Expanded Access Clinical Trial

EXPANDED ACCESS PROTOCOL

DR.SIDDHARTH

KAMERKAR

2

The first step of performing a clinical trial is to prepare a protocol.

It is the written action plan for the clinical trial.

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As defines by ICH GCP guideline, Protocol is a document that describes the objectives, design , methodology, statistical considerations and organization of a trial.

Most human use of investigational new drugs takes place in controlled clinical trials conducted to assess safety and efficacy of new drugs. Sometimes, patients do not qualify for these carefully-controlled trials because of other health problems, age, or other factors. For patients who may benefit from the drug use but don't qualify for the trials, FDA regulations enable manufacturers of investigational new drugs to provide for "expanded access" use of the drug

Definition

The US National Cancer Institute (NCI) describes an expanded access trial as a way to provide an investigational therapy to a patient who is not eligible to receive that therapy in a clinical trial, but who has a serious or life-threatening illness for which other treatments are not available.

The primary intent of a treatment IND/protocol is to provide for access to the new drug for people with a life-threatening or serious disease for which there is no good alternative treatment. A secondary purpose for a treatment IND/protocol is to generate additional information about the drug, especially its safety.

Expanded access protocols can be undertaken only if clinical investigators are actively studying the new treatment in well-controlled studies, or all studies have been completed. There must be evidence that the drug may be an effective treatment in patients like those to be treated under the protocol. The drug cannot expose patients to unreasonable risks given the severity of the disease to be treated.

Expanded access protocols are generally managed by the manufacturer, with the investigational treatment administered by researchers or doctors in office-based practice.

Concerned health professionals and consumers alike have long maintained that even though possibly important new drugs or biologicals haven't yet completed the complex and often lengthy path to FDA approval, physicians should nonetheless be able to use them in willing patients who can't benefit from established therapy.

Listening to concerns

Perception that FDA was inconsistent in application of the procedures– inequitable access, decisions arbitrary

Perception that broader access will confer health benefits

Perception that available mechanisms favored certain diseases

In 1987, FDA changed its regulations on investigational new drugs (INDs) to specifically authorize treatment use of such agents

FDA developed and issued in May 1987 regulations codifying the circumstances under which Treatment INDs can be granted. While the purpose is to make promising investigational drugs available as early as possible to patients with serious or immediately life-threatening diseases, the Treatment IND regulations also ensure that, despite possibly extensive treatment use of an investigational agent, carefully controlled trials will go forward to demonstrate the drug's safety and effectiveness.

Patients/physicians may have access to investigational devices under one of four main mechanisms by which FDA may make an unapproved device available:

Emergency Use Compassionate Use (or Single Patient/Small Group

Access) Treatment Use Continued Access

Emergency Use

Emergency situations may arise in which there will be a need to use an investigational device in a manner inconsistent with the approved investigational plan or by a physician who is not part of the clinical study. Emergency use of an unapproved device may occur before an IDE is approved.

1.Life-threatening or serious disease or condition 2.No alternative 3.No time to obtain FDA approval

Time-frame: Before or after initiation of the clinical trial

Criteria:

1.There are special cases under emergency research in which the human subject is in a life-threatening situation and it is not feasible to obtain informed consent.

2. In order to allow such research to proceed, special provisions for exception from informed consent requirements must be met.

3. In addition, the IRB and a physician not participating in the investigation must review and approve the investigation. The sponsor must also submit a separate IDE application to FDA.

FDA has permitted the emergency use of unapproved, investigational products for many years. Under the general rubric "compassionate use," the agency has permitted sponsors of investigational agents to provide them to doctors not involved in controlled clinical trials for use in individual patients who might be helped by the treatment.

The compassionate use provision allows access for patients who do not meet the requirements for inclusion in the clinical investigation but for whom the treating physician believes the device may provide a benefit in treating and/or diagnosing their disease or condition. This provision is typically approved for individual patients but may be approved to treat a small group

Compassionate Use (or Single Patient/Small Group Access

Criteria:

Serious disease or condition No alternative

Time-frame: During clinical trial

Prior FDA approval is needed before compassionate use occurs. In order to obtain Agency approval, the sponsor should submit an IDE supplement requesting approval for a protocol deviation under section §812.35(a) in order to treat the patient.

•The physician should not treat the patient identified in the supplement until FDA approves use of the device under the proposed circumstances.• In reviewing this type of request, FDA will consider the above information as well as whether the preliminary evidence of safety and effectiveness justifies such use and whether such use would interfere with the conduct of a clinical trial to support marketing approval.

If the request is approved, the attending physician should devise an appropriate schedule for monitoring the patient, taking into consideration the investigational nature of the device and the specific needs of the patient. The patient should be monitored to detect any possible problems arising from the use of the device. Following the compassionate use of the device, a follow-up report should be submitted to FDA as an IDE supplement in which summary information regarding patient outcome is presented. If any problems occurred as a result of device use, these should be discussed in the supplement and reported to the reviewing IRB as soon as possible.

