FDA HCV Hearing on Early Access to New Drugs: report from Jules Levin

FDA HCV Hearing on Early Access to New Drugs: report from Jules Levin


from Jules: At the hearing Friday at the Hilton in Rockville Maryland, the relatively small hearing room, small by FDA hearing standards, was packed with I estimate about 200 people. Many drug companies were represented by high-level people, those heading their clinical and regulatory programs. Also present were some press, some community advocates, and of course other interested parties. The FDA started with 2 oral presentations including an explanation by Jeff Murray from the FDA on the traditional HIV Expanded Access Program. I was the 1st speaker in the public session and explained my proposal to provide 'early access' to needy patients (explained below). I also provided a brief report on the status of the disease stage in today's aging HCV+ patient population. Each presentation was allotted 15 minutes. Gary Davis published a modeling study in Dec Gastroenterology where he said today's patients were in large numbers infected 30 years ago, the so-called HCV+ baby boomers, and today patients have aged many years and 25% today have cirrhosis, 11% have decompensation or HCC and these percentages will increase in the near future but subsequently decline due to them dying if we don't treat them. Several community advocates spoke including folks from the Hemophilia community who submitted a Citizens Petition asking for a public hearing on access about 1 year ago, also Lynda Dee and Tracy Swan spoke. All the community advocates urged the FDA and the companies to provide early access for patients at serious risk for death or progression such as they cannot wait for drugs to be approved. Most of these patients are nonresponders and some are contraindicated for pegylated inteferon/ribavirin so these latter patients are perfect to receive an oral regimen of multiple orals without peg/rbv to see if an all oral regimen could cure HCV. Several drug companies did provide a presentation and these were Idenix, BMS, Vertex, Roche, and Merck. Also present were senior officials from Boehringer Ingelheim, Tibotec and Gilead although they did not make presentations. All these companies expressed support and need for addressing the concern for early access for these patients and expressed the same opinion as me that due to safety and resistance concerns it would be better to provide early access to select patient populations in controlled study situations rather than the old HIV traditional expanded access model. I proposed (read below) to provide the access in phase 2, which is very early in drug development, in HIV expanded access was provided in phase 3. I did this in an effort to have access provided as soon as possible with the premise as I explain below that we must have the proper safety data to provide such access, so safety studies on dosing, PK and such would have to be conducted very early. Without proper safety data and considerations early access will not occur. Several important and noted researchers spoke at the hearing - Maribel Rodriguez, Charles Howell, and Diana Sylvestri. Rodriguez implored the FDA and the companies to do adequate studies in the Latino patient populations as they suffer disproportionately from HCV, which is of course true. Howell implored the FDA and the companies to adequately study African-Americans who also suffer disproportionately from HCV, which they most definitely do as well. And Sylvestri implored the FDA and the companies to adequately study patients with a history of IV drug use, which is a very significant issue, because they are often a challenging patient population but the uniqueness of HCV disease is that IV drug users are the ones perhaps most significantly disproportioately affected and of course there is quite a lot of cross over between these patient populations - African-Americans, Latinos and IV drug users. I closed the meeting with a brief summary saying now that the companies have expressed interest in addressing this problem of the need for early access for these needy patients and of course saying they said they want to study them in a study situation where they can control access and importantly obtain data on these patients, now the companies can submit study protocol to the FDA for review. Also of note in my presentation I said the FDA should provide incentives to the companies to provide the early access studies. I suggested Accelerated Approval for these HCV drugs, as in HIV, would provide incentive for companies. I suggested several other important incentives. A company wants to get their drug(s) through the clinical development process as quickly and safely as possible so they can get to the market and all the companies are competing with each other to get there. We do not want the programs slowed or derailed because obviously patients are anxiously waiting to be able to get these drugs after FDA approval. Providing multiple, 2, 3 or even 4 oral drug with or without peg/rbv, to very sick liver disease patients during early development before having the full opportunity to study the drugs and characterize and understand antiviral effectiveness and most importantly safety may result a patient experiencing a serious toxicity. This toxicity could be due to giving such a sick patient several new oral drugs together, a toxicity that a more healthy HCV+ patient may not experience. So the toxicity could be due to the patient's situation, not necessarily due to the drug, and if this patient who experienced the toxicity is receiving 2 or 3 oral drugs the perception could be the toxicity could be associated with one of the particular drugs. As you can see this is a complicated situation. We do not want the drug or the company to be penalized for being willing to help sick patients through early access, so I also proposed the FDA should be flexible on the issue if a toxicity arises. If a toxicity arises in this manner it could result in the drug program being put on hold or delaying development. Needless to say this creates a real threat to drug development that is not only a great concern to companies who have quite a lot at stake but also to patients who are waiting for these drugs. In this sense patients and the companies are not separate entities but are one. We both very much want and need these development programs to be successful and to bring these drugs to the market as quickly as possible. We do not want undue delay in the time it takes to get these drugs to the market for patients. So, I also suggested if a toxicity does occur the FDA should not give the drug a 'black box' but merely discussing what happened in the label. We must bear in mind that millions of patients are waiting for these drugs and we do not want to delay or risk any drug evelopment program. As I see it another incentive for the companies to conduct early access is that normally as was done with peg/rbv development studies in these sick advanced patient populations were performed in phase 4 after FDA approval, but by doing them before FDA approval we would have data earlier so perhaps the FDA could provide approval for use in these patient populations at the same time they grant approval for the drug in regular patients. What will happen now. I think the hearing put this issue of 'early access' front and center to the FDA and the companies and the ball is now in their park, we will have to wait to see how companies and the FDA respond, but I expect a favorable outcome.

