Seven Ways to Speed Up the Pipeline – Treatment Action Group

June 2013

By Polly Clayden and Mark Harrington

This chapter will discuss how to get the best drugs to the most people as quickly as possible; this requires that the compounds and combination products be:

Discovered and developed in a high-quality research program;
Approved by a national or multinational regulatory authority;
Recommended by national or multinational guidelines groups;
Available in formulations suitable for use in the proposed population;
Affordable to public-sector programs and through private insurance; and
Accessible to patients through local health systems.

1. Continue to invest in better drugs and treatment combinations for all HIV indications.

From 1987 to 2013, the U.S. Food and Drug Administration (FDA) approved 36 drugs and fixed-dose combinations (FDCs) to treat HIV in the United States.¹

Since the FDA initiated the tentative approval (TA) program in 2004 for sale of compounds in developing countries supported by the President’s Emergency Program for AIDS Relief (PEPFAR), the FDA has approved 159 different generic antiretroviral (ARV) drugs, formulations, and combinations.²

Over the past decade since TAG’s first pipeline report in 2003, research and development (R&D) on new anti-HIV drugs has been remarkably successful.

Since 2003, 47 anti-HIV drugs or combinations have been studied in phase II or later under FDA oversight. Of these, 34% (16/49) have been approved by the FDA, 6.4% (3) have been submitted for approval, 21% (10/49) are moving forward in phase II (9) or phase III (1), while 6.4% (3/49) stopped development in phase III, 4.25% (2/49) are stalled in phase II, and 27.7% (13/47) stopped development in phase II.

Table 1A and 1B show what happened to each of the 47 drugs or combinations studied in phase II forward since 2003.

Table 1A. HIV Treatment Pipeline, 2003–2013: Drugs Approved, Submitted, or Active in Phase II/III

Generic Name (Acronym)	Brand Name	Sponsor	Status	Date	Class
Approved (16)
abacavir/lamivudine (ABC/3TC)	Epzicom	GSK	Approved	2003	NRTI 2-FDC
atazanavir	Reyataz	BMS	Approved	2003	PI
emtricitabine (FTC)	Emtriva	Gilead	Approved	2003	NRTI
enfuvirtide (T-20)	Fuzeon	Roche	Approved	2003	FI
fosamprenavir	Lexiva	GSK	Approved	2003	PI
emtricitabine/tenofovir (FTC/TDF)	Truvada	Gilead	Approved	2004	NRTI 2-FDC
tirpanavir	Aptivus	BI	Approved	2005	PI
darunavir	Prezista	Janssen	Approved	2006	PI
efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF)	Atripla	BMS/Gilead	Approved	2006	NNRTI/ 2NRTI 3-FDC
maraviroc	Selzentry	Pfizer	Approved	2007	CCR5RI
raltegravir	Isentress	Merck	Approved	2007	InI
etravirine	Intelence	Janssen	Approved	2008	NNRTI
nevirapine-XL	ViramuneXR	BI	Approved	2011	NNRTI
rilpivirine	Edurant	Janssen	Approved	2011	NNRTI
rilpivirine/emtricitabine/tenofovir	Complera	Janssen/Gilead	Approved	2011	NNRTI/ 2NRTI 3-FDC
elvitegravir/cobicistat/ emtricitabine/tenofovir	Stribild	Gilead	Approved	2012	InI/PK booster/ 2NRTI 4-FDC
Submitted (3)
cobicistat	–	Gilead	Submitted	2012	PK booster (single-agent approval postponed; approved in Stribild 2012)
elvitegravir	–	Gilead	Submitted	2012	InI (single-agent approval postponed; approved in Stribild 2012)
dolutegravir	–	ViiV/GSK	Submitted	2013	InI
Active in Phase III (1) or Phase II (9)
tenofovir alafenamide (TAF)	–	Gilead	In phase III	2013	NRTI
BMS-986001	–	BMS	In phase II	2013	NRTI
BMS-663068	–	BMS	In phase II	2013	AI
cencriviroc	–	Tobira	In phase II	2013	CCR5RI
doravirine (MK-1439)	–	Merck	In phase II	2013	NRTI
GSK126744	–	GSK/Shionogi	In phase II	2013	InI (injectable LA)
rilpivirine-LA	–	Janssen	In phase II	2013	NNRTI (injectable LA)
darunavir/cobicistat/emtricitabine/ tenofovir alafenamide	–	Janssen/Gilead	In phase II	2013	PI/PK booster/ 2NRTI 4-FDC
dolutegravir/abacavir/lamivudine (572-Trii)	–	GSK/ViiV	In phase II	2013	PI/2NRTI 3-FDC
elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide	–	Gilead	In phase II	2013	InI/PK booster/ 2NRTI 4-FDC

Table 1B. HIV Treatment Pipeline, 2003–2013: Drugs Stopped or Stalled in Phase II/III

