple Sclerosis by Elan and Biogen

Global in-market sales of TYSABRI in the second quarter of 2012 were $395 million, an increase of 2% over the second quarter of 2011. The total was comprised of $211 million in U.S. sales and $184 million in sales outside the U.S.

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011.
ITALIAN DISPUTE

Elan derives its revenue almost exclusively from Tysabri and it reported total sales for the three months to June 30 of $288 million, up 6 percent on a year ago once sales from its since-divested drug delivery business are omitted.

That compared to the $299 million forecast by four analysts surveyed by Reuters and was driven by in-market sales of Tysabri that rose 2 percent year-on-year to $395 million, also shy of the $419 million expected by analysts.

Biogen, which detailed the sales numbers when it reported second quarter results on Tuesday, attributed the softer-than-expected Tysabri sales to a dispute with the Italian government over pricing.

The number of patients on Tysabri rose 4 percent to 69,100, maintaining Elan and Biogen’s 10 to 12 percent share of the MS drug market in the face of competition from Swiss drugmaker Novartis AG’s Gilenya treatment, the first multiple sclerosis pill to come on the market.

The average addition of 185 new patients per week was the highest quarterly run-rate since the fourth quarter of 2009.

http://in.reuters.com/article/2012/07/25/elan-idINL6E8IP1VV20120725

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk —

Generic Name:   eptacog alfa
Product NovoSeven
2009 2010 2011
 Total 1,324 1,431 1,559
 Ann. Growth Total 8% 9%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&id=13483&lType=modData&componentID=1002

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca

Product Synagis
2009 2010 2011
 Total 1,042 906 570
 Ann. Growth Total -13% -37%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=91&componentID=1002

Neupogen $1.3 1991 —  (filgrastim) is a man-made form of a protein that stimulates the growth of whiteblood cells in your body. White blood cells help your body fight against infection. Neupogen is used to treat neutropenia, a lack of certain white blood cells caused by cancer,bone marrow transplant, receiving chemotherapy, or by other conditions.

Q1 2012 70 $238,427 0.06% 170 -2.86%
Q4 2011 70 (5) $238,289 0.16% 175 10.76%
Q3 2011 65 (5) $237,915 0.69% 158 0.64%
Q2 2011 70 (4) $236,294 2.51% 157 0.64%
Q1 2011 74 $230,515 156

http://www.drugs.com/stats/neupogen

Betaseron $1.2 1993 — (interferon) is made from human proteins. Interferons help the body fight viral infections. Betaseron is used to treat relapsing multiple sclerosis (MS). Betaseron will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 98 (1) $172,143 2.93% 67 -10.67%
Q4 2011 99 (12) $167,236 -3.76% 75 -5.06%
Q3 2011 87 (2) $173,769 -2.89% 79 -2.47%
Q2 2011 89 (4) $178,938 -2.17% 81 -7.95%
Q1 2011 85 $182,908 88

http://www.drugs.com/stats/betaseron

Humulin $1.1 1992 Insulin Human by Eli Lilly 

Product Humulin R
2009 2010 2011
 Total 1,022 1,089 1,249
 Ann. Growth Total 7% 15%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=12399&componentID=1002

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer

Product Kogenate
2009 2010 2011
 Total 1,238 1,332 1,496
 Ann. Growth Total 8% 12%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=11681&componentID=1002

Conclusion

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.

REFERENCES

http://www.wolfgreenfield.com/files/2426_biosimilars_2_final_pdf.pdf

Read Full Post »


Biosimilars: CMC Issues and Regulatory Requirements

Reporter: Aviva Lev-Ari, PhD, RN

Updated on 6/30/2015

Biosimilars in the US: How much can we learn from Europe?

http://www.xcenda.com/Insights-Library/HTA-Quarterly-Archive-Insights-to-Bridge-Science-and-Policy/HTA-Quarterly-Spring-2015/Biosimilars-in-the-US-How-much-can-we-learn-from-Europe/#.VY-99uehlRA.mailto

Updated on 2/10/2014

Cambridge Healthtech    Institute’s Fifth  Annual Biotherapeutics Analytical Summit
Hyatt Regency    Baltimore | Baltimore,  MD | BiotherapeuticsAnalyticalSummit.com

<http://wec.chi-lifescience.com/t/20344782/1039908871/3650297/1006/>

The    Science and  Regulation of Process Changes for Biologics (Comparability)
Thursday,  March 27, 2014 | 5:30 – 8:30 PM | More Information 

http://wec.chi-lifescience.com/t/20344782/1039908871/4704449/1007/?fb8dc108=YXZpdmFsZXYtYXJpQGFsdW0uYmVya2VsZXkuZWR1&x=9c418447

Manufacturing changes can impact on quality     attributes of biologics, and may affect efficacy and/or safety of the product.   For that reason, a thorough comparability exercise is required, to assess the   impact of the change and whether CMC data alone will suffice to support the     change. This interactive short course will consider comparability exercises     during development, as well as post-approval, addressing regulatory and     technical requirements. This should provide the attendee with the knowledge on   how to prepare a comparability package for discussion with regulatory  agencies,   towards acceptance of the proposed change to the process/product.  Attendees   will  be contacted before the event and asked about topics on which  they would   like to  focus.

