Tuesday, February 21, 2017

Constructing stopping rule for safety monitoring

In many early phase clinical trials, if there is a known risk or theoretically potential risk for patients' safety, it is very common that a DSMB (data safety monitoring board) will be established to review the data on a on-going basis. Usually, there is probably a stopping rule for safety - the stopping rule based on the accumulated safety data that is different from the stopping rule for each individual patient.

The stopping rule can be based on the expert's opinion and more commonly can be derived from the statistical standpoint based on the known background rate. Here are some articles about the safety monitoring and the stopping rule for safety:
In fact, an easy way to construct a stopping rule is to utilize the hypothesis testing approach. The idea is to rule out that the observed event rate is higher than the background event rate and is to stop the trial if excessive event rate is observed.

Here is an example from an early phase clinical trial for ischemic stroke where a known risk for the experimental drug is to cause excessive symptomatic intracranial hemorrhage (SICH). The plan is to enroll and dose up to 20 subjects. The literature reviews reveal that the background rate for SICH in ischemic stroke patients is about 10%. We can then construct a stopping rule based on the background rate for SICH of 10%.

The DSMB is empowered to stop the trial whenever they deem fit to protect the safety of patients. DSMB will consider adopting a stopping rule that evaluates the rate of SICH after 5 enrollments, requiring suspension of trial entry if the observed rate of SICH be sufficient to reject the null hypothesis that the true SICH proportion (P) is 10% or less in favor of the (one-sided) alternative hypothesis that the true SCIH proportion is more than 10%. The table below depicts the stopping guidelines. Exact binomial methods are used to compute the p values and confidence limits. One-sided lower 90% confidence limit is calculated.

Number of Subjects Enrolled in the Study
Number of SICH Needed to Reject Null Hypothesis
Observed Rate of SICH (%)
One-sided p values
Lower 90% Confidence Limit
~5
2
40%
0.0815
11.22%
6-10
3
30%
0.0702
11.58%
11-15
4
27%
0.0556
12.18%
16-20
5
25%
0.0432
12.69%

If 2 SICH events are observed in less than and equal to 5 subjects enrolled, the lower confidence limit of 11.22% will be exceeding the 10% background rate. The stopping rule for safety will be triggered and the study should be stopped.

The SAS program for calculating the stopping rule will be something like below. Notice that we obtain two-sided 80% confidence interval in order to obtain one-sided 90% lower limit. Try-and-error method can be employed to find the lowest number of SICHs that will have lower 90% confidence limit exceed the background event rate (10%).

data stopping;
  input scenario SICH $ count;
  datalines;
  1 Have 2
  1 No   3
  2 Have 3
  2 No   7
  3 Have 4
  3 No   11
  4 Have 5
  4 No   15
run;

proc freq data=stopping;
  weight count;
  tables SICH /  binomial (p=0.10) alpha=0.20 cl;
                    **p=0.10 option indicates the background rate to compare with, here we assume the
                        SICH rate of 10%;
                    ** Alpha=0.20 to obtain two-sided 80% confidence interval;
  exact binomial;  *Obtain the exact p-value;
  by scenario;
run;



Sunday, February 12, 2017

Can drug be approved without demonstrating efficacy?

Pharmaceutical industry is assessing the impact of the Trump administration on regulations in drug approval and drug price. It looks like there will be some government intervention on the drug price after all. It is also likely to have some changes in drug approval process, primarily through the reform in FDA.

There have been a lot of buzz around the Trump’s choice for new FDA commissioner. The choice of the new FDA commissioner could be a signal for the future direction in drug regulation. The most discussed candidate is Jim O’Neill and the most discussed topic is his view about the drug approval without efficacy. 

