DID - Sept. 11, 2008 Issue

Vol. 7 No. 178

Rule for Phase I Trials Takes Effect Monday

A final rule that exempts investigational drugs in Phase I testing from certain good manufacturing practice (GMP) regulations will take effect Monday, replacing one withdrawn roughly two years ago. 

Under the rule, the production of an investigational new drug in a Phase I study is exempt from compliance with 21 CFR 211, Daniel Kuebbing, director of the University of Maryland Biotechnology Institute’s GMP Training and Biomanufacturing Program, said in a recent FDAnews audioconference. The regulation formalizes what the FDA has been doing, he added.

The new rule will give manufacturers a little more flexibility and potentially save them money because less validation will be required, he said.

The FDA’s original direct final rule exempted Phase I investigational drugs from GMP regulations, but the agency withdrew it under pressure from groups as varied as Public Citizen, the Biotechnology Industry Organization and the Parenteral Drug Association  (DID, May 2, 2006).

The new rule, which amends the GMP regulation using the same language as the withdrawn rule, will apply to small-molecule drugs and biologics, including vaccines and gene therapy products (DID, July 15).

The FDA also has issued a guidance recommending approaches to satisfy GMP requirements for drugs in Phase I trials. It applies to investigational new drug and biological products, including but not limited to:

  • Investigational recombinant and non-recombinant therapeutic products;
  • Vaccine products;
  • Allergenic products;
  • In vivo diagnostics;
  • Plasma-derivative products;
  • Blood and blood components;
  • Gene therapy products; and
  • Somatic cellular therapy products (including xenotransplantation products).

Among the recommendations in the guidance, the FDA advises manufacturers to systematically evaluate the manufacturing setting to identify potential hazards and establish an appropriate set of actions before and during manufacturing to eliminate or mitigate the hazards.

Manufacturers also should keep records allowing for the replication of the manufacturing process, incomplete or failed batches and any changes in subsequent batches, including the rationale.

More information on the final rule can be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/oc07114.pdf. A copy of the guidance, “CGMP for Phase 1 Investigational Drugs,” can be viewed at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2005-D-0157-gdl.pdf. — Elizabeth Jones


Clinical Trial Contracts Must Account for State Indemnification Laws

When drafting clinical trial contracts, product sponsors and research sites must remember that regulations on indemnification for negligence vary widely between states, an expert says.

Virginia does not allow a party to indemnify itself against its own negligence, but Michigan allows it as long as it is made plain in the agreement, J. Michael Slocum, president of the Virginia law firm Slocum & Boddie, said in an RxTrials Institute audioconference.

Common law traditionally requires that in the event of a claim, a party to a contract with an indemnification clause pays first and then submits a request for reimbursement, Slocum said, but only a few states have such a law on the books.

Sites should ask sponsors to indemnify them against “any losses caused directly by the [investigational] product itself,” Slocum said. They should get separate letters of indemnification from the sponsor and the contract research organization if both are involved, and must cover the principal investigator separately if he or she is employed by a private practice rather than by the site, Slocum said. Such third parties as the institutional review board also may be covered, he added.

Sponsors have their own concerns. For example, in any indemnification clause, they should reserve the right to mount a legal defense against claims arising from the clinical trial. Otherwise, they run the risk of having the site’s lawyer demand “discovery” of all documents relating to the study.

Also, if the research is conducted at a state institution such as a university, the sponsor may not be allowed to offer indemnification. In such cases, the parties should look to legal alternatives such as unilateral sponsor indemnification or “custom clauses that allocate the risk of malpractice to the institution,” Slocum said.

Malpractice insurance should be a major concern of both sponsors and sites. Standard medical malpractice insurance does not cover clinical research and physicians in private practice frequently are not aware of that, Slocum said.

