Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment | Guideline Explorer

Description

This guidance provides recommendations for the development of antiretroviral drugs regulated within the Center for Drug Evaluation and Research at the Food and Drug Administration (FDA) for the treatment of human immunodeficiency virus-1 (HIV-1 or HIV) infection.2 Specifically, this guidance addresses the FDA’s current thinking regarding the overall development program and clinical trial designs for antiretroviral drugs to support an indication for the treatment of HIV-1 infection. The organization of the guidance parallels the development plan for a particular drug or biologic.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

10

Antiretroviral Drugs

Class of drugs being developed for HIV-1 treatment; Developing antiretroviral drugs for treatment of HIV-1 infection.; developing antiretroviral drugs for treatment; Developing Antiretroviral Drugs for Treatment

PI/MI

Protease Inhibitors/Maturation Inhibitors

INSTI

Integrase Strand Transfer Inhibitor

NRTI

Nucleoside Reverse Transcriptase Inhibitor used as a control arm

NNRTI

PIs and NNRTIs became available; Non-Nucleoside Reverse Transcriptase Inhibitor

Protease Inhibitors

PIs and NNRTIs became available

Nucleoside analogues

individuals receiving only two nucleoside analogues

Nucleo(t)side reverse transcriptase inhibitors

specifically nucleo(t)side reverse transcriptase inhibitors (NRTIs)

Fixed-dose combinations

regulatory considerations regarding fixed-dose combinations; treatment effect for EFV with the use of fixed-dose combinations

Combination antiretroviral therapy

Regimens typically including three drugs from two or more classes.

Stakeholders

8

Pediatric Populations

Subgroups including neonates, infants, and children younger than 12 years of age.

Regulatory Context

Regulatory Activities

9

Accelerated Approval

Pathway for drugs and biologics for serious conditions; Regulatory pathway supported by surrogate or intermediate endpoints; Regulatory pathway based on surrogate or intermediate endpoints; Pathway for products based on surrogate or intermediate clinical endpoints

Switch trials

Clinical trials where patients switch treatment regimens

Efficacy supplements

expanding the indication after initial approval

Breakthrough therapy designation

Expedited program for drugs showing substantial improvement

Fast track

eligible for one or more of FDA's expedited programs

Treatment IND

Investigational New Drug application for treatment use

Traditional approval

Approval based on clinical endpoint trials or durable virologic suppression.

NDA

New Drug Application

IND

Investigational New Drug submissions

Document Types

8

Statistical analysis plan

include the overall strategy for handling different intercurrent events... in the statistical analysis plan

protocol

Submitted to an existing active IND

Drug Label

Several drug labels contain examples of response rates

Product labeling

Prescribing information that should reflect benefits and risks during pregnancy.

Pediatric study plan

required for molecularly targeted AML drugs

Written Request

Process for qualifying for pediatric exclusivity under BPCA; Document issued by FDA to qualify for pediatric exclusivity; Issued by FDA to qualify a sponsor for pediatric exclusivity; Document issued by FDA requesting pediatric studies under BPCA.; FDA can issue a WR that includes nonclinical studies.; FDA issued a WR for pediatric studies; FDA issues WRs for pediatric studies to qualify for exclusivity.; document from FDA requesting pediatric studies

Case Report Forms

Used to delineate dose and timing of administration

HHS Antiretroviral Treatment Guidelines

Reference for selecting recommended protease inhibitors.

Attributes

7

Multidrug resistant

Population for which an investigational drug would be suitable.

phenotypic susceptible score

PSS: number of drugs to which a patient's virus is susceptible

Virologic failure

Term used to describe patients with HIV-RNA above 50 copies

Virologic success

Term used to describe patients with HIV-RNA below 50 copies

Area under the plasma drug concentration versus time curve

exposure variable for virologic suppression analysis

Noninferiority margin

Justification essential for trials using a noninferiority design

Noninferiority margins

Statistical considerations for cUTI trials

Technical Details

Substances

10

Nucleoside analog inhibitors

evaluated in biochemical assays for activity against host DNA polymerases

Etravirine

Drug evaluated in DUET Trials

Raltegravir

Drug evaluated in Benchmark Trials

Maraviroc

Drug evaluated in Motivate Trials

delavirdine

Early NNRTI used in combination trials

ZDV+3TC

Zidovudine and Lamivudine combination

nelfinavir

NFV used as a comparator in clinical trials

EFV

Efavirenz used in treatment-naïve and treatment-experienced studies

Abacavir

ABC (bid)+ 3TC + EFV

Tenofovir

ART drug associated with renal dysfunction

Testing Methods

10

Antiviral activity in cell culture

Nonclinical virology development assessment

phenotypic laboratory resistance tests

Tests used to determine virus susceptibility

Sensitivity analyses

Used to evaluate the robustness of overall survival results

Snapshot approach

Simplified endpoint used for approval at Week 48; The snapshot approach strives for efficiency and consistency

Time to loss of virologic response

TLOVR method previously used in labeling

Phenotypic resistance testing

Should be performed on baseline and on-treatment failure samples.

