Proventus

Outcome Result Success

Treat the Disease - Treat the Person

UK Charity No 1131517

Time Waits for Nobody

Working Together to Make a Difference

UK Charity No 1131517

Some disease modifying drugs work to change the course of a disease others to address the symptoms.

Research

It is well recognised that all drugs take a long time to be developed, the process takes the drug / compound / idea / along a path of multiple research - testing - trials eventually culminating in a phase three trial prior to licensing and submission for use. Phase three trials are considered to be the gold standard that demonstrates the safety and efficacy of a drug, however, there lies a record of drugs being withdraw after demonstrating adverse side effects even though they have passed through the phase three trial gold standard?

Perhaps safety and efficacy may be better served if a drug was assessed, not only by the phase three trial results and its peer review (by who?). Consideration, perhaps, could also be given to information / data obtained from anecdotal evidence and single case studies as well?

Single Case Studies-Getting the Evidence

As Dr David Price clarified in his article about research methods, Drugs and Safety, although the randomised controlled trial is considered by the medical profession as the ‘gold standard’ in drug trials, it does have its limitations, not least in the numbers needed to prove the effectiveness and safety of the drug or intervention.

There are other methods, not looked upon as favourably by the research communities, but which do have certain advantages and are gradually gaining acceptance. One such approach is what is known as the single case study or small-n research (n= number of subjects). It is important to differentiate what is meant by a case study and a single case study experiment.

Case studies are usually retrospective reports made on observations of a particular patient. In fact many of us using Aimspro are effectively writing our own case studies in the daily or weekly diaries we keep on the effects of Aimspro by noting the changes that occur in us. These are always valuable records and may hold clues for future clinical evaluations and the detailed observations that accrue can be used to develop a pool of empirical evidence.

However a single case study or experiment is somewhat different. Instead of a report of what happened, as in the Case Study, the researcher is looking at an individual and the effect the intervention (in this example Aimspro) has on a number of variables – signs and symptoms – so that any changes that occur can be recorded accurately. It can be seen that a number of well -recorded and objective single case studies could collectively provide useful baseline data for the evaluation of a treatment .

As the results of the single case study focus on the individual rather than the average person, in-depth data from a number of individuals may be more reliable than that from a larger group studied superficially. Both quantitative and qualitative methods can be used to generate data that can be analysed in a number of ways. Quantitative data would involve repeated measurements of defined variables in a single person over time– for example the range of active movement in a stiff joint, the severity of spasticity, or frequency of incontinence.

A problem with this approach is associated with obtaining repeated accurate measurements of variables such as pain, spasticity, frequency of incontinence or functional activities. So it is essential that comprehensive baseline data be collected before the treatment begins. Ideally this would mean a full physical assessment by a specialist practitioner in the appropriate discipline (For MS for example, a neurologist or a neuro-physiotherapist) followed by regular reassessments.

There is still value in the qualitative recording of more subjective data through questionnaires and semi-structured interviews. The information gained from the reported experiences, attitudes and judgements of the individual subjects provides rich data that can be subsequently analysed to find key words and common themes that the investigator use to generate theories that might be more widely generalisable.

Each of us in the fortunate position of receiving a treatment as a ‘special’ should consider ourselves suitable research subjects and make sure that we keep accurate diaries recording every change that occurs whilst on the treatment. I know that many of you have developed your own way of recording changes so that the diary is easy to keep, accurate and informative to another reader. If you have examples of such record-keeping methods that you would like to share, please contact me. Perhaps we can assemble a record-keeping format that everyone could use that would be of value to researchers.

Gillian Jordan

Background - Gillian Jordan has an inflammatory condition known as Adhesive Arachnoiditis, as well as Syringomyelia. This results in a range of unpleasant symptoms, probably familiar to many of you with similar conditions. They include severe pain in both legs, flexor and adductor spasticity, increasing leg weakness, numbness in both feet, bladder and bowel dysfunction and episodes of profound and unpleasant sweating.

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Named Patient Basis - ‘Specials’

Drugs being developed may be given permission from the regulatory agency to be made available on a ‘named patient basis’ (a special) when the regulatory agency is satisfied the medication meets certain criteria. That the drug is safe for use, ,and the medication is manufactured correctly under the good manufacturing practice guidelines (GMP) laid down by the regulatory agency. (It is not an indication of its efficacy). The guidelines are strict with regular inspection of the manufacturing premises and process. Monitoring of the drug is undertaken by the regulatory agency.