The above compassionate use criteria and procedures can also be applied when a physician wishes to treat a few patients rather than an individual patient suffering. In this case, the physician should request access to the investigational device through the IDE sponsor. The sponsor should submit an IDE supplement that includes the information identified above and indicates the number of patients to be treated. Such a supplement should include the protocol to be followed or identify deviations from the approved clinical protocol. As with single patient compassionate use, a monitoring schedule should be designed to meet the needs of the patients while recognizing the investigational nature of the device. Follow-up information on the use of the device should be submitted in an IDE supplement after all compassionate use patients have been treated.

An approved IDE specifies the maximum number of clinical sites and the maximum number of human subjects that may be enrolled in the study. During the course of the clinical trial, if the data suggests that the device is effective, then the trial may be expanded to include additional patients with life-threatening or serious diseases.

Treatment Use

A device that is not approved for marketing may be under clinical investigation for a serious or immediately life- threatening disease or condition in patients for whom no comparable or satisfactory alternative device or other therapy is available. During the clinical trial or prior to final action on the marketing application, it may be appropriate to use the device in the treatment of patients not in the trial under the provisions of the treatment investigational device exemptions (IDE) regulation. (§812.36)

What are purpose of treatment IND?

The primary intent of a treatment IND/protocol is to provide for access to the new drug for people with a life-threatening or serious disease for which there is no good alternative treatment.

A secondary purpose for a treatment IND/protocol is to generate additional information about the drug, especially its safety

FDA would consider the use of an investigational device under a treatment IDE if: •The device is intended to treat or diagnose a serious or immediately life-threatening disease or condition; •There is no comparable or satisfactory alternative device or other therapy available to treat or diagnose that stage of the disease or condition in the intended patient population; •The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or such clinical trials have been completed; •The sponsor of the investigation is actively pursuing marketing approval/clearance of the investigational device with due diligence.

Criteria:

•Life-threatening or serious disease •No alternative •Controlled clinical trial •Sponsor pursuing marketing approval Time-frame: During clinical trial

There are four requirements that must be met before a treatment IND can be issued:

the drug is intended to treat a serious or immediately life-threatening

disease; there is no satisfactory alternative treatment available; the drug is already under investigation, or trials have been completed;

and the trial sponsor is actively pursuing marketing approval. These trials are particularly important in therapeutic areas such as

HIV/AIDS and Cancer.

FDA action on treatment IDE applicationsApproval of treatment IDE'sTreatment use may begin 30 days after FDA receives the treatment IDE submission. FDA may notify the sponsor in writing earlier than the 30 days that the treatment use may or may not begin. FDA may approve the treatment use as proposed or approve it with modifications

Notice of disapproval or withdrawalIf FDA disapproves or proposes to withdraw approval of a treatment IDE, FDA will follow the procedures set forth in the IDE regulations [§812.30(c)]

The first class of drugs beta-blocking agents During the mid-1970s, many thousands of patients

were treated with beta blockers for advanced, life-threatening heart and lung conditions for which no effective alternative treatment existed. In one instance, more than 600 cardiologists treated some 20,000 patients with the anti-arrhythmic drug amiodarone before it was approved for marketing as Cordarone in late 1985

zidovudine, Phase 2 trials to assess the drug's safety and effectiveness began in February 1986

These studies were abruptly halted in September 1986 when it was discovered that 19 patients receiving placebo had died, while only one death had occurred among those receiving AZT. Within a week of receiving this information, FDA authorized a treatment protocol for AZT. As a result, more than 4,000 AIDS patients were treated with AZT before its approval as the first anti-AIDS drug under the brand name Retrovir in March 1987

The regulations reiterate the requirement that, as with all clinical use of investigational drugs, informed patient consent must be obtained, and the product cannot be promoted or otherwise commercialized. FDA also requires that a product administered under a Treatment IND must be under (or have completed) active clinical investigation, and its sponsor must be pursuing marketing approval with "due diligence

A treatment IDE application must include, in the following order:

The name, address, and telephone number of the sponsor of the treatment IDE;

The intended use of the device, the criteria for patient selection, and a written protocol describing the treatment use;

An explanation of the rationale for use of the device, including, as appropriate, either a list of the available regimens that ordinarily should be tried before using the investigational device or an explanation of why the use of the investigational device is preferable to the use of available marketed treatments;

A description of clinical procedures, laboratory tests, or other measures that will be used to evaluate the effects of the device and to minimize risk;

Written procedures for monitoring the treatment use and the name and address of the monitor; Instructions for use for the device and all other labeling as required under section §812.5(a) and

(b); Information that is relevant to the safety and effectiveness of the device for the intended

treatment use. Information from other IDE's may be incorporated by reference to support the treatment use;

A statement of the sponsor's commitment to meet all applicable responsibilities under the IDE regulations (21 CFR 812) and Institutional Review Boards regulations (21 CFR 56) and to ensure compliance of all participating investigators with the informed consent requirements of 21 CFR 50;

An example of the agreement to be signed by all investigators participating in the treatment IDE and certification that no investigator will be added to the treatment IDE before the agreement is signed; and

If the device is to be sold, the price to be charged and a statement indicating that the price is based on manufacturing and handling costs only

Information that is relevant to the safety and effectiveness of the device for the intended treatment use. Information from other IDE's may be incorporated by reference to support the treatment use;

A statement of the sponsor's commitment to meet all applicable responsibilities under the IDE regulations (21 CFR 812) and Institutional Review Boards regulations (21 CFR 56) and to ensure compliance of all participating investigators with the informed consent requirements of 21 CFR 50;





Safeguards Treatment use of an investigational device

is conditioned upon the sponsor and investigators complying with the safeguards of the IDE process and the regulations governing informed consent (21 CFR 50) and institutional review boards (21 CFR 56).

