In terms of background, the BPCI Act was passed in March 2010 as part of Affordable Care Act, and it creates an abbreviated licensure pathway for biological products shown to be biosimilar or interchangeable with an FDA-licensed reference product (section 351k of Public Health Service Act). FDA is eager to have an informational discussion on this topic because with the new pathway program, the agency is “essentially launching an entirely new regulatory paradigm” and public needs to understand this, said Sherman.

The BPCI Act adds “protein” to the definition of a biological product which currently includes terms such as a virus, toxin, and blood. Historically, proteins have been approved as drugs under the FD&C Act (505) and under the PHS Act (351). Proteins (except for any chemically synthesized polypeptide) will be regulated going forward under PHS.

FDA can rely on some existing information about the reference product when considering a proposed bisimilar product. Specifically, “biosimilar” means the product has the same mechanism of action as the reference product; the condition of use in proposed labeling has been previously approved for reference product; and has the same route of administration, dosage form, and strength as reference product.

The agency has to decide whether the biosimilar product is highly similar to the reference product and ensure that there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency. A doctor can provide product A or B, for example, and expect the same result. The doctor cannot go back and forth between Product A and B, however (see below), noted Sherman.

The BPCI Act requires FDA to look at three buckets of information for the 351(k) pathway: analytical studies to show that the biosimilar is highly similar to the reference product; animal studies (including toxicity, and as needed); and clinical study(ies) to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed (including, among others, pharmacokinetics and immunogenicity).

A common question: biosimilars are not identical to the reference product but are close—how close? As Sherman explained it, each study adds a piece of information to understand what the biosimilar product is and shows what more is needed to fully understand it. The method is similar to a fingerprint like approach to closely identify the product. There is no one size fits all assessment. Another approach FDA may take is to use the totality of evidence in assessing the biosimilar. Europe has a similar way of evaluating biosimilars. To provide the best advice on required animal and human studies to the biosimilar applicant, FDA should have competed a thorough review of data from structural and functional analyses.

Interchangeability. This term means that the biosimilar product produces the same clinical result as the reference product in any given patient, AND for a product administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater with repeated use of reference product without alternating or switching. An interchangeable biosimilar product may be substituted for reference product without authorization of a healthcare provider. NOTE: Biosimilarity is a prerequisite for interchangeability.

Discussions happening at FDA: The agency is thinking about ways to consider non-US licensed comparator products; the definition of protein (including chemically synthesized polypeptides); standards for interchangeability; naming and tracking standards for biosimilars and interchangeable products; exclusivity issues; and pediatric assessment requirements.

FDA will also be thinking about product class under the Act’s transition provisions. By 2020, every biological product will need to be approved under 351 of the PHS Act versus the FD&C Act.

To date, there have been 35 Pre-IND meeting requests for proposed biosimilars to 11 reference products. 21 PRE IND sponsor meetings held, and 9 INDs received

As for the FDA guidance on biosimilars…. Sherman says it’s still in final stages. No details on timeline specifics.

Most of the “affected” positions (3750) will be in selling, general, and administrative areas. One change already underway at the company is the simplification of its global commercial organisation structure by reducing the number of its sales and marketing regions from five to three. Small countries have also been clumped together in a move that AstraZeneca hopes will optimise its resources by increasing shared services and reducing cost bases.

Another 2200 positions will come from R&D. The statement says, “The R&D function will accelerate its transformation, which the company unveiled in January 2010. Under the new programme announced today, further changes will create a simpler and more innovative R&D organization with a lower and more flexible cost base. Excess capacity in certain R&D functions will be reduced, matching resources to AstraZeneca’s more focused R&D portfolio.”

One of the main focuses for R&D restructuring will be in the company’s neuroscience area. Although AstraZeneca recognises that there is much need in this area for better medicines, it adds that advances have been “elusive”. In response, the company will close one R&D site in Montreal (Canada) and wind down R&D activity at its Södertälje (Sweden) site.

