• Please Join us for our Next Webinar: Evaluating Product Risk in a Rapidly Changing Environment

    Please Join us for our Next Webinar: Evaluating Product Risk in a Rapidly Changing Environment

    “Evaluating Product Risk in a Rapidly Changing Environment” A Webinar Presented by The Weinberg Group Wednesday, July 25, 2012 12 p.m. (EDT) | 9 a.m. (PDT) | 5 p.m. (GMT) Online Registration With the dramatic increase in legislative and regulatory focus on consumer health and safety, and employee health and safety, companies’ products are more vulnerable to attack than ever. These attacks can be based on pseudo-science with regards to...

  • Latest Drug Approval Via the Animal Rule: The Black Death

    To clarify the somewhat misleading title, the latest drug approval using FDA’s Animal Rule is to expand the approved indications for Levaquin to the treatment and prevention of plague due to pulmonic or systemic infection with Yersinia pestis. Although other antibiotics are indicated as treatment for Y. pestis infection, the novel component of the Levaquin indication is its potential widespread use as a preventive agent in emergency...

  • Biologics, Biosimilars and Looking Into the Abyss

    Biologics, Biosimilars and Looking Into the Abyss

    The double-edged aspect, and certainly the more negative side, of being protected by a patent comes at the end of that protection. Patent cliffs have become part of the pharmaceutical industry’s vernacular in that a company’s revenues can appear to be falling off a cliff when a product comes off patent; when the patent term runs out and generic competitors enter the marketplace. In this situation a blockbuster drug can disappear from an...

  • Jun
  • 11
  • 2012

GRAS – One of FDA’s Most Widely Misunderstood Acronyms (Part 3)

Posted by Carrie Rabe In Drug Development, Drug Formulation, FDA, FDA Guidance, Regulations, Uncategorized | No Comments »

The third installment of this series addresses the misconception that in order to be designated “GRAS,” a substance must have been extensively tested and definitively proven to be safe. Many substances have been designated GRAS for their intended use(s) based solely on knowledge of their common use in foods prior to 1958. The presumption of safety for such substances is based on the assumption that a history of safe use adequately predicts future safe use provided that the level and type of use remains essentially the same. For these substances, the absence of a safety concern in the past obviates the need for extensive testing.

Many GRAS substances do not, however, have a history of common use in foods prior to 1958 and GRAS status has been affirmed based on “scientific procedures.” In this context, “scientific procedures” refers to human, animal, analytical, and other scientific studies appropriate to establish the safety of a substance. However, even for substance affirmed to be GRAS based on scientific procedures, this does not necessarily mean that a full battery of safety studies has been completed.

Review of the safety assessments made by the Select Committee on GRAS Substances (SCOGS) in the 1970s for substances later affirmed as GRAS, shows that in many cases safety judgments were made in the absence of a complete safety study dataset. In some cases, the design of toxicity studies was not optimal (e.g., incomplete assessment of usual safety endpoints or small numbers of animals). In other cases, some types of safety studies were missing (e.g., the absence of reproduction studies). In fact, some substances were determined by SCOGS not to present a safety risk with little toxicity data on the specific substance. Safety assessments for chemicals with only very limited substance-specific safety studies may have been based on data showing common metabolites with other more fully-studied substances or on known exposures through the diet to the constituents parts of other GRAS substances (e.g., for salts). These types of arguments supporting safety are widely accepted by qualified experts and support the finding that many substances are GRAS. Ultimately, it is the weight of the available evidence that determines whether a substance is GRAS. Many GRAS substances have been extensively studied for safety and that information constitutes the basis for their GRAS determinations. However, it is important to recognize that a GRAS designation does not necessarily mean that a substance has been thoroughly tested for safety.

Posted by Carrie Rabe, Senior Consultant. For more information, please contact Carrie atcarrie.rabe@weinberggroup.com.

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  • May
  • 29
  • 2012

Latest Guidances on “Nano” Product Development and Regulation

Posted by Bob Roth In Drug Development, Drug Formulation, FDA, FDA Guidance, Regulations, Uncategorized | No Comments »
Latest Guidances on “Nano” Product Development and Regulation

Two new draft guidances related to the use of nano materials in FDA-regulated products have been issued for public consideration and comments. These draft guidances, Safety of Nanomaterials in Cosmetic Products, and Assessing the Effects of Significant Manufacturing Process Changes, follow last year’s general guidance on when nanotechnology applies to FDA-regulated products. These draft guidances are the initial salvos in what promises to be an extensive and likely wide-ranging consideration by FDA of the many issues inherent in these new technologies. How long might this process take? Given that the rapidly advancing field of nanotechnology has a very clear clinical promise in many areas, yet has as many scientific questions as answers, we anticipate the nano dialogue will be long and evolving.