I went to the youtube to find the original speech by Jim O’Neill at a biotech conference. At around 18 minutes, he discussed the ways for speeding up the drug approval process

“...another great, probably better idea is progressive licensing. We should reform the FDA so that there is an approving drug after the sponsor has demonstrated the safety.  Let people start to use them at their own risk, but not much on the safety. Let demonstrate the efficacy after it has been legalized.” 
It is true that FDA may have some bureaucratic practices and has become the roadblock to the drug approval process. A lot of times, FDA is too conservative and too cautious in approving the drugs, this is obvious ever since the Vioxx incidence. Whenever there is any uncertainty (in both safety or efficacy), FDA will rather kill (not approve) a new product. In this way, nobody will blame them for approving an unsafe drug or a drug that is not efficacious. Exceptions are some cases where FDA reluctantly approved the drug because of the pressures from outside (for example, the female Viagra for HSDD in 2015 and eteplirsen for Duchenne Muscular Dystrophy in 2016).  


It is likely that FDA reform is needed to cut bureaucratic red tape that slows the progress of science, reduce the time and cost for bringing the next generation of drugs to the market. However, approving a drug without demonstrating the efficacy (with demonstrating only the safety) will not work. It is jumping from one extreme to another.

As a matter of fact, it is more difficult to demonstrate a drug’s safety than efficacy just because some of the safety signals require a very large sample size to detect. For diabetes drugs, FDA issued a guidance “Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes” with notion that the evaluation is basically based on the meta analysis, not individual study because sample size requirement for detecting the cardiovascular risk is too big for a single trial.

Secondly, if a drug can be marketed without demonstrating the efficacy, the market will be full of the products like the ‘snake oil’ – no harm, but no effect. Wonder who will pay for the cost of these drugs in an era that the health insurance cost has come almost unmanageable?

Thirdly, the safety assessment is usually full of the subjective component in it. The same safety signal could be viewed as critical by some and as not critical or trivial by others. Recently, a new antibiotics, Solithromycin,was not approved by FDA because the data from the pivotal clinical trials indicated more subjects in Solithromycin group had ALT/AST elevations than the control group. However, this imbalance in ATL/AST elevations could be viewed as not critical because the elevations were transient and disappeared after the use antibiotics was stopped. Considering that the use of solithromycin is usually short-term, the risk for solithromycin causing the liver damage can be viewed as a manageable risk. However, FDA declined the approval of solithromycin anyway even at the time that fighting the antibiotics resistant infections was so critical.


My wishful thinking is that FDA will be reformed to speed up the drug approval process by removing some of the regulations, but not go to another extreme to approve a drug without demonstrating the efficacy. To protect the safety of the American people, the clinical trial and drug approval process will remain highly regulated. Even with FDA reform that causes significant reduction in developing time and cost, it will still be a lot more than developing a software.  

Friday, January 20, 2017

the 21st Century Cures Act: Key Provisions

Last week and this week, Hyman, Phelps &McNamara, P.C. gave two excellent webinars to explain the key provisions from the 21st Century Cures Act

The first webinar is about 'Pharmaceutical & Biologics Provisions'. The webinar can be replayed here. The webinar discussed top 13 pharmaceutical & biological issues listed below: 
  • Patient Experience Data (Section 3001)
  • Patient-Focused Drug Development (Sections 3002-3004)
  • Qualification of Drug Development Tools (Section 3011)
  • Priority Review Vouchers (Sections 3013, 3014, & 3086)
  • Human Research Protections (Sections 3023 & 3024)
  • Expanded Access Policies (Section 3032)
  • Limited Population Pathway (Section 3042)
  • Health Care Economic Information (Section 3037)
  • Real World Evidence (Section 3022)
  • Regenerative Advanced Therapies (Sections 3033-3036)
  • Hiring Authority (Section 3072)
  • Targeted Drugs for Rare Diseases (Section 3012)
  • Novel Clinical Trial Designs (Section 3021)


