If animal studies or in vitro data is available, there might be sufficient information to determine if a specific starting dose is considered low risk. However, conventional allometric scaling methods for gene therapies may be less precise than for small molecule drugs, and traditional pharmacokinetic and pharmacodynamic correlations might not be possible. Therefore, it may be difficult to establish an initial starting dose based on the considerations used for small molecule drugs. If available, previous clinical experience with the gene therapy or related products, even if by a different route of administration or for a different condition, might help to justify the clinical starting dose. [1]
For many gene therapy products, dose is based on vector titer. However, some vector types may have specific properties that necessitate dosing using alternative units. For example, viral particles that do not contain the therapeutic gene are unlikely to have therapeutic activity. These particles themselves might produce adverse reactions, such as an allergic response. If there are such safety considerations, the study dose(s) should be based on the total particle number, as is the case with adenoviral vectors. Other considerations for describing dosing may be related to the strengths and weaknesses of the methods available to accurately quantify specific attributes of the gene therapy products. For example, adeno-associated viral (AAV) vectors are typically dosed based on vector genomes, due to the strengths of the quantitative polymerase chain reaction (PCR) assay and the difficulties in quantitating transducing units.
Clinical development of gene therapies has often included dose escalation in half-log (approximately three-fold) increments. However, the dosing increments used for dose escalation should consider pre-clinical and any available clinical data regarding the risks and activity associated with changes in dose. Many gene therapy products can persist in the subject or have an extended duration of activity, so that repeated dosing might not be an acceptable risk until there is a preliminary understanding of the product’s toxicity and duration of activity. Therefore, most first-in-human gene therapy trials use a single administration or one-time dosing regimen.