Generic Truvada could be available soon. We need to ask Teva when.

By Ethan Guillen and Zion Maffeo

Why can a generic for Truvada be registered now? And can it be sold soon?

The very short answer

In early June, the FDA approved generic Truvada (tenofovir disoproxil fumarate [TDF]/emtricitabine [FTC]).

In getting approval for TDF/FTC, generic pharmaceutical company Teva has asserted that it is not infringing on any patents or exclusivity. This is likely related to their earlier litigation with Gilead that was secretly settled, which in 2015 led us to believe generic Truvada might appear in late 2017. Based on the approval by the FDA, unless Gilead now sues Teva, Teva will be free to sell generic TDF/FTC and may have a 180 day exclusivity, which is a big motivator for generics to come to market quickly. Even if it doesn’t have 180 days of formal exclusivity, if it is the first to market it would have an effective duopoly until the entry of another generic that gives it a chance to make a lot more money.

Someone needs to ask Teva their plans, but in general this sort of FDA approval would indicate that Teva will begin marketing generic TDF/FTC soon, unless there is something hidden in their earlier litigation with Gilead that we don’t know about. If Teva choses not to produce and instead to help protect Gilead’s monopoly on the drug, there may be grounds for anti-competition litigation.

The long answer

Since the announcement that the FDA approved a generic version of Truvada, used as a part of treatment for HIV and the only approved treatment for pre-exposure prophylaxis to prevent HIV infection, there have been a lot of questions as to how the FDA could approve a generic from Teva Pharmaceuticals and if Teva could actually sell generic Truvada when some patents run out in 2021.

In this blog we’ll use the generic name for Truvada, tenofovir disoproxil fumarate/emtricitabine, which is abbreviated as TDF/FTC.

There are a number of things that impact when a drug can be released as a generic, but three key considerations are patents, data exclusivity, and litigation challenging patents.

The Food and Drug Administration (FDA) maintains what they call an Orange Book (back when it was a real physical book it must have been orange). The Orange Book lists all the patents that a drug company claims are relevant to a drug they produce along with any data exclusivity.

A patent gives a 20 year exclusive right to use an idea. The tradeoff is that for getting this monopoly, the patent holder is meant to disclose how you use the invention so after the 20 years the public can broadly use it. (The disclosure part often doesn’t really happen: try to figure out how to recreate Google by reading the patent on their algorithm). Drug companies usually get under 10 years of monopoly from a patent given the time it takes to get a drug to market.

The important thing to remember when looking at the Orange Book: the FDA does not do anything to verify that these patents are valid (the work of the USPTO) or actually necessary to make the drug. Just because a patent is approved by the USPTO, doesn’t mean it is valid. A huge proportion of patents that are given a second look by the USPTO (when they are challenged under certain administrative procedures) are either invalidated or narrowed in scope [something like 70% – look up the stat]. This means that a lot of patents aren’t valid. But the FDA doesn’t check that. And patents cover very different parts of the drug including the molecule that is the medicine, how it is formulated, and how it is made: patents on the molecule, the actual medicine, are in general, hard to challenge. Process and formulation patents are, in general, more susceptible to challenge.

There are many caveats to all of this, but the important thing to remember: the FDA lists whatever patents the drug company says are relevant. The company wants as many ways to block generics as possible so they have an incentive to list a lot.

Data exclusivity

Data exclusivity is also listed in the Orange Book. The data in this case is the data that a drug company collects when they run clinical trials to prove a drug is safe and effective. One reason generic drugs are cheaper is because they don’t have to run clinical trials (which would be unethical as you’d be giving a placebo to patients rather than a drug that is proven to work). They are allowed to show that the drug they make is the same as the original drug and then reference the data from the original drug company.

Data exclusivity means that for 5 years (with some variation), this data cannot be referenced to register a generic drug. Data exclusivity cannot be challenged.

So a drug can be covered by either patents, data exclusivity, or often, by both at the same time.

Litigation Challenging Patent

The USPTO often gets things wrong when granting a patent. Patents are granted under very specific conditions and can be challenged in court, and in the case of medicines, this often is carried out by generic drug companies. Generic companies have an incentive to challenge patents 1) to get to make the best new drugs and 2) if they successfully challenge a patent they get 6 months of exclusivity before other generics can make competitors – effectively a duopoly.