The second webinar is about ‘Combination Products andMedical Device Provisions’. The webinar can be replayed here. The following 11 provision topics were discussed.
  • Combination products (Sec. 3038)
  • Breakthrough devices (Sec. 3051)
  • Humanitarian device exempt. (Sec. 3052)
  • Recognition of standards (Sec. 3053)
  • 510(k) exemptions for Class I/II devices (Sec. 3054)
  • Classification panels (Sec. 3055)
  • Institutional review board (IRB) flexibility (Sec. 3056)
  • CLIA waiver improvements (Sec. 3057)
  • Least burdensome device review (Sec. 3058)
  • Cleaning instructions and validation (Sec. 3059)
  • Clarifying medical software regulation  (Sec. 3060)


Thursday, January 12, 2017

FDA Has Just Released Its Draft Guidance for Industry "Multiple Endpoints in Clinical Trials"

For those who are interested in the design and analysis of clinical trials, FDA has just released its long-anticipated draft guidance for industry: Multiple Endpoints in Clinical Trials. The release has been delayed for about 4 years. I have heard several years ago this guidance has been completed and ready to be released. For example, in a presentation by Dr Huque in 2013, it was mentioned "The Draft Guidance, Multiple Endpoints in Clinical Trials, is near completion.  It is expected to be released soon for public comments."

In contrast, EMA issued its guidance “Points to Consider on Multiplicity Issues in Clinical Trials” more than a decade ago. I believe that EMA is considering to update its guidance and its guidance released in 2002 is obsolete now. This can be reflected in its "Workshop on multiplicity issues in clinical trials" organized in 2012. Perhaps this will be delayed due to Brexit.

Similarly to other statistical heavy FDA guidance (such as the guidance on adaptive design and non-inferiority clinical trials), the guidance "Multiple Endpoints in Clinical Trials" provided a lot of details, not only about the situations the adjustment for multiplicity is needed, but also the various procedures for handling the multiplicity issues.

The next FDA guidance in statistical area should be in missing data and Bayesian clinical trial. For missing data, EMA published its "Guidance on Missing Data in Confirmatory Clinical Trials". FDA sort of relies on the report "the Prevention and Treatment of Missing Data in Clinical Trials" as its general guidance. For Bayesian clinical trials, FDA CDRH division is ahead of CDER/CBER and has published its "Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials". This makes sense since Bayesian approach is more often used in medical device trials and CDRH is more amenable to accepting the Bayesian designs.

Reference:
       RAPS (2016) Multiple Endpoints in Clinical Trials: FDA Issues Draft Guidance

Saturday, January 07, 2017

Exclusion of pregnant women from clinical trial and pregnancy test for women of childbearing potential (WOCBP)

Even though it is encouraged for clinical trials to include the women subjects, the clinical trial protocols commonly (almost always) contain the exclusionary criterion "pregnant and lactating women and women of childbearing potential". The term ‘women of childbearing potential’ may be abbreviated as WOCBP and means ‘pregnable women’. The protocols usually have languages in inclusion or exclusion criteria to exclude the pregnant and lactating women. For women of childbearing potential, they have to have acceptable birth control approaches in order to be included in clinical trials.

Here are some example languages for inclusion / exclusion criteria regarding the WOCBP:
Inclusion criteria:

The subject, if female, is physiologically incapable of childbearing or practicing an acceptable method of birth control (i.e., surgical sterilization, approved hormonal contraceptives, barrier methods [such as a condom or diaphragm] used with a spermicide, or an intrauterine device). For women of childbearing potential, a negative serum pregnancy test will be required at Screening.
If a subject is a female of childbearing potential, she must have a negative result on an approved urine pregnancy test at the time of screening, and must agree to practice contraception by a method of proven reliability (includes abstinence) for the duration of the study.
Exclusion criteria:

Females of childbearing age who have not used or do not plan to use acceptable birth control measures, for the duration of the study. Oral, injected or implanted hormonal contraceptive, barrier methods (condom or diaphragm with spermicide), intrauterine device, surgical sterilization, transdermal delivery, congenital sterility or sexual abstinence are considered acceptable forms of birth control. If sexually active the subject must have been using one of the accepted birth control methods at least one months prior to study entry;

The language regarding the exclusion of pregnancy women from clinical trials apparently derived from the Food and Drug Administration's Guidelines for researchers. While the Guidelines are not legally binding, research conducted in accordance with the Guidelines qualifies for FDA consideration in a New Drug Application, and most investigators take the Guidelines seriously.