1. The required criteria [§812.36(b)] are not met or the treatment IDE application does not contain the required information [§812.36(c)];

2. FDA determines that any of the grounds for disapproval or withdrawal of approval apply [§812.30(b)(1) through (b)(5)]. See Approval Process, FDA Actions, for additional information;

3. The device is intended for a serious disease or condition and there is insufficient evidence of safety and effectiveness to support such use;

4. The device is intended for an immediately life-threatening disease or condition and the available scientific evidence, taken as a whole, fails to provide a reasonable basis for concluding that the device: 1. may be effective for its intended use in its

intended population; or 2. would not expose the patients to whom the

device is to be administered to an unreasonable and significant additional risk of illness or injury;

FDA may disapprove or withdraw approval of a treatment IDE if:

5. There is reasonable evidence that the treatment use is impeding enrollment in, or otherwise interfering with the conduct or completion of, a controlled investigation of the same or another investigational device;

6. The device has received marketing approval/clearance or a comparable device or therapy becomes available to treat or diagnose the same indication in the same patient population for which the investigational device is being used;

7. The sponsor of the controlled clinical trial is not pursuing marketing approval/clearance with due diligence;

8. Approval of the IDE for the controlled clinical investigation of the device has been withdrawn; or

9. The clinical investigator(s) named in the treatment IDE are not qualified by reason of their scientific training and/or experience to use the investigational device for the intended treatment use.

Ethical concerns make it difficult for physicians to withhold a promising investigational drug that might forestall severe disability or death. But if the study that showed promise was not well-designed--if, for example, there was no control group--what looked like favorable results may prove to be an illusion. in the case of ganciclovir, an anti-viral drug used to treat an eye infection in AIDS patients

Early suggestions of ganciclovir's effectiveness led to wide use before controlled clinical trials ever started.

approval of ganciclovir was almost certainly delayed for years by the lack of appropriate, controlled clinical investigation

FDA has indicated, for purposes of Treatment INDs, what constitutes serious or immediately life-threatening illness, what scientific information about the drug's safety and potential usefulness must be in hand, and how physicians can obtain investigational drugs for treatment use.

The sponsor of a treatment IDE must submit progress reports on a semi-annual basis to all reviewing IRB's and FDA until the filing of a marketing application. The date of these reports are based on the period of time since initial approval of the treatment IDE. After filing of a marketing application, progress reports must be submitted annually in accordance with the IDE regulation.

The progress report must also include

•the number of patients treated with the device under the treatment IDE

•, the names of the investigators participating in the treatment IDE,

• and a brief description of the sponsor's efforts to pursue marketing approval/ clearance of the device.

The sponsor of a treatment IDE is responsible for submitting all other reports required under §812.150 (Reports), such as unanticipated adverse device effects and final reports. The reports are submitted as supplements to the original IDE application.

As of August 1994, 29 agents had been granted Treatment IND status. The conditions for which they have been used include AIDS and its complications, control of infection in kidney transplant patients, severe obsessive-compulsive disorder, Alzheimer's disease, severe Parkinson's disease, various advanced cancers, and respiratory distress syndrome in premature infants. At press time, 24 of these drugs had been approved by FDA and are on the market

Continued Access

FDA may allow continued enrollment of subjects after the controlled clinical trial under an IDE has been completed in order to allow access to the investigational medical device while the marketing application is being prepared by the sponsor or reviewed by FDA.

•Public health need or •Preliminary evidence that the

devcie will be effective and •there are no significant safety

concerns

Time-frame: After completion of the clinical trial

Criteria:

The sponsor of a clinical investigation is permitted to continue to enroll subjects while a marketing application is being prepared by the sponsor and/or reviewed by the Agency if there is:

1. A public health need for the device; or 2. Preliminary evidence that the device is likely to be

effective and no significant safety concerns have been identified for the proposed indication.

The continued enrollment of subjects in an investigation while a marketing application is being prepared by the sponsor and/or reviewed by ODE is known as an "extended investigation." Extended investigations permit patients and/or physicians continued access to the devices while also allowing the collection of additional safety and effectiveness data to support the marketing application or to address new questions regarding the investigational device. The Continued Access Policy may be applied to any clinical investigation that meets the criteria identified above; however, it is intended to be applied late in the device development process, i.e., after the controlled clinical trial has been completed.