Generic Name (Acronym)	Sponsor	Last Active Year	Class
Stopped in Phase III (3)
capravirine (AG-1549)	Pfizer	2005	NNRTI
vicriviroc (SCH 417690)	Schering	2010	CCR5I
lersivirine (UK-453,061)	Pfizer	2013	NNRTI
Stalled in Phase II (2)
PRO 140	Progenics/Cytodyn	2010	AI mAb
ibalizumab (TNX-355)	Tanox/Biogen	2011	anti-CD4 mAb
Stopped in Phase II (13)
DPC-083 (AI-183)	BMS	2004	NNRTI
PRO 542	Progenics	2004	AI mAb
SCH-C	Schering	2004	CCR5RI
calanolide A	Advanced L.S.	2005	NNRTI
reverset (D-D4FC)	Incyte	2006	NRTI
brecanavir	GSK	2007	PI
alovudine (FLT)	Mefuvir Beijing	2008	NRTI
BILR 355/r BS	BI	2008	NNRTI
elvucitabine	Achillion	2008	NRTI
racivir	Pharmasset	2008	NRTI
amdoxivir (DAPD)	Gilead	2010	NRTI
apricitabine	Avexa	2010	NRTI
bevirimat (PA-457)	Panacos/Myriad	2010	AI

Legend:

AI = attachment inhibitor
CCR5I = CCR5 receptor inhibitor
FDC = fixed-dose combination
FI = fusion inhibitor
InI = integrase inhibitor
LA = long-acting
mAb = monoclonal antibody
MI = maturation inhibitor
NNRTI = non-nucleoside reverse transcriptase inhibitor
NRTI = nucleoside or nucleotide (Nt) reverse transcriptase inhibitor
PI = protease inhibitor
PK booster = pharmacokinetic booster

These data indicate that ARV drug development continues to be a successful investment for R&D companies even after the approval of 36 drugs and combinations.

The best way to improve treatment outcomes is to assure the most rapid uptake of the best first-line ARV drugs and regimens everywhere.

Barriers to this include:

unnecessarily slow development of generic compounds/combinations for developing countries (until recently; there has been gradual improvement: for example, a generic version of dolutegravir is now being produced by Indian manufacturers in partnership with ViiV Healthcare);
regulatory sloth or inexperience in developing countries;
failure to use existing regulatory mechanisms to support Northern/Southern-hemisphere collaboration and development of regulatory capacity in the South;
corporate eagerness for profits in the North before providing access in the South;
pharmaceutical sponsors’ preference for combinations of their own compounds;
intellectual property restrictions on exploring the use of cross-company combinations;
lack of transparency;
delays, e.g., by the World Health Organization (WHO) and many national regulatory and normative authorities, in authorizing the use of the best drugs and combinations;
irrational complexity of regimens available in both North and South; and
excessively high prices of generic compounds in rich countries and of brand-name compounds in poor ones.

Here we examine each of these barriers and suggest ways to overcome them.

2. Expedite regulatory approval of new drugs/regimens everywhere.

Several current mechanisms exist to expedite regulatory approval of drugs in developing countries, including FDA tentative approval (TA), WHO prequalification (PQ), and European Medicines Agency (EMA) Article 58. They, along with some newer proposed mechanisms, are discussed here.

National regulatory authorities (NRAs)—also known as medicines regulatory agencies (MRAs)—in developing countries must take steps to compel the most rapid approval of new products, best adapted for their needs (including those in new regimens not available in rich countries) as soon as stringent regulatory authorities have approved them.

Regulatory delay has posed as much of an obstacle to timely access to antiretrovirals in developing countries as has patent protection, yet it has attracted none of the advocacy attention.

Back in 2004, according to the World Health Organization (WHO), only about 20 percent of member states, largely in developed countries, had the capacity to effectively regulate medicinal products.³

In 2010, the WHO published an assessment of regulation in 26 African countries; it found that while structures exist, in practice they are largely inadequate, failing to form coherent regulatory systems. There were multiple contributing factors, including a fragmented legal basis for regulation, weak management structures and processes, and a severe lack of staff and resources. Most countries lacked the capacity to control the quality, safety, and efficacy of medicines on their markets.⁴

Even South Africa, which the WHO concluded has a fully functional MRA, experienced considerable delay in registering medicines. Table 2 shows the delay in approval for several single-entity and combination antiretroviral products in South Africa.

Table 2: Regulatory Delay by South Africa’s Medicines Control Council (MCC) Compared with the FDA’s^5,6,7

Antiretroviral Drug/Combo	FDA Approval	MCC Approval	Delay (Years)
zidovudine (AZT)	1987	1992	5
lamivudine (3TC)	1995	1996	1
lopinavir/ritonavir (LPV/r; Kaletra*)	2000	2002+	2+
tenofovir (TDF)	2001	2007	6
atazanavir (ATV)	2003	2007	4
emtricitabine (FTC)	2003	2007	4
emtricitabine + tenofovir (FTC/TDF)	2004	2007	3
efavirenz + emtricitabine + tenofovir (EFV/FTC/TDF; Atripla)	2006	2010	4

*Aluvia (Abbott’s lopinavir/ritonavir co-formulation produced for developing countries in a different color than Kaletra’s) was registered by the MCC in 2008.

