6International Applications of Regulatory Science

Publication Details

Key Messages

  • Global regulatory harmonization would lower barriers for drug developers, but payers and, in many countries, health technology assessment bodies still determine if a drug that makes it to the market will succeed.
  • Efforts to increase regulatory capacity in the developing world, combined with cooperation and assistance from regulatory agencies in the developed world, hold promise for increasing the number of drugs developed and approved to treat global diseases, including neglected diseases.
  • An emphasis on training and education will help to overcome the challenges of developing therapeutics for global neglected diseases.

The development of therapeutics is a global endeavor, calling for a global workforce. In addition, regulatory science can enable the development of therapeutics for diseases that affect primarily the developing world.

Xavier Luria, Head, Safety and Efficacy of Medicines, EMA, described efforts to incorporate regulatory science into regulatory decision making from the perspective of a European regulator. Michael Brennan, Senior Advisor for Global Affairs, Aeras Global TB Vaccine Foundation, presented an update on regulatory science needs to develop drugs for neglected diseases that affect primarily developing countries.


Luria provided a worldwide forecast of drug sales in 2016. Oncology drugs are predicted to hold the biggest market share of any drug class, with anticoagulants undergoing explosive sales growth. Antirheumatics, antivirals, antidiabetics, vaccines, and dermatologicals also are expected to show robust growth in sales over the next 4 to 5 years. The number of drugs that will be seeking approval during that time will tax global regulatory mechanisms, he stated. To meet this projected need, the global drug development community will need both more regulators and enhanced regulatory science to improve the efficiency of the regulatory process.

The requirements to approve a drug for marketing can differ across countries. In the EU, pharmaceutical law says that drug approval rests on showing that the balance of benefits and risks is positive, with no mention made of effectiveness, relative effectiveness, or cost-effectiveness. EU law also states that regulators should refuse marketing authorization if quality, safety, or efficacy is not demonstrated sufficiently based on objective criteria, which is aimed at making decisions transparent. EU regulators can grant conditional approvals with a requirement for follow-up measurements, so long as there are adequate data to support such an approval. Luria noted, however, that he does not believe these efforts are succeeding at speeding up drug approvals.

The traditional approach to improving efficiency is through processes such as the EU's harmonization program, which is knitting together the regulatory systems of 27 member nations. This same type of approach could be tried in other regions, said Luria.

Progressive Approval

EMA has developed a 2015 roadmap (EMA, 2010). One of the items in this roadmap, which according to Luria is quite similar to efforts under way in the United States, Canada, and Singapore, is a staggered or progressive approval pathway that is based on sponsors showing a progressive reduction of uncertainty. The proposed new paradigm calls for progressively authorizing increased indications for a drug as knowledge and investment increase. Through iterative phases of information gathering followed by regulatory evaluation and action, progressive authorization seeks to align regulatory decision making with emerging information on benefits and risks. It seeks to maximize the positive impact of new drugs on public health by balancing timely access for patients with the need to provide appropriate information on benefits and risks.

For this approach to work, good regulatory science must be done to answer questions about how to design clinical trials to broaden treatments in increasingly eligible populations, how best to use adaptive clinical trial design, and how to reduce uncertainty around given end points. Regulatory science will be needed to enable combination therapies in this model, to ensure effectiveness beyond simply balancing risks and benefits, and to address rare adverse events.

This approach faces several obstacles, said Luria. First, a progressive approval pathway may not be allowable under current statutes. Second, there is concern that the approach will result in inappropriately lowered approval standards. Issues of alignment among regulators, payers, and prescribers are a concern, as is the possibility that a different reward structure will be needed to incentivize drug development.

The Efficacy-Effectiveness Gap

While it is increasingly difficult to bring new drugs to market, it will be even harder to keep them on the market because of the “efficacy-effectiveness gap,” according to Luria. Regulators evaluate each drug on its own merit based on benefits and risks. Payers and health technology assessment bodies make their decisions to maximize health within a finite budget, forcing them to make allocation decisions between two or more drugs. In a place like the EU, where there is one regulatory authority but 30 different health technology assessment methodologies, each making independent decisions, drug developers face a growing risk that they will receive an approval but not be able to keep a drug on the market.

Luria discussed possibilities for interactions between regulators and health technology assessment bodies. Ongoing efforts include one aimed at integrating more effectiveness data into the European Public Assessment Reports that EMA issues every time regulators take an action for a drug. Another pilot effort involves creating parallel scientific advisory committees in conjunction with health technology assessment bodies. Other opportunities lie in aligning postmarketing research activities with health technology assessment bodies across the member states and in developing scientific guidelines for judging relative efficacy and effectiveness. Such guidelines would require new methods based on scientific data, which points toward the increasing role for academia in the dialogue between regulators and industry.


The development of drugs for global neglected diseases has entered a new paradigm over the past decade, with the emergence of product development partnerships (PDPs). PDPs are intended to lead development of vaccines, therapeutics, and diagnostics for infectious diseases such as AIDS, tuberculosis (TB), and malaria. PDPs must meet all the usual regulatory requirements and approvals for authorization and global distribution of a product. PDPs and other product development sponsors face a landscape of disparate regulation, and often frequent delays in the regulatory review process. Collaboration in the regulatory arena would be very beneficial to save time and to ensure timely regulatory consideration without compromising quality. Brennan also called for capacity building to strengthen local regulatory authorities, including the improvement of clinical trials and inspection processes, as well as to streamline and harmonize regulatory submissions.

FDA assistance can contribute significantly to improving the regulatory environment in these countries. Brennan noted that FDA could

  • host exchange programs,
  • offer training opportunities,
  • increase its acceptance of non-U.S. clinical data,
  • conduct joint reviews of clinical protocols, and
  • sign memoranda of understanding that would enable data exchange between FDA and national review agencies.

FDA has also released guidance documents for sponsors who are developing drugs and vaccines for global illnesses:

  • In September 2008, FDA issued a document entitled “General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases,” which stated that FDA can license vaccines to protect against infectious diseases or conditions not endemic in the United States.3
  • The agency has prepared a new document, “Guidance for Industry Neglected Tropical Diseases of the Developing World: Developing Drugs for Treatment and Prevention,” that was released in draft form for comment in August 2011.4 In the draft guidance, FDA reiterates the agency's commitment to facilitating access to therapies in the developing world. The document reflects the realities of conducting clinical trials for neglected tropical diseases where infrastructure is lacking, said Brennan, noting that for a neglected tropical disease 50 to 60 percent efficacy can save tens of thousands of lives, even though that level of efficacy is not what regulatory authorities in countries such as the United States are used to seeing. Reflecting this, the draft states that the agency would have “considerable latitude to exercise its scientific judgment to determine the kind and quality of data and information … required … to meet standards for approval.” Because many countries base their approvals on actions taken by the United States or the European Union, actions such as these could have powerful effects in poorer countries, said Brennan.

Brennan offered four potential solutions to the problems that organizations face in developing products for global neglected diseases:

  • Establish structures for information sharing among regulators within regional settings.
  • Increase the involvement of regulators from endemic countries in assessment of new products.
  • Expand internationally the model of regional centers of excellence in regulatory science.
  • Build sustainable regulatory capacity in endemic countries by systematizing training programs and exchange programs.



This section is based on the presentation by Xavier Luria, Head, Safety and Efficacy of Medicines, EMA.


This section is based on the presentation by Michael Brennan, Senior Advisor for Global Affairs, Aeras Global TB Vaccine Foundation.