Topics covered     include:

  • Ways that manufacturing changes can impact    on quality attributes
  • Features of a thorough comparability exercise
  • Critical evaluation of quality data
  • The comparability exercise during development
  • Post-approval comparability, ICH Q5E, Comparability Protocols (US) and Change Management Protocols (EU)
  • Regulatory requirements in the EU and US: guidelines, their interpretation and application
  • Discussion with Q&A


Course    Instructors:
       
Christopher J. Holloway, Ph.D., Group     Director, Regulatory Affairs &  CSO, ERA Consulting Group        
Kazumi Kobayashi, Ph.D., Director, Bioprocess Development, Biogen Idec,    Inc.       
Marjorie Shapiro, Ph.D., Chief, Laboratory of Molecular and Developmental  Immunology, Division of Monoclonal Antibodies,            FDA/CDER
 

Comparability and Developability conference program at Biotherapeutics Analytical Summit.

The third track of the Biotherapeutics Analytical    Summit focuses on the practical application of analytical characterization for    Comparability, Biosimilarity and Development purposes. It covers case studies    with a variety of products and a range of analytical technologies. We have    invited the FDA and regulatory experts to advise and to discuss regulatory    challenges being experienced by the industry. This conference also covers the    link between the process and analytical technologies for innovator products and   for biosimilars.

BiotherapeuticsAnalyticalSummit.com/Comparability

http://wec.chi-lifescience.com/t/20344782/1039908871/4665296/1009/?fb8dc108=YXZpdmFsZXYtYXJpQGFsdW0uYmVya2VsZXkuZWR1&x=833e704b>

SOURCE

From: Biotherapeutics Analytical Summit Short Course <lauran@healthtech.com>
Date: Mon, 10 Feb 2014 12:40:59 -0500
To: <avivalev-ari@alum.berkeley.edu>
Subject: The Science and Regulation of Process Changes for Biologics (Comparability)

Comparability: The Final Frontier of Protein Therapies

The rapid expansion of protein therapeutics has crossed into all major disease classes (cancer, metabolic disease, inflammatory disease, infectious disease, immune disorders, etc.).  Due to the lengthy learning curve and high cost of developing these complex products, the development of therapies has been traditionally limited to highly specialized companies.  As protein therapeutics become more mainstream, these products are finding new applications in disease treatment and commercial application beyond the range of the traditional biotech companies.  Unfortunately, the expansion of medical applications for these therapies is outpacing the rate of innovation in product development and, as a result, market availability is becoming constrained by the ability to characterize and control product characteristics.

The Future Opportunity:

The key to most effectively and efficiently developing a biopharmaceutical or biologic to marketing approval is to have a clear understanding of the unique properties of proteins and to use that knowledge to design appropriate manufacturing processes, preclinical pharmacology-toxicology and clinical programs.  It is essential in dealing with complex comparability issues related to the types of manufacturing processes or changes in manufacturing to understand the scientific reasons for requiring a demonstration of comparability and the relationships between bioanalytical differences or changes in a protein and potential alterations in protein functionality in terms of specificity, potency, pharmacological activity, pharmacokinetics, toxicity and ultimately clinical safety and efficacy.  This understanding requires in depth knowledge of protein chemistry, manufacturing processes, pharmacology, immunology and toxicology that comes with extensive training and experience.  The same scientific and regulatory expertise and experience that is required for a successful demonstration of comparability is also applicable to the development of a biosimilar. This type of experience and expertise should prove invaluable as the expansion in the area of protein therapies continues and the development of biosimilars grows in the coming years.

How to Get There from Here:

Product developers can begin today to capitalize on this opportunity.   A number of technology advancements are being explored that will enhance our understanding of relationships between process, product, and clinical safety and efficacy.   One must think through how to integrate the future product comparability into early stage product development.  For new product development, these issues will include more in-depth analysis of the product structure and relationship of various structural features to function andin vivo activity, increased knowledge about the effect of process conditions on the types and mix of final product variants, and careful choice of in vitro binding and functional assays that clearly relate to the proposed mechanism of action of the product and can often also be used as a potency assays.  New technologies are being developed for these assays, and appropriate in vitro functional assays as relates to pharmacological mechanism of action can be very useful for demonstrating comparability.

