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FDA Gets an Extra $10 Million for China

Monday, April 30th, 2012

Mark Crawford

At the end of April the U.S. Senate approved a fiscal 2013 spending bill that provides $2.5 billion for the FDA, including $10 million to fund an expansion of the agency’s Chinaoffice.

The Transforming Food Safety and Protecting Patients Initiatives within the bill provide $10 million in new resources for the FDA to improve collaboration with Chinese inspectors and increase the FDA’s presence in and expertise onChina.

This is in response to increasing pressure to adequately inspect the rapidly increasing trade coming fromChina. From October 1, 2006 to September 30, 2011—the Fiscal Years (FYs) 2007-2011—the total number of shipments of FDA-regulated products from China increased approximately from 1.3 million to 2.1 million. Of the 2.1 million entry lines arriving in FY 2011, 30 percent were drugs and devices and 12 percent were human food products—all in need of adequate review and inspection.

The $10 million ($4.4 million for food inspection and $5.6 million for inspection of drug plants) is intended to:

Strengthen FDA inspection and analytical capabilities by increasing its presence inChinaby sixteen inspectors and by adding three U.S.-basedChinaanalysts.
Broaden the range of its inspections. In addition to inspecting Chinese facilities that manufacture food and medical products for export to the United States, the FDA will inspect sites of clinical trials and conduct follow-up inspections to ensure that firms continue to produce and manufacture food and medical products under safe conditions, and that they apply sound production practices.
Provide unique opportunities for engagement with Chinese regulatory counterparts. Direct observation of FDA inspections can bolster Chinese regulators’ understanding of FDA requirements and processes and strengthenChina’s inspectional capacity.
Support Chinese regulators’ knowledge ofU.S.safety standards through workshops and seminars. These opportunities help facilitate dialogue and encourage scientific exchange on the critical role of inspections in improving the safety and quality of food and medical products.

Considering the volume of incoming trade from China, an extra $10 million won’t go very far; the best bang for these bucks will come from improving relationships with Chinese regulators to streamline communication, understanding, collaboration, and their buy-in to our needs—which means our 16 inspectors heading for China must be highly skilled relationship-building ambassadors as well as thorough inspectors.

Nanotechnology and the FDA

Monday, April 23rd, 2012

Mark Crawford

In June 2011 the FDA issued draft guidance for industry entitled “Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology.” Building on the recommendations within that document, the agency released two new nanotechnology-related guidances in April:

The overall tone is cautionary, rather than restrictive. The FDA is using these documents to re-emphasize how nanotechnology can inherently change the behavior of materials, which can potentially affect the safety, usage, and regulatory status of products made from these materials.

For foods the FDA warns that nanotechnology can:

Affect the identity of the food substance
Affect the safety of the food substance
Affect the regulatory status of the use of the food substance
Require a regulatory submission to FDA

“Altering the manufacturing process of a notified food contact substance to either produce components in the nanometer scale or increase the proportion of nanometer-scale components,” continues the FDA, “can sometimes be a significant manufacturing change that could result in a substantive change to the specifications and/or in the identity of the food contact substance or its impurities, and/or levels of impurities.” The FDA also points out that a food substance manufactured for the purpose of creating very small particle sizes with new functional properties likely would not be covered by an existing GRAS (generally recognized as safe) determination.

For cosmetics, the FDA warns that:

Cosmetics are not subject to premarket approval; however, they must be safe for consumers under labeled or customary conditions use and be properly labeled
Cosmetics manufactured using nanomaterials are subject to the same legal requirements as any other cosmetics
In general, the processes currently in use for assessing safety are appropriate for cosmetics containing nanomaterials; however, standard safety tests may need to be modified or new methods developed to evaluate new or unusual properties or functions exhibited by nanomaterials

The FDA recommends that the safety assessment for cosmetic products using nanomaterials should address a number of important factors, including:

Physio-chemical characteristics
Agglomeration and size distribution of nanomaterials at the toxicity testing conditions that should correspond to those of a final product
Impurities
Potential product exposure levels and the potential for agglomeration of nanoparticles in the final product
Dosimetry for in vitro and in vivo toxicology studies
In vitro and in vivo toxicological data on ingredients and their impurities, dermal penetration, irritation (skin and eye) and sensitization studies, and mutagenicity/ genotoxicity studies
Clinical studies to test the ingredient, or finished product, in human volunteers under controlled conditions

“Industry remains responsible for ensuring that its products meet all applicable legal requirements, including standards for safety—regardless of the emerging nature of a technology involved in the manufacturing a product,” writes the FDA. “We encourage industry to consult early with the agency to address any questions related to the safety, effectiveness, or other attributes of products that contain nanomaterials, or about the regulatory status of such products.”