In a more positive note for neuroscience, however, the company added that it will continue to pursue innovation in this area by combining internal expertise with “innovative external science” using a virtual neuroscience Innovative Medicines (iMed) unit. The unit will be made up of around 40–50 AstraZeneca scientists, who will conduct discovery and development externally using a global network of academia and industry.

Martin Mackay, president of Research and Development, AstraZeneca, said: “We’ve made an active choice to stay in neuroscience though we will work very differently to share cost, risk and reward with partners in this especially challenging but important field of medical research,” Martin Mackay, AstraZeneca’s president of research and development, said in the statement. “The creation of a virtual neuroscience iMed will make us more agile scientifically and financially – we will be able to collaborate flexibly with the best scientific expertise, wherever it exists in the world.”

The remaining job cuts will be in operations as AstraZeneca seeks to make its supply chain more efficient. In particular, the company says it will be looking at its support functions.

The restructuring is expected to deliver around $1.6 billion in annual benefits by the end of 2014, but that will be little consolation for those losing their jobs. An article in the Wall Street journal estimates that around 30000 jobs have been lost at AstraZeneca over the past five years.

“For the purposes of this discussion, ‘regulatory flexibility’ can be defined as a manufacturer having greater freedom to make postapproval changes to a drug-substance manufacturing process and controls, without waiting for prior approval from regulators, than the manufacturer may have had for similar changes approved in the past. ‘Manufacturing flexibility’ can be defined as a manufacturer being more capable of accurately predicting the consequences of changes to a drug substance manufacturing process and controls, based on the increased knowledge and understanding of the drug substance and its manufacturing process obtained from taking an enhanced approach to manufacturing process development.

FDA went on to say that, “manufacturing flexibility is valuable to manufacturers because it provides them with operational flexibility including the assurance that changes can be made without adversely affecting the quality of the material being produced. Regulatory flexibility is valuable to manufacturers because it allows changes to be made more quickly, which in most circumstances will help save money.

“In an ideal world, manufacturing flexibility and regulatory flexibility would go hand in hand. No manufacturer should be granted regulatory flexibility that exceeds the extent of the manufacturer’s manufacturing flexibility. Likewise, a manufacturer’s ability to make changes will be constrained unnecessarily if the extent of the manufacturer’s regulatory flexibility is smaller than the manufacturer’s manufacturing flexibility. Both types of disparities can exist. Manufacturers should not request a degree of regulatory flexibility that exceeds their manufacturing flexibility, and they should provide sufficient information in their submissions to justify the degree of regulatory flexibility being requested. Manufacturers should also consider pursuing the issue of regulatory flexibility internationally: As long as manufacturers receive different degrees of regulatory flexibility in different regions of the world, the full benefits of achieving manufacturing flexibility will be beyond their reach.”

This blog post is part of the February 2012 cover story of Pharmaceutical Technology on ICH Q11

But what’s good for Ranbaxy has been causing some discomfort for FDA. Whistleblowers from FDA’s Center for Devices and Radiological Health have sued the agency over allegedly being harassed and dismissed after publicly questioning the agency’s approval methods for devices. The suit brought by the whistleblowers alleges, among other things, that FDA improperly read private emails to support a case for dismissing the plaintiffs. This prompted a letter to FDA commissioner Margaret A. Hamburg from Senator Charles Grassley, in which he castigates the agency for perceived mistreatment of the whistleblowers, and includes a series of questions for the agency to answer to clarify their actions with respect to email monitoring.

Among the questions to the agency, Grassley asks “What steps have you taken to reassure employees that they have a right to direct communications with Congress?” The answer to that question is an important one. FDA should expect no less from itself with respect to whistleblower protection than it demands of others.

