History of regulatory affairs
Regulatory affairs (RA), also called
government affairs, is a profession within regulated industries, such as
pharmaceuticals, medical devices, energy, and banking. Regulatory affairs also
has a very specific meaning within the healthcare industries (pharmaceuticals,
medical devices, biologics and functional foods).
Regulatory affairs professionals
(aka regulatory professionals) usually have responsibility for the following
general areas:
Ensuring that their companies comply
with all of the regulations and laws pertaining to their business.
Working with federal, state, and
local regulatory agencies and personnel on specific issues affecting their
business. i.e. working with such agencies as the Food and Drug Administration
or European Medicines Agency (pharmaceuticals and medical devices); The
Department of Energy; or the Securities and Exchange Commission (banking).
Advising their companies on the
regulatory aspects and climate that would affect proposed activities. i.e. describing
the "regulatory climate" around issues such as the promotion of
prescription drugs
The regulatory function in
healthcare industries is vital in making safety and effective healthcare
products available worldwide. Individuals who ensure regulatory compliance and
prepare submissions, as well as those whose main job function is clinical
affairs or quality assurance are all considered regulatory professionals.
Regulatory professionals are
employed in industry, government and academia and are involved with a wide
range of products, including:
pharmaceuticals
medical devices
in vitro diagnostics
biologics and biotechnology
nutritional products
cosmetics
veterinary products
The regulatory professional's roles
and responsibilities often begin in the research and development phases, moving
into clinical trials and extending through premarket approvals, manufacturing,
labeling and advertising and postmarket surveillance.
The healthcare industries were the
first to be significantly regulated in the modern era. Much of this regulation
has stemmed from avoiding the repetition of disasters, and has tended to be led
by the USA due to size of the market and its technological lead:
Diphtheria Epidemic led to 1902
Biologics Control Act
Publication of The Jungle by Upton
Sinclair led to 1906 Pure Food and Drugs Act
Elixir of Sulfanilamide led to the
1938 Food Drug and Cosmetic Act
Thalidomide led to the 1962
Kefauver-Harris Amendments
Dalkon Shield led to the 1976
Medical Device Amendments
Bjork-Shiley Heart Valves led to the
1990 Safe Medical Devices Act
In the USA, this regulation is
largely written directly into law and codified in Title 21 of the Code of
Federal Regulations.
Main concepts QSE
The ICH topics are
divided into four categories and ICH topic codes are assigned according to
these categories.
1. Quality Guidelines
Harmonisation
achievements in the Quality area include pivotal milestones such as the conduct
of stability studies, defining relevant thresholds for impurities testing and a
more flexible approach to pharmaceutical quality based on Good Manufacturing
Practice (GMP) risk management.
Stability Q1A - Q1F
Analytical Validation
Q2
Impurities Q3A - Q3D
Pharmacopoeias Q4 -
Q4B
Quality of
Biotechnological Products Q5A - Q5E
Specifications Q6A-
Q6B
Good Manufacturing
Practice Q7
Pharmaceutical
Development Q8
Quality Risk
Management Q9
Pharmaceutical Quality
System Q10
Development and
Manufacture of Drug Substances Q11
Cross-cutting Topics
2. Safety Guidelines
ICH has produced a
comprehensive set of safety Guidelines to uncover potential risks like .
testing strategy for assessing the QT interval prolongation liability: the
single most important cause of drug withdrawals in recent years.
Zip file with all ICH
Safety Guidelines in Word format
Carcinogenicity
Studies S1A - S1C
Genotoxicity Studies
S2
Toxicokinetics and
Pharmacokinetics S3A - S3B
Toxicity Testing S4
Reproductive
Toxicology S5
Biotechnological
Products S6
Pharmacology Studies
S7A - S7B
Immunotoxicology
Studies S8
Nonclinical Evaluation
for Anticancer Pharmaceuticals S9
Photosafety Evaluation
S10
Cross-cutting Topics
3. Efficacy Guidelines
The work carried out
by ICH under the Efficacy heading is concerned with the design, conduct, safety
and reporting of clinical trials. It also covers novel types of medicines
derived from biotechnological processes and the use of pharmacogenetics/
pharmacogenomics techniques to produce better targeted medicines.
Zip file with all
Efficacy Guidelines in Word format
Clinical Safety E1 - E2F
Clinical Study Reports
E3
Dose-Response Studies
E4
Ethnic Factors E5
Good Clinical Practice
E6
Clinical Trials E7 -
E11
Clinical Evaluation by
Therapeutic Category E12
Clinical Evaluation
E14
Pharmacogenomics E15 -
E16
Cross-cutting Topics
(Ref:
http://www.ich.org/products)
Sources of information Regulatory affairs for studies in
human subjects
The Office of Research Compliance
and Regulatory Affairs (“ORCRA”) provides
administrative support to the
Institutional Review Boards and the other research review
committees and compliance functions.
With respect to human subjects’ research, these
committees include the Radiation
Safety Committee, which reviews and provides
approval for all human research
protocols involving the use of ionizing radiation and the
Institutional Biosafety Committee,
which reviews and approves all human research
protocols involving the use of
infectious agents or recombinant DNA. The University’s
Compliance Hotline program for
anonymous reporting of allegations of non compliance
in any aspect of research or
physician billing is administered by ORCRA. The Quality
Assurance/Quality Improvement
program is also a service of ORCRA. It provides postapproval monitoring of
human subjects’ research projects. The office is directed by the Research Compliance Officer, who reports to
the Vice President for Research.
The Institutional Review Board
The University of Cincinnati has
established three Institutional Review Board (“IRB”)
panels to review all proposed
research involving human subjects to ensure that the rights
and welfare of participants in
research are adequately protected. The University of
Cincinnati IRB serves as the IRB of
record for the University of Cincinnati, University
Hospital, Inc., The Shriners’
Institute for Burned Children, The Cincinnati Veterans
Affairs Medical Center, and The
Drake Center. The IRBs are composed primarily of
faculty members from disciplines in
which research involving human subjects is integral
to that discipline's work, as well
as several members from the community whose primary
interest is in non-scientific areas.
