This commentary aims to demonstrate how frequent interactions between a medicines
developer, regulators, Health Technology Assessment (HTA) bodies, and patients during
the development can result in accelerated access by patients to an innovative product,
in this case, a gene therapy medicinal product for beta‐thalassemia. The majority
of patients, who needed at least eight transfusions per year in the last two years
before treatment, remain transfusion independent over 12 months after Zynteglo (bluebird
bio (Netherlands) B.V., Utrecht, The Netherlands) administration. Early approvals,
albeit based on robust data, are only possible if a well thought‐through postapproval
commitment plan is put in place.
The recent European Union marketing authorization of Zynteglo (lentiglobin) illustrates
how well planned and executed interactions among a medicines developer, regulators,
HTA bodies, and patients, can result in accelerated access by patients to an innovative
product targeting an unmet medical need.
Patients with transfusion‐dependent beta‐thalassemia require lifelong blood transfusions,
leading to iron overload that impacts the patients’ quality of life. So far, the only
curative treatment option is allogeneic hematopoietic stem‐cell transplantation (HSCT),
with related considerable morbidity. Mortality for patients with beta‐thalassemia
remains significantly increased compared with the general population.1, 2
Zynteglo, a gene therapy medicinal product,3 represents a paradigm change in management—a
treatment consisting of an autologous CD34+ cell enriched population that contains
hematopoietic stem cells transduced with lentiviral vector encoding the β‐globin gene.
Such innovative treatment modalities break new ground for patients and their clinicians
as well as for developers and regulators, which can make generation of appropriate
data to support licensing and, ultimately, access, a challenge. Preliminary clinical
data for Zynteglo were promising, but important questions were identified early during
clinical development. These were related to clinical trial design and sample size
due to the nature of the clinical end point, the rarity of the condition, and difficulties
in identifying a suitable comparator, type, and duration of postauthorization efficacy
and safety follow‐up, and to the impact of manufacturing changes on the interpretation
of clinical data. Questions related to evidence generation for value assessment by
HTA and reimbursement by healthcare payers also needed to be tackled, to facilitate
patient access after marketing authorization.
Thus, Zynteglo was an ideal candidate for enhanced regulatory dialogue during development.
It was included in a pilot project to explore the use of iterative development and
real‐world data collection, Adaptive Pathways,4 and then granted access to a European
Medicines Agency scheme for priority medicines (PRIME),5 both schemes offering platforms
for more frequent interactions during development.
Cell‐based and gene therapy medicinal products are particularly sensitive to changes
in their manufacturing conditions, and this can often lead to difficulties in the
evaluation process because the commercial product may be produced by a modified process
compared to that used preauthorization for clinical trials. In the case of Zynteglo,
changes in the manufacturing site and processes like improvement of transduction efficiency
in the commercial scale process were discussed with regard to their impact on the
interpretation of clinical data. Other points were the timing of data submission and
qualification of the apheresis collection centers.
Clinical issues were discussed together with patients and HTAs to help support subsequent
patient access. Aspects included:
The suitability of clinical data set (efficacy and safety) to support submission of
a conditional marketing authorization application (a European Union procedure allowing
licensing of a medicine to address an unmet medical need on the basis of less comprehensive
data than normally required), including number of treated patients and their genotype.
Discussion and agreement on the primary end point, “transfusion independence.”
Extrapolation models for prediction of both long‐term efficacy and for inclusion of
children in the trials.
Design of confirmatory trials and real‐world data generation to assess long‐term efficacy
and safety following a conditional marketing authorization.
Proposed pharmacovigilance and risk minimization plans.
Full details of the discussions and assessment can be found in the European Public
Assessment Report available at the European Medicines Agency website (http://www.ema.europa.eu).
A series of scientific advice procedures took place between 2015 and 2017. This iterative
engagement during development ensured that issues were addressed early to prevent
delays in regulatory approval.
As the scientific advice process had allowed prediscussion of the more complex issues,
and given the unmet need, the marketing authorization application, which was submitted
in August 2018, was granted accelerated assessment. This reduced the timelines for
the evaluation and final opinion of Zynteglo (in March 2019) by several months.
The Zynteglo approval provides an example of the advantages resulting from iterative
scientific advice. First, the discussions ensured that the studied patient population
did meet the intended labeling claim (i.e., patients 12 years and older with transfusion‐dependent
β‐thalassemia who do not have a β0 mutation at both alleles of the β‐globin gene (i.e.,
patients with a non‐β0/β0 genotype), for whom HSCT is appropriate but a human leukocyte
antigen (HLA)‐matched related HSCT donor is not available).
