Download FDA, Medical Product Regulation, and Advocate Involvement

FDA, Medical Product Regulation, and Advocate Involvement
How does the FDA make its decisions? Who makes the rules for drug development? What special
accommodations are made for rare diseases? Parent Project Muscular Dystrophy and Cure Duchenne hosted a
two-part live webinar series featuring Dr. David Banks of the FDA Office of Special Health Issues, earlier this
summer. Dr. Banks walked us through the general steps required for approving a drug with special emphasis on
the implications of the Orphan Drug Act, individual INDS, and expanded access programs. These talks provided
some insights into the FDA’s mission--what are its constraints, and what are its goals? Dr. Banks was not able to
address questions about specific therapeutics that are undergoing regulatory review right now. Below are notes
compiled from these webinars.
Webinar #1: PPMD/Cure Duchenne Interview with Dr. David Banks from the FDA
Learning about the FDA process:
The History:
1906 – Pure Food and Drugs Act
1930 – Congress Establishes Food and Drug Administration (FDA)
1938 – Congress passed the Federal Food, Drug and Cosmetic Act (FDCA). The purpose of the law was to
prohibit misbranding of drugs. This law required drugs to be labeled with directions for safe use. It also
required companies or individuals sponsoring new drugs to notify FDA before the drugs were placed on market
and required certain safety data.
1962 –Congresses added a requirement that the FDA assess the effectiveness of new drugs prior to approval and
gave the FDA increased authority over clinical studies and established policies to promote good manufacturing
practice (GMP).
1983 – Orphan Drug Act
7 years market exclusivity for drugs affecting less than 200,000 (definition of a rare
disease).
Tax credit of up to 50% for qualified expenses for clinical research to support approval of
the orphan drug.
Grant opportunities to support development of products in rare diseases.
Exemption from several kinds of user fees.
Guidance from FDA staff to sponsors.
1984 – Specified a process for approval of generic copies of previously approved drugs, eliminating the
requirement for generic drugs to perform clinical trials for safety and effectiveness. The Center for Drug
Evaluation and Research (CDER) administers this program.
1994 – Dietary Supplement Health and Education Act
1997 – FDA Modernization Act: added a sentence clarifying that data to FDA regulations indicating that one
adequate and well-controlled study, together with confirmatory evidence obtained before or after that study,
can constitute “substantial evidence” of effectiveness for any new drug.
The Mission
The mission of the FDA is to protect the public health by assuring the safety, efficacy, and security of human and
veterinary drugs, biological products, medical devices. In addition, their goal is to advance the public health by
helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and
helping the public get the accurate, science-based information they need to use medicines and foods to improve
their health
The Process:
IND – The first formal step required by the sponsor (better known to us as a biotech or pharmaceutical
company) is to request approval of an IND (investigational New Drug Application). This application is very
complex and will provide detailed information about the proposed clinical trial strategy and will include data
from ALREADY conducted animal studies or Toxicology studies (typically 3 animals – mice, rodent, primate) to
demonstrate that the drug is sufficiently safe to initiate studies with people.
For drugs that are intended for individuals with life-threatening conditions or those conditions with high unmet
medical needs, FDA has instituted additional options such as fast track status, accelerated approval, and priority
review. This is done to speed reviews and provide additional guidance to sponsors about what evidence is
required to support approval of the compound.
Fast track applications may also qualify for accelerated approval which may include the use of surrogate
endpoints (secondary) that are determined to be ‘reasonably likely to predict clinical benefit.’ This may include
a laboratory value or physical characteristic that is able to suggest benefit or positive changes in the disease
trajectory. In addition, fast track applications qualify for priority review, which means that the FDA will complete
priority reviews within six months compared to the standard review goal of ten months.
Clinical Trials
The purpose of trials is to conduct adequate and well-controlled investigations by experts to evaluate the
effectiveness of the drug in order to conclude that the drug is safe and will have the intended effect. At least
two clinical studies are required to support new drug approval with only rare exceptions.
Clinical trials are necessary to permit a valid comparison of the individuals taking the drug (experimental group)
with a concurrent control (placebo group). This is necessary to minimize bias, and to adequately and
appropriately assess the response of the research participants. While it feels cumbersome, it is the only way to
understand if a certain drug has the desired effect.
Phase 1 and/or Phase 1/2a – Typically start with small, brief studies/safety studies to indicate safety of
the drug and, depending on the drug and intended effect, may be first done in healthy volunteers.
Phase I/2 – If the drug is not tested in healthy volunteers, this may be the first step-dose escalation
studies (dose comparison ), utilizing cohorts (groups) of individuals with the disease, increasing the dose
with each cohort in an effort to establish therapeutic dose (safety and effect).
Phase 2b/3 – Progression to larger and longer-duration studies that will include randomized placebo
controlled studies.
Phase 4 - Post-marketing evaluation of safety and effects.