It never hurts to be reminded of the obvious, which unfortunately can be overlooked or forgotten in the rush to market, or through incomplete science or testing.

It would be prudent for manufacturers who use nanotechnology to review these guidances to see the latest in FDA thinking. The FDA is also investing in an FDA-wide nanotechnology regulatory science program to further enhance its scientific capabilities, including developing necessary data and tools to identify properties of nanomaterials and assess the impact they may have on products—so expect more guidance (and more informed scrutiny and assessment) from the FDA in the future.

Analysis of a Warning Letter

Wednesday, March 28th, 2012

Mark Crawford

What a difference some wording makes!

On March 6, the U.S. Food and Drug Administration issued a warning letter to Breathable Foods Inc. for false or misleading statements regarding its product AeroShot. It was told this “caffeine inhaler” could pose risk to children and adolescents and in combination with alcohol.

The company states AeroShot provides “breathable energy, anytime, anyplace.” On the website it states the product is intended to be ingested by swallowing. The FDA maintains this labeling is false or misleading because these two claims contradict each other. This could also have major implications as to whether the product is categorized as a dietary supplement or a drug.

FDA is concerned that by calling it “breathable energy” consumers may try to inhale AeroShot directly into their lungs. “Caffeine is not normally inhaled into the lungs and the safety of doing so has not been well studied,” states the FDA. Breathable Foods maintains the particles in AeroShot are too big to enter the lungs, yet does not provide research to support this claim.

The website indicates that AeroShot is “not recommended for those under 18 years of age,” yet the product label states that it is “not intended for people under 12.” This suggests to the FDA “that the product is suitable for children 12 and over. Please provide us with any safety evidence you have relied upon related to the use of your product by children and adolescents so that we can evaluate that evidence.”

Because it is sold as a dietary supplement AeroShot did not require FDA review and approval. However, New York’s U.S. Sen. Charles Schumer met with FDA Commissioner Dr. Margaret Hamburg, who agreed to review the safety and legality of AeroShot.

“I am worried how a product like this impacts kids and teens, who are particularly vulnerable to overusing a product that allows one to take hit after hit after hit, in rapid succession,” Schumer says.

So is AeroShot a supplement or a drug?

According to Neal Fortin, Professor and Director of the Michigan State University Institute for Food Laws and Regulations, who also writes the Food Law Blog (www.foodlawblog.foodlaw.org), states that by definition, according to the FDA, “dietary supplements must be intended for ingestion” and that “a product intended for inhalation is not a dietary supplement.”

“Surprisingly,” says Fortin, “the FDA did not state the consequence of failing to be a dietary supplement—as far as it is intended for caffeine inhalation, Aeroshot would be a drug and medical device.”

Therefore it would seem the actual size of the molecules of the ingredients in AeroShot is critical to this determination. If the particles are small enough to be inhaled through the lungs, then conflicting information exists about safety and usage that could result in the product being ruled as a drug.

Ultimately the take-away message is to be absolutely certain that, in the rush to get to market, your marketing labels and usage labels tell exactly same story and have all the information required by the FDA; why risk everything you have gained by sloppy marketing so late in the game?

Mobile Is the Name of the Game (But Can the FDA Keep Up?)

Monday, March 26th, 2012

Mark Crawford

According to the PricewaterhouseCoopers and the mobile operator industry association GSMA report Touching Lives through Mobile Health: Assessment of the Global Market Opportunity, global mobile health revenues could reach US$23 billion by 2017, driven by rapid growth in Europe and Asia. Monitoring services, such as those for chronic disease management, will account for 65 percent of the market, followed by diagnostic services.

Increased use of smartphones and other wireless devices, as well as the proliferation of mobile broadband networks and services worldwide, makes the mobile industry a major player in the future of health care. High-demand applications include interoperability with other systems like electronic medical records and laboratory information systems and real-time monitoring of patient conditions and vital signs.

“By 2017, mobile technology will be a key enabler of health-care delivery reaching every corner of the globe,” says Jeanine Vos, executive director of m-health at GSMA. “With developed countries needing to reduce the cost of universal health care, and developing countries looking to roll out life-saving services to in-need communities, mobile technology can deliver highly effective, scalable and affordable health care beyond the confines of a hospital or doctor’s surgery.”