A careful determination of appropriate animal models of disease for demonstration of proof-of-concept pharmacology is also important early in development. Identification of appropriate biomarkers of efficacy or safety should also be examined in these early animal models for future use in clinical development as well as demonstration of comparability.  The discovery of appropriate biomarkers can sometimes be carried over to the clinic and used in clinical trials with the appropriate validation.  Finally, as the safety database for the various classes of biopharmaceuticals and biologics expands, the understanding of safety issues associated with each of these various product classes will make it easier to more efficiently demonstrate comparability as well as to develop biosimilar products.

For developers who are trying to bridge comparability on products that lack a complete process/product history due to legacy issues or as in the case for biosimilar development, companies must think about the pharmacology of the product as relates to the proposed indication of either the previous iteration of the product or the innovator product, depending on whether this is a comparability issue or development of a biosimilar. It is the pharmacological activity of a given protein product that determines the efficacy and to a great extent the toxicity of the product.   The pharmacological activity of a product is driven by protein structure, mix of product variants, binding kinetics, dose, dosing regimen, route of administration, and final product formulation, among others.

As the development of biopharmaceuticals and biologics continues to expand, more and more information accrues on potential safety issues related to each of the various product classes, and this information will also prove quite useful to demonstration of comparability and development of biosimilars.

Biologics Consulting Group can assist developers in designing and implementing each of their comparability programs with the greatest chance of rapid regulatory approval.  Our staff has both FDA and industry experience, with a track record of success in helping academic institutions, start-ups, and established biotech and pharma companies.  Our direct knowledge and contemporary experience with all possible regulatory pathways – and every associated nuance — and can provide the requisite preclinical, clinical, quality, analytical, and manufacturing support to increase your chances for success.

Contributors: T. CarrierD. BarngroverJ. JessopV. NarbutJ. HumphriesB. FraserR. WolffN. RitterL. Winberry 

SOURCE

http://www.biologicsconsulting.com/perspectives/comparability-protein-therapies/

For IP and Legal aspects of Biosimilars, go to:

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

For Financial Aspects of Biosimilars, go to:

Biosimilars: Financials 2012 vs. 2008

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-financials-2012-vs-2008/

Tr e n d s  i n  B i o / P h a r m a c e u t i c a l I n d u s t r y , 1 9 -26

Special Report on Biosimilars

About the Author: Dr. Bao-Lu has over 18 years of experience in product development, CMC regulatory, manufacturing management and quality oversight. He is currently the Director of Manufacturing and Process Development at Sangamo BioSciences. In this role, he oversees outsourced GMP production and testing of Sangamo’s gene therapy products and is responsible for the release and disposition of final drug product. He also provides CMC regulatory support and manages the in-house quality system by maintaining GMP database and implementing quality SOPs. Previously, Bao-Lu served as an Associate Director of Formulation at Xencor and Chiron and a Formulation Scientist at Amgen. Bao-Lu graduated with a BS degree from Fudan University and was selected as one of the forty chemistry students in the first year CGP Doering program. Bao-Lu earned his Ph.D. in Chemistry from University of Oregon and performed postdoctoral research in Biology at Massachusetts Institute of Technology.

http://www.tbiweb.org/tbi/file_dir/TBI2009/Bao-lu%20Chen.pdf

CMC Issues and Regulatory Requirements for Biosimilars

Abstract

Chemistry, Manufacturing and Controls (CMC), preclinical and clinical are three critical pieces in biosimilars development. Unlike a small-molecule generic drug, which is approved based on “sameness” to the innovator’s drug; a biosimilar is approved based on high similarity to the original approved biologic drug. This is because biologics are large and complex molecules. Many functional-, safety- and efficacy-related characteristics of a biologic depend on its manufacturing process. A biosimilars manufacturer won’t be able to exactly replicate the innovator’s process. The traditional abbreviated pathway for generic drug approval through the Hatch- Waxman Act of 1984 doesn’t apply for biosimilars as drugs and biologics are regulated under different laws. New laws and regulations are needed for biosimilars approval in the US. The EU has issued biosimilars guidelines based on comparative testing against the reference biologic drug (the original approved biologic). A full scale CMC development is required including expression system, culture, purification, formulation, analytics and packaging. The manufacturing process needs to be developed and optimized using state-of-the-art technologies. Minor differences in structure and impurity profiles are acceptable but should be justified. Abbreviated clinical testing is required to evaluate surrogate markers for efficacy and demonstrate no immunogenic response to the product.

We anticipate the package for a biosimilars approval in the US will be similar to that in the EU and contain a full quality dossier with a comparability program including detailed product characterization comparison and reduced preclinical and clinical requirements.

