As you work towards a successful New Drug Application (NDA) submission, there are many considerations that must be taken into account, specifically for central nervous system (CNS)-active drugs. Molecules or compounds that are centrally active (the parent drug or metabolite[s]), may require additional evaluations to characterize the drug effects and unique safety characteristics.

Not all centrally acting drugs require additional assessments; however, strategic direction early in a drug development program can help determine whether such studies should be planned or can be waived.  

In Issue 14 of The Altascientist, we look into the complex considerations of CNS-active drugs, including:

• The landscape of CNS-active drug studies
• Drug scheduling and the Controlled Substances Act (CSA)
• Reviewing data from early-phase preclinical and clinical studies
• Choosing a CRO for CNS studies

THE IMPORTANCE OF CLINICAL STUDIES FOR CNS-ACTIVE DRUGS

CNS-active drugs have unique attributes that necessitate additional specialized study, such as:

• Cognitive impairing/enhancing effects
• Reinforcing effects (abuse potential)
• Physical dependency and tolerance
• Additive effects (when combined with drugs and alcohol)

Because CNS-active drugs can have unintended effects in the critical neural system that influences so many aspects of human health, the required preclinical and clinical studies are typically more detailed and rigorous than for other types of drugs. In addition, the results of such studies will have a material impact on your development program going forward, both in terms of timelines and budget, so you will want the answers for yourself as much as for the regulatory bodies.  

One of the key considerations in evaluating a CNS-active drug molecule (or its metabolites), is the evaluation of abuse potential. Such data is integral in determining whether or not a new drug approved for medical use may need to be a controlled substance. The FDA uses an eight-factor format for NDA submissions of CNS-active molecules.  

A controlled substance is assigned a schedule based on whether it has a currently accepted medical use in treatment in the United States, and its relative abuse potential and likelihood of causing dependence. Physical dependence is a neuroadaptive process that can occur in the absence of abuse potential. The ability of a drug to produce physical or psychological dependence plays a role in the scheduling placement of an abusable drug under the CSA. 

DRUG SCHEDULING AND THE CONTROLLED SUBSTANCES ACT

The Controlled Substances Act, enacted in 1970, provides a framework for appropriate labelling and controlled distribution of medications with certain attributes. Scheduling of a medication impacts market availability and prescribing behavior. For planning and development purposes, it is important to act on early signals that suggest scheduling will be necessary. Drugs and other substances that are considered ‘controlled substances’ are classified into five schedules.

As the schedule progresses from I through V, the abuse potential reduces and thereby the limitations on prescribing practices are lessened. Schedules I and II both represent drug molecules with the highest known abuse potential. Schedule I drugs are not approved for medical use in the United States, whereas Schedule II drugs are.

Explore all issues of The Altascientist in our Resource Center. And don’t forget to subscribe to “The Altascientist: Audiobooks” on Spotify, Apple Podcasts, or wherever you get your audio content. 

There are many challenges associated with early drug discovery and development. With timelines, budget, and market competition being critical factors, advancing your best candidate for regulatory submissions requires a careful assessment of efficacy and toxicity prior to entering human trials. Partnering with the right CRO early on can increase your chances of success and ensure you meet your milestones. In fact, we recommend initiating discussions with a CRO at least six months in advance to ensure that capacity, resource availability, and animal supply are built into your timelines.

In Issue 11 of The Altascientist, we provide a high-level overview of the preclinical component of your drug development program in preparation for regulatory submission, including:

• A submission checklist
• Pivotal toxicology studies
• Small molecules vs. biologics
• Considerations for before you begin (species selection, formulation, test article, bioanalysis, etc.)
• Small and large molecule timelines
• SEND data
• Selecting the right CRO for you

Preparing For Your IND Submission

Your IND application must contain information in the three following areas, as outlined by the U.S. FDA: 

1. Animal pharmacology and toxicology studies 
2. Manufacturing information 
3. Clinical protocols and investigator information

Moving a drug from preclinical testing into the clinic requires that all conditions outlined by the FDA be met. Therefore, it is important that you and your CRO have a thorough understanding of the requirements. Involving regulatory agencies from the start can help lead you in the right direction and ensure a successful IND submission.

It is essential to communicate with the FDA as early as possible to make certain that the test plan is acceptable. The pre-IND meeting is the first crucial interaction with the FDA. This meeting provides an excellent opportunity for you to enlist the FDA's support as well as validate and optimize a strategy.

Planning Your Pivotal Toxicology Studies

Being proactive in your approach and having a clinical strategy before engaging a CRO will ensure that the data provided by the program of work is sufficient to support your IND, and will reduce the risk of study start-up delays.

Considerations for planning your program include safe starting doses for clinical trials and multiple-dose levels (multiples of expected clinical dose), species selection and justification, routes of administration to mimic clinical use, identification of potential target organs for toxicity, planning for assessing reversibility of toxicities, endpoints, and analytical and bioanalytical methods.

Test Article Considerations 

Proper formulation of drugs and vehicles helps ensure appropriate exposure to the test article. Vehicle/solubility, consistency, characterization, storage conditions and material safety data sheets must all be taken into consideration.

As such, solubility, stability, dose volume, and tolerability of the vehicle in the preclinical species should be considered. For GLP studies, concentration verification of the test article in the vehicle is required. It is also important that the route of administration for the IND portion of preclinical studies -mimic the route you intend to use in the clinic.

A well-characterized test article must be in accordance with GLP and accompanied by a Certificate of Analysis, and test materials should be stored according to the Certificate of Analysis and within the same conditions under which stability has been established.

Additionally, to ensure safe and proper handling of the material, the safety data sheet should be provided to your CRO study team and laboratory personnel before the test article is shipped. 

Explore all issues of The Altascientist in our Resource Center. And don’t forget to subscribe to “The Altascientist: Audiobooks” on Spotify, Apple Podcasts, or wherever you get your audio content.