The generic generation

In the next few years, some of the most widely used HIV drugs will come off patent in the UK. Gus Cairns asks: what are the implications for the tablets we take – and for our health?

From next year, if you’re in the UK, your anti-HIV drugs may start to look different. One pill may be replaced by two or three and their appearance may change, even from one prescription to another. Names you are familiar with – Atripla, Viramune, Sustiva – may start to disappear.

You will still be getting the same drugs, but in a different guise. What you’ll be getting are generics: different versions, but essentially the same things, without a brand name attached and cheaper to produce. A bit like supermarket cola versus Coca-Cola – though without anything ‘secret’ in the recipe.

When patents end

Why now? Because of patents. Patents are intellectual-property documents stating that a particular invention – whether it’s a new drug or a gizmo in your computer – is the inventors’ alone to profit from, usually for 20 years, and usually only in the specific country that issues the patent. A patent gives you the right to stop others from copying and selling your product. Increasingly, trade agreements are being forged that mean that a patent issued in one country will be honoured in others.

Trade agreements are controversial, usually because they involve rich countries such as the US getting poorer countries to adopt their patents. And so is patent law, which, some say, is increasingly abused to help companies grab unfair shares of a market, or help them maintain monopoly of a product longer than they should by changing it in trivial ways.

It can also be very complex: the ongoing row between Apple and Samsung over their smartphones is an example. In medicines, the issues are (usually) simpler: whereas many different patented devices and programmes may go into a smartphone, what’s patented in a drug is usually the active ingredient – a single molecule or combination of molecules.

Once something goes off patent, then any company can make a version of it and sell it without being guilty of selling a pirate copy. This is an issue in HIV because we’re starting to reach that 20-year time limit.

Drug patents last for 20 years from the registration of the active ingredient. This has to happen before efficacy trials start in humans, so the actual time companies have to make a profit is only from when it’s licensed to be sold, which may be only 12 to 15 years.

Name confusion

A patented drug gets a generic name or so-called INN (International Non-proprietary Name), which is registered with the World Health Organization. The INN is global, and permanent: it is the name doctors write on their prescription pads and ensures that wherever you get your prescription filled, you will be getting the same active drug. The same applies to over-the-counter medicines: they may contain all sorts of ingredients, but in small print somewhere on the packet they must list the active drug or drugs they contain.

Once drugs are licensed as safe and effective, they can only be sold under the company’s brand name while the patent is in force. Drugs having two names can be very confusing, and some may have more than two, including several anti-HIV drugs. Take the oldest one as an example. It’s best known as AZT. This stands for its chemical name, azidothymidine. Its generic (INN) name is zidovudine. And it was marketed by its manufacturers as Retrovir. To avoid confusion, NAM’s convention, as above, is to always have brand names capitalised and in italics.

Patents don’t always expire exactly 20 years after the INN was registered because patents are issued by individual countries. Thus zidovudine came off patent in September 2005 in the US and March 2006 in the European Union.

Since 2009, zidovudine has been available in generic form in the UK and if you’re one of the few people who still use it, you will probably already be getting it as a little white pill instead of the old blue-striped capsules.¹ Several other HIV drugs have already come off patent, including didanosine (ddI) in May 2006, saquinavir in January 2011 and stavudine (d4T) in May 2011 (all these are European dates).

But these are hardly used these days. The first widely used drug to come off patent was lamivudine (3TC) in January 2011, and generic versions became available in the UK in July this year. Next year, a generic combination AZT/lamivudine pill will be out for the few people who still take this; it won’t be called Combivir, the name of the patented combination pill.

What’s going generic soon

From next year patents will start falling thick and fast.

Nevirapine (currently branded Viramune) comes off patent in June 2013 and four generic companies have applied to supply a version in the EU (there are already around ten in the US). Nevirapine has always been an alternative rather than first-choice drug though, because of rare but potentially serious side-effects.