A sponsor's request for an extended investigation should be submitted as an IDE supplement and include the following information:

A justification for the extension; A summary of the preliminary safety and effectiveness data

generated under the IDE; A brief discussion of the risks posed by the device; The proposed rate of continued enrollment (the number of sites

and subjects); The clinical protocol, if different from that used for the

controlled clinical trial, as well as the proposed objectives for the extended study; and

A brief discussion of the sponsor's progress in obtaining marketing approval/clearance for the device.

Expanded Access Protocol

FDA requires the following: approval by an investigational review

board, informed consent by the patient adherence to the study protocol submission of case report forms a record of drug disposition.

Current Mechanisms/regulations Treatment Use of an IND

§ 312.34 Emergency Use of an IND

§ 312.36 Promotion and Charging for INDs

§ 312.37 Others:

– parallel track, open protocols, extension protocols, single patient IND

Caveats

Expanded access should not interfere with drug development

Data from access studies:– should be collected

– not be overly burdensome Need for protection of human subjects

FDAMA Sec. 402 Basic Principles Formalized procedures Clear, simple Equitable, non-arbitrary application Opportunity should be available to anyone

with life threatening or seriously debilitating illness for which no, effective, approved therapy available– includes knowledge of availability

402 - dissemination

Secretary may inform medical profession, health associations about the availability of investigational products under expanded access protocols

A licensed practitioner who receives an investigational device for treatment use under a treatment IDE is an "investigator" under the IDE and is responsible for meeting all applicable investigator responsibilities under 21 CFR 812, 21 CFR 50, and 21 CFR 56.

Objectives

Identify federal regulations related to investigational drugs, devices and biologics

Discuss criteria for when an IND is required Discuss criteria for when an IDE is required Discuss the regulations related to humanitarian

use devices Discuss expanded access of investigational drugs

and devices (“compassionate uses”)

Applicable FDA Regulations21 CFR

Part 50: Protection of Human Subjects Part 56: Institutional Review Boards Part 312: Investigational New Drug (IND) Part 314: Application for FDA Approval to Market

New Drug Part 361: Radioactive Drugs Part 601: Biologics Licensing Part 803: Medical Device Reporting Part 812: Investigational Device Exemption (IDE) Part 814: Premarket Approval of Medical Devices &

the Humanitarian Use Device

Waiver of Informed Consent

FDA regulations do not provide for waiver of informed consent like Common Rule

Two exceptions:– Emergency use– Emergency research

When IRB Review is Required21 CFR §56.103

Any clinical investigation as defined in Parts 312 and 812 may not begin without prior IRB approval and must be subject to continuing review

FDA may decide not to consider data collected in support of a research or marketing application when no IRB approval

Exemptions from IRB Review21 CFR §56.104

Following clinical investigations are exempt from Part 56– Any investigation commenced prior to July 27,

1981, and subject to IRB requirements in effect at that time

– Emergency use of a test article– Taste and food quality evaluations and

consumer acceptance studies

Investigational New Drugs 21 CFR Part 312

Subpart A – General Provisions Subpart B – Investigational New Drug Application Subpart C – Administrative Actions Subpart D – Responsibilities of Sponsors and

Investigators Subpart E – Drugs Intended to Treat Life-

Threatening and Severely-Debilitating Illnesses Subpart F - Miscellaneous

FDA Device Advice:Device Classes

Class I or II: exempt or 510(K) “clearance”– Most Class I are exempt by the FDA– Some Class II are exempt; most require 510(k) clearance

» 510(k) means the device is “substantially similar” to a predicate device (one in commerce prior to May 28, 1976)

» 510(k) clearance is not FDA approval, but clears a device for marketing

» Obtain 510(k) clearance by submitting Premarket Notification to FDA

» In some cases, clinical investigations will be used to support a 510(k) application (IDE needed)

FDA Device Advice:Device Classes

Class III: used in supporting or sustaining human life or preventing impairment of human health, or that present a potential unreasonable risk of illness or injury– Cannot market without Premarket Approval

(PMA) by the FDA– PMA requires establishment of device’s safety

and efficacy through clinical trials– Investigational Device Exemption (IDE) permits

shipment for purpose of investigation

IDE Requirements 21 CFR §812.2

Generally, need an IDE whenever conducting a clinical investigation of a device that is not “exempt” from IDE requirements– Conducting a clinical investigation of an unapproved

Class III device

– Unapproved Class II device found not substantially equivalent to a predicate device and cannot be reclassified to Class I

– Clinical investigation of approved or cleared device when use is not consistent with labeling

Exempted Investigations 21 CFR §812.2(c)

The following are exempt from the IDE requirement:– A device that was in commercial distribution

prior to May 28, 1976 when used consistent with labeling (“predicate device”)

– A device in commercial distribution on or after May 28, 1976 that FDA has determined to be substantially equivalent to predicate device when used consistent with labeling (“510(k) clearance”)

Exempted Investigations 21 CFR §812.2(c)