The Board(s) membership, policies, and procedures are
governed by an Assurance agreement
with the Federal government.
Human subjects’ research means any
activity intended to obtain and record information
from or about individuals for
research purposes. Any undertaking in which students,
faculty, or staff investigate and/or
collect data on human subjects or use existing data or
specimens collected from living
human subjects for research purposes, requires review by
the Institutional Review Board prior
to initiation of the project. This includes both funded
and non-funded research, including
dissertations, masters’ theses, pilot studies, class
projects, and non-funded,
faculty-directed research if the following conditions are met:
• the research is sponsored by the
University, or
• the research is conducted by or
under the direction of any University employee or
agent of this institution in
connection with his/her institutional responsibilities, or
• the research is conducted by or
under the direction of any University employee or
agent of this institution using any
University property or facility, or
• the research involves the use of
the University's non-public information to
identify or contact human research
subjects or prospective subjects
Studies involving drugs, devices, or
other invasive interventions will be reviewed by the
Medical IRBs. Those studies
involving surveys, interviews and observation techniques
will be reviewed by the Behavioral
and Social Sciences Board. The human subjects
review process is administered
through the Institutional Review Board Office for the
University
The Office of Research Compliance
Training is responsible for developing and delivering
workshops and training classes, as
well as designing computer-based training courses on
research regulatory compliance
issues. In addition to delivering training that meets the
needs of the research investigators,
courses are developed in response to changing
regulatory and accreditation
requirements, e.g., HIPAA. Efforts are coordinated with the
Regulatory Compliance Officer, the
multiple Institutional Review Boards and IRB
support staff, the Institutional
Animal Care and Use Committee and IACUC support staff,
the Institutional Biosafety
Committee and IBC support staff, and others, as needed. Many
programs are eligible for continuing
education credits.
The following documents must be on
file at HJF before funding is released for any research involving human
subjects:
Initial local Institutional Review
Board (IRB) approval letter with signature(s) (electronically signed is
acceptable).
Second-level/Third-level approval
letter with signature(s) (electronically signed is acceptable) [A second-level
review may be required depending on the funding source and where Principal
Investigator (PI) /Associate Investigator (AI) is located/billeted. If
second-level/third-level approval is required, all documentation must be
submitted through the Office of Regulatory Affairs and Research Compliance, who
in turn will forward to the appropriate agency/department for review/and
approval.
Scientific committee review approval
letter with signature(s) (electronically signed is acceptable)
Protocol application form and final
approved version of protocol with signature(s) where indicated (electronically
signed is acceptable).
Copy of approved stamped informed
consent form(s) and HIPAA authorization form (as applicable). If the IRB has
granted a waiver of informed consent, provide approval letter with signatures
(electronically signed is acceptable).
All protocol appendices:
Questionnaires, instruments, surveys and data collection forms (as applicable),
etc.
For protocols and associated
documents that are conducted internationally and are not in the English
language, the following additional documentation is required:
A translation letter certifying that
the foreign version of the protocol and informed consent is an accurate and
true translation of the English version. The letter should include the
signature, name, address, phone number, fax number, and email of the
translator, and the date translated.
Copies of all documents in the
foreign language
Current copies of HIPAA compliant
CVs for PI, AIs and all personnel listed on the protocol. All personal
identifiers should be deleted from the CVs. The PHS 398/2590 Biographical
Sketch format can be used as a reference.
Human subjects protection training
certificates for all personnel listed on a protocol and for all other personnel
involved in the research. Course must have been completed within the past three
years. Human subjects training can be completed online
athttp://www.citiprogram.org. For HJF employees/HJF contractors: Select HJF as
your affiliation.
Copies of advertisements for
recruiting human subjects and associated IRB approvals for such advertisements.
Current assurances from rDNA,
radiation, biosafety committees, environmental safety committee, and/or
relevant impact statements (Directorate of Information Management, laboratory
and personnel), if required.
Copies of current state licenses and
Basic Life Support (BLS) certification for physicians, nurses, nurse
practitioners, physician's assistants and any other licensed health care
provider(s) listed on the protocol.
For studies that involve an
Investigation New Drug (IND) or Investigational Device Exemption (IDE), the
following additional documents are required:
a copy of the signed form FDA-1572
a copy of the investigator’s
brochure (for drug studies)/product brochure (for device studies)
Good Clinical Practice (GCP)
training certification for personnel listed on protocol and the FDA 1572.
For studies with material transfers
(biological materials, such as select agents, cell lines, plasmids, and vectors,
chemical compounds, data, and even some types of software and machinery), a
copy of the Material Transfer Agreement (MTA).
Copy of any Data Use Agreements
(DUAs) between collaborating parties.
Documents Required Until Study
Closure
Continuing review/annual progress
reporting:
Copies of continuing review/annual
progress report (APR) with signature(s)(electronically signed is acceptable)
submitted to the IRB.
IRB approval letter for continuing
review
Stamped informed consent form(s) and
HIPAA form from continuing review (if applicable).
Amendment documents:
Copies of protocol amendment
request(s) with signature(s) (electronically signed is acceptable) with all
supporting documents submitted to the IRB.
IRB approval letter and any approved
forms for amended protocols (informed consent forms, HIPAA, etc.).
Copies of advertisement(s) (not
previously submitted) for recruiting human subjects and IRB approvals with
signature(s) (electronically signed is acceptable) for such advertisements.
Copies of all adverse event reports
and protocol deviations submitted to the IRB(s) and corresponding
approval/acknowledgement by the IRB(s). All adverse events must be reported as
indicated in the protocol and according to the institutions’ policies where the
research is conducted, Department of Defense requirements, and federal
regulations.
Copies of approved presentations and
publications resulting from the study. This includes all submissions, whether
or not they are accepted for publication. Approval from the relevant IRB(s) and
other departments as required by the institution where study is conducted.