Biosimilars Become Inevitable

 Biologics developed through biotechnology constitute an essential part of the pipeline for medicines available to patients today. Biologic drugs are quite expensive and many of them are top-selling medicines (see Table 1). Since they come at extremely high prices to consumers, some patients may not be able to afford the use of biologics as the best-available treatments to their conditions. The patent protection on a large number of biologics has expired since 2001. These off-patent biologics include Neupogen, Novolin, Protropin, Activase, Epogen or Procrit, Nutropin, Humatrope, Avonex, Intron A, and Humulin. Traditionally, when a drug patent expires, a generic drug will be quickly developed and marketed. Similarly, generic version of off-patent biologic drugs (also referred to biosimilars or follow-on biologics or biogenerics) represents an extraordinary opportunity to companies that want to seize the potentially great commercial rewards in this unexploited territory. Biosimilars not only benefit the biosimilar manufacturers but also can save patients, and insurance companies, substantial cost and allow patients to gain access to more affordable biologics resulting in market expansion. The government can use biosimilars to reduce healthcare costs. Therefore, development and marketing of bosimilars are supported by both manufacturers and consumers.

Differences between Generic Drugs and Biosimilars

Enacted in 1984, the US Drug Price Competition and Patent Term Restoration Act, informally known as the “Hatch-Waxman Act of 1984” standardized US procedures for an abbreviated pathway for the approval of small-molecule generic drugs. The generic drug approval

is based on “sameness”. In comparison to the innovator’s drug, a generic drug is a product that has the same active ingredient, identical in dose, strength, route of administration, safety, efficacy, and intended use. For approval, the generic companies can go through the Abbreviated

New Drug Application (ANDA) process with reduced requirement in comparison to approval for a new drug entity. The generic drugs need to show bioequivalence to the innovator drugs typically based on pharmacokinetic parameters such as the rate of absorption or bioavailability in 24 to 36 healthy volunteers. No large clinical trials for safety and efficacy are required. The generic companies can rely on the FDA’s previous findings of safety and effectiveness of the innovator’s drugs.

However, the abbreviated pathway for generic drugs legally doesn’t apply to biologics as small-molecule drugs and biologics are regulated under different laws and approved through different pathways in the US (Table 2). Small-molecule drugs are regulated under the Food, Drug and Cosmetic Act (FD&C) and require submission of a New Drug Application (NDA) to FDA for drug review and approval. Biologics are regulated under the Public Health Service Act (PHS) and require submission of a Biologic License Application (BLA) to FDA for review and approval. The Hatch-Waxman Act of 1984 doesn’t apply for biosimilars. New laws are needed to establish a pathway for biosimilar approval.

There are some crucial differences between biologics and small-molecule drugs (Table 3). Small-molecule drugs are made from chemical synthesis. They are not sensitive to process changes. The final product of a small-molecule drug can be fully characterized. The developmentand production of generic drugs are relatively straightforward. Biologics are made from living organisms so that its functional-, efficacy- and safety-related properties depend on its manufacturing and processing conditions. They are sensitive to process changes. Even minor modifications of the manufacturing process can cause variations in important properties of a biological product. Thus it is believed that a biologic product is defined by its manufacturing process. Biologics are 100- or 1,000-fold larger than small-molecule drugs, possess sophisticated three-dimensional structures, and contain mixtures of protein isoforms. A biological product is a heterogeneous mixture and the current analytical methods cannot characterize these complex molecules sufficiently to confirm structural equivalence with the reference biologics.

Laws and Regulatory Pathways for Drug Approval in the US

Law/Application           Small-molecule            Drug Biologics                     

Law                     Food, Drug and Cosmetic Act (FD&C)             Public Health Service Act (PHS)

Drug application                 New Drug Application (NDA)   Biologic License Application (BLA)

Generic application   Abbreviated New Drug   Application(ANDA)   No pathway yet

 Immunogenicity Poses a Concern

One of the major complications that biologics can produce is immunogenicity as therapeutic proteins are inherently immunogenic [2]. Immunogenicity is related to biologics structure and formulation and is dependent on dose, route of administration and frequency of administration.

Clinical implications of immunogenicity are not always predictable. Formation of antibodies can result in harmless clinical effect or produce significant adverse events or severe disease. Examples are provided below. The Eprex (Erythropoietin, EPO) has been marketed by Johnson & Johnson (J&J) in the European Union (EU) countries for 10 years with no noticeable

Differences between small-molecule drugs and biologics

Product characteristics

Small-molecule generics Small, simple molecule

(Molecular weight: 100-1,000 Da)

Biosimilars   Large, complex molecules, Higher order structures, Post-translational, modifications

(Molecular weight: 15,000-150,000 Da)

Production

Small-molecule generics Produced by chemical synthesis

Biosimilars  Produced in living organisms

Analytical testing

Small-molecule  Well-defined chemical structure, all its various components in the finished drug can be determined

Biosimilars  Heterogeneous mixture, difficult to characterize, some of the components of a finished biologic may be unknown

Process dependence

Small-molecule   Not sensitive to manufacturing process changes. The finished product can be analyzed to establish the sameness.