Currently almost all developing countries are guided by regulatory decisions made by stringent regulatory authorities in developed countries, mainly the FDA and the EMA.

While countries must continue to build the capacity to perform evaluations of medicines for their own markets, the FDA and the EMA, as well as the WHO, have mechanisms that could assist with expediting applications.⁸ Some of these are woefully underused and none of them are perfect, but they are a huge improvement on piling up regulatory in-trays or corridors, while people go without or put up with suboptimal treatment.

a. Tentative Approval by the FDA

The FDA introduced TA in May 2004 to support PEPFAR. This process expedites review and approval of marketing applications for single-entity, combination, and co-packaged generic versions of previously approved antiretrovirals, even when there is patent exclusivity in the United States.⁹

The program was introduced despite concerted lobbying of the U.S. government by industry and right-wing think tanks, including the Hudson Institute, which raised alarms about the quality of generic antiretrovirals. This often succeeded in muddying the waters between generic drugs (which are used all the time in medicine) and counterfeit drugs.¹⁰

There are now 159 generic antiretroviral products approved through the process for adults and children. Although many products are no longer preferred options, the list includes novel combination products that are unavailable in rich countries, such as an FDC of efavirenz plus lamivudine plus tenofovir DF, and ritonavir-boosted atazanavir. There are no generic versions of regimens or components of regimens approved since 2006: tenofovir DF plus emtricitabine plus efavirenz being the most recent (innovator product Atripla). There is no generic version of darunavir/ritonavir.

Table 3. FDA Delay from U.S. to Tentative Antiretroviral Approval^11,12

Antiretroviral Drug/Combo	FDA U.S. Approval	FDA TA Approval	Delay (Years)	From 2004*
zidovudine (AZT)	1987	2005	18	1
lamivudine (3TC)	1995	2005	10	1
lopinavir/ritonavir (LPV/r)	2000	2009	9	5
tenofovir (TDF)	2001	2007	6	3
atazanavir (ATV)	2003	2008	5	4
emtricitabine (FTC)	2003	2008	5	4
tenofovir + emtricitabine (FTC/TDF)	2004	2009	5	5
efavirenz + emtricitabine + tenofovir (EFV/FTC/TDF)	2006	2009	3	–

* Tentative approval began in 2004.

In the past, license agreements were negotiated three to five years after products were already approved in rich countries. Table 3 shows the time lag. A trend is gaining momentum though and, more recently, companies have signed agreements a year or two before FDA approval: Gilead for cobicistat, elvitegravir, and Stribild with Mylan, Strides, Hetero, and Ranbaxy (also licensing these and tenofovir DF to the Medicines Patent Pool); Janssen for rilpivirine with Aspen, Emcure, Mylan, Strides, and Hetero; and ViiV, which is already negotiating licenses for dolutegravir.

The Clinton Health Access Initiative (CHAI) made some recommendations to innovators to encourage making new products available more quickly than they have been to date, including:¹³

Sign license agreements early enough in product development so that generic licensees can file with the FDA or the WHO within one year of innovator filings (this is beginning to happen but needs to be even earlier in the cycle to further abbreviate the process).
Agree on plans for technology transfer and the generic product development no later than the 48-week readout from phase III trials.
Have joint FDA meeting (alongside the generic company) to discuss clinical data requirements for an FDC, if the regimen components are different from those of the innovator product.
Innovator and generic file for registration in the generic-licensed territories within 12 months of their respective FDA approvals.

Despite concerns from innovator companies that such discussions with the generic companies might be slated for promoting their products prior to approval, some of this is starting to occur. A strong signal from the FDA (and the EMA) that early negotiations will not be frowned on would not go amiss.

The 2006 FDA Guidance for Industry Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV 2006 includes a list of regimens and components for which the agency is satisfied that safety and efficacy have been established (and demonstrated in product labeling or peer-reviewed literature).¹⁴ It suggests that FDC or co-packaged products for combinations on this list could be developed without conducting new clinical studies.

Updated guidance from the FDA on a list of acceptable FDCs that can be approved without further clinical testing is badly needed, as is a clear regulatory pathway for the approval of FDCs that are different from the innovators.

b. The WHO Drug Prequalification (PQ)

WHO established its vaccine prequalification program in 1987 to ensure the quality of products for immunization programs purchased through UN systems.¹⁵

WHO prequalification of medicines was established in 2001, initially focusing on drugs for HIV, tuberculosis, and malaria. More recently it expanded to include medicines and products for reproductive health, influenza, and acute diarrhea in children.¹⁶ Several hundred products are prequalified to treat HIV.¹⁷ Many developing countries rely on prequalification; the program has helped countries to build regulatory capacity as it engages their regulators in the process and offers training in evaluation.