Approval must be received prior to submission of data for publication or
presentation.Copy of updated Investigator Brochure /Product brochure (as
required for studies conducted under an IND or IDE application).
Copies of any audit reports received
from the IRBs, clinical investigations departments, Food and Drug
Administration or other regulatory agencies. If you are notified that you will
be audited, please contact HJF Regulatory Affairs as soon as possible, so that
we are aware of the audit and can help you prepare.
Final report submitted to IRB and
IRB approval letter of study closure with signature(s) (electronically signed
is acceptable) and second and third level approvals as required.
What data is needed
Current Federal law
requires that a drug be the subject of an approved marketing application before
it is transported or distributed across state lines. Because a sponsor will
probably want to ship the investigational drug to clinical investigators in
many states, it must seek an exemption from that legal requirement. The IND is
the means through which the sponsor technically obtains this exemption from the
FDA.
During a new drug's
early preclinical development, the sponsor's primary goal is to determine if
the product is reasonably safe for initial use in humans, and if the compound
exhibits pharmacological activity that justifies commercial development. When a
product is identified as a viable candidate for further development, the
sponsor then focuses on collecting the data and information necessary to establish
that the product will not expose humans to unreasonable risks when used in
limited, early-stage clinical studies.
FDA's role in the
development of a new drug begins when the drug's sponsor (usually the
manufacturer or potential marketer) having screened the new molecule for
pharmacological activity and acute toxicity potential in animals, wants to test
its diagnostic or therapeutic potential in humans. At that point, the
molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act
and becomes a new drug subject to specific requirements of the drug regulatory
system.
There are three IND
types:
An Investigator IND is
submitted by a physician who both initiates and conducts an investigation, and
under whose immediate direction the investigational drug is administered or
dispensed. A physician might submit a research IND to propose studying an
unapproved drug, or an approved product for a new indication or in a new
patient population.
Emergency Use
IND allows the FDA to authorize use of an experimental drug in an
emergency situation that does not allow time for submission of an IND in
accordance with 21CFR , Sec. 312.23 or Sec. 312.34. It is also used
for patients who do not meet the criteria of an existing study protocol, or if
an approved study protocol does not exist.
Treatment IND is
submitted for experimental drugs showing promise in clinical testing for
serious or immediately life-threatening conditions while the final clinical
work is conducted and the FDA review takes place.
There are two IND
categories:
Commercial
Research
(non-commercial)
The IND application
must contain information in three broad areas:
Animal Pharmacology
and Toxicology Studies - Preclinical data to permit an assessment as to whether
the product is reasonably safe for initial testing in humans. Also
included are any previous experience with the drug in humans (often foreign
use).
Manufacturing
Information - Information pertaining to the composition, manufacturer,
stability, and controls used for manufacturing the drug substance and the drug
product. This information is assessed to ensure that the company can
adequately produce and supply consistent batches of the drug.
Clinical Protocols and
Investigator Information - Detailed protocols for proposed clinical studies to
assess whether the initial-phase trials will expose subjects to unnecessary
risks. Also, information on the qualifications of clinical
investigators--professionals (generally physicians) who oversee the
administration of the experimental compound--to assess whether they are
qualified to fulfill their clinical trial duties. Finally, commitments to
obtain informed consent from the research subjects, to obtain review of the
study by an institutional review board (IRB), and to adhere to the investigational
new drug regulations.
Once the IND is
submitted, the sponsor must wait 30 calendar days before initiating any
clinical trials. During this time, FDA has an opportunity to review
the IND for safety to assure that research subjects will not be subjected to
unreasonable risk.
(ref:
http://www.fda.gov/drugs/)
Current and future European requirements and procedures
On 17 July, the European Commission
released the long-awaited proposal for a Regulation on
clinical trials on medicinal
products for human use (the Proposal). The future regulation will
replace the Clinical Trials
Directive 2001/20/EC, the revision of which has been advocated by
the pharmaceutical industry,
academia, and patients for years. Directive 2001/20/EC aims at
harmonising the requirements
throughout the EU but has not prevented divergent national
requirements that, especially for
multinational clinical trials, substantially hinder a swift handling
of clinical trial applications and
generate a very burdensome and costly administration. The
Proposal primarily seeks to cut the
red tape and to facilitate the conduct of multinational trials
and restore competitiveness in
clinical research in Europe.
The future Regulation will be more
complete and detailed than Directive 2001/20/EC (more than
90 articles and five annexes) and
will revise current rules, in particular as regards the
authorisation procedures, and
introduce new principles, such as co-sponsoring. Overall, the new
regime should reduce administrative
costs for industry and better reflect the variety of clinical
trials. The Commission chose a
Regulation as legislative instrument to ensure that identical rules
will apply throughout European
Union. This will increase harmonisation of the rules, but certain
issues, such as ethics and sponsor
liability, will remain governed by national law.
The submission of the Proposal to
the European Parliament and Council is the first step of the
legislative process. The Proposal
will probably be heavily debated and substantially amended, in
particular by the Council as the
Member States are keen on preserving their powers over clinical
trials conducted in their
territories. It is difficult to determine how long the legislative process will
last. The Commission expects the new rules to come into effect in 2016 after a
transitional
period of two years.
Scope
The future regulation has the same
scope as Directive 2001/20/EC, i.e., interventional clinical
trials and investigational medicinal
products (IMPs). The Proposal, however, amends the existing
definitions (clinical trial,
non-interventional clinical trial) and introduces new definitions, such as
“clinical study”, “low-intervention
clinical trial”, or “auxiliary medicinal product” (to replace the
concept of “non-investigational
medicinal product”).
The concept of “normal clinical
practice” at the Member State level is key for distinguishing
between a clinical study and a
clinical trial and between a standard clinical trial and a lowintervention
clinical trial. Although legally defined, the term refers to the clinical
practice as it exists in each Member State and could lead to national
divergences on the qualification of a
study.
