Saturday, December 06, 2014

Clinical trial design for treatment of Ebola virus disease versus Ebola vaccine

Ebola outbreak in West Africa has brought a lot of attentions to this deadly virus. The world is so unprepared for the Ebola treatment and prevention. Now that the developed countries including US are starting to develop the drugs for treating and preventing the Ebola virus, the discussions about the Ebola drug trials are in the center stage.

First of all, there is a big distinction between developing the drugs for treating Ebola virus disease and developing the Ebola vaccine. Many people may discuss the Ebola trial without clear distinction of the treatment and prevention. In a Forbes article “FDA: Some Ebola Patients Need To Get Placebo”, the author clearly mis-interpreted the original FDA paper and blurred the distinction between drug for treating Ebola patients and the Ebola vaccine.

The ethical dilemma and debate about the randomized, controlled trial are on the issues for drug trials targeting the treatment of the Ebola patients, not the Ebola vaccine. FDA’s article in New England Journal of Medicine “Evaluating Ebola Therapies — The Case for RCTs” discussed the issues with clinical trial design for Ebola therapies (treating Ebola infected patients), not for Ebola vaccine (preventing people from Ebola infection).

So far, the majority of the clinical trials are focusing on the Ebola virus vaccine, not on the Ebola treatment. According to, there are 21 clinical trials registered, except for 2 trials that are conducted in ebola patients or ebola virus infested patients, all other trials are for Ebola vaccine and conducted in healthy volunteers

The immediate need is to find effective therapies for treating the Ebola virus infected patients. Down the road, developing effective vaccines to prevent the Ebola virus infection (at least prevent the similar outbreaks) is more important. Without any incentives, the drug companies may be more interested in developing the Ebola vaccine because of its much greater marketing potential.

 A Comparison of Ebola Therapy and Ebola Vaccine

Ebola Therapy
Ebola Vaccine
Treatment of Ebola Virus Infected patients
Prevention people from Ebola virus infection
Target population
Ebola virus infected patients
General public or population at risk for Ebola infection (such as health care workers)
Study population
Ebola virus infected patients
Healthy volunteers
Efficacy Measure
Survival rate (proportion of patients who can survive in two weeks)

the immunogeneicity (i.e., the occurrence or titer of the anti-ebola virus antibodies).

Control group
Placebo-controlled study is not feasible, but the best supportive care as control group is feasible.
Placebo control is feasible.
Study endpoint
Survival is a hard endpoint
Titer of antibodies is a surrogate, soft endpoint. The overall effectiveness is difficult to measure.
Tolerance for safety
Comparing to the vaccine, there may be more tolerance in terms of the safety.
The new drug / therapy must be extremely safe since the vaccine will be used by the healthy people

Specifically for clinical trials to find effective therapies for Ebola virus infected patients, the clinical trial design is at the center of the debate. The experts in European countries prefer the clinical trials using the historical control (i.e., without the concurrent control group) while US (FDA and NIH) prefers the traditional randomized controlled trials with the best supportive care as the control group.

With very high mortality rate, it is understandable to think that a randomized, supportive care controlled or placebo controlled study is ridiculous. If there is a new experimental therapy with even a slim of hope, people will jump on it. Just as it said in the article “The Ethical Issues In Using An Experimental Ebola Drug”.
“the World Health Organization said in a statement today that it is ethical to offer unproven drugs to treat or prevent the spread of the Ebola virus
Under American law, the Food and Drug Administration can permit a drug manufacturer to provide an unapproved drug to patients if they don't have any alternatives and the consequences are severe. It's called "compassionate use" and most of these exceptions are granted when the drug is in a clinical trial testing its safety, proper dose and efficacy.
The most profound example of this comes from the 1980s, in the early days of the AIDS epidemic. There was no approved drug that had any effect, and people were dying. Dr. Anthony Fauci [director of the National Institute of Allergy and Infectious Diseases] was key to changing this approach, and expanding access to AZT outside of clinical trials. But this is different in that the drugs for the Ebola virus have not yet entered clinical trials in humans.”

Considering the high mortality rate and no proven therapy for treating the Ebola virus disease, using a historical control seems to an easy choice. With this design, all patients will be given the experimental drug(s). If the survival rate in patients treated with experimental drug(s) is lower than a fixed number (historical control), the experimental treatment would be considered as effective. However, it all depends on how reliable the historical control is and whether or not the other best supportive cares have changed over time. The study design can still be randomized and controlled. It is just the concurrent control group is another experimental drug(s).

It is generally agreed that the clinical trials for Ebola virus disease treatment should have more than one arms and should be randomized, controlled. The European countries seem to prefer a study design with multiple experimental therapies to compare each other. US (FDA and NIH) seems to prefer a study design with experimental therapy compared with the concurrent control of the best supportive care. This can be essentially viewed as an add-on study design with one group to be the best supportive care only and another group to be the best supportive care + the experimental therapy. For the purpose of demonstrating the efficacy of the experimental therapy, this seems to be the most reasonable approach.