Several other aspects of indemnification are frequently overlooked. For example, “sites and sponsors don’t think enough about use by the sponsor of the results of the study,” Slocum said. Another example is “outlying liability” due to a drug’s potential impact on patients’ family members or people who come into contact with them. This is rarely covered in an indemnification clause, “but in a Phase I study it may well be at issue,” he said.

Typical Contract “Carve-Outs”

Normally, indemnification clauses deny indemnification if a party breaches the agreement, although a clause for intentional misconduct should distinguish between corporate and individual employee actions, Slocum said. Other standard “carve-outs” include:

  • Failure to follow the protocol;
  • Failure to obtain informed consent or comply with other laws and regulations. “Violations of laws and regulations are almost always carved out by public policy,” Slocum said;
  • “False warranties” or unauthorized promises by principal investigators to a patient not in the protocol or to which the sponsor has not agreed;
  • Damages caused by the party seeking indemnification; and
  • Material admissions by one party, which prejudice defense against a claim. While this is a standard request, large institutional sites “should be careful of that, because a doctor or nurse may have said something that will harm the case,” Slocum said.

Indemnification clauses in clinical trial contracts usually involve the most negotiation and apparently lead to little or no litigation, Slocum said. “I am not aware of any litigation in years involving indemnification of research sites and sponsoring institutions,” he added. — Martin Gidron


University of Iowa Sues Amgen Over Two Patents

The University of Iowa has sued Amgen, claiming its manufacturing of drugs, including arthritis drug Enbrel, infringes on patents owned by the school’s research foundation.

In the complaint filed in the U.S. District Court for the Southern District of Iowa, the school alleges that Amgen and its affiliates have knowingly and illegally used the ’062 and ’839 patents to manufacture pharmaceutical products, including the rheumatoid arthritis and psoriasis treatment Enbrel (etanercept) and Vectibix (panitumumab), which is used to treat metastatic colorectal carcinoma that has not responded to chemotherapy.

The University of Iowa Research Foundation has granted 113 active licenses based on the patents, including 13 royalty-bearing products, allowing research institutions and commercial ventures to use the inventions. However, “diligent” efforts by the plaintiffs have not convinced Amgen to respect the patents, according to the university’s court filings.

On both counts of patent infringement, the plaintiffs have asked for treble damages.

Enbrel had $841 million in sales in the second quarter, which ended June 30, while Vectibix had sales of $32 million, according to Amgen. — Elizabeth Jones


Take Nothing for Granted in a Corporate Integrity Agreement

Companies that have corporate integrity agreements (CIAs) should never assume that “just because it’s on paper at your company, it’s being observed,” Thomas Costa, vice president of U.S. pharmaceuticals compliance at Bristol-Myers Squibb (BMS), said this week at the Food and Drug Law Institute’s conference on advertising and promotion.

Costa discussed details of the CIA that BMS entered into with the HHS Office of Inspector General (OIG) in September 2007 as part of a civil settlement in a pricing, sales and marketing investigation (DID, Oct. 2, 2007). Its key elements include:

  • Written standards of conduct;
  • A chief compliance and ethics officer;
  • Education and training programs;
  • Communication and compliance processes;
  • Auditing and monitoring of sales and marketing;
  • Investigations of noncompliance and misconduct; and
  • Corrective actions such as coaching and disciplinary action of errant salespeople, including termination if necessary.

BMS agreed to the settlement and a fine of $499 million plus more than $16 million in interest after the government alleged it had paid consulting fees and offered lavish entertainment to influence healthcare professionals’ prescribing habits.

Many of the elements of a CIA are just good corporate practice, Douglas Farquhar, principal of Hyman, Phelps & McNamara, said. “Many of our clients … would not have been under CIAs if they had had the kind of compliance programs required under CIAs,” he added.

Companies have to be actively involved with a CIA starting with development of the program, Costa said. “Do not assume that settlements come down from the mountain on tablets. The company will be involved and significant resources will be spent. We were engaged. You can’t just go in there [to OIG] and say, ‘What are we supposed to do now?’

