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Drugs, vaccines, and diagnostics: The Problem

The drug and vaccine development process does not work well for Ebola and other rare diseases.

Problem 1: There is no market

As we said earlier, the process of taking a drug or vaccine from an idea to a product that is available for use is a long and expensive one. When the product under development seems destined to make a lot of money, companies are eager to make the investment. They know that a pill that will be taken by hundreds of millions of people every day – one that lowers bad cholesterol or controls diabetes, for instance – will more than make back the money they spend developing it. The same is true for a vaccine that prevents diarrheal diseases in young children or cancer-causing human papillomavirus infections.

But that is not the reality for drugs or vaccines for Ebola and other rare diseases such as Marburg fever (Ebola’s cousin), MERS (Middle East respiratory syndrome), SARS or Nipah virus. Drug companies cannot expect to sell drugs or vaccines for these conditions to hundreds of thousands of people every year. They cannot even expect to sell thousands of doses in a year.

In the case of Ebola, that may seem counterintuitive, given the size of the epidemic that unfolded in 2014. (At one point, researchers even projected that there might be more than a million cases.) But this epidemic was highly unusual; before it started, there was little reason to bring an Ebola vaccine to the market. Why?

  • The need for these products is unpredictable. Ebola outbreaks occur only sporadically; as we explained in Ebola: The Basic Facts there have been about two dozen in the nearly 40 years since the disease was first recognized. In 2012, there were three outbreaks, but three years passed without a single outbreak between 2004 and 2007.
  • The market is small. Before the West African outbreak, fewer than 2,500 people ever were known to have been infected with Ebola. That was over a 40-year history, and the people lived across a vast geographical area that would have been difficult to cover with a vaccine.
  • Most of the people who are at risk of contracting Ebola cannot afford to pay high prices for Ebola vaccines or drugs.
An example of why market forces don’t work for an Ebola vaccine

The Democratic Republic of the Congo (DRC) had the first known Ebola outbreak, and it has had more Ebola outbreaks – six — than any other country. Yet fewer than 1,050 of DRC’s citizens have been known to have been infected with Ebola.  This is out of a country whose current population is 77 million. Would a government agree to vaccinate 77 million current citizens and all future citizens because 26 people a year (on average) have been infected with a virus?

If the vaccine cost pennies a person, maybe they would. But an Ebola vaccine will not cost pennies, at least not in its early years on the market. In December 2014, GAVI (the Global Vaccine Alliance) agreed to buy 12 million doses at a cost of $25 per dose. That’s likely the cheapest price manufacturers will agree to; direct company-to-country sales will probably be at a higher price. However, $25 per dose is more than DRC spends on healthcare per citizen per year; the World Bank says the country spent $15 per person per year from 2010 to 2012.

Because they cannot expect to recoup their development costs through sales, pharmaceutical companies typically avoid vaccines and drugs that target rare diseases and diseases that afflict people in low-income countries.

So until recently almost all of the funding for research on Ebola drugs and vaccines has come from governments. The U.S. government has led the way on this type of investment, but other countries have funded research as well. One reason that the U.S. government is so interested in Ebola drugs and vaccines is that the virus could potentially be used as a bio-weapon. A lot of the research has taken place at a U.S. Army laboratory.

With government funding, this research advanced slowly. Universities and publicly funded research institutions also do not have the capacity to make and market vaccines and drugs at commercial scale, produced to a quality that can be given to people. They need the help of big drug companies. And until 2014, they did not have it.

The West African outbreak appears to have changed the dynamics for Ebola, at least. (It remains to be seen whether drugs and vaccines for other neglected diseases will have an easier time finding developers going forward.) Several big companies have entered the race to develop an Ebola vaccine. And some are trying to see if they can re-purpose some existing drugs to be used against the Ebola virus.