In terms of market opportunity, GSMA indicates the provision of pervasive m-health services and applications worldwide could provide mobile operators with revenues worth approximately $11.5 billion by 2017. Device vendors could benefit from a revenue opportunity of $6.6 billion, content and application providers $2.6 billion, and health-care providers $2.4 billion by 2017.

However, to make this happen, warns the GSMA, governments, regulators, health-care providers, and device makers must collaborate to support the roll-out and adoption of new m-health services—a task much easier said than done.

“There’s no doubt that collaboration is critical,” says Eleanor Chye, executive director of mobility health care and pharma for AT&T Business Solutions. “Leading carriers, device manufacturers, health plans, and providers all need to come together to help transform m-health from a niche play into wide-scale implementation as a standard of care.”

In the murky regulatory realm, regulators need to proactively address the top issues that currently limit the growth of m-health services, such as certification, interoperability, and standardization. The FDA once again finds itself in the middle, wanting to proceed with care but also feeling the pressure to keep up with the quickly evolving wireless medical market and the benefits it can provide, including lowering the overall cost of health care.

Organizations like the American Medical Informatics Association (AMIA) have suggested holding clinical decision support (CDS) information delivery channels and mechanisms, devices, and applications intended primarily for use by clinicians and other providers to a different regulatory standard compared to those intended for patients, consumers, and their caregivers. The AMIA also questioned the singling out of “stand-alone” CDS delivered via “mobile medical devices” as being suitable for FDA oversight, more than other kinds of clinical software environments, such as desktop computers.

Other key issues raised by the AMIA include:

The need for the FDA to articulate how it characterizes and defines CDS
The need to coordinate efforts among federal agencies and public- and private-sector research and practice communities
The potential limitations if FDA focuses too narrowly on CDS, and considers CDS on mobile devices as somehow separate from CDS based on other delivery methods or contexts
The importance of addressing rapidly emerging and converging technologies and devices along with new and evolving forms of patient care delivery (such as medical homes and accountable care organizations) and payment methods

“The health sector is exploding with an array of clinical information systems for potential use in a broad range of settings,” says AMIA president and CEO Edward H. Shortliffe. “It is important to have regulations that keep pace with clinicians, many of whom are becoming quite expert at using technology to access pertinent information, thereby streamlining health-care delivery and improving overall health.”

Breast Implant Fiasco in France Could Have U.S. Ramifications

Monday, March 12th, 2012

Mark Crawford

On February 9 European Health and Consumer Policy Commissioner John Dalli called for immediate action from the EU to ensure stringent implementation of the current legislation on medical devices. This was in response to the fraudulent use of non-medical grade silicone in breast implants manufactured by the Poly Implant Prothèse (PIP) Company inFrance. The European Commission is now scrambling to tighten controls on the approval of medical devices and restore patient confidence.

Actions proposed by Commissioner Dalli include:

Verify the designations of notified bodies to ensure that they are designated only for the assessment of medical devices and technologies that correspond to their proven expertise and competence
Ensure that all notified bodies in the context of the conformity assessment make full use of their powers, including conducting unannounced inspections
Reinforce market surveillance by national authorities, in particular, spot checks in respect of certain types of devices
Improve the functioning of the vigilance system for medical devices—for example, giving systematic access for notified bodies to reports of adverse events and enhancing coordination in analyzing reported incidents
Support the development of tools ensuring the traceability of medical devices as well as their long-term monitoring in terms of safety and performance, such as Unique Device Identification systems and implant registers

In addition, the European medical device industry trade association Eucomed has suggested using “only the best” notified bodies, developing a single approach to vigilance and market surveillance, and strengthening harmonized standards.

There is no doubt this will have impact to thoseU.S.companies working in European markets.

“Some doctors, regulators, and even the medical devices industry itself say this affair exposes Europe’s weak regulation system, one that allowed PIP to operate for longer than it could have under a more rigorous regime,” says Kate Kelland in the February 3, 2012 issue of Insurance Journal.

In fact, she points out that the FDA rejected PIP’s application to sell its breast implants in 2000, over a decade ago, for failure to investigate deflation problems and not disclosing the many complains the company had already received from women around the world.

Medical devices are regulated under the Conformite Europeenne (CE mark) system inEurope; however, gaining this designation is relatively easy.

“Because Europehas no centralized process for approving medical devices, manufacturers don’t go directly to a national or Europe-wide regulator,” states Kelland. “Instead, they seek a CE mark through any one of 70-80 organizations known as Notified Bodies, which largely are private companies. Scientists who published a review of the system in the European Heart Journal in May 2011 found that the fragmentary setup encourages manufacturers to shop around for countries or Notified Bodies most likely to offer hassle-free certification.”