FDA guidance (1977) General Considerations for the Clinical Evaluation of Drugs has a specific chapter about the “Women of Childbearing Potential”
A woman of childbearing potential is defined as a premenopausal female capable of becoming pregnant. This includes women on oral, injectable, or mechanical contraception; women who are single; women whose husbands have been vasectomized or whose husbands have received or are utilizing mechanical contraceptive devices. Women in certain institutions, e.g., prisions, although of childbearing potential, could be considered as not in the appropriate environment to become pregnant during administration of an investigational drug. However, women in mental institutions could become pregnant.

In general, women of childbearing potential should be excluded from the earliest dose ranging studies. If adequate information on efficacy and relative safety has been amassed during Phase II, women of childbearing potential may be included in further studies provided Segment II and the female part of Segment I of the FDA Animal Reproduction Guidelines have been completed. All three Segments should be completed before large-scale clinical trials are initiated in women of childbearing potential.
In some cases, women of childbearing potential may receive investigational drugs in the absence of adequate reproduction studies in animals. These include, for example, the use of the drug as a life-saving or life-prolonging measure; use of a drug belonging to a class of compounds (e.g., anti-metabolites) where a teratogenic potential has already been established in animals; use of women who have been institutionalized for a time period adequate to establish a non-pregnant state.
When an investigational drug is used in a woman of childbearing potential for treatment of a serious disease and animal reproduction studies have not been performed, the lack of reproduction studies should be pointed out and fully informed consent should be obtained.

Pregnancy tests should be performed prior to introduction of the investigational drugs and the patient should be advised about suitable contraceptive measures.

For drugs that are absorbed systemically, transplacental passage and secretion in milk of the drug should be assumed until proven otherwise. Fetal follow-up should be carried out in women who become pregnant while on the drug. Excretion of the drug or its metabolites in the milk of lactating women should be determined, when feasible, prior to use of the drug in nursing mothers.
National Academy Press (1999) Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies. Chapter :11 Impact of Current Federal Regulations on the Inclusion of Female Subjects in Clinical Studies had extensive discussion about the exclusion of pregnant women. It also mentioned the following:
The head of the FDA's Office on Drug Evaluation, Dr. Robert Temple, maintains that the Guidelines should not be interpreted by researchers to require the exclusion of women from protocols. This observation is a welcome one, but apparently it has not been widely disseminated and is not widely shared by researchers.
Excluding the pregnant women from clinical trials may also be driven by the fears of the liability issues. The clinical trial sponsors usually don’t want to deal with the potential effect on the pregnancy by the investigational drug. The risk of liability issue is much greater than benefit of including the pregnant women in the clinical trials.

We expect that it will remain as the norm for clinical trials to exclude the pregnant women (and the lactating women).

The pregnancy test at the screening can identify the female subjects who are pregnant. The pregnancy tests are usually performed periodically throughout the study to make sure that any pregnancy during the study can be caught as early as possible. Once study subjects are found to be pregnant, they will be immediately discontinued for the study drug. The subsequent study assessments will also usually not be performed (for efficacy analysis purpose, the missing data will be created). The new pregnancy will be reported using the pregnancy registration form. I have a blog article about this topic a while ago. “Report pregnancies in clinical trials

I remembered the discussions with my colleagues about some of the issues related to the pregnancy test:

Is there an age cut point for childbearing potential? 
For a study including pediatric subjects, we were debating what would be the appropriate age cut point so that the pregnancy test would not be needed for girls below the age cut point because they would not be considered as ‘childbearing potential”. We could not decide on an age cut point. There is also no age limit in the childbearing potential definition in FDA’s guidance. Essentially, for all female subjects (regardless of the age), the pregnancy were tested.
Should the information about pregnancies of female partners of male subjects in clinical trial be collected?
In another time, we were debating whether or not the information about pregnancies of female partners of male subjects should be collected. While this topic has been raised and discussed, the norm at this point is still not to collect. First Clinical Research website has a discussion about this topic.

