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  • 1.  Adjuvants: clinical demonstration of added benefit

    Posted 08-Dec-2017 13:00
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    Dear Community,

    According to the attached presentation slides from Phil Krause (CBER; 2014) - slides 26-27: 

    Manufacturers should provide a rationale for the use of adjuvant in their vaccine formulation, supportive data may be derived from:

    • Preclinical studies (e.g., in vitro assays and/or proof-of-concept studies in animal models)
    • Early clinical immunogenicity trials comparing adjuvanted vs. unadjuvanted vaccines to include
      • evidence of enhanced immune response,
      • antigen sparing effects, or
      • other advantages
    • Data from use of adjuvant with related vaccine antigens
    • If available, information about the presumed mechanism of action of the adjuvant

    Questions:
    1. Are the above requirements (to support the rationale for the use of an adjuvant) defined in any guidance/regulation?
    2. Regarding bullet 2: Is a clinical trial of adjuvanted vs. unajuvanted vaccine definitely required, or just is this just one possible source of evidence to support the added benefit of the adjuvant?
    3. If a vaccine has multiple adjuvants, would a multi-arm clinical trial be needed to test the added benefit of each adjuvant separately?
    4. The attached presentation applies to vaccines for infectious diseases.  Would the same principles bulletted above also apply therapeutic vaccines (ie vaccines to treat diseases that are not infectious in nature)?

    Input on any or all questions would be greatly appreciated. 

    Thank you.
    Best regards,
    Monique

    ------------------------------
    Monique Franc
    Scientific Director
    North America Regulatory Lead - Neuroscience
    Janssen
    NJ, USA
    ------------------------------

    Attachment(s)

    pdf
    2014_CMCE_KrausePhil (1).pdf   928 KB 1 version


  • 2.  RE: Adjuvants: clinical demonstration of added benefit

    This message was posted by a user wishing to remain anonymous
    Posted 11-Dec-2017 09:10
    This message was posted by a user wishing to remain anonymous

    As you are aware that inactivated vaccines require use of adjuvants to stimulate a stronger immune response. If so, is your proposed new adjuvant a new entity that ​has not been proven to do what it is supposed to do along with your proposed vaccine?
    If so, I would think that a new adjuvant needs to demonstrate first, its effectiveness or ineffectiveness or damaging (i.e. safety) either via preclinical studies (if its a new entity) or in early clinical studies (POC) i.e. added to your primary vaccine prior to the use of this combination in the registration trial. This is a basic development 101 regardless of what the so called "requirements" or guidance calls for.

    Regarding the use of clinical trial of adjuvanted vs. unadjuvanted vaccine, this is again a basic add-on therapy development situation done very commonly in the oncology trials and its no different to vaccine development spectrum. For example in oncology, you add a new drug to the SOC and compare to the SOC (X + SOC Vs. SOC) to demonstrate that it is better than standard of care alone. Otherwise why should anyone approve this combination if it is not better than the unadjuvanted vaccine?

    Very surprised that your clinical development personnel are not aware of this!!!
    Original Message


  • 3.  RE: Adjuvants: clinical demonstration of added benefit

    Posted 12-Dec-2017 09:36
    ​Monique,

    Thank you for including the slides they were very informative.  Per the slides and also my experience with adjuvants, the adjuvanted vaccine is tested as a whole product.  We typically do safety studies preclinically to determine if the adjuvant is safe but have not clinically compared adjuvanted vs. non-adjuvanted vaccine.  Please note in slide 22 the "Adjuvants are not considered active ingredients" and is therefore tested as a single product.  Of course a call or email to your project manager at FDA may clear up any outstanding issues.
    Marci

    ------------------------------
    Marci Aderiye
    Associate Director, Regulatory Affairs
    Aeras
    Rockville MD
    United States
    ------------------------------

    Original Message


  • 4.  RE: Adjuvants: clinical demonstration of added benefit

    Posted 13-Dec-2017 12:23

    Dear Monique,

    Marci is correct, adjuvants are not separate products and are essentially considered excipients. Our respective organizations have considerable experience developing adjuvanted vaccines. To your specific questions:

    1)      Check out the WHO "Guidelines on the nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines", 2013. Despite the title, it also includes clinical recommendations. There are various FDA guidances that address different aspects, but the WHO guidance has everything in one place. FDA thinking follows the WHO guidance closely, with the exception that FDA wants "n+1" doses for the pivotal toxicity study.

    2)      Clinical trials of unadjuvanted vs adjuvanted are desired, but not required by FDA. Some of our programs tested antigen alone, but not others. You certainly need justification, but the animal studies can suffice. And keep in mind that adjuvant-only arms are generally not acceptable due to concerns about autoimmunity.

    3)      I don't think so. As Marci said, adjuvanted vaccines are a single product, so your preclinical package should be sufficient to justify their inclusion.

    4)      Yes. Our adjuvants are also used in therapeutic and/or non-infectious disease indications and I'm not aware of a different regulatory bar.

    Best regards,

    Zack




    Original Message


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