Generics - out of the past

 Dr Dermot J Ward


As I awakened on May 26 last to breaking news, I could mop my brow with relief. The clash of pharmaceutical Titans, Pfizer on the US side bent on an aggressive takeover bid and AstraZeneca, a British/ Swedish company based in the UK corner batting it off. The attempt had failed despite tempting offers to AstraZeneca shareholders. There can be no further bid for at least six months. The battle is over but perhaps the war continues. The capital considerations are mind bogglingly massive. And it is honestly difficult to know if the bid had succeeded or does eventually triumph, whether or not the result would ultimately benefit patients, medicine and healthcare services generally or indeed in national business interest.

I suspect there are a few readers who recall the “Ethical Pharmaceutical Industry”. For years, even decades now, Pharma and Big Pharma have permeated the media medicines coverage. It has not and is not invariably associated with the scent of roses. Yet in 1963 I recall approaching a then flourishing pharmaceutical company (now no longer in existence), Allen and Hanbury seeking information about side effects on one of its products, Fentazin. They behaved impeccably and generously supplied me with information and publications both in-house and outside which resulted in my being able to publish an article in the BMJ which altered in a small beneficial way the management of attempted suicide. (Vol ii,p432). There was no advantage to them in assisting me.              

This is not suggesting that the then or now industry was richly populated by saints but neither is or was our profession or the priesthood. Lets get to generics. Back in the early 1980s I was still working as consultant and clinical director in Dublin’s St Loman’s Hospital. That was when generic prescribing was being forcefully pushed by DoHs on both sides of the Irish Sea as the proper and responsible way for doctors, in the main, to prescribe in the interest of cost control: that where there was a generic drug form of the now out-of-patent brand drug the former should be prescribed; there was we were told no therapeutic difference between them. Apart from the coercion aspect, on the surface that did not seem wholly unreasonable. Though a year later when I moved to practise in England it was clear that doctors there were more swift to conform to politically driven DoH diktat than their Irish counterparts.

While still in Dublin, during one routine Monday ward round we saw a patient who had been on weekend leave prior to immanent discharge. Being, as a number of us are, a sun worshipper, her medication for what was to be a sunny summer’s weekend, we had switched from her usual chlorpromazine (Largactil) to Melleril (thioridazine) because unlike chlorpromazine it didn’t have side effect photosensitivity. Yet our patient had returned with a face like a beetroot. Ward sister and I went to the drugs cupboard and the thioridazine tin with a manufacture label of a company we’d never heard of based in a rural part of Ireland. Clearly, this was not a generic with the same therapeutic spectrum as the Sandoz branded Melleril. Off we tripped to the hospital pharmacy and set that matter to rights. But that was not the only generic medication we found, purportedly therapeutically equivalent to its brand parent but evidently not so.              

I decided the matter of generics was worthy of deeper investigation and approached one of the then large companies and requested views and comments. As expected, my enquiry was welcomed and one could be cynical about that. But evidence is what matters. They were eager to facilitate me then and delivered useful relevant article reprints in addition to some I already had, one of which was a BMJ leading article (Genetic prescribing and the drug industry 1982; 284-919).

It stated:

“We believe however that generic substitution would be a clumsy and ineffective way of reducing NHS drug cost and one which might discourage foreign investment in the British pharmaceutical industry. Long-term, a world wide trend towards using generics could further reduce the pace and breadth of research by the pharmaceutical industry.” Prescient indeed.

In the November, 29, 1985 issue of IMT I published a piece, “ Generics: more expensive than brand drugs?”. It touched on issues  such as varying bioavailability. There were some 32 or more factors which could alter markedly the pharmacological action of a drug. (Sadov, MS et al, 1965, “What is a generic equivalent?” Amer. prof. Pharmacol.) This may seem merely esoteric until generic problems occur on one’s own clinical doorstep.

Ethical companies which previously manufactured ampoules (as well as ingestables) as a service to medicine not a s a profit making line (that resided in ingestibles)  decided it was no longer economically viable when the less troublesome, less less expensive and less difficult to manufacture tablets were being marketed by undercutting generic companies. Fair enough you may say but it is only fair provided market forces are nor being artificially skewed and the generics were bioequivalent. Of course our profession’s major concerns here are medication quality control and patient safety.  Yet, inevitably, cost consideration, especially in any national health service when additional hazard is that long-term the pharmaceutical industry as we know it becomes the focus of reforming zeal of government policies aimed at cutting medicine funding.

Further cost considerations have long since emerged; increased litigation, insurance and victim compensation. That started with the non-generic thalidomide disaster of the late 1950s. This happened despite massive investment and correct company behaviour in R and D and then existing  safety measures of an ethical company. Currently it costs about £5billion to bring a new medicine from its earliest lab development to open market clearance.  

Generics have been a recurring news media item . Benefits and failings. About ten years ago I decided to revisit the scene and again approached a large pharmaceutical player about possible, concerns and perceptions surrounding generics. Much to my surprise and unlike my 1980s experience of eagerness  to engage on the issue my informant wasn’t really interested, let alone fired up about generics. I was left puzzled at this seeming volte face

Then, just a few years back, skimming the business pages of the Telegraph there was a piece about pharma and its survival mechanism vis-a-vis generics. The suggestion was that the previously ethical companies  were buying up small generic manufacturing companies and marketing low risk me-too out-of-patent older meds. If such were indeed the case could you blame them? No £5billon losses for starters: no nightmares of newly patented medication revelations possibly destroying the huge investment overnight.    

Fast back to Richard Smith Editor BMJ 1982; 285: 761......”every outpatient department is thronged with patients with chronic diseases for which current drugs are ineffective or have serious side effects or both. Our society does need new drugs; only the pharmaceutical industry (warts and all) will provide them”.

Might their be a connection between events examined above and the recent consternation surrounding the failure of  pharmaceutical new product risk-taking companies to develop, eg, new effective antibiotics? It is a serious question.

Truth: generics can be as effective as, and bioequivalent to, brand drugs. The FDA in the USA  has achieved this status. It insists on generic company products being subjected to a detailed rigorous protocols as are brand drugs. Tap “ FDA and generics” into your search engine and you will see its detailed bioequivalence requirements of brand and generic medicines. Follow that with  “EU equivalent of FDA” and you get European Medicines Agency (EMA). This seems, by comparison an inchoate organisation, doubtless well intentioned, broadly concerned with medicines regulation.  USA, more strictly monitored generic companies would incur higher production cost. This could be the deciding factor in discouraging shoddy generic companies thriving and equally encourage respected brand companies into the necessary capital risk-taking associated with product innovation - new more effective drugs.         

Unlike doctors in the USA, when a doctor in these islands prescribes a generic for an individual patient they have less reason to be confident that it is truly bioequivalent to the brand version than their American colleagues as adjudged by FDA protocol on generics when the latter is compared with that of the EMA. Our doctors are not luddites in considered exercising of a brand prescribtion . They are instead the last thin line of patient medical defence, especially in those muddied waters of pressurised generic prescribing..