A clinician may prescribe the drug available on a ‘named patient basis’ (a ‘special’) if they are satisfied that it would be of a direct benefit to the sufferer and there is nothing else to help them. A request to the manufacturer of the drug by the clinician asking them if they would make the medication available, and their agreement to do so, is needed. Permission has to be obtained from the relevant regulatory agency to enable the drug to be delivered to the clinician.

The benefit of making medications available on a ‘named patient basis’ is recognised internationally, the majority of countries throughout the world have a system in place that enables drugs classified as ‘specials’ to be made available.

Clinical Trials - Bringing a new drug through to licence in the UK. A Simple guide.

The cost of bringing a new drug through its various stages, that is from its discovery through research until it might be available on the NHS may be as high as £500 million.

Several thousands of compounds are being researched at any one time from which only a handful will develop into a medication with a very real benefit and make it onto the world wide health systems, the path of research and proving a drug follows many stages.

Stage 1 Research.

Usually amongst natural substances ~ plants ~ fungus ~ flowers ~ foodstuffs etc. Seeking chemicals that have potential curative actions.

Stage 2 Uncovering Effect.

Analysing and testing of potential pharmaceuticals in the laboratory, separating potential compounds from useless compounds. Asking “do the seemingly potential compounds in a test tube have an effect against disorder”?

Stage 3 Pre Clinical Work.

When chemicals are considered to have potential as a pharmaceutical they are then developed into a drug, it is a long and expensive process that leads to establishing a formula which is easily administered and is stable. Extensive animal studies take place at this stage. Once permission has been received for the compound to be tested in the human body it moves into three trial phases.

Stage 4 Phase 1 Clinical Trial.

A small number of human volunteers are injected with various strengths of the proposed new medication under strict protocols.

Its purpose is not to discover whether the medication works but to study whether it is safe and how it reacts in the human body, how long it remains in the body and if there are any side / adverse effects.

Healthy human volunteers are recruited for this stage.

Stage 5 Phase 2 Clinical Trial.

The medication is then trialed on a number of sufferers of the disorder the drug is designed to treat.

This is to assess whether the medication really does help the disorder, to what extent and what dosages will be required.

Stage 6 Phase 3 Clinical Trial.

A larger trial is now undertaken amongst a greater number of sufferers recruited with the particular disorder undergoing investigation, usually held over a year to two years, some receive a placebo, some receive the medication, detailed information regarding those on the trial is scrupulously recorded the observations being;

How effective is the medication?
Are their any side / adverse effects?
How safe is it?
Comparison may be made with other existing drugs. (how does that work - if the comparison is made to an innocuous drug? 70% better than innocuous = what?).

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New uses of a medicine.

After the phase three trial a licence may be granted for a specific use and in a particular group of people. However, once a medicine has been approved for one purpose, doctors are free to prescribe it for any other purpose that in their professional judgment is both safe and effective - this is known as off-label use.

New treatment opportunities may become apparent or different categories of patients may be defined. A new treatment opportunity when uncovered, would require the pharmaceutical company to conduct further clinical trials and present new data to the regulatory agencies in order to expand the current licence.

All trials are carefully monitored by an independent body. Once complete the trial results are written up and presented for peer review. (A series of scientific papers). Application for licensing is made to a regulatory agency, (MHRA in the UK). That is permission to sell the drug, the application will include the trial results and may comprise of hundreds of sheets of documentation. Within the EU the European Agency for the Evaluation of Medicinal Products (EMEA) may also licence medications.

Before approving marketing authorisation the regulatory agency will ascertain if the drug :

Is safe?
How well it work? (efficacy)
What it treats?
That it is manufactured under GMP standards (quality control)

Once approval has been given the clinician may prescribe the medication. No assumption, at this point, may be made that the drug would be available on a national health system (NHS within the UK) Drug discovery, research and development is a complex, lengthy and costly process.

If a suspected side / adverse effect is suspected or confirmed, depending on its severity, the PIL (patient information leaflet) may be amended, extra warnings may be issued or the medicine may be withdrawn.

