Mass Tort Defense : Mass Tort Defense Lawyer & Attorney : Sean P. Wajert : Dechert Law Firm : Products Liability, Class Actions, Pharmaceutical Litigation

Last week, the Consumer Healthcare Products Association (CHPA) submitted comments on the FDA’s draft guidance on nanotechnology, "Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology, "  which we posted on before.

CHPA is the not-for-profit association representing the makers of over-the-counter medicines and dietary supplements, and the consumers who rely on these healthcare products. CHPA is one of the oldest trade associations in the United States. Nanotechnology holds great promise for this industry.

CHPA agreed with the FDA that proposing a "definition" for nanotechnology is not a straight forward process; applying a strict, universal definition of nanotechnology to the fields of drug research, drug product development and drug manufacturing would not be, in CHPA's view, an appropriate science-based approach.

Defining a nanomaterial as a structure between 1 and 100 nm, and using this definition to establish new regulations on products containing nano-sized materials, would, they asserted,  erroneously group drug products together to form a new category based on size of ingredients.  Nanotechnology is not a separate drug category, but a technology used to, among other things, generate nanometer-sized ingredients and excipients. Inclusion of nanometer-sized active ingredients or excipients in a drug product does not by itself determine a product's safety and efficacy (i.e. size alone is not itself an indicator of toxicity). 

CHPA agreed that the agency should distinguish between engineered nanomaterials and those
naturally occurring at the nanoscale.  There exist common pharmaceutical ingredients with a long history of use that should not be considered as "engineered nanomaterials" or as agglomerates of nanomaterials but which may have particles whose size naturally falls within this range.

CHPA also noted that NIOSH accurately refers to nanotechnology as the manipulation of matter on a near-atomic scale to produce new structures, materials, and devices.  Nanomaterials are mainly engineered for their novel chemical, physical, and quantum mechanical properties; at the nanometer size, many materials exhibit such unique beneficial properties that may not exist when at the micron size. CHPA argued it is appropriate to include in the description the notion of particles that are deliberately manipulated and controlled at the nanoscale, which also exhibit changes in physical, chemical, or electromagnetic properties, the existence of unique phenomena to enable novel applications.

For example, milling, a beneficial process for the manufacturing of many individual pharmaceutical ingredients, may create particles with a portion of the particle size distribution under 1 micron; however, the chemical properties of the milled ingredient usually do not differ drastically from that of the bulk ingredient.

The agency should give further consideration, said CHPA,  to the possibility that not all materials should be considered equal; each material must be evaluated on a case-by-case basis. For example, soluble nanomaterials might not be treated the same as insoluble ones.  

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The U.S. Food and Drug Administration last week released draft guidance designed to move the process forward of providing its regulated industries with greater certainty about the use of nanotechnology (which generally involves materials made up of particles that are one billionth of a meter in size). The guidance outlines the agency’s current view on certain issues about regulated products that contain nanomaterials or involve the application of nanotechnology.

FDA has not to date established regulatory definitions of “nanotechnology,” “nanoscale” or related terms. The term is perhaps most commonly used to refer to the engineering (i.e., deliberate manipulation, manufacture or selection) of materials that have at least one dimension in the size range of approximately 1 to 100 nanometers. For example, theNational Nanotechnology Initiative Program defines nanotechnology as the understanding and control of matter at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications. Other factors such as function, shape, charge, the ratio of surface area to volume, or other physical or chemical properties have also been mentioned in various published definitions.

Our readers know that nanotechnology, the science involving manipulation of materials on an atomic or molecular scale, is an emerging technology with a broad range of potential applications, such as increasing bio-availability of a drug, improving food packaging, and in cosmetics.

The draft guidance document, “Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology,” represents a first step toward providing some regulatory clarity on the FDA’s approach to nanotechnology. Specifically, the agency named certain characteristics – such as the size of nanomaterials used and the exhibited properties of those materials – that may be considered when attempting to identify applications of nanotechnology in regulated products.

For products subject to premarket review, the FDA intends to apply the points contained in the draft guidance, when finalized, to better understand the properties and behavior of engineered nanomaterials. For products not subject to premarket review, the FDA will urge manufacturers to consult with the agency early in the product development process so questions related to the regulatory status, safety, effectiveness, or public health impact of these products can be adequately addressed.