Risk Categorization
The proposed new rules show a
risk-based approach to clinical trials and distinguish between
low-intervention clinical trials and
other clinical trials. A “low-intervention clinical trial” is a clinical trial where the IMPs are authorised and used
in-label (or their use is a standard treatment in any f the Member States concerned) and any
additional diagnostic or monitoring procedures pose minimal additional risk or burden for the
subjects compared to normal clinical practice in “any” Member State concerned.
The reference to ”any of the Member States concerned” suggests that a trial which qualifies as a
low-interventional clinical trial in one Member State should also qualify as
such in other Member States, but that does not seem to be the intention (as
illustrated by the German version of the Proposal). Because of their very low risk profile,
low-intervention clinical trials benefit from less burdensome requirements (safety reporting, labelling,
and insurance) and shorter authorisation timelines.
Streamlined Authorisation Procedures
Currently, a clinical trial is approved
by a competent national authority and an ethics committee
in each Member State where the
sponsor wants to conduct the trial, and the authorisation
procedure is conducted in parallel
in all the Member States. These parallel national procedures
are replaced by a form of
decentralised procedure , which also applies to purely national trials.
Authorisation
The key features of the new
authorisation procedure for clinical trials are the following:
Submission of a single and
harmonised application dossier through an EU portal linked to an
EU database. The content and format
of the dossier are defined in an annex to the Proposal
(which can be amended by delegated
acts).
Choice of a Reporting Member State
(RMS) by the sponsor. The RMS is the interface
between the sponsor and the other
Member States for the assessment of Part I aspects of
the trial.
Validation of the application by
the RMS.
Two-part assessment of the
application:
o Each part covers specific aspects
that are exhaustively listed in the Proposal.
o Part I covers general aspects,
such as the anticipated therapeutic and public health
benefits, the risks and
inconveniences for the trial subjects, or the investigator brochure.
It is to be assessed by the RMS in
coordination with the other involved Member States.
o Part II covers ethical, local, and
national aspects, such as the informed consent or the
arrangements for compensating
investigators or recruiting trial subjects. It is to be
assessed separately by each Member
State.
o Parallel assessment of Part I and
Part II.
Single decision by each Member
State, which covers Part I and Part II and must be notified to
the sponsor within 10 days of the
assessment.
Tacit approval system based on the
positive assessment of Part I by the RMS:
The RMS assessment of Part I is
binding on the other Member States unless they refuse the
assessment (“opt-out”). The refusal
can only be based on two, mainly ethical, grounds.
In the absence of a notification
of the decision within the deadline, the conclusion of the RMS
assessment of Part I qualifies as
the authorisation decision of the Member State on the
application (also for Part II).
The impact of a negative RMS
assessment of Part I is unclear.
Timelines are set out for each
phase of the procedure. They vary depending on the nature of
the clinical trial (shorter for
low-intervention trials) or the medicinal product (longer for
advanced therapy medicinal
products). Except for low-intervention clinical trials, they are
longer than under Directive 2001/20,
but the tacit approval system provides for better
compliance.
The Commission manages the EU
portal, and supports the cooperation of the Member States
with the assistance of a Clinical
Trials Coordination and Advisory Group (group of the national
contact points). There is no role
for the EMA.
Addition of a new Member States
The procedure for extending the
trial to a new Member State is similar to the authorisation
procedure, but with shorter
timelines. The RMS is the same as for the authorisation procedure,
but its role is limited as there is
no additional assessment of Part I aspects.
Substantial Amendments
After having been authorised, a
clinical trial may be modified. The modification is subject to
authorisation where it has a
substantial impact on the safety or rights of the subjects or on the
reliability and robustness of the
data generated. Non-substantial amendments should simply be
entered into the EU database. The
Proposal does not define or further describe what constitutes
a substantial amendment, and the
current Commission guideline may remain applicable. The
deadlines for authorisation are
shorter than for the authorisation procedure. The RMS is the
same as for the main authorisation
procedure.
Streamlined Safety Reporting
The rules on safety reporting are
streamlined and simplified. So, reporting of certain adverse
events by the investigator to the
sponsor can be excluded in the protocol, and suspected
unexpected serious adverse reactions
(SUSARs) can be reported by the sponsor directly to
EudraVigilance (EU pharmacovigilance
database). More detailed rules on safety reporting, which
partly codify the current Commission
guidance, are contained in an annex to the Proposal.
Conduct of Clinical Trials Outside of the EU
An increasing number of clinical
trials are conducted outside the EU and the results are also used
to support marketing authorisation
applications in the EU. Building on an EMA reflection paper,
the Proposal implicitly requires that
clinical trials conducted outside the EU comply with
regulatory requirements at least
equivalent to those in the EU. This obligation however is already
included in Annex I to Directive
2001/83/EC. Also, it is unclear how the equivalence between
foreign and EU clinical trial
regimes will be assessed and, more importantly, how third countries
will be convinced to adopt rules
that are similar to the EU rules.
Indemnity and Insurance
Directive 2001/20 introduced an
obligation for the sponsors to compensate trial subjects for
damages resulting from clinical
trials (in accordance with national law) by way of an indemnity or
insurance. Under the Proposal,
low-intervention clinical trials are exempted from the mandatory
indemnity or insurance requirement.
For the other (interventional) clinical trials, the sponsor
must ensure compensation through an
insurance or an indemnification mechanism, and the
Proposal requires the Member States
to set up a national indemnification mechanism that works
on a not-for-profit basis (and may
require payment of a fee by commercial sponsors).
Transparency
Under Directive 2001/20, clinical
trials are registered in a central database (EudraCT). That
database is not publicly available
except for paediatric trials, but protocol-related information and
trial results are indirectly made
public through another database (EudraPharm). The Proposal
makes EudraCT fully accessible to
the public, subject to personal data, commercially confidential
information, and the need for
effective supervision of the conduct of the clinical trial by a
Member State. This increased
clinical trial transparency is in line with the general European
trend in the pharmaceutical sector,
but adequate attention is needed to protect business
secrets.