A diagnostic device if the testing:– Is noninvasive– Does not require an invasive sampling procedure

that presents significant risk– Does not by design or intention introduce energy

into a subject, and– Is not used as a diagnostic procedure without

confirmation of the diagnosis by another medically established diagnostic product or procedure

FDA 2006 Guidance on Informed Consent for In Vitro Diagnostic Device Studies

Studies that are exempt from IDE requirements still need IRB review and informed consent of subject

FDA has decided to exercise enforcement discretion with respect to informed consent requirements for in vitro diagnostic device

No informed consent required if: – Study uses leftover specimens not collected for this research– Specimens are not identifiable to investigator or sponsor– Individuals caring for patients are not part of research – IRB reviewed

“Compassionate Use” or Expanded Access

Treatment IND or IDE Open label protocol Group C treatment IND Parallel track Emergency use

http://www.fda.gov/oc/ohrt/irbs/drugsbiologics.html#emergency

http://www.fda.gov/oc/ohrt/irbs/irbreview.pdf

Treatment IND or IDE21 CFR §312.34, §812.36

Facilitates availability of promising new drugs/devices to desperately ill as early as possible in development

Obtain additional data on safety/efficacy Permits use of drug/device currently under

investigation in treatment of patients not in clinical trials

Must have IRB approval and informed consent

Treatment IND or IDE

Criteria for Treatment IND or IDE:– Serious or immediately life-threatening disease or

condition

– No comparable or satisfactory alternative

– Drug/device under investigation in controlled trial

– Sponsor is actively pursuing marketing approval

Sponsor and investigators must comply with all applicable Parts of FDA regs (IC, IRB review)

FDA 1998 Information Sheet:Drugs and Biologics

“Life-threatening” means diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted, and diseases or condition with potentially fatal outcomes. The criteria for life-threatening do not require the condition to be immediately life-threatening or to immediately result in death. Includes “severely debilitating” which relates to diseases or conditions that cause major irreversible morbitity.

www.fda.gov/oc/ohrt/irbs/drugsbiologics.html


Open label protocol– Usually uncontrolled Phase III– Carried out to obtain additional safety data– Controlled trial has ended and treatment

continued so that subjects can receive drug until marketing is approved

– Require prospective IRB review and consent


Group C treatment IND:– Established by agreement between FDA and NCI

– Distribution of investigational agents to oncologists for treatment of cancer

– Protocol is outside of controlled trial

– Distributed only by NIH under NCI protocol

– Primary objective is treatment, but safety and efficacy data collected

– But not research intent, so FDA has generally waived IRB review requirement


Parallel track– Permits wider access to new drugs for

AIDS/HIV– Separate “expanded access” protocol that

“parallels” controlled trials– Requires IRB review and informed consent

Humanitarian Use Device (HUD)21 CFR §814.100

Medical device that is intended to benefit patients in treatment or diagnosis of disease or condition that affects or is manifested in fewer than 4,000 patients per year

No marketed comparable device Exempt from effectiveness requirements of the PMA Device is approved and may be marketed once it has HUD

designation and Humanitarian Device Exemption (HDE) is submitted

If sponsor wants PMA, must obtain IDE and undergo clinical investigation

Humanitarian Use Device

Use of HUD does not constitute research Thus, FDA does not require research consent Under FDA regs, IRBs must approve use of HUD FDA strongly encourages IRBs to require and

review HUD consent forms Because use of HUD is clinical, may be required

to use hospital standard surgical consent form in addition to more specific IC form

Emergency Uses

21 CFR §50.23 – Exception to informed consent 21 CFR §56.104 – Exception to IRB review 21 CFR §312.36 – Exception to IND requirement 21 CFR §812.35 – Exception to IDE requirement 21 CFR §814.124 – Emergency Use of HUD

Exception to Informed Consent 21 CFR §50.23

Investigator and unaffiliated physician certify in writing:– Life threatening situation requiring use of test article

– Subject cannot communicate or cannot provide legally effective IC

– No time to obtain IC from LAR

– No available alternative that provides equal or greater likelihood of saving subject’s life

If no time to consult unaffiliated physician, get physician review within 5 days of use

Exception to IRB Review21 CFR §56.104

Life-threatening disease or condition No standard acceptable treatment available No sufficient time to obtain IRB approval Notify IRB chair or Director if possible, but

this is not IRB review Notify IRB within 5 working days

Exception to IND or IDE Requirement21 CFR §312.36, §812.35

Life threatening disease or condition Need for investigational drug/device prior to

submission of IND or IDE, or patient does not qualify for current protocol

Generally limited to few patients Notify sponsor who submits report to FDA Must follow patient protection measures if

possible:– Independent assessment by uninvolved physician; IRB

chair concurrence; institutional clearance; informed consent

Emergency Use of HUDFDA 2001 HDE Guidance

HUD may be used off-label in an emergency Physician and HDE holder should follow same

patient protection measures set out for emergency use of an investigational device

Authorization from HDE holder needed prior to use

Physician should submit follow up report to HDE holder and IRB if no prior IRB approval (within 5 working days)