In 2006, the FDA formed the Nanotechnology Task Force, charged with identifying and addressing ways to better enable the agency to evaluate possible adverse health effects from FDA-regulated nanotechnology products.  The agency issued a report by the task force in 2007 that recommended that the FDA issue additional guidance and take steps to address the potential risks and benefits of drugs, medical devices and other FDA-regulated products using nanotechnology.

 

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Readers of MassTortDefense know how the conduct and results of clinical trials can reach out and affect later product liability litigation: plaintiffs frequently assert that drug makers missed or ignored safety signals present in those trials. 

In reality, developing new therapies to treat disease and to improve quality of life is a long and complex process. And a critical part of that process is clinical research -- without clinical research studies, no new medicines could be made available to patients.

Last week PhRMA issued revised Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results with a goal of helping assure that the clinical research conducted by pharmaceutical research and biotechnology companies continues to be carefully conducted and that meaningful medical research results are communicated to healthcare professionals and patients.

Among the key changes in the updated Principles: Increased transparency about clinical trials for patients and healthcare professionals; enhanced standards for medical research authorship; and improved disclosure to better manage potential conflicts of interest in medical research.

PhRMA members have indeed had a longstanding commitment to sponsoring clinical research that fully complies with all legal and regulatory requirements. And actually, many different entities and individuals contribute to the safe and appropriate conduct of clinical research, including not only sponsoring companies but also regulatory agencies; investigative site staff and medical professionals who serve as clinical investigators; hospitals and other institutions where research is conducted; and Institutional Review Boards and Ethics Committees.

The key issues addressed are:
• Protecting Research Participants
• Conduct of Clinical Trials
• Ensuring Objectivity in Research
• Providing Information About Clinical Trials

Of particular note to my readers may be the document's call for consistency with standards of the International Committee of Medical Journal Editors as journal guidelines for authorship;  under these, anyone who: (1) provides substantial contributions into the conception or design of a study, or data acquisition, or data analysis and interpretation; and/or (2) writes or revises the manuscript involving important intellectual content; and/or (3) has final approval of the version to be published, should receive appropriate recognition as an author when the manuscript is published. Conversely, individuals who do not contribute in this manner do not warrant authorship. We have posted about this issue before.

As always, the guidelines are purely voluntary, and even member companies are free to adopt their own best practices and mold general guidance to their particular situations.

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Readers of MassTortDefense know how FDA regulatory treatment of advertising and promotion can impact product liability litigation involving drugs and medical devices. Earlier this year, the FDA issued draft Guidance for Industry Presenting Risk Information in Prescription Drug and Medical Device Promotion.  This draft guidance describes factors FDA considers when evaluating advertisements (ads) and promotional labeling for prescription drugs, ads for restricted medical devices, and promotional labeling for all medical devices for their compliance with the Federal Food, Drug, and Cosmetic Act and relevant regulations. The draft guidance discusses factors that are relevant to the disclosure of risk information and provides numerous examples to illustrate FDA’s thinking on these factors. The recommendations contained in this draft guidance apply to promotional materials directed to both consumers and healthcare professionals.

As the comment period has drawn to a close, the medical device trade group AdvaMed has weighed in, arguing that the FDA's draft guidance on presentation of risk information in advertisements fails to adequately distinguish between devices and drugs.  The group asserts that the draft lacks content and specificity for device makers, and that a separate guidance document for medical devices is probably warranted. One example is the discussion in the draft of the important concept of over-warning, which is done solely with drug examples.

The comments also not the inherent differences between drugs as therapy and a device which requires a separate intervention (surgery) to be used. Because devices are often used in conjunction with other devices and drugs, communications with consumers of medical devices may need to focus more on a broader spectrum of risks and benefits of ongoing therapies, with a larger group of health care professionals.

AdvaMed also questions the draft's notion that risk information should be spread throughout a promotional piece, rather than located in one easy spot for the consumer to find.  Overall, the draft appears to focus on risk information without adequately discussing the intersection with benefit information.

The group agrees with a move towards the "reasonable consumer" standard for evaluating promotional pieces, and suggests the same direction be taken with DTC advertisements. Highly trained regulators cannot easily evaluate DTC ads as would an average consumer.   Finally, the group argues the draft should provide more specific guidance on use of the Internet for promotion, and the use of hyperlinks.  Increasingly the Internet is a source of information for medical consumers.

