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Setting and Implementing Standards for Narrow Therapeutic Index Drugs

CDER reviews drug applications to ensure the products are safe and effective.  When we review applications, we always evaluate the appropriate drug dose that should be delivered to a patient for their condition. All drugs have a therapeutic window, which is the dose range that provides effective therapy and avoids serious adverse effects (or side effects). Doses above the therapeutic window can produce serious side effects and doses below the therapeutic window are likely to be ineffective. Most drugs have a wide therapeutic window but a small set of drugs, narrow therapeutic index (NTI) drugs, have a much tighter therapeutic window and require more careful consideration to determine their optimal dose.

In this CDER Conversation, Liang Zhao, PhD, director of the Division of Quantitative Methods and Modeling in the Office of Generic Drugs (OGD), and Mehul Mehta, PhD, FAAPS, director of the Division of Neuropsychiatric Pharmacology in the Office of Translational Sciences (OTS), discuss how CDER helps ensure the dosage range of these NTI drugs falls within a safe and effective therapeutic window for patients. The experts also discuss the specific challenges and opportunities in developing NTI generic drugs.  

What are narrow therapeutic index drugs, called NTI drugs for short?

Mehul Mehta, PhD, FAAPS
Mehul Mehta, PhD, FAAPS

Mehta: For NTI drugs, small differences in dose or blood concentration (the amount of drug in the body) may lead to therapeutic failures (that is to say, the drug is not working because it is the wrong amount for the patient) or adverse side effects that can be life-threatening or result in significant disability. Because of this, NTI drugs require careful dosing and patient monitoring.

NTI drugs have five general characteristics:

  1. There is little separation between therapeutic and toxic doses (or the associated blood or target site concentrations). That means a small change in the dose can be toxic.
  2. Too low or too high therapeutic concentrations may cause serious therapeutic failure (e.g., epilepsy, immunosuppression) or side effects.
  3. The drugs are subject to therapeutic monitoring (measuring the amount of drug in the blood to ensure safety and efficacy) based on laboratory measures from patients.
  4. The drugs have low within-subject variability (the change in drug exposure when the same person receives the same drug over time).
  5. In clinical practice, doses are often adjusted in very small amounts.

Examples of NTI drugs include the anticoagulant warfarin and the synthetic thyroid hormone levothyroxine.

How does CDER determine which drugs are NTI drugs?

Mehta: OGD and OTS co-lead CDER’s NTI Drug working group (NTID WG), with the Office of New Drugs participating as well. The group works to resolve key NTI scientific and regulatory issues and ensures consistency between new and generic drug evaluation of NTI drugs.

As part of our ongoing work, the NTID WG assesses approved drugs and new drug applications for their potential to be designated as an NTI drug.

In the case of new drugs, we examine the relationship of drug exposure to efficacy and serious side effects. If we see that only a small increase in drug exposure causes serious side effects, the NTID WG may conduct further evaluation before designating a drug as an NTI drug.

As with all FDA approved drugs, we look at drug applicant’s annual safety reports, safety reports submitted to the FDA Adverse Event Report System, medical literature, and any other relevant information to assess the NTI potential.  If we find new information that would affect approved labeling, CDER works with the drug applicant to update the labeling with new information and communicates the labeling change.

Labeling information for dosage and administration for FDA-approved drugs, including NTI drugs typically provides the recommended starting dosage (dose and frequency); method of titration (slowly increasing the dose), if applicable; dosage range; maximum dosage; dosages in specific populations; and instructions for therapeutic drug monitoring, if required.

How is CDER advancing the development of NTI generic drugs?

Liang Zhao, PhD
Liang Zhao, PhD

Zhao: Determining that a brand-name drug has an NTI designation is important for setting appropriate bioequivalence (BE) (meaning the generic will behave the same in the body as the brand-name drug) criteria for generic drugs.  This is because OGD applies tighter quality and BE criteria for generic NTI drugs than for generic non-NTI drugs. Generic NTI drugs, like all generic drugs, are FDA-approved as clinically substitutable with their brand-name versions.

What have we learned about pharmacists’ experiences dispensing generic NTI drugs?  

Zhao: Because the lower cost of generic drugs may enhance medication adherence and, ultimately, patient health outcomes, ensuring that health care professionals (HCPs) and patients have access to safe and effective generic NTI drugs is an important regulatory goal. Pharmacists who manage substitution and dispensing can provide valuable perspectives on reaching this goal. To that end, FDA funded a national survey among pharmacists to learn about their experiences dispensing generic NTI drugs. 

From this study, we learned that pharmacists are confident in the safety and efficacy of generic NTI drugs, and they frequently substitute generic NTI drugs for the brand-name drug. Our survey also revealed important gaps. For example, pharmacists in non-chain settings and in pharmacy practice longer were less likely to substitute initial prescriptions with NTI drugs. Educational efforts targeting non-chain and veteran pharmacists may lead to greater generic NTI substitution, which could help reduce healthcare costs and improve patient adherence.

In 2022, CDER hosted a continuing education webinar to provide HCPs with information and knowledge on the importance and application of stricter standards for BE in NTI generic drugs.

How is CDER working with international bodies on NTI drug issues?  

Zhao: Right now, there are global variations in NTI and BE assessment criteria. International harmonization of BE approaches among global regulatory agencies can help streamline industry interactions with individual agencies and ease the barriers to global entry for generic drugs. OGD, and other CDER offices, participate in several international harmonization efforts with our regulatory counterparts in other countries, such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, to align standards and help generic drugs, including generic NTI drugs, come to market faster.

What's the most important thing for patients to know about NTI drugs?

NTI drugs are important drugs for the treatment of certain conditions. Identification of a drug as an NTI drug allows HCPs to make the most informed decision on the risks and benefits of the available drug treatments for a patient’s medical condition. By setting and communicating clear NTI drug standards, CDER helps support HCPs in making critical risk management decisions for their patients, which in turn, ultimately improve patient outcomes.

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