There is an agreement with the FDA that tentatively approved antiretrovirals are also prequalified. Although generally considered to be useful, WHO PQ is horribly slow, taking about two years to prequalify a drug.

c. EMA Article 58

Article 58 is a mechanism of the EMA by which the agency, in collaboration with the WHO, can provide a scientific opinion for medicinal products intended for use in countries outside the European Union.^18,19

With this mechanism, the EMA conduct an identical regulatory review to that which they would for a standard one for Europe, but with input from WHO-recommended experts, largely from developing countries. This process does not result in a regulatory approval, but instead the EMA’s Committee for Medicinal Products for Human Use (CHMP) issues a scientific opinion on the product. Under Article 58, the EMA can also provide scientific advice.

Two published reviews of regulatory mechanisms^20,21 highlighted the pros and cons of this process. Among the advantages, both reviews emphasize that WHO experts and, in some cases, regulators from developing countries can participate in plenary discussions on the product and the inspection of manufacturing facilities, helping to build regulatory capacity. Assessments are quick and rigorous—averaging about two and a half months—and they incorporate risk/benefit considerations that reflect the countries where the products will be marketed.²²

Although promising, there are several downsides: “Article 58 also has drawbacks. It has been poorly understood, poorly positioned, and has lacked good advocates and, as a result, has barely been used,” stated one review.²⁰ Importantly, the obligations of developing countries and the WHO are not made clear in the process; nor is it clear who will be responsible for postmarketing surveillance and pharmacovigilance once the product is in use outside the E.U. A massive obstacle is the article—unlike E.U. orphan-drug approval—has no incentives (such as tax breaks, research grants, free scientific advice, or marketing exclusivity) to tempt companies to use it in favor of other regulatory mechanisms. Notably with the FDA, sponsors can benefit from several incentive schemes simultaneously.

The collaboration with the WHO was also intended to support its prequalification mechanism.²³ Scientific opinions from Article 58 have been used for three antiretroviral products on the WHO List of Prequalified Medicinal Products: lamivudine,²⁴ lamivudine/zidovudine,²⁵ and lopinavir/ritonavir (Aluvia)²⁶ for adults and children, adults and children over 12, and adults and children over two years, respectively. Given that the WHO has prequalified several hundred HIV products, this mechanism is not performing impressively, nor does it compare well to TA.

“The procedure continues to be ill-suited and heavily underused,” write Saidu et al. “In fact, since its inception in 2004, only six applications have been submitted to the process, five of which received a positive opinion, including three antiretroviral drugs.”

d. “Twinned” Regulatory Review

Expediting regulatory review in high-burden countries will require new approaches. Some have discussed possibilities such as parallel or “twinned” reviews.²⁰

With parallel approval, it is possible for product developers to submit dossiers to a stringent authority and MRAs in developing countries, which conduct their regulatory reviews simultaneously but independently. This approach is more typically taken by product development partnerships (PDPs) than companies. Although the review notes that the gains offered by this approach might be illusory, as in practice MRAs wait for WHO prequalification or approval by a stringent authority. They highlight with concern the exception of weaker MRAs—some of which have approved products prior to any other review despite their lack of capacity to conduct a rigorous review.

The drawback with parallel review is that it offers no assistance or capacity building to the MRAs. Twinned review is a process where a developing-country regulator could access a dossier with a reviewer from a stringent authority. A DNDi/George Institute for International Health review points out that a twinned review of a dossier has not yet occurred, but PDPs have taken steps in this direction since 2006.²⁰ This approach could potentially offer a superior outcome, as the twinning would combine experience with product assessment with local experience of the disease and its treatment.

Our recommendations are that:

a. FDA tentative approval should be broadened to include drugs for HIV, HCV, and TB, and should expand to include regulatory support for national regulatory authorities in developing countries.

b. WHO should maintain support for its prequalification program through the end of the current decade while supporting NRAs to scale up their in-country regulatory capacity.

c. EMA should broaden the use of Article 58 activities to foster regulatory modernization in developing countries.

d. Organisation for Economic Co-operation and Development (OECD) countries should partner (“twin”) with NRAs in developing countries to foster regulatory modernization and allow modern regulatory authorities to emerge around the world.

e. Duplicative reviews should be avoided and regional reviews adopted where possible.

3. Address developing-world needs up front during drug development.

Key research questions for developing countries need to be addressed early on in drug development programs to meet their regulatory requirements.

The needs of people with HIV may differ between developed and developing countries—where populations include significantly larger proportions women of childbearing age, children, and people with tuberculosis, malaria, and other coinfections. Yet antiretrovirals are primarily developed for markets in developed countries, so research is conducted in order to provide information to register them accordingly.