Biosimilars   Sensitive to minor changes in manufacturing process. The product is defined by the process

Identity and purity

Small-molecule Often meeting pharmacopeia or other standards of identity (e.g., minimums for purity and potency)

Biosimilars   Most have no pharmacopeia monographs

immunogenicity issues prior to 1998. When J&J made a change in the Eprex formulation by replacing human serum albumin (HAS) with polysobate 80 and glycine in response to the

request from European health authorities, some patients developed pure red-cell aplasia (PRCA), a severe form of anemia. Eprex induced antibodies neutralize all the exogenous rHuEPO and cross-react with endogenous erythropoietic proteins. As a result, serum EPO is undetectable

and erythropoiesis becomes ineffective. Upon investigation, J&J found that polysorbate 80 might have caused uncoated rubber stoppers in single-use Eprex syringes to leach plasticizers, which stimulated an immune response that resulted in PRCA. Replacing with Teflon coated stoppers resulted in 90% decrease in PRCA by 2003 [3,4]. The effect of neutralizing antibodies has not always resulted in serious clinical consequences. Three interferon beta products, Betaseron, Rebif and Avonex, are marketed by three different companies. These products induce neutralizing antibodies in multiple sclerosis patients from 5 to 50% after one year treatment. Although these antibodies might be associated with loss of efficacy of treatment resulting in some patients to withdraw from the treatment, it seems no other severe adverse effects were detected [5,6].

Regulatory Landscape

The US, the EU and Japan are the three cornerstonemembers of the International Conference on Harmonization (ICH), which intends to harmonize the regulatory requirements for drug or biologic approval in these three regions. With the other two members, the EU and Japan, already have established biosimilar approval procedures (see below), the US lags behind in the biosimilar race. There are no formal approval pathways for biosimilars in the US. Congress needs to establish a legal framework in order for FDA to develop guidelines. Legislation has been under discussion in Congress since 2007. The legislative debate is centered on patient safety and preserving incentives to innovate with introduction of biosimilars. Two bills introduced in March 2009 deserve attentions [7,8]. The Waxman bill (H.R. 1427) proposes 5 years of market exclusivity to the innovator companies and requires no clinical trials for biosimilar development. The Eshoo bill (H.R. 1548) proposes 12 years of market exclusivity to the innovator companies and requires clinical trials for biosimilar development. Obama administration appears to favor a 7-year market exclusivity [9]. Once a legal framework is established for biosimilars, the FDA will likely take a conservative approach using the comparability as an approval principle. Clinical proof of efficacy and safety will be required, probably in reduced scale.

In the EU, the European Medicines Agency (EMEA) issued regulatory guidelines for approving biosimilars in 2005 (Figure 1) [10-16]. These include two general guidelines for quality issues [11] and non-clinical and clinical issues [12] and four class-specific annexes for specific data requirements for Granulocyte-Colony Stimulating factor (G-CSF) [13], Insulin [14], Growth hormone [15] and Erythropoietin [16]. In addition, a concept paper on interferon alpha [17] is also available. So far, there are eleven biosimilar products which received market authorization in the EU and they are biosimilar versions of human growth hormone, Epoetin and filgrastim. It is estimated six to eight years on average for a biosimilar to be developed [18].

The EMEA treats a biosimilar medicine as a medicine which is similar to a biological medicine that has already been authorized (the “biological reference medicine”) in the EU, The active substance of a biosimilar medicine is similar to the one of the biological reference medicine.

A biosimilar and the biological reference medicine are used in general at the same dose to treat the same disease. A biosimilar and the biological reference medicine are not automatically interchangeable because biosimilar and biological reference medicine are only similar but not identical. A physician or a qualified healthcare professional should make the decision to treat a patient with a reference or a biosimilar medicine. Since the biosimilar may contain different inactive ingredients, the name, appearance and packaging of a biosimilar medicine differ to those of the biological reference medicine. In addition, a pharmacovigilance plan must be in place for post-marketing safety monitoring.

Japan’s Ministry of Health, Labor and Welfare (MHLW) issued guidelines for follow-on proteins or biosimilars approval in March 2009. The first biosimilar, Sandoz’ growth hormone Somatropin, was approved in June 2009. The MHLW’s guidelines consider biosimilars drugs which are equivalent and homogeneous to the original biopharmaceuticals in terms of quality, efficacy and safety. Biosimilars are also requested to be developed with updated technologies and knowledge. Biosimilars need to demonstrate enough similarity to guarantee the safety and efficacy instead of absolute identity to the original biologics. Biosimilars’ regulatory approval applications will be categorized separately from conventional generic drugs. In general, the applications should be submitted, as the new drug applications, with data from clinical trials, manufacturing methods, long-term stability and information on overseas use. The MHLW will assess the data on absorption, distribution, metabolism and excretion (ADME) on a case-by-case basis. The applications do not need to provide data on accessory pharmacology, safety pharmacology and genotoxicity.