Anna Brewster of Viramune manufacturers Boehringer Ingelheim said she expected her company to continue making the drug, “but it would have to compete on price”. In addition, there is a double-strength one-pill-a-day version of Viramune that is still on patent. Managing director, John Dixon, affirms “Boehringer Ingelheim has, for 15 years, been committed to providing high-quality innovative medicines to people living with HIV. Importantly, our commitment to our patients will not end after the patent for nevirapine expires in June 2013 as we will continue to produce and supply both Viramune and Viramune prolonged-release”.

The first real blockbuster is efavirenz (currently Sustiva or, in some countries, Stocrin) in November 2013. Efavirenz, as well as being used in its own right, is an ingredient of Atripla, the once-a-day combination pill used by a large number of people as their first-line therapy. It’s rumoured the Israeli generic manufacturer Teva will start shipping out generic efavirenz the day the patent expires.

The protease inhibitor booster ritonavir (Norvir) comes off patent around the same time. However, while the active substance comes off patent, the process that manufacturers Abbott devised to turn it from a capsule needing refrigeration to a heat-stable pill remains patented. The company’s Dirk van Eeden told HTU that the World Health Organization had ‘prequalified’ pills made by several generic companies and was presumably satisfied as to their efficacy, so there should be no return to ritonavir capsules.

We’ll have to wait longer for others; abacavir (Ziagen, and - with lamivudine - in the combination pill Kivexa) at the beginning of 2016; boosted lopinavir (Kaletra) at its end; and, in 2017, the biggest fish of all, tenofovir (Viread), the drug that’s also in Truvada (along with emtricitabine [FTC], a drug easily substituted by lamivudine), Atripla and Eviplera.

How much do generics save?

Why will the NHS and other health systems start prescribing generics? Simple: cost. Generic drugs cost a fraction of the price of brand-name drugs. This is largely because generic companies don’t have to go through the costly process of drug discovery and approval, which involves an escalating series of randomised controlled trials (although it is striking how patent holders have been able to reduce prices for lower-income countries when there is generic competition). 

All they have to show is that their formulation of the generic drug is pretty much as effective as the branded drug: they’ll be allowed to sell their drug if their tests show it’s up to 5% less - or more - effective than the branded drug.

A presentation² at the recent International AIDS Conference in Washington found that, even using very conservative estimates of efficacy, replacing Atripla with generic efavirenz and lamivudine, plus tenofovir, would save US$4000 per quality-adjusted year of life (QALY) for each individual on treatment in the US, and would save the country $920 million on its annual drugs bill.

That’s just anti-HIV drugs. Overall savings from generic medicines in the US were estimated to be $139 billion in 2009.³ That’s one dollar in every $18 saved of the $2.5 trillion the US spends on health care, and whereas generics represent 70% of the drugs prescribed in the US, they comprise 83% of those prescribed in the UK.⁴

“By the end of 2013 I’d expect the price of a first-line regimen of Truvada [the branded tenofovir/emtricitabine combination pill] and generic efavirenz to come down by about a third, compared with Atripla,” says Professor Brian Gazzard. Best known as an HIV consultant, Gazzard has also been a key member of the London Specialised Commissioning Group’s Drugs and Treatments Subcommittee (LSCG DTSC), which provides clinical support for the negotiation of HIV drug prices for London. 

The emtricitabine in Truvada could also be replaced by the closely similar lamivudine, he adds, which would cut the price by as much as two-thirds. The London group has calculated that adopting generic efavirenz alone could save the capital’s NHS at least £2.6 million and possibly as much as £9 million. Add in generic nevirapine and you’re talking about a potential saving of £13.3 million. This is without having to take controversial measures such as switching drugs, which London commissioners urged clinics to do last year in order to save £8 million.

