FDA Leader: We Need To Remove Surprises From Gene Therapy Development
Peter Marks Addresses Commercial And Regulatory Hurdles
Executive Summary
Embattled gene therapy companies will take comfort from desire of FDA and EMA help smooth the process of bringing the novel treatments to market.
Amid ongoing difficulties in the development and approval of gene therapies, US and EU regulatory leaders have said they want to help biopharma to reduce the hold-ups and surprises which have plagued the sector - though the industry may well reflect that this is a two-way street.
Speaking at a cell and gene therapy conference, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER) at the US Food and Drug Administration and the European Medicines Agency’s head of advanced therapies, Ana Hidalgo-Simon, said regulators and industry needed to work together to address bottlenecks such as trial endpoints, manufacturing issues and even market access.
Their comments will be encouraging for the many gene therapy companies which are running low on cash and investor confidence. (Also see "Is The Downturn A ‘Darwinian Moment’ For Biotech? The View From The Frontline" - Scrip, 21 Apr, 2022.)
The number of FDA-imposed clinical holds surged last year, and research conducted by Jefferies found 40% of these were for cell and gene therapies.
Among the potential blockbuster products which have suffered serious delays are BioMarin’s potential first-in-class hemophilia A therapy valrox and bluebird bio’s beta thalassemia candidate Zynteglo (betibeglogene autotemcel) over efficacy and safety and quality control issues, respectively.
Consistency Is Key
Marks told the American Society of Gene & Cell Therapy conference on 17 May that a recent survey of trial sponsors conducted by the FDA’s Office of Tissues and Advanced Therapies (OTAT) had given a clear message – give us more consistent rulings and better communication.
“Sponsors were very vocal about the fact that they found it highly problematic when one of their gene therapy programs got advice on for example, manufacturing, that was different than another one of their gene therapies that were very similar,” he said.
However, he and his European counterpart Hidalgo-Simon stressed that agency “bandwidth” was finite, and sponsors could not expect regulators to replicate the 24/7 communications established for COVID-19 vaccines during the pandemic.
The FDA is nevertheless undertaking an internal review to help free up its experts’ time and allow for greater engagement with industry, while the EMA is spreading its workload out across more of the regulatory agencies in its 27 member states to speed reviews.
Marks said problems of quality control in manufacturing, clinical trial endpoints and durability of efficacy were the biggest causes for regulatory delay and review. In manufacturing, the US regulator has frequently found inconsistencies between gene therapies products used in early studies and the versions manufactured later at a larger scale, raising questions about safety and efficacy.
The FDA was also sufficiently alarmed about the safety of AAV gene therapies to convene a panel of outside experts to review the issue in September 2021.
Agreeing Surrogate Markers Upfront
Marks said one simple improvement to the gene therapy development pathway would be to agree surrogate endpoints and post-marketing study commitments before trials are begun, as presently these are often suggested only once studies are underway. This would allow sponsors to have their “eyes wide open” as their gene therapy is developed, and would reduce the risk of a surprise, he added.
That point might raise eyebrows at some companies, which claim the FDA has sometimes moved the goalposts on pre-agreed trial data requirements, and sprung surprises in complete response letters (CRLs).
BioMarin is one such company; it raised objections after valrox received a CRL in August 2020. The firm claimed the agency had previously asked for one year’s post-treatment data, and that the first mention of the need for two-year follow-up data came only in the CRL. (Also see "BioMarin Gears Up To Give Roctavian Another Go" - Scrip, 13 Jan, 2022.)
Referring to the hemophilia field, Marks confessed that the agency had been surprised a number of issues, including problems of durability in the AAV candidates and measurements of Factor VIII. He said assays had not always provided an accurate picture of the patient’s condition, but nevertheless expressed confidence that these issues would be only a ”bump in the road.”
He added that the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation allowed many ways for post-approval commitments to be met and could be agreed in advance.
Ongoing delays by some companies in meeting post-marketing commitments – eg, with Biogen’s Alzheimer’s drug Aduhelm (aducanumab), Sarepta’s Duchenne muscular dystrophy drugs and numerous cancer therapies – have generated so much controversy that the US Congress will now review whether to limit the accelerated approval pathways. (Also see "Moving Beyond Aduhelm: Cell/Gene Therapy May Be ‘Poster Child’ For What Comes Next" - Pink Sheet, 25 Apr, 2022.)
Marks said he hoped no major changes would be made, but admitted that the FDA needed to become “better policemen” to ensure confirmatory studies are completed in good time.
Confronting The Gorilla
While market access issues are traditionally outside the remit of regulators, both Marks and Hidalgo-Simon said these were a big stumbling block to bringing more cell and gene therapies to patients with rare or incurable diseases.
Marks called reimbursement “the 800 pound gorilla in the room” and said it was the reason why there was so much nervousness about drugs given US accelerated approval.
He added that the value proposition for Novartis’s spinal muscular atrophy therapy Zolgensma (onasemnogene abeparvovec) had been “overwhelming” – even with its record-breaking $2.1m cost. (Also see "US Vs. EU: Is Cell And Gene Therapy Reimbursement Easier Stateside?" - Scrip, 14 Oct, 2021.)
Peter Marks
However, a therapy’s value is more contentious in non-life threatening diseases. “How that issue is resolved, will potentially affect how many people go into this field to try to develop therapies,” he added.
In Europe, the problem has been even more stark, with health technology assessment (HTA) bodies setting a high bar for cost effectiveness evidence, and being uncomfortable with accelerated approval based on surrogate endpoints.
There have been several examples of rare disease therapies which gained EU approval, only for companies to decide they were not commercially viable. Last year, bluebird bio announced it was withdrawing its beta thalassemia gene therapy from all EU countries after failing to secure reimbursement in the key German market.
“That is a catastrophe for everybody, above all for the patients,” said Hidalgo-Simon, adding that efforts of companies, regulators and patients in clinical trials must not go to waste.
The two regulatory leaders agreed that international convergence on regulation was needed to support global gene therapy studies for smaller, rare disease patient groups, and to make the research more commercially viable, and to encourage early discussions between sponsors and HTA organizations.
The fortunes of the sector could be lifted by some expected approval decisions. Three of the next biggest milestones will be for BioMarin’s hemophilia A therapy, which was filed with the EMA in December and is expected to be filed with the FDA at the end of June, and the US agency’s decision on two bluebird candidates: beti-cel for beta-thalassemia and elivaldogene autotemcel (eli-cel) for cerebral adrenoleukodystrophy, the latter two both to be reviewed by an FDA advisory committee on 9-10 June.