Biosmilars are already thriving in Eastern Europe and Asia, where regulatory and intellectual property (IP) standards for biosimilars are more liberal. Biosimilars developed in these regions are primarily sold domestically. These markets are considered less controlled. The quality of the biosimilars may not be in full compliance with ICH guidelines although they are often developed through comparative quality testing and clinical trials against the biologics which are already approved in Western countries

CMC Development

The CMC requirements for biosimilars in the EU are those described in the ICH Common Technical Document (CTD) Quality Module 3 with supplemental information demonstrating comparability or similarity on quality attributes to the reference medicine product.

Since the US is a member of ICH and encourages submission using CTD format, once the legal framework for approving biosimilars is established in the US, the CMC development will be similar to those in the EU.

Biosimilar manufacturers will have no access to the manufacturing process and product specifications of the innovator’s products because these are proprietary knowledges. To develop a biosimilar, a biosimilar manufacturer will need to first identify a marketed biologic product to serve as the reference biologic product. Then a detailed characterization of the reference biologic product will be performed. The information obtained from the characterization of the reference biologic product will be utilized to direct the process development of the biosimilar product and comparative testing to demonstrate bioequivalence between the biosimilar product and the reference biologic product. A biosimilar will be manufactured from a completely new process, which may be based on different host/vector system with different process steps, facilities and equipment.

A flow chart for a typical work flow from production to drug use is shown in Figure 2. The CMC development starts with establishment of the expression system. A cell-line will be selected among bacterial, yeast and mammalian host strains and then the correct DNA sequence will be inserted. Elaborate cell-screening and selection methods are then used to establish a master cell bank. Extensive characterization on the master cell bank needs to be carried out to provide microbiological purity or sterility and identity [19].

Bulk protein production involves developing robust and scalable fermentation and purification processes. The goals for fermentation are to increase the expression level and efficiency without compromising the correct amino acid sequence and post translational modification. Achieving high expression requires optimizing culture medium and growth conditions, and efficient extraction and recovery procedures. Correct amino acid sequence and post translati0nal modification will need to be verified.

Cell Bank

Fermentation

Purification

Drug Substance

Formulation

Fill/finish

Drug Product

Shipment

Administration

Typical flow chart for a biologics from production to drug use, above

Solubilization and refolding of insoluble proteins are sometimes necessary for proteins which have tendency to aggregate under the processing condition. Differences in the cell bank and production processes may create impurities that are different from the innovator’s product. The purification process needs to remove impurities such as host-cell proteins, DNA, medium constituents, viruses and metabolic by-products as much as possible. It is important for biosimilar manufacturers to accept appropriate yield losses to achieve high purity, because any increase in yield at the expense of purity is unacceptable and can have clinical consequences.

The final product is produced by going through formulation, sterile filtration and fill/finish into the final containers. Selection of formulation components starts from basic buffer species for proper pH control and salt for isotonicity adjustment. Surfactants may be needed to prevent proteins from being absorbed onto container surface or water-air interface or other hydrophobic surfaces. Stabilizers are required to inhibit aggregation, oxidation, deamidation and other degradations. The container and closure system can be glass vials, rubber stoppers and aluminum seals or pre-filled syringes or IV bags. The container and closure integrity needs to be verified by sterility or dyeleak test.

Biologics are not pure substances. They are heterogeneous mixtures. Each batch of a biologic product for clinical or commercial use needs to be produced in compliance with current Good Manufacturing Practice (cGMP) and is typically tested by a panel of assays to ensure the product meets pre-defined specifications for quality, purity, potency, strength, identity and safety. The product purity is often measured by multiple assays, which measure different product related variants (biologically active) or product related impurities (biologically inactive). Biologics are parenteral drugs and filled into the final containers through the aseptic process so that microbiological control is critical. It is advisable to set up product specifications for a biosimilar within the variation of the reference biologic product. Product characterization can be performed on selected batches for primary sequence, high order structures, isoform profiles, heterogeneity, product variants and impurities and process impurity profiles. Physicochemical characterization tests include IEF, CE, HIC, LCMS, carbohydrate analysis, N & C terminal sequencing, amino acid analysis, analytical ultracentrifugation, CD and DSC [20,21]. Biologics are highly sensitive to environmental influences during storage, shipment and handling. Temperature excursion, movement, and exposure to UV light can lead to protein degradation. Product expiry needs to be based on the real time stability data. Stability program should also include accelerated or stress studies to gain insight of the degradation profiles. In-use stability studies are carried out to verify shipping conditions or handling procedures cause no detrimental effect to the drug product.

