The draft Guidance of FDA specifically cautions ANDA applicants not to confuse the terms RLD and RS.  Ordinarily, the reference standard selected by FDA will be the RLD; however, that is not always so.  If FDA has selected a reference standard for use in in vivo bioequivalence studies different from the RLD, then the ANDA applicant must compare its proposed product’s labeling and formulation to that of the RLD and not to the reference standard.

Difference between reference listed drug and reference standard

RLD vs. RS

  • A reference listed drug (RLD) is the listed drug identified by FDA as the drug product which is  referred to a generic drug manufacturer to compare between RLD and Test product.
  • A “reference standard” is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting an in vivo bioequivalence study.

  • The applicant must submit a new ANDA to change its RLD.
  • The applicant may submit controlled correspondence to FDA asking it to select a reference standard for that drug product.

  • Where the RLD is marketed, ordinarily it is also the drug product selected by FDA as the reference standard.
  • Where the RLD has been discontinued from market FDA may select a different approved drug to serve as the reference standard.

  • RLD symbolized in orange book as “+”
  • RS symbolized in orange book as “!”

  • The ANDA applicant must also demonstrate that the proposed generic drug is bioequivalent to the RLD.
  • Reference standards represent FDA’s best judgment to the appropriate comparator for purposes of conducting any in vivobioequivalencestudies required for approval.

  • RLD to be available for all strength in case of multiple strength.
  • FDA usually selects as the reference standard the highest strength available for drug products with multiple strengths.

What is the difference between pharmaceutical equivalent and therapeutic equivalence?

  • Pharmaceutical equivalent means a drug product having the same active ingredient, same dosage form, same route of administration with same strength or concentration as a given reference listed drug.
  • Therapeutic equivalent means a drug product is pharmaceutical equivalents and can be expected to show the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.

Difference Between Innovator Medicine and Generic Medicine

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