Second, although the number of subjects included in the marketing authorization application
was only 19 and the follow‐up time relatively limited (12 months), the data presented
showed robust results by achieving transfusion independence in 15 of 19 patients.
Because these patients had consistently required eight or more transfusions per year
in the last 2 years preceding enrollment, it was considered that transfusion independence
in the majority of patients is extremely unlikely to be a result of disease fluctuation
or a chance finding, but demonstrated an effect that is both patient‐relevant and
of high magnitude. The safety profile included the expected adverse events related
to mobilization, apheresis, and myeloablative conditions. This was deemed acceptable
in light of the clear beneficial effect.
During the clinical studies, the drug manufacturing process was changed and optimized.
At the time of approval, only three patients with the β0/β0 genotype had been treated
with product manufactured by the commercial process. A comparability exercise between
the previous process used for clinical trial material and the commercial manufacturing
processes at the quality level had been extensively discussed before the evaluation.
Given the well‐known sensitivity of gene therapies to changes in the manufacturing
process, and resulting uncertainties regarding their impact on drug product potency
and clinical outcome, these changes might have contributed to a negative regulatory
decision. However, in this particular case, pharmacodynamic parameters and efficacy
results were consistent across studies. To address these uncertainties, the Agency
decided to impose the following obligations: (i) tight control of the finished product
potency attributes and (ii) reevaluation of the acceptance criteria for attributes
related to the drug product potency tests using batch release data and clinical results
after 6 months follow‐up of 20 patients treated with commercial batches. It is up
to the company to resolve the issues speedily and launch the product.
As consequence of the limited data base at marketing authorization, additional safety
and efficacy data need to be collected during ongoing clinical development, such as
in patients 12 years and older who do not have a β0/β0 genotype. In addition, all
patients treated with Zynteglo need to be followed up to assess the duration of efficacy
and to further specify the safety of the product. This includes the assessment of
a theoretical risk for insertional mutagenesis that is common for CD34+ genetically
modified cells. Although this risk has been minimized by the design of the lentiviral
construct and through the manufacturing process and no evidence of such risk was observed
at the time of the marketing authorization, all patients need to be monitored for
development of leukemia or lymphoma until 15 years posttreatment with Zynteglo.
To comply with the requirements for long‐term follow‐up, a product registry has been
set up for patients treated with Zynteglo and patients treated with transfusions or
HLA‐matched allogenic HSCT‐treated patients. All of these topics had been considered
in the earlier interactions with the company and helped to facilitate the definition
of postapproval commitments.
This marketing authorization procedure and the preceding intensified regulatory support
have also shown how regulatory advice with involvement of reimbursement bodies, up
to the time of market authorization, can help to foster patient access. HTA bodies
expressed their data needs to ensure that—once the product received regulatory approval—they
would have the tools to swiftly make a value assessment informing pricing and reimbursement
decisions. In addition, HTA bodies and payers could be given reasonable assurance
that treated patients would be monitored for efficacy and safety as a result of the
well‐defined postmarketing commitments agreed on with the manufacturer. The Zynteglo
experience highlights the value of European regulatory tools for early access (i.e.,
conditional marketing authorization and accelerated assessment), when the nature of
the data required for the authorization and postapproval to confirm the initial opinion
have been discussed upfront. It underlines the importance of setting up processes
that enable such early interactions without compromising impartiality when assessing
the results generated by the experiment.
The required effort on all sides is high and such resource‐intensive support should
be reserved for products that are highly likely to offer true advancements for patients.
In our experience, there is specific value for innovative and first‐in‐class medicines
for patients with rare diseases and high unmet medical need. Due to their overall
complexity and novelty, gene and cell therapy medicinal products particularly benefit
from this enhanced support.
We believe that this is an important avenue to pursue to ensure robust data are collected
in the most efficient way and genuinely innovative products reach patients with unmet
needs without undue delays.
Funding
No funding was received for this work.
Conflict of Interest
As an Associate Editor for Clinical Pharmacology & Therapeutics, Spiros Vamvakas was
not involved in the review or decision process for this paper. The authors declared
no competing interests for this work.
Disclaimer
The views expressed in this paper are the personal views of the author(s) and may
not be understood or quoted as being made on behalf of or reflecting the position
of the European Medicines Agency or one of its committees or working parties.