Emergency Research 21 CFR §50.24

Research that is aimed at class of subjects in an emergency (i.e. cardiac arrest, stroke, head trauma)

IRB (which must include one physician) may approve study without requiring informed consent if:– Life-threatening situation, no alternatives, collection of

evidence is necessary to determine safety/efficacy of intervention

– Obtaining informed consent not feasible– Prospect of direct benefit


– Investigation could not practicably be carried out if consent required

– Protocol defines potential therapeutic window (sponsor responsibility) and investigator attempts to contact LAR or family member in that window for consent

– IRB has approved a consent form to be used when feasible

– Additional protections for rights and welfare of subjects:

» Consultation with community members, notice to community of research, and disclosure of results to community

» Establishment of independent DMC


Protocols performed under this section require separate IND or IDE

True even if IND or IDE already exists for same drug/device

IND or IDE must state that some subjects will be unable to provide consent

Issues for consideration

Defining categories– indications not being developed

Evidentiary standards to support each type of access

Procedures Safeguards

– IRB, informed consent

It is clearly too soon to know whether efforts to make drugs and biologics more rapidly and widely available to the desperately ill are contributing to genuine advances in health care. But many thousands of patients who might otherwise be beyond hope are now able to seek help from investigational agents, and all of us stand to gain from a more efficient, more responsive system by which to bring important new agents to market

THE END

THANK YOU

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SOME ISSUES IN DEVELOPING COUNTRIES

Another mechanism to permit wider availability of experimental agents is the "parallel track" policy developed by the U.S. Public Health Service in response to the AIDS epidemic. Under this policy, patients with AIDS whose condition prevents them from participating in controlled clinical trials can receive investigational drugs shown in preliminary studies to be potentially useful. At press time, one drug (D4T) had been made available under the parallel track mechanism. D4T was approved for marketing in mid-1994

Less dramatic, perhaps, than rushing investigational drugs to the desperately ill, but almost certainly of more long-range benefit to society, are measures to streamline FDA's review and approval process and expand the agency's resources for this task

One change FDA has adopted in recent years to speed drug review is categorizing new drugs as either standard or priority. Standard drugs are those that offer only minor improvement (or none) over drugs already on the market. Priority drugs, on the other hand--which may in fact be a new dosage form of, or new use for, an existing drug--are believed to represent potential major advances in health care. Distinguishing the two categories of drugs permits speedier review even before a new drug application is submitted.

FDA and sponsors of priority drugs may meet at the earliest stages of clinical testing to plan studies that will help develop the information necessary for a final decision on a product's approvability. Then, when a marketing application is submitted, FDA can mobilize available personnel and other resources needed to review the often large amounts of technical information contained in a priority new drug application

In another effort to speed the review of marketing applications, the review process is becoming increasingly computerized. New drug applications that commonly run to thousands of pages are now arriving from sponsors in a form suitable for computer processing. This makes review and communication with the sponsor more efficient, saving time for both FDA and the firm

A highly specialized mechanism for speeding the approval of drugs or biologics that promise significant benefit over existing therapy for serious or life-threatening illnesses-is the accelerated approval. Accelerated review, established by 1991 regulations, can be used in two very special circumstances: when approval is based on evidence of the product's effect on a "surrogate endpoint," and when FDA determines that safe use of a product depends on restricting its distribution or use. l.

A "surrogate endpoint" is a laboratory finding or physical sign that may not, in itself, be a direct measurement of how a patient feels, functions or survives, but nevertheless is considered likely to predict therapeutic benefit. For example, high blood pressure and elevated serum cholesterol are risk factors for heart and blood vessel disease. Drugs that control blood pressure or cholesterol can reasonably be expected to help control or prevent direct signs of disease, such as angina, congestive heart failure after a heart attack, paralysis following a stroke, and sudden death. Once a drug has been shown effective as measured against such a surrogate endpoint, FDA can grant marketing approva

As a condition of approval, however, FDA can require the sponsor to carry out post-marketing studies to confirm that the drug does in fact produce a clinical benefit, such as increased survival time. And if further research or experience shows that a product that received accelerated approval cannot safely remain on the market, FDA can order its prompt withdrawal. As a further safeguard, distribution of accelerated-approval drugs can be limited to institutions that have the capability to use them safely and to physicians with specialized training or experience. The agency can also require that specific medical procedures, such as blood tests, be carried out if they are deemed essential for safe and effective use of the product.

Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias – A CASE STUDY

Compassionate use of bevacizumab (Avastin®) in children and young adults with refractory or recurrent solid tumors-A CASE STUDY

issues regarding post-trial treatment for individuals who participate in these trials must be addressed. Discontinuation of antiretroviral treatment when a trial ends could have negative health effects, which include the increased risk of mortality. To help prevent the possibility of such adverse effects, the NIH developed this Guidance. 6. Why does the Guidance apply only to trials being conducted in developing countries? The Guidance addresses inequities in resources available to participants in developed versus developing countries. For trials conducted domestically, there are existing programs (e.g., pharmaceutical company patient assistance/compassionate use programs, Ryan White CARE Act, Medicaid, private insurance coverage) that can help trial participants continue to receive antiretroviral treatment following their completion of an antiretroviral treatment trial. Participants in developing countries may not have the same types of programs available to them

7. What definition does the NIH use for “Developing” Countries? For purposes of this Guidance, “developing countries” are defined as the low- and middle-income economies, using World Bank classifications. The World Bank's main criterion for classifying economies is gross national income (GNI) per capita, calculated using the World Bank Atlas method. Classification by income does not necessarily reflect development status. The developing countries include: low income , $735 or less; lower middle income , $736 - $2,935; and upper middle income , $2,936 - $9,075. See http://www.worldbank.org/data/countryclass/classgroups.htm for a list of the countries included in each group

11. Does the antiretroviral treatment identified for post-trial provision have to be the same regimen that the participant received during the trial? No. The purpose of this Guidance is to assert the importance of trial participants being able to continue to receive effective antiretroviral treatment after the trial ends but not to specify a particular type of treatment. Treatment regimens should be determined based on individual medical needs, what is available in the host country, and progress in the field

Bevacizumab was administered on a compassionate basis out of a specific protocol assuming that the potential benefits and toxicity would compare favorably with other conventional cytotoxic drugs in these heavily pretreated patients. In the majority of patients, bevacizumab was given as third- or fourth-line therapy following failure to previous relapse therapies. The drug dose and intervals of administration were on the basis of the currently available clinical studies in adult patients [12, 14–17]. Bevacizumab was administered at 5–10 mg/kg body weight (BW) intravenously every 2–3 weeks. Patients and/or their legal guardians were informed about the potential benefits and side-effects of this experimental approach and gave their informed consent before the initiation of bevacizumab administration. During administration of bevacizumab, patients were monitored according to center guidelines for side-effects with special emphasis on hypertension, proteinuria, bleeding, thromboembolic complications, and delays in wound healing. Assessment of response was done using clinical and radiographic evaluations at regular intervals. The total duration of bevacizumab treatment was on the basis of the decision of the treating physician

In the present retrospective study bevacizumab was used on a

compassionate basis in 13 heavily pretreated patients with progressing malignant diseases and in two patients with nonmalignant angiomatous tumors. Although assessment of the efficacy of bevacizumab was not the primary goal of the present report, we did observe objective radiographic responses in patients who received bevacizumab in combination with other cytotoxic drugs.The ‘off-label’ use of a new drug such as bevacizumab in children and young adults out of a specifically designed protocol might raise some ethical concerns. It is, however, well known that carrying out clinical studies in children is nowadays hampered by many factors. First the pharmaceutical industry is generally very reluctant to carry out studies on new drugs in children, because the commercial profit can be expected to be conceivably small compared with the adult population. The imminent high legal risks further prevent many pharmaceutical companies from carrying out clinical studies in children. Secondly, the new EU Clinical Trials Directive to be included in the national legislation by May 2004 hinders the conduct particularly of investigator-initiated trials by a dramatic increase of legal regulations, administrative work and stringent responsibilities for investigators [31,32]. Adherence with these legal regulations significantly increases the costs for the development and conduct of clinical trials, mainly attributable to additional personnel required. So far pediatric hematologists/oncologists are faced with a tremendous ethical dilemma, when they have to decide whether or not to use new drugs off-label for the treatment of children with progressive malignant diseases. As all our patients with malignant diseases would have died before a possible approval of bevacizumab in pediatric cancer patients, we decided to use this drug off-label on a compassionate basis, particularly because the toxicity and safety was expected to be favorable compared with other cytotoxic drug combinations

DR.SIDDHARTHKAMERKAR

Describe Treatment Access or Expanded Access Protocol, why are they important.

Are there regulations in developing countries that mandate these types of

studies?

Expanded Access Protocol

“Expanded access refers to the inclusion of patients in a clinical trial for a new treatment, where those patients would not satisfy the inclusion criteria for the scientific study in progress. ”

“The guidelines for additional inclusion determined by the agency running the clinical trial is called an Expanded access protocol. ”

• Investigational new drug under control clinical trial

• • •

No availability of alternateDrug

Administration of New Investigational Drug

Patient not eligible to receive investigational new drug

Patient suffering from life- threatening diseases (HIV, Cancer)

History• Access to unapproved therapies - unrecognized need.• Before 1987 investigational drugs made available

informally for treatment .• Informal policies : “Compassionate use protocol” ,

“Single-patient protocol exceptions” and “Large open protocols”.

• Formal policies-USFDA Regulation1987,FDAMA regulations 1997,EMEA Guidelines 2007,CDSCO Guidelines 2008

• EA programs made promising investigational drugs to large population.

(E.g.- More than 10,000 patients obtained access to “cardioselective beta-blockers”)

EAP- Purpose

Primary purpose is to provide access to the new drug for the people with life threatening or serious disease for which there is no good alternative treatment.

Secondary purpose is to generate additional information about the drug especially its safety.

