Drug Safety - What It Is and How It Came About

Drug Safety - What it is and how it came about

If you have ever asked yourself whether some medicine you’re about to ingest is safe, why did you ask? And if you didn’t ask, why did you assume it was? We all place values on our safety and our quality of life, and inherently we divest and place our trust in others to ensure it is not compromised. We assume public transport is fit for purpose and won’t crash, but tragic accidents do happen. We hope that the electrical appliances we use will fulfil their task without fault but we hear of mobile phone batteries overheating, washing machines shaking themselves apart mid spin and toasters going up in flames. The same is true with medicines safety.

So, what is safety? What is safe? How can we guarantee it or ensure it? Well the reality is we cannot. Safety is a relative term and safe is the ultimate on that relative scale. Only after certain activities and observations have been undertaken and the results appraised can we know the relative risk and inherently the safety of something. So going back to the start, how do we know medication is safe?

Looking at the history books we see that traditions around the world employed medicine in very different ways and today’s medicine is a mixture of herbal remedies and synthetic substances, some of which have origins from the plant world e.g. digoxin from the foxglove, digitalis purpurea.

That history would have placed trust in a doctor’s or equivalent’s hands to diagnose and offer, in their experience, the most appropriate remedy. Before the onset of modern communication, this choice was probably based on tradition of what has worked before in that geographical locality. Modern travel and communication has enabled the sharing of this experience and knowledge. Investigation of the reasons some things work and some don’t has brought about the more recent methods employed to identify new treatments.

Discoveries such as penicillin and quinine, as well as modern immunisation programmes have prevented ill health and death and led to improvements in life expectancy and quality. Many battles have been won with certain conditions eradicated entirely in most of the world, such as smallpox and leprosy.

Twentieth century drug safety revolved around testing new treatments in minute quantities and then increasing the dose. Sometimes, and still controversially, this might be preceded by tests on animals. But whether the relevance of testing on a particular animal species confers to humans is still open for debate. Nevertheless, it is still commonplace for drugs to go through animal studies first; followed by human volunteer trials then trials on actual sufferers of the condition seeking to be treated. Nowadays, pharmaceutical research companies can employ toxicology and pharmacology algorithms to computer design chemical molecules similar to those with known activity to finely tune out harmful characteristics and improve beneficial ones. This can improve the likely safety profile before entering into any testing.

The road to this approach has not been smooth and has evolved in response to many significant events over the decades.

 In 1957, the German pharmaceutical company Grunenthal promoted the hypnotic anxiolytic thalidomide for nausea including morning sickness in pregnancy. Thousands of children around the world were born with shortened limbs (phocomelia) and other deformities to their eyes and organs. This led to withdrawal of the product and tougher development and drug licensing rules. Interestingly, thalidomide has returned 50 years later, for selective use in niche indications.  In the 1960’s a range of hypnotic benzodiazepines became popular and were used by millions around the world e.g. nitrazepam (Mogadon®), lorazepam (Ativan®) and chlordiazepoxide (Librium®). Their effectiveness was clear, but it was soon evident that many had become dependent upon these medications and could not stop them without developing a withdrawal syndrome. Thus modern prescribing of hypnotics discourages long term use. Indeed, the lowest dose for the shortest time, intermittently if necessary, retains effectiveness without developing dependence.  An anti-inflammatory for arthritis called Opren®, used for arthritis, was shown to cause extreme photosensitivity, serious liver damage and even deaths, despite not revealing any likelihood of such in animal testing. It was withdrawn from the market in 1982.  In 2006, TeGenero was trialling a novel monoclonal antibody, TGN1412 in Northwick Park Hospital. The volunteers injected with it developed a life threatening reaction now termed a ‘cytokine storm’. One person had to have their fingers and toes amputated. The ensuing inquiry concluded in the Duff Report 22 recommendations of a pharmacological and toxicological nature that should be applied to clinical trials in the future.

These are just a few examples of the learnings about drug safety over the years. They show that despite animal testing, clinical trials, following protocols and getting a licence, things go wrong. Rare or novel events cannot always be anticipated nor do they necessarily show up until after a drug is launched into the more variable and less controlled real world of the general human population. To embrace all the good practice, rules and processes we have learned over the years, there are national and international regulatory bodies established to ensure standards are maintained and upheld in order to prevent safety issues arising and help deal with them when they do.

The UK’s Department of Health has the Medicines and Healthcare products Regulatory Agency, MHRA, to fulfil these duties for medicines and medical devices. One of the roles undertaken is legislating and overseeing drug safety surveillance or pharmacovigilance. This notion embraces capturing and responding to safety data at all stages of a drug’s life from trials to post marketing reports from prescribers and the public. The latest pharmacovigilance legislation is set out in Directive 2010/84/EU and Regulation 1235/2010 of the European Parliament and Council.

