Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 51
6
International Applications
of Regulatory Science
Key Messages
• lobal regulatory harmonization would lower barriers for drug developers,
G
but payers and, in many countries, health technology assessment bodies still
determine if a drug that makes it to the market will succeed.
• fforts to increase regulatory capacity in the developing world, combined with
E
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.
• n emphasis on training and education will help to overcome the challenges
A
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 develop -
ment 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 mak -
ing 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.
51
OCR for page 52
52 STRENGTHENING A WORKFORCE FOR INNOVATIVE REGULATORY SCIENCE
MAINTAINING A ROBUST GLOBAL THERAPEUTICS PIPELINE1
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 num -
ber 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 regula-
tors 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 men-
tion 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 pro-
gressive approval pathway that is based on sponsors showing a progres -
sive reduction of uncertainty. The proposed new paradigm calls for pro-
gressively 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
1 This section is based on the presentation by Xavier Luria, Head, Safety and Efficacy of
Medicines, EMA.
OCR for page 53
53
INTERNATIONAL APPLICATIONS OF REGULATORY SCIENCE
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. Regula -
tory 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 Assess-
ment 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 effec -
tiveness. 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.
OCR for page 54
54 STRENGTHENING A WORKFORCE FOR INNOVATIVE REGULATORY SCIENCE
THERAPEUTICS DEVELOPMENT FOR
GLOBAL NEGLECTED DISEASES2
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 develop-
ment 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 har-
monize regulatory submissions.
FDA assistance can contribute significantly to improving the regula-
tory environment in these countries. Brennan noted that FDA could
• host exchange programs,
• offer training opportunities,
• increase its acceptance of nonU.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 Prin-
ciples 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
2 This section is based on the presentation by Michael Brennan, Senior Advisor for Global
Affairs, Aeras Global TB Vaccine Foundation.
3 For more information, see http://www.fda.gov/BiologicsBloodVaccines/Guidance
ComplianceRegulatoryInformation/Guidances/Vaccines/ucm074762.htm (accessed No-
vember 28, 2011).
OCR for page 55
55
INTERNATIONAL APPLICATIONS OF REGULATORY SCIENCE
form for comment in August 2011.4 In the draft guidance, FDA
reiterates the agency’s commitment to facilitating access to thera-
pies 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 “con-
siderable 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 organi -
zations 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 sys-
tematizing training programs and exchange programs.
4 Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM269221.pdf (accessed November 28, 2011).
OCR for page 56