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The FDA recently issued a new draft Guidance for Industry titled “Presenting Risk Information in Prescription Drug and Medical Device Promotion.”  This new guidance document represents a comprehensive and fairly detailed overview of the FDA’s approach to reviewing drug and device advertising, albeit with a somewhat surprising omission regarding Internet-specific guidance.

As readers of MassTortDefense know, promotional pieces: (1) cannot be false or misleading, (2) must reveal material facts, including facts about consequences, and (3) should present information about effectiveness and risk in a balanced manner. The guidance confirms that promotional pieces will be judged based on the “reasonable consumer” standard, essentially adopting the definition used by the Federal Trade Commission. Importantly, the FDA also adopts the FTC position that multiple interpretations of a claim are possible if they are all reasonable, and a violation will be found if any one reasonable interpretation violates regulations.

Finally, while the guidance acknowledges the different levels of expertise of consumers and healthcare professionals and notes that the FDA takes account the intended audience in determining compliance, the guidance specifically highlights the social science research finding that experts are “subject to the same cognitive biases and processing limitations as non-experts.”  As a result, it arguably gives insufficient credit to physicians’ abilities to understand important information and make appropriate prescribing decisions;  the recommendations listed in the guidance seemingly apply equally to promotional materials directed to consumers and healthcare professionals.

The general considerations the FDA will use in assessment include (1) use of language appropriate for the target audience, (2) appropriate use of signals (e.g., headlines, change of announcer), (3) appropriate framing of risk information (e.g., severity, specificity), and (4) hierarchy of risk information (i.e., most important risk information should come first).

More specifically, the FDA considers the quantity, materiality, and comprehensiveness of the risk information contained in the piece. Concerning quantity, the FDA notes that risk information should be comparable to benefit information and should include enough detail to convey an “accurate” impression of the product. Among the relevant factors are (1) the number of statements about benefits and risk, (2) the completeness and depth of detail about benefits and risks, (3) the amount of time or space devoted to benefits and risks, and (4) the use of components that enhance or distract from the presentation of risk or benefit information. In assessing materiality and comprehensiveness, the guidance notes that material risks are those that would influence a reasonable member of the target audience—often the most serious and the most frequently occurring risks.

Despite the guidance’s clear and intentional application to Internet advertisements, it makes no special mention of such advertisements and provides no specific guidance on issues unique to Internet promotion.

The comment period for this draft guidance ends August 25, 2009. Additional information, including information on how to submit comments, can be found here.

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The FDA has finalized guidelines for how manufacturers can distribute information to doctors about unapproved uses for drugs or medical devices. The ‘‘Good Reprint Practices for the
Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices’’ allows for the limited dissemination of medical journal articles describing off-label uses. The FDA proposed the guidelines in February, 2008 and took public comments before finalizing them.
 

Allegations of off-label promotion are common in mass tort litigation involving drugs and medical devices. Off-label promotion is illegal, but many critics of the industry and plaintiff lawyers seem to forget that doctors can prescribe drugs for any use they see as medically appropriate. The FDA in its guidelines confirms that the public health can be served when health-care professionals receive truthful and non-misleading scientific and medical information on unapproved uses. It will likely help practitioners to receive timely and accurate medical information in an environment where off-label use is common. The FDA's guidance will help assure that medical professionals receive timely and accurate medical information prior to the lengthy process of securing FDA approval for wider use. Such off-label use can save lives, especially in practice areas where there are few effective treatments. These off-label uses or treatment regimens thus may be quite important and may even constitute the medically recognized standard of care. Accordingly, the public health may be advanced by healthcare professionals' receipt of medical journal articles and medical or scientific reference publications on unapproved new uses of approved or cleared medical products that are truthful and not misleading.

This guidance is being issued consistent with FDA’s good guidance practices regulation (21 CFR 10.115), and suggest that the distribution be in the form of an unabridged reprint, copy of an article, or reference publication;  not be marked, highlighted, summarized, or characterized by the manufacturer in any way (except to provide the accompanying disclosures discussed in the guidance), and be accompanied by the approved labeling for the drug or medical device.

The guidance represents the agency’s current thinking on the dissemination of medical journal articles and medical or scientific reference publications on unapproved uses of approved drugs and approved or cleared medical devices to healthcare professionals and healthcare entities.
 

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