Medicines are designed to prevent or treat illnesses, or relieve symptoms. Any medicine may cause side / adverse effects and these may not be uncovered until many people have used the medicine over a period of time. Side / adverse effects can occasionally appear after a person has stopped taking a medicine.

You can help to make medicines safer for everyone by filling in a Yellow Card about a suspected side/ adverse effect.

The yellow card scheme is jointly operated by the MHRA and Committee on Human Medicines and is open to patient reporting ~ if you have experienced any adverse side effects from a medication - report it. Obtain details of the drug and fill in the form online.

yellowcard.gov.uk - Hotline 0808 100 3352

You are capable of making an informed decision, and it is vital that you understand what you are taking before you take it. Why would you assume doctors know everything?

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New drug development collaboration

Collaboration in more meaningful ways in the pharmaceutical industry could carry research and development forward further and faster, shared knowledge, resources and finances would lead to meaningful and constructive research paths being followed with greater efficiency being achieved, leading to growth in research productivity instead of decline.

The opportunity to expand research and development even further and faster may be by way of collaboration between the pharmaceutical industry and public research institutions, universities. The sharing of expertise would lower costs and reduce the time taken for a successful drug / treatment to become available. Lowering the cost and reducing the time taken would be reflected in the end price of such drugs/ treatments, making them available to a wider patient base, especially amongst poor people.

The Internet is sometimes used to profit on the back of peoples / patients lack of information. A whole industry has sprung up bringing counterfeit drugs onto the market.

The ease of communicating over the Internet greatly adds to the problem. This can only undermine confidence in bona-fide drugs. Governments ought to look at these issues for the benefit of easing disease and disorder throughout the world, and making treatment affordable, not just for those who can pay.

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Protection & Safeguards - A Viewpoint

Therapeutic licensing agencies the world over are becoming ever more demanding of safety and efficacy evidence prior to licensing of treatment and we would agree that this has been a very good thing for the population at large.

Standards have continued to be raised and made ever stricter in the push for quality. Unfortunately this has a negative aspect in which the timescale's and other inherent costs associated with following and enforcing these standards can very well mean that the availability of treatments are substantially delayed to the very serious detriment of some of those who could / should be benefiting.

New regulations imposed in the EU certainly raise the bar for the production of new medications but just how far should this process go?

In the case of small Pharmaceutical Companies trying to retain the ability to develop newer treatments, the burden of cost (both in terms of the requirement for clinical data and the higher costs of production) may actually mean that some treatments may never get to market at all.

Even for larger corporations these burdens will lead to delay and higher cost which ultimately will impact the end-user directly.

As a healthy individual with a healthy family, one could easily be swayed by the logic of greater protection and safeguards being given to the public at large but when viewed from the other side things start to take a very different perspective

Those suffering from progressive and debilitating conditions often spend years under increasing stress and depression as they wait in hope for a solution of some sort.

New drugs are being developed all the time and they stand ready to help many thousands of people in dire straits - they may also turn out to be a serious risk for some! Our greatest concern in this sphere is that holding treatments back because they have not yet jumped over the highest hurdles so far devised may end up harming and even killing more people from lack of prompt care than would actually have been at risk in the first place!

Thalidomide was undoubtedly a big mistake when viewed from one simple perspective - it had no effective trialling in the area of reproductive medicine and it was also being prescribed for a comparatively minor ailment, morning sickness. Whilst this can be extremely unpleasant, it is not by and large a life-threatening or severely debilitating complaint. Even so, Thalidomide has now come back into use - for treating leprosy - having undergone further research and testing and is now accepted as a worthwhile and valid therapy.

The risk / benefit analysis can work both ways.

One of our concerns is that apparently effective therapies for serious conditions may be delayed or even halted by the regulations which are supposed to protect us, to the point of leading to numbers of deaths of the very public they are supposed to be safeguarding.

This is a conundrum which has strong arguments on both sides - the public must be protected from ineffective or dangerous treatments but then again do not the individuals whose very lives are at risk from their conditions deserve a particular right to be able to try new medicines, especially if this is decided upon in a humane and ethical manner. Do they not also have the right to disclaim others from culpable responsibility?

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Drugs & Safety - A Viewpoint 2006

Safety considerations in relation to a drug, new or old, depend on the disease which it is destined to treat and the risk the physician is willing to accept. It does not depend on the risk that the patient is prepared to accept, the patients wishes are generally not taken into consideration.

