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.

“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

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

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.

As a doctoral student at Harvard Medical School, Moshe Pritsker asked to recreate a method of culturing embryonic stem cells that had been reported by researchers in the United Kingdom. He tried following the steps in a related article but could not get the experiment to work, so he ended up flying to the UK to spend time with the scientists who authored the article to watch how they conducted the experiment. With a first-hand look, Pritsker was able to replicate the method—but not everyone has the resources to fly around the world to get an in-person perspective on a particular lab’s methods.
Based on that experience, Pritsker, along with Nikita Bernstein and Klaus Korak, founded the Journal of Visualized Experiments (JoVE). The site provides step-by-step video demonstrations of experimental techniques and procedures. The site was established in 2006 and today, contains many detailed descriptions of advanced research methods through videos. Each video is published together with a peer-reviewed article to explain the video’s scientific quality, applicability, and technical details.

To date, Harvard, MIT, Yale, Oxford, Cambridge, Max Planck, and others have participated in the online journal. About 50 video articles are published per month.

Although journal articles and training workshops provide scientists with insight into how others do something, not every step comes across. “Even if they had the time, experimenters would probably not bother to document many of these nuances or tricks because they are a personal habit or established practice at the lab they are working at,” says JoVE about why the site is useful.  And yet, “these details can often mean the difference between success and failure,” JoVE adds.

The industry has been talking about the idea of sharing information for some time. JoVE offers a new way to help share best practices and to help train train those new to the laboratory or new to certain manufacturing methods.

2012 will be a transition year for pharma, one of the most important in the industry’s history of product cycles that spin from plenty to penury. On the positive side, the fires of drug discovery are finally being stoked by a growing understanding of how genomics shape the biology of disease. This is leading to promising new treatments that target critical areas of unmet medical need while also increasing the efficacy of interventions geared to the individual patient. Evidence that these next-generation innovations can advance the science while improving outcomes will hopefully lead to ready acceptance in the market, despite the growing leverage of a much more skeptical and discerning customer base.

The challenge is that many new treatments may not complete the move from ‘bench to bedside’ in time to plug the yawning revenue gap from a second record year of patent expiries. This year’s drop off the patent cliff is the longest and steepest, with a $50 billion loss coming on top of the $30 billion ceded to generics in 2011. Most companies will struggle to play catchup, with margins under intense pressure due to the immediate fallout from genericization of the product base; in the U.S. alone, off-patent penetration has reached 80 percent of all scrip, and IMS forecasts this figure will rise to 86 percent by 2015.

Meanwhile, the fiscal crisis in Europe has voided the entire concept of patenting as a reward for innovation in providing a temporary period of price exclusivity. Therapeutic reference pricing is clustering brands with the cheapest generics, and some countries in the region are now moving toward a straight bulk procurement model for drugs reimbursed through state-sponsored systems. Quality? Innovation? These are yesterday’s questions.

So what is the preferred Big Pharma strategy to manage through this year of transition? Pharm Exec highlights four strategic drivers that should compel the attention of our “C-suite” readers in 2012.

1) A reinvented business model won’t change what is fundamental: Higher pipeline productivity in the form of new patented products is still the best source of future profits.
This year will see new therapeutic breakthroughs that may revitalize the blockbuster, to include biologic drugs intended for targeted patient populations with few treatment alternatives. Many are novel not only for their indications and superior efficacy and safety profiles; they also mark an advance in the mode of delivery, replacing injectables with a once-a-day pill or acting in combination with other compounds to provide more precise dosing with fewer side effects.

Overall, the trend illustrates the impact of company efforts to integrate within their R&D organizations a more overt commercial benchmark in addition to science and regulatory indicators. If trial and regulatory milestones are an ingrained part of the development timeline, why not add criteria for achieving access or reimbursement as well? Few companies today are inclined to say no.

Growing optimism about a return to innovation doesn’t mean that the debate over the best blueprint  for R&D will be resolved—at least not in 2012. It takes on average a decade to commercialize a promising compound from proof of concept, so much of the current discussion around alternative approaches—from outsourcing key aspects of development to the “string of pearls” focus on science generated in-house—amounts to sheer background noise. Consultants can’t charge for this, and the evidence is purely anecdotal, but what does seem to matter is a long-term commitment to the science; retaining good people; acknowledging that internal competition can boost overall productivity and performance against agreed targets; a knack for finding and keeping a diverse circle of partners; and a healthy helping of luck. Analysts call it the “hybrid” model and companies will continue to tailor R&D strategies to fit their own circumstances.

2) 2012 will signal the industry is transitioning to an era of lowered expectations; pricing, reimbursement, value, and policy will combine in complex ways to drive down margins.
The bottom line is that it is becoming harder to make the contacts that drive sales with providers and the patient. Consolidation in the payer community gives them greater leverage in controlling the use of medicines, generic penetration limits the scope of argument about competitive differentiation, and increased government regulation has ended many of the promotions that helped build relationships with physicians. More therapeutic “crowding” in the specialty segment is another trend that will depress margins because payers now have a choice and can restrict access or demand rebates and discounts, as they have done with devastating effect in primary care.

Moreover, to cope with these developments, brand manufacturers are spending heavily on incentive programs like copay cards as well as patient support activities geared to raising adherence to therapy. Much of this activity is geared toward influencing the commercial business, and the added cost exposures will sharply depress margins there just as higher rebates mandated by health reform turn the public Medicaid and Medicare Part D programs into loss makers.

As a result, 2012 will see more effort to change the incentive package for sales reps, on the premise that “not all prescriptions are considered equal.” Pay incentives will motivate reps to win more non-controlled, third-tier reimbursed prescriptions rather than just focusing on the volume of scrip. This in turn will provide the rationale for more culling of the ranks—selective deployment of this human resource is key.

