Are current regulatory frameworks hindering  development of promising regenerative medicines?

As a “cure of tomorrow”, as described by Dr Rob Buckle, UKRMP Director and MRC Chief Science Officer, regenerative medicine is attracting a lot of attention. In 2017, a record £128 million in funding was invested towards the research and development of regenerative medicine in the UK. The 2013 House of Lords regenerative medicine report identified these therapies as one of the “eight great technologies”, which would “propel the UK to future growth” defining them as “methods to replace or regenerate human cells, tissues or organs in order to restore or establish normal function".

There is high demand at both national and international level for regenerative medicine strategies to address common health problems, which is reflected in the significant investment level towards the development of new therapies by pharmaceutical and healthcare companies. The expected ageing of the UK’s population will continue to boost market opportunities for regenerative medicine products, as well as increase cost pressures on healthcare providers. There are also large and growing unmet medical needs; for example neurodegenerative diseases, stroke and heart failure currently have no significant therapeutic options and are therefore often managed with palliative care. The increase in population obesity and the accompanying rise in type 2 diabetes results in a growing market for related products, such as advanced wound-care for diabetic ulcers and cardiovascular devices.

Despite the significant medical need for regenerative medicine the regulatory approval rate for products is surprisingly low. Of the 500 clinical trials using ATMP (Advanced Therapeutic Medicinal Products) in 2009–2017, nine have been approved of which only five are still on the market, with three being withdrawn and one suspended. Signs of rising development activities in new advanced therapy medicines continue however, with a significant increase in companies seeking scientific advice in the area in 2012–2017. Between a quarter and a third of users of EMA’s PRIME (Priority Medicines) support scheme for developers of medicines for unmet medical needs are now involved in ATMP innovations.

The low ATMP approval figures are even more remarkable considering that several EU regulatory pathways exist to facilitate accelerated access to ATMP treatments where there is an unmet patient need. These include approval under exceptional circumstances, conditional marketing authorisations, accelerated assessments, parallel scientific advice between EMA and FDA and the adaptive licensing pilot programme.

Hence, many stakeholders have asked what is holding back the approval of regenerative medicines and sought the key reasons for the comparably high level of therapy withdrawals from the marketplace.

Current regulatory governance

Regenerative medicine comes with an unusual anatomy because of its cross-disciplinary approach and regulatory requirements. It bridges chemistry, medicine, computer science and engineering, which means it requires expertise from a variety of professionals and is governed via a multifaceted regulatory framework.

The translational pipeline from basic research to the delivery of innovative stem cell-based therapies is covered by a variety of European legal instruments ranging from regulations on marketing authorisation (Regulation (EC) no. 1394/2007) to Directives about Clinical Trials (Directive 2001/20/EC) and Guidelines of Good Clinical Practice (GCP) (Directive 2001/83/EC, Directive 2009/120/EC). Each EU member state has to implement these legal provisions at the national level, thus accounting for a second level of heterogeneity. In this respect, regulation is far from being totally homogeneous in Europe therefore not all the steps in the translational pipeline are equally addressed from a legal point of view. This heterogeneity in legal requirements amongst member states is viewed as a significant factor which contributes to the slowing down of the innovation process.

Such legal hurdles were the main focus of a regulatory affairs conference held in London in December 2017 organised by European Biopharmaceutical Enterprises (EBE). The lack of succinct EU GMP rules and post-marketing regulations on ATMPs has also been a significant gap in the regulations of such medicines, which is of importance given the requirement for GMP grade material to be used in both clinical studies and the final commercial grade product. In addition, there are currently no published international standards documents available to guide the testing and regulatory manufacture of ATMPs or Human Cell Tissue (HCT/Ps).These deficiencies increase the regulatory burden upon developers by limiting their understanding of how they must fulfil requirements and creating uncertainty over business practice.

Another aspect of the current regulation that is often highlighted is the lack of clarity of certain important regulatory product characteristics, namely the notion of substantial manipulation, that of non-homologous use and, finally, that of making the product available through the hospital exemption approval route. While the former categories create ambiguity in the classification of ATMPs, the latter is seen as a disincentive to engage in the complex, lengthy and expensive pathway that should lead to marketing approval.

Some stakeholders in the field also point out that the ATMP Regulation should be more specific, especially with regards to technical requirements for clinical trials and GMP for advanced therapies; cells are inherently more variable than conventional chemical compounds and, since they are viable, it is obviously hard to fully assimilate them in to drugs. This calls for more specific safety and efficacy criteria. Moreover, quite a number of promising advanced therapies in an early translational phase target rare diseases and may be difficult to validate on large cohorts: this has to be taken into account, and clinical trial design has to be adapted accordingly.

Future direction

The enormous potential and rapidly progressing science in this field of medicine depends significantly on achieving a flexible balance between the advancement of scientific innovation and having a robust legal regulatory environment to ensure that the most promising innovative therapies are made available to patients.

Proposals that were announced by the UK Department of Health (2016) (10) to develop a more enabling environment for ‘strategically important transformative products’ are regarded as an additional vehicle through which ATMPs might be fostered. Crucial to this will be the establishing of ‘accelerated access partnerships’ between public and private sectors and the NHS of a form not seen before, suggesting that its success will depend as much on identifying transformative processes as it will on products. In any debates on regulation and regenerative medicine, it is important that ongoing public dialogue continues so that public concerns and expectations can be addressed and managed.

A clearer and better-defined regulatory pathway, many argue, would be more encouraging for investors. For this aim, better coordination between the EMA and national regulatory agencies would be appropriate, so that researchers and their commercial partners can receive improved advice on the complex requirements for ATMP approval.

Cliodhna McDonough is a qualified clinical dietitian and a life sciences regulatory lawyer at Stephenson Harwood.