Latest FDA News and Regulation Changes
Medical Safety and Clinical Trial experts are constantly up to date on all the latest FDA news and regulation changes. Here are the most recent and notable updates.
FDAAA 801 legislation:
In 2016, the U.S. Department of Health and Human Services issued a final rule that clarifies and increases the regulatory requirements and measures for submitting registration and summary findings of clinical trials at ClinicalTrials.gov, in accordance with Food and Drug Administration Amendments Act (FDAAA) 801. The final rule requires that sponsors, investigators, and all others involved in clinical trials, which trials must be presented, when they must be presented, and whether compliance has been accomplished. For instance, the final rule clarifies the meaning of which clinical trials are included in this Act. The final rule also expands the FDAAA 801 requirements by requiring the submission of clinical trial results information for trials of unapproved products. The regulation is effective after January 18, 2017 and responsible companies are expected to be in compliance by April 18, 2017.
In general, FDAAA 801 also mandates registration and reporting of summary results of clinical trials of medicines and devices subject to FDA regulation on the freely-accessible site ClinicalTrials.gov, no later than 12 months after the Completion Date. Prior to the FDAAA ruling, companies were able to hide finding of clinical trials if the results were negative or otherwise potentially damaging to drug marketing and sales.
President George W. Bush signed the Food and Drug Administration Amendments Act of 2007 (FDAAA), in 2007. This law reviewed, expanded, and reaffirmed several existing pieces of legislation regulating the FDA. These changes allow the FDA to perform more comprehensive reviews of potential new drugs and devices.
President Barack Obama signed an 11th hour 21st Century Cures act (Cures Act) at the end of 2016 which speeds up and by default weakens the drug review process by relying more heavily on surrogate endpoints and biomarkers instead of long-term outcomes trials with hard endpoints. Its okat to spread this logic to some biomarkers that gave been studied extensively, such as LDL, serum glucose, and hemoglobin A1c, they have been correlated with clinical endpoints in innumerable studies, but most biomarkers don’t have the scientific data backing them like these four do.
Rather than elicit the opinions in independent top scientists, the 21st Century Cures Act had the input of over 1,455 lobbyists and was also one of the most heavily lobbied bills in the 114th Congress. It included input from at least 78 pharmaceutical manufacturers, 24 device manufacturers, and 26 biotech companies. The Pharmaceutical Researchers and Manufacturers of America (PhRMA), the trade group representing the pharmaceutical manufacturers industry, spent $24.7 million of its overall $30.3 million on lobbying for the act, which clearly shows their interest in the Act.
This bill decreases the time it takes for drugs to get to market by reducing clinical trial requirements and weakens the safety and efficacy of both drugs and medical devices.
Statutory Requirements for new drug approval in 2016:
- Substantial evidence of effectiveness for treatment of the proposed indication.
- Benefits for proposed population outweigh risks
- Manufacturing that ensures product identity, strength, quality (purity)
- Evidence-based drug labeling that adequately guides providers and patients to use the drug safely and effectively
Substantial Evidence of Effectiveness will continue to be a requirement, and demonstration of substantial evidence of effectiveness requires studies designed well enough and quoting 21CFR 314.50 and 21CFR 314.126: “to distinguish the effect of a drug from other influences, such as random phenomenology, spontaneous change, the placebo effect, or biased observation” The Usual approval standard is two adequate and well-controlled studies
To A Degree, Flexibility Is Part of FDA Regulation Paradigm (21 CFR 314 (APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG)
- Regulations allow for flexibility and judgment in applying the standards, and the FDA has a solid record of appropriately applying regulatory flexibility.
“While the statutory standards apply to all drugs… the many kinds of drugs… and wide range of uses for those drugs demand flexibility in applying the standards.
Thus FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet the statutory standards.” (21 CFR 314.105 Approval of an Application)
How Much Evidence Is Enough to Obtain FDA Approval?
FDA may consider “data from one adequate and well‐controlled clinical investigation and confirmatory evidence” to constitute substantial evidence
(FDA Modernization Act (FDAMA)) However, flexibility in FDA regulations does not mean marketing approval prior to demonstration of substantial evidence of effectiveness.
Four Programs Exist to Expedite Drug Development for Certain Types of New Drug Applications (Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics, May 2015)
- Fast Track Designation FDAMA /FDASIA 2012
- Breakthrough Therapy Designation FD&C Act/FDASIA 2012
- Priority Review PDUFA 1992
- Accelerated Approval 21CFR314 subpart H, 601 subpart E/FDASIA 2012
These four programs have been utilized as follows over the past year: (October 2015 – 03 October 2016)
- 17 Approvals for Rare Disease Indications (10 for were for oncology indications)
- 7 BLAs and 10 NDAs
- 8 Designated as Breakthrough Therapy
- 2 Received a Rare Pediatric Disease Priority Review Voucher
- 6 Received Accelerated Approval (4 of those 6 were for oncology Indications)
- 1 Employed a novel End Point
- 12 Approved with fewer than 2 Adequate and Well Controlled Trials
Two pathways exist for FDA Drug Approval
- Accelerated approval
- Traditional approval
Accelerated approval is not about faster review – it is a regulatory pathway to speed availability of drugs for serious unmet need by using an appropriate, more readily measured, surrogate or intermediate clinical endpoint when a lengthy trial would be needed to measure direct clinical benefit of a drug
In accelerated approval, the candidate drug must provide a meaningful advantage over available therapies to treat a serious condition, generally irreversible morbidity or mortality.
