Developing a new treatment for a disease is a long and complex process. A great deal of laboratory research is needed, but turning this research into a treatment that's ready for patients involves many other steps too. Commercial organisations play a key role in this process.
It is estimated that a new therapy costs on average 760 million Euros to develop from initial scientific discovery to medical product.
Cells for use in treating patients must be produced in specialised 'GMP' facilities to meet high quality standards
Therapies using stem cells pose some new challenges compared to conventional drugs that can be readily standardised and mass-produced
Under European law, anything that treats or diagnoses a disease is classed as a Medicinal Product and must have a government licence before it can be offered to patients (with a few specific exceptions for hospitals). To apply for a licence, the producer of the new treatment must show that it is safe, effective in treating a particular disease and manufactured to a high quality standard known as Good Manufacturing Practice or GMP. This may sound quite simple, but it can take many years and numerous clinical trials to gather the huge amount of supporting evidence needed to show that these requirements have been met.
It can cost hundreds of millions of Euros to carry out the research needed to show that a new treatment is safe and effective enough to be given a full Marketing License. A great number of potential products fail at some point in this process, so the development of new therapies is a very risky enterprise for funders and businesses. Although most of the research into stem cell therapies is currently carried out in university laboratories and funded by national, European-level and international governments, these public funds are unlikely to provide enough financial support to gather all the data needed for a full marketing licence. Regulatory agencies such as the European Medicines Agency appreciate that this may mean it takes longer for patients to benefit from new breakthrough therapies and have provided schemes to allow exceptions to the usual licencing system for a few carefully chosen non-routine uses of experimental treatments.
The majority of new treatments will have to pass through the full licencing process. For most existing medicines, such as conventional pharmaceutical drugs or biological medicines like antibodies, the work needed to obtain a marketing licence has traditionally been carried out by the pharmaceutical and biotechnology industry. Companies and investors take the enormous financial risks of developing a product in return for the large potential revenues that may be generated by selling a licenced and effective medicinal therapy. There is currently considerable debate about exactly how this process will work for future stem cell therapies, which pose some new challenges. Development of a licenced stem cell therapy may require partnership between publicly funded groups and commercial companies, but it is clear that companies will play an important role.
The pharmaceutical and biotechnology industry is massive, with thousands of companies around the world working in different specialist areas, using different technologies and business strategies. However, all these companies can be divided into two general types:
Both types of company have to go through the same process to develop a licenced medical product that will provide a return on their investment. However, the different types of companies have very different ways of operating and taking risk. Stem cell technology is relatively new and is seen by commercial organisations as risky because there are a great many unknowns that could prevent any one particular therapy from gaining a licence. Although all of the world’s ten largest pharmaceutical companies are to some extent involved in the commercialisation of stem cells, they are only investing on a relatively small scale. Most of the advances are currently taking place in smaller (type 1) companies, sometimes in collaboration with large company partners.
At its most basic, the process of turning a medical research discovery into a product is quite simple and has just two key elements: a licence to market the product and agreement from someone to pay for it. However, there are a great many ways in which these two elements could be obtained and the correct strategy depends upon the product, the medical condition it is intended to treat and the countries where the product will be made available. Developing stem-cell-based medical products has some unique challenges and will require some new systems of gathering and assessing evidence, but the main types of information required to take research discoveries to the clinic will be very similar to those needed for other types of medical products.
Step 1: Identifying what evidence is needed
Two of the most critical decisions any researcher makes in the long road to developing a new medical product are what specific disease will be treated and what type of technology will be used to address it. These decisions will impact every subsequent stage in the development of the new treatment. They will determine how regulators view the medical risks associated with the treatment and therefore the amount of evidence they demand with the licence application. They will also be critical in the health economics of the treatment: what will it cost and how will managers of health systems decide whether to pay this price for the product? The risks, benefits and costs will be weighed in a very different way for a new treatment targeting a rare, life-threatening disease with no alternative therapy than for a treatment aimed at a common chronic disease that is rarely fatal and for which alternative therapies already exist. Both types of treatment will need the basic aspects of product quality, safety, medical effectiveness and cost-effectiveness, but the amount of evidence required will vary significantly.
Step 2: Collecting the evidence
At the heart of the established system used to develop most of today’s medicines are clinical trials on human patients. A new treatment usually goes through three main phases of clinical trials before it is made available to patients:
The first cell-based therapies using cells that are NOT stem cells have been available to patients for over a decade. The first stem-cell-based therapies to go through this clinical trials process are now entering Phase I or II trials. Scientists, social scientists, companies and policy makers are discussing some of the challenges these cell-based approaches pose. For example, some stem cell therapies hope to use each patient’s own cells in their treatment. This will make large-scale testing on many patients more expensive and harder to standardise than tests of a drug that can be produced as thousands of identical pills. The clinical trials system may need to be adapted to take into account new methods and types of evidence.
Step 3: What does the evidence show?
Over 90% of all potential therapies fail at some point during the development process. This may be because:
Deciding whether a new treatment is better than an existing one is a complicated issue. To make sure a clinical trial result is really significant and not just down to chance, a certain minimum number of patients must be tested. This number is defined by well-established statistical methods and depends on the expected effect of the treatment. If the effect is expected to be large then a small number of patients may be sufficient to establish that researchers are seeing a real and meaningful, or ‘statistically significant’ result; if the effect of the treatment is anticipated to be small, then a larger number of patients must be studied in order to see the effect clearly and make sure any positive results are genuine.
The number of patients needed to trial a new therapy can range from around 100 to several thousand. Extensive data must be gathered for each individual and a clinical trial costs around €20,000 to €40,000 per patient. Even a relatively small series of Phase I, II and III studies costs well over a million Euros, while some larger trials cost over a hundred times more.
Step 3: Applying for a licence
Once all the necessary evidence has been obtained, a new treatment must be submitted to the regulatory authority: The European Medicines Agency (EMA) in Europe, or the US Food and Drug Administration (FDA) in the USA. Any stem cell therapy must meet the specific requirements of Europe’s Advanced Therapy Medicinal Product (ATMP) legislation to obtain a licence. These agencies typically take 1-2 years to review the data, will ask hundreds of detailed questions and charge a fee for this assessment process. The initial application submission can also cost around €300,000 (US and EU fees combined) although these fees are reduced for small companies and sometimes waived entirely.
Step 4: Getting the treatment to patients
If the licence application for a new treatment is approved, then the organisation that developed the new medical product begins a long process to obtain payment from health systems and health insurers in countries where the treatment is to be used. In Europe this payment or reimbursement process takes place country by country and in the USA state by state. Additional evidence is sometimes needed to support the price requested for the product. It can take several years after approval of the product licence before healthcare providers and insurers begin to pay for the therapy. There is currently considerable work being done to develop systems that enable patients to get breakthrough treatments for unmet medical conditions more rapidly whilst this long process is continuing. The FDA in the USA has set up a system called expanded access and similar systems are under consideration at the European Medicines Agency.
The road from initial laboratory research to a new treatment for patients involves many hundreds of people with a wide range of expertise and views: patients themselves, regulators, academic scientists, commercial organisations, the reimbursement agencies who will pay for the treatments. Commercial organisations have played an important central role in this process for most existing medicines, developing the evidence needed to obtain a medical product licence and financial reimbursement for a new treatment, then manufacturing and distributing the product to patients. The development of future stem cell therapies may require changes in our clinical trials and licencing systems, but commercial companies will no doubt continue to play a vital role.
Hope Beyond Hype comic: a story about stem cell therapies from science discovery to working therapy
Commercial cell therapies in Europe - a brief introduction by Michael Morrison
Interview with Allen Eaves: academic turned company CEO
The Road to the Clinic flow chart showing the traditional path from research to treatment
European Medicines Agency (EMA) information on stem cells
UK Stem Cell Toolkit of specialist information on regulatory requirements for stem cell projects