Expanded Access Mechanism

*IND (Investigational New Drug): Is one that is under study but does not have permission from the U.S. Food and Drug Administration (FDA) to be legally marketed and sold in the United States.

Treatment IND• Final regulation issued in May 1987.• Made available to person with serious and life threatening illness, no comparative or

satisfactory treatment/ therapy.• Generally granted when the product is well into clinical trial/ trial is completed, and the

sponsor is pursuing marketing approval with due diligence (according to 21 CFR 312.34 b)

Parallel Track Published in the Federal Register on April 15, 1992. Applies only to the person with AIDS and HIV related diseases. IND made available early in developmental process. Eg.stavudine

Group C treatment IND Established by agreement between FDA and NCI Phase 3 study drugs for the treatment of cancer


Investigational Device Exemption- IDE


Criteria for use When can it be used

FDA approval needed?

Patient protection Measures

Emergency Use 1. Life threatening condition

2. No alternative and 3. No time to obtain

FDA approval

Before or after initiation of clinical trial

No; submit report to FDA following device use

1. Independent assessment by uninvolved doctor

2. IRB Chairperson Concurrence;

3. Institutional clearance and4. Informed consent

Compassionate Use

1. Serious disease or condition and

2. No alternative

During Clinical trial

Yes 1. Independent assessment by uninvolved doctor

2. IRB Chairperson Concurrence;

3. Institutional clearance and4. Informed consent


Criteria for use When can it be used

FDA approval needed?

Patient protection Measures

Treatment use

1. Life threatening or serious disease,

2. No alternative3. Controlled clinical

trial; and4. Sponsor pursuing

marketing approval with due diligence

During Clinical trial

Yes 1. IRB approval and2. Informed consent

Continued access 1. Public health need; or2. Preliminary evidence

that device will be effective and no significant safety concerns.

After completion of clinical trial

Yes 1. IRB approval and2. Informed consent.

Procedure to receive Treatment IND

Regulations for EAP in developed countries (USFDA)

21 CFR:

• Part 312: Investigational New Drug (IND)

• Part 312.34: Treatment Use of an IND

• Part 312.37 : Promotion and Charging for INDs

• Part 812: Investigational Device Exemption (IDE)

• Part 814: Premarket Approval of Medical Devices & the

Humanitarian Use Device

Investigational New Drugs 21 CFR Part 312

Subpart A – General Provisions Subpart B – Investigational New Drug Application Subpart C – Administrative Actions Subpart D – Responsibilities of Sponsors and

Investigators Subpart E – Drugs Intended to Treat Life-Threatening

and Severely-Debilitating Illnesses Subpart F - Miscellaneous

Section 402- Expanded Access to Investigational Devices (US FDAMA, Effective: February 19, 1998):

• Emergency Use:– FDA can permit the shipment of an investigational device for the purpose of

diagnosing, monitoring or treating a serious disease or condition in an emergency situation.

• Criteria to be met:1. Licensed physician determines there is no comparable or satisfactory

alternative treatment .

2. Evidence of safety and effectiveness to support the use of the device.

3. Device will not interfere with clinical investigations to support marketing approval.

4. Sponsor or investigator submits a protocol to FDA describing the use of the device in a single patient or in small groups of patients.

Regulations for EAP in developing countries

CDSCO GCP Guidelines-

A “compassionate use” of the experimental evaluation is ethically justified if disease cannot

otherwise be treated

In India, approval for DCGI is required for conducting Expanded access

• (Ref-Dr. Arun Bhatt , Pharmabiz)

Case Study

• Imatinib- Selective inhibitor of BCR/ABL tyrosine

kinase.

• Remarkable results of Phase- I trial published in 1999

prompted initiation of Phase- II trial.

• Interest from patients, clinician.

• Demand for access to imatinib before market approval.

• A worldwide EAP for imatinib implemented in May

2000.

7380 patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia

Enrolled in 106 centers in 34 countries

Results obtained were similar to those obtained in phase-II trial

Imatinib EAP successfully provided therapy to patients before marketing approval

The program provides efficient framework for development of global EAPs for innovative investigational anticancer agents in patients without satisfactory therapeutic alternative.

Result:

Conclusion:

Ref: Annals of Oncology,2008 19 (7):1320-26

Advantage/Disadvantage of EAP

• Advantage:• To make the drug available to people who normally would have to

wait till the drug reaches the market.

• For large industries, learning about Side effects and Efficacy of their drug.

• Strong way to influence market.

• Disadvantage:• Sponsor angle-Economic disincentives is concern for small companies

• Investigator Dynamics

• Hard to get.

• Time-consuming and frustrating.

• List of all the drugs for use not available

• Reimbursement

• Regulations

Conclusion

It is clearly too soon to know whether efforts to make

drugs more rapidly available to the seriously ill are

contributing to genuine advances in health care. But

many thousands of patients who might otherwise be

beyond hope are now able to seek help from

investigational drugs, and all of us stand to gain from a

more efficient system by which to bring important new

agents to market.

Thank You

Documents

Expanded Access Clinical Trial