- Relies on a more readily measured surrogate or intermediate clinical endpoint
- A post-approval confirmatory study to further define clinical benefit is generally required
Clinical vs. Surrogate Endpoints
- Clinical endpoint: characteristic or variable that directly measures a therapeutic effect – how a patient feels, functions, or survives
- Surrogate endpoint for accelerated approval: marker thought reasonably likely to predict clinical benefit; not itself a measure of benefit
Need more information? Get a free consultation with a Clinical Trial Expert who can help with trials, testimonies, depositions, and any other questions.
FDA Approvals in rare disease programs: a 1016 update
- A poorly planned and executed development program for a rare disease misuses valuable patient resources and serves to delay obtaining the knowledge required to understand the benefits and risks of a drug to support regulatory review and approval FDA provides valuable advice and guidance to sponsors, we cannot require sponsors to follow our advice
- Sarepta’s approval of Exondys 51 in2016 was a unique case where their drug did not have a well-controlled trial or any efficacy. With Sarepta, a grass-roots effort involving a a small but very vocal minority was able to influence high-profile individuals and administrator at the FDA to to bypass the normal review process and approve the drug. Path taken by Sarepta NOT a good model for other development programs
- Assays for biomarkers should be well validated before use to avoid obtaining misleading information and wasting clinical specimens Particularly true when invasive procedure required to collect tissue in children
- Rigorous blinding and control procedures should be in place to minimize bias in assay interpretation Protocol should specify blinding procedures, adjudication methods, independence of readers, etc.
- In many cases, randomized controlled clinical trials represent the fastest way to determine if a drug is effective
- Randomize as early as possible in development to avoid potentially misleading and uninterpretable findings from open-label trials
- Employ methods to limit time on placebo (e.g., dose-response, delayed start, randomized withdrawal, interim analysis)
- Report early trial results accurately, post hoc analyses of failed trials are generally hypothesis generating for next trial, not evidence to support approval
- Knowledge of natural history of disease critical to intelligent design of clinical trials for FDA approval of a rare disease.
- Conduct natural history trials before clinical trials begin
- If a natural history external control group is proposed, it should be identified prospectively to ensure comparability to treatment group
- Natural history external control group created post hoc is very difficult to interpret, unless effect of test drug is very large, due to known and unknown confounding
- Use of accelerated approval pathway should be prospectively planned, NOT as a “rescue” for a failed program Sponsor and FDA should agree on the surrogate and drug effect considered “reasonably likely” to predict clinical benefit before un-blinding data
- Just “Any” effect of a drug on a biomarker is not a basis for accelerated approval
- Ideally, the confirmatory trial to further define clinical benefit should be started before AA is granted to ensure the trial will be completed in a timely manner
- FDA encourages the engagement of patients and caregivers in helping to design development programs that will result in drugs that provide meaningful clinical benefit to those with disease
- Approval decisions must be based on data from adequate and well-controlled clinical trials, which may include PROs and other patient-derived measures
- Experience of patients enrolled in trials can be very helpful; discordant results between trial data and patient anecdotes are very hard to reconcile
- FDA is obligated in facilitating development of effective and safe drugs for rare diseases
- Upholding statutory standards for approval in face of hopes and desires of patients, families, sponsors, and investors is a very difficult job and a reviewer must separate themselves from non-scientific opinion, in keeping with the FDA’s scientific mission.
On August 8th, 2016, the FDA ruled that electronic smoking devices (like vape pens and e-cigarettes e-cigarettes and other tobacco products like hookahs and premium cigars in the same way it regulates traditional cigarettes and smokeless tobacco making it more difficult for minors to vape, and requiring scientific reviews of some products) in a step to protect public health, all vaping liquids will be considered “tobacco products” and, as such, will not be available to consumers under 18 years of age.
Going forward, the FDA will be able to evaluate new tobacco/vaping products not yet on the market, help prevent misinforming claims by tobacco product makers, evaluate the components of tobacco products and how they are made, and communicate the potential dangers of tobacco products
E-cigarette use among adults has gone up about 12.6%, according to Centers for Disease Control and Prevention data from 2014.
Among the adults who tried to quit smoking that year, more than a half had tried e-cigarettes as an alternative, and more than 20% started using them. Only a little more than 3% of people who had never smoked tried them, but what has troubled public health leaders is the news that people between ages 18 and 24 had the highest number of new users.
With the new regulations, people under the age of 18 won’t be able to buy these products in order to prevent lifelong nicotine addiction in America’s young people. The vaping and tobacco products will also have to come in child-resistant containers. Vaping liquids come in flavorings specifically tailored to children including: cookies and cream, atomic fireball candy, and. gummy bears.
Research has showed that e-cigarettes have become a problem for children. This year, the CDC found that e-cigarette use had tripled among teens in just one year, and recent investigation found that teens who used them were more than three times as likely to smoke conventional cigarettes a year later, which is greatly troubling.
In 2014, the CDC found that the number of calls to poison centers about e-cigarettes had risen steeply. Most of those calls involved children under the age of five swallowing the liquid or getting it into their eyes or on their skin.
The new 2016 regulations also mean that the government can have a say in what goes into the products.
Before the 2016 FDA regulation, there was no law mandating that manufacturers tell you what you are inhaling when you try one of their commodities.