The "Critical Path" is the scientific process through which a potential pharmaceutical, or medical device is transformed from a discovery into a medical product. Along the critical path, scientific tests and tools are used to predict whether a product candidate will be safe and effective, to assess how prototypes interact with the human body, and to guide the sponsor in choosing an appropriate dose and regimen or device size and/or placement. To bring a product to market successfully and efficiently, product sponsors need scientifically sound approaches.
The "Critical Path" is the scientific process through which a potential pharmaceutical, or medical device is transformed from a discovery into a medical product. Along the critical path, scientific tests and tools are used to predict whether a product candidate will be safe and effective, to assess how prototypes interact with the human body, and to guide the sponsor in choosing an appropriate dose and regimen or device size and/or placement. To bring a product to market successfully and efficiently, product sponsors need scientifically sound approaches. (See an official definition of the FDA's Critical Path Initiative for medical product development at http://www.fda.gov/oc/initiatives/criticalpath/faq.html.)
Janet Woodcock, MD, Deputy Commissioner for Operations, FDA Q: In a recent presentation you noted that the societal investment in R&D to improve drug development, which is intertwined with FDA standards, is lacking. Can you explain this further?
A: By societal investment, I mean the infrastructure and academic underpinnings for product development science. Where are the "departments of clinical methodology," the well-funded academic centers researching better evaluation methods, or the "departments of biostatistics in clinical trials"? These types of research centers should be funded to study clinical trials. Where are they? They don't exist. Part of the thesis of the Critical Path Initiative is if improving the development process is for the collective good of society, we need to invest in it as a collective enterprise to improve our applied sciences. Improving the science of evaluation is not solely the role of the pharmaceutical industry. Although the pharmaceutical industry works to improve evaluation, the information often is not shared; and it is not generalizable because it is always tied to specific projects.
Q: One of the speakers at the conference asked, "where was academia in all of this now that the pharmaceutical industry is expected to register trials, etc.?" In your opinion, do you think academia is funded to do just research?
A: Academia is simply not funded to do research on the science of the critical path. In contrast, if you take the field of molecular biology, funding exists to do academic research and the scientists create a scholarly product that can lead to greater understanding of the field. If you utilize pharmaceutical industry money or NIH money to do a specific trial, you are usually not doing research on the fundamentals of clinical trials. You are focusing on a specific question and are expected to generate a specific answer. For this reason, scholarly research on clinical trials methods is not widespread.
Q: It was mentioned that the FDA needs to intensify its involvement in Critical Path standards development. How does the FDA propose to do that? What specific aspect of standards development are you considering, i.e., common language in documentation, labs, etc? Do you foresee a standardization that will include health care and extend right up through trials?
A: We are partnering with a number of organizations in a very open and transparent way to develop terminology standards and interoperability standards for use in animal and human studies. With these standards, trialists could use any computer systems as long as the terminology is stable and standard. Some protocols for interoperability already exist. For example, the CDISC organization is working on standards and HL7 has accredited some standards. One problem is that a national health architecture has not been established yet. So at this point it is not known how clinical trial systems would interface with, for example, electronic health records. In the clinical trial area, the FDA is working closely with CDISC and HL7 to move this effort along. We endorse development of common standards, and the agency will accept the standards as they evolve. Because clinical trial data acquisition is already extensively electronic, it is hoped that further standardization can be accomplished quickly and that these standards will also help inform the health care sector.
Q: So you are saying that once you establish this common language on the clinical trial side, you will be able to work it back to the health care end?
A: Or we may be able to link or bridge or map one to the other. For instance, the health care system is using SNOMED. This can be mapped to adverse events in clinical trials as long as the terminology is somewhat stable. The problem is that at this point in time, people use diverse nonstandard terminology to describe clinical events.
Q: The guidance mentions a new mechanism to voluntarily submit research data to further exchange of scientific information. How do you foresee this working, i.e., will it be anonymous? Will it be free and in the public domain?
A: This is functioning now. Companies are submitting research to the FDA through the voluntary genomic data submission process. A company comes in with genomic data and the data are anonymized. If the data were from clinical trials in a marketing submission, the FDA would be able to go in and inspect the site from a regulatory perspective. We could view the patients' names, and the patients would know that this could happen when they sign informed consents. But the submissions right now do not have patient identifiers, and the mechanism is working very well.
Q: You indicated that the FDA may undertake a limited number of projects and/or seek partnerships. When would that process begin and what criteria would you be including in such projects/partnerships? Who would be included in such partnerships, i.e., organizations, academia, pharmaceutical companies?
A: The answer is yes. We have already begun to set up mechanisms to partner, and we are learning how to prioritize. We also have moved ahead with some initiatives. The initiatives are with federal partners, in areas where there are obvious needs and obvious partners.
Q: Are you looking for partnerships with other organizations? I assume that they would put up the money.
A: Yes, we are moving toward setting up public–private partnerships as well. There is a lot of interest on the part of all the different sectors. We will need a prioritization process because there is so much interest. We have heard from quite a few potential partners who are willing to help financially support various projects.
Q: You also mentioned at the meeting that it was important to make sure that the government and pharmaceutical industry clearly communicated with the public. Would you elaborate on this?
A: Well, the Critical Path Initiative is a pretty esoteric subject to the general public. However, we did hear from many patient groups responding to our docket. Many of the comments were very thoughtful. As a matter of fact, the patient groups understood this concept sooner than just about anybody else. I think the reason is that they have been frustrated about the lack of therapies in their disease areas. They have been putting in money to research and they want to know why they are not seeing more results. The Critical Path report addressed why we are not seeing more results. We plan to include these patient groups as we plan these public–private partnerships. They have lots of members who reach out to other members to help translate this information. The patients have a stake in this, and they are committed to participate.
Q: Taking this a step further, with regard to the clinical trial registries, will the public really be able to understand the information the drug companies will be putting up? Do you see this as something that will have to be translated, or will there have to be a common language as well?
A: The FDA has long experience with reviewing the raw data from clinical trials. This can be very difficult, and there are many pitfalls. I believe that the general public would benefit most from impartial summaries of the findings. For example, it is often difficult for members of the academic community to analyze such data and at times we see analyses that are widely divergent from standard interpretations. So if there is disagreement among experts, imagine the gulf with the lay public. The statistics often are counterintuitive. It has been frequently demonstrated that doctors are poor at interpreting statistical data. They are not well trained in statistical analysis. If they are the learned intermediary and they have trouble with interpretation, this is a problem. However, if a drug company tries to simplify data and put it in simple language, so much nuance is lost that they may be accused of bias in their explanation. I am not sure what the best outcome or approach is. It is going to be very interesting.
Q: You mentioned long-term commitment. Do you think this will happen?
A: Yes, we are committed and patient in our dedication to the critical path, and we think that great benefits will result, but it may take several years.
(Editor's Note: ACT would like to thank Dr. Woodcock for giving us the time from her busy schedule to share her thoughts and insights —Toby Hindin, EdD, Editor in Chief, ACT Magazine)