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Uncertain Future for Early Access?

January-March 2006

In the bad old days -- before effective combinations of HIV medications dramatically rolled back the tide of suffering and death from AIDS in this country -- informed patients-turned-activists helped institute a revolution in drug development that allowed people with no hope to obtain promising new antiretroviral (ARV) drugs before the FDA had approved them. Initially called "parallel track" -- because it was a separate way to simultaneously access drugs outside of ongoing clinical trials -- early or expanded access programs (EAPs) became an expectation with every new drug. The first parallel track program for ddI in 1990 enrolled over 20,000 people to receive the drug for up to 12 months before it was finally approved in late 1991. There may well be hundreds or thousands of people alive today because early access to ddI or another drug gave them a six-month reprieve that kept HIV at bay long enough for something else to come along.

But the ddI experience showed that early access to experimental drugs could also give an early warning about uncommon adverse events that are only noticed after a large number of people have taken the drug. Because the ddI access protocol called for fairly rigorous safety reporting, the several cases of fatal pancreatitis identified let doctors know that this was something to watch out for once the drug hit pharmacy shelves.

Beyond addressing the humanitarian need for rapid access to new lifesaving drugs and offering an early look at safety data in a relatively large patient population, early access also gave drug makers a head start in building the market for a new drug. Because doctors and patients were already using the drug when FDA approval came and the company could begin charging money for it, the time required to achieve market acceptance -- and profitability -- was dramatically shortened. For people with HIV, their doctors, and the drug companies, early access programs were a win-win-win situation.

If there was one downside it was that patients chasing the next new drug were burning though their options as fast as HIV could develop resistance to each single active agent added as monotherapy or, when its companion drugs had already failed, virtual monotherapy. Even after combination therapy was recognized as the way to go, it was several years before industry and the HIV medical community generally accepted that the only safe way to add a new drug was to be sure that it was supported by other active agents in the rest of the regimen. Tragically, many expanded access participants from the 1990s are today resistant to nearly all of the 20-plus approved HIV drugs. Many still worry that early access to the next promising drug is all that can rescue them from the brink of runaway HIV infection.

When treatment activists meet with drug companies about an ARV in development, planning for an expanded access program is always near the top of the agenda. From the mid-1990s forward, treatment activists have consistently demanded that EAPs be made available to "any patient unable to construct a viable treatment regimen." Most companies eventually adopted this broad and rational criterion, although many initially limited expanded access eligibility to people with very low T cell counts -- those most in need -- due to a limited supply of drug or perhaps too sparse data safety. One continuing community complaint is that EAPs sometimes open too late to offer a significant advantage to many people -- sometimes beginning enrollment only a few months before approval. Typically, people receiving a drug for free through an expanded access program will continue to receive it for a few months after approval until a stable method of reimbursement is established.

Ten years after the advent of truly effective antiretroviral therapy and 15 years after parallel track, there are emerging signs that expanded access programs may no longer be filling the need they once did, and that the burden of running these programs may be forcing some doctors in large clinics and research sites to say "no thanks" to early access.

Early access programs are actually formal studies conducted under FDA-approved protocols. Participants must be informed about the risks of taking the experimental drug and they must give their written consent. The protocols are vetted by ethical review boards and the data may be monitored by safety review committees. Patients give blood samples and are examined according to the protocol. All adverse events -- whether considered caused by the drug or not -- must be reported to the FDA, the ethical review boards, and to every investigator using the drug, whether in a clinical trial or through an EAP.

In 2005, one new protease inhibitor, Aptivus (tipranavir), was approved, and in 2006 another new protease inhibitor, Prezista (darunavir), was approved in June. Each of these drugs were available to patients before approval through expanded access programs that ran in parallel with the main clinical trials designed to support approval. In an attempt to roll back the window of early access earlier still, Open Label Safety Studies (OLSS) allowed a small group of the most desperate patients to obtain drug under very strict protocols before the large clinical trials had even finished enrolling. After a few months the entry criteria were relaxed a bit and the drugs became available to a broader group through conventional early access protocols.

Despite what was thought to be an urgent need for a new protease inhibitor with activity against PI-resistant HIV, enrollment in the tipranavir EAP was disappointing, with less than 1,000 patents having enrolled by the time of approval. Many observers thought this low enrollment for a badly needed new drug may have been due to concerns about liver toxicity associated with tipranavir and with the fact that another new drug with a better safety profile, darunavir from Tibotec, was making rapid progress towards becoming available in its own EAP.