Thursday, December 22, 2016

Control for Type I Error (or Adjustment for Multiplicity) for Secondary Endpoints

In clinical trial protocols, we usually specify one or more primary efficacy endpoints, then a list of secondary efficacy endpoints, and then more tertiary endpoints or exploratory endpoints. It is pretty standard that the primary efficacy endpoints are those the hypothesis testing or inferential statistics and sample size estimation are based on. If we have more than one primary efficacy endpoints, we will need to adjust for multiple tests or multiplicity. It is also clear that the tertiary or exploratory endpoints are for hypothesis generating or more bluntly for fishing expedition.  

Questions we are asked very often are:
  • For secondary efficacy endpoints, do we need to do formal hypothesis testing?
  • If so, do we need to adjust for multiple tests and multiplicity?
  • What is the purpose of controlling the type I error for secondary efficacy endpoints?  

While controlling Family Wise Error Rate (FWER) for primary efficacy endpoints (if multiple test situation exists) is necessary, controlling FWER for secondary efficacy endpoints is often questioned.

Controlling the FWER for secondary efficacy endpoints is valuable or is necessary if we are planning to include the secondary efficacy endpoints in the product label if the product is approved. In other words, if we would like to make the claim of the benefits based on the secondary efficacy endpoints. It is advisable to perform the formal hypothesis testing with controlling for FWER.

In FDA’s guidance for industry “Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products — Content and Format”, there is a statement about the primary and secondary endpoints:
§   Primary and Secondary Endpoints: The terms primary endpoint and secondary endpoint are used so variably that they are rarely helpful. The appropriate inquiry is whether there is a well-documented, statistically and clinically meaningful effect on a prospectively defined endpoint, not whether the endpoint was identified as primary or secondary.
FDA does not care whether or not a study endpoint is called primary or secondary. However, if the information from these endpoints are used for supporting evidence and for product label, the endpoints need to be predefined and tests for these endpoints need to be controlled for the overall alpha or overall type I error.

Even though FDA does not care about the terminology of primary/secondary endpoints, it is still very common in practice that the clinical trials (especially the industry-sponsored clinical trials) specify primary, secondary, and exploratory endpoints.

In a presentation by Kathleen Fritsch from FDA “Multiplicity Issues in FDA-Reviewed Clinical Trials”, the difference between primary, secondary, and exploratory efficacy endpoints are clearly specified and it is stated that the secondary efficacy endpoints may be included in the product label if multiplicity issue is addressed.



It is not needed or rarely needed to control for FWER for exploratory efficacy endpoints.

In EMA’s guidance “Points to Consider on Multiplicity Issues in Clinical Trials”, adjustment for multiplicity is explicitly required if the secondary variables are used for additional claims.





A slide presentation regarding EMA guidance further explained the secondary efficacy endpoints for claims.

In FDA’s guidance on “Clinical Investigations of Devices Indicated for the Treatment of Urinary Incontinence”, the secondary endpoints were called out:

                Secondary Endpoints
      FDA believes secondary endpoint measures, by themselves, are not sufficient to characterize fully the treatment benefit. However, these measures may provide additional characterization of the treatment effect. Specifically, secondary endpoints can:

  • supply background and understanding of the primary endpoints, in terms of overall direction and strength of the treatment effect;
  • be the individual components of a composite primary endpoint, if used;
  • include variables for which the study is underpowered to definitively assess;
  • aid in the understanding of the treatment’s mechanism of action;
  • be associated with relevant sub-hypotheses (separate from the major objective of the treatment); or
  • be used to perform exploratory analyses.