But even today, it is unclear how far the development of these products will go. The epidemic has not become as bad as it looked it might in the summer of 2014; cases began dropping sharply in the fall of 2014, and the focus is now on bringing down the number of cases to zero. Though it looked at a point like a vaccine might be required to extinguish the West African outbreak, the prospect of using vaccines on a large scale there now seems much less likely. Moreover, nobody knows whether we’ll ever see a big epidemic like this again. Hopefully, the current epidemic will cause future outbreaks to be battled more aggressively, and they will be stopped in their tracks much earlier. But that may also mean there is less demand for a vaccine.

UNMEER

Problem 2: Proving these products work

While lack of funding is a big part of why there are no approved Ebola vaccines or drugs, it is not the only problem. The critical part of the development process described above is showing that a drug or vaccine works. And that is exceedingly hard to do with drugs and vaccines designed to combat a rare disease that crops up sporadically, over a wide geographic area.

Consider a disease like measles. Before vaccines existed, most children everywhere contracted measles while growing up. So proving a measles vaccine works was straightforward: You vaccinate a bunch of kids, you give an equal-sized group of children a placebo* and then you wait. If the vaccine works – and it does – you will see a lot of measles cases in the children who got the placebo, and few or none in the ones who got the measles vaccine.

But as we have said, Ebola cases have long been very rare. You could give a vaccine to, say 10,000 people in the Democratic Republic of the Congo, a country that has seen a number of outbreaks, but the villages where those people live may never be hit by an outbreak–and so after five years, you still have no evidence that the vaccine worked. By the time the next outbreak occurs, the protection the vaccine produced may have worn off. Or you might have vaccinated people in western Gabon, but the outbreak is in eastern Gabon.

The only time scientists can test whether Ebola vaccines and drugs work in people is during an Ebola outbreak. And that has proved to be an almost impossible challenge for the researchers struggling to develop vaccines in the past.

  • Ebola strikes without warning, and outbreaks have started in at least 6 countries (and spread from them elsewhere).
  • Most Ebola outbreaks are small. They are not instantly recognized as Ebola, which allows for early spread. But when countries realize what is going on and alert the World Health Organization and MSF, outbreaks are generally brought under control within a few months.
  • Three different strains of Ebola (Zaire, Sudan and Bundibugyo) cause human outbreaks. Vaccine that protects against one strain will not protect against the others. Someday there will likely be a vaccine that protects against all three strains, but first each individual vaccine needs to be shown to work.
  • There are legitimate ethical concerns about running clinical trials during an outbreak. MSF, for example, refused to randomly assign some patients to receive an experimental drug and others a placebo.
  • During outbreaks, trying to control the spread of disease is the Number 1 priority. Finding extra manpower to run clinical trials in addition may be challenging.

This all means that when an Ebola outbreak is recognized, vaccine developers and scientists have to scramble to get approval from the country’s health ministry and drug regulator, and an international drug regulator like the US FDA**. They would need to have on-hand supplies of the potential Ebola drug. If they want to test a vaccine they will need supplies of the right Ebola vaccine, the one that protect against the outbreak strain. They will need to get to the location, set up mobile laboratories and start a trial. And in most outbreaks, they would have only weeks to do this.

Of course, the current outbreak in West Africa was different; its sheer size made it easier to set up trials. But even this time, public health officials and companies working on Ebola drugs and vaccines have struggled. They started talking about and planning for clinical trials in West Africa in the summer of 2014, and it was December before the first ones started – and those were with drugs that had already been approved for other diseases. The trials of new drugs and vaccines took even longer to begin, largely because it took time to make enough of the products to run the trials. All previous Ebola outbreaks would be over after that length of time.

The U.S. Food and Drug Administration does have another process for approving drugs or vaccines against rare diseases like Ebola. The so-called “Animal Rule” allows such products to be approved after being tested in animals only if companies can show that the animal evidence can be translated to humans. This, too, is a very complicated process, and very few drugs or vaccines have been approved this way. None of them target Ebola.

** Companies making Ebola vaccines and drugs will want to have them licensed in the United States or Europe to be able to sell them to countries that might want to stockpile them for defense purposes.

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