“Make sure you have a dialogue with the OIG,” he added. “You will have a 60-month relationship with them.” CIAs typically are imposed for that duration.

OIG expects companies operating with a CIA to find problems when they conduct internal auditing and monitoring. “If you don’t find anything, there’s something wrong with your program,” Costa said.

A company that has a CIA also must never assume that its institutional knowledge is static because new people are hired and veteran employees retire. “You have to make sure new people are up to speed and personally involved,” Costa said. New salespeople must be trained within 30 days of being hired, with no exceptions. It also is vital to ensure there is no “sloppiness” in home office and field monitoring, he added.

“When you’re under a CIA, the compliance division ends up running the company in a lot of ways, and they’re beholden to [OIG],” Farquhar noted.

When developing sales call plans and coaching salespeople in implementing them, “never underestimate the sophistication of certain members of the sales team who have read these plans with savvy and business acumen,” Costa said. “There are people who fully understand it and will challenge us back.”

Another key element of a CIA is monitoring, which should include surveys of physicians to find out what the company’s salespeople told them, as well as the deployment of field monitors with salespeople on trips. To encourage employee cooperation, a toll-free number should be set up and a policy against retaliation established. — Martin Gidron


HHS’ Leavitt Confirms More Inspections to Protect Import Safety

The U.S., Europe and Australia will conduct more frequent facility inspections and regulators will focus more resources on drug products that present demonstrably higher risk, HHS Secretary Michael Leavitt says in remarks prepared for the EU Health Ministers forum in Angers, France.

“To improve the safety of imported pharmaceuticals, the United States, the European Commission, and Australia recently launched a pilot project to conduct joint inspections of pharmaceutical manufacturers,” Leavitt said this week. It is part of the Bush administration’s Interagency Import Safety Action Plan (DID, Nov. 8, 2007).

“We will also exchange information to help identify and inspect suppliers of pharmaceutical ingredients in other countries,” he adds. Leavitt gave a similar address at last year’s Global Health Security Initiative meeting in Washington, D.C.

In the pilot program, the FDA, European Medicines Agency and Australia’s Therapeutic Goods Administration will jointly plan and conduct inspections of facilities that manufacture active pharmaceutical ingredients. If successful, the program will be expanded to other types of facilities, such as finished-dose manufacturing plants (DID, July 10).

While noting that unnecessary inspections damage competitiveness, he says, “Independent certification can go a long way toward ensuring that our expectations of safety are met. … Those who cannot demonstrate certification can expect increased scrutiny at our borders.”

Leavitt’s remarks are available at www.hhs.gov/news/speech/2008/sp20080908a.html. — David Grant


Clinical Trial Conducted Without IRB Approval for Year

A drug trial was continued for roughly a year during which institutional review board (IRB) approval had lapsed, according to an FDA warning letter that also cited failure to obtain informed consent from at least one subject and failure to keep records for the required amount of time.

Details of the clinical trial were redacted from the version of the warning letter addressed to Gregory Gardziola that the FDA posted on its website this week. The letter says that he conducted the trial from October 2003 until he “left the practice in May 2006,” when he handed it over to a physician whose name is redacted.

IRB approval for the study expired Oct. 7, 2005, and was not renewed until Oct. 19, 2006, according to the warning letter, which was sent Sept. 3 and based on an investigation conducted May 9–30. During the year that IRB approval was no longer in effect, Gardziola “screened, enrolled or randomized 16 subjects … and continued to perform research activities (study visits and phone contacts),” the warning letter says.

The alleged informed consent failure involved a subject who signed a “sub-study consent document” but did not sign one for the main study, the warning letter says.

The documentation failure involved a subject who signed an informed consent March 5, 2004, which was documented in the case report form but was missing when the FDA investigation was conducted earlier this year.
Gardziola did not return calls to his office for comment by press time. The warning letter can be viewed at www.fda.gov/foi/warning_letters/s6901c.htm. — Martin Gidron

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