(Ref: http://www.cov.com/files/Publication/b7133e14-05a4-47c4-9229 39b21218825/Presentation/PublicationAttachment/5f11bb6d-be8f-47c2-8818-28c45a6bd135/New_Rules_for_Clinical_Trials_Proposed_in_Europe.pdf)
US perspective
Since at least the mid-1990s, college
and university students, faculty, and staff who conduct oral history interviews
have increasingly found their interviewing protocols subject to review by their
local Institutional Review Board (commonly referred to as an IRB), a body
charged by the federal government with protecting the rights, interests, and
dignity of human research subjects – or, as some prefer, research participants.
The review has generally not been a constructive process for oral historians,
indeed, in many cases has been quite contentious as principles and practices
developed within biomedical and behavioral frameworks have been applied to a
more humanistic form of inquiry. The following sections will:
outline the regulatory framework and
historical context for IRB review of research involving what are termed “living
individuals;”
explain why IRBs claim authority to
review oral history and suggest why they are increasingly choosing to do so; identify
primary difficulties oral historians face when submitting interview protocols for
IRB review; explain efforts to address these problems made by professional
bodies including the Oral History Association; and suggest what to do when
facing IRB review of oral history interviewing projects.
Framework and Context: Authority to
review research involving living individuals resides with the federal
government, as authorized by Title II of the National Research Act of 1974
(P.L. 93-348) and codified in Title 45 (Public Welfare), Part 46 (Protection of
Human Subjects) of the Code of Federal Regulations, commonly referred to as 45
CFR 46 or the Common Rule. The Office of Human Research Protections (OHRP)
within the U.S. Department of Health and Human Services (HHS) oversees
implementation of 45 CFR 46; however, actual responsibility falls to local,
typically campus-based IRBs. IRBs are empowered by 45 CFR 46 to approve or
disapprove research protocols – or more typically, request their revision –
based on their conformity to the principles and practices delineated by the
regulations, as well as subsequent guidance issued by OHRP.
The result of lengthy and at times
contentious deliberations within government and professional circles, 45 CFR 46
was first codified in 1981 and, in its current form, in 1991. However, its
origins date to the 1960s and 1970s, with policies established first by the
U.S. Public Health Service and then by the entire U.S. Department of Health,
Education, and Welfare (HEW, predecessor to HHS) requiring independent review
of research involving human subjects funded by these agencies. More broadly,
concern for the welfare of human subjects of research was provoked, on the one
hand, by the explosion of government funded medical research in the years after
World War II; and on the other, by outrage at the violation of human rights
demonstrated by certain medical experiments, including Nazi doctors’
experiments on Holocaust victims and the Tuskegee Syphilis Study.
Three ethical principles underlie 45
CFR 46, each codified in procedures to ensure adherence to the principle. These
were first articulated in The Belmont Report, issued in 1979 by the federally
mandated National Commission for the Protection of Human Subjects of Biomedical
and Behavioral Research, which was charged with identifying the ethical
principles underlying the conduct of research involving living human beings.
These principles are: a respect for persons as autonomous individuals capable
of making decisions about their own behavior, or, in the case of individuals
with “diminished autonomy,” as needing specific protections, codified in 45 CFR
46 as procedures for securing informed consent from research subjects; beneficence,
or the obligation to minimize harm and maximize benefits to research subjects,
codified as a directive to assess and balance risks and benefits of research; and
justice, or the equitable selection of research subjects, codified as terms for
selection of subjects.
Oral History: The Common Rule
defines “research” as “a systematic investigation, including research
development, testing and evaluation, designed to develop or contribute to
generalizable knowledge;” and “human subject” as “a living individual about
whom an investigator (whether professional or student) conducting research
obtains (1) data through intervention or interaction with the individual, or
(2) identifiable private information” (46.102[d] and [f]). Most IRBs – and oral
historians – assume that oral history interviewing is “research” (even though
it doesn’t exactly fit the above definition) and because it involves
“interaction,” further defined as “communication or interpersonal contact
between investigator and subject (46.102 [f]),” that it is subject to IRB review.
However, 45 CFR 46 also exempts most
oral history from regulatory oversight. The regulations state that “research
involving . . . interview procedures . . . [is exempt from this policy] unless
(i) information obtained is recorded in such a manner that human subjects can
be identified directly or through identifiers linked to the subjects and [this
“and” is all important] (ii) disclosure of the human subjects’ responses
outside the research could reasonably place the subjects at risk of criminal or
civil liability, or be damaging to the subjects’ financial standing,
employability, or reputation” ( 46.101 [b] [2]). In other words, while most
oral history narrators can be identified if by no other means than their
recorded voice, most do not reveal information that could “reasonably place
[them] at risk.” However, following advice issued by OHRP in 1995, the IRB –
not the researcher – determines exemption, so we find ourselves in the position
of submitting a description of our oral history research protocols to an IRB in
order to apply for an exemption from applying to the IRB.
Oral history’s relationship to IRB
review is further complicated by the fact that in 1998 ORHP, in an effort to
ease the regulatory burden increasingly imposed upon oral history – and in a
perverse example of the cure being worse than the disease – issued guidance
that included oral history in a list of research modes that could enjoy
“expedited review,” which means that the full IRB does not need to review a
research proposal, that review can be delegated to one or more members of the
Board. “Exempt” or “expedited”? – a contradiction that OHRP has never
clarified.
Federal and institutional policies
also support IRB review of oral history. The Common Rule itself applies only to
research funded by the seventeen federal agencies that subscribe to its terms –
and notably, the National Endowment for the Humanities, which is the federal
agency most likely to support research in history and other humanities fields,
is not among them. In fact, however, most universities and research centers
that receive funding from any of these seventeen agencies – and very few do not
– apply the terms of 45 CFR 46 to all research conducted within or sponsored by
the institution, whether or not the research receives funding from one of these
agencies, or is funded at all. For it is in an institution’s self-interest to
apply the same oversight to all research conducted within the institution. The
regulations themselves also require assurance that ethical safeguards are in
place for all human subjects research conducted within an institution for that
institution to be eligible for funds from any of the seventeen agencies
subscribing to the Common Rule. Most institutions simply choose to extend the
terms of the Common Rule – and hence IRB review – to all such research.