       Assuming that the primary safety and effectiveness endpoints of the study are successfully met, we recommend you analyze the secondary endpoints to provide supportive evidence concerning the safety and effectiveness of the device, as well as to support descriptions of device performance in the labeling. To minimize bias, your protocol should prospectively identify all secondary endpoints, indicating how the data will be analyzed and what success criteria will be applied.
 Secondary Endpoint Analyses
We recommend your protocol prospectively define the statistical plan for performing secondary endpoint analyses in the event that the primary endpoint analysis has been successfully met. If the secondary endpoint analyses are intended purely as exploratory analyses, or are not intended to support the indication for use or device performance, we recommend you submit only simple descriptions of the analyses. If, on the other hand, any of the secondary endpoint analyses are intended to support the indication for use or the performance of your device in the labeling (e.g., comparing treatment and control groups using p-values or confidence intervals), we recommend you pre-specify this intention in your study protocol and describe in detail the statistical methods you plan to follow.
In summary, if we don’t perform the hypothesis testing for these secondary endpoints or not having appropriate control for overall type I error, we will lose the chance to claim the benefit on the secondary endpoints and to list secondary endpoints into the product label. Therefore, it is always a wise decision to perform the hypothesis testing for secondary endpoints with appropriate control for type I error. 

Tuesday, December 20, 2016

the 21st Century Cures Act and Innovations in Clinical Trials

After the bill passed through house and senator, the president Obama signed the bill into law on December 13, 2016. The 21st Century Cures Act is now officially a law in effect.

If you have trouble to find the final version of the cures act, Here is the one signed into the law by the President Obama.

H.R.34 - 21st Century Cures Act

The NPR has a good summary of "who wins and who loses with the 21st Century Cures Act".
The 21st Century Cures Act will greatly benefit the NIH and NCI. Here is a latest article published in New England Journal of Medicine regarding NIH's perspectives on the Act.

The 21st Century Cures Act — A View from the NIH


Some sections in this act are very relevant to design and analysis of clinical trials. The section 3021 calls out the adaptive design and other novel clinical trial designs. 

SEC. 3021. Novel clinical trial designs.(a) Proposals for use of novel clinical trial designs for drugs and biological products.—For purposes of assisting sponsors in incorporating complex adaptive and other novel trial designs into proposed clinical protocols and applications for new drugs under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) and biological products under section 351 of the Public Health Service Act (42 U.S.C. 262), the Secretary of Health and Human Services (referred to in this section as the “Secretary”) shall conduct a public meeting and issue guidance in accordance with subsection (b).
(b) Guidance addressing use of novel clinical trial designs.—
(1) IN GENERAL.—The Secretary, acting through the Commissioner of Food and Drugs, shall update or issue guidance addressing the use of complex adaptive and other novel trial design in the development and regulatory review and approval or licensure for drugs and biological products.
(2) CONTENTS.—The guidance under paragraph (1) shall address—
(A) the use of complex adaptive and other novel trial designs, including how such clinical trials proposed or submitted help to satisfy the substantial evidence standard under section 505(d) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(d));
(B) how sponsors may obtain feedback from the Secretary on technical issues related to modeling and simulations prior to—
(i) completion of such modeling or simulations; or
(ii) the submission of resulting information to the Secretary;
(C) the types of quantitative and qualitative information that should be submitted for review; and
(D) recommended analysis methodologies.
(3) PUBLIC MEETING.—Prior to updating or issuing the guidance required by paragraph (1), the Secretary shall consult with stakeholders, including representatives of regulated industry, academia, patient advocacy organizations, consumer groups, and disease research foundations, through a public meeting to be held not later than 18 months after the date of enactment of this Act.
(4) TIMING.—The Secretary shall update or issue a draft version of the guidance required by paragraph (1) not later than 18 months after the date of the public meeting required by paragraph (3) and finalize such guidance not later than 1 year after the date on which the public comment period for the draft guidance closes.




















