Shenzhen IVPS Technology Co (SMOK) MDO

Based on a review of the FDA's denial letter, the SMOK products did not receive a marketing granted order for the following key reasons:

1. Inconsistent and highly variable HPHC (Harmful and Potentially Harmful Constituent) data:

• The aerosol yield data for HPHCs like nickel, chromium, acetaldehyde, acrolein, formaldehyde and nicotine showed extremely high variability (0-252% relative standard deviation).

• This variability made the data unreliable for estimating actual HPHC yields and consumer exposure.

• Without reliable HPHC estimates, FDA could not properly evaluate the health risks of the products.

2. Inadequate stability data:

• The stability studies showed high variability and inconsistent trends in HPHC yields over time.

• The small sample sizes and variability made the data unreliable for determining product stability.

• FDA could not determine how HPHC levels might change over the product's shelf life.

3. Insufficient abuse liability information:

• The clinical studies did not adequately compare abuse liability outcomes (e.g. nicotine exposure) between the SMOK products and combustible cigarettes under ad libitum (free) use conditions.

• There were concerns that nicotine exposure and abuse liability could exceed that of cigarettes when used with high nicotine content e-liquids.

• The applicant did not provide sufficient evidence to address these concerns.

Possible remedies to these deficiencies, the manufacturers could take the following steps:

1. For HPHC data:

• Conduct new studies with larger sample sizes and improved controls to reduce variability

• Use consistent methods, equipment, and testing conditions

• Provide full datasets and statistical analyses

• Justify any bridging of data between products

2. For stability data:

• Conduct longer-term stability studies with more timepoints and replicates

• Provide statistical analyses of trends over time

• Explain any variability or inconsistencies observed

3. For abuse liability:

• Conduct new clinical studies comparing the SMOK products to cigarettes under ad libitum use conditions

• Measure nicotine pharmacokinetics, user topography, and subjective effects

• Evaluate abuse liability with high-nicotine e-liquids specifically

• Provide data on consumer understanding of product instructions/limitations

4. Overall:

• Improve quality control in manufacturing to reduce product variability

• Provide more robust scientific justifications for methods and conclusions

• Address all points raised in the FDA's deficiency letter

Brief on Review Process and Outcome:

The FDA conducted a substantive scientific review of Shenzhen IVPS Technology's Premarket Tobacco Product Applications (PMTAs) for multiple SMOK electronic nicotine delivery system (ENDS) products. The review evaluated whether permitting the marketing of these products would be "appropriate for the protection of public health" (APPH), considering risks and benefits to the population as a whole.

Key aspects of the review included:

• Product characterization and design

• Manufacturing practices

• Stability and shelf life

• Harmful and Potentially Harmful Constituent (HPHC) levels

• Abuse liability and addiction potential

• Clinical pharmacology data

• Behavioral and clinical studies

• Potential impact on current tobacco users and non-users

The FDA identified significant deficiencies in three main areas:

1. Highly variable and unreliable HPHC yield data

2. Inadequate product stability data

3. Insufficient information on abuse liability compared to cigarettes

Due to these deficiencies, the FDA concluded there was insufficient evidence to determine that marketing of the products would be APPH. As a result, the applications were denied and marketing denial orders were issued for the SMOK products.