A 2010StanfordUniversitysurvey of medical device manufacturers showed that high-risk devices took an average of 54 months to get through the FDA to market, compared to just 11 months inEurope. The European system is often used as an example of a faster system that works better than the FDA’s. Congress is still considering an overhaul of the device review process and wants to make a decision by the fall. But what sort of impact will the PIP scandal have on the decision-making process?

“Medical device makers have spent the last year urging U.S. officials to approve high-risk products faster, like their European counterparts,” says Alex Nussbaum in a recent article on www.bloomberg.com. He adds that experts like Carl Heneghan, an Oxford University professor, believe the PIP problem, along with other EU device failures, should give lawmakers pause. “All the industry guys in the U.S. say, ‘we should have access to these products much sooner, like in Europe,’” says Heneghan, who is an expert in device recalls. “The flip side is the European people are being used as guinea pigs.”

Rottenstein Law Group inHewlett,New Yorkhopes the breast implant recall will help convinceU.S.regulators that the FDA’s medical device approval process should not be accelerated. In a press release they cite a similar problem where thousands ofU.S.women have suffered injuries as a result of vaginal mesh implants that, in their opinion, were not properly reviewed.

“Categorized by the FDA as medical devices that the agency can clear for sale based on similarity to medical devices already on the market, and without the benefit of human testing, the implants have so far spawned more than 650 lawsuits filed by patients alleging that they have been significantly injured as a result of having the mesh products implanted,” states the law firm.

New FDA Deal on Medical Device User Fees

Tuesday, February 28th, 2012

Mark Crawford

In early February, the FDA and representatives from the medical device industry (Advanced Medical Technology Association, Medical Device Manufacturers Association, Medical Imaging and Technology Alliance) reached an agreement on recommendations for the third reauthorization of the Medical Device User Fee and Modernization Act.

The deal authorizes the FDA to collect $595 million in user fees, essentially doubling the amount.

In return the FDA has agreed to higher performance goals, including reviewing more applications more quickly, resulting in overall shorter review periods for 510(k) submissions. The FDA will also meet with an applicant midway through the process to ensure the company has enough time to respond to questions and requests. A third-party consulting firm will review the FDA’s procedures and recommend corrective actions if needed. The FDA must also publish regular metrics regarding review times, withdrawal rates, clearances, and other measurements of its medical device pathways. There is also a section of the agreement dubbed “Leave No Submission Behind” which requires the FDA to contact device-makers when their applications fall behind the ideal time frame.

The higher fees allow the FDA to hire over 200 full-time equivalent workers by the end of the five-year program. The $595 million will support about 35 percent of the FDA’s review activities (currently fees cover 20 percent).

According to the Massachusetts Biotechnology Council (MassBio), the FDA has agreed to time frames for pre-market approval applications and 510(k) submissions that will consider total review time in calendar days in addition to “FDA days.”

“‘FDA days’ measure how many working days the agency has spent on a particular application, but do not include periods when the agency has ‘stopped the clock’ by, for example, putting the ball back in the device maker’s court by asking for more information on an application,” says MassBio.

“By having a total-time goal that works in concert with an FDA-day goal we will, for the first time, be measuring—and performance will be tracked on—a total-time basis,” adds Stephen Ubl, president and CEO of AdvaMed. “We think that will have the net effect of reducing total review time, which is the most important measurement you can make.”

The industry wants to see an average total review time of 385 calendar days for PMAs and 124 calendar days for 510(k) applications by the final year of the deal.

“If this is tied to faster, better visibility and more efficiency, it’s worth its weight in gold,” says Thomas Gunderson, a Piper Jaffray & Co. analyst based inMinneapolis.

Even though many MDM leaders have applauded the deal, a few—such as Cook Medical president Kem Hawkins—are withholding praise until results start coming in.

“There is a long history of higher fees without a commensurate improvement in the time it takes to receive an FDA approval for a device that has been proven to save lives or reduce suffering,” he cautions.

The FDA Gets Moving (A Bit) on Biosimilar Guidance

Friday, February 17th, 2012

Mark Crawford

On February 9 the U.S. Food and Drug Administration (FDA) released three draft guidance documents to assist biosimilar product development in theU.S.

The FDA guidance recommends a stepwise approach toward demonstrating biosimilarity that could ease trial requirements if biosimilarity can be demonstrated in earlier steps—such as a comparison between the proposed biosimilar and reference product on structure, function, animal toxicity, human pharmacokinetics and pharmacodynamics, clinical immunogenicity, and clinical safety and effectiveness.