If these draft guidances are the first you have encountered, we highly recommend taking a step back to review the report of the 2007 Nanotechnology Task Force. This internal FDA group of experts was tasked with considering issues, with regard to safety, of the wide range of FDA-regulated products that are anticipated to use nanomaterials. Such materials, technically defined as having at least one dimension on the order of nanometers, were anticipated to have applications to human and animal drugs, medical devices, foods, cosmetics, etc., as well as non-medical products. Of greatest importance, these aren’t “your father’s Ford;” that is, a product that incorporates nanotechnology will be dramatically different in terms of chemical and structural properties, and risks, from those products previously available. Until proven otherwise, it is necessary to expect that surface reactivities, general biological activities, toxicologic reactions, structure-function relationships, environmental interactions, etc., will be novel for nanoproducts. Accordingly, the methods used to evaluate nanoproducts may need to be specially designed, and predicting how nanomaterials will interact with biological systems cannot be assumed or inferred from what is known before.

We believe it is important that FDA gradually develop considerable in-house, hands-on experience with these products, both from a research approach and from independent testing procedures. Some basic principles will certainly develop over time, principles that are likely to be applicable to many types of nanomaterials and nanoproducts. Even as such expertise develops it seems clear that not all issues can possibly be identified and understood at the time of a nanotechnology product’s approval, and we expect that post-market safety surveillance activities will similarly undergo revisions over time.

Although many FDA drug and device approvals represent incrementally improved versions of known active ingredients in previously-approved products, the likely result of incorporating nanomaterials will be quantum leaps to new FDA-regulated products. Just as DNA technology has revolutionized the field of disease understanding and drug development, we think nanotechnology has equivalent potential to dramatically alter the products we use every day. This is an FDA blog, and therefore there is an unavoidable focus on regulatory issues, yet in this particular arena the science will drive the regulation more than vice-versa.

Posted by Bob Roth, Vice President and Worldwide Medical Director. For more information, please contact Bob at bob.roth@weinberggroup.com.
 

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  • Apr
  • 09
  • 2012

New Draft Guidance Proposes to Limit the Use of Certain Phthalates as Excipients in CDER-Regulated Products

Posted by Theresa Allio and Nick Fleischer In FDA, FDA Guidance, Uncategorized | No Comments »
New Draft Guidance Proposes to Limit the Use of Certain Phthalates as Excipients in CDER-Regulated Products

In March 2012, a Draft Guidance proposing to limit the use of certain phthalates as excipients in CDER regulated products was issued and is now open for a 90 day comment period. Depending on how the final version of this guidance document evolves, it could have a major impact on the industry.

Phthalate esters (phthalates) are used primarily as plasticizers in enteric-coatings of solid oral drug products, but can also be found in other dosage forms. The draft guidance focuses on two specific phthalates—dibutyl phthalate (DBP) and di (2-ethyl-hexyl) phthalate (DEHP) in CDER regulated drug and biologic products and their developmental and reproductive toxicities. In the guidance, CDER states that safer alternatives are available and that the use of DBP and DEHP as excipients in drug and biologic products should be avoided. The guidance applies to drug products at all stages of their lifecycle—investigational new drugs, drug products not requiring pre-approval including products marketed under OTC drug monographs, drug products currently under review for marketing consideration (NDAs, ANDAs and BLAs), and currently marketed approved drug products. While it appears that this guidance is applicable only to the aforementioned drug products, we could envision extension of phthalate restriction to dietary supplements, medical foods, medical devices and cosmetics.

Essentially, the agency is hoping to remove DBP and DEHP from the inactive ingredient list (IIG) if possible. Given all of the references to the SUPAC and Changes to an approved NDA or ANDA guidances, it is clear that sponsors are being asked to take heed. If the sponsor cannot identify an appropriate substitute, then a justification for continuing the use of DBP or DEHP should be submitted. Depending on the formulation change involved, additional nonclinical and clinical studies may also be required to support the change, especially since the phthalates may be considered rate-controlling excipients in modified-release drug products.

It is not known just how many products will be impacted by this guidance or when CDER expects sponsors to conform to this change. A quick search of the IIG revealed 4 entries for approved products with DHP, but it can be assumed that many others used DHP based on the levels cited. The guidance is available on the FDA’s website and comments to the guidance may be submitted at http://www.regulations.gov under Docket No. FDA-2012-D-0108. The Docket is open for comment until May 31, 2012.

Posted by Theresa Allio, Senior Consultant and Nick Fleischer, Vice President. For more information, please contact Theresa (theresa.allio@weinberggroup.com) or Nick (nick.fleischer@weinberggroup.com).

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