 Comparability Demonstration

 A comparability exercise based on the ICH guideline [22] needs to be performed to demonstrate that the biosimilar product and the reference biologic product have similar profiles with respect to product quality, safety, and efficacy. This is accomplished by comparative testing of the biosimilar product and the reference biologic product to demonstrate they have comparable molecular structure, in vitro and in vivo biological activities, pre-clinical safety and pharmacokinetics, and safety and efficacy in human patients. Comparison of quality attributes between the biosimilar and the reference biologic product employs physicochemical

Product release assays for biologics

Type                         Assays

Quality              Appearance, particulates, pH, osmolality

Purity                 SDS-PAGE, SEC-HPLC, IEX-HPLC, RP-HPLC

Potency             In vitro or in vivo bioactivity assays

Strength             Protein concentration by A280

Identity               Western blot, peptide mapping, isoelectric focusing

Safety                  Endotoxin, sterility, residual DNA, host cell proteins

and biological characterization. Comparability on physical properties, amino acid sequence, high order structures, post-translationally modified forms are evaluated by physicochemical tests. In vitro receptor-binding or cell-based (binding) assays or even the in vivo potency studies in animals need to be performed to demonstrate comparable activity despite they are often imprecise. Levels of product related impurities (aggregates, oxidized forms, deamidated forms) and process related impurities and contaminants (host cell proteins, residual genomic DNA, reagents, downstream impurities) need to be assessed and quantified. Stability profiles of the biosimilar product and the reference biologic product also need to be studies by placing the products under stressed conditions. The rate of degradation and degradation profiles (oxidation, deamidation, aggregation and other degradation reactions) will be compared. If unknown degradation species are detected, they need to be studied to determine if they affect safety and efficacy. If differences on product purities and stability profiles are present between the biosimilar product and the reference biologic product, these differences need to be justified using scientific knowledge or preclinical or clinical studies. Changes in the impurity profile should be justified as well.

The demonstration of comparability in quality attributes does not necessarily mean that the biosimilars and the reference biologics are identical, but that they are highly similar. In many cases, the relationship between specific quality attributes and safety and efficacy has not been fully established. For example, physicochemical characterization cannot easily predict immunogenicity and slight changes in manufacturing processes or product composition can give rise to unpredicted changes in safety and efficacy. Changes in bioavailability, pharmacokinetics, bioactivity bioactivity, and immunogenicity are the main risks associated with the manufacturing of biosimilars. In vivo studies should be designed to measure the pharmacokinetics and pharmacodynamics relevant to clinical studies. Such in vivo studies should be designed to detect response differences between the biosimilar and the reference biologic not just responses per se. In vivo studies of the biosimilar’s safety in animals may be used to research any concerns into the safety of the biosimilar in human patients. Although extensive clinical testing is not necessary for biosimilars, some degree of clinical testing is needed to establish therapeutic comparability on efficacy and safety between the biosimilar and the reference biologic product [23,24]. This includes using surrogate markers of specific biologic activity as endpoints for demonstrating efficacy, and showing that patients didn’t develop immunogenic responses to the product. In general, the approval of biosimilars will be based on the demonstration of comparable efficacy and safety to an innovator reference product in a relevant patient population. Clinical data requirement for each individual product will be different and will be determined on a case-by-case basis.

Small-molecule Generics versus Biosimilars

 Small-molecule

  • Approval based on “sameness”

Biosimilars

  • Approval based on “high similarity”

Small-molecule

  • Replicate the innovator’s process and product and perform a bioavailability study demonstrating similar pharmacokinetic properties

Biosimilars

  • Full CMC development with comparative testing, conduct substantial clinical trials for efficacy and safety including immunogenicity

Small-molecule

  • Abbreviated registration procedures in Europe and US

Biosimilars

  • Regulatory pathway is defined in EU on “Comparability” status, no pathway yet in US under BLA

Small-molecule

  • Therapeutically equivalent, thus interchangeable

Biosimilars

  • Lack of automatic substitutability

Small-molecule

  • $1 to $5 million to develop

Biosimilars

  • $100-$200 million to develop

Small-molecule

  • Brand-to-generic competition

Biosimilars

  • Brand-to-Brand competition

Conclusion

The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approvaland eventually biosimilar generic drugs.

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars. 2009 and 2012 represent milestones in the regulatory provisions for biosimilars in the US.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.

