While the field of advanced therapy medicinal products (ATMPs) continues to mature, the process remains slow. Because they are classified as medicinal products, advanced therapeutics face the same requirements as any other medicinal product submitted for Market Authorization, as outlined under current European pharmaceutical manufacturing guidelines. Not surprisingly, the challenge of complying with these regulatory expectations in terms of quality, safety and efficacy was a recurring theme throughout discussions at PDA’s Advanced Therapy Medicinal Products conference in June in Madrid.

In particular, the complex nature of these products can make it difficult to determine what constitutes a complete control strategy. Speakers Jean-Hugues Trouvin, PharmD, Professor, Universite Paris Descartes, Jean Stanton, Director, Regulatory Compliance, Johnson & Johnson, and Karen Walker, Global Head Biologics and Biopharma Ops, QA, Novartis, brought attention to this topic. All noted how crucial it is to establish critical quality attributes (CQAs) and a quality target product profile (QTPP). The challenge with complex products like ATMPS, however, is ascertaining when those metrics are correct.

Many developers of small molecule pharmaceuticals have embraced QbD principles, but ATMP developers cannot apply QbD principles as strictly to their products. A possible path to initiating QbD for ATMPs could entail prioritizing product development to achieve the level of product control and understanding needed to progress through commercial development. Product knowledge will evolve throughout the development process, so flexibility and adaptability along with a risk-based approach are keys to successful CQA determination. The speakers recommended developing the QTPP as early as possible as a strategy. As Stanton noted, however, the QTPP cannot be successfully created in a silo; a multidisciplinary team is required to properly assess the CQAs that feed into the QTPP. Beyond this point, but still related to product development and understanding, reliable functional assays should be in place to determine how the product really works long before administration to the patient.

Safety concerns such as unexpected toxicity, inappropriate cellular differentiation and cross-reactivity are of special interest to the regulators tasked with approving ATMPs. Margarida Menezes Ferreira of Infarmed (Portugal’s regulatory authority) noted that a consistent, safe and effective product is required for Market Authorization and reiterated the paramount importance of product characterization. She also recommended that ATMP developers take time to meet with their respective regulatory authorities to discuss expectations and solutions. Trouvin spoke to this point as well, pointing out that the regulatory bodies understand the difficulties in developing ATMPs, are willing to collaborate further and have acted accordingly. Of particular note, the EMA has modified some regulatory guidelines specifically to allow for the peculiarities and challenges of ATMPs (Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal product; issued Feb. 2013). This guidance details a greater flexibility and allowances for nontraditional background qualification, assays and methods. The Committee for Advanced Therapies will review applications on case-by-case basis showing that there is no one standard road to approval. The key, as repeatedly stated throughout the conference, is well-validated and well-characterized products and processes.

As the presentations progressed, speakers pointed out how pharmacovigilance and long-term risk monitoring has allowed some technologies to continue development as well as aided in the approval of other ATMPs, notably Genzyme’s matrix-induced autologous chondrocyte implantation (MACI) therapy for the treatment of cartilage damage.

Practical considerations discussed included the marketing and distribution of tissue-based products, such as whether a company should apply for a CE mark first or go to market via another route. Ferreira responded that products have to be CE marked for their intended use in order to be distributed in the European Union. The problem arises, however, that—just as with many pharmaceuticals—ATMPs do not always end up being prescribed for their original intended use. Even beyond approval, since the target populations are often very small, reimbursement concerns were noted as one of the many hurdles for companies trying to develop successful ATMPs.

The promise of ATMPs is being realized, as seen with ChondroCelect (autologous cartilage repair therapy from TiGenix), Glybera (a gene therapy from UniQure that aids in fat digestion for those with defective enzymes), and Provenge (Dendreon’s autologous cellular immunotherapy for the treatment of prostate cancer). Support from regulatory bodies is behind them as evidenced by the collaborative process developed to work through the development and approval processes. Both parties understand that there is no one way, uniform answer, or magic solution for a successful application, and that development of ATMPs is not a “tick box” exercise as has been developed over the years with small molecule pharmaceuticals.

While more changes and challenges may be in store now that the EMA issued a draft guidance on the classification of ATMPs in June, the will and dedication to persevere in developing lifesaving and life-changing ATMPs is alive and well.