Genotypic resistance testing

Should be performed on baseline and on-treatment failure samples.

Viral load assay

Using a sensitive, FDA-approved viral load assay for efficacy endpoints.

Genotypic assay

Used for baseline resistance scoring and stratification.; detecting treatment-emergent substitutions

Phenotypic assay

Used for baseline resistance scoring and stratification.; evaluating resistance-associated polymorphisms

Processes

6

Pharmacology/Toxicology Development

Nonclinical development considerations

Functional monotherapy

Trial design modification involving adding a new drug to a failing regimen.

Resistance testing

optimized by use of resistance testing; Used to determine true virologic failure

Mechanistic modeling

Sponsors should conduct mechanistic modeling of the drug concentration-viral kinetics; relating drug concentrations and viral kinetics

Toxicological evaluation

Conducted to support clinical trials for combination drugs.

Toxicology studies

should incorporate elements of the planned clinical trial

Clinical Concepts

10

Human Immunodeficiency Virus-1 Infection

Disease state for specific clinical trial data sets

virologic failure

Proportion of patients with HIV-RNA equal to or above 50 copies/mL

Adverse events

Safety findings including deaths and post-mortem examinations

Death

Section D.9 regarding patient mortality

Adverse event

Safety monitoring concept defined in the protocol

Virologic rebound

Defined as a 1 log10 increase in HIV-RNA from nadir value.

CD4+ cell count

Secondary endpoint and stratification factor for HIV trials.

HIV-RNA

Viral load monitoring used to identify active antiretroviral drugs.

Heavily treatment-experienced patients

Population with multiple-drug resistance requiring new trial designs.

Adverse reactions

Increased risk when daily wear lenses are worn overnight

Identified Hazards

Hazards

4

Mitochondrial toxicity

FDA encourages detailed study reports describing... mitochondrial toxicity

Drug toxicity

Risk factor necessitating therapeutic drug monitoring

Resistant virus

Emergence of virus expressing novel substitutions

Viral resistance

Emerges from incomplete viral suppression.

Standards & References

Specifications

10

Noninferiority margin

acceptance depends on the type and degree of unmet need

M2 margin

Clinical margin representing the amount of treatment effect not to be lost

HIV-RNA levels

Measurement of viral load in plasma

10 to 12 percent

recommended noninferiority margin (M2)

HIV-RNA below 400 copies/mL

Virologic outcome based on the snapshot approach

HIV-RNA below 50 copies/mL

Virologic outcome based on the snapshot approach

HIV-RNA below 50 copies

Threshold for virologic success

Viral RNA kinetics

suspecting resistance based on rebounding viral load

HIV-RNA

Primary efficacy endpoint based on HIV-RNA levels.; collected to assess activity and resistance

0.5 log10 decrease

Primary efficacy endpoint for Group 2 trials at an early time point.

ICH References (6)

ICH E9

Statistical Principles for Clinical Trials; Discourages deterministic procedures due to high risk of bias; Notes that the use of Bayesian methods in clinical trials may be considered.

ICH E11

Clinical Investigation of Medicinal Products in the Pediatric Population.

ICH E10

Choice of Control Group in Clinical Trials.

ICH M3(R2)

Guidance on when particular studies can be abbreviated or deferred for life-threatening diseases

ICH S6

Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

ICH guidance

combination toxicology studies completed according to ICH

Related CFR Sections (1)

21CFR300.50§ 300.50 Fixed-combination prescription drugs for humans.
The Food and Drug Administration's policy in administering the new-drug, antibiotic, and other regulatory provisions of the Federal Food, Drug, and Cosmetic Act regarding fixed combination dosage form prescription drugs for humans is as follows:Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to ensure that the investigation was conducted according to the investigational plan

21

Failure to submit an Investigational New Drug application (IND)

9

Failure to obtain informed consent

5

Unapproved new drug

5

Misbranded drug

4

Failed to ensure that the investigation was conducted according to the investigational plan

3

Enrollment of subjects who do not meet eligibility criteria

3

Failure to submit INDs for the conduct of clinical investigations

3

Unlicensed biological product

2

unapproved new drugs

2

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics