Charlotte your question is very open ended, every drug before reaching the market and be allowed for use in humans for specific diseases treatments goes through a long research and development process, which goes by stages, and many factors influence the time and details of the investigations required. Each jurisdiction has its own regulatory system e.g. FDA in the USA, HPFB in Health Canada and so on. New procedures, molecules usually have a longer pre-clinical testing and clinical testing may require larger and longer period for patient recruiting. Macular degeneration is a chronic progressive irreversible condition associated with aging, recruiting of patients may be a challenge by itself. Regarding if an individual can be allowed to use a procedure or drug  before it is approved by a regulatory agency, most agencies also have the mechanism to allow such requests. The request is usually made by the treating physician, and has to follow specific guidelines and filling of forms which are given by the regulatory agency of your jurisdiction. There are specific office in each organization that does this type of work. 

For further information on the R&D of new therapies I suggest consult:  Haschek and Rousseaux’s Eds., Handbook of Toxicologic Pathology 3e, Elsevier, 2013

and consult the web pages of the FDA and Health Canada

Drug development is a lengthy process. A new molecule after its development, first undergoes evaluation in animal models or on isolated tissues. This gives the clues to the pharmacological activities present in the compound. The toxicological screening is also done in animals. It includes studies on acute toxicity, chronic toxicity, mutagenic/carcinogenic potential, teratogenic potential and specific organ toxicities. Pharmacokinetic studies are also conducted in animals initially. Once the efficacy and safety in animals has been established, the drug enters into the phase of clinical trials. After evaluation in limited number of volunteers/patients in the phase-1 and phase-2 trials, the drug is allowed to be used in larger number of patients in phase-3 trials. The regulatory process of concerned countries may start side by side with phase-2 or phase-3 trials. The phase-4 encompasses the post marketing surveillance and is an ongoing process. The patients do have a say in allowing the use of drugs in them as all the clinical trials require informed consent of the patients.

Dear Charlotte,

what means very promising ? Animal experiments, in particular data in mice do not guarantee at all success in clinical trials in humans. Regulatory bodies have to make sure that patients are not endangered and that the risks associated with the treatment are (more or less) controlled. Stem cells are not the cure-all they might seem, for example, adult stem cells injected into tissues tend to die off fast, they do not necessarily hang around for long. This raises the question of what the stem cells might actually be doing besides releasing cytokines as their swan song. Secondly , iPS or HES can form tumors, teratomas. Thats something you dont want to give to a patient , ironically teratoma formation is a quality criterium ensuring stemness (pluipotentcy).  The original assumption that stem cells, such as MSCs blend into their microenvironment and help build new/ or regenerate tissue has changed to a view that MSCs are immunomodulatory, not much talk of tissue regeneration anymore. Now MSCs, are seen like a micropharmacy, at least a temporary one, but talk about adding themselves to tissue biomass has become rare.

 So the promises of cell-based therapies are being refined, while a lot of crooks offer unproven cell therapies. Unproven means, unproven safety and unproven efficacy, two main criteria, that regulatory bodies postulate. And to show all this takes a long time and logistics and costs a lot. The alternative is to get treated in some shady clinics and the best case scenario is that it has not worked. Google these incidences. Our understanding of what stem cells taken from yourself or someone else can do is just evolving, Data from developmental biologists on zebrafish etc are quite enlightening but to cast this into a therapeutic approach is a completely different thing. Also, the core problem is the following: taking stem cells out of the body and growing them ex vivo in cell culture systems has a major impact on their ultility. Growing stem cells well is an art and this is the current bottleneck. I predict that advances in cell cutlure will increase the ultility of stem cells, however, this is translational work for which you dont get a Nature paper and so is not interesting to basic stem cell scientists. So you dont get funding easily for this kind of "mundane: work, and so this slows progress down considerably. This is another facet that shows that progress in reality is a snail. Patients can choose, but mostly will be just parted from their money, and this hasnt changed since the middle ages. I personally would not like to get a stem cell injected into my body that might form a tumour with a certain degree of probability. We are working with clinicians on MSC therapy and realise the all over the world stem cells are given back to patients, but withouth an idea how well their utility was preserved, there are hardly functional assessments. In contrast to drugs which are taken with the expection to have a certain effects, stem cells are given in the hope of the same. That is not the level we would like to remain at, hence more work needs to be done. Hope that helped, a bit. Cheers, Michael

Thanks for all your answers, they have been a great help.

I am aware that animal trials often show different results to trials in humans as we are not the same. I would really like to know more about why some stem cells turn cancerous if you have time please.

It would appear that funding is the major obstacle in the process of testing drugs. This means that ideas for potential cures take a very long time before they are hopefully offered to patients, but without the trials it would be far too risky to offer them. For example, a certain lab my not have an animal clinic and therefore cannot take their ideas to the next stage. Is this correct? 

Also, what do you mean by there not being much talk of stem cells in tissue regeneration?

Do you also have any examples of the shady clinics that you mentioned please? 

Thank you, Charlotte

The long time and high cost required to bring forward effective new treatments are because it is very difficult to assess the benefit and risk of a new treatment using currently available research methods.  This will only change once we have discovered more effective and much quicker ways to predict and assess human disease modifying benefit, and to predict and assess infrequent but clinically concerning human adverse effects that in the most severe instances may be life threatening.  Once these new approaches have been invented, it will be feasible to consider more widespread "fast tracking" of approaches that have both a high level of therapeutic promise and a low risk of causing human adverse effects.  Currently such fast tracking is only realistic for life threatening conditions where there are no useful treatments.  A lot of work is being done in this area and progress is being made.  But it is tough and there are no easy answers.  Until then, the current and slow status quo will continue, unfortunately.

In theory, how could we potentially make research methods faster and more effective? Please could you outline some of the progress and work being done in this area?

1.  Better models of human disease, which enable to value of new treatment opportunities to be assessed more effectively. 2.  Better models for investigation and understanding of human adverse reactions.  3.  A new drug discovery and development paradigm, which integrates these new approaches and enables timely decision making.  In my opinion, focussing on more and better studies in animals is mostly a blind alley and should be de-prioritised.  That is why I joined FRAME! Physiologically relevant in vitro cell culture based models have a lot of untapped potential and are improving rapidly.  The outputs from these need to be interpreted using multi-parametric mathematical models, which can describe and simulate human biology and physiology.  Again, enormous progress is being made.  We also need much better biomarkers of human disease, which can be used to support smarter clinical trials by enabling quick and easy identification of responders and non-responders (to new therapies).

This is very interesting! just out of interest, do you think animal testing should be stopped altogether or should we just change the way we do it to make it kinder and more sustainable? and are the reasons because of animal welfare or because it is less effective research? Do you think that because humans are so different to animals, that it can sometimes be less relevant than the in vitro cell culture based models that you suggested? 

Good questions!   Overall, animal experimentation can only be justified when it provides essential information that can improve human health, which cannot be obtained in other ways - when suffering is minimised.  Given a choice, it's always preferable to work with non-animal methods because they are cheaper, quicker and more ethical.

Nevertheless, studies in animals are essential prior to moving new drugs into humans, since they flag up a lot of issues which are not human-specific or individual specific.  Early clinical trialsl are very safe overall because animal studies (plus other focussed studies, such as genetic toxicity testing) protect patients well.

Even so, animal studies are expensive, slow and ethically undesirable.  So they need to be preceded (and ultimately replaced) by non-animal studies which can filter out lots of bad compounds that are unfit for testing in animals.  As it happens, the non-animal methods used for this purpose are also turning out to be much better at detecting bad effects that can lead to infrequent and human specific adverse reactions than animal studies.  This is a hot area of science right now.

Animal studies are of limited use for assessing beneficial disease modifying effects of drugs.  This is especially true for inflammatory diseases and CNS diseases.   We don't really know why that is.  It's likely to be because animal models are unable to reproduce all of the complex processes that cause disease in humans.  Many people have tried and fail to tackle this problem using animals.  Hence my recommendation that we should now focus much more attention on non-animal methods. 

Gerry, my research is focused on stem cells being used to cure macular degeneration (this is for my third year dissertation). I was wondering if you could please try and apply your theory to this. In your opinion, are animal experiments necessary for the development of stem cells, or for the development of treatments for the macular? Is this something that might change in the future?

As Gerry has alluded to the major reason it takes so long to get a treatment to clinic is that so many of our ideas turn out to be useless. I think this reflects

1. the signal we rely on is not good. I agree with his comments about animal work (we have been curing cancer in mice since the 50s) but am much less hopeful that in vitro work will be better.

2. we rely on a promising mechanism to suggest a treatment is useful. Basic scientists tend to be very interested in mechanism. In cancer treatment mechanism has been a poor predictor of the value of a therapy. Just because stem cells could regrow a tissue doesnt mean they will, and in fact as discussed above it may not even be how they actually work in humans

3. there is conflict of interest.  Most humans over-estimate the clinical value of their work: its good for funding and business after all, and for big pharma having a lot of drugs in the pipeline is good for share price

Sir Mark Oliphant the nuclear physicist was in his old age of the opinion that the elderly were the best model we could use, an idea which hasnt proven popular. Not entirely surprising given some of the historical precedent. Some authors have suggested using ill companion animals as test subjects in trials rather than lab rats but if anything people tend to care more about their pets than their elderly kin.

. .    

Dear Charlotte,

It is all about money and system. If both are compromised than it takes ages to get the treatment. Also, it is possible that in some countries doctors may not be able to deliver the relevant service in national setting but are happy to do so in private sector.

Best wishes

It is a long process from the conceptualization of the compound either synthetic or extracted from nature, followed by chemical testing and characterization, pre-clinical testing to assess safety in experimental models including teratogenesis, toxicology etc, clinical testing in humans considered healthy, and at last clinical testing for safety and efficacy in the selected group with the condition the product is aimed at having therapeutic properties, each of these stages need to be reported by stages to the regulatory agencies, which in turn need time to review the information and make a decision, ask questions and often request additional data to make a decision regarding safety for use in humans and efficacy usually as compared to an established therapy. Of course there is a high cost involved.