Reproductive Toxicology 2.0, or rather 1.8
Safety Assessment
Alan Hoberman

Reproductive Toxicology 2.0, or rather 1.8

After two decades, the guidelines affecting reproductive toxicology are being revised to reflect changing methods. Not everyone is pleased with the results so far.  

About six months ago, regulatory authorities issued the first draft for a revised 20-year guideline affecting the field of reproductive toxicology, and reaction has been, well, a bit explosive.

The International Conference on Harmonisation, S5 group, which wrote the 65-page document, embraced a more thoughtful approach for developing a testing strategy. To quote the ICH, the guideline “recommends the use of information about the pharmaceutical and patient … in order to perform only those studies essential to evaluate the stages for which there is insufficient knowledge to inform about the risk to reproduction and development.”

Toxicologists responded to the revisions with a lot of head-scratching and questions. Their primary observation has been that the revisions make the process of reproductive toxicology testing more complicated. I helped develop the original guidance, and while I’m happy that it held up so well over time, I think the changes are well-timed. Here are a few comments that people, myself included, have been pondering since the guidance was released.

What are the main differences between the first ICH S5 guideline and the current draft version, and why did it take so long to update it?

The primary difference between the two documents is that the updated version includes alternative methods for developmental toxicity testing, and instructions on validating these alternate methods. The recognition that these methods might be useful for regulatory decisions is good but may be premature. It also includes information on how to conduct a risk assessment with the data produced by a study, and more alternative mammalian designs, which use less animals for early-stage evaluation of any hazard to the fetus.

The original guidance provided minimum outlines for study designs and emphasized that good science would dictate the final design of a study based on the nature of the compound being tested. This is why the original document could last 25 years without revision. But the field is at a point now where we need more clarity for testing the new classes of drugs that have been developed since the original guidance was issued.

So why all the criticism over the draft guidelines. What is wrong with it?

I guess you could say that it has too many moving parts. Unlike the initial document approved 25 years ago, which was only 25 pages long, this updated guidance offers more than just basic outlines of the study designs. In fact, it attempts to answer all questions for the drug maker and agency reviewer, which is creating confusion for both groups. For instance, drug makers will be confused by all the choices for evaluating a drug prior to use in a limited number of women of child-bearing age. What combination of studies will be appropriate for their new drug is not clear and probably will take consultation with the agency prior to selecting the designs to use.

If it’s causing all this confusions, why make the revisions?

Harmonization with other ICH guidelines is probably the most important reason driving these changes. The ICH was formed to bring together the regulatory authorities of Europe, Japan and the United States. To remain relevant it needs to ensure that all of its recommendations are able to respond to the global face of drug development, and these revisions are helping the ICH stay abreast of all this change. The revisions also address ways of reducing research animals—something, I think, we all are in favor of doing. It also addresses ways of reducing drug development costs for compounds that may not make it to market by moving out the conduct of some studies until later in the development process with the assumption that some new drug candidates will drop out of clinical testing prior to the need to conduct the reproductive assessments in animals. Lastly, the revisions address the introduction of new classes of biopharmaceuticals that were not around when the original guidance was issued.

Who will benefit from the revised guidance?

Drug makers will benefit from the revised guidance by spending less money, needing less test material for non-clinical and clinical trials and accelerating the clinical trial process by getting more drugs into clinical trial sooner. Patients, regulatory authorities and even the animals used in research will be helped by these clarifications.

How will the new guidelines change our testing of drugs for use in pregnant women?

I believe it will lead to better-designed studies by placing greater emphasis on understanding the product and the purpose of each test, rather than simply being a checkbox exercise to design and conduct each study. In the end, we should be able to get the most information out of each test.

So as a participant in the writing of the first set of guidelines, how would I rate this draft revision?

I think the current draft accomplishes the goal of harmonizing this guideline with subsequent ICH guidelines and incorporates some of the advances in our field that have occurred since the first guidance was issued. With that said, I would still give it a C+. The current draft is not really written for a non–reproductive toxicologist. I commend all those involved in producing this draft and look forward to a new simplified version that still builds on the original guideline. It also might be prudent to issue a companion document, such as the OECD seems to be issuing, that helps the reader understand how to use the revised guidance.