www.biopharminternational.com March 2020 BioPharm International eBook 11
CMC requirements in the final
guidance (2):
• Def inition of batch-scale
and quantification of drug
substance (such as vector
genomes), and harvesting
or intermediate pooling and
storage conditions to be estab-
lished for each pool
• Preference for non-animal
derived reagents and some
explanation of current think-
ing on qualification of differ-
ent cell banking systems
• Written standard operating
procedures for all stages of
manufacturing development
• Use of comparability studies
to determine the impact of
manufacturing changes on
product safety
• Analytical procedure valida-
tion, in particular, the use of
qualifying assays to determine
the initial clinical dose.
• Verification of the compatibil-
ity of drug product with the
diluent used to reconstitute or
deliver the therapy
• Use of in-process sterility tests
for releasing drug product for
ex-vivo genetically modified
cells
• Use of assays to determine
safety and dose, and for prod-
uct release
• Use of sterility, endotoxin, and
identity testing on containers
of final product
• Specification of facility infor-
mation, including manufac-
turing flow diagrams and
some details showing differ-
ent aspect4s of facility design
• Assessing the potential risk,
and avoiding contamination
of product by adventitious
and non-adventitious agents.
For Module 1, the administrative
information section of the CTD, the
final guidance sets requirements for
labeling autologous vs. allogeneic
materials. For any manufacturing
change amendments made to the
IND, FDA has asked for a "review-
er's g uide," essentially, a docu-
ment with Microsoft Word's "track
changes" enabled. The regulators
have also asked that developers
give them 30 days to review any
changes before releasing a new lot
of clinical trial materials.
ORIGINAL GUIDANCES
LEFT LARGELY INTACT
Experts note that there were few
changes to draft guidance for the
testing of retroviral vector-based gene
therapy products, except that a new
section was added discouraging the
use of replication-competent retro-
virus testing for vectors produced
using a vector producer cell working
cell bank, and revising recommenda-
tions on test assays (7,8,9). Similarly,
final guidance for long-term patient
follow-up remained similar to draft
guidance, except that a footnote was
added to clarify conditions to which
the final guidance will not apply
(e.g., vaccines for infectious diseases
or bacteriophage products) (7,10).
Experts note few changes from
FDA's draft to its final guidance for
gene therapies developed to treat
retinal disorders (7, 11). In moving
from draft to final guidance for rare
diseases in general (12), they note
changes to the CMC section, to bring
the document in line with the final
CMC guidance (5,7), as well as the
inclusion of more information on
biomarkers.
The final guidance for gene ther-
apies designed to treat hemophilia
includes revisions to recommenda-
tions on specific clinical efficacy end-
points. It also recommends enhanced
pediatric studies as well as more
frequent communication with the
agency (7, 13).
Gene and cell therapy develop-
ment shows no signs of slowing, and,
quoting FDA projections, McKinsey
analysts expect to see from 10 to 20
cell and gene therapy approvals per
year over the next five years. These
therapies will involve familiar plat-
forms including adeno-associated
virus and lentivirus, but also anti-
sense oligonucleotides and ribonu-
cleic acid interference (14). FDA's new
guidance documents should help
clarify expectations, thereby improv-
ing communication between regu-
lators and developers, and speeding
the overall commercialization of
more gene and cell therapies.
REFERENCES
1. FDA, "FDA Continues Strong Support
of Innovation in Development of Gene
Therapies," Press Release, Jan. 28,
2020.
2. K. Hacker, "FDA Gene Therapy
Guidances: The Latest Updates
Explained," Clarkstonconsulting.com,
February 17, 2020.
3. FDA, "Cellular and Gene Therapy
Guidances," fda.gov, Feb. 14, 2020.
4. E. Bender, "Regulating the Gene-
Therapy Revolution," nature.com, Dec.
12, 2018.
5. FDA, Interpreting the Sameness of Gene
Therapy Products Under the Orphan
Drug Regulations, Draft Guidance (CBER,
January 2020).
6. FDA, CMC information for Human Gene
Therapy Investigational New Drug
Applications, Final Guidance (CBER,
January 2020).
7. K. Auchincloss, "An Analysis of
FDA's Recently Issued Gene Therapy
Guidances," cellandgene.com, Feb. 20,
2020.
8. Ropes & Gray Regulatory Practice,
"FDA Issues Gene Therapy Guidances,"
ropesgray.com, February 3, 2020.
9. FDA, Testing of Retroviral Vector-Based
Human Gene Therapy Products and
Replication-Competent Retrovirus Drug
Manufacturing and Patient Follow-Up,
Final Guidance (CBER, January 2020).
10. FDA, Long-Term Follow-up After
Administration of Human Gene Therapy
Products, Final Guidance (CBER, January
2020).
11. FDA, Human Gene Therapies for Retinal
Disorders, Final Guidance (CBER,
January 2020).
12. FDA, Human Gene Therapies for Rare
Diseases, Final Guidance (CBER,
January 2020).
13. FDA, Human Gene Therapies for
Hemophilia, Final Guidance (CBER,
January 2020).
14. E. Capra et al., "Gene Therapy Coming
of Age: Opportunities and Challenges to
Getting Ahead," mckinsey.com, October
2019.
BP
Regulatory Sourcebook Gene and Cell Therapies