“These draft documents are designed to help industry develop biosimilar versions of currently approved biological products, which can enhance competition and may lead to better patient access and lower cost to consumers,” says Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.

The new guidance was created in response to the Patient Protection and Affordable Care Act, which called for an abbreviated approval pathway under section 351(k) for biosimilars that are interchangeable with FDA-licensed biological products.

Biological products are therapies used to treat diseases and health conditions. They include a wide variety of products including vaccines, blood and blood components, gene therapies, tissues, and proteins. Unlike most prescription drugs made through chemical processes, biological products generally are made from human and/or animal materials.

Biosimilars (also known as follow-on biologics) are biological products that are highly similar to an already approved biological product, for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.

The three guidance documents are:

> “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”—intended to assist companies in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting an application, called a “351(k)” application, to the FDA

> “Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product”—provides an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product for the purpose of submitting a 351(k) application

> “Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009”—provides answers to common questions from people interested in developing biosimilar products

Jumping In

This new approach could speed the development of cheaper versions of top-performing drugs, but it’s too early to tell how many companies want to assume the risks of making biosimilar drugs at this early stage.

“Copying biological molecules is a stickier proposition than making ordinary generic medicines because proteins are typically much larger and more complex than small-molecule drugs,” writes Heidi Ledford on the Nature Blog. “They are also often produced in cell cultures, and even small variations in how the cells are grown can change the properties of the protein produced. As a result of this complexity, it has been unclear just how ‘abbreviated’ an abbreviated approval process for biosimilars could be. Would clinical trials in humans be mandatory? How large would those clinical trials need to be?”

Ledford also indicates the FDA has committed to providing a guidance document that shows what standards need to be met for a biosimilar drug to be considered interchangeable with the original drug. “That designation may allow pharmacists to substitute the biosimilar drug when a doctor has prescribed the original medicine, a move that historically has allowed generics to whittle away more of a branded drug’s market,” she adds.

Will They Save Money?

As Woodcock mentioned, the FDA hopes this accelerated pathway will lead to lower costs for consumers.

So does Novation, a leading supply contracting company for VHA, UHC, and Provista. Novation has been actively monitoring the development process for biosimilars, especially inEurope. Based upon the European market, Novation reports that these “highly similar” versions of reference biologics could result in price decreases of 20% to 30%.

“However, adoption of biosimilars will be a more complex process and will require greater physician involvement in contrast to what traditionally happens with small-molecule generics,” says Steven Lucio, director of pharmacy clinical solutions for Novation.

A possible downside to this streamlined approval process is reduced innovation as companies scramble to get their piece of the biosimilar market.

In an interview with Mass High Tech (www.masshightech.com), Konstantin Linnik, an intellectual property attorney at Nutter McClennen & Fish inBoston, sees potential risk in creating this legislation to save money. “It could drag the whole industry down,” he cautions. “People are focused on me-too drugs instead of innovation, though it does generate competition.”

“While the issuance of these guidances is an important and meaningful first step in FDA’s implementation of the law, the guidances themselves are at a very high level of generality,” adds James N. Czaban, attorney and partner with Wiley Rein LLP inMcLean,Virginia. “Moreover, some of the most interesting and challenging legal and procedural issues under the BPCIA [Biologics Price Competition and Innovation Act], such as exclusivity standards for reference products, interchangeablility standards for biosimilar products, and issues surrounding the patent litigation procedures established by the BPCIA—remain unaddressed by the agency. For the most part, the guidances do not provide any clear road maps for the development and approval of any particular biosimilar product.”

For an excellent overview of the guidances, read Czaban’s “First Biosimilars Guidances Issued by FDA” at: http://www.wileyrein.com/publications.cfm?sp=articles&id=7796.

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Posts Tagged ‘FDA’

FDA Gets an Extra $10 Million for China

Nanotechnology and the FDA

Analysis of a Warning Letter

What a difference some wording makes!

Mobile Is the Name of the Game (But Can the FDA Keep Up?)

Breast Implant Fiasco in France Could Have U.S. Ramifications

New FDA Deal on Medical Device User Fees

The FDA Gets Moving (A Bit) on Biosimilar Guidance

As Woodcock mentioned, the FDA hopes this accelerated pathway will lead to lower costs for consumers.

For an excellent overview of the guidances, read Czaban’s “First Biosimilars Guidances Issued by FDA” at: http://www.wileyrein.com/publications.cfm?sp=articles&id=7796.

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