But reports about Tibotec's experience with darunavir suggest that something else may be going on. Early access to darunavir began in the fall of 2005 through an OLSS before opening up to a wider group with an expanded access protocol in October 2005. There was a lot of positive buzz about darunavir (TMC114) because it seemed to be very effective, minimally toxic (compared to tipranavir), and because the FDA had given it an extraordinarily fast track based on data from Phase II trials. Yet at the time of approval in June 2006, perhaps only 800 people had taken advantage of early access to darunavir. Was it that patients were finding all the drugs they needed elsewhere? Or were the barriers to running an expanded access protocol becoming too great for the research sites that traditionally enroll most patients in EAPs?

The industry has estimated that there may be over 120,000 patients on a third or fourth regimen in 2006 and that 45,000 of these will switch therapies during the year. So if only 10% of those switching went to an EAP for a new drug, that would suggest enrollment numbers could reach several thousand.

With evidence accumulating that staying on a failing regimen may have benefits, and with several new drugs in the development pipeline, it may be that patients and doctors aren't feeling a desperate need to switch and are deciding to wait until they can put together a potent regimen that will last. Perhaps the tide of multidrug resistance due to serial monotherapy has crested.

In 2006, several new expanded access programs are expected to open as the pipeline surges with the first of a new wave of drugs. Pfizer's entry inhibitor, maraviroc, Merck's integrase inhibitor, MK-0518, and Tibotec's NNRTI, TMC125 may soon be in competition for research sites and patients -- not only for expanded access, but for pivotal clinical trials as well. Will the network of experienced research sites have enough time and staff to handle all of the clinical trials -- for which they are reimbursed -- and still have the capacity to host more than one unfunded expanded access program? Perhaps another reason that expanded access programs are falling by the wayside is because so many promising new drugs are becoming available through clinical trials. In late May 2006, Gilead Sciences announced that it had met Phase II enrollment targets for its new integrase inhibitor ahead of schedule and was closing the study to new patients. Larger, Phase III trials for Merck's similar compound are also said to be enrolling swiftly.

If the number of people who can benefit from early access has declined, the sense of desperation for people who truly have no treatment options has not lessened. If the large, geographically diverse, expanded access program is becoming a dinosaur, then treatment activists, drug companies, and the FDA need to agree on creative new ways to get experimental drugs to those in need without strangling patients in red tape. One proposal is for a streamlined individual treatment IND -- a protocol for a study of one -- using a simple, standard, web-based form, and a central ethical review committee, that can offer early access to a new agent based on a doctor's medical judgment -- not on his capacity for battling bureaucracy.

Whether they serve the numbers they once did or not, sponsors are unlikely to stop planning for EAPs. Community pressure for continuing the programs remains consistent -- and there will always be some patients for whom they are lifesaving. But simply offering an expanded access protocol to ordinary treating physicians gives companies a valuable chance to educate HIV doctors about a new drug or a new drug target prior to approval. In the win-win logic of expanded access, this is an advantage that will likely keep EAPs part of the HIV landscape for the forseeable future.

History of Antiretroviral Expanded Access Programs (EAPs) in the United States
DrugDates of EAPPts in EAPApproval Date
Zidovudine (AZT)1986-874,804March 1987
Didanosine (ddI)1989-91~22,000October 1991
Zalcitabine (ddC)1990-926,705June 1992
Stavudine (d4T)1992-9412,561June 1994
Lamivudine (3TC)1993-9529,430Nov 1995
Saquinavir (SQV)19952,200December 1995
Indinavir (IDV)19951,500March 1996
Ritonavir (RTV)19952,000March 1996
Nevirapine (NVP)1996421June 1996
Delavirdine (DLV)1996-971,527April 1997
Nelfinavir (NFV)1996-973,100March 1997
Efavirenz (EFV)1997-998,281September 1998
Abacavir (ABC)1997-98<5,000December 1998
Amprenavir (APV)1998-992,217April 1999
Kaletra (LPV/r)1999-00~2,400September 2000
Tenofovir (TDF)20013,111October 2001
Enfuvirtide (ENV)2002-03~3,000March 2003
Atazanavir (ATV)2002-033,610June 2003
Tipranavir (TPV)2004-05972June 2005
Darunavir (DRV)2005-06~800June 2006

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
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