Sometimes the outcome is clear and the generic company loses and the patent stands or they win and a patent is eliminated. But sometimes the generic company will settle with the original drug company agreeing to drop the challenge, but agreeing in secret (often) that the generic can begin to produce a generic after a certain amount of time.

So When Can a Generic Medicine Be Registered?

So how to know when a drug can potentially be produced as a generic?

  • Look at the date of expiration of the last patent in the FDA Orange Book [link to Orange Book] and the date of expiration of the drug’s data exclusivity. Take whichever date is latest.
  • BUT, you then also have to look at any litigation from generic companies challenging the patents. If there are public court decisions or settlements you can understand the patent situation and potential dates when a generic version of a drug can be registered. If there are private settlements, you can sometimes still guess at when a drug will be registered as a generic.

Often based on court challenges, the date that a generic can be registered is earlier than the dates in the Orange Book.

For Truvada, the patents would show expiry in 2021, but due to patent challenges by a large number of generic companies, a number of the patents are no longer valid. Some of the settlements are secret, but there are good reasons to have guessed that a generic could be registered in 2017. You can read the long version of why, here.

It would be useful to contact Teva to see their production plans. The FDA will only approve a drug when a company believes it has the ability to produce it and it is up to the originator drug company (in this case Gilead) to sue to stop them if they don’t believe it should be sold on the market in violation of any claimed patents or exclusivity. In this case, given that Teva had a secret settlement with Gilead, we’d guess that they’ll be able to go ahead and bring the drug to market. Teva settled their litigation with Gilead either to launch their product and use the 180 day exclusivity OR because they received a ‘pay-for-delay’ type settlement and/or Teva may be hoping to park their exclusivity (a strategy to deter quick follow on of other generics).  Pushing for answers seems key to ensuring the public is aware of when a generic will be available

Teva said as much in it’s application to the FDA. They asserted “paragraph 4” that claims the patent is not infringed or is not invalid. They also claim that the time to sue them has passed based on previous litigation. Whether Gilead believes that is true will be up to Gilead. But Teva may now have 180 days of exclusivity, barring any lawsuit from Gilead or entry of a second generic (the 180 days of exclusivity is complicated in this situation). There is no reason they would waste that 180 days of exclusivity or the effective exclusivity they would have by being first to market, unless they were colluding with Gilead to keep prices high, which could open them to competition complaints. The FDA notice indicated that there are issues with Teva’s “risk evaluation and mitigation strategies” (REMS) filings. How quickly Teva complies with the REMS filing requirement will likely be a good clue as to Teva’s actual generic TDF/FTC plans.

We’d expect to see generic TDF/FTC soon. Gilead is not the right target for questions as they have an incentive to make their shareholders believe it will be as long as possible. We need to be asking Teva exactly when.

When Might Generic Truvada Be Available for PrEP in the US?

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By Ethan Guillen and Zion Maffeo

I’ve written previously about the pricing of PrEP. To recap, currently, only Gilead’s Truvada is approved for use as PrEP, and in the US Truvada can be $14,000 while in developing countries Truvada can be as low as $70. While for many potential PrEP users in the US the cost would be largely shouldered by private or public health insurance or Gilead through access programs, there are still those that are uninsured. And some insurance companies are making PrEP more difficult to obtain due to the high cost. And no matter who pays, public or private, someone pays and it places an additional burden on an underfunded health system.

The short answer: Our best guess is that generic Truvada could be available in December 2017, initially produced by Teva, a major generic producer. Two other generic companies, Lupin Pharmaceuticals and Cipla may follow soon after creating competition that can really bring prices down.

The long answer: The intricacies of the US patent and drug registration system mean that it is hard to know when a generic of a medicine might become available. The patents a company lists as being relevant to a given brand drug may not actually be from the perspective of a generic producer or the patents may be weak and open to challenge by a generic company. Generic companies have an incentive to challenge patents because they can also get a small period of exclusivity when they are the only generic on the market. This all means that the date of expiration of the last patent on a medicine may be relevant but often isn’t.