Expanded access:
There are a variety of vehicles for expanded access. While expanded access could be a single patient, under
certain circumstances, groups of individuals are afforded expanded access. In order to complete an application
for expanded access, the patient has to be willing, a physician has to agree to administer the drug, and the
sponsor must agree to give access. Expanded access is typically withheld until the safety of a drug is
demonstrated and if done, may be considered during a Phase 2 or mid-phase trial. Once the completed
application is delivered to the FDA, approval may be as quick as a day to several days or up to one month,
depending on the individual situation. Once the application for access has been approved by FDA, an IRB
(institutional review board) approval is required before the patient has access to the drug. (Academic Centers
and hospitals have an internal IRB, but physicians in private practice would utilize an independent IRB to seek
approval.)
In circumstances where there is a Phase 2 trial outside the United States, a US patient could apply for an
individual IND for access to that treatment. The FDA could use data generated from anywhere in the world
assuming the study sponsor has applied the same standards as the FDA. . Difficulties may occur when FDA
standards differ from those of the country in which the study is being performed, or when the sponsoring
company is unwilling to supply the complete data package required to allow the individual IND in the US. This is
done on a case per case basis.
Webinar #2: PPMD/Cure Duchenne Interview with Dr. David Banks from the FDA
Questions are asked, interview style primarily by Sharon Hesterlee of PPMD. Debra Miller’s questions labeled.
Q1. How is risk versus benefit determined when the FDA evaluates drugs?
This is derived from the Food and Drug Act. The drug product must have some verifiable benefit—you have to
know benefit before you can judge risk. Additionally, the product has to be thoroughly tested and have
appropriate safety data. The “risk/benefit ratio” is not a real thing. FDA experts must consider the degree of
benefits and range of risks coupled with how well the product was tested and therapies are currently available.
They also compare the product to how it will be used, whether it will be a first line treatment, alternative for
non-responders of currently drugs, or as a last resort. They also poll informed patients willing to take risks for
the product and assess their willingness.
Q2. What are the roles of Patient Representatives and when are they used?
Patient Representatives are recruited by the FDA, as needed, before a trial begins. FDA also welcomes
applications from patient advocates at any time. They seek people with a background in advocacy who have no
specific agenda and are able to look broadly and objectively at data. Most serve in evaluation of marketing
applications. The FDA is currently expanding the program to meet with FDA and individual applicants
concerning INDs.
Q3. Can advocates participate as guests of the pharma/biotech contingent that is seeking approval?
Any drug company or investigator may use Patient Representatives inviting them to participate in the process
for a specific product, yet the FDA invites people to be consultants to the FDA.
To apply, go the FDA website and look for “patient/advocates.” While we have people affected by disease, we
are looking for people who are unbiased, regardless of whether they are affected by a specific disorder.
Q4. General Duchenne question. Drugs for rare diseases are almost always tested worldwide, including in the
US and EU (European Union). Much of this testing is done in parallel, which appears to be a duplication of
effort. Are there instances where the FDA will accept data from outside the US?
Yes, we are able to accept data provided it meets US standards—efforts to harmonize data requirements in the
US and the EU have resulted in international standards. Additionally, drugs may be marketed in the US if
appropriately tested outside the US. While he knows of no examples, Dr. Banks stated the FDA is willing to
accept such applications.
Sharon comments: “What I hear you saying is the interpretation of data, not the regulatory requirements, is
where most differences occur when assessing the results of international trial drugs. So harmonizing data
requirements isn’t the key to doing single international trials instead of parallel trials—rather it’s harmonizing
the interpretation of data.”
Dr. Banks: Yes, there is no international standard for drug trials.
Q5. If a drug is being tested outside of the US, can an individual patient receive an individual IND?
It is possible, yet requires having all investigational requirements, including toxicology information, provided to
the FDA. This is a substantial regulatory submission. Typically a sponsor or drug manufacturer would be
unwilling to accept the requirements needed for approval.
Q6. What about US use of drugs not approved in the US that are approved in the EU?
The FDA allows discretion with personal use of drugs approved outside the US. There are less stringent
requirements for importation.
Q7 (Debra Miller). Would a new drug need to show better outcome compared to those in current use?
No, in some instances a Comparative Use Study is needed. There are many different applications for use and
outcomes. The standard is, what would a reasonable person do?
Q8 (Debra). A widely used drug approved outside the US could be approved when the manufacturer submits all
data related to the drug.
Yes, it is possible. The FDA has a support team to help manufacturers from start to the completion of the
approval process.
Q9. Who controls expanded access?
A company controls access to their drug. They can approve or limit access. They cannot show favoritism which
is often avoided using a patient lottery. Having multiple individual INDs with many different doctors and
patients is not appropriate as information collected is less controlled. It is often more productive in a case like
that to have the manufacturer establish the treatment IND or protocol.
Q10. Even if multiple physicians agree to conduct trials can a company still limit access?
Yes, for any reason.
Q11. Can a company restrict access of people who previously participated in a trial?
Yes, all access can be restricted.
Q12. Are there mechanisms in the FDA that control the agency’s efficacy and time efficiency?
The FDA has an ombudsman who oversees the agency’s performance. A manufacturer is able to release
information during a trial, yet the FDA is prohibited from commenting. People are held accountable for
timeliness and quality of review, measured from the patient’s perspective which is the measure that matters
most to the FDA.
Thanks to Debra Miller of CureDuchenne and Brian Denger of PPMD for taking notes.