Regulatory Focus™ > News Articles > FDA Draft Guidance Outlines Risk-Based Approach to Assessing Therapeutic Proteins

FDA Draft Guidance Outlines Risk-Based Approach to Assessing Therapeutic Proteins

Posted 08 February 2013 | By Alexander Gaffney, RAC

A new draft guidance document released by the US Food and Drug Administration's (FDA) drug and biologics research centers seeks to assist manufacturers and clinical investigators working on therapeutic protein products.


Such proteins, of which FDA has approved dozens for use, are regulated by either the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) (or both) depending upon the characteristics of the product.

A 2012 article in the journal Methods of Molecular Biology noted the therapeutic protein products sector grossed US sales of $108 billion, of which monoclonal antibodies (mAbs) accounted for roughly half. That same article notes that they can be divided into five general categories:

  • proteins that act as a replacement for an abnormal or deficient protein
  • proteins that act to augment an existing pathway
  • proteins that act to induce activity
  • proteins that act to deliver other compounds or proteins
  • proteins that interfere with molecules or organisms

But as useful and widespread as therapeutic proteins are, they are subject to more serious concerns regarding their effect on the body's immune system than their chemically-based pharmaceutical counterparts.

"Immunologically based adverse events, such as anaphylaxis, cytokine release syndrome, so-called "infusion reactions," and nonacute immune reactions such as immune complex, have caused sponsors to terminate the development of therapeutic protein products or limited the use of otherwise effective therapies," FDA explained. These unwanted responses, which range from the clinically insignificant to the life-threatening, can also neutralize the therapeutic benefits of the drug, compounding potential harms to the patient.

A Risk-Based, Case-by-Case Approach

To better mitigate those immune response risks, FDA's draft guidance (Immunogenicity Assessment for Therapeutic Protein Products) proposes a case-by-case, risk-based approach to immunogenicity assessment informed by a number of factors explained in the guidance.

For example, FDA noted that sponsors should "develop and implement sensitive, qualified immunoassays commensurate with the overall product development program" to provide early assessments regarding the product's immunogenicity.

Clinical trial participants should also be assessed to determine their baseline anti-product antibodies, with that baseline used as the source of comparison for future, regular testing. "Banking of serum samples … under appropriate storage conditions for future testing is always advisable,
 FDA wrote.

Dosing, meanwhile, should follow a "conservative approach" and be risk-based and take into account all previous data.

Comparative studies between products should provide a "strong rationale and, when possible, pre-specified criteria" regarding what differences would be unacceptable.

If adverse events are observed, sponsors are "encouraged" to determine its underlying cause and contributing factors, both of which were touted by FDA as ways sponsors can facilitate development of strategies to mitigate harms, such as reformulating products or restricting use to lower-risk patients. These strategies should extend to the postmarketing settings as well, regulators wrote.

Patients should also be carefully assessed for a number of factors, including current immunologic status, health, prior history of allergies, available route of administration, genetic status and immune tolerance. "In the development of therapeutic protein products, a rationale should be provided to support the selection of an appropriate study population, especially for first-in-human studies," FDA noted.

The products, too, should be subject to an assessment of inherent risk, including where or what the protein is sourced from, the structure of the protein, the production process used to make the protein, impurities present in the final product, any immunomodulatory properties present in the product, additives and excipients used in the final product, the product's container and the stability of the product after production.

Comments on the guidance are due by 11 April 2013.

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