Yet another reason for the extension
of IRB review to oral history interviewing is what some have termed “mission
creep.” Within the last several years, egregious violations of requirements for
human subjects review in biomedical research have led to the suspension of all
human subjects research at several major institutions. Simultaneously, colleges
and universities have become increasingly fearful of litigation or bad press
over dangerous or controversial research. As a result, IRBs, already
risk-averse bodies, have tended to become hyper-vigilant, extending review to
forms of minimal risk research in the social sciences and humanities that
previously had escaped their purview. Arguably, oral history’s increasing
visibility and acceptance within the academy during this same period have also
served to bring it to the attention of local IRBs.
Difficulties: Not surprisingly given
the abuses that formed the context within which 45 CFR 46 was developed, the regulations
assume a scientific, largely biomedical, model of research. While the social
sciences have always been included within the regulatory embrace, their
inclusion has been disputed by critics among both policy makers and scholars
since the 1960s. The lack of fit between the epistemologies of various social
science disciplines and the terms of regulation has never been given due
consideration. Psychology is the discipline that has most concerned regulators
and with which they are most familiar; history – and the humanities in general
– have been a “foreign language.”2 As a result, IRB review of oral history is
an awkward and at times contentious affair.
The problems oral historians
confront cluster in two areas: 1.) the potential an interview might have for
inflicting psychological harm on the narrator within the interview; and 2.)
maintaining narrator privacy in any subsequent use of the interview. Concern
about psychological harm derives rather awkwardly from that section of the
Common Rule that defines minimal risk as the “harm or discomfort . . .
encountered . . . during the performance of routine physical or psychological
examinations or tests” (46.102 [i]). The Guidebook issued by OHRP explicates
the notion of psychological harm, stating that “stress and feelings of guilt or
embarrassment may arise simply from thinking or talking about one’s own
behavior or attitudes on sensitive topics.” In fact, the assumption that harm
can result from talking about sensitive topics is contradicted by both anecdotal
and more scientific evidence, which suggests that talking about even the most
difficult of subjects is generally not perceived as harmful but indeed as
having a salutary effect.3 And insofar as oral history narrators freely agree
to be interviewed about past experiences (one area in which oral historians and
IRBs do agree is the need for informed consent!), it seems patronizing to
assume they need to be protected from talking about those experiences, that
they cannot decide which experiences, including traumatic experiences, they
wish to talk about and which they do not.
Still, concerns about psychological
harm have led some IRBs to require oral historians to submit lists of interview
questions for review, advise against or prevent them from asking questions
about potentially sensitive subjects, and require interviewers who do ask
potentially sensitive questions to make referrals to counseling services
available to narrators at the conclusion of the interview. These proscriptions
make little sense to oral historians: our inquiries are open-ended dialogues
that cannot be confined to a prescripted set of questions and we do not always
know in advance if an inquiry will enter into a sensitive area – or what might
even be a sensitive area for any given narrator. Our practice often requires a
series of ethically sensitive decisions within the context of a specific
interview relationship.4 The Oral History Association’s Evaluation Guidelines,
which codifies the fundamental principles of oral history, provides more
appropriate guidance, stating that interviewers “should encourage interviewees
. . . to address issues that reflect their concerns” and “must respect the
rights of interviewees to refuse to discuss certain subjects,” and “clearly
explain [this option] to all interviewees.”
The second area of concern, privacy,
also arises from language in the Common Rule, which does not exempt – and hence
raises concern about – interviews for which “disclosure of the human subjects’
responses outside the research could reasonably place the subjects at risk of
criminal or civil liability, or be damaging to the subjects’ financial
standing, employability, or reputation” ( 46.101 [b] ). In an effort to protect
narrators from such potential risk or damage, IRBs frequently require that they
remain anonymous; and that researchers either retain completed interviews in
their possession or, preferably, destroy them after the research is completed.
For those who come to oral history via anthropology or sociology, maintaining confidentiality
of sources is quite compatible with normal disciplinary practice. Yet requiring
anonymity violates a fundamental principle of oral history. For historians,
anonymous sources lack credibility – knowing the identity of a narrator allows
the historian to gauge that person’s relationship to the topic at hand and
hence assess the perspective from which he speaks. While OHA’s Evaluation
Guidelines do allow interviewees to choose anonymity “under extreme
circumstances,” when failure to do so could have adverse consequences, the
operating assumption is for narrators to be identified and most, in fact,
choose to be. Typically, narrators are proud of having contributed their story
to the permanent record and wish to be associated with it.
Furthermore, historians neither keep
to themselves nor destroy evidence but rather are enjoined by their own
disciplinary ethics to provide open access to sources, so that others can
evaluate and build upon their scholarship. Oral history is fundamentally an
archival practice, defined by the assumption that interviews are conducted for
the permanent record and are to be made publicly available. Again to cite the
Evaluation Guidelines: “With the permission of interviewees, interviewers
should arrange to deposit their interviews in an archival repository that is
capable of both preserving the interviews and eventually making them available
for general use.”
For all matters of privacy, “with
the permission of interviewees” is the operative phrase within oral history,
not the terms of 45 CFR 46: Because oral history interviews are a copyrightable
document, owned by the narrator, he or she must sign over – to either an
individual researcher or a public archive – rights to the interview via a legal
release form. Without this, no one, including the interviewer, can legally use
the interview. This release allows the narrator to define the terms with which
the interview can be used, including if he/she wishes to remain anonymous or
restrict access to the interview for a period of years. The Evaluation
Guidelines also recognize the potential for exploitation in oral history, if
not “risk of criminal or civil liability,” or damage to a narrator’s “financial
standing, employability, or reputation.” They state that “interviewers should guard
against possible exploitation of interviewees and be sensitive to the ways in
which their interviews might be used;” and “should be sensitive to the
communities from which they have collected oral histories, taking care not to
reinforce thoughtless stereotypes or to bring undue notoriety to them.” In
fact, these principles are more expansive – and more appropriate to oral
history – than the terms of 45 CFR 46.