Won’t drug companies just put up the price of their branded drugs, which as yet still form an essential part of antiretroviral therapy regimens, to compensate, I ask. “No,” says Gazzard, “because it’s illegal in the UK to raise the price of a drug above the list price set when it was originally licensed for sale. Locally, NHS trusts usually manage to negotiate discounts on the list price, but these are usually in the order of 10%. You’d still save money.”

How will this be managed?

In England the move to using more generics will happen at the same time as changes in the NHS which will, amongst other things, see HIV treatment and care commissioned nationally from 1 April next year.

Claire Foreman, Assistant Director of the London Specialised Commissioning Group, says: “In the context of the English NHS’s quality improvement programme, this represents an excellent opportunity not just to meet the target of finding £20 billion in savings in the NHS by 2015 but also to expand treatment to more patients, with higher CD4 counts, including patients who may be seeking treatment for reasons of prevention.”

I ask whether national commissioning presents a possible threat to patients, as well as an opportunity. Will generics be so much cheaper that there will be pressure to put or keep people on regimens that are less easy to tolerate, are marginally more likely to fail, or that have worse side-effect profiles (especially ones that don’t show up in tests, like psychological unease) when newer, on-patent drugs might be better? Will the new NHS Commissioning Board mandate rigid treatment protocols and budgets that won’t take into account the differing needs of individuals?

“I don’t think national commissioning will involve producing a new set of treatment guidelines,” she says. “We already have those. You could have a general set of guidelines, but allow for local variations.”

Simon Collins, editor of HIV Treatment Bulletin at i-Base and, like me, a patient rep on the DTSC, does worry that there may be pressure to adopt cheaper regimens. 

“Most combinations in the UK are now £6000 to £7000 a year. Though highly cost effective, to a funder £3000 to £4000 for a generic regimen looks a lot better. There may be underlying pressure for preferential use of drugs [that are generic] such as efavirenz that have a subtle side-effects profile. There are already incentives in the latest agreements to prescribe cheaper drugs for relatively small cost differences and if potential savings increase, the pressure might increase.” Switching for tolerability, rather than outright virological failure, might get that bit more difficult, in other words.  

Different kinds of changes to your pills

Changing to generics may involve different levels of change that people may be more, or less, happy with. There is no implication that people who need the branded drugs for medical reasons will have to take generics.

The first is that the appearance of your drugs may change. This, which may sound trivial, may be the thing that matters most to some people.

Douglas Kamerow, associate editor of the British Medical Journal, commented in an article last year: “Confusion may arise in patients when they find that their dependably round yellow pill is now a green oblong. Patients, especially elderly patients, use colour to identify their pills, and report great concern when the appearance, packaging and labelling change. This…may lead to a decrease in adherence.”⁵      

Secondly, one pill once a day may become two or more, either because the new suppliers, as with nevirapine, do not make the higher-dose version, or because a combination pill is split into its components. (Or two could become one: generic companies already make combinations for the low-income countries that you won’t find in the UK, and there’s no reason a company couldn’t make, say, an efavirenz/lamivudine pill for the UK market from 2014.)

People are often concerned that splitting combination pills into their components will result in lower adherence. While combination pills are undoubtedly popular amongst both physicians and patients, especially in situations where patients pay and a combination pill counts as a single medicine, there’s little evidence that there’s any difference in outcome or adherence.

One study presented at the Glasgow HIV drug therapy conference two years ago (funded by Atripla manufacturers Gilead) found that people who took one pill a day were 60% more likely to miss fewer than one in 20 doses than those taking three or more pills a day.⁶ But that study purely compared numbers of pills. People on one pill a day could only have been on Atripla, but those on three or more could have been on all sorts of combinations and would include a much higher proportion of people who were treatment-experienced and had drug-resistant HIV.

A more recent study presented at the International AIDS Conference in July⁷ found no difference in adherence between people using single-tablet regimens and multiple-tablet ones, as long as the regimen was a once-a-day one. Even this, however, did not directly compare a fixed-dose pill with its component drugs.