A review by Médecins Sans Frontières provides the example of concomitant treatment of HIV and malaria for which WHO guidelines provided no evidence-based guidance in spite of the fact that 80 percent of HIV-positive people live in regions where malaria is endemic.²⁷ They contrast this with the practice in the developed world, where drug regulatory authorities frequently insist that data regarding a drug’s use in particular populations be submitted.

The review, conducted in 2008, examines four antiretroviral drugs that had been recently approved or advanced along the pipeline—maraviroc, raltegravir, etravirine, and rilpivirine—considering dose selection, comparability and compatibility with other antiretrovirals, and use in specific populations. They found a lack of free access to company information, which limited their analysis. They noted that until information is made more freely available, the rationale for companies’ clinical development decisions will remain unclear, and the scientific community will be unable to advise and contribute with research in developing countries.

Their recommendations can be summarized as follows:

a. Pharmaceutical companies have a responsibility to initiate and contribute to studies that are relevant for resource-limited settings if they are seriously committed to contributing to global health.

b. The scientific community should also play a bigger part than they do currently by conducting studies that are of global public benefit. Public funding could be sought for such research as long as there is very clear agreement between the private- and the public sectors on future accessibility in terms of price, in-country registration, and possible licensing to other producers.

c. Regulatory agencies also have an important role to play by requiring data for relevant populations in different settings as part of the drug approval process.

d. Originator companies that hold the intellectual property and clinical data for the compounds should also take proactive steps.

There are numerous recent examples of high-quality studies examining the interaction of, for example, new HIV or TB drugs with existing ones.^28,29,30,31

4. Close development and regulatory approval gaps between adult and pediatric medications.

The FDA needs to be given legal authority to require sponsors seeking approval for new agents treating diseases that are important domestically or globally among infants and children to develop and submit to regulatory approval a pediatric investigational program (PIP), as has been done successfully by the EMA.³² Although the FDA has included incentives to industry to encourage pediatric development since 199733 and the EMA regulations were only adopted in 2007, over the past years, these have been insufficient. Table 4 shows the time lag with recently approved pediatric indications—particularly for the youngest age group.

Table 4. Adult/Pediatric ARV Approval Gap: Delay Between FDA Approval in Adults and for Each Age-Banded Pediatric Group³⁴

Antiretroviral	Approval for Adults	Approval for Children (Age in Years)
		12–18	6–12	2–6	0–2	Delay (years)
atazanavir (ATV)	2003	2008	2008i			5 (incomplete)
darunavir (DRV)	2006	2008	2008	2011ii		5
raltegravir (RAL)	2007	2011	2011	2011iii		4 (incomplete)
etravirine (ETR)	2008	2012	2012iv			4 (incomplete)
tenofovir (TDF)	2000	2010	2012	2012v		10–12
efavirenz (EFV)	1998	1998	1998	1998	2013	0–15

i Studies >3 months to 6 years ongoing.
ii Waiver < 3 years old.
iii Studies >4 weeks to 2 years planned.
iv Studies >2 months to 6 years planned.
v Deferral until more data on bone toxicities.

Our recommendations include:

a. Accelerate the development and regulatory approval of pediatric drugs and combinations.

b. Change U.S. law to mandate the development of pediatric ARVs and other drugs.

5. Continue to simplify and streamline global and national ARV guidelines.

The WHO is releasing updated and consolidated antiretroviral treatment guidelines this summer.³⁵ These guidelines combine adult and adolescent, pediatric, and pregnancy treatment recommendations. They are laudably simpler than previous iterations.

Table 5. 2013 WHO Guidelines–Recommended ART Regimens

First-line

tenofovir DF + lamivudine (or emtricitabine) + efavirenz preferred

(including pregnant women)

zidovudine alternative to tenofovir DF

nevirapine alternative to efavirenz

Second-line

atazanavir/ritonavir or lopinavir/ritonavir preferred

+ tenofovir DF + lamivudine preferred backbone

(if zidovudine or stavudine first-line)

+ zidovudine + lamivudine preferred

(if tenofovir DF first-line)

Third-line

No specific recommendations: integrase inhibitor (INI) or
second-generation PI or NNRTI are mentioned

The new WHO guidelines are simple, but they have missed a chance to move the optimal modern protease inhibitor, darunavir, into preferred second-line recommendations—particularly after Johnson & Johnson announced in late November 2012 that it would not enforce patents on darunavir in sub-Saharan Africa.³⁶ It is currently included as an alternative only because there is no generic, heat-stable, co-formulated version of darunavir/ritonavir. Hopefully, this cautious inclusion will spur on generic development, approval and access, and dose optimization work for this drug.

