November 21, 2005

**Re: Docket No. 2005D-0310, CBER 200523.**

**Draft Guidance for Industry on Gene Therapy Clinical
Trials---Observing Participants for Delayed Adverse Events**

Schering-Plough appreciates the opportunity to comment on the Food and
Drug Administration's (FDA's) "Draft Guidance for Industry on Gene
Therapy Clinical Trials---Observing Participants for Delayed Adverse
Events."

Reference is made to CBER's Draft Guidance for Industry on *Gene Therapy
Clinical Trials---Observing Participants for Delayed Adverse Events*,
published August 23, 2005 (Docket No. 2005D-0310, CBER 200523).

In general we believe that this draft guidance is very clear and
logically written. However, we do have some comments for your
consideration.

1.  The following are general comments.

> a\. Further guidance on how much effort needs to be expended to avoid
> "lost-to-follow-up" would be helpful.
>
> b\. The expectation is clear for 15 years of follow-up; what is the
> expectation when less than 15 years of follow-up is appropriate?

c\. How will this guidance apply to marketed products?

2.  In section II.a. second paragraph, we propose that "unpredictable
    adverse events" and "unpredictable and unpredictable biologic
    events" both be revised to "unexpected adverse events' and
    "unexpected and undesirable biologic events."

3.  The following comments pertain to section III. DEFINTIONS AND
    ABBREVIATIONS.

> a\. We propose that the definition of **Integration (of DNA)**, read
> as follows: "The process of whereby exogenous DNA sequences become
> incorporated into a [host]{.underline} genome."
>
> b\. We propose the definition of **Persistence** read as follows:
> "With respect to transferred genetic material, the continued presence
> of genetic sequences in the host after acute exposure to a gene
> transfer vector, whether due to integration of...genetic sequence." A
> timeframe for "persistence" should also be defined in the guidance. In
> addition, we believe that non-integrating vectors should be excluded
> and the timeframe for persistent expression should be defined.
>
> c\. We propose the definition of **Transgene** should read as follows:
> "A gene exogenous to the host and expressed as part of the gene
> transfer technology in order to implement the intended therapeutic
> effect."
>
> 4\. The following comments pertain to sectio IV PRECLINICAL DATA USED
> FOR ASSESSMENT OF DELAYED RISKS IN GENE THERAPY CLINICAL TRIALS.
>
> a\. At bottom of paragraph 4, we suggest adding the following sentence
> for clarification, "Thus data and/or publication citations should be
> submitted with the justification of the follow up plan."
>
> b\. With regard to Figure 1 in section IV.A., what follow-up is
> required besides the 15 year long-term follow-up is not explained. Is
> there specific expectation for some other shortened follow-up?
>
> c\. In section IV.B.2. we propose the following wording for the first
> paragraph: "Sample the following panel of tissues, at a minimum:
> blood, injection site(s), gonads, brain, liver, kidneys, lung, heart,
> and spleen. Consider other tissues for evaluation, depending on the
> vector type and the transgene, as well as the route of administration
> (e.g., draining lymph nodes and contralateral sites for
> subcutaneous/intramuscular injection, bone marrow, eyes, etc.). At a
> minimum, the blood samples will be analyzed. Analysis of the other
> collected tissues will depend on the degree of system exposure and
> other relevant study data."
>
> In addition we propose the addition of a new bullet at the end of
> section IV.B.2. which would read as follows:

-   An alternative to including spiked vector DNA in the third sample
    replicate for every tissue sample is to perform a validation study
    using vector DNA spikes into non-study animal tissue. The assay of
    the study animal tissue samples should then include QC control
    samples that mimic the test tissue samples but contain spiked vector
    DNA; i.e., tissue matrix with vector DNA aliquoted and stored
    similarly to the test samples. In either case the purpose els to
    control for sample storage condition, extraction efficiency, and
    sample matrix interference in the PCR reaction.

> d\. With regard to Table 1 in Section IV.C., what is the normal
> follow-up if long-term does not apply? For example: A further year or
> two of follow-up after a gene product is cleared completely seems
> reasonable and sufficient using the requirements as specified for the
> last 10 years of follow up.
>
> 5\. The following comments pertain to section V.D.
>
> a\. With regard to the recommendation that sponsors ensure that
> investigators contact participants once a year, etc., for a minimum of
> ten year, we feel that a further one to two years of follow-up after a
> gene product is cleared completely is more reasonable and is
> sufficient.
>
> b\. With regard to section V.D.5. on [Vector Sequences]{.underline},
> we have the following comment: Assays for persistent vector sequences
> would be limited to blood cells or limited biopsies depending on ROA
> and vector.