In the end, the action is always better than debate. Let’s put aside the debate and start the clinical trials for Ebola treatment. The clinical trials for Ebola virus disease treatment (new therapies) have begun.
 “US scientists have not yet announced which treatments will be tested in clinical trials that they plan to run in the United States and, possibly, in Liberia. Doctors and researchers organizing the trials met at the US National Institutes of Health in Bethesda, Maryland, on 11 November.
"We had good discussions,” says Clifford Lane, deputy director for clinical research and special projects at the US National Institute of Allergy and Infectious Diseases in Bethesda. “We are working on refining our adaptive-design protocol with specific arms based upon those discussions.”
MSF says that the trials at its sites will test whether the interventions boost the proportion of patients who survive for two weeks. It hopes to report initial results from the trials as early as February 2015.
MSF said previously that none of the trials run at its sites will assign patients to receive standard of care treatment rather than an experimental intervention. Whether or not to use a standard of care control group in these trials is a thorny and hotly debated question. The US trials plan to use a control group, but have not made final decisions about the trial design.”
It is reported that the first Ebola treatment trial has started in January, 2015. The study lead by Dr Jake Dunning is a study without concurrent control group - there is no randomization. The Ebola virus positive patients are asked if they are willing to participate in the trial to receive the experimental treatment. if they decline the participation, the patients will receive the standard supportive care. Hopefully, they will track the at least the mortality rate in those who decline the participation.

The Ebola vaccine trials has also begun and some of the studies have reported the success (safe and generating antibody response in healthy volunteers).

Monday, December 01, 2014

FDA's Priority Review Voucher Programs

A voucher is a bond of the redeemable transaction type which is worth a certain monetary value and which may be spent only for specific reasons or on specific goods. Examples include (but are not limited to) housing, travel, and food vouchers.

You may find it surprising, the voucher has been used by FDA as a tool to encourage the drug development in certain areas.

In 2008, FDA issued its 1st voucher guidance titled “Tropical Disease Priority Review Vouchers”. Last month, FDA has published its second guidance related to voucher. The draft guidance is called “Rare Pediatric Disease Priority Review Vouchers, Guidance for Industry

How does it work?
  • Sponsors must first have an NDA/BLA approved for an indication in designated tropical disease area or in qualified rare pediatric disease area. 
  • Sponsor will then submit the application for priority review voucher
  • Sponsor may need to pay additional application fee for voucher
  • Once the priority review voucher is approved, the voucher can be sold and transferred to other sponsors
  • Voucher can be redeemed for priority review for any NDA/BLA submission 
Both voucher programs are designed to provide incentives for drug developers to invest in the neglected disease area or in the disease area that return on investment (ROI) is very low.
According to FDA's MAPP "Review Designation Policy: Priority (P) and Standard (S)", applications or supplements submitted with a priority review voucher will automatically receive a priority review designation.

The tropical disease priority review voucher was issued in 2008 and it was not used often by the sponsors. However, the tropical disease priority review voucher may find new popularity thanks to the global fight against Ebola. Ironically, at the time when the Tropical Disease Priority Review Voucher guidance was issued, the deadly Ebola disease was not on the list of tropical disease areas.
Product applications for the prevention or treatment of the following tropical diseases may qualify:

• Tuberculosis
• Malaria
• Blinding trachoma
• Buruli Ulcer
• Cholera
• Dengue/Dengue haemorrhagic fever
• Dracunculiasis (guinea-worm disease)
• Fascioliasis
• Human African trypanosomiasis
• Leishmaniasis
• Leprosy
• Lymphatic filariasis
• Onchocerciasis
• Schistosomiasis
• Soil transmitted helminthiasis
• Yaws
• Any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations, designated by regulation by the Secretary (section 524(a)(3))

One may argue that the Ebola can be included in the last item “any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations, designated by regulation by the Secretary”.

To ensure that Ebola is included in the Tropical Disease Priority Review Voucher program and to remove the obstacles for voucher program to become popular, a Senate bill has been proposed. The bill passed the senate in November.

The newly issued guidance on Rare Pediatric Disease Priority Review Voucher program seems to be better designed and hopefully it will gain more popularity than the Tropical Disease Priority Review Voucher program. To avoid incentivizing sponsors to exclude adults affected by the rare pediatric disease from clinical trials, FDA expects adult patients to play a prominent role in process. Sponsors remain eligible for a voucher if they use adult patients in clinical trials or seek an adult indication in addition to the primary pediatric indication. The qualified rare pediatric disease will most likely also qualify for the orphan disease category. A sponsor may obtain the Orphan Drug Designation Status to avoid paying the application fee for voucher application.

How much is a priority review voucher worth?

The value of a priority review voucher is not entirely clear. There are very few transactions of a priority review voucher sold from one sponsor to another.
  • On 30 July 2014, BioMarin announced that it had sold its voucher to Sanofi and Regeneron for $67.5 million.
  • The Canadian pharmaceutical company Knight Therapeutics has reportedly sold its Neglected Tropical Disease Priority Review Voucher to Gilead Sciences for $125 million
  • On May 27, 2015, Retrophin sold their priority review voucher to Sanofi for $245 million
         Everything you need to know about priority review voucher