Our recommendations:

a. The WHO should drop the inferior legacy PI lopinavir/ritonavir in its 2013 guidelines as soon as possible and replace it with the superior darunavir/ritonavir for second-line treatment.

b. Johnson & Johnson should broaden its patent-free region to include all high-HIV-burden countries outside of sub-Saharan Africa and provide licenses for its HIV drugs to the Medicines Patent Pool (MPP).

c. The WHO should prioritize review of dolutegravir and the role of integrase inhibitors after this drug is approved by the FDA/EMA, particularly since dolutegravir appears to be superior to current first-line therapies and may be accessible and affordable if ViiV Healthcare carries out its planned collaborations with generic companies.

The U.S. Department of Health and Human Services (DHHS) preferred first-line therapy recommendations for adults and adolescents are commendably simple—just four combinations are offered. But there are still too many alternative first-line therapy recommendations and a thoroughly confusing “less satisfactory” category of combinations that should not be included in first-line therapy recommendations at all.

Table 6. DHHS Preferred and Alternative First-Line ARV Regimens³⁷

Regimen	Rating	Branded components	Pill count
DHHS preferred first-line regimens (4 regimens; 3 once-daily, 1 twice-daily)
efavirenz + emtricitabine + tenofovir (EFV/FTC/TDF)	AI	Atripla	1
atazanavir/ritonavir + emtricitabine + tenofovir (ATV/r/FTC/TDF)	AI	Reyataz + Norvir + Truvada	3
darunavir/ritonavir + emtricitabine + tenofovir (DRV/r/FTC/TDF)	AI	Prezista + Norvir + Truvada	3
raltegravir + emtricitabine + tenofovir (RAL/FTC/TDF)	AI	Isentress twice-daily + Truvada	3
DHHS alternative regimens (15 regimens; 8 once-daily, 3 twice-daily)
efavirenz + abacavir + lamivudine (EFV/ABC/3TC)	BI	Sustiva + Epzicom	2
rilpivirine + emtricitabine + tenofovir (RPV/FTC/TDF)	BI	Complera	2
rilpivirine + abacavir + lamivudine (RPV/ABC/3TC)	BIII	Edurant + Epzicom	2
atazanavir/ritonavir + abacavir + lamivudine (ATV/r/ABC/3TC)	BI	Reyataz + Norvir + Epzicom	3
darunavir/ritonavir + abacavir + lamivudine (DRV/r/ABC/3TC)	BII	Prezista + Norvir + Epzicom	3
fosamprenavir/ritonavir + abacavir + lamivudine (FPV/r/ABC/3TC)	BI	Lexiva once- or twice-daily + Epzicom	3–4
fosamprenavir/ritonavir + emtricitabine + tenofovir (FPV/r/FTC/TDF)	BI	Lexiva once- or twice-daily + Truvada	3–4
lopinavir/ritonavir + abacavir + lamivudine (LPV/r/ABC/3TC)	BI	Kaletra once- or twice-daily + Epzicom	3–4
lopinavir/ritonavir + emtricitabine + tenofovir (LPV/r/FTC/TDF)	BI	Kaletra once- or twice-daily + Truvada	3–4
elvitegravir/cobicistat + emtricitabine + tenofovir (EVG/COBI/FTC/TDF)	BI	Stribild	1
raltegravir + abacavir + lamivudine (RAL/ABC/3TC)	BIII	Isentress + Epzicom	2

Our recommendations:

d. Despite apparent simplification, DHHS ARV regimen guidelines are still too complicated.

e. DHHS should drop clinically inferior PIs with less simple dosing schedules (fosamprenavir/r and lopinavir/r) from the first-line alternative recommended category.

f. DHHS should eliminate the “less satisfactory” category from its first-line therapy recommendations. If they are “less satisfactory,” they should not be recommended.

6. Rationalize optimal combinations and assure the rapid availability of preferred/alternative new compounds and regimens when their use can improve treatment outcomes in developing countries.

Innovator companies need to assure the rapid availability of preferred/alternative new compounds or combinations when their use can improve treatment outcomes in developing countries.

The antiretroviral and dose optimization chapters in the 2013 Pipeline Report describe a number of FDCs, either filed with the FDA/EMA or in phase III, targeted to markets in rich countries. These are combinations of compounds from the same manufacturer, e.g., elvitegravir/cobicistat/tenofovir DF/emtricitabine (Stribild); elvitegravir/cobicistat/tenofovir AF/emtricitabine; and dolutegravir/abacavir/lamivudine (572-Trii). In her chapter, Tracy Swan discusses similar issues afflicting the HCV pipeline.

Alternatively, they are licensing agreements between companies where there is no competing alternative component, such as that between Gilead and Janssen to formulate darunavir/cobicistat/emtricitabine/tenofovir AF.

Gilead, Janssen, and BMS are also investigating cobicistat with darunavir and atazanavir as co-formulated boosted PIs, although it is unclear whether cobicistat offers any advantages over ritonavir.

Of the FDCs in development, Stribild is not expected to become a preferred option in developing countries, with dolutegravir on the horizon, elvitegravir requiring a boosting agent, and lamivudine preferred to emtricitabine.