In this case, Teva has not challenged Truvada directly. In separate litigation they have challenged components of Truvada – tenofovir disoproxil fumarate (also known as TDF) and emtricitibine (also known as FTC). For TDF, they challenged the patents on the drug and reached a settlement which allows Teva to start selling TDF generic in December 2017. In the same case Teva challenged the patents on the combination of TDF/FTC together – which is Truvada. We don’t know the details of the settlement – only the December 2017 date for generic TDF that was noted in the press release. In a separate case, Teva challenged a combination used for HIV treatment TDF/FTC/EFV (EFV is efavirenz; this combination is Truvada plus EFV, a three-in-one combination used to treat HIV). The settlement of that case has not been disclosed.

However, we do know that most companies have stopped pursuing cases against FTC. While we can’t say definitively why, we suspect this is for several reasons: 1) In the non-PrEP, HIV treatment market, there may be a belief that suitable off-patent drugs already exist – i.e. another drug, lamivudine, is considered by many to be interchangeable with FTC for HIV treatment; 2) since the first key FTC patent expires in September 2015, companies may have felt they could use that expiration to bring FTC to market; 3) publicly traded companies must answer to their shareholders. TDF is the key money maker so primary resources were directed toward challenging the TDF patents; and 4) at the time the Teva litigation started, Truvada had not yet been approved for PrEP and so it may have been a lower priority.

Does this mean that Teva will start producing Truvada in December 2017? We do not know Teva’s plans. Given that PrEP represents a significant new market for Truvada beyond its traditional use for treatment of HIV, it would seem to make sense that they would.

Also of note: due to the uncertainty of the settlements, we do not know what the settlement was on the combination patent for TDF/FTC together as one pill. It is possible that initially they would have to be sold as two pills packaged together in a blister pack, but we can’t know for sure due to the secret settlements. (A side note: the secret settlements are likely what is called pay-for-delay deals in which a pharmaceutical company pays cash to get a generic to drop its challenge of a drug. This allows the pharmaceutical company to keep the price high for longer, reaping extra profits. The practice has recently been a point of well-deserved controversy.)

Will the cost drop immediately to developing country-level prices in December 2017? No. There may be a period when only Gilead and Teva are selling Truvada and usually this means a price drop of only 20%. But as more generics enter the market, the price may drop by more than 80%. We don’t know exactly when that will happen but given that both Lupin Pharmaceuticals and Cipla, additional generic firms, followed Teva in reaching settlements with Gilead, it may not be long. We don’t know the details, however, as both settlements were confidential. Mylan, another major generic company, only recently launched a challenge to key Truvada patents meaning it may have an eye on the Truvada market as well.

An additional point: 7 generic companies have already filed abbreviated new drug applications with the FDA indicating that once patent barriers are removed, they are in theory prepared to manufacture Truvada. This is another indication that generic competition for Truvada may be strong, bringing the price down dramatically if many of them do indeed come to market.

What to do? As advocates, now would be a good time to start talking to Teva and other generic companies to find out their plans for generic Truvada. Having more information on what the timelines are for rollout of generic PrEP can help us better understand how to afford to get it to everyone who needs and wants it.

Below you can see charts showing the patents relevant to Truvada and its components, TDF and FTC. A second chart shows recent litigation related to TDF and FTC.

As always, thoughts, questions, and critiques are appreciated.

Special thanks to guest star, Zion, for all the help he provided getting much deeper into certain legal questions than I ever like to do.

Litigation campaigns to invalidate Gilead patents on TDF, FTC, and TDF/FTC.

Campaign Company Length of Campaign ANDAs and coverage Outcome
1 Teva Dec. 12, 2008 – Feb. 13, 2014 90894 – FTC91612 – TDF90894 – TDF Settled under mostly confidential terms. Teva may produce at least TDF in Dec. 2017.
2 Lupin Aug. 16, 2012 – Sep 23, 2014 204131 – TDF204402 – TDF205590 – TFC + Truvada Settled under confidential terms at pleading stage
3 Cipla Aug. 20, 2012 – Jul. 28, 2014 078800 – TDF Settled under confidential terms at pretrial stage
4 Mylan Jun 02, 2014 – current 206436 – FTC + Truvada Ongoing

 

TDF, FTC and TDF/FTC (Truvada) patents that have been challenged.