These require companies who market drugs (Marketing Authorisation or ‘MA’ Holders) to:

o Submit a summary of their own pharmacovigilance systems i.e. who is qualified to undertake such duties in their company and how the system is set up to capture safety information o With new drug applications submit a summary of the drug safety data they have available and a risk management plan to explain clinically why a certain approach is proposed o With any renewal or change to the licence, include new safety data captured in the time since launch, to inform the prescribing information e.g. restrict usage or dosage to patients with certain pre-existing medical complaints such as liver impairment

The prescribing information or Summary of medicinal Product Characteristics (SmPC) is the key regulated document reflecting the current known information about any drug. This is distilled down into the labelling, such as the Patient Information Leaflet (PIL) and packaging wording. As data evolves with time, these documents are updated to show any revisions of indications (who it’s for), contraindications (who must not take it), cautions and warnings (care in use in certain circumstances), dose and side effects.

Prescribers and healthcare professional are encouraged and have a duty to report any serious or unexpected (non-listed) side effects. The mainstay of this information may arise from hospital admissions or GP observations at clinic. However, nurses, pharmacists and patients can all report their suspicions to the MHRA via the ‘Yellow Card Scheme’ by post or e-mail. See yellowcard.mhra.gov.uk

From time to time, trend analysis of the yellow card data or real world events force the authorities to instigate post-authorisation safety studies. These are non-interventional but look more closely at the data available to explore answers to certain specific questions. For example, if side effect reports to the MHRA are displaying a trend that one new drug seems to have a greater incidence of a particular side effect than expected, is it because reporting structures are better and reporters are more aware? Or is it because the drug is genuinely causing more problems and the dose or who takes it need to be reviewed?

The MHRA does not merely take a passive data analysis role either. It actively inspects sites of manufacture to ensure processes agreed in the licensing agreement are followed and that quality and safety of the constituents and the finished medicine are not compromised, e.g. contamination, storage, staff training and following agreed processes, undertaking pharmacovigilance and reporting data centrally to the authorities to use alongside anecdotal reports via the yellow card scheme.

Such inspections can reveal deficiencies and cause the MHRA to exercise precautionary recalls of product to protect the public. For example, an inspection of one Indian factory of the generic company Wockhardt showed deficiencies in Good Manufacturing Practice (GMP) such that a precautionary recall of some batches of some products made there and on the UK market was instigated in July 2013. Manufacture was diverted to other sites whilst remedial action was undertaken.

Recalls can occur for various reasons and to various extents depending on the extent and nature of the safety concern. In some cases the recalled product includes that in use at the patient’s home or in the hospital setting. A recall of the following drugs from pharmacies, clinics and wholesalers was instigated in June 2013. The wording was taken from the recall notice:

Hydroxyethyl Starch (HES) products

Tetraspan 10% solution for infusion (500ml)

Tetraspan 6% solution for infusion (500ml)

Venofundin 60mg/ml solution for infusion (500ml)

Voluven 10% solution for infusion (500ml)

Voluven 6% solution for infusion (500ml)

Volulyte 6% solution for infusion (500ml)

All unexpired stock of these products is being recalled to pharmacy, clinic and wholesaler level irrespective of batch number and expiry date. These products are being withdrawn after results from large randomised clinical trials reported an increased risk of renal dysfunction and mortality in critically ill or septic patients who received hydroxyethyl starch (HES) compared with crystalloids (simple salt solutions). The UK Commission on Human Medicines (CHM) has concluded that the benefits no longer outweigh the risks.

No further hydroxyethyl starch (HES) products should be dispensed. An alternative resuscitation fluid should be selected according to clinical guidelines. Remaining stocks of the affected batches should be quarantined and returned to the original supplier for credit.

These example shows that authorities will act upon safety concerns putting safety paramount. It also shows how the pharmacovigilance mechanisms do work in reducing the risk and improving safety.

There are some situations where safety data may be lacking despite the obvious importance we would attribute to it, and that is use of drugs in pregnancy and children. It is traditional to exclude these populations from clinical trials of new drugs to avoid the possibility of deformed babies or harming the physical or mental development of children. Therefore most of the data available about the safety of drugs in these people is anecdotal and comes from accidental or unintended exposure e.g. a child taking a parent’s/grandparent’s medication or a woman taking a drug without knowing she was pregnant. Since these events are unplanned and not undertaken in a controlled set of circumstances, we cannot be certain therefore whether a drug is indeed safe. We only know case reports of people being harmed in some way or unharmed. If a baby was born with a problem to someone who was unintentionally exposed to a drug, was that problem the drug or would it have happened anyway? This area is where pharmacovigilance trend analysis by authorities such as the MHRA and more recently the European Medicines Agency (EMA), can help sort the wheat from the chaff. Additionally there is a European directive to research certain medicines for use in children which gives detailed guidance helping companies take the right steps to capture safety data and conduct themselves ethically in their research protocols. This is an alternative approach to giving a fraction of an adult dose and seeing if it works and causes no harm. Nevertheless the mainstay of paediatric medicine safety knowledge has had to come from just such an approach, where toxicology and pharmacology have been assessed for that child.

In the developing world where life threatening diseases are so prevalent, the risk benefit analysis allows for widespread adoption of vaccines that could so easily save millions of lives with only rare allergic reactions. In the developed world, where such disease is much less common, attention focuses to risk assessment of drugs for conditions such as high blood pressure, raised cholesterol or arthritis. Will it make you dizzy, come out in a rash or upset your stomach? So, whatever the medical priority is, you see drug safety has a key and pivotal role. It is never static, but forever evolving.

So now when you pop a pill in your mouth, will you think differently about that question of safety?