Still, it must also be said that for
historians, a deep disjunction exists between the Common Rule’s concern for
privacy and the canons of historical inquiry. At times information in an
interview, if made public, can indeed place a person at risk of criminal or
civil liability, or be damaging to his financial standing, employability, or
reputation. Yet historians’ deepest responsibility is to follow the evidence
where it leads, to discern and make sense of the past in all its complexity;
not necessarily to protect individuals from their past actions. The American
Historical Association’s (AHA) “Statement on Standards of Professional Conduct”
puts it this way: “Professional integrity in the practice of history requires
awareness of one’s own biases and a readiness to follow sound method and
analysis wherever they may lead” (bold face in the original). And the OHA
Guidelines suggest a similarly critical approach, calling on both interviewees
and interviewers to “mutually strive to record candid information of lasting
value” and enjoining interviewers to “strive to prompt informative dialogue
through challenging and perceptive inquiry.” In this we are akin to journalists
and unlike medical professionals, who are indeed enjoined to do no harm.
Historians are not alone in their
concern that 45 CFR 46 can be used to constrain critical inquiry. Legal scholar
Philip Hamburger has argued that insofar as it requires researchers to get
permission to conduct research, 45 CFR 46 violates First Amendment rights of
freedom of speech and the press.5 In a 2006 report, “Research on Human
Subjects: Academic Freedom and the Institutional Review Board,” the American
Association of University Professors recommends that “research on autonomous
adults whose methodology consists entirely in collecting data by surveys,
conducting interviews, or observing behavior in public places, be exempt from
the requirement of IRB review—straightforwardly exempt, with no provisos, and
no requirement of IRB approval of the exemption.”6 The Illinois White Paper,
“Improving the System for Protecting Human Subjects: Counteracting IRB ‘Mission
Creep’“, produced by the Center for Advanced Study at the University of
Illinois, concludes that “most journalism and oral history cannot be appropriately
reviewed under the Common Rule.”
Efforts to Address the Problems:
Responding to increasing concerns about the lack of congruence between the
terms of Common Rule and the practice of oral history, in 2003 the OHA and AHA,
after a series of discussions, secured the Office of Human Research
Protections’ concurrence with a policy statement that excluded most oral
history interviewing from IRB review on the grounds that it does not conform to
the regulatory definition of research as seeking “generalizable knowledge,”
that is to say historians “do not reach for generalizable principles of
historical or social development; nor do they seek underlying principles or
laws of nature that have predictive value and can be applied to other
circumstances for the purpose of controlling outcomes.”
Some IRBs, however, questioned this
policy and subsequent commentary from OHRP, developed in response to inquiries
from the University of California Los Angeles IRB, refined its concurrence with
a policy of exclusion by attempting to distinguish between interviews that are
not intended “to draw conclusions, inform policy, or generalize findings” and
hence are not subject to IRB review, and those that are so intended and hence
are subject to review, including “creat[ion of an] archives for the purpose of
providing a resource for others to do research.” To complicate matters even
more, in response to further questions raised by OHA and AHA, OHRP also
affirmed its original policy statement.7 If this sounds contradictory, it is:
Oral history’s status vis-à-vis 45 CFR 46 and hence its relationship to IRB
review remains unresolved at the federal level.8 Meanwhile, a few IRBs have
attempted to address apparently contradictory advice from OHRP and adopted
reasonable policies regarding IRB review of oral history.9 Others exclude
interviews conducted for classroom assignments, if they are not made public
beyond the classroom, on the grounds that they are pedagogy, not research. Most
IRBs, however, which have considerable decision-making autonomy, continue to
require review of oral history without parsing OHRP’s statements and without
considered attention either to ways oral history differs from biomedical or
social science research or to historians’ concerns. The AHA continues to monitor
the situation and responds on behalf of all historians to requests by OHRP for
public comment on various proposed policy changes.
What To Do: Some oral historians, it
must be said, are supportive – or at least tolerant – of IRB review and
willingly submit interview protocols. Others, with less vigilant IRBs, simply
fly below the regulatory radar. And some researchers have insisted that the
regulations do not, or should not, apply to them and have refused compliance
with apparently no adverse consequence.11 Still, while a tenured professor
might ignore or refuse compliance with impunity, this may not be an acceptable
course of action for many and is especially ill advised for graduate students,
whose dissertations can – indeed have – been held up at the administrative
level for failure to comply with IRB review.
So, for a college or university
affiliated student, scholar, or staff member confronting IRB review for a
forthcoming oral history project, the following might be a reasonable course of
action:
Inform yourself of the federal
regulations governing research on human subjects, the context within which they
were developed, and recent critiques of human subjects review in the humanities
and social sciences.
Seek allies within your department
or relevant administrative unit as you develop an approach to the IRB.
Take a proactive approach with the
IRB, informing it of the principles and practices governing history in general
and oral history in particular and insisting that it conform to the federal
requirement that an IRB include or consult with individuals who can
knowledgeably review any proposed research, in this case an individual with
adequate knowledge of oral history.12
Oral historians might also consider cooperating with the IRB to develop
a review policy appropriate to oral history, one that might include, as some
have suggested, departmental review of oral history research projects with some
minimal reporting to the IRB .
(ref: http://www.oralhistory.org/about/do-oral-history/oral-history-and-irb-review/)
Recognizing why clinical research has to meet the needs of
regulatory affairs
The regulatory landscape has continued to evolve in
response to product safety, regulatory
compliance, new technologies, improved understanding
of disease states, stakeholder and
customer needs and global imperatives, with new and
increasing regulations, regulatory guidance and oversight. The global
regulatory affairs group and the regulatory professionals in the
biopharmaceutical industry occupy a central and
pivotal role to all the functional groups. The
regulatory team is charged with a strong leadership
role that ensures compliance with regulations and enables understanding and
interpretation of the dynamic regulatory landscape,
while creating opportunities in the highly-regulated
and complex environment.