The act specifies that the real world evidence can be used to support the drug approval where Real world evidence means data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.

The act creates a new pathway for medical device - breakthrough medical device - a similar pathway for breakthrough drug. 

The act specified the importance of the biomarker in drug approval process where biomarker “(A) means a characteristic (such as a physiologic, pathologic, or anatomic characteristic or measurement) that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to a therapeutic intervention; and


“(B) includes a surrogate endpoint.

The act contains a section for "targeted drugs for rare diseases"

SEC. 3012. Targeted drugs for rare diseases.Subchapter B of chapter V of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360aa et seq.) is amended by inserting after section 529 the following:
“SEC. 529A. Targeted drugs for rare diseases.“(a) Purpose.—The purpose of this section, through the approach provided for in subsection (b), is to—
“(1) facilitate the development, review, and approval of genetically targeted drugs and variant protein targeted drugs to address an unmet medical need in one or more patient subgroups, including subgroups of patients with different mutations of a gene, with respect to rare diseases or conditions that are serious or life-threatening; and
“(2) maximize the use of scientific tools or methods, including surrogate endpoints and other biomarkers, for such purposes.
“(b) Leveraging of data from previously approved drug application or applications.—The Secretary may, consistent with applicable standards for approval under this Act or section 351(a) of the Public Health Service Act, allow the sponsor of an application under section 505(b)(1) of this Act or section 351(a) of the Public Health Service Act for a genetically targeted drug or a variant protein targeted drug to rely upon data and information—
“(1) previously developed by the same sponsor (or another sponsor that has provided the sponsor with a contractual right of reference to such data and information); and
“(2) submitted by a sponsor described in paragraph (1) in support of one or more previously approved applications that were submitted under section 505(b)(1) of this Act or section 351(a) of the Public Health Service Act,
for a drug that incorporates or utilizes the same or similar genetically targeted technology as the drug or drugs that are the subject of an application or applications described in paragraph (2) or for a variant protein targeted drug that is the same or incorporates or utilizes the same variant protein targeted drug, as the drug or drugs that are the subject of an application or applications described in paragraph (2).“(c) Definitions.—For purposes of this section—
“(1) the term ‘genetically targeted drug’ means a drug that—
“(A) is the subject of an application under section 505(b)(1) of this Act or section 351(a) of the Public Health Service Act for the treatment of a rare disease or condition (as such term is defined in section 526) that is serious or life-threatening;
“(B) may result in the modulation (including suppression, up-regulation, or activation) of the function of a gene or its associated gene product; and
“(C) incorporates or utilizes a genetically targeted technology;
“(2) the term ‘genetically targeted technology’ means a technology comprising non-replicating nucleic acid or analogous compounds with a common or similar chemistry that is intended to treat one or more patient subgroups, including subgroups of patients with different mutations of a gene, with the same disease or condition, including a disease or condition due to other variants in the same gene; and
“(3) the term ‘variant protein targeted drug’ means a drug that—
“(A) is the subject of an application under section 505(b)(1) of this Act or section 351(a) of the Public Health Service Act for the treatment of a rare disease or condition (as such term is defined in section 526) that is serious or life-threatening;
“(B) modulates the function of a product of a mutated gene where such mutation is responsible in whole or in part for a given disease or condition; and
“(C) is intended to treat one or more patient subgroups, including subgroups of patients with different mutations of a gene, with the same disease or condition.
“(d) Rule of construction.—Nothing in this section shall be construed to—
“(1) alter the authority of the Secretary to approve drugs pursuant to this Act or section 351 of the Public Health Service Act (as authorized prior to the date of enactment of the 21st Century Cures Act), including the standards of evidence, and applicable conditions, for approval under such applicable Act; or
“(2) confer any new rights, beyond those authorized under this Act or the Public Health Service Act prior to enactment of this section, with respect to the permissibility of a sponsor referencing information contained in another application submitted under section 505(b)(1) of this Act or section 351(a) of the Public Health Service Act.”.