Today, the FDA approved Kalydeco (ivacaftor) to treat a specific subgroup of patients with cystic fibrosis (CF). Cystic fibrosis is an inherited genetic disease that affects a person’s lungs and other organs and may lead to an early death. What makes the availability of Kalydeco even more unique is that the drug’s developer, Vertex Pharmaceuticals, teamed up with the Cystic Fibrosis Foundation to develop and study the drug.

This success story began in 1989 when a team of researchers, including Francis Collins, now the director of the National Institutes of Health, discovered the gene that is involved in cystic fibrosis. This gene, known as CFTR, plays an important role in producing a protein that regulates the flow of salt and water out of the cells that line the cavities of the body. There are a number of different mutations that can cause the CFTR gene to produce a defective protein. This results in lung congestion and digestive problems.

Kalydeco targets a gene mutation that only occurs in about 4 percent of CF patients. Before using this medicine, doctors will test CF patients to determine whether they have this mutation (many CF patients have already been tested to understand what caused their CF). If the patient is a match, the drug may provide substantial benefits including improved lung function and weight gain.

Patients have played an important role in how new drugs are developed and studied since the HIV/AIDS activists in the 1980s and 1990s. But what the Cystic Fibrosis Foundation pioneered is a new form of patient power that some have called venture philanthropy. The Foundation helped with a portion of the drug’s development costs, provided researchers with useful insights about the CF patient population and helped in the recruitment of study participants – contributions that were critical to quickly bringing the innovative new therapy to patients.

The unique and mutually beneficial partnership that led to the approval of this new therapy for some CF patients serves as a great model for future drug development and patient group collaboration moving forward.

Here’s to innovation and continued cooperation and progress for patients!

This blog was originally published on the FDA blog, FDAVoice

Roche, perhaps, more than any other pharmaceutical company, is banking heavily on the combination of diagnostics and drug development to drive pharmaceutical innovation. In reporting its 2010 results in February 2011, Roche reported that it had 12 new molecular entities in late-stage development, of which six were potential personalized healthcare medicines with planned companion diagnostic tests, which included Zelboraf (vemurafenib) and its companion diagnostic for BRAF mutation-positive metastatic melanoma. FDA approved Zelboraf for treating BRAF V600E mutation-positive, inoperable, or metastatic melanoma and the cobas 4800 BRAF V600 Mutation Test, a diagnostic test developed by Roche, in August 2011.

Earlier this month, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended that Zelboraf be granted full marketing authorization as a monotherapy for treating adult patients with BRAF V600 mutation-positive unresectable or metastatic melanom. The corresponding European Commission decision on the marketing authorization of Zelboraf is expected in February 2012. Marketing authorization submissions for Zelboraf also are under review by health authorities in Australia, New Zealand, Brazil, India, Mexico, Canada, and other countries worldwide.

Roche also is using its diagnostic strategy to support new indications for existing drugs. Last month, Roche reported that the cobas EGFR Mutation Test was CE-marked, an indicator of a product’s conformity with EU requirements, and is now commercially availabile in Europe and other countries that recognize the CE mark. The cobas EGFR Mutation Test is a companion diagnostic to identify patients with non-small-cell lung cancer (NSCLC) who harbor mutations in the EGFR (epidermal growth factor receptor) gene and who may benefit from treatment with anti-EGFR tyrosine kinase inhibitors, such as Roche’ Tarceva (erlotinib). Tarceva, an oral EGFR inhibitor, was first approved in September 2004 to treat locally advanced or metastatic NSCLC after failure of at least one other chemotherapy treatment. It later was approved by the European Commission in September 2011 as a first-line monotherapy in people with locally advanced or metastatic NSCLC with EGFR-activating mutations.

Other companies also are reporting success with certain personalized medicines. In August 2011, FDA approved Pfizer’s Xalkori (crizotinib) for treating locally advanced or metastatic NSCLC that expresses the abnormal anaplastic lymphoma kinase (ALK) as detected by an FDA-approved test. The agency approved the drug along with a diagnostic test for the ALK gene abnormality, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit. Up to 7% of those patients with NSCLC, typically patients without a history of smoking, have the gene abnormality.