3) Advances in information technology will continue to shape the conversation with customers on access, value, and price.
That conversation is going to take place in public, as evidenced by the growth of cloud computing, which “hyper-democratizes” access to the vast resources of the Web—it’s the everyman’s Google. But Big Pharma is a business, with proprietary interests, so a key priority that will play out through 2012 is marking progress in defining basic standards on the application of IT. The goal is to ensure those business interests are protected while adding benefits through agreed channels for data sharing—the new Pistoia Alliance of companies engaged in precompetitive research is a good example—as well as improved IT management processes that raise efficiencies and lower costs.

Government regulators can help speed this trend—or delay it. The problem is that key agencies like the FDA are way behind industry in adapting to the IT revolution. Internal reforms are vital, because done right IT can help advance the portfolio through faster lead times and building that better case for competitive differentiation.

4) Preserve those reputational assets. 
Maintaining a “license to operate” is becoming more important as the reach of governments extend from regulatory oversight to direct involvement in the business—as a payer and customer. The gap between strict legal prohibition and the more murky terrain of ethical lapses is narrowing; overall, the “zone of vulnerability” is expanding and is now global in scope. 2012 will see major new efforts by U.S. and European regulators to apply anti-bribery statutes to companies’ overseas promotional activity, including inducements by CROs and other third parties to influence the conduct of foreign clinical trials. Active management of the drug shortage problem is another imperative; it is not enough to blame the problem on FDA or on quality issues linked to generics.

Yes, doing surveys is a pain.  So there’d better be a darn good reason.  Here’s a survey with 7 good reasons that I consider worth the effort.  The industry and participants benefit from the 9th Annual Report and Survey of Biopharmaceutical Manufacturing, and here’s why.
1)    The study questions are relevant and based on real-world experience. They are developed by a nonprofit global panel of industry experts—The Biotechnology Industry Council, which is a group of 270 biomanufacturers and key vendors that provide subject matter expertise, and submit, each year, a set of the most urgent questions and issues on strategic areas projected to become problematic in the coming year(s).
2)    Few comprehensive, quantitative analyses of this industry exist—The Annual Report includes responses from between 350 and 450 biomanufacturers annually. An additional 180-200 vendors also participate each year.  That’s a lot of detailed global production data!
3)    Trends over time present a compelling story—Measuring biopharma trends over years delivers far more than a simple snapshot of the industry’s current situation.  Measuring changes over time, and correlating those changes with real-world trends and experiences provides a compelling picture of the industry’s strengths, weaknesses, and future direction.
4)    Participants get trend data first, and for free—the study provides hundreds of respondents with free, extensive summaries of the current data, and aggregated responses from participants in over 30 countries.  Information is aggregated; no respondent information is provided. So data are more accurate, and valid.  (If more detailed information is needed, the annual reports are also available for sale).
5)    Participants see the most urgent issues—by reading the study questions, you’ll understand what is most important to industry thought-leaders.
6)    Contributing to industry benchmarking—perhaps most important, by participating in this study, you’re contributing to accurate benchmarking of the current issues affecting the industry today:
a.    Budget trends
b.    New technologies developed by suppliers
c.    New technologies demanded by end-users
d.    Hiring trends
e.    Outsourcing and offshoring effects on current jobs
f.    Productivity, and the impact of layoffs
g.    Impact of biosimilars on industry capacity
h.    Capacity bottlenecks associated with downstream production
i.    Implementation of quality management processes
j.    New technology adoption rates
7)    Contributing to global health—Participants not only receive a summary of the study, but also a $10 donation on their behalf goes to global health charities—up to $10,000.

With all these personal and societal benefits, few qualified biomanufacturers have reasons not to participate. So take the survey today.

Specifically, Hamburg noted that the drug’s benefits for breast cancer patients do not outweigh the drug’s risks to these patients, which can include heart attack, bleeding, and other significant side effects. Studies did not show reduction in tumor size or lengthening of life for breast cancer patients taking the drug. Avastin was approved through FDA’s accelerated pathway in 2008 for this indication. Avastin will continue to hold approval for treating colon, lung, kidney and brain cancer. FDA is not in the practice of medicine, said Hamburg, and recommended that breast cancer patients taking the drug speak with their doctors about potential risks and treatment plans.

Avastin’s breast cancer indication has been in question since June 2011 when an FDA advisory panel recommended removing the approval. Genentech disagreed with the panel, said Hamburg during today’s briefing, and it was ultimately her decision to officially revoke the approval today. Hamburg recommended that the drug sponsor conduct additional studies on the breast cancer indication.

ICH Q6B, approved in 1999 by the three ICH regions, outlines specifications, test procedures, and acceptance criteria for biotech products. Q6B specifically calls for structural characterization and confirmation of the amino acid sequence and composition, terminal amino acid sequences, peptide map, sulfhydryl group and disulfide bridges, and the carbohydrate structure. With the more recent passage of the ICH quality guidelines, Q8, Q9, Q10 and the pending Q11, industry has even more information (as well as more expectation) on how to conduct a risk- and quality-based analysis of these products to ensure their safety.

A series of presentations on how to conduct biopharmaceutical characterization in detail was given yesterday in Valley Forge, Pennsylvania, by SGS Life Science Services and its recently acquired M-Scan Group, which focuses on mass spectrometry and gas chromatography for chemical analysis of both small and large molecule products.

Also discussed were biosimilars, which while making headway in Europe (14 have been approved since 2006), are still awaiting an implementation plan for approval in the US. Once that plan is in place—FDA continues to promise that it will be soon—bioequivalence, interchangeability, and comparability tests will become more commonplace. In the meantime, fully understanding and characterizing one’s product—down to the tiniest and most random chromatographic peak—remains a crucial part of the process and an expectation that is here to stay.