Patent Number** Relevant Medicine/Molecule What is patented Expiry of patent Who challenged?
5814639 FTC FTC molecule and its use to treat HIV Sep 9, 2015 Teva, Lupin, Cipla, Mylan – Mylan litigation still active
5914331 FTC FTC esters and their use to treat HIV Jul 2, 2017 Teva
5922695 TDF Synthesis of TDF   and the TDF molecule Jul 25, 2015 Teva, Lupin, Cipla
5935946 TDF Synthesis of TDF , the TDF molecule, and oral antiviral use. Jul 25, 2015 Teva, Lupin, Cipla
5977089 TDF TDF molecule and oral use to treat HIV Jul 25, 2015 Teva, Lupin, Cipla
6043230 TDF TDF compounds Jul 25, 2015 Teva, Lupin, Cipla
6642245 FTC Selection of most effective FTC enantiomer* and its use to treat HIV Nov 4, 2020 Teva, Lupin, Cipla, Mylan – Mylan litigation still active
6703396 FTC Selection of most effective FTC enantiomer* and its use to treat HIV Mar 9, 2021 Teva, Lupin, Cipla, Mylan – Mylan litigation still active
8592397 Truvada Combination of FTC/TDF used to treat HIV Jan 13, 2024 Teva, Lupin, Cipla, Mylan – Mylan litigation still active
8716264 Truvada Combination of FTC/TDF with enhanced shelf life used to treat HIV Jan 13, 2024 Lupin

 

* This appears to be a classic example of pharmaceutical patent “ever-greening.” . Here one enantiomer was identified as particularly effective so methods to isolating that enantiomer were both patented and subsequently listed in the Orange Book. Ever-greening is a general term for a strategy pharmaceutical companies use to keep their medicines patented for as long as possible.

** see Orange Book http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021752&Product_No=001&table1=OB_Rx

Companies Ready to Produce Generic Truvada and Its Individual Components

There are a number of generic companies waiting who have filed ANDAs (the application filed by a company wanting to produce a generic of an existing drug) covering either Truvada or its components but most have not litigated the issue. The complete list of all ANDAs follows. Note: these are companies who are prepared to bring a generic to market once the patent barrier is removed.

For FTC

Name                           ANDA

Aurobindo Pharm      079188

Matrix Labs                 090049

Matrix Labs                 090488

Aurobindo Pharm      090513

Teva Pharm                 090894

Cipla                             090958

Strides Arcolab           091055

Cipla                             091168

Hetero Labs Unit 3    201806

Mylan Labs                 206042

For TDF

Name                          ANDA

Cipla                            078800

Matrix Labs                079071

Invagen Pharm          090636

Aurobindo Pharm     090647

Strides Arcolab          090742

Teva Pharm                091612

Macleods Pharm       203232

Lupin                           204402

For Truvada

Name                          ANDA

Matrix Labs                090049

Aurobindo Pharm     090513

Teva Pharm                090894

Cipla Ltd                      090958

Strides Arcolab          091055

Hetero Labs Unit 3    201806

Mylan Labs                 206436

Source: http://fdazilla.com/maude/application

‘EIT’ used to whitewash torture, American linguists can’t even

IMG_0329Every year the American Dialect Society has the final say on the word of the year. They gather at a conference along with the Linguistic Society of America and in a fun and rowdy (for linguists) event nominate, debate, and vote on the word of the year.

The playful winner in the “most useful” category was:

even: v. to deal with or reconcile difficult situations or emotions (from “I can’t even”)

The “most euphemistic” category brought up the serious topic of torture and I, an interloper, enthusiastically voted for:

EIT: abbreviation for the already euphemistic “enhanced interrogation technique.”