Although personalized medicines will likely hold only a small part of the overall pharmaceutical market by value and volume in the near term, these successes portend of a changing paradigm in drug development.

In April 2011, the EMA’s Committee for Medicinal Products for Human Use recommended a label update for Biogen and Elan’s multiple sclerosis drug Tysabri (natalizumab). Late in January 2012, the FDA also approved the label change in the US.

Although touted as an effective treatment, Tysabri has also been associated with the risk of developing a serious and, often fatal, brain infection called progressive multifocal leukoencephalopathy (PML). The new label identifies that a certain antibody status (presence of anti-JCV antibodies) is a risk factor for developing PML. A test to detect these antibodies can identify at-risk patients, which is a development that marks a step towards personalised medicine — matching the right treatments with the right patients to maximize therapeutic effect.

In their press statement, Biogen and Elan added that Quest Diagnostics will be producing the STRATIFY JCV Antibody ELISA testing service in the US, which is the first blood test authorised by the FDA for the qualitative detection of JCV antibodies. When used with other clinical data from the patient, the test can help healthcare providers determine the risk for developing PML. Such testing has already been used in Europe since the label was updated last year.

Biogen and Elan have also identified two other PML risk factors: over two years of treatment with Tysabri, and previous treatment with medicines known to weaken the immune system.

Tysabri has had a rickety life. It was voluntarily withdrawn from the US market in 2005 because of concerns over PML, but relaunched in 2006 with a black box warning and a strict monitoring plan. In Europe, Tysabri was approved in 2006 but has been under close scrutiny by the EMA. The EMA has also kept a tight watch and finalised a review of the medicine in January 2010, concluding that the benefits of the medicine outweigh the risks.

As well as improving the safety of patients, the new label could also help to boost Tysabri sales. According to an article by Bloomberg, financial analysts have forecast that Tysabri could see its global sales grow to as much as $3 billion by 2016. Without the label change, the drug may only have seen sales of $1.5 to 2 billion.

The JCV diagnostic test is a good example of how pharma companies can improve their medicines. All drugs, unfortunately, have side effects but a lot can be gained by understanding how those effects occur—and in which patients. Biogen and Elan are not the only companies making efforts to personalise their medicines. As was well publicised last year, Sanofi’s Avastin had its breast cancer indication removed in the US. However, Sanofi is looking hard at the drug in order to evaluate a potential biomarker that could help identify which people might derive more substantial benefit from the drug. Interestingly, Avastin was in the headlines yesterday with Bloomberg running a news piece about how Avastin studies have pointed to potential benefits when used in early-stage breast cancer.

No doubt there is more to come in the world of biomarkers, diagnostics and personalized treatments.

In a rare response to those findings, the Department of Health and Human Services, acting on advice from The National Science Advisory Board for Biosecurity (NSABB) asked the authors of the papers and the editors of the journals to publish the papers in redacted form, where the conclusions would be published, but the methodology would not be made public. HHS also asked that language be added to the publications outlining the goals and potential health benefits of the research and detailing the safety measures taken to protect the laboratory workers and the public. In a press release issued by the National Institutes of Health, the agency said “Recognizing the significant potential benefit of the information about the experimental details to the global influenza surveillance and research communities, the US government is working to establish a mechanism to allow secure access to the information to those with a legitimate need in order to achieve important public health goals. The US government is also developing a proposed oversight policy that would augment existing approaches to evaluating research that has the potential to be misused for harmful purposes.”

The authors agreed to the government’s request, and went a step further. In open letters published in Science and Nature, the authors of the papers jointly called for a 60-day moratorium on the creation of new H5N1 strains, to allow time for public discourse on the merits of the research as well as its risk. In the letter, the authors state: “We recognize that we and the rest of the scientific community need to clearly explain the benefits of this important research and the measures taken to minimize its possible risks. We propose to do so in an international forum in which the scientific community comes together to discuss and debate these issues. We realize that organizations and governments around the world need time to find the best solutions for opportunities and challenges that stem from the work.”

