The theoretical basis for cell therapy dates back to the 16th century, when a physician named Paracelsus wrote, “Heart heals the heart, lung heals lung, spleen heals spleen; like cures like.” That quote reflects the belief of many early physicians that the best way to treat illness was to use living tissue to rebuild and revitalize diseased or aging tissue. Today, many different types of cell therapies are being studied in clinical trials, with potential uses in a wide range of disease states, including genetic deficiencies, cancer, and metabolic disorders. Cell therapy has distinct advantages over other treatments because it stimulates the body’s own healing power, thereby providing long-term effects while offering hope of a potential cure with minimal side effects. The types of cells used in therapeutic applications include stem cells, dendritic cells, immune cells, and cells from organs such as the liver, pancreas, bladder, and retina. The source of the cells can be autologous (the patient’s own cells) or allogeneic (from a related or matched donor). Once harvested, the cells can be used to stimulate growth of new blood vessels and organs, as well as to reconstruct and repair cardiac and other types of tissues, to name just a few examples. The possibilities seem endless.
Yet despite their great promise, development of cell therapies has been hindered by the lack of precedent for approved products in this area. The development process and business models for cell therapies vary greatly from those for traditional drugs and biologics, largely because cell therapies tend to be individualized and expensive to produce. For example, Dendreon’s Provenge®, which was recently approved for the treatment of prostate cancer, cost about $1 billion to develop and will cost patients around $93,000 for a full treatment, or about $23,000 per month of life extension Moreover, product lots for cell therapies generally provide the dose for one patient or for one dose in a few patients; by contrast, product lots for some traditional drugs and biologics can provide as many as several thousand doses. In addition, most cell therapies are living cell products and have a shelf life of a few hours to perhaps a few days.
Such developmental nuances can impact the design and conduct of cell therapy clinical trials, which differ greatly from traditional clinical trials. For example, cell therapy trials require a great deal of coordination between the manufacturing site and the trial site to facilitate delivery of the living product after final formulation for immediate administration to the patient. Additionally, because many cell therapies require remodeling within the body to exert their effects, efficacy and safety endpoints may not be reached for several months or years. Indeed, most efficacy studies for cell therapies average at least 12 months, and some last from 2 to 5 years. Furthermore, since the cells incorporate into the body, regulatory agencies are insisting that marketing applications include data showing duration of response and long-term safety. Those challenges can conspire to prolong the development process for cell therapies while making the process even more expensive.
As for the regulatory process, there are no harmonized global regulations such as the International Conference on Harmonisation (ICH) guidelines for traditional drugs and biologics. In the US, cell therapies fall under drug and biologic regulations, and a Biologic License Application (BLA) must be filed to obtain marketing approval. In Europe, cell therapies are regulated under the European Union’s Advanced Medicinal Products Directive, whereby each member state must approve clinical trials conducted in that state, and a marketing authorization application must be submitted to the European Medicines Agency (EMA) through the agency’s centralized review and approval process.
Very few cell therapies have been approved to date. In the US the first cell therapy approved was Genzyme’s autologous chondrocyte for knee repair. On April 29, 2010, the Food and Drug Administration (FDA) licensed Dendreon’s Provenge, an autologous antigen-presenting cell, for the treatment of metastatic, castrate-resistant prostate cancer. This therapy is the first in its class and is designed to use the patient’s own cells to boost the immune system to fight cancer. In Europe, TiGenix received approval to market ChondroCelect® on October 6, 2009. An autologous chondrocyte for treatment of damaged knee cartilage, ChondroCelect is the first product to be approved under the Advanced Medicinal Products Directive.
The number of companies developing cell therapies continues to increase, and several companies’ pipelines include cell therapies that are slowly moving toward marketing applications. However, most of these companies are very small, and thus, very cost-sensitive. Although big pharmaceutical companies are increasingly interested in stem cell therapies, the inherent developmental and logistical challenges, as outlined above, make it difficult for many large drug companies to master the manufacture and delivery of cell therapies. Nevertheless, Pfizer has made a major investment in stem cell therapies, and Novartis recently acquired Opexa’s stem cell product for diabetes. It is therefore hoped that big pharma can provide the impetus and resources to bring these promising therapies to market faster so that patients can benefit.