As consultants we have the privilege of assisting many clients with FDA communications on a variety of topics and working with them to support many different types of drug product applications. Through our work we often identify common themes or issues that our clients are facing and one of the biggest headaches for our ANDA clients seems to be around the topic of maximum daily dose for their drug products. Maximum daily dose, or MDD, is a value that is used to set safety limits for impurities in drug products, both degradants of the drug product itself, as well as extractables and leachables that make their way into a drug through manufacturing or from the packaging on stability. MDD is a critical piece of the generic product development plan for any prospective ANDA applicant and if they get it wrong, it can mean extra time and expense to re-assess data or even repeating studies that can prolong development or significantly delay ANDA approval which can impede access for patients.
Drugs are approved by FDA as indicated for use in a specific patient population and are approved for use with specific dosing regimens that were proven safe and effective by the NDA applicant. Once a new product is approved, it can then be used by a licensed prescriber to treat any indication, and in any dose they feel is appropriate for their patient as part of the practice of medicine. It would therefore be impossible for anyone to know how a product could be used by individual healthcare providers, but it appears that FDA is attempting to do just that with the latest information they are providing ANDA applicants with respect to MDD values. There has been an increase in the number of review comments related to “incorrect” MDD values such that several clients are now proactively submitting controlled correspondences during development to verify the MDD before moving into extractable/leachable studies and the responses have been enlightening.
Clients generally will propose MDD values sent to FDA in controlled correspondences based on statements in the RLD labeling such as an overt statement of maximum dose, a statement of dose in the summary basis of approval posted by FDA, or if a rate of use is specified with an indication and can be used to calculate the maximum a patient would be exposed to in one day following the approved label. Where there is a clear statement in the labeling or review information, OGD generally agrees with the value, however there are also examples where this is not the case. The practice of aligning MDD based on the approved conditions of use should be one that FDA vigorously agrees with as FDA has approved these conditions and any other conditions are unapproved and outside the scope of the approved labeling.
One recent MDD proposal was based on a statement in the RLD label for PK data and the dose applied, however FDA disagreed and said the MDD was lower with no justification given. The converse can also be true as one proposed MDD matched the largest dose discussed in the approved label, but OGD noted that the MDD was higher and provided their MDD value with no explanation. Some of the values provided by OGD also appear to be absurd as in the case of one topical product where the proposal was based on literature uses the prospective applicant submitted, but the MDD value OGD returned was over 200 times the proposed value! One applicant received an unsatisfactory correspondence response based on the labeled use where OGD noted that the MDD was related to the doses studied in phase 3, so the next MDD they proposed for a similar product provided the MDD based on the amount of product applied for that product’s phase 3 clinical studies, however the response was a disagreement from OGD to say the MDD is lower with no explanation given.
Sometimes the MDD value does not appear to be linked to the dosage form. A shampoo dosage form that would commonly be used on the scalp included a proposed MDD based on the indications for use with the RLD and a single application per the label. OGD’s response was that the indication can occur on more than just the scalp, so the MDD given in return was nearly 3 times what the applicant proposed as the same condition appears on the trunk and upper extremities per FDA.
While more recent controlled correspondence responses have provided more information as to the source of the MDD values given by FDA, there is less transparency than could be provided as to where some of these values are coming from that could assist prospective applicants. In these extreme examples, there is no reasonable expectation that an applicant could estimate the MDD on their own.
This confusion on MDD harkens back to the days of trying to propose the amount of an inactive ingredient that is acceptable for use in a generic formulation. The games of hi/lo that could be played with the controlled correspondence staff to get to the value before the maximum daily exposure values were added to the Inactive Ingredient Database suggest a similar resolution could be employed for MDD values. If applicants cannot guess the MDD that OGD is going to insist upon and it takes a significant amount of time to find out if the proposal is wrong, is there a way to get these values published in a database? A controlled correspondence requesting verification of MDD is a level 2 correspondence which should see a response withing 120 days. That’s a long time for a generic applicant to wait, and as level 2 correspondences they may also take a significant number of resources within FDA to research and respond to these queries. That could mean that greater transparency could bring significant efficiencies for both the Agency and Industry if these values were made public.
Perhaps this is a good topic for discussion in the upcoming GDUFA IV negotiations, but in the meantime, if you have questions on finding the maximum daily dose of your product, or need help drafting and/or submitting controlled correspondences, please contact Lachman Consultants at www.LachmanConsultants.com/contact.