REFERENCES

1. Federal Trade Commission Report, June 2009.

2. Schellekens, H.; Nat. Rev. Drug Discov. 2002, 1: 457-462.

3. Van Regenmortel, M.H.V.; Boven, K. and F. Bader, BioPharm International, August 1, 2005, Vol 18, Issue 8.

4. Locatelli, F.; Del Vecchio, L. and P. Pozzoni, Peritoneal Dialysis International, 2007, 27(Supplement 2): S303-S307.

5. Hartung, H.P.; Munschauer, F. And Schellekens, H., Eur J. Neurol., 2005, 12, 588-601.

6. Malucchi, S. et al., Neurol. Sci., 2005, 26, suppl, 4:S213-S214.

7. Greb, E., Pharmaceutical technology, June 2009, pp. 36-42.

8. Del Buono, B.J., BioPharm International, July 2009, pp 46-53.

9. Usdin, S., Biocentury, July 20, 2009, 17(32): A1-A6.

10. “Guideline on Similar Biological Medicinal Products”, (Doc. Ref.: EMEA/CHMP/437/04, London, 30 October 2005).

11. “Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues”, (Doc. Ref.: EMEA/ CHMP/BWP/49348/2005, London, 22 February 2006).

12. “Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues”, (Doc. Ref.: EMEA/CHMP/BMWP/42832/2005, London, 22 February 2006).

13. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Granulocyte-Colony Stimulating Factor”, (Doc. Ref.: EMEA/CHMP/ BMWP/31329/2005, London, 22 February 2006).

14. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Human Soluble Insulin”,(Doc. Ref.: EMEA/CHMP/BMWP/32775/2005, London, 22 February 2006).

15. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Somatropin”, (Doc. Ref.: EMEA/ CHMP/BMWP/94528/2005, London, 22 February 2006).

16. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Erythropoietins”, (Doc. Ref.: EMEA/CHMP/BMWP/94526/2005 Corr., London, 22 February 2006).

17. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: (Non) Clinical Issues – Concept paper on similar biological medicinal products containing recombinant alpha-interfero  (Doc. Ref.: CHMP/BMWP/7241/2006, London, 26 April 2006).

18. “EGA Handbook on Biosimilar Medicines”, European Generic Medicines Association, Received August 2009).

19. “Points to Consider in the Characterization of Cell Lines to Produce Biologicals”, FDA CBER, 1993.

20. Chirino, A.J. and A. Mire-Sluis, Nature Biotechnology, 2004, 22(11): 1383-1391.

21. Kendrick, B.S. et al., BioPharm International, 2009, August, pp 32-44.

22. “Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process”, ICH Harmonized Tripartite Guideline Q5E, 18 November 2004.

23. Mellstedt, H.; Niederwieser, D. and H. Ludwig, Annals of Oncology, September 14, 2007, pp. 1-9.

24 Schellekens, H., NDT Plus, 2009, 2 [suppl 1]: i27- i36.

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Reported by: Dr. V.S. Karra, Ph.D.

The European equivalent of the US Food and Drug Administration (FDA) yesterday recommended withdrawing calcitonin nasal spray — indicated for treating osteoporosis in the European Union — because of an increased risk for cancer.
The European Medicines Agency (EMA) also said that the long-term use of calcitonin-containing medicines delivered by injection or infusion increases the risk for cancer. Calcitonin in any formulation should not be used to treat osteoporosis at all, the agency said.

In the United States, 2 nasal-spray versions of calcitonin are FDA-approved for treating postmenopausal osteoporosis in women: Fortical (Upsher-Smith Laboratories) and Miacalcin (Novartis). Neither of the labels for the 2 drugs contains restrictions on how they should be used or a warning about the risk for cancer.

Calcitonin, also called calcitonin-salmon, is a synthetic copy of a polypeptide hormone secreted by the ultimobranchial gland of salmon.

The EMA said it based its recommendations on a review of the benefits and risks of calcitonin-containing medicines. Conducted by the agency’s Committee for Medicinal Products for Human Use (CHMP), the review encompassed available data from the companies that market these drugs, postmarketing safety data, randomized controlled studies, 2 studies of unlicensed oral calcitonin drugs, and experimental cancer studies, among other sources.

CHMP found that “a higher proportion of patients treated with calcitonin for long periods of time develop cancer of various types, compared with patients taking placebo.” The increase in cancer rates ranged from 0.7% for oral formulations to 2.4% for the nasal formulation. CHMP concluded that the benefits of calcitonin for osteoporosis did not exceed the risks. The nasal spray’s only indication is for osteoporosis, thus justifying the drug’s removal from the market.

As a solution for injection or infusion, calcitonin should be administered for no more than 4 weeks to prevent acute bone loss resulting from sudden immobilization, and normally for no more than 3 months to treat Paget’s disease, the EMA said. The agency did not specify a time frame for the short-term use of calcitonin for treating hypercalcemia caused by cancer.

For further details go to their website

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