A drug to treat a life threatening disease such as cancer is worth the risk associated with taking it even if there is no robust evidence of its safety record. It is perhaps because for this that there are a few experimental treatments which are used to treat cancer patients. To stem the pain from a headache needs drugs which are completely safe, for who would consider taking a drug with even a minuscule risk of serious consequences for a condition which will probably go after a good nights sleep?

Doctors and drug companies, always stress the importance of safety testing for new pharmaceutical products, whilst regulatory bodies like the FDA and the MHRA have little choice but to follow guidelines set down. It is often stated that robust safety information is required before new drugs can be administered to patients and there are means of assessing the safety of a drug by comparison with similar compounds but this is merely an informed guess, anecdotal evidence, rather than rigorous testing.

“No drug has ever been adequately tested for safety before fielding and no drug ever will be!. A bold and confident statement, perhaps arrogant, but nevertheless true. The mathematics does not permit adequate pre fielding testing. Moreover any statistician will affirm that it is impossible to adequately test any MS drug for safety. Why is this when perhaps many thousands of doses of a drug have been given with no adverse effects, surely this gives us an indication that he product is safe? Well yes but with some severe reservations!

Standard statistical theory shows that to stand a decent chance of detecting serious side effects that occur in 1 in n people, a sample size, that is the number of patients in the trial, needs to be 8 * n2. Thus for a normal sized trial with 72 patients, a figure chosen carefully so that I can work with integer mathematics, leads to a confidence that side effects will not occur in more than 1 in 3 patients, provided of course that there are no reactions in any of the patients.

Are you surprised? Would you consider taking such a drug for a non life threatening condition?

Now approach the problem from the other end. If it is deemed reasonable that serious side effects should not occur in more than one in a thousand patients then a trail involving 8 * 10002 people is needed. This is 8,000,000 people. It is generally thought that there are at least 80,000 MS sufferers in the UK so to conduct such a trial we have to find 100 times as many patients, a further 7,920,000. A quick search of the Internet, thanks to my friend goooogle, reveals that there are about 2.5 million people worldwide with Multiple Sclerosis. We are still short by 5,500,000. Next stop Mars - Alpha Centauri - Andromeda? Tighter regulation would not be appropriate for it could not significantly increase the safety testing.

To detect side effects in one in ten people rather than the one in three quoted above requires the trial size to be increased from 72 to 800. Just about feasible but still not a provably safe drug. To take this one step further to one in one hundred, which begins to become an ‘acceptable risk’ for severe MS, requires a trial involving 80,000 patients. This is just about feasible using all the MS patients in the UK but of course no placebo control group would be possible so the trial would be of dubious value to assess the effectiveness of the drug.

There will never be a drug for MS which is adequately tested for safety before it is fielded. A change in the law is needed to allow patients to take novel medication at their own risk for diseases for which there is otherwise no effective treatment. The prescribing doctor needs to be totally exonerated from any blame should the treatment go wrong – the risk must be entirely that of the informed patient. There must be some common sense injected into the system to allow patients to make their own decision on their treatment.

The MHRA / EMEA and other governmental regulatory agencies understandably have to regulate drugs for safety, a task which they perform conscientiously, – we would be shocked if drugs bought over the counter were not known to be safe – but when this is not practical and the patients are in desperate need of medication, is it not time that we allowed them to make their own decisions and take their own risks?

Author Dr D Price Ph D

Ref.

A Risk we have to Swallow, New Scientist, 5 March 2005

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Note.

Proventus as a group does not yet hold any particular position in this debate but we wish to raise the matter to greater prominence and see it debated more openly. It may be justifiable to take up a stance in favour of higher standards but it is certainly difficult to see the logic of this when your quality of life, even your life itself, is at grave risk when inaction or dangerous delay is the alternative. In this age when we openly debate and consider the right, or otherwise, of individuals to end their lives, do we not owe just as much consideration to those who might want to take a risk in just maintaining theirs.

The lists are by no means complete and are only intended to provide a limited amount of insight. The opinions expressed on these pages are not meant to be unequivocal nor should they replace professional medical advice. It is important that drugs - treatments are tested for both effectiveness AND safety; the difficulty lies in how long to wait for studies whilst patients continue to suffer, deteriorate and even die!