One linguist who spoke in support of the nomination emphasized the doubly euphemistic nature of EIT. EIT adds layer upon layer of cover up to the unconscionable reality that our government has been torturing people. We went from understanding torture quite clearly as a bad thing, to a somewhat benign sounding “enhanced interrogation technique” that made one wonder if we might not just be asking questions with a firm hand, to the completely banal “EIT” which evokes nothing greater than the acronyms EKG or CPR do. As Orwell said: “Political language is designed to make lies sound truthful and murder respectable…”

Such is the use of EIT, which won the category.

EIT has been used to hide the criminality of some of the leaders of our country and prevent any significant accountability for a widespread torture program that is a stain on our collective conscience. The media has been complicit in this linguistic cover up.

Examples abound, but a quick comparison of coverage of the release of the Senate Torture Report, as it’s commonly called, and the Central Intelligence Agency response to the report, demonstrates how some media outlets have been complicit in the whitewashing.

In a CBS News report on John Brennan, head of the Central Intelligence Agency, and his response to the report, the word “torture” is only used once, simply to state the director of the CIA wouldn’t characterize the EITs as “torture.” In the accompanying video the reporters use either “enhanced interrogation techniques” or “enhanced techniques.” The accompanying text uses EIT five times.

An ABC News story on the Senate report uses “torture” in the headline and text only because the Senate report was commonly called the “Senate Torture Report.” The only other use of torture is to say that human rights groups describe the CIA’s activities as “torture.” ABC then goes on to use EIT three times.

Based on the reporting of CBS and ABC, one might be left questioning if the US government tortured people, which is clearly did.

Time has an online article that is meant to help guide readers through the 6,000 page Senate Torture Report. They use “torture” twice in the text, once in the headline. They then use EIT 16 times, always as “EIT program” even though the report itself, as far as I can tell, does not use this term. The report does use the term torture, which Time decided to use sparingly.

By contrast, the New York Times in discussing Brennan’s reaction to the torture report uses torture five times. It uses EIT only three times when quoting people talking about torture. The AP similarly uses “torture” in it’s reporting of Brennan’s reaction and also uses EIT twice, only in quotes.

In contrast to ABC, CBS, and Time who seem to question whether torture has happened, the New York Times and the AP state the truth and describe torture as what it is.

Major American news outlets like CBS and ABC are using the veneer of objectivity to hide the fact that by any common standard, the US government has been torturing people in contravention of domestic and international law.

I’m impressed that this group of linguists has taken a stand to remind us of the moral significance of our word choice.

Facebook: Please Be Friends with Men You’ve Chatted with on Scruff and Grindr and Thought You’d Never See Again

IMG_7220Grindr and Scruff are two gay social apps that live on the phones of many, many gay men. It’s not revealing much to say they are also on mine.

Grindr says they don’t give data to Facebook. Facebook agrees. Still, last Thursday, Facebook’s “People You May Know” started blowing up with folks I’d met on Grindr and Scruff over the years. Over 40 of the first 70 suggestions I went through were from these apps. I have many (if not all) of these people’s phone numbers in my phone, which Facebook has access to. Most of those numbers have been there for years. So what changed last Thursday that made Facebook suggest them as friends? I don’t know.

I’m lucky to not be in the position of needing to keep the fact that I’m gay a secret and I happily don’t feel the need to avoid most of these guys. It’s been nice to connect with a few of them. But I’m guessing for many other folks, this was a pretty unwelcome collision of worlds.

It’s reminiscent of news in 2012 that Target could predict someone was pregnant with creepy precision, and perhaps even before they knew themselves.

I made a collage of the “People You May Know” Grindr/Scruff connections from Facebook (shrunk and obscured to maintain their privacy even if Facebook is not).

Ebola, neglected diseases, and how to fix the medicines R&D system.

Recently, Al Jazeera interviewed me about the dearth of drug development for Ebola treatments. It comes down to the fact that patients suffering from Ebola live in the poorest countries in the world. As a result, they don’t represent a market that is interesting to pharmaceutical companies who are used to a blockbuster model of drug development which aims for sales of at least $1 billion per year.

We’ve seen a rush to develop drugs for Ebola now that it’s shown up in rich countries – evidence of the deeply unjust system we’ve created.