572-Trii is also not entirely appropriate as the cost of abacavir and concerns about hypersensitivity have meant this NRTI is not recommended or widely used (except in pediatric treatment).

Governments and regulators must ensure that the best possible combinations are studied, validated, and produced together, regardless of who discovered or patented them, or who manufactures them. If studies result in proof that cross-company (or multicompany) combinations are safe and highly effective, regulators need to authorize them, and those who manufacture combinations and blister packs need to be able to co-package or co-formulate them so that people can receive optimal treatment. This will require flexibility on the part of regulators, innovators, generic companies, purchasers, and providers. Getting the best combinations to as many people as possible as quickly as possible should override commercial considerations.

If two drugs are generic and one is still patented, the patent holder should license the patented drug so it can be co-formulated or co-packaged with the generics. In the case of HCV, where everything is moving so fast, regulators and guidelines panels should require that sponsors study the most promising combination therapies regardless of who discovered or makes them. This is just as important in developed as in developing countries—where occasionally more rational products are available such as an FDC of efavirenz/tenofovir DF/lamivudine and co-packaged atazanavir/ritonavir plus lamivudine/tenofovir DF.

Our recommendations:

a. Gilead needs to study optimal companion drugs for tenofovir AF, and tenofovir AF dosing without cobicistat, irrespective of the sponsor.

b. ViiV needs to study dolutegravir with tenofovir DF and lamivudine rather than abacavir—as in 572-Trii.

c. Expedite the availability of optimized fixed-dose combinations and blister packs using high-quality generics as soon as available in the United States and elsewhere.

7. People with HIV in developed countries should benefit from generics innovations, and the savings should be reinvested in high-quality HIV prevention and treatment programs to end HIV transmission and illness, and death from AIDS.

The next decade will see rich countries begin to benefit from the most astounding vigor and expansion of generics innovation in HIV treatment since Cipla’s bold move in 2001 to manufacture a cross-sponsor off-patent combination, which revolutionized treatment access in developing countries.

Table 7. Schedule of ARV Generic Availability in the United States

Drug	U.S. Patent expiration	With 18-month extension	Plus 6-month exclusivity
zidovudine/Retrovir	September 2005	February 2007	August 2007
didanosine/Videx EC	August 2006	January 2008	July 2008
zalcitabine/Hivid	November 2006	April 2008	October 2008
stavudine/Zerit	September 2008	February 2010	August 2010
lamivudine/Epivir	February 2009	July 2010	January 2011
saquinavir/Invirase	December 2010	May 2012	November 2012
nelvirapine/Viramune	November 2012	April 2013	October 2013
efavirenz/Sustiva	August 2012	January 2014	July 2014
ritonavir/Norvir	December 2012	May 2014	November 2014
indinavir/Crixivan	May 2013	October 2014	April 2015
delavirdine/Rescriptor	October 2013	March 2015	September 2015
nelfinavir/Viracept	October 2013	March 2015	September 2015
From E-MedTV – earliest possible
abacavir/Ziagen	June 2012	November 2013	May 2014
enfuvirtide/Fuzeon	June 2013	November 2014	May 2015
emtricitabine/Emtriva	March 2016	August 2017	February 2018
lopinavir/Kaletra	June 2016	November 2017	May 2018
atazanavir/Reyataz	April 2017	September 2018	March 2019
tenofovir/Viread	June 2017	November 2018	May 2019
fosamprenavir/Lexiva	December 2017	May 2019	November 2019

We see the coming decade as an opportunity for the introduction of high-quality generic ARV drugs and the most rational combinations in both developed and developing countries, with billions of dollars and millions more lives saved.

However, data on 2011 expenditures from the United States AIDS Drug Assistance Programs (ADAPs) indicate that generic ARV procurement represented just 0.7% of expenditures (the data are on total costs and do not demonstrate sales by volume).