Scientists are divided on whether redaction of the data is really in the public interest. Nonetheless, the willingness to pause for an open discussion about the risks versus benefits of this type of research will go some way towards balancing public safety with public health goals.

The President noted that the economy had been weakened in part by outsourcing, and he used the terms manufacture, manufacturing, and manufacturers no less than 18 times in his speech.

But just how will this alleged opportunity to “bring manufacturing back” affect the pharma industry? Outsourcing is a huge part of the industry.

The global contract manufacturing market for pharma has been estimated at around $40 billion. Contract manufacturing of bulk and dosage form drugs alone may reach $86 billion worldwide by 2016, according to MarketResearch. Emerging nations such as India and China are largely reaping the benefits of this spend.

PharmTech’s most recent annual outsourcing survey, done in conjunction with PharmSource, showed that bio/pharmaceutical companies who are actively outsourcing to these two nations rose to 32% between 2010 and 2011. Those percentages are expected to keep rising.

We want to hear your thoughts on this issue. Is it feasible and/or desirable for pharma manufacturers based in the US to bring manufacturing back? Why or why not?

Addendum: Several industry reps  have commented on this topic via Pharm Tech’s LinkedIn Group. Check it out at LinkedIn.com and search for the Pharm Tech group.

They’ve also overlooked a lot of the positive aspects of the project. Deen will be offering diabetes-friendly recipes that do not comprise taste and appearing at diabetes cooking events across the US. The initiative is called Diabetes in a New Light.

But if you’re familiar with Deen’s cooking, you’ll be aware that a lot of her dishes are not exactly promotional of a healthy diet (examples include bacon cheeseburger meatloaf and southern fried chicken – you can take a look at the recipes on her website), which is where media criticism has been directed. Deen herself was also diagnosed with Type II diabetes three years ago, but only revealed this to the public this week, another aspect that has attracted criticism since she’s maintained her cooking style, despite the fact that diet is an important part of managing diabetes.

However, Deen makes a good point of saying in a press statement that “diabetes does not have to stop you from enjoying the things you love”.

At a time when obesity is rising, it’s important for us to be aware of healthy food, and chefs need to take some responsibility. Let’s be honest though, most of us don’t want to be healthy all the time, so we want to know how to make the best of our butter!

In their criticism, a lot of news sources have overlooked the contributions Deen is making to the diabetes battle. She claims to have made small dietary changes and to have worked more exercise into her day. Being a celebrity spokesperson for diabetes will also be a good influence – some sources have made snide comments about the connection between Deen’s weight, her recipes and diabetes, which will no doubt influence some people into avoiding unhealthy foods.

And with all the attention being focused on the responsibility of celebrities and chefs to promote healthy eating, Novo Nordisk and the pharmaceutical industry has gotten a bit lost. The pharma industry also has a responsibility to promote good health; indeed, this focus is becoming increasingly important in pharmaceutical business strategies as non-traditional companies, such as food and IT companies, muscle into the healthcare sector. Ernst and Young has a really good report about this trend available on their website.

Even though the diabetes campaign is partly to promote Novo Nordisk’s diabetes drug, Victoza, it’s also a step towards health education. According to one news report, many diabetes patients have trouble managing their diet. Havilah Clarke, senior manager, product communications at Novo Nordisk is quoted in the report as saying, “Based on what were hearing from some primary research we were doing, people living with diabetes thought that food was one of the most difficult challenges to address in their social lives. They thought they had to deprive themselves.”

Whatever Novo Nordisk’s intentions, it remains to be seen whether using Paula Deen will be a successful strategy given the amount of criticism the partnership has received. But there’s no such thing as bad publicity, right?