Saturday, May 24, 2008

"Trials on trial"

Nature magazine has an editorial in the May 21st edition subtitled "The Food and Drug Administration should rethink its rejection of the Declaration of Helsinki". The article begins:
Later this year, the US Food and Drug Administration (FDA) will adopt new standards for human clinical trials conducted without its advance sign-off in foreign countries. The rules will govern whether data from such trials can be used in applications to market the drug in question in the United States. Although these new standards specify how to run such trials to meet US requirements, they are worryingly silent on key issues relating to human rights, in contrast with the rules currently in effect. As a result, they could open the way to some ethically fraught decisions.
I think the article raises an interesting point.

We certainly do not want to encourage companies to circumvent the restrictions placed on drug trials in the United States by doing their trials in other countries with less restrictive human subject protection. The risks for drug trials should be born by the population that the drug is to benefit. Moreover, the risks to subjects might be increased by going to a country in which there was less protection for the human subject. Since many countries have regulators who are more prone to graft and corruption than those of the United States, there might be moral hazard involved.

On the other hand, if trials are ethically in another country under their guidelines (and for products intended to benefit that country's people), why should the information so developed not be used by the FDA in considering the licensing of the product in the United States. Accepting the data would be likely to save money and time in the review process, and thus benefit the potential U.S. beneficiaries of the products, both by reducing costs and making them available sooner.

I might mention that the results of foreign trials do not always transfer directly to the efficacy and safety of a drug in the United States. Populations in different countries differ genetically, they differ in general health and robustness, they differ in the availability of the health system to deal with complications, and they differ in the compliance of the patients with drug regimens. Note that the interactions are not always obvious. For example, there are situations where the existence of one disease endows the victim with some protection against another disease. Thus a "less healthy" population with a high prevalence of the protective disease might appear to do better with a given drug against the second disease that a "healthier" population with a low prevalence of the protective disease.

Still, information is information, and given the costs and delays in obtaining information from clinical trials, imperfect information is always used in the licensing of new drugs. (Which is why it would be great to have better tracking data for the efficacy and risks of approved drugs as they are used in the general population.)

It would seem important to examine the intentions of the company conducting the drug trials to evaluate whether the resulting data was ethically obtained or not. Of course, the executives of drug companies are not known for their open discussion of the ethical basis of their decisions on drug trials, and there would be moral hazard in a system that allowed information that was affirmed by the company likely to profit from early acceptance of the drug that the foreign trials were conducted ethically.

There is of course another issue, which has been with us since the Nazi medical experiments and the Tuskegee Syphilis studies. What do we do with information that exists in the public domain that was gained by past trials that were clearly conducted unethically, or that appear unethical by current standards? Again, we don't want to create a moral hazard by allowing people to gain from information that they obtained unethically. Equally, however, we don't want to deprive blameless patients of therapeutic techniques which might benefit them, simply because someone else was unethical in developing and testing those techniques.

I wish I had a better answer to this moral dilemma. Still, it would be a crying shame if drugs developed in Europe, Canada or Australia were required to be proven by new, excessive trials in the United States simply because the FDA had not been asked in advance if it agreed with the trial protocol. There are companies in the United States that profit from the delays and added costs imposed on potential competitors, and the opponents to the transfer of results may not always be pure in their motives.

There is also a grave imbalance in the knowledge and understanding of the different parties to this debate. The ethical pharmaceutical companies have staffs with great knowledge of the risks and costs of drug trials, as do the FDA, universities, and some civil society organizations. Other non-governmental organizations which are quite appropriately entering the debate based on their ethical concerns for the wellbeing of potential human subjects in developing countries, do not have comparably extensive and detailed understanding of clinical research. We in the general public are likely to know much less than we should about the whole subject, as are the legislators that we empower to make decision on these matters for us.

1 comment:

Anonymous said...

John, you make some interesting points.

I have also commented on this issue on my own blog; as I wrote there, I think that the main driver for this change is the increasing gulf between the WMA and the way modern drug development is carried out, with one eye on what might be changed in the 2008 redrafting of the Declaration of Helsinki (which, interestingly, will be adopted 10 days before the FDA amendment comes into force).

However, it is also indicative of an increasing mutual trust and respect being shown between regulatory authorities around the world, and recognition of the increasing quality of clinical research conducted around the world. Even countries that have previously had a "poor reputation" are now conducting high quality, ethical clinical trials, precisely because industry knows that the data generated will be used to support applications in ICH countries, and processes may be inspected accordingly.

In that context, is the FDA merely cutting away some unnecessary red tape?