Table 8. U.S. ADAP ARV Expenditures FY 2011

Drug name	Company	Total	Adjusted for missing	% of total
DHHS preferred first-line regimens/drugs
efavirenz + emtricitabine + tenofovir DF (Atripla)	BMS/Gilead	$431,120,237.66	$452,495,957.75	30.19%
emtricitabine + tenofovir DF (Truvada)	Gilead	$292,104,331.29	$306,587,391.65	20.46%
atazanavir (Reyataz)	BMS	$158,616,528.61	$166,481,022.60	11.11%
darunavir (Prezista)	Janssen	$95,579,834.05	$100,307,883.21	6.69%
raltegravir (Isentress)	Merck	$95,569,380.70	$100,307,883.21	6.69%
ritonavir (Norvir)	Abbott	$60,813,528.16	$52,524,628.65	3.50%
tenofovir DF (Viread)	Gilead	$26,329,560.99	$27,635,028.18	1.84%
efavirenz (Sustiva)	BMS	$19,774,996.94	$20,755,477.01	1.38%
emtricitabine (Emtriva)	Gilead	$1,459,579.54	$1,531,948.13	0.10%
DHHS preferred first-line subtotal		$1,181,367,977.94	$1,228,627,220.39	81.98%
DHHS alternative first-line regimens/drugs
abacavir + lamivudine (Epzicom)	ViiV/GSK	$55,834,785.63	$58,603,175.15	3.91%
lopinavir + ritonavir (Kaletra)	Abbott	$50,043,387.13	$52,524,628.65	3.50%
fosamprenavir (Lexiva)	ViiV/GSK	$19,928,279.49	$20,916,359.58	1.40%
abacavir (Ziagen)	ViV/GSK	$8,795,481.78	$9,231,577.65	0.62%
lamuvudine (Epivir)	ViiV/GSK	$5,674,252.91	$5,955,592.62	0.40%
rilpivirine + emtricitabine + tenofovir (Complera)	Janssen/Gilead	$2,864,832.88	$3,006,876.47	0.20%
rilpivirine (Edurant)	Janssen	$1,096,477.71	$1,150,843.06	0.08%
DHHS alternative first-line subtotal		$144,237,497.53	$151,389,053.18	10.10%
DHHS “other” or not recommended for first-line
nevirapine (Viramune)	BI	$24,988,441.21	$26,227,413.26	1.75%
lamivudine + zidovudine (Combivir)	ViiV/GSK	$22,315,624.03	$23,422,072.98	1.56%
etravirine (Intelence)	Janssen	$19,928,279.49	$20,916,359.58	1.40%
abacavir + lamivudine + zidovudine (Trizivir)	ViiV/GSK	$12,959,115.09	$13,601,651.42	0.91%
nelfinavir (Viracept)	ViiV/Pfizer	$8,557,770.47	$8,982,080.19	0.60%
lamivudine + zidovudine (generic)	generic	$7,211,626.31	$7,569,191.77	0.51%
maraviroc (Selzentry)	ViiV/Pfizer	$5,336,449.20	$5,601,039.99	0.37%
saquinavir (Invirase)	Roche	$3,348,907.36	$3,514,952.24	0.23%
enfuvirtide (Fuzeon)	Roche	$2,292,461.56	$2,406,125.94	0.16%
didanosine (generic)	generic	$1,396,960.75	$1,466,224.60	0.10%
lamivudine (generic)	generic	$1,142,613.47	$1,199,266.31	0.08%
tipranavir (Aptivus)	BI	$1,086,042.91	$1,139,890.88	0.08%
zidovudine (Retrovir)	ViiV/GSK	$619,694.00	$649,555.30	0.04%
indinavir (Crixivan)	Merck	$618,870.58	$649,555.30	0.04%
stavudine (Zerit)	BMS	$496,566.23	$521,186.88	0.03%
didanosine (Videx)	BMS	$347,914.45	$365,165.68	0.02%
zidovudine (generic)	generic	$287,349.94	$301,597.27	0.02%
delavirdine (Rescriptor)	ViiV/Pfizer	$57,854.10	$60,772.61	0.00%
DHHS “other” / not recommended for first-line subtotal		$112,992,541.15	$118,594,102.20	7.91%
U.S. ADAP ARV 2011 total		$1,438,598,016.62	$1,498,610,375.77
All generics combined		$10,038,550.47	$10,536,279.95	0.70%

Source: National Alliance of State and Territorial AIDS Directors (NASTAD)

Our recommendations:

a. Generic ARVs in the United States and other developed countries should be priced at 25 percent of the brand-name/innovator price or less.

b. Ideally, given the U.S. taxpayers’ generosity to people with HIV in other countries though the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) and PEPFAR, the U.S. generic price should equal the best global generic price of an equivalent FDA TA regimen; similar benefits should accrue to other developed countries when patents expire.

c. Prices of generic ARVs are far too high in the United States. For example, generic abacavir and nevirapine cost about 90 percent of that of the innovator, while generic AZT costs about 65 percent as much as branded Retrovir.

d. This year’s imminent patent expiration of efavirenz provides an opportunity to begin a much-needed transition to generic preferred drugs and combinations. The coming decade will see a number of such innovator/generic transitions.

e. The potential of these changes to accelerate a reduction in ARV drug prices must be realized.

f. Countries such as the United States must carry out public tenders to accelerate the availability of inexpensive high-quality generic drugs and combinations as soon as practicable.

g. Savings from their use should be reapplied to allow broader, earlier treatment of HIV and related conditions such as HCV, and to improve HIV prevention, care, and support services.

Conclusion: Summary of Recommendations to Speed Up the Pipeline

The best way to improve treatment outcomes is to assure the most rapid uptake of the best first-line ARV drugs and regimens everywhere.

1. Continue to invest in better drugs and treatment combinations for all HIV indications.

2. Expedite regulatory approval of new drugs/regimens everywhere.