The challenging landscape is largely a result of the
success of the biopharmaceutical industry
in delivering medical therapies for many disease
states, safety catastrophes from use of products
post-approval; and product quality compliance
issues. These have sharpened regulatory authorities’ focus on product
benefit/risk profiles and related stakeholders’ views on cost effectiveness
and patient access. The regulatory professional has
to be equipped and poised to effectively guide
the organization to success with a credible voice,
informed strategic guidance and objective evaluation.
The demand for globally acceptable products
heightens the imperative for harmonization of
regulatory requirements to lend efficiency and cost
effectiveness to the process of product development, manufacturing and
expediency to global access. In addition, biopharmaceutical companies have
continued to expand their frontiers to attain a global reach, with presence in
many regions and countries, and
therefore exposed to myriad, and sometimes diverse, regulatory requirements and
operating standards. The challenges of globalization in a heterogeneous world
with an evolving regulatory landscape and
expectations of multiple stakeholders have increased
the complexity, unpredictability and intensity of
the biopharmaceutical product development
and registration process. These challenges likewise
reinforce the crucial role of the regulatory
team and underscore the need for enhanced global
regulatory function with regulatory professionals who are strong leaders,
business partners and strategic contributors.
The scope of the regulatory affairs group function
spans the entire spectrum of product development, manufacturing, registration,
post-marketing activities and lifecycle optimization. This span of involvement
and responsibility is sometimes referred to as bench to bedside and
beyond, from cradle to grave, from
inception through lifecycle optimization, from laboratory to launch, etc. The
regulatory team and professional hold a unique position of importance with
impressive diversity in function and significant breadth and depth of
responsibility.
This chapter focuses on the role of the global
regulatory affairs team in the biopharmaceutical industry and draws upon its crucial
and unique position to highlight the strong leadership function, critical
business partner, strategic contributor and honest broker for some of
industry’s most important decisions.
Global
regulatory affairs organization
Functional
units
Global regulatory affairs groups in industry provide
worldwide, strategic leadership in and
comprehensive direction of the government regulatory
requirements for product introduction
and commercialization, utilizing regulatory
knowledge to ensure compliance and regulatory
intelligence and create opportunities in a
highly-regulated environment.
The global regulatory affairs group has strategic
and operational functions, both requiring
precision and flawless execution, as a company’s
success relies on, in part, the guidance and rigorous assessment provided by
the regulatory affairs team. The key product development, manufacturing and
registration milestones (such as Investigational New Drug filing, end of phase
II, phase III, New Drug Application submissions, regulatory agency review
timetable and product approvals), which are the corporate valuation and
decision points, are based on critical regulatory interface goalposts and
milestones. This underscores the importance of strategic regulatory contribution
to the industry. In order to be valuable contributors and critical business
partners, the global regulatory affairs organization must develop mechanisms
and establish systems to ensure it has the right people and talent, proficient
processes, prolific productivity, phenomenal performance and precision in
planning.
What
comprises global regulatory affairs
The global regulatory affairs groups within
different pharmaceutical companies have different organizational structures and
functional reporting. However, most are comprised of fundamental units that
house the various specialists or experts within the regulatory function.
The global regulatory affairs group has
traditionally resided within the research and development group of
biopharmaceutical companies, but that, too, is evolving. Many companies
have recognized the central role of the group to all
technical functions—development, manufacturing and marketing—and therefore are
aligning the group’s reporting to a central and
neutral executive. In some companies, the global
regulatory group reports to the Chief Execu tive Officer—a
statement of the importance of this function. The typical functional units are
represented and may vary from company to company;
therefore, this chapter will address the
typical functional units of importance.
The key functions of the global regulatory affairs
group include:
● Leading and providing strategic regulatory
guidance and delivering the global regulatory strategy for product development,
manufacturing and registration
● Building and maintaining a credible relationship
with regulatory authorities with effective written and verbal communication
● Establishing an efficient repository and archive
for correspondence compliant with
regulatory standards for audits
● Providing high-quality, complete
user/reviewer-friendly documents electronically
transmissible and reproducible
● Developing and maintaining product information and
label
● Providing regulatory intelligence, from paying
attention to regulatory environment and
changing landscape, to participating in external
industry partnerships and developing
policy with regulatory agencies
● Ensuring published information and
promotional/advertising material meet regulatory
requirements
● Ensuring functional units comply with regulatory
requirements and good regulatory
practices.
Role
of global regulatory affairs
The enhanced role of the regulatory affairs
professional
The past 10 years have brought both an exciting
evolution and challenging times for the biopharmaceutical industry with an
increasingly complex and demanding regulatory environment, creating
opportunities for both the regulatory profession and the pharmaceutical
industry. This evolution in the regulatory function has been driven largely by
the expanding scope
and global reach of the industry, global regulatory
environment and intelligence, scientific
breakthrough and innovation, cutting-edge
technologies including e-submissions, complexity of disease area targets for
development and multiple stakeholder demand for rigorous and
competitive product differentiation. These have
heightened the need for highly-skilled regulatory professionals with area
specialization and broad leadership capability.
In this changing and enhanced regulatory role, the
regulatory team is expected to provide
regulatory leadership and excellence in a changing
environment. It requires the regulatory team
to have at the core of its focus the end deliverable
goal, which is expeditious patient access to highquality, well-differentiated
products.
This end goal drives the need for the regulatory
team to:
● Deliver innovative, breakthrough regulatory
strategies for product development and
registration.
● Become more anticipatory of the company success
imperatives.
● Be proactive and forward thinking, provide timely,
comprehensive and robust global
regulatory guidance.
● Understand the biopharmaceutical environment and
regulatory actions on precedents
and utilize such regulatory intelligence.
● Forge new standards to deliver more predictable
outcomes.
● Increase focus on building and strengthening
relationship with regulatory authorities to
provide timely expert input into product
development, manufacturing and registration.
(ref: http://www.centerwatch.com/pdfs/s11701_ch2_sample.pdf)