How do we fix the system? Prizes. I’ll write more about prizes another time, but the short version is that rather than a patent monopoly to drive innovation, we could offer large cash prizes based on the health impact of a new drug. The greater the health impact, the greater the proportion of the prize you receive. In exchange for the prize, the developer would immediately allow affordable generic versions of the medicine to be sold.

Can PrEP be cheaper?

There is no doubt that PrEP offers a true breakthrough in HIV prevention. It will be a critical addition to other proven prevention tools such as condoms, needle exchange, and voluntary male medical circumcision.

The key downside in rich countries is that it is expensive. At $8,000 to $14,000 per year, getting everyone on PrEP who needs it will not be cheap. Insurance companies have largely been covering PrEP and some governments – like state Medicaid programs and the city of San Francisco – are stepping up to help expand access to populations particularly impacted by HIV where prevalence remains high. But much more will have to be done to get PrEP to the populations that are most heavily impacted by HIV – especially men who have sex with men of color – who due to structural racism and mass incarceration in America are much more likely to be uninsured and not connected with the health care system. While Gilead Sciences, the maker of Truvada, the only medicine currently approved for PrEP, has access programs, governments will have to take on the major costs, not to mention programmatic responsibilities, of extending access to PrEP (and hopefully one day health insurance) to these populations.

Clearly all parties spending on PrEP would benefit from lower prices, but will this happen and when? The good news in almost every developing country is that Truvada is available for as little as $70 per year. Following new WHO recommendations on the use of PrEP, governments and global funders should be able to provide it at very low cost to populations that are particularly at risk for HIV infection.

In the US and other rich countries, there is a different story. Truvada is a combination of two drugs – tenofovir disoproxil fumarate (TDF) 300mg and emtricitabine (FTC) 200mg. The patent on TDF ends in 2018 in the US but the combination patents on TDF/FTC together lasts until 2024 meaning that for Truvada itself prices will likely remain high for a long time.

However, there is a potential way around this problem. Another HIV medicine, lamivudine (3TC), is considered to be interchangeable with FTC. 3TC is already off patent and there are no combination patents with TDF. This means that potentially from 2018 there could be TDF/3TC used for PrEP at generic prices a fraction of the current cost of Truvada. Over time, generic medicines tend to drop to 20% of the cost of the original branded product or less which would mean prices below $3,000 per year. Another solution could be to take TDF and FTC as separate, individual pills.

There is another chapter to this story. Gilead Sciences, the company that developed TDF, is currently developing a new version of tenofovir called tenofovir alafenamide (TAF). TAF is in phase III clinical trials and could be approved by the FDA by next year. TAF has a number of advantages including fewer side effects and a lower dose, meaning that it will be cheaper to manufacture – though that will only affect the eventual generic price and not the price it is sold at by Gilead.

For treatment of HIV, it is likely that TAF will become the new standard of care and Truvada will be replaced with a TAF/FTC combination. TAF patents last until 2021. To-date, TAF has not been tested to show if it is effective for use in PrEP but there is a likely chance that it is. If TAF proves to be as effective for PrEP as TDF is, TAF/FTC would likely become the new standard of care for PrEP, meaning that prices could stay high.

So what can be done? As I said, PrEP in developing countries is already available at very low cost. Steps taken by organizations such as the Medicines Patent Pool in collaboration with Gilead will ensure that any new PrEP combination with TAF would also be available at low cost in most developing countries.

For the US and other rich countries, the path would seem to be focusing on the combination of TDF/3TC. TDF is very effective and has few side effects for most people who take PrEP and the millions of patients who take TDF for treatment of HIV around the world. So it would make sense to continue to use it for patients who tolerate it well even if TAF becomes the new standard of care. This will be particularly critical for government programs to increase the number of people who can receive PrEP per dollar spent and in European countries that have been slow to take up PrEP due to the cost.

Looking further down the road, patients will likely receive quarterly injections for PrEP. The initial costs of these drugs is likely to be quite high, but in the long run for a variety of reasons, these injectables may be more affordable once they become available as generics. I’ll write about all this another time.

Disclosure: I consult for the Medicines Patent Pool. The views expressed here are my own.

Thanks to Patrick Hazelton and Luke Habberstad who provided very helpful comments.