A study last month⁸ found that patients prescribed single-pill regimens were no more likely to take them than multi-pill ones. Eight per cent of patients prescribed single pills failed to even fill their prescriptions compared with 10 to 12% taking other regimens (not a significant difference). This was, however, in the USA, where patients are more likely to be non-adherent for financial reasons.

Some researchers in the UK are looking for funding to conduct a trial comparing adherence rates and outcomes between people starting ART with Atripla and those starting on the component drugs tenofovir, emtricitabine and efavirenz.

Others argue that comparing people starting on the two different formulations doesn’t account for the fact that switching in itself may exact some penalty, and instead suggest a trial design in which 50% of participants are randomised to switch away from their existing Atripla to the component drugs.

The third level of generic switching is to substitute one drug for another that is closely equivalent: an example from outside the HIV field would be the cholesterol-lowering statins, where one of the most powerful, rosuvastatin, is still on patent as Crestor but the others are all available as generics. Inside HIV, one example would be switching branded emtricitabine, as Emtriva or in Truvada, Atripla or Eviplera, for generic lamivudine. These drugs are thought to be closely similar in efficacy.

They’re not identical, though. One recent study from France⁹ compared people on regimens including tenofovir/emtricitabine with ones taking tenofovir/lamivudine. It found that although the two drugs were comparably effective, if lamivudine-containing regimens stopped working, people’s HIV was more likely to develop drug resistance than if emtricitabine-based regimens failed, even though resistance to these two drugs is conveyed by the same mutation in HIV.

More controversial would be a switch already done in some areas for reasons of cost: using abacavir instead of tenofovir in people’s first regimen. We have previously covered the decision in London (see HTU 205 and 212) to offer patients abacavir as first preference; as yet we don’t have the results from audits to know whether there has been any change in the efficacy, tolerability or adherence to first-line regimens as a result. There is still argument as to whether abacavir is less efficacious in people with high viral loads, or associated with more heart attacks. Actually switching people to generic abacavir once it became available, says Brian Gazzard, “would need to be re-discussed in some detail”; he isn’t sure how acceptable it would be.

Finally, there’s the option of switching from a once-daily regimen to a twice-daily one. Here the data are clear: taking pills twice a day is associated with significantly poorer adherence. In the study quoted above,¹⁰ adherence was 3% higher in people on once-a-day compared to twice-a-day regimens, 4% higher if they were new to ART and 7% higher if they had already experienced treatment failure on one regimen with a detectable viral load. In terms of clinical efficacy, there was no difference, but it’s clear a lot of people wouldn’t like it.

Will generics stifle innovation?

Finally, will the switch to generic medicines stifle innovation and starve the pharmaceutical industry of money to develop new drugs?

Claire Foreman notes drily that “it’s not entirely accurate to suggest the NHS should forego the opportunity of cheaper drugs in order to ensure drug companies can innovate”, and Simon Collins says: “Forecasts suggest that the financial potential for developing new HIV drugs will be lucrative for at least the next ten years.”

The bar for new HIV drugs will get ever higher though; any new drug would have to be so clearly superior for a significant number of people, so that spending anything up to ten times as much on each prescription would be justifiable to the bodies that regulate these decisions.

We are already running into a situation where the prices charged for new HIV drugs are meeting more criticism than ever before. This is seen in the case of Gilead’s new three-drug-plus-booster ‘Quad’ pill (marketed as Stribild in the US, approval is still pending in the European Union), which in the US has been set at 36% more expensive than Atripla (the equivalent of about £18,000 a year; UK prices have not yet been determined but are usually cheaper – see i-Base’s piece on Stribild for more information¹¹).

Drug companies may be gambling on there being enough providers, especially in the US, willing to pay for innovative but expensive drugs before the window of opportunity closes and the economic argument for generics becomes overwhelming. In the UK, it may become increasingly difficult to demonstrate clear medical need for something so much pricier than its near-equivalents. Watch this space, as they say, and keep an eye on your pills too.