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FDA Considers Expanded Use of HCV Drugs

MedPage Today
Published: April 30, 2010

from Jules: I spoke at the hearing and proposed a concept for 'early access' for patients with advanced HCV disease, the concept has several components. (1) The access program would include only patients who are at risk for death or they are so advanced that if they had to wait for new drugs they might not be able to take them when they become available. (2) I proposed the 'early access' program would be conducted in phase 2 after companies collect the proper safety and dosing data. (3) The access would only be provided in controlled studies not open expanded access, because we are concerned that patients with advanced disease would be at risk for serious toxicity since they may have impaired renal and liver function requiring the need to colect PK and dosing data because the fact that they have impaired hepatic function might require different drug dosing. The other concern necessiting a controlled study environment rather than a loosely controlled situation as is the tradition in HIV Expanded Access is because we do not want to create drug resistance inpatients which might result in the patients becoming cross-resistance to other drugs in the same class. These patients are probably nonresponders so my proposal is they receive at least 2 or 3 or even 4 orals in these 'early access studies'. (4) The proper patient populations would have to be selected for early access, these would be patients who can safely receive the drugs and would be in need like for example pre and post transplant patients or advanced compensated disease, and again patients whose disease stage allows them to wait for availability upon approval should wait. This is in part because in the old HIV Expanded Access programs were so easy to gain access to that many patients who could have waited didn't because they thought they couldn't wait and drug resistance resulted for which to this day 14 years later these patients have had drug resistance hampering their therapy all through these years. In HIV since its lifetime therapy companies and researchers dedicated resources to developing 'salvage' drugs that could effectively suppress this resistant virus. HCV is different, it is time-limited therapy, on average 24 week therapy to achieve a cure, and with a certain amount of years perhaps 12 years so many patients may be cured making the market in the USA so small that incentive to develop salvage drugs may not be enough for companies to develop new salvage drugs, as costs to develop a new drug is 100s of millions of dollars.

ROCKVILLE, Md. -- The FDA heard public testimony Friday on establishing a compassionate use program that would allow severely ill hepatitis C (HCV) patients access to investigational, direct-acting antiviral agents.

One of the current treatments for HCV -- pegylated interferon alfa-2a and ribavirin (Rebetol) -- is highly toxic with a response rate of about 50%, clinical data show. That number is much lower in real-world cases, according to a number of physicians who testified during the public hearing.

The FDA understands current treatment options are not good enough, an official said. "Current control of hepatitis C is not working," said Peter Lurie, MD, of the FDA's Office of the Commissioner.

Friday's meeting was called in response to a petition by groups seeking access to the drugs for individuals often excluded from clinical trials.

Clinical trials are only open to a small subset of real-world HCV patients, noted Diana Sylvestre, MD, who treats HCV-infected intravenous drug users in the San Francisco area. Yet, there are many HCV patients who cannot tolerate current treatments, she said.

Her patients are rarely accepted into clinical trials, she said, because of their drug use, comorbidities, and mental illnesses.

Other patient populations who might benefit from expanded access include those with cirrhosis, HIV, or hemophilia; those awaiting transplant or post-transplant patients who have a recurrence of HCV; and African Americans and Hispanics.

Several physicians urged special consideration for minority patients, who are disproportionately left out of clinical trials. A recent study confirmed that members of ethnic minorities do not fare as well as expected with current HCV treatments.

The FDA instituted compassionate use programs in the 1970s and such drugs as trastuzumab (Herceptin), bevacizumab (Avastin), and erlotinib (Tarceva) have all been made available before formal FDA approval under an expanded access protocol.

One major expanded access program involved breakthrough HIV therapies in the '90s. "Anecdotally, the results were so striking," said Jeffrey Murray, MD, deputy director of the FDA's antiviral products division. "They did save lives."

Murray noted that the FDA is working on a guidance document on the use of direct-acting antiviral agents, which should be released sometime this year.

If approved, an expanded access program could be applied to several novel HCV treatments currently in clinical trials.

One of the most advanced is the protease inhibitor telaprevir from Vertex and Johnson & Johnson.

Results from a phase II trial showed that when telaprevir was added to pegylated interferon alfa-2a and ribavirin among patients who hadn't responded to treatment, the virus was significantly more likely to be eradicated.